Benzothiadiazepine compounds for treatment of HBV and HDV

Abstract

The present disclosure provides, in part, benzothiazapine compounds and pharmaceutical compositions thereof, as well as methods of treating hepatitis B virus (HBV) and hepatitis D virus (HDV) infection.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 446,976, filed February 20, 2023, and U.S. Provisional Application No. 63 / 534,249, filed August 23, 2023, the contents of which are hereby incorporated by reference. Background Technology

[0003] Hepatitis B virus (HBV) causes viral hepatitis, which can further lead to chronic liver disease and increase the risk of cirrhosis and liver cancer (hepatocellular carcinoma). According to the World Health Organization website, approximately 2 billion people worldwide are infected with HBV, with about 296 million chronically infected in 2019, and HBV infection causes more than half a million deaths annually. HBV can be transmitted through bodily fluids: from mother to child, through sexual contact, and through blood products. Children born to HBV-positive mothers can also be infected unless vaccinated at birth.

[0004] HBV particles consist of a lipid envelope filled with hepatitis B surface antigen (HBsAg) surrounding the viral nucleus. The nucleus is composed of a protein shell or capsid, constructed from a dimer of 120 nucleoproteins (Cp), which in turn contains the relaxed circular DNA (rcDNA) viral genome, along with viral and host proteins. In infected cells, the genome is found as a covalently closed circular DNA (cccDNA) within the host cell nucleus. cccDNA serves as a template for the viral RNA and is therefore the viral protein. In the cytoplasm, Cp assembles around the full-length viral RNA (so-called pregenomic RNA or pgRNA) and a complex of viral polymerase (P). After capsid assembly, P transcribes the pgRNA into rcDNA within the capsid to produce a DNA-filled viral nucleus.

[0005] Currently, chronic HBV is primarily treated with nucleoside (acid) analogs (e.g., entecavir), which suppress the virus while the patient continues treatment, but do not eliminate the infection even after years of treatment. Once a patient starts taking nucleoside (acid) analogs, most must continue taking them, otherwise they may suffer a life-threatening immune response due to viral rebound. Furthermore, nucleoside therapy can lead to the development of antiviral drug resistance.

[0006] The only FDA-approved alternative to nucleoside (acid) analogues is treatment with interferon-alpha or pegylated interferon-alpha. Unfortunately, the incidence and profile of adverse events with interferon-alpha can lead to poor tolerability, and many patients fail to complete the therapy. Furthermore, only a small percentage of patients are considered suitable for interferon therapy because only a small fraction are likely to develop a sustained clinical response to a course of interferon therapy. Therefore, interferon-based therapies are used only in a small percentage of all diagnosed patients who have undergone all selected treatments.

[0007] Therefore, current HBV treatment options range from palliative care to wait-and-see approaches. Nucleotide analogs suppress viral production, thus treating symptoms but leaving the infection intact. Interferon-alpha has serious side effects and is poorly tolerated in patients, and has only been successful as a limited treatment strategy in a small number of patients. A clearer understanding of more effective treatments for HBV infection is needed.

[0008] Another form of viral hepatitis is hepatitis D virus (HDV), a defective RNA virus that causes chronic viral hepatitis and eventually cirrhosis. However, the HDV life cycle depends on the presence of HBsAg for viral particle assembly. Therefore, in a small percentage of patients already infected with HBV, HDV presents as a form of co-infection / reinfection with HBV. See, for example, Sagnelli et al., Life (Basel). Feb. 2021; 11(2): 169, published online on 22 Feb. 2021. doi: 10.3390 / life11020169, which is incorporated herein by reference for such background teaching. For patients already infected with HBV, co-infection / reinfection with HDV may further exacerbate HBV symptoms, thereby 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). Similar to HBV, treatment options for HDV infection or HBV / HDV co-infection are limited, and include treatment options for HBV. Therefore, there is a need for effective treatment options for HDV infection or HBV / HDV co-infection / reinfection.

[0009] WO2022253997 relates to 1,5-benzothiapine and 1,2,5-benzothiadiapine derivatives of formula (I). These compounds are bile acid modulators with apical sodium-dependent bile acid transporter (ASBT) and / or hepatic bile acid transporter (LBAT) inhibitory activity. The 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 disorders, and liver diseases.

[0010] The WO2023237728 granted to Albireo relates to methods for treating hepatitis B and / or hepatitis D with Na+ / taurocholate cotransport polypeptide (NTCP) inhibitors (such as compounds of formula (I) or pharmaceutically acceptable salts thereof, or compounds of formula (II) or pharmaceutically acceptable salts thereof). Such methods may include reducing the concentration of hepatitis B DNA, reducing the concentration of hepatitis D DNA, reducing hepatitis B surface antigen, and reducing hepatitis B nuclear antigen (HBcAg).

[0011] NTCP acts as a cellular receptor for HBV and HDV viral entry, which is consequently a major cause of liver disease and HCC. Additional bile acid modulating compounds are needed, with improved profiles in terms of efficacy, safety, selectivity, and / or bioavailability. Summary of the Invention

[0012] This disclosure partially provides benzothiazide compounds and pharmaceutical compositions thereof that can be used to inhibit HBV or HDV replication, inhibit HBV or HDV viral entry, and methods for treating HBV infection, HDV infection, or HBV / HDV co-infection.

[0013] In one aspect, this disclosure provides a compound of formula I:

[0014] Formula I

[0015] Or a pharmaceutically acceptable salt thereof, wherein the variables are described in the specific implementation.

[0016] In another aspect, this disclosure provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0017] In another aspect, this disclosure provides a method for treating HBV infection in a subject with such need, the method comprising: administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0018] In another aspect, this disclosure provides a method for treating HBV infection in a subject with such need, the method comprising: administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0019] In another aspect, this disclosure provides a method for treating an HDV infection in a subject who requires such treatment, the method comprising: administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0020] In another aspect, this disclosure provides a method for treating an HDV infection in a subject with such need, the method comprising: administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Attached Figure Description

[0021] Figure 1 The ORTEP diagram for Example 10b is shown.

[0022] Figure 2 The ORTEP diagram for Example 11a is shown. Detailed Implementation

[0023] 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, round RNA virus. It depends on hepatitis B virus (HBV) infection and replication in hepatocytes. HDV is a defective virus that lacks the ability to produce its own envelope protein and is therefore dependent on the presence of HBV, which provides the envelope protein. New HDV progeny particles can only be produced in hepatocytes that have already been infected with HBV.

[0024] Globally, approximately 300 million people are chronically infected with HBV. An estimated 15-20 million more are chronically infected with hepatitis delta. Co-infection leads to more severe liver disease compared to HBV infection alone. It is associated with faster progression of liver fibrosis, an increased risk of liver cancer, and early compensated cirrhosis and liver failure, which can lead to fatal outcomes within days without transplantation. Hepatitis delta can develop through co-infection: simultaneous infection with both hepatitis B and hepatitis delta. It can also develop through reinfection: infection with hepatitis D after a person has already developed hepatitis B.

[0025] There is currently no vaccine for hepatitis B. However, prevention can be achieved through hepatitis B vaccination, which helps eliminate the risk of HBV infection. Hepcludex Myrcludex B (Bulevirtide, BLV) was approved for HDV in the EU in July 2020 and is available in France, Germany, Austria, Italy, and the UK as of June 2023. This drug binds to essential HDV receptors on hepatocytes, thus preventing cellular infection. BLV's binding to NTCP simultaneously inhibits its natural biological function of transporting bile acids into cells. Previously, the only treatment found to be somewhat effective against hepatitis delta was pegylated interferon-alpha, which works by stimulating the body's innate immune system to fight the virus.

[0026] Although Hepcludex is a 47-amino acid peptide that inhibits Na+-taurine cotransport polypeptide (NTCP), the viral entry receptor, and requires subcutaneous (SubQ) administration, the small molecule oral bioavailable NTCP inhibitor of the present invention provides more flexible administration, increased convenience, and more combination options with other HBV / HDV treatments.

[0027] The WO2022 / 253997 granted to Albireo relates to 1,5-benzothiapine and 1,2,5-benzothiadiazepine derivatives of formula (I):

[0028]

[0029] These compounds are bile acid modulators with inhibitory activity against apical sodium-dependent bile acid transporters (ASBTs) and / or hepatic bile acid transporters (LBATs). The present 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 disorders, and liver diseases.

[0030] The applicant points out that the compound of formula (I) in WO2022 / 253997 is chiral, due to the presence of R... 1 A chiral center exists at the carbon atom. Furthermore, M is limited to -CH2- and -NR. 5 -, where R 5 Is it hydrogen or C? 1-4 Alkyl; R 1- Limited to C 1-4 Alkyl, and R 3 Limited to hydrogen, halogenated, cyano, C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, C 1-4 Alkylthio, C 3-6 Cycloalkylthio, amino, N-(C1-4 alkyl)amino, and N,N-di(C1-4 alkyl)amino. Therefore, there is no information regarding R. 1 or R 3 The teaching or suggestion is that the alkyl halogroup at the position or M is a substituted carbon atom. It should be noted that when M is a monosubstituted carbon atom, a new chiral center is introduced, resulting in four diastereomers.

[0031] In contrast, Example 10b is an exemplary compound of the present invention, having the structure and absolute stereochemistry shown below:

[0032] Example 10b

[0033] Among them, the halogenated alkyl group is in R1 (i.e., -CH2CH2CF2CH3) and R 3 The introduction of a second chiral center (i.e., CF3) at M, where M is a monosubstituted carbon atom (i.e., -CHF-), creates a center outside the scope of WO2022 / 253997. The applicant has found that one or more of these structural modifications produce unexpectedly improved biological activity, selectivity profiles, and PK profiles against HBV and HDV. The compound of Example 10b can exist as four diastereomers:

[0034]

[0035] Table 1 provides comparative data on the potency and transporter selectivity of each of the four diastereomers.

[0036] Table 1: Comparative data on potency and transporter selectivity of each of the four diastereomers of the compound of Example 10b of the present invention.

[0037] diastereomer 1 diastereomer 2 diastereomer 3 diastereomer 4 <![CDATA[HBeAg EC 50 (nM)]]> 4.2 68.3 22.2 1174 <![CDATA[NTCP IC 50 (nM)]]> 7.3 28 17 524 <![CDATA[ASBT IC 50 / NTCP IC 50 The ratio (multiple) 323 NA 226 58

[0038] As used herein, the diastereomer 1 of Example 10b of the present invention is also referred to as compound 1.

[0039] For comparison, the applicant has prepared and tested the compounds of Examples 9 and 13 of WO2022 / 253997 according to procedures known in the art. Both are described in WO2022 / 253997 as racemic mixtures of the corresponding enantiomers.

[0040]

[0041] Example 9 of WO2022 / 253997 Example 13 of WO2022 / 253997

[0042] (racemic mixture) (racemic mixture)

[0043] Enantiomers 1 and 2 of Example 14 are the separated R and S enantiomers (unspecified absolute stereochemistry) of Example 13. Table 8 of WO2022 / 253997 indicates that Examples 9 and 13 have similar NTCP(hLBAT) inhibitory activities, but enantiomer 2 of Example 14 is significantly more active than enantiomer 1 of Example 14 in inhibiting NTCP(hLBAT). However, no assay data directly indicating bioactivity against HDV or HBV are provided.

[0044] Table 2 provides comparative data on the potency and transporter selectivity of compound 1 relative to compounds in Examples 9 and 14 of WO2022 / 253997.

[0045] Table 2: Comparison data on potency and transporter selectivity

[0046] Compound 1 Example 9 (racemic mixture) Example 9 (Best Enantiomer) Example 14 (enantiomer 2) <![CDATA[HBeAg EC 50 (nM)]]> 4.2 108 45 24 <![CDATA[NTCP IC 50 (nM)]]> 7.3 34.5 75.6 21 <![CDATA[ASBT IC 50 (nM)]]> 2,400 NA NA 190 <![CDATA[ASBT IC 50 / NTCP IC 50 The ratio (multiple) 323 NA NA 9

[0047] As shown in the table, the half-maximal inhibitory concentration (IC50) of compound 1 relative to human NTCP and ASBT is... 50 The values ​​were 7.3 and 2,400 nM, respectively, with the NTCP selectivity ratio (ASBT IC) being... 50 / NTCP IC 50 Compound 1 also showed an IC50 value of 320 times greater than that of compound 1 at 4.2 nM. 50 It can prevent HBV infection of human liver cancer cells without affecting cell viability.

[0048] In contrast, compared to human NTCP and ASBT, the IC of instance 14 (enantiomer 2) 50 The values ​​were 21 and 190 nM, respectively, where the NTCP selectivity ratio (ASBT IC) was... 50 / NTCP IC 50 The value was 9 times higher. This compound had an IC50 concentration of 24 nM. 50 It prevents HBV infection of human liver cancer cells without affecting cell viability. Similarly, compared to human NTCP, Example 9 (best enantiomer) showed higher IC50 values. 50 It is 75.6 nM, and with an IC of 45 nM 50 It can prevent HBV infection of human liver cancer cells without affecting cell viability.

[0049] Therefore, in hepatocellular carcinoma cells infected with HBV, compound 1 exhibited higher anti-HBV potency than enantiomer 2 (Example 14), where IC50... 50 The value is the IC of this instance. 50 Approximately 1 / 6 of the value. IC 50 IC value of Example 9 (best enantiomer) 50 The value is approximately 1 / 11. Compound 1 also inhibits NTCP more effectively, with its IC... 50 IC value of instance 14 (enantiomer 2) 50 The value is approximately 1 / 3, and the IC is for example 9 (the best enantiomer). 50 The value is approximately 1 / 10. Finally, compound 1 exhibits NTCP selectivity (ASBT IC). 50 / NTCP IC 50The NTCP selectivity of Example 14 (enantiomer 2) is approximately 36 times that of Example 14 (enantiomer 2), indicating its superior selectivity.

[0050] Table 3 provides comparative monkey pharmacokinetic data for compound 1 relative to Albireo compound A7387. Data for compound 1 were obtained using the methods and procedures described herein, while data for A7387 were digitized from the 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 relates to Example 14 of WO2022 / 253997 as compound 2, and provides in vivo primate results on page 77, cross-referencing compound 2 as A7387.

[0051] Table 3: Comparison of monkey p-γ spectra of compound 1 versus A7387

[0052] Dosage (mg / kg) compound <![CDATA[AUC 0_24 (hr*ng / mL)]]> <![CDATA[C 最大 (ng / mL)]]> <![CDATA[T 1 / 2 (hr)]]> 3 Compound 1 58178 5147 14 3 A7387 13784 2299 3 3 ratio 4.2 2.2 4.2 10 Compound 1 290412 23100 17 10 A7387 18733 1694 6 10 ratio 15.5 13.6 2.6 30 Compound 1 1082543 64900 13 30 A7387 321545 26405 4 30 ratio 3.4 2.5 3.6

[0053] In monkeys, compound 1 showed higher exposure after oral administration of 3 mg / kg, with AUC [missing information]. 0-24 It is 58178hr*ng / mL and C 最大 The concentration was 5147 ng / mL, which was 320% and 120% higher than those observed for A7387, respectively.

[0054] In monkeys, compound 1 showed higher exposure after oral administration of 10 mg / kg, with AUC [missing information]. 0-24 It was 290412 hr*ng / mL and C 最大 The concentration was 23,100 ng / mL, which was 1,450% and 1,260% higher than those observed for A7387, respectively.

[0055] In monkeys, compound 1 showed higher exposure after oral administration of 30 mg / kg, with AUC [missing information]. 0-24 It is 1082543 hr*ng / mL and C 最大 The concentration was 64,900 ng / mL, which was 240% and 150% higher than those observed for A7387, respectively.

[0056] The apparent oral PK terminal half-life of compound 1 ranged from 13 to 17 hours, which was 160% to 320% longer than that observed for A7387.

[0057] The features and other details of this disclosure will now be described in more specific terms. Before further describing this disclosure, certain terms used in the specification, examples, and appended claims are collected herein. These definitions should be understood in accordance with the remainder of this disclosure and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0058] definition

[0059] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, straight-chain or branched groups with 2-6 carbon atoms (referred to herein as C1). 2--6 Alkenyl groups. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and pentenyl.

[0060] As used herein, the term "alkoxy" refers to a straight-chain or branched alkyl group attached to an oxygen atom (i.e., alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups with 1-6 or 1-4 carbon atoms (referred to herein as C14-C2 ... 1-6 Alkoxy and C 1-4 Alkoxy groups). Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, and isopropoxy.

[0061] As used herein, the term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group. Examples include, but are not limited to, CH3CH2OCH2-, CH3OCH2CH2-, and CH3OCH2-.

[0062] As used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight-chain or branched hydrocarbons with 1-6 or 1-4 carbon atoms (referred to herein as C14-C2 ... 1-6 Alkyl and C 1-4 Alkyl groups. 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, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. As used herein, the term "alkylene" refers to a dialkyl group.

[0063] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight-chain or branched groups with 2-6 carbon atoms (referred to herein as C1). 2-6 Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, penynyl, hexynyl, and methylpropynyl.

[0064] As used herein, the term "carbonyl" refers to the di-C(O)- group.

[0065] As used in this article, the term “co-infection” refers to the simultaneous infection of a host by more than one viral pathogen.

[0066] As used herein, the term "cyano" refers to the -CN group.

[0067] As used herein, the term "cycloalkyl" refers to, for example, a saturated monocyclic hydrocarbon group with 3-7 carbons (referred to herein as C14). 3-7 Monocyclic alkyl groups or bicyclic hydrocarbon ring structures with 5-12 carbons (referred to herein as C164-C ... 5-12 (Bicycloalkyl). For bicycloalkyl groups, the two rings can be linked by the same or different carbon atoms. Exemplary monocycloalkyl groups include, but are not limited to, cycloheptyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, and cyclopropyl. Exemplary bicyclic alkyl groups include, but are not limited to, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[4.5]decyl, spiro[5.5]undecyl, spiro[2.4]heptyl, spiro[3.4]octyl, spiro[4.4]nonyl, spiro[2.3]hexyl, spiro[3.3]heptyl, decahydronaphthalene, octahydro-1H-indene, bicyclic[4.2.0]octyl, bicyclic[4.1.0]heptyl, octahydropentenyl, bicyclic[3.2.0]heptyl, bicyclic[3.1.0]hexyl, bicyclic[2.2.2]octyl, bicyclic[2.2.1]heptyl, bicyclic[3.1.1]heptyl, and bicyclic[1.1.1]pentyl.

[0068] As used herein, the term “halogenated” or “halogen” refers to F, Cl, Br, or I.

[0069] As used herein, the term "halogenated alkyl" refers to an alkyl group substituted with one or more halogen atoms. For example, halogenated C 1-6 Alkyl refers to a straight-chain or branched alkyl group consisting of 1 to 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-.

[0070] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, CCl3O-, CF3O-, CHF2O-, CF3CH2O-, and CF3CF2O-.

[0071] As used herein, the term "heteroaryl" refers to a 5-6 membered monocyclic aromatic group (referred to herein as a monocyclic group). 5-6 (Heteroaryl) or 8-12 membered bicyclic aromatic ring systems (referred to as bicyclic in this paper) 8-12 Heteroaryl groups contain one to four independently chosen heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, the heteroaryl ring can be linked to a neighboring group via carbon or nitrogen. Monocyclic rings... 5-6 Examples of heteroaryl groups include, but are not limited to, furanyl, phenylthio (also known as thiophene), pyrrole, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl (also known 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. Bicyclic 8-12 Heteroaryl groups include, but are not limited to, benzofuranyl, isobenzofuranyl, benzo[b]phenylthio, benzo[c]phenylthio, indolyl, isoindolyl, benzo[d]isooxazolyl, benzo[c]isooxazolyl, benzo[d]oxazolyl, benzo[d]isothiazolyl, benzo[c]isothiazolyl, benzo[d]thiazolyl, indazole, benzo[d]imidazolyl, benzo[d]imidazolyl and benzo[d][1,2,3]triazolyl.

[0072] The term "heterocyclic alkyl" refers to a monocyclic alkyl group (e.g., C10, C20, C30, C40, C50, C60, C7 ... 3-7 Monocyclic alkyl) or bicyclic alkyl groups (e.g., C10) 5-12 Bicycloalkyl groups, wherein 1-3 carbon atoms are replaced by independently selected heteroatoms (such as nitrogen, oxygen, and sulfur (including their oxidation states: S(O) and SO2)), referred to herein as monoalkyl groups. 3-7 Heterocyclic alkyl and bicyclic 5-12 Heterocyclic alkyl groups. Monocyclic alkyl groups. 3-7 Examples of heterocyclic alkyl groups include, but are not limited to, aziridinyl, ethylene oxide, thiocyclopropyl 1,1-dioxide, oxetane, aziridane, thiocyclobutane 1,1-dioxide, pyrrolyl, tetrahydrofuranyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, thiomorpholinyl, and piperazine. 5-12Examples of heterocyclic alkyl groups include, but are not limited to, 1,4-dioxaspiro[4.5]decyl and 1,5-dioxaspiro[5.5]undecyl.

[0073] As used herein, the term "hydroxyl (hydroxy and hydroxyl)" refers to the -OH group.

[0074] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups. Examples include, but are not limited to, HOCH2-, HOCH2CH2-, CH3CH(OH)CH2-, and HOCH2CH(OH)CH2-.

[0075] As used herein, the term "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxyl groups. Examples include, but are not limited to, HOCH2O-, HOCH2CH2O-, CH3CH(OH)CH2O-, and HOCH2CH(OH)CH2O-.

[0076] As used in this article, the term "R" a R b NC 1-6 "alkyl-" refers to R as defined herein. a R b An alkyl group substituted with an N- group. Examples include, but are not limited to, NH2CH2-, NH(CH3)CH2-, N(CH3)2CH2CH2-, and CH3CH(NH2)CH2-.

[0077] As used in this article, the term "R" a R b NC 1-6 "Alkoxy" refers to R as defined in this article. a R b An alkoxy group substituted with an N- group. Examples include, but are not limited to, NH2CH2-, NH(CH3)CH2O-, N(CH3)2CH2CH2O-, and CH3CH(NH2)CH2O-.

[0078] As used herein, the term "oxo" refers to the =O group.

[0079] As used herein, when a bicyclic ring is shown as having floating connection points and / or floating substituents, for example in In this context, it is shown that bicyclic rings can be linked via carbon atoms on either ring, and that substituents (e.g., R...) can be used... 33 The group can be independently attached to any one or two rings.

[0080] As used herein, the terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans. The compounds or pharmaceutical compositions of this disclosure can be administered to mammals such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, such as domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, etc.). The mammals treated in the methods of this disclosure are preferably mammals requiring treatment for HBV infection.

[0081] The term “regulation” includes antagonistic effects (e.g., inhibition), agonistic effects, partial antagonistic effects, and / or partial agonistic effects.

[0082] The term "pharmaceutical acceptable" includes molecular entities and compositions that, when administered to animals or humans under appropriate conditions, do not produce harmful, allergic, or other adverse reactions. For human use, formulations should meet the sterility, pyrogenicity, and general safety and purity standards required by the FDA's Office of Biologics Standards.

[0083] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceuticalally acceptable excipient" refer to any and all solvents, dispersion media, coatings, isotonic agents and absorption delay agents, fillers, etc., compatible with drug administration. The use of such media and pharmaceutical preparations for the active pharmaceutical ingredient is well known in the art. The composition may also include other active compounds that provide supplemental, additional, or enhanced therapeutic functions.

[0084] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound as disclosed herein, formulated with one or more pharmaceutically acceptable excipients.

[0085] As used herein, the term "pharmaceutically acceptable salt" refers to a salt containing an acidic or basic group that may be present in the compound used in the composition. The basic compounds contained in the compositions of the present invention are capable of forming a wide variety of salts with various inorganic and organic acids. The pharmaceutically acceptable acids that can be used to prepare such basic compounds are those acids that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, bisulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannins, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentisinates, fumarates, gluconates, glucurons, sucrose salts, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthylcarbamate)). The acidic compounds contained in this composition are capable of forming basic salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, specifically calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds comprising basic or acidic moieties in this composition can also form pharmaceutically acceptable salts with various amino acids. The compounds disclosed herein may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In such cases, the compound may exist as an acid addition salt, a zwitterion, or a basic salt.

[0086] As used herein, the term "therapeuticly effective amount" or "effective amount" refers to the amount of a subject compound that a researcher, veterinarian, physician, or other clinician is looking for to elicit a biological or medical response in a tissue, system, or animal (e.g., a mammal or a human). The compounds or pharmaceutical compositions disclosed herein are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or preventative effect.

[0087] The term "treatment" includes any effect, such as alleviating, reducing, moderating, or eliminating a viral infection, which improves the condition.

[0088] The compounds disclosed herein may contain one or more chiral centers and thus exist as stereoisomers. The term "stereoisomer," as used herein, comprises all enantiomers and diastereomers. These compounds may be designated by the symbols "(+)", "(-)", "R", or "S" depending on the configuration of the substituents surrounding the stereoisomeric carbon atom; however, those skilled in the art will recognize that the structure may implicitly refer to the chiral center. This disclosure covers various stereoisomers of these compounds and mixtures thereof. In nomenclature, enantiomers or mixtures of diastereomers may be designated as "(±)", but those skilled in the art will recognize that the structure may implicitly refer to the chiral center.

[0089] The compounds disclosed herein may contain one or more double bonds and thus exist as geometric isomers resulting from the arrangement of substituents around the carbon-carbon double bonds. (Symbol) The term can refer to a single, double, or triple bond as described herein. Substituents surrounding a carbon-carbon double bond are indicated as being in the “Z” or “E” configuration, where the terms “Z” and “E” are used according to IUPAC standards. Unless otherwise specified, the structure describing the double bond encompasses both the “E” and “Z” isomers. Substituents surrounding a carbon-carbon double bond can alternatively be referred to as “cis” or “trans”, where “cis” indicates a substituent on the same side of the double bond and “trans” indicates a substituent on the opposite side of the double bond.

[0090] The compounds disclosed herein may comprise carbocyclic or heterocyclic rings and thus exist as geometric isomers resulting from the arrangement of substituents around the ring. Substituents arranged around the carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration, wherein the terms “Z” and “E” are used according to IUPAC standards. Unless otherwise specified, the description of the structure of the carbocyclic or heterocyclic ring encompasses both the “Z” and “E” isomers. Substituents around the carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, where “cis” indicates a substituent on the same side of the plane of the ring and “trans” indicates a substituent on the opposite side of the plane of the ring. Mixtures of compounds in which substituents are arranged on the same and opposite sides of the plane of the ring are designated as “cis / trans”.

[0091] Individual enantiomers and diastereomers of the compounds disclosed herein can be prepared by synthesis from commercially available starting materials containing asymmetric or stereoisomeric centers, or by preparing racemic mixtures followed by decomposition methods well known to those skilled in the art. These decomposition methods are exemplified by: (1) the conjugation of an enantiomer mixture with a chiral auxiliary agent, followed by recrystallization or chromatographic analysis of the resulting diastereomer mixture by release from the auxiliary agent; (2) salt formation using an optically active resolving agent; (3) direct separation of optically enantiomer mixtures on a chiral liquid chromatography column; or (4) kinetic decomposition using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be decomposed into their constituent enantiomers by well-known methods such as chiral phased liquid chromatography or crystallization of the compounds into chiral solvents. Stereoselective synthesis, chemical or enzymatic reactions of individual reactants forming heterogeneous mixtures of stereoisomers during the creation of new stereocenters or during the transformation of pre-existing stereocenters, are well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transitions and can involve the use of chiral auxiliaries. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0092] The compounds disclosed herein can exist in both solvated and unsolvated forms with pharmaceutically acceptable solvents (such as water, ethanol, etc.), and this disclosure is intended to cover 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 yet another embodiment, the compound is in crystalline form.

[0093] This disclosure also covers isotopically labeled compounds of this disclosure, which are identical to the compounds described herein except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into the compounds of this disclosure 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 36Cl. For example, compounds disclosed herein may have one or more H atoms substituted with deuterium.

[0094] Disclosed compounds labeled with certain isotopes (e.g., using...) 3 H and 14 C-labeled compounds can be used for the determination of compound and / or substrate tissue distribution. Tritium-labeled compounds (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, heavier isotopes such as deuterium (i.e., 2 Substitution of H) can provide certain therapeutic advantages due to better metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in some cases. The isotopically labeled compounds of this disclosure can generally be prepared by substituting the non-isotopically labeled reagent with the isotopically labeled reagent using procedures similar to those disclosed in the examples herein.

[0095] The term "prodrug" refers to a compound that is converted in vivo to produce the disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. Conversion can occur at various sites, such as in the intestinal lumen or during transport in the intestine, blood, or liver, via various mechanisms, such as esterases, amidases, phosphatases, oxidative and / or reductive metabolism. Prodrugs are well known in the art (e.g., see Rautio, Kumpulainen et al., Nature Reviews DrugDiscovery 2008, 7, 255).

[0096] benzothiazopine compounds

[0097] In one respect, this disclosure provides compounds of formula I.

[0098] Formula I

[0099] or its pharmaceutically acceptable salt, wherein:

[0100] M is NR x or CR y R z ;

[0101] X is either N or CH;

[0102] R a R b and R c Each time it appears, independently select the group consisting of the following items: hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and C 3-6Monocycloalkyl;

[0103] R x It is hydrogen or C 1-4 alkyl;

[0104] R y and R z Independently select the group consisting of the following items: hydrogen, halogenated, CN, C 1-4 Alkyl and Halogenated C 1-4 alkyl;

[0105] R 1 For OH, CH3, -C(O)NH2, -C(O)OH, -C(O)OC 1-6 Alkyl, -P(O)(OH)2, -S(O)2OH or ;

[0106] R 2a and R 2b Choose independently from the group consisting of: hydrogen, halo, OH, methyl, ethyl, and CH2OH; or R 2a and R 2b Together with the carbon atoms they are attached to, they form C=CH2, C 3-6 Monocycloalkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, or 1,3-dioxyl group, wherein the C 3-6 The monocycloalkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl or 1,3-dioxyl group is optionally substituted by one to three independently selected halogenated and methyl groups;

[0107] R 3 Choose from the following groups: hydrogen, halogen, cyano, R a R b N-, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkylthio, C 3-7 Monocycloalkyl, C 3-7 Monocycloalkoxy, C 3-7 Monocyclic alkyl thiols, C 3-7 Monocyclic alkyl-CH2-thio and C 5-12 Bicycloalkylthio group, wherein the C 3-7 Monocycloalkyl, C 3-7 Monocycloalkoxy, C 3-7 Monocyclic alkyl thiols, C 3-7 Monocyclic alkyl-CH2-thio and C 5-12The bicycloalkylthio group is optionally substituted with 1 to 3 halogenated groups;

[0108] R 4 For hydrogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, CH3SO2CH2CH2-, CH3SO2CH2CH2CH2-, R 4a CH2- or R 4a CH2CH2-;

[0109] R 4a It is a phenyl, imidazolyl, N-methylimidazolyl or C-type phenyl group optionally substituted with 1 to 3 halogenated groups. 3-6 Monocycloalkyl;

[0110] R 5 For phenyl, C 3-7 Monocycloalkyl or C 5-12 Bicycloalkyl, wherein the phenyl, C 3-7 Monocycloalkyl or C 5-12 The bicycloalkyl group is optionally substituted by one to six independent substituents selected from the group consisting of: halogen, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-; and

[0111] Each time q appears, it independently chooses a group consisting of 0, 1, and 2;

[0112] The condition is: R 3 Halogenated C 1-4 Alkyl; M is CR y R z And R y and R z At least one of them is halogenated, CN, C 1-4 Alkyl or halogenated C 1-4 Alkyl; or R 4 Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, CH3SO2CH2CH2-, CH3SO2CH2CH2CH2-, R 4a CH2- or R 4a CH2CH2-; or combinations thereof.

[0113] The following examples further describe compounds of Formula I or pharmaceutically acceptable salts thereof. It should be understood that all chemically permissible combinations of the examples described herein are considered further embodiments of the invention.

[0114] In some embodiments, the compound of formula I has formula Ia

[0115] Formula Ia

[0116] Or its pharmaceutically acceptable salt.

[0117] In some embodiments, the compound of formula I has formula Ib

[0118] Formula Ib

[0119] Or its pharmaceutically acceptable salt.

[0120] In some embodiments, X is N.

[0121] In some embodiments, X is CH.

[0122] In some embodiments, M is NR x .

[0123] In some embodiments, M is NH or NCH3.

[0124] In some embodiments, M is CR y R z .

[0125] In some embodiments, M is -CH2-.

[0126] In some embodiments, M is CR y R z And R y and R z At least one of them is halogenated, CN, C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0127] In some embodiments, M is -CH(CH3)-, -CF(CH3)-, -CHF-, -C(CH3)2-, or -CF2-.

[0128] In some embodiments, M is -CF(CH3)-.

[0129] In some embodiments, M is -C(CH3)2-.

[0130] In some embodiments, M is -CHF-.

[0131] In some embodiments, M is -CF2-.

[0132] In some embodiments, R 1 It is C(O)OH.

[0133] In some embodiments, R 1 It is S(O)2OH.

[0134] In some embodiments, R 1 It is P(O)(OH)2.

[0135] In some embodiments, R 2a and R 2b Choose independently from the group consisting of: hydrogen, halogen, OH, and methyl.

[0136] In some embodiments, R 2a and R 2b It is a methyl group.

[0137] In some embodiments, R 2a It is hydrogen, and R 2b It is a methyl group.

[0138] In some embodiments, R 2a and R 2bTogether with the carbon atoms to which they are attached, they form C=CH2, cyclopropyl, cyclobutyl, or oxacyclobutane groups, wherein the cyclopropyl or cyclobutyl group is optionally substituted with 1 to 3 halogenated groups.

[0139] In some embodiments, R 2a and R 2b Together with the carbon atoms they are attached to, they form C=CH2, cyclopropyl, cyclobutyl, or oxecyclobutane groups.

[0140] In some embodiments, R 2a and R 2b Together with the carbon atoms they are attached to, they form cyclopropyl groups.

[0141] In some embodiments, R 3 C 5-12 Bicycloalkylthio-.

[0142] In some embodiments, R 3 Halogenated C 3-7 Monocyclic alkylthio-.

[0143] In some embodiments, R 3 Halogenated C 1-2 alkyl-.

[0144] In some embodiments, R 3 It is CF3.

[0145] In some embodiments, R 4 Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, CH3SO2CH2CH2-, CH3SO2CH2CH2CH2-, R 4a CH2- or R 4a CH2CH2-.

[0146] In some embodiments, R 4 Halogenated C 1-4 alkyl-.

[0147] In some embodiments, R 4 Halogenated C 3-4 alkyl-.

[0148] In some embodiments, R 4 It is a n-butyl group substituted with 1 to 6 halo atoms.

[0149] In some embodiments, R 4 It is a n-butyl group substituted with 1 to 6 F atoms.

[0150] In some embodiments, R 4 It is -CH2CH2CF2CH3.

[0151] In some embodiments, R 4 It is a n-propyl group substituted with 1 to 6 halogen atoms.

[0152] In some embodiments, R 4 It is a n-propyl group substituted with 1 to 6 F atoms.

[0153] In some embodiments, R 4 It is -CH2CH2CF3.

[0154] In some embodiments, R 5 C is a C-type compound that is optionally substituted with one to six independently selected substituents from the group consisting of the following items. 3-7 Monocycloalkyl groups: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC1-4 alkyl-.

[0155] In some embodiments, R 5 for or .

[0156] In some embodiments, R 5 C is a C-type compound that is optionally substituted with one to six independently selected substituents from the group consisting of the following items. 5-12 Bicycloalkyl: Halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0157] In some embodiments, R 5A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0158] In some embodiments, R 5 for .

[0159] In some embodiments, R 5 for .

[0160] In some embodiments, X is CH, R 3 Halogenated C 1-4 alkyl-, and R 4 Halogenated C 1-4 alkyl-.

[0161] In some embodiments, X is CH, R 3 It is CF3, and R 4 It is -CH2CH2CF2CH3.

[0162] In some embodiments, X is CH, R 3 It is CF3, and R 4 It is -CH2CH2CF3.

[0163] In some embodiments, X is CH, M is -CHF-, and R 3 Halogenated C 1-4 alkyl- ， And R 4 Halogenated C 1-4 alkyl-.

[0164] In some embodiments, X is CH, M is -CHF-, and R 3 For CF 3， And R 4 It is -CH2CH2CF2CH3.

[0165] In some embodiments, X is CH, M is -CHF-, and R 3 For CF 3， And R 4 It is -CH2CH2CF3.

[0166] In some embodiments, X is CH, M is -CHF-, and R 1 For C(O)OH, R 3 Halogenated C 1-4 alkyl- ， And R 4 Halogenated C 1-4 alkyl-.

[0167] In some embodiments, X is CH, M is -CHF-, and R 1 For C(O)OH, R 3 It is CF3, and R 4 It is -CH2CH2CF2CH3.

[0168] In some embodiments, X is CH, M is -CHF-, and R 1 For C(O)OH, R 3 It is CF3, and R 4 It is -CH2CH2CF3.

[0169] In some embodiments, X is CH, M is -CHF-, and R 1 For C(O)OH, R 3 Halogenated C1-4 alkyl- ， R 4 Halogenated C 1-4 alkyl- ， And R 5 A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0170] In some embodiments, X is CH, M is -CHF-, and R 1 For C(O)OH, R 3 For CF 3， R 4 -CH2CH2CF2CH 3， And R5 A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0171] In some embodiments, X is CH, M is -CHF-, and R 1 For C(O)OH, R 3 For CF 3， R 4 -CH2CH2CF 3， And R 5 A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, OH, CN, HOC(O)-, R a R bN-, R a R b NS(O) q -、C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0172] In some embodiments, X is CH, M is -CHF-, and R 1 For C(O)OH, R 3 Halogenated C 1-2 Alkyl, R 4 Halogenated C 1-2 Alkyl; and R 5 for , , or .

[0173] In some embodiments, X is CH, M is -CHF-, and R 1 For C(O)OH, R 3 For CF 3， R4 -CH2CH2CF2CH 3， And R 5 for , , or .

[0174] In some embodiments, X is CH, M is -CHF-, and R 1 For C(O)OH, R 3 For CF 3， R 4 -CH2CH2CF 3， And R 5 for , , or .

[0175] In some embodiments, the compound of formula I has formula Ia, where X is CH, R 3 Halogenated C 1-4 alkyl-, and R 4 Halogenated C 1-4 alkyl-.

[0176] In some embodiments, the compound of formula I has formula Ia, where X is CH, R 3 It is CF3, and R 4 It is -CH2CH2CF2CH3.

[0177] In some embodiments, the compound of formula I has formula Ia, where X is CH, R 3 It is CF3, and R 4 It is -CH2CH2CF3.

[0178] In some embodiments, the compound of formula I has formula Ia, where X is CH, M is -CHF-, and R... 3 Halogenated C 1-4 alkyl- ， And R 4 Halogenated C 1-4 alkyl-.

[0179] In some embodiments, the compound of formula I has formula Ia, where X is CH, M is -CHF-, and R... 3 It is CF3, and R 4 It is -CH2CH2CF2CH3.

[0180] In some embodiments, the compound of formula I has formula Ia, where X is CH, M is -CHF-, and R... 3 It is CF3, and R 4 It is -CH2CH2CF3.

[0181] In some embodiments, the compound of formula I has formula Ia, where X is CH, M is -CHF-, and R... 1 For C(O)OH, R 3 Halogenated C 1-4 alkyl- ， And R 4 Halogenated C 1-4 alkyl-.

[0182] In some embodiments, the compound of formula I has formula Ia, where X is CH, M is -CHF-, and R... 1 For C(O)OH, R 3 It is CF3, and R 4 It is -CH2CH2CF2CH3.

[0183] In some embodiments, the compound of formula I has formula Ia, where X is CH, M is -CHF-, and R... 1 For C(O)OH, R 3 It is CF3, and R 4 It is -CH2CH2CF3.

[0184] In some embodiments, the compound of formula I has formula Ia, where X is CH, M is -CHF-, and R... 1 For C(O)OH, R 3 Halogenated C 1-4 alkyl- ， R 4 Halogenated C 1-4 alkyl- ， And R 5 A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0185] In some embodiments, the compound of formula I has formula Ia, where X is CH, M is -CHF-, and R... 1 For C(O)OH, R 3 For CF 3， R 4 -CH2CH2CF2CH 3， And R 5 A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a Rb NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0186] In some embodiments, the compound of formula I has formula Ia, where X is CH, M is -CHF-, and R... 1 For C(O)OH, R 3 For CF 3， R 4 -CH2CH2CF 3， And R 5 A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0187] In some embodiments, the compound of formula I has formula Ia, where X is CH, M is -CHF-, and R... 1 For C(O)OH, R 3 Halogenated C 1-2 Alkyl, R 4 Halogenated C 1-2 Alkyl; and R 5 for , , or .

[0188] In some embodiments, the compound of formula I has formula Ia, where X is CH, M is -CHF-, and R... 1 For C(O)OH, R 3 For CF 3， R 4 -CH2CH2CF2CH 3， And R 5 for , , or .

[0189] In some embodiments, the compound of formula I has formula Ia, where X is CH, M is -CHF-, and R... 1 For C(O)OH, R 3 For CF 3， R 4 -CH2CH2CF 3， And R 5 for , , or .

[0190] In some embodiments of the present invention, the compound of formula I has the formula of formula II.

[0191] Formula II

[0192] or its pharmaceutically acceptable salt, wherein:

[0193] M is -CHF-, -CH(CH3)-, -CF(CH3)-, -CF2-, or -C(CH3)2-;

[0194] R a R b and R c Each time it appears, independently select the group consisting of the following items: hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and C 3-6 Monocycloalkyl;

[0195] R 1 For OH, CH3, -C(O)NH2, -C(O)OH, -C(O)OC 1-6 Alkyl, -P(O)(OH)2, -S(O)2OH or ;

[0196] R 2a and R 2b Choose independently from the group consisting of: hydrogen, halo, OH, methyl, ethyl, and CH2OH; or R 2a and R 2b Together with the carbon atoms they are attached to, they form C=CH2, C 3-6 Monocycloalkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, or 1,3-dioxyl group, wherein the C 3-6 The monocycloalkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl or 1,3-dioxyl group is optionally substituted by one to three independently selected halogenated and methyl groups;

[0197] R 3 Choose from the following groups: hydrogen, halogen, cyano, R a R b N-, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkylthio, C 3-7 Monocycloalkyl, C 3-7 Monocycloalkoxy, C 3-7 Monocyclic alkyl thiols, C 3-7 Monocyclic alkyl-CH2-thio and C 5-12 Bicycloalkylthio group, wherein the C 3-7 Monocycloalkyl, C 3-7 Monocycloalkoxy, C 3-7 Monocyclic alkyl thiols, C 3-7Monocyclic alkyl-CH2-thio and C 5-12 The bicycloalkylthio group is optionally substituted with 1 to 3 halogenated groups;

[0198] R 4 Halogenated C 3-4 alkyl;

[0199] R 5 For phenyl, C 3-7 Monocycloalkyl or C 5-12 Bicycloalkyl, wherein the phenyl, C 3-7 Monocycloalkyl or C 5-12 The bicycloalkyl group is optionally substituted by one to six independent substituents selected from the group consisting of: halogen, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-; and

[0200] Each time q appears, it independently chooses a group consisting of 0, 1, and 2.

[0201] The following examples further describe compounds of Formula II or pharmaceutically acceptable salts thereof. It should be understood that all chemically permissible combinations of the examples described herein are considered further embodiments of the invention.

[0202] In some embodiments, the compound of formula II has formula IIa

[0203] Formula IIa

[0204] Or, or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the compound of formula II has formula IIb

[0206] Formula IIb

[0207] Or, or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, the compound of formula II has formula IIc

[0209] Formula IIc

[0210] Or, or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, the compound of formula II has formula IId

[0212] Formula IId

[0213] Or, or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, M is -CHF-, -CH(CH3)-, or -CF(CH3)-.

[0215] In some embodiments, M is -CHF-.

[0216] In some embodiments, M is -CH(CH3)-.

[0217] In some embodiments, M is -CF(CH3)-.

[0218] In some embodiments, M is -CF2- or -C(CH3)2-.

[0219] In some embodiments, M is -CF2-.

[0220] In some embodiments, M is -C(CH3)2-.

[0221] In some embodiments, R 1 It is C(O)OH.

[0222] In some embodiments, R 1 It is S(O)2OH.

[0223] In some embodiments, R 1 It is P(O)(OH)2.

[0224] In some embodiments, R 2a and R 2b Choose independently from the group consisting of: hydrogen, halogen, OH, and methyl.

[0225] In some embodiments, R 2a and R 2b It is a methyl group.

[0226] In some embodiments, R 2a It is hydrogen, and R 2b It is a methyl group.

[0227] In some embodiments, R 2a and R 2b Together with the carbon atoms to which they are attached, they form C=CH2, cyclopropyl, cyclobutyl, or oxacyclobutane groups, wherein the cyclopropyl or cyclobutyl group is optionally substituted with 1 to 3 halogenated groups.

[0228] In some embodiments, R 2a and R 2b Together with the carbon atoms they are attached to, they form C=CH2, cyclopropyl, cyclobutyl, or oxecyclobutane groups.

[0229] In some embodiments, R 2a and R 2b Together with the carbon atoms they are attached to, they form cyclopropyl groups.

[0230] In some embodiments, R 3 C 5-12 Bicycloalkylthio-.

[0231] In some embodiments, R 3 Halogenated C 3-7 Monocyclic alkylthio-.

[0232] In some embodiments, R 3 Halogenated C 1-2 alkyl-.

[0233] In some embodiments, R 3 It is CF3.

[0234] In some embodiments, R4 It is a n-butyl group substituted with 1 to 6 halo atoms.

[0235] In some embodiments, R 4 It is a n-butyl group substituted with 1 to 6 F atoms.

[0236] In some embodiments, R 4 It is -CH2CH2CF2CH3.

[0237] In some embodiments, R 4 It is a n-propyl group substituted with 1 to 6 halogen atoms.

[0238] In some embodiments, R 4 It is a n-propyl group substituted with 1 to 6 F atoms.

[0239] In some embodiments, R 4 It is -CH2CH2CF3.

[0240] In some embodiments, R 5 C is a C-type compound that is optionally substituted with one to six independently selected substituents from the group consisting of the following items. 3-7 Monocycloalkyl groups: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0241] In some embodiments, R 5 for or .

[0242] In some embodiments, R 5 A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0243] In some embodiments, R 5 for .

[0244] In some embodiments, R 5 for .

[0245] In some embodiments, R 3 Halogenated C 1-4 alkyl-, and R 4 It is -CH2CH2CF2CH3.

[0246] In some embodiments, R 3 Halogenated C 1-4 alkyl-, and R 4 It is -CH2CH2CF3.

[0247] In some embodiments, R 3 It is CF3, and R 4 It is -CH2CH2CF2CH3.

[0248] In some embodiments, R 3 It is CF3, and R 4 It is -CH2CH2CF3.

[0249] In some embodiments, M is -CHF-, and R 3 Halogenated C 1-4 alkyl- 。

[0250] In some embodiments, M is -CHF-, and R 3 For CF 3。

[0251] In some embodiments, M is -CHF-, R 3 Halogenated C 1-4 alkyl-, and R 4 It is -CH2CH2CF2CH3.

[0252] In some embodiments, M is -CHF-, R 3 Halogenated C 1-4 alkyl-, and R 4 It is -CH2CH2CF3.

[0253] In some embodiments, M is -CHF-, R 3 It is CF3, and R4 It is -CH2CH2CF2CH3.

[0254] In some embodiments, M is -CHF-, R 3 It is CF3, and R 4 It is -CH2CH2CF3.

[0255] In some embodiments, M is -CHF-, R 1 It is C(O)OH, and R 3 Halogenated C 1-4 alkyl.

[0256] In some embodiments, M is -CHF-, R 1 For C(O)OH, R 3 Halogenated C 1-4 Alkyl, and R 4 It is -CH2CH2CF2CH3.

[0257] In some embodiments, M is -CHF-, R 1 For C(O)OH, R 3 Halogenated C 1-4 Alkyl, and R 4 It is -CH2CH2CF3.

[0258] In some embodiments, M is -CHF-, R 1 For C(O)OH, R 3 It is CF3, and R 4 It is -CH2CH2CF2CH3.

[0259] In some embodiments, M is -CHF-, R 1 For C(O)OH, R 3 It is CF3, and R 4 It is -CH2CH2CF3.

[0260] In some embodiments, M is -CHF-, R 1 For C(O)OH, R 3 Halogenated C 1-4 alkyl- ， R 4 It is -CH2CH2CF2CH3, and R 5 A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -、C 1-4 Alkyl, C2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0261] In some embodiments, M is -CHF-, R 1 For C(O)OH, R 3 Halogenated C 1-4 alkyl- ， R 4 It is -CH2CH2CF3, and R 5 A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a Rb NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0262] In some embodiments, M is -CHF-, R 1 For C(O)OH, R 3 For CF3, R 4 It is -CH2CH2CF2CH3, and R 5 A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a Rb NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0263] In some embodiments, M is -CHF-, R 1 For C(O)OH, R 3 For CF3, R 4 It is -CH2CH2CF3, and R 5 A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R aR b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0264] In some embodiments, M is -CHF-, R 1 For C(O)OH, R 3 Halogenated C 1-2 Alkyl, R 4 It is -CH2CH2CF2CH3, and R 5 for , , or .

[0265] In some embodiments, M is -CHF-, R 1 For C(O)OH, R 3 Halogenated C 1-2 Alkyl, and R 4 It is -CH2CH2CF3, and R 5 for , , or

[0266] In some embodiments, M is -CHF-, R 1 For C(O)OH, R 3 For CF 3， R 4 -CH2CH2CF2CH 3， And R 5 for , , or .

[0267] In some embodiments, M is -CHF-, R 1 For C(O)OH, R 3 For CF 3，R 4 -CH2CH2CF 3， And R 5 for , , or .

[0268] In some embodiments, the compound of formula II has formula IIa, R 3 Halogenated C 1-4 alkyl-, and R 4 It is -CH2CH2CF2CH3.

[0269] In some embodiments, the compound of formula II has formula IIa, R 3 Halogenated C 1-4 alkyl-, and R 4 It is -CH2CH2CF3.

[0270] In some embodiments, the compound of formula II has formula IIa, R 3 It is CF3, and R 4 It is -CH2CH2CF2CH3.

[0271] In some embodiments, the compound of formula II has formula IIa, R 3 It is CF3, and R 4 It is -CH2CH2CF3.

[0272] In some embodiments, the compound of formula II has formula IIa, M is -CHF-, R 3 Halogenated C 1-4 alkyl- ， And R 4 It is -CH2CH2CF2CH3.

[0273] In some embodiments, the compound of formula II has formula IIa, M is -CHF-, R 3 Halogenated C 1-4 alkyl- ， And R 4 It is -CH2CH2CF3.

[0274] In some embodiments, the compound of formula II has formula IIa, M is -CHF-, R 3 It is CF3, and R 4 It is -CH2CH2CF2CH3.

[0275] In some embodiments, the compound of formula II has formula IIa, M is -CHF-, R 3 It is CF3, and R 4 It is -CH2CH2CF3.

[0276] In some embodiments, the compound of formula II has formula IIa, M is -CHF-, R 1 For C(O)OH, R 3 Halogenated C 1-4 alkyl- ， And R 4 It is -CH2CH2CF2CH3.

[0277] In some embodiments, the compound of formula II has formula IIa, M is -CHF-, R 1 For C(O)OH, R 3 Halogenated C 1-4 alkyl- ， And R 4 It is -CH2CH2CF3.

[0278] In some embodiments, the compound of formula II has formula IIa, M is -CHF-, R 1 For C(O)OH, R 3 It is CF3, and R 4 It is -CH2CH2CF2CH3.

[0279] In some embodiments, the compound of formula II has formula IIa, M is -CHF-, R 1 For C(O)OH, R 3 It is CF3, and R 4 It is -CH2CH2CF3.

[0280] In some embodiments, the compound of formula II has formula IIa, M is -CHF-, R 1 For C(O)OH, R 3 Halogenated C 1-4 alkyl- ， R 4 -CH2CH2CF2CH 3， And R 5 A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0281] In some embodiments, the compound of formula II has formula IIa, M is -CHF-, R 1 For C(O)OH, R 3 Halogenated C 1-4 alkyl- ， R 4 -CH2CH2CF 3， And R 5 A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, Ra R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0282] In some embodiments, the compound of formula II has formula IIa, M is -CHF-, R 1 For C(O)OH, R 3 For CF 3， R 4 -CH2CH2CF2CH 3， And R 5 A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0283] In some embodiments, the compound of formula II has formula IIa, M is -CHF-, R 1 For C(O)OH, R 3 For CF 3， R 4 -CH2CH2CF 3， And R 5 A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

[0284] In some embodiments, the compound of formula II has formula IIa, M is -CHF-, R 1 For C(O)OH, R 3 Halogenated C 1-2 Alkyl, R 4 It is CH2CH2CF2CH3, and R 5 for , , or .

[0285] In some embodiments, the compound of formula II has formula IIa, M is -CHF-, R 1 For C(O)OH, R 3 Halogenated C 1-2 Alkyl, R 4 It is CH2CH2CF3, and R 5 for , , or .

[0286] In some embodiments, the compound of formula II has formula IIa, M is -CHF-, R 1 For C(O)OH, R 3 For CF 3， R 4 -CH2CH2CF2CH 3， And R 5 for , , or .

[0287] In some embodiments, the compound of formula II has formula IIa, M is -CHF-, R 1 For C(O)OH, R3 For CF 3， R 4 -CH2CH2CF 3， And R 5 for , , or .

[0288] Pharmaceutical Compositions and Kits

[0289] On the other hand, this disclosure provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Specifically, this disclosure provides pharmaceutical compositions comprising compounds as disclosed herein, formulated with one or more pharmaceutically acceptable carriers. These formulations are suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, even though the most suitable form of administration in any given case will depend on the extent and severity of the condition being treated and on the nature of the particular compound being used. For example, the disclosed compositions may be formulated as unit doses and / or may be formulated for oral or subcutaneous administration.

[0290] On the other hand, this disclosure provides a pharmaceutical composition comprising any combination of compounds according to the examples described herein, or pharmaceutically acceptable salts and / or stereoisomers thereof.

[0291] The exemplary pharmaceutical compositions of this disclosure can be used in the form of pharmaceutical formulations (e.g., solid, semi-solid, or liquid forms) containing one or more compounds of this disclosure in the form of an active ingredient, mixed with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral application. The active ingredient may be combined with a generally non-toxic, pharmaceutically acceptable carrier, such as that used in tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable form. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce a desired effect on the course or symptoms of a disease.

[0292] To prepare solid compositions (such as tablets), the main active ingredient can be mixed with a drug carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum) and other drug diluents (e.g., water) to form a solid preformed composition containing a homogeneous mixture of the compounds of this disclosure or a pharmaceutically acceptable non-toxic salt thereof. When referring to these preformed compositions as homogeneous, this means that the active ingredient is uniformly dispersed throughout the composition, allowing the composition to be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0293] In solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) for oral administration, 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 starch, lactose, sucrose, glucose, mannitol, and / or silica; (2) binders, such as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, Examples of fillers include: (4) disintegrants such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; (5) solution retarders such as paraffin; (6) absorption promoters such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glyceryl monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof; and (10) colorants. In the case of capsules, tablets, and pills, the composition may also contain a buffer. Similar types of solid compositions may also use excipients such as lactose or toffee and high molecular weight polyethylene glycol as fillers in soft-filled and hard-filled gelatin capsules.

[0294] Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium carboxymethyl starch or cross-linked sodium carboxymethyl cellulose), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of a subject compound wetted with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms (such as sugar-coated pills, capsules, pellets, and granules) can optionally be coated or prepared with coatings and shells (such as enteric coatings and other coatings well known in the field of pharmaceutical formulation).

[0295] Compositions for inhalation or inhalation comprise solutions and suspensions or mixtures thereof in pharmaceutically acceptable aqueous or organic solvents, as well as powders. Liquid dosage forms for oral administration comprise pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject composition, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranol, fatty acid esters of polyethylene glycol and sorbitan, cyclodextrins, and mixtures thereof.

[0296] In addition to the main composition, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and astragalus gum, and mixtures thereof.

[0297] Formulations for rectal or vaginal application can be present as suppositories, which can be prepared by mixing the subject composition with one or more suitable non-irritating excipients or carriers (including, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylates) and are solid at room temperature but liquid at body temperature and thus melt into the body cavity and release the active agent.

[0298] Dosage forms for transdermal application of the subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active ingredient can be mixed under aseptic conditions with pharmaceutically acceptable carriers and any preservatives, buffers, or propellants that may be required.

[0299] In addition to the main composition, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, astragalus gum, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0300] In addition to the main composition, powders and aerosols may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders or mixtures thereof. Aerosols may also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0301] Alternatively, the compositions and compounds of this disclosure can be administered via aerosols. This is achieved by preparing aqueous aerosols, liposome formulations, or solid particles containing the compounds. Non-aqueous suspensions (e.g., fluorocarbon propellants) can be used. Sonic aerosols can be used because they minimize exposure of the agent to shear, which could cause degradation of the compounds contained in the subject composition. Typically, aqueous aerosols are prepared by formulation of an aqueous solution or suspension of the subject composition with conventionally pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the specific subject composition but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), harmless proteins (such as serum albumin), sorbitan esters, oleic acid, lecithin, amino acids (such as glycine), buffers, salts, sugars, or sugar alcohols. Aerosols are typically prepared from isotonic solutions.

[0302] Pharmaceutical compositions of the present disclosure suitable for parenteral administration comprise one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions only prior to use, and may contain antioxidants, buffers, antibacterial agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0303] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions disclosed herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate), and cyclodextrins. Suitable flowability can be maintained, for example, by using coating materials (such as lecithin), by maintaining the desired particle size in the case of a dispersion, and by using surfactants.

[0304] On the other hand, this disclosure provides enteric pharmaceutical formulations comprising the disclosed compounds and intestinal materials, as well as pharmaceutically acceptable carriers or excipients thereof. Enteric-coated materials refer to polymers that are substantially insoluble in the acidic environment of the stomach and primarily soluble in intestinal fluid at a specific pH. The small intestine is part of the gastrointestinal tract (intestine) between the stomach and large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the distal ileum is approximately 7.5. Therefore, enteric materials are insoluble up to, for example, the following pH values: about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose hexahydrophthalate, cellulose propionate, cellulose maleate, cellulose butyrate, cellulose propionate, copolymers of methyl methacrylate and methyl methacrylate, methyl acrylate, copolymers of methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-trimethylammonium chloride ethyl acrylate copolymers, 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 known or readily determined in vitro. The foregoing is a list of possible materials, but those skilled in the art who have the benefits of this disclosure will recognize that it is not exhaustive, and that there are other intestinal materials that would meet the objectives of this disclosure.

[0305] Advantageously, this disclosure also provides kits for use, for example, by consumers requiring treatment for HBV infection. Such kits include a suitable dosage form (such as those described above) and instructions describing methods for mediating, reducing, or preventing HBV infection using such a dosage form. The instructions will instruct consumers or healthcare professionals to administer the dosage form according to administration methods known to those skilled in the art. Such kits can be advantageously packaged and sold as single or multi-kit units. An example of such kits is the so-called blister pack. Blister packs are well-known in the packaging industry and are widely used for packaging unit dosage forms of pharmaceuticals (tablets, capsules, etc.). A blister pack typically consists of a relatively rigid sheet of material covered with a foil, preferably a transparent plastic material. During the packaging process, a recess is formed in the plastic foil. The recess has the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the recess, and a relatively rigid sheet of material is sealed against the plastic foil at the foil side, opposite to the direction in which the recess is formed. Thus, the tablet or capsule is sealed in the recess between the plastic foil and the sheet. Preferably, the sheet is strong enough that pressure can be applied manually to the recess, thereby creating an opening in the sheet at the recess location, allowing tablets or capsules to be removed from the blister pack. The tablets or capsules can then be removed through said opening.

[0306] It may be desirable to provide memory aids on the kit, for example, in the form of numbers next to the tablets or capsules, whereby these numbers correspond to the number of days in the regimen in which the specified tablets or capsules should be taken. Another example of such a memory aid is a calendar printed on a card, for example, "Week 1, Monday, Tuesday, ... etc... Week 2, Monday, Tuesday, ... etc." Variations of other memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or several tablets or capsules to be taken on a given day. Moreover, the daily dose of a first compound may consist of one tablet or capsule, while the daily dose of a second compound may consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0307] method

[0308] On another aspect, a method for treating hepatitis B infection in a patient with this need is provided, the method comprising administering to a subject or patient an effective amount of the disclosed compound, and / or administering a first disclosed compound, and optionally additional different disclosed compounds. In another embodiment, a method for treating hepatitis B infection in a patient with this need is provided, the method comprising administering to a subject or patient a therapeutically effective amount of the disclosed pharmaceutical composition, or a pharmaceutical composition comprising the disclosed compound or two or more disclosed compounds and a pharmaceutically acceptable excipient.

[0309] Regarding HBV / HDV co-infection, HDV encodes HDAg, the HDV protein responsible for HDV RNA replication. HDV infection is facilitated by the interaction of HDAg with the HBV viral envelope protein HBsAg, enabling entry into hepatocytes and the assembly and release of HDV virions. See, for example, Negro, Cold Spring Harb Perspect Med. 2014 Nov 3;4(11):a021550. doi: 10.1101 / cshperspect.a021550, which is incorporated herein by reference in this contextual teaching. Therefore, since HDV infection depends on the presence of existing HBV infection, strategies for treating HBV / HDV co-infection may focus on targeting HBV alone, HDV alone, or both viruses together.

[0310] Therefore, this disclosure also contemplates a method for treating HBV or HDV infection or HBV / HDV co-infection in patients with this need, the method comprising administering to a subject or patient an effective amount of the disclosed compound, and / or administering a first disclosed compound, and optionally additional different disclosed compounds. In another embodiment, a method for treating HBV or HDV infection or HBV / HDV co-infection in patients with this need is provided, the method comprising administering to a subject or patient a therapeutically effective amount of the disclosed pharmaceutical composition, or a pharmaceutical composition comprising the disclosed compound or two or more disclosed compounds and a pharmaceutically acceptable excipient.

[0311] Without being constrained by any theoretical framework, various mechanisms of action can facilitate therapeutic approaches. One therapeutic possibility involves targeting mechanisms involved in viral particle assembly. In the case of HBV, inhibiting the assembly of the HBV envelope or nucleus by targeting HBsAg would disrupt HBV particle assembly. A second strategy would be to inhibit viral replication of HBV and / or HDV. Existing antiviral therapies can employ this approach in the form of replication inhibitors that target, for example, specific viral RNA polymerases.

[0312] Therefore, another aspect of this disclosure is a method for inhibiting HBV or HDV viral replication in a patient with this need, the method comprising administering to a subject or patient an effective amount of the disclosed compound, and / or administering a first disclosed compound, and optionally additional different disclosed compounds. In another embodiment, a method for inhibiting HBV or HDV viral replication in a patient with this need is provided, the method comprising administering to a subject or patient a therapeutically effective amount of the disclosed pharmaceutical composition, or a pharmaceutical composition comprising the disclosed compound or two or more disclosed compounds and pharmaceutically acceptable excipients.

[0313] Treatment methods may further include targeting bile acid transporter networks, which are considered “gateways” for HBV or HDV infection to enter hepatocytes. See, for example, Slijepcevic et al., Digestive Diseases, 2017;35:251-258, which is incorporated herein by reference in connection with such background teachings. The bile acid transport system, including sodium taurocholate cotransfer peptide (NTCP) and apical sodium-dependent bile acid transporter (ASBT), is a set of receptors that ensure efficient bile acid transport between the ileum and hepatocytes. HBV / HDV co-infection of hepatocytes is believed to be mediated via NTCP receptors, making it a potential therapeutic target. Without being bound by any theory, “entry inhibitors” can target any possible bile acid transport receptors, including but not limited to sodium taurocholate cotransfer peptide (NTCP) and apical sodium-dependent bile acid transporter (ASBT), to prevent HBV or HDV virus entry into cells. Such entry inhibitors can target all or part of the transport receptors to inhibit viral entry.

[0314] Therefore, another aspect of this disclosure is a method for inhibiting viral entry into the hepatocytes of a patient in need, the method comprising administering to a subject or patient an effective amount of the disclosed compound, and / or administering a first disclosed compound, and optionally additional different disclosed compounds. In another embodiment, a method for inhibiting viral entry into the hepatocytes of a patient in need is provided, the method comprising administering to a subject or patient a therapeutically effective amount of the disclosed pharmaceutical composition, or a pharmaceutical composition comprising the disclosed compound or two or more disclosed compounds and a pharmaceutically acceptable excipient.

[0315] Regardless of the targeted mechanism, treatment of patients with HBV or HDV infection or HBV / HDV co-infection can be measured by seroconversion of any viral antigen (including but not limited to HBsAg or HBeAg) or maintenance of undetectable levels of these antigens.

[0316] For use in accordance with the various aspects described herein, the appropriate dosage of the compounds described herein is expected to vary, for example, depending on the specific compound used, the method of administration, and the nature and severity of the infection to be treated, and is within the scope of the attending physician. Typically, the indicated dosage range can be from about 0.1 to about 1000 μg / kg body weight. In some cases, the dosage of the compound may be less than 400 μg / kg body weight. In other cases, the dosage may be less than 200 μg / kg body weight. In still other cases, the indicated dosage range can be from about 0.1 to about 100 μg / kg body weight. The dosage can be conveniently administered once daily, or in fractions, such as four times daily, or in a continuous release formulation.

[0317] The compounds disclosed herein can be administered via any conventional route, specifically: enterically, topically, orally, nasally, for example in tablet or capsule form, via suppositories, or parenterally, for example in injectable solutions or suspensions, for intravenous, intramuscular, subcutaneous, or intraperitoneal injection. Suitable formulations and pharmaceutical compositions will include formulations and pharmaceutical compositions conventionally formulated using one or more physiologically acceptable carriers or excipients, as well as any known and commercially available formulations and pharmaceutical compositions currently used in the clinical setting. Thus, the compounds can be formulated for oral, buccal, topically, parenterally, rectal, or transdermal administration, or in a manner suitable for administration by inhalation or blowing (oral or nasal).

[0318] For oral administration, pharmaceutical compositions may be in the form of tablets or capsules prepared by conventional means using pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn 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 hydroxyacetic acid starch); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated using methods well known in the art. Liquid formulations for oral administration may be in the form of, for example, solutions, syrups, or suspensions, or they may be present as a dried product composed of water or other suitable media prior to use. Such liquid formulations can be prepared by conventional means using pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous mediators (e.g., almond oil, oily esters, ethanol, or fractionated vegetable oils); and preservatives (e.g., methyl or p-hydroxybenzoate or sorbic acid). The formulations may also appropriately contain buffer salts, flavoring agents, coloring agents, and sweeteners.

[0319] Formulations for oral administration can also be appropriately formulated to achieve controlled or sustained release of the active compound over an extended period of time. For buccal administration, the composition can be in the form of tablets or lozenges formulated in a manner known to those skilled in the art.

[0320] The disclosed compounds can also be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Formulations for injection may be present in unit dosage forms (e.g., in ampoules or multi-dose containers) and may contain preservatives. The compositions may be in the form of suspensions, solutions, or emulsions in oily or aqueous media and may contain additives such as suspending agents, stabilizers, and / or dispersants. Alternatively, the compounds may be in powder form for preparation with a suitable mediator (e.g., sterile, pyrogen-free water) prior to use. The compounds can also be formulated for rectal administration in the form of suppositories or retention enemas, for example, containing a conventional suppository base (such as cocoa butter or other glycerides).

[0321] This article also considers methods and compositions that include a second active agent or the administration of a second active agent. For example, in addition to HBV infection, the subject or patient may further suffer from HBV infection-related comorbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or accelerated by HBV infection. This article considers combinations of the disclosed compounds with at least one agent previously demonstrated to treat these HBV infection-related symptoms.

[0322] In some cases, the disclosed compounds may be administered as part of a combination therapy in combination with one or more antiviral agents. Example antiviral agents include nucleoside analogs, interferon-alpha, and other assembly effectors, such as heteroaryl dihydropyrimidines (HAPs), such as methyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (HAP-1). For example, this document provides a method for treating a patient with hepatitis B infection, the method comprising administering to the patient a first amount of the disclosed compound and a second amount of an antiviral agent or other anti-HBV agent, for example, the second amount of a second compound selected from the group consisting of HBV capsid assembly promoters (e.g., GLS4, BAY 41-4109, AT-130, DVR-23 (e.g., as described below)).

[0323] ;

[0324] NVR 3-778, NVR1221 (via code); and N890 (described below):

[0325] ;

[0326] Other capsid inhibitors, such as those disclosed in the following patent applications which are hereby incorporated by reference: WO2014037480, WO2014184328, WO2013006394, WO2014089296, WO2014106019, WO2013102655, WO2014184350, WO2014184365, WO2014161888, WO2014131847. WO2014033176, WO2014033167 and WO2014033170; nucleoside (acid) analogs that interfere with viral polymerases, 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:

[0327] ;

[0328] Viral entry inhibitors, such as Myrcludex B and related lipopeptide derivatives; HBsAg secretion inhibitors, such as REP 9AC' and related nucleic acid-based amphiphilic polymers, as described below for HBF-0529 (PBHBV-001) and PBHBV-2-15:

[0329] ;

[0330] And BM601 as described below:

[0331] ;

[0332] Disruptors of nucleocapsid formation or integrity, such as NZ-4 / W28F:

[0333] ;

[0334] cccDNA formation inhibitors, such as BSBI-25, CCC-0346, and CCC-0975 (as described below):

[0335] 。

[0336] HBc-directed cell-penetrating antibodies, such as Wang Y et al., Transbody against hepatitis B virus core protein inhibits hepatitis B virus replication in vitro, Int. Immunopharmacol (2014), at / / dx.doi.org / 10.1016 / j.intimp.2015.01.028; antiviral nucleoprotein mutants (such as Cp183-V124W and related mutations as described in WO / 2013 / 010069, WO2014 / 074906, each incorporated by reference); HBx interaction inhibitors, such as RNAi, antisense and nucleic acid-based polymers targeting HBV RNA; for example, RNAi (e.g., ALN-HBV, ARC-520, TKM-HBV, ddRNAi), antisense (ISIS-HBV) or nucleic acid-based polymers: (REP 2139-Ca); immunostimulants, such as interferon α2a (Roferon), intron A (interferon α2b), pegylated interferon (pegylated interferon α2a), pegylated IFN 2b, IFNλ1a and PEG. IFNλ1a, Wellferon, Roferon, Infergen, lymphotoxin β agonists such as CBE11 and BS1; non-interferon immune enhancers such as thymosin α-1 (Zadaxin) and interleukin-7 (CYT107); TLR-7 / 9 agonists such as GS-9620, CYT003, and Resiquimod; cyclophilin inhibitors such as NVP018, OCB-030, SCY-635, and Alisporivir; NIM811 and related cyclosporine analogs; vaccines such as GS-4774, TG1050, and nuclear antigen vaccines; SMAC mimics such as Birinapant and other IAP-antagonists; epigenetic regulators 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; JMJDHDM inhibitors; and bromine domain antagonists; kinase inhibitors, such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, ATM and ATR kinase inhibitors; STING agonists; Ribavirin; N-acetylcysteine; NOV-205 (BAM205); Nitazoxanide (Alinia), Tizoxanide; SB 9200 small molecule nucleic acid hybrid (SMNH); DV-601; Arbidol; FXR agonists (such as GW 4064 and Fexaramin); antibodies, therapeutic proteins, gene therapies, and biologics targeting viral components or interacting host proteins.

[0337] In some embodiments, this disclosure provides a method of treating hepatitis B infection in a patient with this need, the method comprising administering a first compound selected from any of the disclosed compounds and one or more other HBV agents selected from the group consisting of: HBV capsid assembly promoters, HBF viral polymerase-infected nucleotides, viral entry inhibitors, HBsAg secretion inhibitors, nucleocapsid formation disruptors, cccDNA formation inhibitors, antiviral nucleoprotein mutants, HBc-directed cell-penetrating antibodies, HBV RNA targeting RNAi, immunostimulants, TLR-7 / 9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimics, epigenetic regulators, kinase inhibitors, and STING agonists. In some embodiments, this disclosure provides a method of treating hepatitis B infection in a patient with this need, the method comprising administering an amount of the disclosed compound and administering another HBV therapeutic agent.

[0338] In some embodiments, this disclosure further provides a method for treating HBV or HDV infection or HBV / HDV co-infection in patients with this need, the method comprising administering a first compound selected from any of the disclosed compounds and one or more other additional antiviral agents, said one or more additional antiviral agents comprising HDV therapy and one or more HBV agents, said one or more HBV agents each selected from the group consisting of: HBV capsid assembly promoters, HBF viral polymerase-infected nucleotides, viral entry inhibitors, HBsAg secretion inhibitors, nucleocapsid formation disruptors, cccDNA formation inhibitors, antiviral nucleoprotein mutants, HBc-directed cell-penetrating antibodies, HBV RNA targeting RNAi, immunostimulants, TLR-7 / 9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimics, epigenetic regulators, kinase inhibitors, and STING agonists. In some embodiments, this disclosure provides a method for treating HBV or HBV infection or HBV / HDV co-infection in patients with this need, the method comprising administering an amount of the disclosed compound and administering another HBV therapeutic agent or HDV therapeutic agent.

[0339] In some embodiments, the first and second amounts together comprise an effective amount of the drug. The first, second, or both amounts may be the same, more or less than the effective amount of each compound administered as a monotherapy. Therapeutic amounts of the disclosed compounds and the antiviral drug may be co-administered to the subject, i.e., administered simultaneously or separately to the subject in any given order or via the same or different routes of administration. In some cases, it is advantageous to begin administration of the disclosed compounds first, for example, one or more days or one or more weeks before initiating administration of the antiviral drug. Furthermore, additional drugs may be administered in combination with the aforementioned combination therapies.

[0340] In another embodiment, the disclosed compound may be conjugated to a detection moiety (e.g., a fluorophore moiety, which may re-emit a light frequency, for example, upon binding to a virus and / or upon photon excitation) (e.g., directly or via a molecular linker to the free carbon, nitrogen (e.g., amino group), or oxygen (e.g., active ester) of the disclosed compound). Considered fluorophores include AlexaFluor. ® 488 (Invitrogen) and BODIPY FL (Invitrogen), as well as fluorescein, rhodamine, cyanine, indole-carbon cyanine, anthraquinone, fluorescent protein, aminocoumarin, methoxycoumarin, hydroxycoumarin, Cy2, Cy3, etc. Such disclosed compounds, when combined with the detection portion, can be used, for example, in methods for detecting HBV infection or biological pathways, e.g., in vitro or in vivo; and / or in methods for evaluating the biological activity of novel compounds.

[0341] Example

[0342] The compounds described herein can be prepared in a variety 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 should be understood that, unless otherwise specified, all proposed reaction conditions (including solvents, reaction atmospheres, reaction temperatures, experimental durations, and the choice of processing procedures) can be selected to suit the conditions of the stated reaction criteria. Those skilled in the art of organic synthesis will understand that the functionality present at each part of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be apparent to those skilled in the art, and therefore alternative methods are indicated. The starting materials of the examples are commercially available or readily prepared from known materials by standard methods.

[0343] At least some of the compounds identified as "intermediates" in this document are contemplated as compounds of this disclosure.

[0344] Abbreviations:

[0345] AcOH (acetic acid)

[0346] ACN acetonitrile

[0347] aq. pirfenidone

[0348] BAST bis(2-methoxyethyl)aminosulfuric acid

[0349] Boc2O ditert-butyl dicarbonate

[0350] nBuLi n-Butyllithium

[0351] compd. compound

[0352] concd. concentrated

[0353] COSY homonuclear correlation spectroscopy

[0354] DCM dichloromethane

[0355] DIAD diisopropyl azodicarbonate

[0356] DIEA diisopropylethylamine

[0357] DMFN, N-dimethylformamide

[0358] DMS dimethyl sulfide

[0359] DMSO (dimethyl sulfoxide)

[0360] EA, EtOAc (ethyl acetate)

[0361] Et3N Triethylamine

[0362] ESI Electrospray Ionization

[0363] HATU hexafluorophosphate aziridinetriazole tetramethylurea

[0364] h,hr hours

[0365] HMBC heteronuclear multibond correlation

[0366] HPLC (High Performance Liquid Chromatography)

[0367] HSQC heteronuclear single quantum coherence

[0368] IPA, iPrOH isopropanol

[0369] LiHMDS bis(trimethylsilyl)aminolithium

[0370] LCMS (Liquid Chromatography-Mass Spectrometry)

[0371] MeOH methanol

[0372] MS mass spectrometry

[0373] NOESY nuclear Overhauser effect spectroscopy

[0374] NFSIN-Fluorobenzenesulfonylimide

[0375] NMPN-methyl-2-pyrrolidone

[0376] NMR nuclear magnetic resonance

[0377] PE petroleum ether

[0378] rac. racemic

[0379] rel. relative

[0380] R f Retention factor

[0381] rt, rt room temperature

[0382] RT, t R Retention time

[0383] sat. saturation

[0384] SFC Supercritical Fluid Chromatography

[0385] TEA Triethylamine

[0386] TFA (trifluoroacetic acid)

[0387] THF tetrahydrofuran

[0388] TLC (Thin-Layer Chromatography)

[0389] Example 1. (R)-2-((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxane-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)ethane-1-sulfonic acid

[0390]

[0391] Step 1. Synthesis of ethyl (R)-2-((tert-butoxycarbonyl)amino)-5-oxohexanoate (1-2). MeMgBr (51.8 mL, 155.3 mmol, 3.0 M) was added dropwise to a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)-2-ethyl ester (1-1) (38.0 g, 147.9 mmol) in THF (380 mL) under nitrogen atmosphere in an ice bath. The mixture was stirred at rt for 6 hr. The resulting mixture was then quenched with a saturated aqueous solution of NH4Cl (200 mL). The mixture was extracted with EA (200 mL x 2), and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA / PE (v / v)) to give 1-2 (32.0 g, 79%) as a yellow solid. TLC: 25% EA / PE (v / v)(R f : 0.4). MS (ESI): C 13 H 23 Calculated value of NO5: 273.2; Experimental value: 174.1 [M] -Boc + 1] + .

[0392] Step 2. Synthesis of (R)-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoate ethyl ester (1-3). BAST (77.7 g, 351.6 mmol) was added dropwise to a solution of 1-2 (32 g, 117.2 mmol) in THF (320 mL) under nitrogen in an ice bath, and the reaction mixture was stirred at rt for 4 days. The reaction mixture was slowly poured into a saturated aqueous solution of NaHCO3 (150 mL) at 0 °C and extracted with EA (150 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (8% EA / PE (v / v)) to give 1-3 (13.8 g, 40%) as a yellow oil. TLC: 10% EA / PE (v / v) (R) f : 0.4). MS (ESI): C 13 H 23 Calculated value of F2NO4: 295.2 MS; Experimental value: 196.2 [M - Boc + 1] + .

[0393] Step 3. Synthesis of (R)-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoic acid (1-4). LiOH (3.4 g, 140.3 mmol) was added to a solution of 1-3 (13.8 g, 46.8 mmol) in THF / H₂O = 5 / 1 (v / v) (100 mL). After stirring at rt for 4 hr, the reaction mixture was diluted with water (100 mL), acidified to pH ~ 3 with 1N HCl aqueous solution, and concentrated to remove the organic solvent. The residue was extracted with EA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was dried under vacuum to give 1-4 (11.3 g, 90%) as a yellow oil, which could be used in the next step without further purification. TLC: 35% EA / PE (v / v) (R) f : 0.4). MS (ESI): C 11 H 19 Calculated value of F2NO4: 267.1; Experimental value: 168.2 [M-Boc] + 1] + .

[0394] Step 4. Synthesis of (R)-(5,5-difluoro-1-oxo-1-(phenylamino)hexane-2-yl)carbamate tert-butyl (1-5). HATU (24.1 g, 63.5 mmol) was added dropwise 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) under nitrogen in an ice bath. After stirring for 40 min, PhNH2 (5.9 g, 63.5 mmol) was added dropwise. 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) (R f : 0.4). MS (ESI): C 17 H 24 Calculated value of F2N2O3: 342.2; Experimental value: 287.2 [M - tBu] + 1] + .

[0395] 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 for 4 hr at room temperature and concentrated. The residue was diluted with DCM (100 mL) and alkalized to pH ~ 8 with a saturated aqueous solution of NaHCO3. The resulting mixture was extracted with DCM (100 mL x 4). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was dried under vacuum to give crude product 1-6 (4.8 g, 89%) as a yellow oil, which could be used in the next step without further purification. TLC: 8% MeOH / DCM (v / v) (R) f : 0.5). MS (ESI): C 12 H 16 Calculated value of F₂N₂O: 242.2; Experimental value: 243.2 [M +1] + .

[0396] Step 6. Synthesis of (R)-5,5-difluoro-N1-phenylhexane-1,2-diamine (1-7). LAH (23.8 mL, 59.5 mmol, 2.5 M in THF) was added dropwise to a stirred solution of 1-6 (4.8 g, 19.8 mmol) in THF (100 mL) at 0 °C. The resulting mixture was stirred at 70 °C for 4 hr. The reaction was quenched at 0 °C with H2O (2.3 mL) and 15% NaOH aqueous solution (2.3 mL). 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) (R) f : 0.3). MS(ESI): C 12 H 18 Calculated F2N2 value: 228.1; Experimental value: 229.3 [M] + 1] + .

[0397] Step 7. Synthesis of (R)-2-bromo-N-(5,5-difluoro-1-(phenylamino)hexane-2-yl)-5-methoxy-4-(trifluoromethyl)benzenesulfonamides (1-8). 2-bromo-5-methoxy-4-(trifluoromethyl)benzenesulfonamide chloride (2.3 g, 6.59 mmol) was added fractionally to a stirred solution of 1-7 (1.0 g, 4.39 mmol) and TEA (886 mg, 8.77 mmol) in THF (10 mL) under rt. After stirring for 16 hr under rt, 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) (R) f : 0.4). MS (ESI): C 20 H 22 Calculated value of BrF5N2O3S: 544.0; Experimental value: 545.1 [M] + 1] + .

[0398] 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), pyridinecarboxylic acid (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 for 3 h at 90 °C under a 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 saturated LiCl aqueous solution (30 mL) and brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was dried under vacuum to give crude product 1-9 (1.2 g, 88.2%) as a brown oil, which could be used in the next step without further purification. TLC: 25% EA / PE (v / v) (R f :0.4). MS (ESI): C 20 H 21 Calculated value of F5N2O3S: 464.1; Experimental value: 465.1 [M] + 1] + .

[0399] 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). MeI (1.1 g, 7.77 mmol) was added to a suspension of 1-9 (1.2 g, 2.59 mmol) and Cs₂CO₃ (1.1 g, 3.36 mmol) in NMP (10 mL) 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 layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was dried under vacuum to give crude product 1-10 (1.1 g, 88.9%) as a brown oil, which could be used in the next step without further purification. TLC: 25% EA / PE (v / v) (R f : 0.6). MS (ESI): C 21 H 23 Calculated value of F5N2O3S: 478.1; Experimental value: 479.1 [M] + 1] + .

[0400] 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). NaSMe (1.6 g, 23.0 mmol) was added to a solution of 1-10 (1.1 g, 2.30 mmol) in DMF (6.0 mL), and the reaction mixture was stirred at 100 °C for 16 hr. The reaction mixture was diluted with water (30 mL), acidified to pH 5-6 with 4 NHCl aqueous solution, and extracted with EA (50 mL x 3). The combined organic layers were washed with saturated LiCl aqueous 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) (R f : 0.4). MS (ESI): C 20 H 21 Calculated value of F5N2O3S: 464.1; Experimental value: 465.3 [M] + 1] + .

[0401] Step 11. Synthesis of (R)-2-((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)ethanesulfonic acid (Example 1). Sodium 2-bromoethane-1-sulfonate (611 mg, 2.91 mmol) was added to a suspension of 1-11 (450 mg, 0.97 mmol) and Cs₂CO₃ (1264 mg, 3.88 mmol) in DMF (10 mL), and the reaction mixture was stirred at 130 °C for 16 h. The reaction mixture was diluted with water (20 mL) and acidified to pH ~5 with 4N HCl aqueous solution. The resulting mixture was extracted with EA (25 mL x 3). The combined organic layers were dried anhydrously over Na₂SO₄ and concentrated. The residue was purified by preparative HPLC to give Example 1 (112 mg, 20.2%) as a white solid. TLC: 5% MeOH / EA (v / v) (R f : 0.5). MS (ESI): C 22 H 25 Calculated value of F5N2O6S2: 572.1; Experimental value: 573.0 [M + 1] +. 1 H 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.

[0402] Example 2. (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0403]

[0404] Step 1. Synthesis of ethyl 1-(((methanesulfonyl)oxy)methyl)cyclopropane-1-carboxylate (2-2). MsCl (119 mg, 1.04 mmol) was added 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). After stirring at rt for 1 hr, ice-cold water (10 mL) was added to the reaction mixture, and extraction was performed with DCM (20 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried under vacuum to give 2-2 (140 mg, 91%) as a yellow oil. TLC: 10% EA / PE (v / v) (R f : 0.6) (phosphomolybdic acid). MS (ESI): C8H 14 Calculated value of O5S: 222.1; Experimental value: 240.1 [M + 18] + .

[0405] Step 2. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid ethyl ester (2-3). 10-2 (71 mg, 0.32 mmol) was added to a stirred solution of 1-11 (75 mg, 0.16 mmol) and Cs₂CO₃ (156 mg, 0.48 mmol) in DMF (2 mL), and the reaction mixture was heated at -70 °C for 3 hr. After the reaction was complete (monitored by LCMS), the reaction mixture was added to water (10 mL). The precipitate was collected by filtration, washed with water (5 mL x 3), and dried under vacuum to give crude product 2-3 (120 mg) as a white solid, which could be used in the next step without further purification. TLC: 40% EA / PE (v / v) (R) f : 0.5). MS (ESI): C 27 H 31 Calculated value of F5N2O5S: 590.2; Experimental value: 591.3 [M + 1] + .

[0406] Step 3. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 2). NaOH (22 mg, 0.55 mmol) was added to a stirred solution of 2–3 (80 mg, crude product, 0.11 mmol) in MeOH / H₂O = 2 / 1 (v / v) (3 mL), and the reaction mixture was stirred at rt for 2 hr. After the reaction was complete (monitored by LCMS), the reaction mixture was neutralized with 1 NHCl aqueous solution and concentrated to remove the 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 preparative HPLC to give Example 2 (28 mg, 45%) as a white solid. TLC: 10% MeOH / DCM (v / v) (R f :0.5). MS (ESI): C 25 H 27 Calculated value of F5N2O5S: 562.2; Experimental value: 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 = 7.2Hz, 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.

[0407] Example 3. (R)-3-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)methyl)oxetane-3-carboxylic acid

[0408]

[0409] Step 1. Synthesis of (R)-3-(3,3-difluorobutyl)-8-((3-(hydroxymethyl)oxetane-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), add (3-(bromomethyl)oxetane-3-yl)methanol (156 mg, 0.86 mmol) and Cs₂CO₃ (420 mg, 1.29 mmol). Stir the mixture overnight at 70 °C. Treat the reaction mixture with LiCl solution (8 mL) and extract with ethyl acetate (10 mL x 2). Dry the combined organic extracts with anhydrous Na₂SO₄ and concentrate. The residue was dried under vacuum to give crude product 3-1 (243 mg) as a brown solid, which could be used in the next step without further purification. MS (ESI): C 25 H 29 Calculated value of F5N2O5S: 564.2; Experimental value: 565.2 [M + 1] + .

[0410] Step 2. Synthesis of (R)-3-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazopen-8-yl)oxy)methyl)oxetane-3-carboxylic acid (Example 3). To a solution of 3-1 (crude product 243 mg, 0.43 mmol) in DCM (10 mL), Dys-Martin reagent (729 mg, 1.72 mmol) was added. After stirring at rt for 5 hr, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give Example 3 (60 mg, 24%) as a white solid. MS (ESI): C 25 H 27 Calculated value of F5N2O6S: 578.2; Experimental value: 579.3 [M + 1] + . 1 H 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, 1.4Hz, 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.

[0411] Example 4. (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)methyl)-3,3-difluorocyclobutane-1-carboxylic acid

[0412]

[0413] Step 1. Synthesis of isopropyl 3,3-difluoro-1-(hydroxymethyl)cyclobutanecarboxylate (4-2). At 0 °C, a solution of 3,3-difluorocyclobutane-1,1-dicarboxylate (4-1) (2.0 g, 7.60 mmol) in anhydrous THF (60 mL) was added to THF containing 1N tritert-butoxylithium aluminum hydride (18.9 mL, 18.9 mmol). After stirring at 70 °C for 16 hr, the reaction was quenched at 0 °C with a saturated aqueous NH4Cl solution until no foaming was observed. The mixture was diluted with water (80 mL), concentrated to remove the 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): C9H 14 Calculated value of F₂O₃: 208.2; Experimental value: 209.2 [M + 1] + .

[0414] Step 2. Synthesis of isopropyl 3,3-difluoro-1-((((trifluoromethyl)sulfonyl)oxy)methyl)cyclobutanecarboxylate (4-3). Tf₂O (400 mg, 1.92 mmol) was added to a solution of 4-2 (400 mg, 1.92 mmol) and 2,6-dimethylpyridine (308 mg, 2.88 mmol) in DCM (5 mL) 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 under vacuum to give crude product 4-3 (200 mg, 31%) as a yellow solid, which could be used in the next step without further purification.

[0415] Step 3. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)methyl)-3,3-difluorocyclobutanecarboxylate (4-4). 4-3 (200 mg, 0.59 mmol) was added to a solution of 1-11 (100 mg, 0.21 mmol) and Cs₂CO₃ (205 mg, 0.63 mmol) in DMF (3 mL), 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 under vacuum to give crude product 4-4 (160 mg, 84%) as a yellow solid, which could be used in the next step without further purification. MS (ESI): C 29 H 33 Calculated value of F7N2O5S: 654.2; Experimental value: 655.4 [M+1] + .

[0416] Step 4. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)methyl)-3,3-difluorocyclobutanecarboxylic acid (Example 4). 1 N LiOH aqueous solution (1 mL) was added to a solution of 4-4 (150 mg, 0.23 mmol) in THF (4 mL), and the reaction mixture was stirred at rt for 16 hr. The reaction mixture was adjusted to pH = 6 with 1 N HCl aqueous solution and then purified by preparative HPLC to give Example 4 (30 mg, 24%) as a grayish-white solid. MS (ESI): C 26 H 27 Calculated value of F7N2O5S: 612.2; Experimental value: 613.0 [M + 1] + . 1H NMR (400 MHz, CD3OD): δ7.68 (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.

[0417] Example 5. (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0418]

[0419] Step 1. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)methyl)cyclopropanecarboxylate (5-2). Ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (116 mg, 0.53 mmol) was added to a stirred solution of 5-1 (140 mg, 0.29 mmol) in DMF (4 mL) prepared by readily following the same procedure as for preparing 1-11 by replacing aniline with 4-F-aniline and Cs₂CO₃ (284 mg, 0.87 mmol). After stirring at 65 °C for 3 hr, the reaction mixture was added to water (10 mL). The precipitate was filtered, washed with water (10 mL x 3), and dried under vacuum to give crude product 5-2 (120 mg) as a white solid, which could be used in the next step without further purification. TLC: EA / PE = 3 / 7 (v / v) (R f : 0.5). MS (ESI): C 27 H 30Calculated value of F6N2O5S: 608.2; Experimental value: 609.2 [M + 1] + .

[0420] Step 2. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)methyl)cyclopropanecarboxylic acid (Example 5). NaOH (79 mg, 1.97 mmol) was added to a stirred solution of 5-2 (120 mg, crude product, 0.20 mmol) in MeOH / H2O = 2 / 1 (v / v) (6 mL), and the reaction mixture was stirred at rt for 16 hr. After the reaction was complete (monitored by LCMS), the reaction mixture was neutralized with 1 NHCl aqueous solution and concentrated to remove the 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 preparative HPLC to give Example 5 (49 mg, 43%) as a white solid. TLC: EA / PE = 1 / 1 (v / v)(R f : 0.5). MS (ESI): C 25 H 26 Calculated value of F6N2O5S: 580.1; Experimental value: 581.3 [M] + 1] + . 1 H NMR (400MHz, 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.

[0421] Example 6a. (R)-3-(((R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)-2-methylpropionic acid

[0422]

[0423] Step 1. Synthesis of methyl (R)-3-(((R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)-2-methylpropionate (5-2). Methyl (R)-3-hydroxy-2-methylpropionate (1.8 g, 15.2 mmol) and PPh3 (2.4 g, 9.3 mmol) were added to a solution of 5-1 (1.5 g, 3.1 mmol) in toluene (15 mL). Then, DIAD (6.3 g, 31.1 mmol) was added at 110 °C under a nitrogen atmosphere. After stirring at 110 °C for 4 hr, the reaction mixture was poured into water and extracted with EtOAc (200 mL x 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography to give 6a-1 (1.6 g, 89%) as a yellow solid. MS (ESI): C 26 H 30 Calculated value of F6N2O5S: 582.1; Experimental value: 583.2 [M + 1] + .

[0424] Step 2. Synthesis of (R)-3-(((R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazopen-8-yl)oxy)-2-methylpropionic acid (Example 6a). LiOH (660 mg, 27.5 mmol) was added to a solution of 6a-1 (1.6 g, 2.7 mmol) in THF (40 mL) / H₂O (10 mL). After stirring at rt for 4 hr, the reaction mixture was poured into water. The mixture was adjusted to pH 3 with 3 NHCl aqueous solution, and the resulting 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 preparative HPLC to give Example 6a (600 mg, 40%) as a white solid. MS (ESI): C 24 H 26 Calculated value of F6N2O5S: 568.1; Experimental value: 569.2 [M + 1] + . 1H NMR (400 MHz, CD3OD): δ7.63 (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.

[0425] Example 6b. (S)-3-(((R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)-2-methylpropionic acid

[0426]

[0427] Following the same procedure as in the preparation of Example 6a by replacing (R)-3-hydroxy-2-methylpropionate with its enantiomer (S)-3-hydroxy-2-methylpropionate, Example 6b was obtained as a white solid. MS (ESI): C 24 H 26 Calculated value of F6N2O5S: 568.1; Experimental value: 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.

[0428] Example 7. (R)-3-((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)-2,2-dimethylpropionic acid

[0429]

[0430] Step 1. Synthesis of ethyl 2,2-dimethyl-3-((methanesulfonyl)oxy)propionate (7-2). TEA (2.08 g, 20.56 mmol) was added to a solution of ethyl 3-hydroxy-2,2-dimethylpropionate (7-1) (1.5 g, 10.26 mmol) in DCM (30 mL), followed by the addition of methanesulfonic anhydride (2.68 g, 15.39 mmol) at 0 °C. 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 over anhydrous Na2SO4 and concentrated. The residue was dried under vacuum to give crude product 7-2 (2.8 g, 100%, crude product) as a pale yellow oil, which could be used in the next step without further purification. MS (ESI): C8H 16 Calculated value of O5S: 224.1; Experimental value: 242.2 [M] + 18] + .

[0431] Step 2. Synthesis of (R)-3-((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)-2,2-dimethylpropionate ethyl ester (7-3). K₂CO₃ (1.29 g, 9.33 mmol) and 7-2 (1.4 g, 6.2 mmol, crude product) were sequentially added to a solution of 5-1 (1.5 g, 3.1 mmol) in DMF (10 mL). After stirring at 110 °C for 48 hr, the reaction mixture was diluted with H₂O (80 mL) and extracted with EA (50 mL x 3). The combined organic extracts were washed with saturated LiCl aqueous solution (100 mL) and brine, dried over 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): C 27 H 32 Calculated value of F6N2O5S: 610.2; Experimental value: 611.0 [M] + 1] + .

[0432] Step 3. Synthesis of (R)-3-((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazidepine-8-yl)oxy)-2,2-dimethylpropionic acid (Example 7). LiOH was added to a solution of 7-3 (1.8 g, 2.95 mmol) in CH3OH / THF / H2O (8 mL / 8 mL / 8 mL). . H2O (1.24 g, 29.55 mmol). After stirring at 35 °C for 3 hr, the reaction mixture was diluted with H2O (100 mL), adjusted to pH = 2 with 2 NHCl aqueous solution, and extracted with EtOAc (60 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by reverse column chromatography (CH3CN / H2O = 40% (v / v)) to give Example 7 (740 mg, 43%) as a white solid. MS (ESI): C 25 H 28 Calculated value of F6N2O5S: 582.2; Experimental value: 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.

[0433] Examples 8a and 8b. 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (8a) and 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (8b)

[0434]

[0435] Step 1. Synthesis of methyl 5,5-difluoro-2-(((methanesulfonyl)oxy)methyl)hexanoate (8-2). MsCl (70.06 g, 611.64 mmol) was added dropwise 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) at 0 °C. After stirring at rt for 2 hr, H₂O (500 mL) was added to the reaction mixture 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 under vacuum to give 8-2 (110 g, 79%) as a brown liquid, which could be used in the next step without further purification.

[0436] Step 2. Synthesis of methyl 2-(bromomethyl)-5,5-difluorohexanoate (8-3). Lithium bromide (104.48 g, 1203.15 mmol) was added in portions to a stirred solution of 8-2 (110 g, 401.05 mmol) in acetone (500 mL) under reflux. After stirring at 60 °C for 3 hr, the mixture was cooled to reflux and H2O (200 mL) was added under reflux. 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 under vacuum to give 8-3 (100 g, 96%) as a brown liquid, which could be used in the next step without further purification. 1 H 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.

[0437] Step 3. Synthesis of methyl 2-(((2-amino-5-methoxyphenyl)thio)methyl)-5,5-difluorohexanoate (8-4). 8-3 (100.15 g, 386.56 mmol) was added dropwise to a stirred solution of 2-amino-5-methoxythiophenol (60 g, 386.55 mmol) and Cs₂CO₃ (151.60 g, 463.85 mmol) in ACN (500 mL) under reflux. After stirring for 4 hr under reflux, water (50 mL) was added to the reaction mixture under reflux. 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 and diluted with PE / EA = 4 / 1 (v / v) to give 8-4 (80 g, 62%) as a brown solid. MS (ESI): C 15 H 21 Calculated value of F₂NO₃S: 333.1; Experimental value: 334.1 [M] + 1] + .

[0438] Step 4. Synthesis of 2-(((2-amino-5-methoxyphenyl)thio)methyl)-5,5-difluorohexanoic acid (8-5). LiOH (20.26 g, 845.87 mmol) was added to a stirred solution of 8-4 (94 g, 281.95 mmol) in dioxane (800 mL) and H₂O (200 mL) under reflux. The resulting mixture was stirred under reflux for 2 hr. The mixture was acidified to pH ~ 6 with 2 NHCl aqueous solution. 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. The residue was dried under vacuum to give 8-5 (80 g, 89%) as a brown solid, which could be used in the next step without further purification. MS (ESI): C 14 H 19 Calculated value of F₂NO₃S: 319.1; Experimental value: 320.1 [M] + 1] + .

[0439] Step 5. Synthesis of 3-(3,3-difluorobutyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiapine-4(5H)-one (8-6). DIEA (38.85 g, 300.59 mmol) was added dropwise to a stirred solution of 8-5 (80 g, 250.49 mmol) and HATU (104.77 g, 275.54 mmol) in DCM (1000 mL) under rt. The reaction mixture was stirred under rt for 2 hr, and then H2O (50 mL) was added. 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 and diluted with PE / EA = 7 / 3 (v / v) to give 8-6 (67 g, 89%) as a yellow solid. MS (ESI): C 14 H 17 Calculated value of F₂NO₂S: 301.1; Experimental value: 302.1 [M] + 1] + .

[0440] Step 6. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiapine-4(5H)-one (8-7). NBS (20.79 g, 116.80 mmol) was added in portions to a stirred solution of 8-6 (32 g, 106.18 mmol) in DCM (200 mL) and ACN (200 mL) under rt. The resulting mixture was stirred under rt for 4 hr, and then H2O (100 mL) was added. 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 wet milling 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 under vacuum to give 8-7 (22 g, 54%) as a white solid. MS (ESI): C 14 H 16 Calculated value of BrF₂NO₂S: 379.0; Experimental value: 380.0 [M] + 1] + . 1 H 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.

[0441] Step 7. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(3-fluorophenyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiapine-4(5H)-one (8-8). 1-fluoro-3-iodobenzene (1.75 g, 7.89 mmol), CuI (1.50 g, 7.89 mmol), and K₂CO₃ (3.27 g, 23.67 mmol) were added to a solution of 8-7 (3 g, 7.89 mmol) in DMF (30 mL) under nitrogen atmosphere at rt. The resulting mixture was stirred at 130 °C for 16 hr and then cooled to rt and water (100 mL) was added. 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 and diluted with PE / EA = 3 / 1 (v / v) to give 8-8 (3 g, 80%) as a yellow solid. MS (ESI): C 20 H 19 Calculated value of BrF3NO2S: 473.0; Experimental value: 474.0 [M] + 1] + .

[0442] Step 8. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(3-fluorophenyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiapine-4(5H)-one 1,1-dioxide (8-9). Oxone was added to a solution of 8-8 (3 g, 6.33 mmol) in THF (40 mL) and H2O (20 mL) under rt. ® (63.81 g, 379.500 mmol). After stirring at rt for 16 hr, the mixture was filtered, and the filter cake was washed with ethyl acetate (25 mL x 3). The filtrate was concentrated, and the residue was diluted with saturated NaHCO3 aqueous solution (25 mL) and EtOAc (150 mL). The separated organic layer was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated. The residue was dried under vacuum to give 8-9 (2.5 g, 78%) as a yellow solid, which could be used in the next step without further purification. MS (ESI): C 20 H 19 Calculated value of BrF3NO4S: 505.0; Experimental value: 506.0 [M] + 1] + .

[0443] Step 9. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(3-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine 1,1-dioxide (8-10). THF containing 1 M BH3-Me2S (2.81 mL, 29.622 mmol) was added to a solution of 8-9 (2.5 g, 4.94 mmol) in THF (30 mL) under rt. After stirring at 75 °C for 16 hr, the mixture was cooled to 0 °C, ice water (30 mL) was added, and the mixture was concentrated to remove the 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 and diluted with PE / EA = 5 / 1 (v / v) to give 8-10 (1.6 g, 67%) as a yellow solid. MS (ESI): C 20 H 21 Calculated value of BrF3NO3S: 491.0; Experimental value: 492.0 [M] + 1] + .

[0444] 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]thiapine 1,1-dioxide (8-11). LiHMDS (6.5 mL, 1 mol / L in THF) was added dropwise to a solution of 8-10 (1.6 g, 3.25 mmol) in 20 mL of THF at -78 °C. After stirring at -78 °C for 30 min, NFSI (1.23 g, 3.90 mmol) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for an additional 2 hr. A saturated aqueous solution of NH4Cl was added to the reaction mixture at rt, and then concentrated to remove the 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 and diluted with PE / EA = 5 / 1 (v / v) to give 8-11 (1 g, 60%) as a yellow solid. MS (ESI): C 20 H 20 Calculated value of BrF4NO3S: 509.0; Experimental value: 510.0 [M] + 1] + .

[0445] 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]thiapine 1,1-dioxide (8-12). Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (602.30 mg, 3.14 mmol) and CuBr (224.87 mg, 1.57 mmol) were added to a solution of 8-11 (400 mg, 0.78 mmol) in DMF (5 mL) under nitrogen atmosphere at rt. The resulting mixture was stirred at 120 °C for 16 hr, and then water (15 mL) was added 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 preparative TLC (PE / EA = 3 / 1 (v / v)) to give 8-12 (200 mg, 51%) as a yellow solid. MS (ESI): C 21 H 20 Calculated value of F7NO3S: 499.1; Experimental value: 500.1 [M] + 1] + .

[0446] 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]thiapine 1,1-dioxide (8-13). Lithium chloride (509.25 mg, 12.00 mmol) was added to a solution of 8-12 (200 mg, 0.40 mmol) in DMSO (5 mL) under reflux. The resulting mixture was stirred at 140 °C for 8 hr, and then water (15 mL) was added under reflux. The mixture was acidified to pH ~ 5 with saturated aqueous citric acid solution. 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 preparative TLC (PE / EA = 3 / 1 (v / v)) to give cis-racemic 8-13 (50 mg, 26%) as a yellow solid. MS (ESI): C 20 H 18 Calculated value of F7NO3S: 485.1; Experimental value: 486.2 [M] + 1] + .

[0447] Step 13. Synthesize (2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine 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]thiapine 1,1-dioxide (8-13b). Racemic 8-13 (40 mg) was separated by preparative SFC under the following conditions: column: (R, R)-WHELK-O1-Kromasil, 3*25 cm, 5 μm; mobile phase A: CO2; gradient: isocratic 20% B; RT1 (min) = 2.6 (8-13a as a single diastereomer, stereochemistry arbitrarily specified); RT2 (min) = 3.6 (8-13b as a single diastereomer, stereochemistry arbitrarily specified); sample solvent: MeOH-HPLC; injection volume: 4 mL, to obtain 8-13a (15 mg) and 8-13b (15 mg) as pale yellow solids. MS (ESI): C 20 H 18 Calculated value of F7NO3S: 485.1; Experimental value: 486.2 [M] + 1] + .

[0448] Step 14a. Synthesis of ethyl 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine-8-yl)oxy)methyl)cyclopropane-1-carboxylate (8-14a). ethyl 1-(bromomethyl)cyclopropane-1-carboxylate (9.20 mg, 0.045 mmol) and CsCO3 (20.40 mg, 0.06 mmol) were added to a solution of 8-13a (15 mg, 0.03 mmol) in DMF (2 mL) at rt. After stirring at 80 °C for 2 hr, the reaction mixture was cooled to rt, water (15 mL) was added, and extraction was performed using 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 preparative TLC (PE / EA = 3 / 1 (v / v)) to give 8-14a (16 mg, 79%) as a yellow solid (monodiameric, stereochemistry arbitrarily specified). MS (ESI): C 27 H 28Calculated value of F7NO5S: 611.2; Experimental value: 612.1 [M] + 1] + .

[0449] Step 15a. Synthesis of 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 8a). LiOH (35.25 mg, 1.47 mmol) and H2O (1 mL) were added to a solution of 8-14a (16 mg, 0.025 mmol) in 1,4-dioxane (4 mL) under rt. After stirring under rt for 16 hr, the reaction mixture was diluted with water (10 mL) and concentrated to remove the organic solvent. The residue was acidified to pH ~ 5 with saturated aqueous citric acid 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 residues were purified by preparative HPLC under the following conditions: column: SunFire Prep C18 OBD column, 19 x 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 30 mL / min; gradient: 50% B to 78% B over 8 min; wavelength: 220 nm, 254 nm; RT1 (min) = 6.38, to give Example 8a (10 mg, 69%) as a white solid (single diastereomer, stereochemistry arbitrarily specified). MS (ESI): C 25 H 24 Calculated value of F7NO5S: 583.1; Experimental value: 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.

[0450] Step 14b. Synthesis of ethyl 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine-8-yl)oxy)methyl)cyclopropane-1-carboxylate (8-14b). Following the same procedure described above for the preparation of 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 (monodiameric, stereochemistry arbitrarily specified). MS (ESI): C 27 H 28 Calculated value of F7NO5S: 611.2; Experimental value: 612.1 [M] + 1] + .

[0451] Step 15b. Synthesis of 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 8b). Following the same procedure as described above for the preparation of Example 8a by replacing 8-14a with 8-14b (16 mg, 0.025 mmol), Example 8b (10 mg, 69%) was obtained as a white solid (monodiameric, stereochemistry arbitrarily specified). Preparative HPLC conditions: Column: SunFire Prep C18 OBD column, 19*150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 30 mL / min; Gradient: 55% B to 75% B over 8 min; Wavelength: 220 nm, 254 nm; RT1 (min) = 5.92. MS (ESI): C 25 H 24 Calculated value of F7NO5S: 583.1; Experimental value: 584.2 [M] + 1] + . 1 HNMR (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.

[0452] Synthesized rac-(2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine 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]thiapine 1,1-dioxide (9-1b).

[0453]

[0454] Step 1. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiapine-4(5H)-one (9A-1). A solution of 7-bromo-3-(3,3-difluorobutyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiapine-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). The resulting mixture was stirred at 80 °C under an oxygen atmosphere for 16 h. The mixture was cooled to room temperature and quenched with EtOAc (300 mL) and a saturated aqueous solution of NH4Cl (900 mL). The resulting solution was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with water (300 mL x 3) and brine (300 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried under vacuum to give crude product 9A-1 (25 g) as a black solid, which could be used in the next step without further purification. MS (ESI): C 20 H 19 Calculated value of BrF3NO2S: 473.0; Experimental value: 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.

[0455] Step 2. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiapine-4(5H)-one 1,1-dioxide (9A-2). Oxone was added in portions to a stirred solution of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiapine-4(5H)-one (9A-1) (25 g, 52.71 mmol) in THF (500 mL) and H2O (500 mL) under rt. ® (107 g, 0.31 mol). The resulting mixture was stirred at rt for 16 h. The mixture was filtered. The filtrate was concentrated to remove the 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 under vacuum to give crude product 9A-2 (24 g) as a brown solid, which could be used in the next step without further purification. MS (ESI): C 20 H 19 Calculated value of BrF3NO4S: 505.0; Experimental value: 506.0 [M] + 1] + . 1H NMR (300MHz, DMSO-d6): δ 7.47 (s, 1H), 7.42 (s, 1H), 7.38 – 7.24 (m, 4H), 4.00 (s,3H), 4.09 – 3.88 (m, 1H), 3.75 (dd, J = 13.6, 12.0 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.

[0456] Step 3. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine 1,1-dioxide (9A-3). Under reflux, 48 mL of THF containing 10 M BH3•Me2S was added dropwise to a stirred solution of 24 g (47.40 mmol) of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiapine-4(5H)-one 1,1-dioxide (9A-2) in THF (120 mL). The resulting mixture was stirred at 60 °C for 16 hr. The reaction was quenched under reflux by adding 100 mL of H2O. 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 the eluent to give 9A-3 (20 g, 85.7%) as a brown solid. MS (ESI): C 20 H 21 Calculated value of BrF3NO3S: 491.0; Experimental value: 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.

[0457] 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]thiapine 1,1-dioxide (9A-4). LiHMDS (1 mol / L in THF) (2.8 mL, 10.15 mmol) was added dropwise to a solution of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine 1,1-dioxide (9A-3) (2.5 g, 5.07 mmol) in tetrahydrofuran (50 mL) under a nitrogen atmosphere at -78 °C. The reaction mixture was stirred at -78 °C for 30 min. The solution of NFSI (1.60 g, 5.07 mmol) in tetrahydrofuran (5 mL) was then added dropwise, and the mixture was stirred at -78 °C for 30 min. The reaction was carried out with saturated NH4Cl aqueous solution (50 mL), and the mixture was then 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 the eluent to give 9A-4 (1.5 g, 57.9%) as a brown solid. MS (ESI): C 20 H 20 Calculated value of BrF4NO3S: 509.0; Experimental value: 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.

[0458] Step 5. Synthesize rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine 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]thiapine 1,1-dioxide (9A-5b). CuBr (95.57 g, 0.67 mol) was added in portions 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]thiapine 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) under a nitrogen atmosphere at rest. The resulting mixture was stirred at 130 °C under a nitrogen atmosphere for 16 h. The mixture was then cooled to rest. The reaction was quenched at rest by adding H2O (10 L). 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 residues were purified by silica gel column chromatography using PE / EA = 3 / 1 (v / v) as the eluent to obtain 9A-5a (60 g, 36.1%, cis-racemate) and 9A-5b (45 g, 27.1%, trans-racemate) as yellow solids, respectively.

[0459] 9A-5a: MS (ESI): C 21 H 20 Calculated value of F7NO3S: 499.1; Experimental value: 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.

[0460] 9A-5b: MS (ESI): C 21 H 20 Calculated value of F7NO3S: 499.1; Experimental value: 500.1 [M] + 1] + . 1 H 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.

[0461] 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]thiapine 1,1-dioxide (9-1a). LiCl (50.5 g, 1.21 mol) was added to a mixture of rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine 1,1-dioxide (60 g, 0.12 mol) (9A-5a) in DMSO (600 mL) at room temperature. After stirring at 140 °C under a nitrogen atmosphere for 16 h, 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 the eluent to give 9-1a (43 g, 73.7%, cis-racemic) as a yellow oil. MS (ESI): C 20 H 18 Calculated value of F7NO3S: 485.1; Experimental value: 486.3 [M] + 1] + . 1 H NMR (300 MHz, DMSO-d6): δ11.68 (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.

[0462] The rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine 1,1-dioxide (9-1a) was passed through an SFC column (column: (R,R)-WHELK-O1, 50*4.6 mm, 3.5 µm; co-eluting buffer: MeOH; gradient (B%): 10% to 50% over 2.0 min, hold at 50% for 1.0 min; back pressure (bar): 150; flow rate (mL / min): 3.0; column temperature (°C): 35; UV detection wavelength: 220 nm). (nm) separation was performed to obtain (2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine 1,1-dioxide (154-4) (t) as a white solid. R = 0.43 min; monodiastere); and (2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine 1,1-dioxide (t) as a white solid R = 0.69 min; single diastereomer).

[0463] 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]thiapine 1,1-dioxide (9-1b). LiCl (38.19 g, 0.90 mol) was added to a mixture of rac-(2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine 1,1-dioxide (9A-5b) (45 g, 90.10 mmol) in DMSO (450 mL) at room temperature. After stirring at 140 °C under a nitrogen atmosphere for 16 h, 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 the eluent to give 9-1b (30 g, 68.6%) as a yellow oil. MS (ESI): C 20 H 18Calculated value of F7NO3S: 485.1; Experimental value: 486.2 [M] + 1] + . 1 H 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.

[0464] The relative stereochemistry 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]thiapine 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]thiapine 1,1-dioxide (9A-5b) was determined. 1 H, 13 C 19 F, HH COSY, CH HSQC, CH HMBC, H-HNOESY, and FH NOESY NMR techniques were used to elucidate the relative stereochemistry of the cis-racemate 9A-5a and its corresponding trans-racemate 9A-5b.

[0465]

[0466] 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, 11.2Hz, 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. 13 C NMR (101 MHz, CDCl3): δ157.15 (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. FH NOESY NMR data indicate that F29 is correlated with H4, but not with H5.

[0467]

[0468] 1 H 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. 19 FNMR (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. FH NOESYNMR data indicate that F29 is correlated with H5, but not with H4.

[0469] Examples 9a and 9b. 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (9a) and 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (9b)

[0470]

[0471] Step 1. Synthesis of ethyl rac-1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine-8-yl)oxy)methyl)cyclopropane-1-carboxylate (9-2). 1-(bromomethyl)cyclopropane-1-carboxylate (19.20 mg, 0.09 mmol) was added dropwise to a stirred solution of 9-1a (30 mg, 0.06 mmol) in DMF (2 mL) following the same procedure as described above for the preparation of racemic 8-13 and replacing 3-fluoroiodobenzene with 4-fluoro-iodobenzene and cesium carbonate (40.40 mg, 0.12 mmol). After stirring at 80 °C for 3 hr, the reaction mixture was cooled to rt, water (10 mL) was added, and extraction was performed using 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 preparative TLC (PE / EA = 4 / 1 (v / v)) to give 9-2 (30 mg, 79%) as a brown solid. MS (ESI): C 27 H 28 Calculated value of F7NO5S: 611.2; Experimental value: 500.2 [M] + 1] + .

[0472] Step 2. Synthesis of rac-1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine-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 to pH ~ 4 with 2 NHCl aqueous solution. 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 preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 19*250 mm, 10 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 55% B to 78% B, 78% B over 8 min; wavelength: 220 nm, 254 nm; RT1 (min) = 5.26, to obtain 9-3 (15 mg) as a white solid.

[0473] Step 3. Synthesize 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-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-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 9b). Racemic 9-3 (15 mg) was purified by preparative SFC under the following conditions: (Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: MeOH; Flow rate: 80 mL / min; Gradient: 25 percent isocratic 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 obtain Example 9a (a single diastereomer, stereochemistry arbitrarily specified) (4.1 mg) as a white solid). MS (ESI): C 25 H24 Calculated value of F7NO5S: 583.1; Experimental value: 584.2 [M] + 1] + . 1 H NMR (300 MHz, CD3OD): δ 7.80 (s, 1H), 7.54 (s, 1H), 6.96 (t, J = 9.0 Hz, 2H), 6.71 ‒ 6.66(m, 2H), 5.67 (d, J = 45.3 Hz, 1H), 4.42 (s, 2H), 4.18 (d, J = 15.0 Hz, 1H),3.27 ‒ 3.21 (m, 1H), 2.77 ‒ 2.63 (m, 1H), 2.21 ‒ 2.03 (m, 2H), 1.79 ‒ 1.57(m, 5H), 1.31 (s, 2H), 1.07 (s, 2H) ppm; and example 9b (a single diastereomer, stereochemistry arbitrarily specified) (2.2 mg) as a white solid. MS (ESI): C 25 H 24 Calculated value of F7NO5S: 583.1; Experimental value: 584.2 [M] + 1] + . 1 H 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.

[0474] Examples 10a and 10b. 3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionic acid (10a) and 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionic acid (10b).

[0475]

[0476] Step 1. Synthesize methyl rac-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionate (10-1). KI (1.23 g, 7.41 mmol) and methyl 2,2-dimethyl-3-((methanesulfonyl)oxy)propionate (1.04 g, 4.94 mmol) were added dropwise 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]thiapine 1,1-dioxide (9-1a) (1.20 g, 2.47 mmol) and Cs₂CO₃ (2.42 g, 7.41 mmol) in DMF (50 mL) under reflux. The resulting mixture was stirred at 100 °C for 16 h. The mixture was then cooled to reflux. The reaction was quenched by adding H₂O (150 mL) under reflux. 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 and diluted with PE / EtOAc = 2 / 1 (v / v) to give 10⁻¹ (800 mg, 54.0%) as a brown solid. MS (ESI): C 26 H 28 Calculated value of F7NO5S: 599.2; Experimental value: 600.2 [M] + 1] + .

[0477] Step 2. Synthesize methyl 3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionate (10-2a) and methyl 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionate (10-2b). The product methyl rac-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionate (800 mg) was purified by preparative SFC under 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: 20 percent isocratic B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm; RT1 (min): 3.8; RT2 (min): 6.5; sample solvent: MeOH; injection volume: 9 mL. The collected fractions were concentrated, and the residue was dried under vacuum to give 10⁻²a (260 mg) (a single diastereomer, stereochemistry arbitrarily specified) and 10⁻²b (240 mg) (a single diastereomer, stereochemistry arbitrarily specified) as white solids, respectively. MS(ESI): C 26 H 28 Calculated value of F7NO5S: 599.2; Experimental value: 600.2 [M] + 1] + .

[0478] Step 3a. Synthesis of 3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionic 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 NHCl aqueous 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 preparative HPLC under 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 over 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) as a white solid (a single diastereomer, stereochemistry arbitrarily specified). MS (ESI): C 25 H 26 Calculated value of F7NO5S: 585.1; Experimental value: 586.2 [M] + 1] + . 1 H 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.

[0479] Step 3b. Synthesis of 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionic 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 NHCl aqueous 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 preparative HPLC under 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 over 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) as a white solid (a single diastereomer, stereochemistry arbitrarily specified). MS (ESI): C 25 H 26 Calculated value of F7NO5S: 585.1; Experimental value: 586.2 [M] + 1] + . 1 H 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.

[0480] The relative stereochemistry of 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionic acid (Example 10b) was determined.1 H, 13 C 19 F, HH COSY, CH HSQC, CH HMBC, HH NOESY, and FH NOESY NMR techniques were used to elucidate the relative stereochemistry of Example 10b.

[0481]

[0482] 1 H 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 = 7.7Hz, 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). 19 F 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. FH NOESY NMR data indicate that F19 is correlated with H4, but not with H5.

[0483] Examples 10c and 10d. 3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionic acid (10c) and 3-(((2S,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionic acid (10d)

[0484]

[0485] Step 1. Synthesize methyl rac-3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionate (9-1b). At room temperature, KI (205.19 mg, 1.24 mmol) and methyl 2,2-dimethyl-3-((methanesulfonyl)oxy)propionate (137.36 mg, 0.62 mmol) were added dropwise 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]thiapine 1,1-dioxide (9-1b, trans-racemic) (200 mg, 0.41 mmol) and Cs₂CO₃ (402.73 mg, 1.24 mmol) in DMF (5 mL). The resulting mixture was stirred at 100 °C for 16 h. The mixture was cooled to room temperature, and the reaction was quenched by adding water. 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 preparative TLC (PE / EA = 5 / 1 (v / v)) to give 10A-1 (130 mg, 52.63%, trans-racemic) as a white solid. MS (ESI): C 26 H 28 Calculated value of F7NO5S: 599.2; Experimental value: 600.1 [M] + 1] + .

[0486] Step 2. Synthesize methyl 3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionate (10A-2a) and methyl 3-(((2S,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluorophenyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionate (10A-2b). Methyl rac-3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine-8-yl)oxy)-2,2-dimethylpropionate (10A-1) (90 mg) was subjected to preparative Chiral-HPLC (column: CHIRALPAK IC, 2*25 cm, 5 μm; mobile phase A: Hex--HPLC, mobile phase B: EtOH--HPLC; flow rate: 25 mL / min; gradient: isocratic 10; wavelength: 240 nm; RT1 (min): 5.6; RT2 (min): 7.2; sample solvent: EtOH--HPLC; injection volume: 1 mL; number of runs: 5). The collected fractions were concentrated, and the residues were dried under vacuum to give 10A-2a (25 mg, 56%, monodiaphemine, MS (ESI)) as a white solid: C 26 H 28 Calculated value of F7NO5S: 599.2; Experimental value: 600.1 [M] + 1] + ) and 10A-2b (24 mg, 53%, monodiazimeric, MS (ESI)): C 26 H 28 Calculated value of F7NO5S: 599.2; Experimental value: 600.1 [M] + 1] + ).

[0487] Step 3a. Synthesis of 3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionic acid (Example 10c). A solution of methyl 2,2-dimethylpropionate (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 °C for 12 h. The mixture was then acidified to pH 4 with 2 NHCl aqueous 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 preparative HPLC (column: Sunfire Prep C18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 30 mL / min; gradient: 50% to 80% B over 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%, monodiazimeric) as a white solid. MS (ESI): C 25 H 26 Calculated value of F7NO5S: 585.1; Experimental value: 586.1 [M] + 1] + . 1 HNMR (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.

[0488] Step 3b. Synthesis of 3-(((2S,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionic acid (Example 10d). A solution of methyl 2,2-dimethylpropionate (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 NHCl aqueous 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 preparative HPLC (column: Sunfire Prep C18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 30 mL / min; gradient: 50% to 80% B over 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%, monodiazimeric) as a white solid. MS (ESI): C 25 H 26 Calculated value of F7NO5S: 585.1; Experimental value: 586.1 [M] + 1] + . 1 H 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.

[0489] Example 10c / d. rac-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionic acid.

[0490]

[0491] Step 1. Synthesis of rac-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionic acid (Example 10 c / d). A solution of rac-1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid ethyl ester (10A-1, trans-racemic) (40 mg, 0.24 mmol) in dioxane (4 mL) was treated with water (1 mL) for 3 min at room temperature, followed by dropwise addition of LiOH (47.62 mg, 2.26 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 12 h. Next, the mixture was acidified to pH = 3 with concentrated aqueous HCl. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Sunfire Prep C18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 30 mL / min; gradient: 50% to 75% B over 8 min; wavelength: 254 nm / 220 nm; RT1 (min): 5.94). The collected fraction was concentrated under vacuum to remove ACN, and the resulting solution was lyophilized to give Example 10 c / d (10.4 mg, 48.6%, trans-racemic) as a white solid. MS (ESI): C 25 H 28 Calculated value of F7NO5S: 585.1; Experimental value: 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, 5.8Hz, 1H), 4.26 - 4.13 (m, 3H), 3.74 - 3.69 (m, 1H), 2.45 - 2.41 (m, 1H), 2.05- 1.78 (m, 4H), 1.45 (t, J = 18.3 Hz, 3H), 1.36 (s, 6H) ppm.

[0492] The relative stereochemistry 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]thiapine 1,1-dioxide (Example 10c / d) was determined. 1 H, 13 C 19 F, HH COSY, CH HSQC, CH HMBC, HH NOESY, and FH NOESY NMR techniques were used to elucidate the relative stereochemistry of the trans-racemic mixture of Example 10c / d.

[0493]

[0494] 1 H NMR (300 MHz, CD3OD): δ 7.75 (s, 1H, H13), 7.33 (s, 1H, H9), 7.12 –6.99 (m, 4H, H34, H33 H31&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. 19 F NMR (282 MHz, CD3OD): δ -64.51 (F37, F38 & F39), -92.49 (F26 & F27), -123.43 (F35), -178.25 (F19). FH NOESY NMR data indicate that F19 is correlated with H5, but not with H4.

[0495] Examples 11a and 11b. (R)-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2-methylpropionic acid (11a) and (R)-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2-methylpropionic acid (11b)

[0496]

[0497] Step 1. Synthesize methyl rac-(R)-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2-dimethylpropionate (11-1). Triphenylphosphine (2.59 g, 9.89 mmol) and (R)-3-hydroxy-2-methylpropionate (0.58 g, 4.944 mmol) were added 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]thiapine 1,1-dioxide (9-1a) (1.2 g, 2.47 mmol) and DIAD (1.29 g, 9.89 mmol) in DMF (50 mL) under a nitrogen atmosphere and at rest. The resulting mixture was stirred at 110 °C for 6 hr. The mixture was then cooled to rest. The reaction was quenched with H2O at rest. 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): C 25 H 26 Calculated value of F7NO5S: 585.1; Experimental value: 586.2 [M] + 1] + .

[0498] Step 2. Synthesize (R)-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxon-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2-methylpropionate methyl ester (11-2a) and (R)-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxon-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2-methylpropionate methyl ester (11-2b). The product methyl rac-(R)-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2-methylpropionate (11-1) (700 mg) was purified by preparative SFC under 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: 30 percent isocratic B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm; RT1 (min): 3.3; RT2 (min): 4.8; sample solvent: MeOH; injection volume: 5 mL. The collected solution was concentrated to give 11-2a (270 mg) (a single diastereomer, stereochemistry arbitrarily specified) and 11-2b (260 mg) (a single diastereomer, stereochemistry arbitrarily specified) as white solids, respectively. MS (ESI): C 25 H 26 Calculated value of F7NO5S: 585.1; Experimental value: 586.2 [M] + 1] + .

[0499] Step 3a. Synthesis of (R)-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2-methylpropionic 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 NHCl aqueous 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 preparative HPLC under the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3•H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 55% B over 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 1.29. The collected solution was concentrated under vacuum to remove ACN, and the resulting solution was lyophilized to give Example 11a (108 mg) as a white solid (a single diastereomer, stereochemistry arbitrarily specified). MS (ESI): C 24 H 24 Calculated value of F7NO5S: 571.1; Experimental value: 572.2 [M] + 1] + . 1 H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H), 7.54 (s, 1H), 6.97(t, J = 8.7 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.

[0500] Step 3b. Synthesis of (R)-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2-methylpropionic 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 NHCl aqueous 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 preparative HPLC under the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3•H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 55% B over 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 0.92. The collected solution was concentrated under vacuum to remove ACN, and the resulting solution was lyophilized to give Example 11b (a single diastereomer, stereochemistry arbitrarily specified) (106 mg) as a white solid. MS (ESI): C 24 H 24 Calculated value of F7NO5S: 571.1; Experimental value: 572.2 [M] +1] + . 1 H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H), 7.54 (s, 1H), 6.97 (t, J = 8.7Hz, 2H), 6.70 (dd, J = 9.1, 4.2 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.

[0501] Examples 12a and 12b. (R)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (12a) and (S)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (12b)

[0502]

[0503] Step 1. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiapine-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 under nitrogen atmosphere for 6 h. The mixture was cooled 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): C 20 H 19 Calculated value of BrF3NO2S: 473.0; Experimental value: 474.0 [M] + 1] + .

[0504] Step 2. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiapine-4(5H)-one 1,1-dioxide (12-2). 12-1 (10.5 g, 22.14 mmol) and Oxone ®A solution of (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 saturated 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 under vacuum to give crude product 12-2 (12.6 g, 89.9%) as a brown solid, which could be used in the next step without further purification. MS (ESI): C 20 H 19 Calculated value of BrF3NO4S: 505.0; Experimental value: 506.0 [M] + 1] + .

[0505] Step 3. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine 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 cooled to 0 °C with ice water, and MeOH (50 mL) was added 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): C 20 H 21 Calculated value of BrF3NO3S: 491.0; Experimental value: 492.0 [M] + 1] + .

[0506] Step 4. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine 1,1-dioxide (12-4). LiHMDS (2.04 g, 12.19 mmol) was added to a solution of 12-3 (2 g, 4.06 mmol) in THF (30 mL) at -78 °C under a nitrogen atmosphere for 30 min. After stirring at -78 °C for 30 min, NFSI (3.20 g, 10.16 mmol) was added dropwise to a solution of THF (20 mL) at -78 °C. The resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 3 h, followed by the addition of water (100 mL) at 0 °C. The mixture was then concentrated to remove the organic solvent, and the residue was extracted with EtOAc (80 mL 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): C 20 H 19 Calculated value of BrF5NO3S: 527.0; Experimental value: 528.0 [M] + 1] + . 1 H 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.

[0507] 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]thiapine 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 a nitrogen atmosphere. After stirring at 130 °C under a nitrogen atmosphere for 16 h, the mixture was cooled 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 pale yellow oil. MS (ESI): C 21 H 19 Calculated value of F8NO3S: 517.1; Experimental value: 518.0 [M] + 1] + .

[0508] 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]thiapine 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 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 pale yellow oil. MS (ESI): C 20 H 17 Calculated value of F8NO3S: 503.1; Experimental value: 504.0 [M] + 1] + .

[0509] Step 7. Synthesis of ethyl 1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine-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 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 pale yellow oil. MS (ESI): C 27 H 27 Calculated value of F8NO5S: 629.1; Experimental value: 630.1 [M] + 1] + .

[0510] Step 8. Synthesize (R)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)methyl)cyclopropane-1-ethyl ester (12-8a) and (S)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)methyl)cyclopropane-1-ethyl ester (12-8b). Compound 12-7 (80 mg) was purified by preparative HPLC (column: (R, R)-WHELK-O, 3*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH; flow rate: 80 mL / min; gradient: isocratic 30 percent B; wavelength: 220 nm) to obtain 12-8a (35 mg) as a white solid, MS (ESI): C 27 H 27 Calculated value of F8NO5S: 629.1; Experimental value: 630.1 [M] + 1]+ And 12-8b (33 mg), MS (ESI): C 27 H 29 Calculated value of F6NO5S: 593.2; Experimental value: 630.1 [M] +1] + .

[0511] Step 9a. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine-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 to rt, acidified to pH 3 with 2 NHCl aqueous 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 preparative HPLC (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 45% B to 60% B, 60% B over 8 min; wavelength: 254 / 220 nm) to give Example 12a (18.2 mg, 53.5%) as a white solid. MS (ESI): C 25 H 23 Calculated value of F8NO5S: 601.1; Experimental value: 602.1 [M] + 1] + . 1 H 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.

[0512] Step 9b. (S)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine-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 to rt, acidified to pH 3 with 2 NHCl aqueous 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 preparative HPLC (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 45% B to 60% B, 60% B over 8 min; wavelength: 254 / 220 nm) to give Example 12b (21.2 mg, 66.9%) as a white solid. MS (ESI): C 25 H 23 Calculated value of F8NO5S: 601.1; Experimental value: 602.1 [M] + 1] + . 1 H 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.

[0513] Examples 13a and 13b. (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxano-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-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-dioxano-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (13b)

[0514]

[0515] 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]thiazapine 1,1-dioxide (13-2). NaH (55% suspension in mineral oil) (0.446 g, 18.59 mmol) was added in portions to a stirred mixture in DMF (15 mL) containing 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) and 3,3-difluorocyclobutanethiol (0.89 g, 7.15 mmol) in mineral oil. The mixture was stirred at 0 °C for 30 min and then at rt for 2 hr, followed by stirring at 70 °C for 12 hr. The mixture was then diluted with ice water (5 mL), acidified with a saturated aqueous solution of NaHSO4, 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 preparative HPLC to give 13-2 (700 mg, 66%) as a white solid.

[0516] Step 2. Synthesis of ethyl 1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxano-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)methyl)cyclopropanecarboxylate (13-3). A mixture of 13-2 (0.2 g, 0.39 mmol), cesium carbonate (0.314 g, 0.96 mmol), and methyl 1-(bromomethyl)cyclopropanecarboxylate (0.112 g, 0.58 mmol) in DMF (2 mL) was stirred at 60 °C for 16 hr. The mixture was cooled to rt and filtered. The filtrate was purified by preparative HPLC to give 13-3 (0.172 g, 71%) as a white solid.

[0517] Step 3. Synthesize (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxano-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)methyl)cyclopropane-1-carboxylate (13-3a) and (R)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxano-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)methyl)cyclopropane-1-carboxylate (13-3b). 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: 24 °C; wavelength: 205 nm). R 1 = 20.60 min (single enantiomer, stereochemistry is arbitrarily specified); and t R 2 = 27.17 min (single enantiomer, stereochemistry is arbitrarily specified) to obtain 13-3a (45.3 mg) and 13-3b (45.2 mg) as white solids, respectively.

[0518] Step 4a. Synthesis of (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxano-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazine-8-yl)oxy)methyl)cyclopropanecarboxylic acid (Example 13a). Lithium hydroxide hydrate (9.0 mg, 214.0 µmol) was added to a stirred solution of 13-3a (45.3 mg, 71.82 µmol) in THF / H2O = 4 / 1 (v / v) (2 mL). After stirring at rt for 12 hr, the reaction mixture was adjusted to pH ~2 with 2 NHCl aqueous solution. The resulting mixture was purified by preparative HPLC to give Example 13a (24.8 mg, 56%) as a white solid (monoenantiomer, stereochemistry arbitrarily specified). MS (ESI): C 28 H 32 Calculated value of F4N2O5S2: 616.2; Experimental value: 614.9 [M-1] - . 1 H 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 = 16.0Hz, 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 = 3.3Hz, 2H) ppm.

[0519] Step 4b. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxano-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazopen-8-yl)oxy)methyl)cyclopropanecarboxylic acid (Example 13b). Following the same procedure as described in Step 4a, but replacing 13-3a with 13-3b (45.2 mg, 71.66 µmol), Example 13b (27.5 mg, 63%) was obtained as a white solid (monoenantiomer, stereochemistry arbitrarily specified). MS (ESI): C 28 H 32 Calculated value of F4N2O5S2: 616.2; Experimental value: 614.9 [M-1] - . 1 H 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 = 3.0Hz, 2H), 1.06 (s, 2H) ppm.

[0520] Example 14. (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-7-(methylthio)-1,1-dioxane-5-phenyl-2,3,4,5-tetrahydropyridino[2,3-f][1,2,5]thiazapine-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0521]

[0522] Step 1. Synthesis of (R)-2-bromo-6-chloro-N-(5,5-difluoro-1-sulfonamide hexane-2-yl)-5-methoxypyridine-3-sulfonamide (14-1). A solution of 2,6-dibromo-5-methoxypyridine-3-sulfonyl chloride (1.9 g, 5.3 mmol) in DCM (5 mL) was added 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) at 0 °C. The resulting reaction mixture was stirred at rt for 5 hr. After the reaction was complete (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) (R f : 0.4). MS (ESI): C 18 H 21 Calculated value of BrClF₂N₃O₃S: 511.0; Experimental value: 512.1 [M + 1] + .

[0523] 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). Cu (150 mg, 2.35 mmol) was added to a stirred solution of 14-1 (1.2 g, 2.4 mmol) and K2CO3 (972 mg, 7.1 mmol) in DMF (30 mL), and the resulting mixture was heated at -115 °C for 5 hr. After the reaction was complete (monitored by LCMS), the reaction mixture was quenched with saturated NH4Cl aqueous 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 under vacuum to give crude product 14-2 (1.2 g) as a brown solid, which could be used in the next step without further purification. TLC: EA / PE = 1 / 5 (v / v) (R f :0.5). MS (ESI): C 18 H 20Calculated value of ClF₂N₃O₃S: 431.1; Experimental value: 432.2 [M + 1] + .

[0524] 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). MeI (1.2 g, 8.4 mmol) was added 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), and the reaction mixture was stirred at rt for 3 hr. After the reaction was complete (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) (R f : 0.4). MS(ESI): C 19 H 22 Calculated value of ClF₂N₃O₃S: 445.1; Experimental value: 446.2 [M + 1] + .

[0525] 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). CH3SNa (519 mg, 7.4 mmol) was added to a stirred solution of 14-3 (1.1 g, 2.5 mmol) in DMF (10 mL), and the reaction mixture was heated at 95 °C for 16 hr. After the reaction was complete (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) (R f : 0.6). MS (ESI): C 19 H23 Calculated value of F2N3O3S2: 443.1; Experimental value: 444.1 [M + 1] + .

[0526] Step 5. Synthesis of (R)-ethyl 1-(((3-(3,3-difluorobutyl)-2-methyl-7-(methylthio)-1,1-dioxano-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazopen-8-yl)oxy)methyl)cyclopropanecarboxylate (14-5). 1-(((methanesulfonyl)oxy)methyl)cyclopropane-1-carboxylate (50 mg, 0.23 mmol) was added to a stirred solution of 14-4 (50 mg, 0.11 mmol) and Cs₂CO₃ (110 mg, 0.34 mmol) in DMF (3 mL), and the reaction mixture was heated at -65 °C for 3 hr. After the reaction was complete (monitored by LCMS), the reaction mixture was added to water (10 mL). The precipitate was filtered, washed with water (10 mL x 3), and dried under vacuum to give crude product 14-5 (58 mg) as a yellow solid, which could be used in the next step without further purification. TLC: EA / PE = 3 / 7 (v / v) (Rf: 0.5). MS (ESI): C 26 H 33 Calculated value of F2N3O5S2: 569.2; Experimental value: 570.2 [M + 1] + .

[0527] Step 6. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-7-(methylthio)-1,1-dioxano-5-phenyl-2,3,4,5-tetrahydropyridino[2,3-f][1,2,5]thiadiazopen-8-yl)oxy)methyl)cyclopropanecarboxylic acid (Example 14). NaOH (43 mg, 1.02 mmol) was added to a stirred solution of 14-5 (58 mg, crude product, 0.10 mmol) in MeOH / H2O = 2 / 1 (v / v) 3 mL, and the reaction mixture was stirred at rt for 16 hr. After the reaction was complete (monitored by LCMS), the reaction mixture was neutralized with 1 N HCl aqueous 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 preparative HPLC to give Example 14 (31 mg, 56%) as a white solid. TLC: EA / PE = 3 / 2 (v / v) (R f : 0.5). MS (ESI): C 24 H 29Calculated value of F2N3O5S2: 541.2; Experimental value: 542.2 [M] + 1] + . 1 H 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.

[0528] Example 15. (R)-1-(((3-(3,3-difluorobutyl)-5-(3-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxane-2,3,4,5-tetrahydropyridino[2,3-f][1,2,5]thiazapine-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0529]

[0530] Following the same procedure as in Example 14, Example 15 (16 mg) was obtained as a white solid by replacing aniline with 3-F-aniline. TLC: EA / PE = 1 / 1 (v / v) (R f : 0.3). MS (ESI): C 24 H 28 Calculated value of F3N3O5S2: 559.1; Experimental value: 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

[0531] Example 16. (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxane-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiazapine-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0532]

[0533] Following the same procedure as in Example 14, Example 16 (12 mg) was obtained as a white solid by replacing aniline with 4-F-aniline. TLC: EA / PE = 1 / 1 (v / v) (R f : 0.3). MS (ESI): C 24 H 28 Calculated value of F3N3O5S2: 559.1; Experimental value: 560.2 [M] + 1] + . 1 H 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.

[0534] Examples 17a and 17b. (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxano-5-phenyl-2,3,4,5-tetrahydropyridano[2,3-f][1,2,5]thiazapine-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-dioxano-5-phenyl-2,3,4,5-tetrahydropyridano[2,3-f][1,2,5]thiazapine-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (17b).

[0535]

[0536] 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). NaH (55% suspension in mineral oil) (0.502 g, 20.92 mmol) was added in portions to a stirred mixture of 14-3 (1 g, 8.05 mmol) in DMF (15 mL) at -10 °C. 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 increased to 70 °C, and the reaction mixture was maintained with stirring for 12 hr. Next, the reaction mixture was diluted with ice water (15 mL), acidified with a saturated aqueous solution of NaHSO4, and extracted with 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 preparative HPLC to give 17-1 (768 mg, 64%) as a grayish-white solid.

[0537] Step 2. Synthesis of methyl 1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxano-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiazapine-8-yl)oxy)methyl)cyclopropanecarboxylate (17-2). A mixture of 17-1 (0.245 g, 0.47 mmol), cesium carbonate (0.384 g, 1.18 mmol), and methyl 1-(bromomethyl)cyclopropanecarboxylate (0.137 g, 0.71 mmol) in DMF (2.5 mL) was stirred at 60 °C for 16 hr. Subsequently, the mixture was diluted with ice 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 preparative HPLC to give 17-2 (0.222 g, 75%) as a grayish-white solid.

[0538] Step 3. Chiral separation of methyl 1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxano-5-phenyl-2,3,4,5-tetrahydropyridino[2,3-f][1,2,5]thiazapine-8-yl)oxy)methyl)cyclopropanecarboxylate (17-2). Compound 17-2 (170 mg) was separated by chiral HPLC to give 17-2a (77 mg) and 17-2b (79 mg) as white solids, respectively. Stereochemistry of any designated enantiomer.

[0539] Preparative HPLC conditions: Column: CHIRALPAK IB (250 × 20 mm, 5 µm); Mobile phase: Hexane / IPA / MeOH = 70 / 15 / 15 (v / v / v); Flow rate: 20 mL / min; Column temperature: 24℃; Wavelength: 205 nm. R = 13.03 min (enantiomer 17-2a); and t R = 18.59 min (enantiomer 17-2b).

[0540] Step 4a. Synthesis of (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxano-5-phenyl-2,3,4,5-tetrahydropyridino[2,3-f][1,2,5]thiazapine-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 17a). Lithium hydroxide hydrate (15.3 mg, 0.36 mmol) was added to a stirred solution of 17-2a (77.3 mg, 0.12 mmol) in THF / H2O = 4 / 1 (v / v) (2 mL), and the reaction mixture was stirred at rt for 12 hr. Subsequently, the mixture was acidified with 2 NHCl aqueous solution to ρN ~2. The resulting mixture was purified by preparative HPLC to give Example 17a (55.1 mg, 73%) as a white solid. MS (ESI): C 27 H 31 Calculated value of F4N3O5S2: 617.2; Experimental value: 616.2 [M – 1] - . 1 H 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.

[0541] Step 4b. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxano-5-phenyl-2,3,4,5-tetrahydropyridino[2,3-f][1,2,5]thiadiazopen-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 17b). Lithium hydroxide hydrate (15.6 mg, 0.37 mmol) was added to a stirred solution of 17-2b (78.9 mg, 0.12 mmol) in THF / H2O = 4 / 1 (v / v) (2 mL), and the reaction mixture was stirred at rt for 12 hr. Subsequently, the mixture was acidified with 2 NHCl aqueous solution to ρN ~2. The resulting mixture was purified by HPLC to give Example 17b (53.9 mg, 71%). MS (ESI): C 27 H 31 Calculated value of F4N3O5S2: 617.2; Experimental value: 616.2 [M –1] - . 1 H NMR (500 MHz, DMSO-d6): δ 12.42 (s, 1H), 7.43 (s, 1H), 7.31 (t, J = 7.8Hz, 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.

[0542] Examples 18a and 18b: 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7-(methylthio)-1,1-dioxano-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-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-dioxano-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (18b).

[0543]

[0544] 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]thiapine 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 and diluted with PE / EA (10 / 1 (v / v)) to give 18-1 (500 mg, 59.4%) as a white solid. MS (ESI): C 21 H 23 Calculated value of F4NO3S2: 477.1; Experimental value: 478.0 [M] + 1] + .

[0545] 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]thiapine 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 and diluted with PE / EA (5 / 1 (v / v)) to give 18-2 (240 mg, 49.5%) as a white solid. MS (ESI): C 20 H 21 Calculated value of F4NO3S2: 463.1; Experimental value: 464.0 [M] + 1] + .

[0546] Step 3. Synthesis of rac-1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7-(methylthio)-1,1-dioxano-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid ethyl ester (18-3). KI (114.61 mg, 0.69 mmol) and 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylic acid ethyl ester (57.54 mg, 0.26 mmol) were added dropwise to a stirred solution of 18-2 (80 mg, 0.17 mmol) and Cs₂CO₃ (224.94 mg, 0.69 mmol) in DMF (10 mL) under 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 preparative TLC (PE / EA = 5 / 1 (v / v)) to give 18-3 (60 mg, 59.0%) as a white solid. MS (ESI): C 27 H 31 Calculated value of F4NO5S2: 589.2; Experimental value: 590.1 [M] + 1] + .

[0547] Step 4. Synthesize ethyl 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7-(methylthio)-1,1-dioxano-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-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-dioxano-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (18-3b). Compound 18-3 (60 mg) was purified by preparative chiral HPLC under 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, monodiamericone, stereochemistry arbitrarily specified) and 18-3b (25 mg) (RT1 = 15.8 min, monodiamericone, stereochemistry arbitrarily specified) as white solids. MS (ESI): C 27 H 31 Calculated value of F4NO5S2: 589.2; Experimental value: 590.2 [M] + 1] + .

[0548] Step 5a. Synthesis of 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7-(methylthio)-1,1-dioxane-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-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 at 40 °C for 24 h. The mixture was acidified to pH = 4 with 2 NHCl aqueous 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 preparative HPLC under 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 over 8 min; wavelength: 254 nm / 220 nm; RT1 (min): 4.48. The collected solution was concentrated under vacuum to remove ACN, and the resulting solution was lyophilized to give Example 18a (17 mg) as a white solid (a single diastereomer, stereochemistry arbitrarily specified). MS (ESI): C 25 H 27 Calculated value of F4NO5S2: 561.1; Experimental value: 562.2 [M] + 1] + . 1 H NMR (300MHz, CD3OD): δ 7.52 (s, 1H), 7.22 ‒ 7.14 (m, 2H), 6.50 ‒ 6.42 (m, 2H), 6.34 ‒6.30 (m, 1H), 5.58 (d, J = 45.3 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.

[0549] Step 5b. Synthesis of 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7-(methylthio)-1,1-dioxane-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-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 at 40 °C for 24 h. The mixture was acidified to pH = 4 with 2 NHCl aqueous 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 preparative HPLC under 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 over 8 min; wavelength: 254 nm / 220 nm; RT1 (min): 2.84. The collected solution was concentrated under vacuum to remove ACN, and the resulting solution was lyophilized to give Example 18b (22 mg) as a white solid (a single diastereomer, stereochemistry arbitrarily specified). MS (ESI): C 25 H 27 Calculated value of F4NO5S2: 561.1; Experimental value: 562.2 [M] + 1] + . 1 HNMR (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.

[0550] Examples 19a and 19b. 1-((((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-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-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (19b)

[0551]

[0552] Step 1. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-8-methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine 1,1-dioxide (19-2). PhSiH3 (2.45 g, 22.60 mmol) and Bu2SnCl2 (4.58 g, 15.06 mmol) were added to a stirred solution of 7-bromo-3-(3,3-difluorobutyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiapine-4(5H)-one 1,1-dioxide (8-7) prepared readily by BH3 reduction of 7-bromo-3-(3,3-difluorobutyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiapine-4(5H)-one 1,1-dioxide (8-7) in THF (50 mL). The resulting mixture was refluxed for 24 h. The mixture was then cooled to rt and concentrated. The residue was purified by silica gel column chromatography and diluted with PE / EA = 4 / 1 (v / v) to give 19-2 (2.6 g, 66.8%) as a brown liquid. MS (ESI): C 20 H 26 Calculated value of BrF4NO3S: 515.1; Experimental value: 516.0 [M] + 1] + .

[0553] 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]thiapine 1,1-dioxide (19-3). In a 250 mL round-bottom flask, THF (10.07 mL, 10.07 mmol) containing 1 M LiHMDS was added dropwise to a solution of 19-2 (2.6 g, 5.04 mmol) in THF (20 mL) at 78 °C under a N2 atmosphere. The reaction mixture was stirred at -78 °C for 30 min. Then, NFSI (1.59 g, 5.04 mmol) in 2 mL of THF was added dropwise, and the mixture was stirred for another 4 h. The reaction was carried out with saturated NH4Cl aqueous solution (20 mL), and the mixture was then 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 rapid chromatography (PE / EA = 2 / 1 (v / v)) to give 19-3 (1 g, 37.2%) as a brown solid. MS (ESI): C 20 H 25 Calculated value of BrF5NO3S: 533.1; Experimental value: 534.0 [M] + 1] + .

[0554] 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]thiapine 1,1-dioxide (19-4). CuBr (872.44 mg, 6.08 mmol) was added in portions 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) under N2 atmosphere at rest. The resulting mixture was stirred at 130 °C for 16 hr under N2 atmosphere. The mixture was cooled to rest 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 and diluted with PE / EA = 2 / 1 (v / v) to give 19-4 (400 mg, 62.8%) as a brown solid. MS (ESI): C 21 H 25 Calculated value of F8NO3S: 523.1; Experimental value: 524.0 [M] + 1] + .

[0555] 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]thiapine 1,1-dioxide (19-5). NaOMe (180.60 mg, 3.35 mmol) was added to a stirred solution of 19-4 (350 mg, 0.67 mmol) and 1-dodecyl mercaptan (676.63 mg, 3.35 mmol) in DMF (5 mL) under rt. The resulting mixture was stirred at 100 °C under N2 atmosphere for 2 h. 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 and diluted with PE / EA = 2 / 1 (v / v) to give 19-5 (180 mg, 52.8%) as a brown solid. MS (ESI): C 20 H 23 Calculated value of F8NO3S: 509.1; Experimental value: 510.0 [M] + 1] + .

[0556] 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]thiapine 1,1-dioxide (19-6). LiHMDS (3.50 mL, 3.5 mmol) was added dropwise to a stirred solution of 19-5 (180 mg, 0.35 mmol) in THF (10 mL) at -40 °C under a nitrogen atmosphere. The resulting mixture was stirred at -40 °C for 2 h. The reaction was quenched at -40 °C by adding a saturated aqueous solution of NH4Cl (100 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 and diluted with PE / EA = 2 / 1 (v / v) to give 19-6 (120 mg, 77.0%) as a yellow solid. MS (ESI): C 20 H 23 Calculated value of F8NO3S: 509.1; Experimental value: 510.0 [M] + 1] + .

[0557] Step 6. Synthesis of rac-1-((((2S,3R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid ethyl ester (19-7). KI (42.36 mg, 0.27 mmol) and 1-(((methanesulfonyl)oxy)methyl)cyclopropane-1-carboxylic acid ethyl ester (179.17 mg, 0.49 mmol) were added dropwise to a stirred solution of 19-6 (65 mg, 0.19 mmol) and Cs₂CO₃ (125.10 mg, 0.38 mmol) in DMF (2 mL) under rt. The resulting mixture was stirred at 100 °C for 16 hr. 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 preparative TLC (PE / EA = 4 / 1 (v / v)) to give 19-7 (60 mg, 75.7%) as a brown solid. MS (ESI): C 27 H 33 Calculated value of F8NO5S: 635.2; Experimental value: 636.1 [M] + 1] + .

[0558] Step 7. Synthesize ethyl 1-((((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxon-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-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-dioxon-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (19-7b). Compound 19-7 (60 mg) was purified by preparative SFC under 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: 30 percent isocratic B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm; RT1 (min): 3.3; RT2 (min): 4.8; sample solvent: MeOH; injection volume: 5 mL. The collected fractions were concentrated under vacuum to obtain 19-7a (27 mg) (RT2 = 4.8 min, monodiaphemeris, stereochemistry arbitrarily specified) and 19-7b (26 mg) (RT1 = 3.3 min, monodiaphemeris, stereochemistry arbitrarily specified) as white solids. MS (ESI): C 27 H 33 Calculated value of F8NO5S: 635.2; Experimental value: 636.1 [M] + 1] + .

[0559] Step 8a. Synthesis of 1-((((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine-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 NHCl aqueous 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 preparative HPLC under the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 55% B to 78% B over 8 min; wavelength: 254 nm / 220 nm; RT1 (min): 1.88. The collected solution was concentrated under vacuum to remove ACN, and the resulting solution was lyophilized to give Example 19a (10 mg) as a white solid (a single diastereomer, stereochemistry arbitrarily specified). MS (ESI): C 25 H 29 Calculated value of F8NO5S: 607.2; Experimental value: 608.2 [M] + 1] + . 1 HNMR (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.

[0560] Step 8b. Synthesis of 1-((((2S,3R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiapine-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 at rt for 16 h. The mixture was acidified to pH = 4 with 2N HCl aqueous 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 preparative HPLC under the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 55% B to 78% B over 8 min; wavelength: 254 nm / 220 nm; RT1 (min): 1.37. The collected solution was concentrated under vacuum to remove ACN, and the resulting solution was lyophilized to give Example 19b (10 mg) as a white solid (a single diastereomer, stereochemistry arbitrarily specified). MS (ESI): C 25 H 29 Calculated value of F8NO5S: 607.2; Experimental value: 608.2 [M] + 1] + . 1 H NMR (300 MHz, CD3OD): δ 7.67 (s, 1H), 7.54 (s, 1H), 5.60 (d, J = 46.2Hz, 1H), 4.34 – 4.27 (m, 2H), 3.58 – 3.45 (m, 1H), 3.32 – 3.31 (m, 1H), 2.85– 2.76 (m, 1H), 2.57 – 2.34 (m, 1H), 2.18 – 1.83 (m, 9H), 1.77 – 1.52 (m,6H), 1.35 – 1.26 (m, 2H), 1.17 – 1.09 (m, 2H) ppm.

[0561] Examples 20a and 20b. 3-(((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionic acid (20a) and 3-(((2S,3R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionic acid (20b).

[0562]

[0563] Step 1. Synthesis of ethyl rac-3-(((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionate (20-1). KI (112.42 mg, 0.68 mmol) and methyl 2,2-dimethyl-3-((methanesulfonyl)oxy)propionate (142.37 mg, 0.68 mmol) were added dropwise to a stirred solution of cis-racemate 19-6 (115 mg, 0.23 mmol) and Cs₂CO₃ (221.32 mg, 0.68 mmol) in DMF (5 mL). The resulting mixture was stirred at 100 °C for 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 preparative TLC (PE / EA = 4 / 1 (v / v)) to give 20-1 (65 mg, 46.2%) as a brown solid. MS (ESI): C 26 H 33 Calculated value of F8NO5S: 623.2; Experimental value: 624.1 [M] + 1] + .

[0564] Step 2. Synthesize ethyl 3-(((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxon-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionate (20-1a) and ethyl 3-(((2S,3R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxon-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionate (20-1b). Compound 20-1 (65 mg) was purified by preparative HPLC under 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, monodiamericone, stereochemistry arbitrarily specified) and 20-1b (27 mg) (RT1 = 5.9 min, monodiamericone, stereochemistry arbitrarily specified) as white solids. MS (ESI): C 26 H 33 Calculated value of F8NO5S: 623.2; Experimental value: 624.1 [M] + 1] + .

[0565] Step 3a. Synthesis of 3-(((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionic 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 at rt for 16 h. The mixture was acidified to pH = 4 with 2 NHCl aqueous 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 preparative HPLC under the following conditions: column: Xbridge Prep Shield RP18 5 μm OBD 30*150 mm column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% to 60% B over 8 min; wavelength: 254 nm / 220 nm; RT1 (min): 1.95. The collected fraction was concentrated under vacuum to remove ACN, and the resulting solution was lyophilized to give Example 20a (14 mg) as a white solid (a single diastereomer, stereochemistry arbitrarily specified). MS (ESI): C 25 H 31 Calculated value of F8NO5S: 609.2; Experimental value: 610.2 [M] + 1] + . 1 H NMR (300 MHz, CD3OD): δ 7.67 (s, 1H), 7.58 (s, 1H), 5.64 (d, J = 46.5Hz, 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.

[0566] Step 3b. Synthesis of 3-(((2S,3R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thipin-8-yl)oxy)-2,2-dimethylpropionic 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 at rt for 16 h. The mixture was acidified to pH = 4 with 2 NHCl aqueous 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 preparative HPLC under the following conditions: column: Xbridge Prep Shield RP18 5 μm OBD 30*150 mm column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% to 60% B over 8 min; wavelength: 254 nm / 220 nm; RT1 (min): 1.72. The collected fraction was concentrated under vacuum to remove ACN, and the resulting solution was lyophilized to give Example 20b (13 mg) as a white solid (a single diastereomer, stereochemistry arbitrarily specified). MS (ESI): C 25 H 31 Calculated value of F8NO5S: 609.2; Experimental value: 610.2 [M] + 1] + . 1 H NMR (300 MHz, CD3OD): δ 7.67 (s, 1H), 7.58 (s, 1H), 5.64 (d, J = 46.2Hz, 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.

[0567] Example 21. (R)-3-((3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-methyl-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)-2,2-dimethylpropionic acid

[0568]

[0569] Step 1. Synthesis of (R)-2-bromo-N-(1-((4,4-difluorocyclohexyl)amino)-5,5-difluorohexane-2-yl)-5-methoxy-4-(trifluoromethyl)benzenesulfonamide (21-2). A solution of 2-bromo-5-methoxy-4-(trifluoromethyl)benzenesulfonamide (21-1) (500 mg, 1.85 mmol) and TEA (374 mg, 3.7 mmol) in THF (6 mL) was added to a stirred solution of (R)-N1-(4,4-difluorocyclohexyl)-5,5-difluorohexane-1,2-diamine (21-1) (500 mg, 1.85 mmol) and TEA (374 mg, 3.7 mmol) in THF (6 mL) following the same procedure as in steps 1-7, with aniline replaced by 4,4-difluorocyclohexylamine. The resulting reaction mixture was stirred at rt for 3 hr. After the reaction was complete (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 layers were 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) (R f : 0.4). MS (ESI): C 20 H 26 Calculated value of BrF7N2O3S: 586.1; Experimental value: 587.2 [M + 1] + .

[0570] 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). CuI (190 mg, 1.0 mmol) was added to a stirred solution of 21-2 (600 mg, 1.0 mmol) and K2CO3 (276 mg, 2.0 mmol) in DMF (5 mL), and the mixture was heated at 100 °C for 3 hr. After the reaction was complete (monitored by LCMS), the reaction mixture was quenched with saturated NH4Cl aqueous solution (15 mL), and the aqueous layer was extracted with EA (20 mL x 3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried under vacuum to give crude product 21-3 (450 mg) as a yellow oil, which could be used in the next step without further purification. TLC: 15% EA / PE (v / v) (R f : 0.5). MS(ESI): C 20 H 25 Calculated value of F7N2O3S: 506.1; Experimental value: 507.2 [M + 1] + .

[0571] 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). MeI (379 mg, 2.67 mmol) was added 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), and the reaction was stirred at rt for 5 hr. After the reaction was complete (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 layers were 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) (R f : 0.4). MS (ESI): C 21 H 27 Calculated value of F7N2O3S: 520.2; Experimental value: 521.2 [M + 1] + .

[0572] 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). CH3SNa (203 mg, 2.9 mmol) was added to a stirred solution of 21-4 (300 mg, 0.58 mmol) in DMF (3 mL), and the reaction was heated at 95 °C for 16 hr. After the reaction was complete (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 layers were 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) (R f : 0.6). MS (ESI): C 20 H 25 Calculated value of F7N2O3S: 506.1; Experimental value: 507.2 [M + 1] + .

[0573] Step 5. Synthesis of (R)-3-((3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-methyl-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazopen-8-yl)oxy)-2,2-dimethylpropionate ethyl ester (21-6). 2,2-Dimethyl-3-((methanesulfonyl)oxy)propionate ethyl ester (134 mg, 0.6 mmol) was added dropwise to a stirred solution of 21-5 (150 mg, 0.30 mmol) and Cs₂CO₃ (293 mg, 0.9 mmol) in DMF (2 mL) under rt. The reaction was heated at 100 °C for 3 hr. After the reaction was complete (monitored by LCMS), the reaction mixture was poured into water (10 mL) and extracted with EA (15 mL x 3). The combined organic layers were 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) (R f : 0.5). MS (ESI): C 27 H 37 Calculated value of F7N2O5S: 634.2; Experimental value: 635.2 [M + 1]+ .

[0574] Step 6. Synthesis of (R)-3-((3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-methyl-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)-2,2-dimethylpropionic acid (Example 21). LiOH was added to a stirred solution of 21-6 (40 mg, 0.064 g) in MeOH / THF / H2O (1 mL / 1 mL / 0.5 mL). . H2O (14.3 mg, 0.34 mmol) was added, and the reaction mixture was stirred at rt for 3 hr. After the reaction was complete (monitored by LCMS), the reaction was neutralized with 1 N HCl aqueous 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 preparative HPLC to give Example 21 (20 mg, 53%) as a white solid. MS (ESI): C 25 H 33 Calculated value of F7N2O5S: 606.2; Experimental value: 607.3 [M] + 1] + . 1 H 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.

[0575] Example 22. (R)-3-((5-cyclopentyl-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxane-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)-2,2-dimethylpropionic acid

[0576]

[0577] Step 1. Synthesis of (R)-2-bromo-N-(1-(cyclopentylamino)-5,5-difluorohexane-2-yl)-5-methoxy-4-(trifluoromethyl)benzenesulfonamide (22-2). A solution of 2-bromo-5-methoxy-4-(trifluoromethyl)benzenesulfonamide chloride (1.9 g, 5.4 mmol) in THF (10 mL) was added to a stirred solution of (R)-N1-cyclopentyl-5,5-difluorohexane-1,2-diamine (22-1) (1.0 g, 4.5 mmol) and TEA (1.4 g, 13.5 mmol) prepared by following the same procedure as 1-7, but with cyclopentamine replacing aniline. The resulting reaction mixture was stirred at rt for 3 hr. After the reaction was complete (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) (R f : 0.4). MS (ESI): C 19 H 26 Calculated value of BrF5N2O3S: 536.1; Experimental value: 537.2 [M + 1] + .

[0578] 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). Cu (640 mg, 10.0 mmol) was added to a stirred solution of 22-2 (1.05 g, 2.0 mmol) and K2CO3 (828 mg, 6.0 mmol) in DMF (15 mL) and heated at -115 °C for 16 hr. After the reaction was complete (monitored by LCMS), the reaction mixture was quenched with saturated NH4Cl aqueous solution (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 under vacuum to give crude product 22-3 (1.0 g) as a yellow oil, which could be used in the next step without further purification. TLC: 15% EA / PE (v / v) (R f : 0.5). MS (ESI): C 19 H25 Calculated value of F5N2O3S: 456.2; Experimental value: 457.3 [M + 1] + .

[0579] 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). MeI (852 mg, 6.0 mmol) was added 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), and the reaction mixture was stirred at rt for 5 hr. After the reaction was complete (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) (R f : 0.4). MS(ESI): C 20 H 27 Calculated value of F5N2O3S: 470.2; Experimental value: 471.3 [M + 1] + .

[0580] 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). CH3SNa (382 mg, 5.30 mmol) was added to a stirred solution of 22-4 (500 mg, 1.06 mmol) in DMF (10 mL), and the reaction mixture was heated at 95 °C for 16 hr. After the reaction was complete (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) (R f : 0.6). MS (ESI): C 19 H25 Calculated value of F5N2O3S: 456.2; Experimental value: 457.3 [M + 1] + .

[0581] Step 5. Synthesis of (R)-3-((5-cyclopentyl-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)-2,2-dimethylpropionate ethyl ester (22-6). 2,2-Dimethyl-3-((methanesulfonyl)oxy)propionate ethyl ester (148 mg, 0.66 mmol) was added dropwise to a stirred solution of 22-5 (150 mg, 0.33 mmol) and Cs₂CO₃ (323 mg, 0.99 mmol) in DMF (2 mL) under rt. The reaction was heated at 100 °C for 3 hr. After the reaction was complete (monitored by LCMS), the reaction mixture 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) (R f : 0.5). MS (ESI): C 26 H 37 Calculated value of F5N2O5S: 584.2; Experimental value: 585.2 [M + 1] + .

[0582] Step 6. Synthesis of (R)-3-((5-cyclopentyl-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazidepine-8-yl)oxy)-2,2-dimethylpropionic acid (Example 22). LiOH was added to a stirred solution of 22-6 (40 mg, 0.068 mmol) in MeOH / THF / H2O (1 mL / 1 mL / 0.5 mL). . H2O (14.3 mg, 0.34 mmol) was added, and the reaction was stirred at rt for 3 hr. After the reaction was complete (monitored by LCMS), the reaction was neutralized with 1 N HCl aqueous 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 preparative HPLC to give Example 22 (26 mg, 68%) as a white solid. MS (ESI): C 24 H33 Calculated value of F5N2O5S: 556.2; Experimental value: 557.3 [M] + 1] + . 1 H NMR (400MHz, CDCl3): δ 7.45 (s, 1H), 7.27 (s, 1H), 4.06 (dd, J = 16.5, 8.1 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.

[0583] Example 23.1-((((3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahedrocyclopentadien-2-yl)-2-methyl-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0584]

[0585] Step 1. Synthesis of (3aR,6aS)-5,5-difluorohexahydrocyclopentadien-2(1H)-one (23-2). A small amount of DAST (48.3 g, 0.3 mol) was added to a stirred solution of (3aS,6aS)-tetrahydrocyclopentadien-2,5(1H,3H)-dione (23-1) (13.8 g, 0.1 mol) in DCM (200 mL) at 0 °C. The mixture was stirred at rt for 16 h, and the reaction mixture was diluted with a saturated aqueous solution of NaHCO3 (200 mL). The reaction mixture was extracted with EA (150 mL x 2). The combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography and diluted with PE / EA = 3 / 1 (v / v) to give 23-2 (8.0 g, 50%) as a colorless oil. TLC: 20% EA / PE (Rf: 0.4). MS(ESI):C8H 10 Calculated value of F₂O: 160.1; Experimental value: 160.2 [M+H] + .

[0586] Step 2. Synthesis of 5,5-difluorooctahedrocyclopentadien-2-ol (23-3). NaBH4 (1.55 g, 40 mmol) was added to a solution of 23-2 (3.16 g, 19.8 mmol) in MeOH (30 mL) in an ice bath. The reaction was stirred at room temperature for 2 h. The reaction was monitored by TLC. The starting material disappeared, and new spots were 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, and concentrated. The residue was dried under vacuum to give crude product 23-3 (2.95 g, 92%) as a colorless oil, which could be used in the next step without further purification. TLC: 25% EA / PE (v / v) (R f : 0.5). MS (ESI): C8H 12 Calculated value of F₂O: 162.1; Experimental value: 162.2 [M+H] + .

[0587] Step 3. Synthesis of 2-(5,5-difluorooctahedrocyclopentadien-2-yl)isoindoline-1,3-dione (23-4). DIAD (6.62 g, 32.8 mmol) was added 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) 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) (R f : 0.5).MS (ESI): C 16 H 15 Calculated value of F2NO2: 291.1; Experimental value: 292.3 [M+H] + .

[0588] Step 4. Synthesis of 5,5-difluorooctahedrocyclopentadien-2-amine (23-5). NH₂(4.1 g, 65.3 mmol) was added to a solution of 23-4 (3.8 g, 13.1 mmol) in MeOH (30 mL). The reaction was stirred at 60 °C for 5 h. The mixture was filtered and the solid was washed with MeOH (20 mL). The filtrate was concentrated. The residue was diluted with Et₂O (100 mL) and filtered. The filtrate was extracted with dioxane (20 mL) containing 4N HCl. After stirring for 30 min, the solution was concentrated under vacuum to give a crude product mixed with ACN (40 mL). The solid was collected and dried under vacuum to give 23-5 (1.5 g, 58%) as a pale yellow solid, which could be used in the next step without further purification. TLC: 15% MeOH / DCM (v / v) (R f :0.3). MS (ESI): C8H 13 Calculated value of F2N: 161.1; Experimental value: 162.2 [M+H] + .

[0589] Step 5. Synthesis of tert-butyl carbamate (23-6) of ((2R)-1-((5,5-difluorooctahedrocyclopentadien-2-yl)amino)-5,5-difluoro-1-oxohexane-2-yl)carbamate. DIEA (2.0 g, 15.7 mmol) and HATU (2.56 g, 6.74 mmol) were added to a solution of (R)-2-((tert-butyloxycarbonyl)amino)-5,5-difluorohexanoic acid (1.2 g, 4.49 mmol) in DMF (15.0 ml) in an ice bath. After stirring for 30 min, 23-5 (885 mg, 4.49 mmol) was added. The reaction mixture 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) (R f : 0.3). MS (ESI): C 19 H 30 Calculated value of F4N2O3: 410.2; Experimental value: 355.2 [M + H - 56] + .

[0590] Step 6. Synthesis of (2R)-2-amino-N-(5,5-difluorooctahedrocyclopentadien-2-yl)-5,5-difluorohexamamide (23-7). TFA (3.0 mL) was added to a solution of 23-6 (370 mg, 0.90 mmol) in DCM (9.0 mL) in an ice bath. The reaction mixture was stirred at rt for 2 hr and concentrated. The residue was diluted with saturated aqueous NaHCO3 solution and extracted with DCM (30 mL x 3). The combined organic extracts were dried over Na2SO4 and concentrated. The residue was dried under vacuum to give crude product 23-7 (260 mg, 93%) as a yellow oil, which could be used in the next step without further purification. MS (ESI): C 14 H 22 Calculated value of F4N2O: 310.2; Experimental value: 311.2 [M+H] + .

[0591] Step 7. Synthesis of (2R)-N1-(5,5-difluorooctahedrocyclopentadien-2-yl)-5,5-difluorohexane-1,2-diamine (23-8). LAH (2.5 M in THF, 1.7 mL) was added to a solution of 23-7 (260 mg, 0.84 mmol) in THF (6 mL) in an ice bath. The reaction mixture was stirred at 60 °C for 16 hr and cooled to 0 °C. The reaction mixture was quenched with H2O (160 mg), followed by quenching with 10% NaOH aqueous solution (w / w) (160 mg) and Et2O (50 mL). The resulting mixture was dried over anhydrous Na2SO4 and concentrated. The residue was dried under vacuum to give crude product 23-8 (200 mg, 81%) as a yellow oil, which could be used in the next step without further purification. TLC: 12% MeOH / DCM (v / v) (R f : 0.3). MS(ESI): C 14 H 24 Calculated value of F4N2: 296.2; Experimental value: 297.1 [M+H] + .

[0592] Step 8. Synthesis of 2-bromo-N-((2R)-1-((5,5-difluorooctahedrocyclopentadien-2-yl)amino)-5,5-difluorohexane-2-yl)-5-methoxy-4-(trifluoromethyl)benzenesulfonamide (23-9). Sulfonyl chloride (373 mg, 1.06 mmol) was added to a solution of 23-8 (250 mg, 1.06 mmol) in DCM (3.0 mL) and TEA (375 mg, 3.71 mmol) in an ice bath. The reaction mixture 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 was purified by silica gel column chromatography (50% EA / PE (v / v)) to give 23-9 (400 mg, 62%) as a yellow oil. TLC: 50% EA / PE (v / v) (R) f :0.3). MS (ESI): C 22 H 28 Calculated value of BrF7N2O3S: 612.1; Experimental value: 613.2 [M+H] + .

[0593] Step 9. Synthesis of (3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahedrocyclopentadien-2-yl)-8-methoxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (23-10). Cu (21 mg, 0.32 mmol) was added to a solution of 23-9 (100 mg, 0.16 mmol) and K2CO3 (67 mg, 0.48 mmol) in DMF (2.0 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 120 °C 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 under vacuum to give crude product 23-10 (100 mg) as a yellow oil, which could be used in the next step without further purification. TLC: 35% EA / PE (v / v) (R f : 0.3).MS (ESI): C 22 H 27 Calculated value of F7N2O3S: 532.2; Experimental value: 533.3 [M+H] + .

[0594] Step 10. Synthesis of (3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahedrocyclopentadien-2-yl)-8-methoxy-2-methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (23-11). MeI (0.46 mL, 7.32 mmol) was added in portions to a stirred solution of 23-10 (1.3 g, 2.44 mmol) and K₂CO₃ (507 mg, 3.66 mmol) in NMP (13 mL) 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 and diluted with PE / EA = 3 / 1 (v / v) to give 23-11 (692 mg, 52%) as a colorless oil. TLC: 33% EA / PE (v / v) (R f : 0.5). MS(ESI): C 23 H 29 Calculated value of F7N2O3S: 546.2; Experimental value: 546.7 [M+H] + .

[0595] Step 11. Synthesis of (3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahedrocyclopentadien-2-yl)-8-hydroxy-2-methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (23-12). MeSNa (21 mg, 0.292 mmol) was added to a solution of 23-11 (40 mg, 0.073 mmol) in DMF (0.5 mL), and the reaction mixture was stirred at 100 °C for 16 hr. The reaction mixture was diluted with saturated NH4Cl aqueous solution (10 mL), acidified to pH = 5–6 with 4 NHCl aqueous solution, and extracted with EA (10 mL x 2). The combined organic extracts were washed with saturated LiCl aqueous solution (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (60% EA / PE (v / v)) to give 23-12 (33 mg, 87%) as a colorless oil. TLC: 40% EA / PE (v / v) (R f : 0.3). MS (ESI): C 22 H 27 Calculated value of F7N2O3S: 532.2; Experimental value: 532.8 [M+H]+

[0596] Step 12. Synthesis of ethyl 1-((((3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahedrocyclopentadien-2-yl)-2-methyl-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)methyl)cyclopropane-1-carboxylate (23-13). ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (82 mg, 0.369 mmol) was added to a solution of 23-12 (113 mg, 0.205 mmol) and Cs₂CO₃ (200 mg, 0.615 mmol) in DMF (1 ml) at rt, and the reaction mixture was stirred at -70 °C for 5 hr. The mixture was then diluted with water (5 mL) and extracted with EA (10 mL x 2). The combined organic extracts were washed with saturated LiCl aqueous 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) (R f : 0.5). MS (ESI): C 29 H 37 Calculated value of F7N2O5S: 658.2; Experimental value: 659.0 [M+H] + . 1 H 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, 4.2Hz, 2H), 1.24 ‒ 1.13 (m, 3H), 1.09 (dd, J = 7.1, 4.1 Hz, 2H) ppm.

[0597] Step 13. Synthesis of 1-((((3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahedrocyclopentadien-2-yl)-2-methyl-1,1-dioxano-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 23). NaOH (12 mg, 0.303 mmol) was added to a solution of 23-13 (20 mg, 0.030 mmol) in MeOH / THF / H2O (0.75 mL, v / v / v = 1 / 2 / 2), and the reaction was stirred at rt for 3 hr. After the reaction was complete, the reaction mixture was diluted with water (5 mL), acidified to pH = 6-7 with 3N HCl aqueous solution, and extracted with EA (10 mL x 2). The combined organic extracts were dried over Na₂SO₄ and concentrated. The residue was purified by preparative HPLC to give Example 23 (10.6 mg, 56%) as a white solid. TLC: 10% MeOH / DCM (v / v) (R f :0.5). MS (ESI): C 27 H 33 Calculated value of F7N2O5S: 630.2, experimental value: 631.2 [M+H] + . 1 H 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.

[0598] Examples 24a and 24b. (R)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)propionic acid (24a) and (S)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)propionic acid (24b)

[0599]

[0600] Step 1. Synthesis of tert-butyl 2-cyclopropylacetate (24-2). One drop of DMF was added to a solution of 5 g (50 mmol) cyclopropylacetic acid (24-1) in 25 mL of dichloromethane at 0 °C, followed by dropwise addition of 6.99 g (55 mmol) oxalyl chloride. The reaction mixture was stirred between 0 °C and 10 °C for 2 h and then concentrated under reduced pressure. The residue was briefly (approximately 5 min) dried under high vacuum and then dissolved in dry THF (10 mL), and the resulting mixture was cooled to 0 °C. Subsequently, THF containing 1 M potassium tert-butoxide (45 mL, 45 mmol) was added dropwise, and the mixture was stirred at rt for 2 hr and then concentrated. Diethyl ether and a 0.5 N NaOH aqueous solution were added to the residue. The organic layer was dried over anhydrous MgSO4 and concentrated. The residue was dried under vacuum to give crude product 24-2 (2.1 g, 27%) as a pale yellow oil, which could be used in the next step without further purification.

[0601] Step 2. Synthesis of tert-butyl 3-(benzyloxy)-2-cyclopropylpropionate (24-3). HMPA (1.38 g, 76.8 mmol) and LDA (38.4 mL, 76.8 mmol, 2.0 mol / L in THF / n-heptane) were added to 30 mL of THF containing compound 24-2 (4 g, 25.6 mmol) at -78 °C. After stirring the solution at -78 °C for 20 min, ((chloromethoxy)methyl)benzene (6 g, 38.4 mmol) was added dropwise to a solution of THF (10 mL). The reaction mixture was stirred at -78 °C for 2 h and then warmed to rt. After stirring at rt for 5 hr, the reaction mixture was quenched with saturated NH4Cl aqueous solution (10 mL) and concentrated. The residue was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to obtain 24-3 (1.8 g, 26%).

[0602] Step 3. Synthesis of tert-butyl 2-cyclopropyl-3-hydroxypropionate (24-4). A mixture of 24-3 (1 g, 3.6 mmol) and 10% Pd / C (200 mg) in MeOH (20 mL) was stirred overnight under H2 atmosphere at rt. The mixture was filtered and the residue was dried under vacuum to give crude product 24-4 (450 mg, 67%), which could be used in the next step without further purification.

[0603] Step 4. Synthesis of tert-butyl 2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxane-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine-8-yl)oxy)propionate (24-5). Triphenylphosphine (637 mg, 2.43 mmol) and 24-4 (450 mg, 2.42 mmol) were added 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). The solution was heated to 110°C, and then DIAD (4.9 g, 24.2) was added. After stirring at 110°C for 4 hours, the reaction mixture was cooled to rt and diluted with EA (20 mL). The organic layer was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography to give 24-5 (130 mg, 15%) as a pale yellow solid. MS (ESI): C 30 H 37 Calculated value of F5N2O5S: 632.2; Experimental value: 633.2 [M + 1] + .

[0604] Step 5. Synthesize (R)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)tert-butyl propionate (24-5a) and (S)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)tert-butyl propionate (24-5b). Compound 24-5 was isolated by chiral SFC to give 24-5a and 24-5b as white solids, respectively. The stereochemistry of the 2-cyclopropyl-3-hydroxypropionic acid moiety is arbitrarily specified. MS (ESI): C 30 H 37 Calculated value of F5N2O5S: 632.2; Experimental value: 633.2 [M + 1] + .

[0605] Step 6a. Synthesis of (S)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazidepine-8-yl)oxy)propionic acid (Example 24a). TFA (1 mL) was added dropwise to a mixture of 24-5a (80 mg, 0.13 mmol) in DCM (5 mL) under rt. After stirring for 5 hr under rt, the mixture was concentrated, and the residue was purified by preparative HPLC to give Example 24a (35 mg, 48%). MS (ESI): C 26 H 29 Calculated value of F5N2O5S: 576.2; Experimental value: 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.

[0606] Step 6b. Synthesis of (S)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxano-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazopen-8-yl)oxy)propionic acid (Example 24a). Following the same procedure as in the preparation of Example 24a, Example 24b (33 mg, 48%) was obtained as a white solid by replacing 24-5a with 24-5b (78 mg, 0.13 mmol). MS (ESI): C 26 H 29 Calculated value of F5N2O5S: 576.2; Experimental value: 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 = 6.4Hz, 2H), 4.17 ‒ 4.13 (m, 1H), 3.85 ‒ 3.81 (m, 1H), 3.57 ‒ 3.52 (m, 1H), 2.62(s, 3H), 2.13 ‒ 1.99 (m, 3H), 1.95 ‒ 1.84 (m, 1H), 1.70 ‒ 1.60 (m, 4H), 1.00‒ 0.70 (m, 1H), 0.65 ‒ 0.48 (m, 2H), 0.46 ‒ 0.43 (m, 2H) ppm.

[0607] Example 25. (R)-3-(((R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxane-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)-2-methylpropionic acid

[0608]

[0609] 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]thiazapine 1,1-dioxide (25-2). Under rt and N2, 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-dioxane (365 mg, 2.37 mmol) were added to dioxane (4 mL) containing (R)-7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine 1,1-dioxide (25-1) (400 mg, 0.79 mmol) at N2. The mixture was stirred overnight at 100 °C, then diluted with water (15 mL) at rt and extracted with EA (15 mL x 3). The organic extract was washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography using EA / PE as the eluent to give 25-2 (300 mg, 84%) as a pale yellow solid. MS (ESI): C 22 H 25 Calculated value of F3N2O3S: 454.2; Experimental value: 455.2 [M + 1] + .

[0610] 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-carboxaldehyde-1,1-dioxide (25-3). Osmium tetroxide (2.5% wt in t-BuOH, 336 mg, 0.033 mmol) and sodium periodate (570 mg, 2.64 mmol) were added to a mixture of 25-2 (300 mg, 0.66 mmol) in dioxane / H2O (4 / 1 (v / v), 6 mL) under rt. After stirring under 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 over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography using EA / PE as the eluent to give 25-3 (240 mg, 80%) as a pale yellow solid. MS (ESI): C 21 H23 Calculated value of F3N2O4S: 456.1; Experimental value: 457.2 [M + 1] + .

[0611] 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). DAST (387 mg, 2.4 mmol) was added to a solution of 25-3 (220 mg, 0.48 mmol) in DCM (3 mL) under rt. After stirring for 2 days under rt, the reaction mixture was poured into a saturated aqueous solution of NaHCO3 (20 mL). The resulting mixture was extracted with DCM (15 mL x 3), and the combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was dried under vacuum to give crude product 25-4 (180 mg, 78%) as a brown oil, which could be used in the next step without further purification. MS (ESI): C 21 H 23 Calculated value of F5N2O3S: 478.1; Experimental value: 479.1 [M + 1] + .

[0612] 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-carboxaldehyde-1,1-dioxide (25-5). Compound 25-4 (180 mg, 0.31 mmol) was added to a solution of NaSMe in DMF (100 mg / mL, 1.08 mL) under rt. After stirring at 100 °C for 3 hr, the reaction mixture was diluted with water (10 mL) under rt and extracted with EA (15 mL x 2). 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 the eluent to give 25-5 (150 mg, 85%) as a pale yellow solid. MS (ESI): C 20 H 21 Calculated value of F3N2O4S: 442.1; Experimental value: 443.1 [M + 1] + .

[0613] 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). DAST (387 mg, 2.4 mmol) was added to a mixture of 25-5 (130 mg, 0.29 mmol) in DCM (3 mL) under rt. After stirring under rt for 2 days, the reaction mixture was poured into a saturated aqueous solution of NaHCO3 (20 mL), and the resulting mixture was extracted with DCM (15 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was dried under vacuum to give crude product 25-6 (130 mg) as a brown solid, which could be used in the next step without further purification. MS (ESI): C 20 H 21 The calculated value of F5N2O3S is 464.1; the experimental value is 465.1 [M + 1]. + .

[0614] Step 6. Synthesis of methyl (R)-3-(((R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxano-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)-2-methylpropionate (25-7). Methyl (R)-3-hydroxy-2-methylpropionate (165 mg, 1.4 mmol) and triphenylphosphine (221 mg, 0.84 mmol) were added to a solution of 25-6 (130 mg, 0.28 mmol) in toluene (1.5 mL) at rt. After warming the solution to 110 °C, DIAD (565 mg, 2.8 mmol) was added, and the resulting reaction mixture was stirred at 110 °C for 5 hr. The mixture was then concentrated, and the residue was purified by silica gel column chromatography using EA / PE as the eluent to give 25-7 (130 mg, 82%) as a pale yellow solid. MS (ESI): C 25 H 29 Calculated value of F5N2O5S: 564.2; Experimental value: 565.1 [M+1] + .

[0615] Step 7. Synthesis of (R)-3-(((R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxano-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazopen-8-yl)oxy)-2-methylpropionic acid (Example 25). LiOH was added to a solution of 25-7 (130 mg, 0.23 mmol) in THF / H2O (4:1 (v / v), 5 ml) under rt. . H2O (97 mg, 2.3 mmol). After stirring overnight at rt, the reaction mixture was adjusted to pH 2–3 with 10% HCl aqueous solution. The resulting mixture was extracted with EA (10 mL x 2), and the combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative HPLC to give Example 25 (8 mg, 6.3%) as a white solid. MS (ESI): C 24 H 27 Calculated value of F5N2O5S: 550.2; Experimental value: 551.2 [M + 1] + . 1 H NMR (400MHz, 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.

[0616] Example 26. (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octane-1-yl)-2-methyl-7-(methylthio)-1,1-dioxane-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiazapine-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0617]

[0618] Step 1. Synthesis of methyl 4-fluorobicyclo[2.2.2]octane-1-carboxylate (26-2). 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (26-1) (10 g, 47.12 mmol), water (100 mL), and Selectfluor (33.38 g, 94.23 mmol) were added to a 250 mL 3-necked round-bottom flask at rt. The resulting mixture was stirred at 70 °C for 24 hr under a nitrogen atmosphere. The mixture was cooled to rt and acidified to pH = 5 with a saturated aqueous 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 under vacuum to give 26-2 (8 g, 91.2%) as a white solid, which could be used in the next step without further purification. MS (ESI): C 10 H 15 Calculated value of FO2: 186.1; Experimental value: 187.1 [M] + 1] + .

[0619] Step 2. Synthesis of 4-fluorobicyclo[2.2.2]octane-1-carboxylic acid (26-3). 26-2 (8 g, 42.96 mmol), THF (80 mL), water (10 mL), and LiOH (3.09 g, 128.87 mmol) were added to a 250 mL round-bottom flask under reflux. The resulting mixture was stirred under nitrogen atmosphere for 24 hr. The mixture was acidified to pH = 5 with 2 NHCl aqueous 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 under vacuum to give 26-3 (7 g, 94.6%) as a colorless oil, which could be used in the next step without further purification. MS (ESI): C9H 13 Calculated value of FO2: 172.1; Experimental value: 173.1 [M] + 1] + .

[0620] Step 3. Synthesis of N-{4-fluorobicyclo[2.2.2]octane-1-yl}tert-butyl carbamate (26-4). 26-3 (7 g, 40.65 mmol), 2-methyl-2-propanol (70 mL), DPPA (16.78 g, 60.98 mmol), and TEA (12.34 g, 121.95 mmol) were added to a 250 mL round-bottom flask under reflux. The resulting mixture was stirred at 85 °C for 24 hr under nitrogen atmosphere. The mixture was cooled to reflux, 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 under vacuum to give 26-4 (9 g, 91.0%) as a light brown oil, which could be used in the next step without further purification. MS (ESI): C 13 H 22 Calculated value of FNO2: 243.2; Experimental value: 244.3 [M] + 1] + .

[0621] Step 4. Synthesis of 4-fluorobicyclo[2.2.2]octane-1-amine (26-5). 26-4 (9 g, 36.99 mmol) and dioxane (4 M, 90 mL) containing HCl (gas) were added to a 250 mL round-bottom flask at set time. The resulting mixture was stirred at set time for 24 hr under a nitrogen atmosphere. The mixture was diluted with water (90 mL), alkalized to pH = 8 with a saturated aqueous solution of 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 under vacuum to give 26-5 (5 g, 94.40%) as a white solid, which could be used in the next step without further purification. MS (ESI): C8H 14 Calculated value of FN: 143.1; Experimental value: 144.2 [M] + 1] + .

[0622] Step 5. Synthesis of methyl (R)-2-((tert-butoxycarbonyl)amino)-5-oxohexanoate (26-7). 1-(tert-butyl)-2-methyl (R)-5-oxopyrrolidine-1,2-dicarboxylic acid (30 g, 123.33 mmol), THF (300 mL), and diethyl ether (17.65 g, 147.99 mmol) containing 3 M MeMgBr solution were added to a 500 mL 3-necked round-bottom flask at -55 °C. The resulting mixture was stirred at -20 °C for 18 hr under a nitrogen atmosphere. The reaction was quenched with a saturated aqueous solution of NH4Cl at 0 °C and concentrated to remove the 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 and diluted with PE / EA (5 / 1 (v / v)) to give 26-7 (20 g, 62.5%) as a colorless oil. MS (ESI): C 12 H 21 Calculated value of NO5: 259.1; Experimental value: 331.1 [M] + Na + ACN] + .

[0623] Step 6. Synthesis of (R)-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoate methyl ester (26-8). 26-7 (20 g, 77.13 mmol), DCM (200 mL), and DAST (37.30 g, 231.39 mmol) were added to a 500 mL 3-necked round-bottom flask at 0 °C. The resulting mixture was stirred at rt for 12 h under a nitrogen atmosphere. The reaction was quenched with a saturated aqueous solution of NaHCO3 at 0 °C and concentrated to remove the 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 and diluted with PE / EA (8 / 1 (v / v)) to give 26-8 (2.8 g, 12.9%) as a colorless oil. MS (ESI): C 12 H 21 Calculated value of F2NO4: 281.1; Experimental value: 282.1 [M] + 1] + .

[0624] Step 7. Synthesis of (R)-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoic acid (26-9). 26-8 (2.8 g, 9.95 mmol), THF (30 mL), water (7.5 mL), and LiOH (0.72 g, 29.86 mmol) were added to a 100 mL 3-necked round-bottom flask at set time. The resulting mixture was stirred at set time for 24 hr under a nitrogen atmosphere. The mixture was acidified to pH = 5 with 1 NHCl aqueous solution and concentrated to remove the 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 under vacuum to give crude product 26-9 (2.5 g) as a light brown oil, which could be used in the next step without further purification. MS (ESI): C 11 H 19 Calculated value of F2NO4: 267.1; Experimental value: 253.1 [M – Boc +1] + .

[0625] Step 8. Synthesis of (R)-(5,5-difluoro-1-((4-fluorobicyclo[2.2.2]octane-1-yl)amino)-1-oxohexane-2-yl)tert-butyl carbamate (26-10). 26-9 (2.5 g, 9.35 mmol), DMF (25 mL), HATU (4.27 g, 11.22 mmol), DIEA (1.81 g, 14.03 mmol), and 26-5 (1.61 g, 11.22 mmol) were added to a 50 mL 3-necked round-bottom flask under reflux. The resulting mixture was stirred under reflux for 4 hr under a 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 under vacuum to give crude product 26-10 (2.3 g, 62.6%) as a brown oil, which could be used in the next step without further purification. MS (ESI): C 19 H 31 Calculated value of F3N2O3: 392.2; Experimental value: 393.2 [M] + 1] + .

[0626] Step 9. Synthesis of (R)-2-amino-5,5-difluoro-N-(4-fluorobicyclo[2.2.2]octane-1-yl)hexamamide (26-11). 26-10 (2.3 g, 5.86 mmol) and EtOAc (2 M, 25 mL) containing HCl were added to a 100 mL round-bottom flask at set time. The resulting mixture was stirred at set time for 16 hr under a nitrogen atmosphere. The mixture was alkalized to pH = 8 with a saturated aqueous solution of NaHCO3. 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 under vacuum to give crude product 26-11 (1.6 g, 93.4%) as a light brown oil, which could be used in the next step without further purification. MS (ESI): C 14 H 23 Calculated value of F3N2O: 292.2; Experimental value: 293.2 [M] + 1] + .

[0627] Step 10. Synthesis of (R)-2-((2,4-dibromo-5-methoxyphenyl)sulfonamido)-5,5-difluoro-N-(4-fluorobicyclo[2.2.2]octane-1-yl)hexamamide (26-12). 26-11 (1.8 g, 6.16 mmol), 2,4-dibromo-5-methoxybenzenesulfonyl chloride (2.69 g, 7.39 mmol), THF (18 mL), and TEA (1.87 g, 18.47 mmol) were added to a 50 mL round-bottom flask under reflux. The resulting mixture was stirred under nitrogen atmosphere for 16 h. The resulting mixture was diluted with water (50 mL) and concentrated to remove the organic solvent. The resulting mixture was extracted with EtOAc (50 mL 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 and diluted with PE / EA (3 / 1 (v / v)) to give 26-12 (1.5 g, 39.3%) as a yellow solid. MS (ESI): C 21 H 27 Calculated value of Br2F3N2O4S: 618.0; Experimental value: 618.9 [M] + 1] + .

[0628] Step 11. Synthesis of (R)-2,4-dibromo-N-(5,5-difluoro-1-((4-fluorobicyclo[2.2.2]octane-1-yl)amino)hexane-2-yl)-5-methoxybenzenesulfonamide (26-13). 26-12 (1.5 g, 2.42 mmol), THF (30 mL), and BH3•Me2S (0.75 mL, 7.91 mmol) were added to a 50 mL round-bottom flask at rt. The resulting mixture was stirred at 75 °C under a nitrogen atmosphere for 16 h. 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 and diluted with PE / EA (5 / 1 (v / v)) to give 26-13 (1.0 g, 68.2%) as a brown solid. MS (ESI): C 21 H 29 Calculated value of Br2F3N2O3S: 604.0; Experimental value: 605.0 [M] + 1] + .

[0629] Step 12. Synthesis of (R)-7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octane-1-yl)-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (26-14). 26-13 (1.0 g, 1.65 mmol), DMSO (10 mL), K₂CO₃ (0.69 g, 4.947 mmol), and CuI (0.16 g, 0.83 mmol) were added to a 40 mL vial at rt. The resulting mixture was stirred at 130 °C under a nitrogen atmosphere for 16 h. 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 and diluted with PE / EA (1 / 1 (v / v)) to give 26-14 (200 mg, 23.1%) as a brown solid. MS (ESI): C 21 H 28 Calculated value of BrF3N2O3S: 524.1; Experimental value: 525.1 [M] + 1] + .

[0630] Step 13. Synthesis of (R)-7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octane-1-yl)-8-methoxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (26-15). 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) were added to an 8 mL vial under rt. The resulting mixture was stirred under nitrogen atmosphere for 16 h. 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 and diluted with PE / EA (1 / 1 (v / v)) to give 26-15 (145 mg, 70.6%) as a brown oil. MS (ESI): C 22 H 30 Calculated value of BrF3N2O3S: 538.1; Experimental value: 539.1 [M] + 1] + .

[0631] Step 14. Synthesis of (R)-3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octane-1-yl)-8-hydroxy-2-methyl-7-(methylthio)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (26-16). 26-15 (90 mg, 0.17 mmol), DMF (3 mL), and MeSNa (64.31 mg, 0.92 mmol) were added to an 8 mL vial at rt. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 h. 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 and diluted with PE / EA (4 / 1 (v / v)) to give 26-16 (50 mg, 60.8%) as a brown solid. MS (ESI): C 22 H 31 Calculated value of F3N2O3S2: 492.2; Experimental value: 493.2 [M] + 1] + .

[0632] Step 15. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octane-1-yl)-2-methyl-7-(methylthio)-1,1-dioxane-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid ethyl ester (26-17). 26-16 (50 mg, 0.10 mmol), DMF (1 mL), 1-(bromomethyl)cyclopropane-1-carboxylic acid ethyl ester (25.22 mg, 0.12 mmol), and Cs₂CO₃ (99.52 mg, 0.30 mmol) were added to an 8 mL vial at rt. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 16 h. 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 and diluted with PE / EA (3 / 1 (v / v)) to give 26–17 (8 mg, 12.7%) as a brown solid. MS (ESI): C 29 H 41 Calculated value of F3N2O5S2: 618.2; Experimental value: 619.2 [M] + 1] + .

[0633] Step 16. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octane-1-yl)-2-methyl-7-(methylthio)-1,1-dioxane-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazide-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 26). 26-17 (8 mg, 0.01 mmol), LiOH (0.93 mg, 0.04 mmol), water (1 mL), and THF (4 mL) were added to an 8 mL vial under rt. The resulting mixture was stirred under nitrogen atmosphere for 2 h. The resulting mixture was acidified to pH 3 with 2 NHCl aqueous solution and concentrated. The residue was purified by chiral preparative HPLC under the following conditions: column: CHIRAL ART Amylose-C NEO, 3*25 cm, 5 μm; mobile phase A: Hex (0.1% FA)-HPLC, mobile phase B: IPA-HPLC; flow rate: 35 mL / min; gradient: 30% B to 30% B over 15 min; wavelength: 220 / 254 nm; RT1 (min): 0.82; sample solvent: IPA: CAN = 3: 1; injection volume: 0.8 mL; the collected solution was concentrated under vacuum to remove ACN, and the resulting solution was lyophilized to give Example 26 (2.5 mg, 32.7%) as a white solid. MS (ESI): C 27 H 37 Calculated value of F3N2O5S2: 590.2; Experimental value: 591.2 [M] + 1] + . 1 H 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 = 11.2Hz, 3H), 2.03 (s, 2H), 1.94 ‒ 1.87 (m, 9H), 1.77 ‒ 1.51 (m, 6H), 1.32 (s,2H), 1.13 (s, 2H)ppm.

[0634] Synthesis of (R)-2-(bromomethyl)-5,5-difluorohexanoate methyl ester (27-9)

[0635]

[0636] Step 1. Synthesis of (R)-1-(4-benzyl-2-oxozolidine-3-yl)hexane-1,5-dione (27-2). 5-oxohexanoic acid (27-1) (1.113 kg, 8.56 mol), THF (24 L), and TEA (0.95 kg, 9.40 mol) were added to a 50 L 4-necked round-bottom flask at room temperature. Pivaloyl chloride (1.14 kg, 9.40 mol) was added dropwise to the mixture over 2 h at 5 °C. The resulting mixture was stirred at room temperature for another 2 h. (4R)-4-benzyl-1,3-oxozolidine-2-one (1.44 kg, 8.12 mol) and THF (16 L) were added to a 20 L 4-necked round-bottom flask at room temperature. n-BuLi (3.25 L, 8.12 mol) was added dropwise to the mixture over 4 h at -50 °C. The resulting mixture was stirred at -50°C for another 1 h. The lithium reagent was then transferred via a tube to the mixed anhydride in a 50 L flask under reduced pressure. The resulting mixture was stirred at -20°C under a nitrogen atmosphere for 4 h. The resulting mixture was diluted with EtOAc (50 L). The resulting mixture was washed with aqueous NaHCO3 solution (20 L x 2) and brine (20 L x 2), dried over anhydrous Na2SO4, and concentrated. The residue was wet-milled three times with PE / EA = 20 / 1 (v / v) (60 L). The precipitate was collected and dried under vacuum to give 27-2 (1.7 kg, 68.7%) as a white solid. MS (ESI): C 16 H 19 Calculated value of NO4: 289.1; Experimental value: 290.1 ​​[M] + 1] + .

[0637] Step 2. Synthesis of (R)-4-benzyl-3-(5,5-difluorohexanoyl)oxazolidine-2-one (27-3). (R)-1-(4-benzyl-2-oxooxazolidine-3-yl)hexane-1,5-dione (27-2) (200 g, 691.25 mol) and DCE (600 mL) were added to a 2 L 3-necked round-bottom flask at room temperature. BAST (382.33 g, 1728.13 mol) was added to the mixture at room temperature. The resulting mixture was stirred at 70 °C for another 6 h. The mixture was cooled to room temperature. The resulting mixture was diluted with DCM (1 L). The reaction mixture was slowly poured into a saturated aqueous solution of NaHCO3. 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 and diluted with PE / THF (10:1 (v / v)) to give 27-3 (153 g, 71.1%) as a brown oil. MS (ESI): C 16 H 19 Calculated value of F2NO3: 311.1; Experimental value: 312.1 [M] + 1] + . 1 H 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.

[0638] 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 a nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min. The solution was then treated dropwise with TEA (362.90 g, 3.59 mol) at 0 °C under a nitrogen atmosphere, followed by stirring at 0 °C for 2 h. Following this, ((chloromethoxy)methyl)benzene (1021 g, 6.52 mol) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 2 h. The reaction was quenched at 0 °C with a saturated aqueous solution of NH4Cl (3.5 L). The resulting mixture was separated, and the aqueous layer was extracted with DCM (2 L x 2). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (5 L x 2) and brine (5 L), dried over anhydrous Na2SO4, and concentrated. The residue was purified by wet milling at PE / EA = 30 / 1 (v / v) (60 L x 3). The precipitate was collected and dried under vacuum to give 27-4 (1160 g) as a light brown solid, which could be used directly in the next step without further purification. MS (ESI): C 24 H 27 Calculated value of F2NO4: 431.2; Experimental value: 432.2 [M] + 1] + . 1 H 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, 3.2Hz, 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.

[0639] 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 dropwise with H2O2 (1051 g, 9.27 mol, 30%) at 0 °C under a nitrogen atmosphere for 30 min. The mixture was stirred at 0 °C for 30 min, and then subjected to a reaction at 0 °C with LiOH. . The mixture was treated with 2 L of H2O (194.49 g, 4.64 mol). The resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched by adding 5 L of Na2SO3 at 0 °C, followed by concentration under vacuum. The resulting solution was adjusted to pH = 12 with 1 N NaOH aqueous solution and extracted with DCM (5 L x 3). The aqueous layer was adjusted to pH = 2 with saturated HCl aqueous 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 under vacuum to give product 27-5 (600 g) as a pale yellow oil, which could be used directly in the next step without further purification. MS (ESI): C 14 H 18 Calculated value of F₂O₃: 272.1; Experimental value: 273.1 [M] + 1] + .

[0640] Step 5. Synthesis of methyl (S)-2-((benzyloxy)methyl)-5,5-difluorohexanoate (27-6). A solution of (S)-2-((benzyloxy)methyl)-5,5-difluorohexanoate (27-5) (1.80 kg, 6.6 mol) in MeOH (9 L) was treated dropwise with SOCl2 (1.65 kg, 13.88 mol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for another 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and diluted with PE / EA (10:1 (v / v)) to give 27-6 (1.5 kg, 81.4%) as a brown oil. ...

Claims

1. A compound of formula II Formula II, or a pharmaceutically acceptable salt thereof, wherein: M is -CHF-, -CH(CH3)-, -CF(CH3)-, -CF2-, or -C(CH3)2-; R a R b and R c Each time it appears, independently select the group consisting of the following items: hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and C 3-6 Monocycloalkyl; R 1 For OH, CH3, -C(O)NH2, -C(O)OH, -C(O)OC 1-6 Alkyl, -P(O)(OH)2, -S(O)2OH or ; R 2a and R 2b Choose independently from the group consisting of: hydrogen, halo, OH, methyl, ethyl, and CH2OH; or R 2a and R 2b Together with the carbon atoms they are attached to, they form C=CH2, C 3-6 Monocycloalkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, or 1,3-dioxyl group, wherein the C 3-6 The monocycloalkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl or 1,3-dioxyl group is optionally substituted by one to three independently selected halogenated and methyl groups; R 3 Choose from the following groups: hydrogen, halogen, cyano, R a R b N-, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkylthio, C 3-7 Monocycloalkyl, C 3-7 Monocycloalkoxy, C 3-7 Monocyclic alkyl thiols, C 3-7 Monocyclic alkyl-CH2-thio and C 5-12 Bicycloalkylthio group, wherein the C 3-7 Monocycloalkyl, C 3-7 Monocycloalkoxy, C 3-7 Monocyclic alkyl thiols, C 3-7 Monocyclic alkyl-CH2-thio and C 5-12 The bicycloalkylthio group is optionally substituted with 1 to 3 halogenated groups; R 4 Halogenated C 3-4 alkyl; R 5 For phenyl, C 3-7 Monocycloalkyl or C 5-12 Bicycloalkyl, wherein the phenyl, C 3-7 Monocycloalkyl or C 5-12 The bicycloalkyl group is optionally substituted by one to six independent substituents selected from the group consisting of: halogen, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-; and Each time q appears, it independently chooses a 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 according to claim 1 or 2, wherein formula II has formula IIa. Formula IIa, or a pharmaceutically acceptable salt thereof.

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

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

6. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 1 It is -P(O)(OH)2.

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

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

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

10. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Together with the carbon atoms to which they are attached, they form C=CH2, cyclopropyl, cyclobutyl, or oxacyclobutane groups, wherein the cyclopropyl or cyclobutyl groups are optionally substituted with 1 to 3 halogenated groups.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Together with the carbon atoms they are attached to, they form C=CH2, cyclopropyl, cyclobutyl, or oxecyclobutane groups.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Together with the carbon atoms they are attached to, they form cyclopropyl groups.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 3 Halogenated C 1-2 alkyl.

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R 3 It is CF3.

15. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 3 C 5-12 Bicycloalkylthio group.

16. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 3 Halogenated C 3-7 Monocyclic alkylthio group.

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

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

19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein R 4 It is -CH2CH2CF2CH3.

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

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

22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein R 4 It is -CH2CH2CF3.

23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 5 C is a C-type compound that is optionally substituted with one to six independently selected substituents from the group consisting of the following items. 3-7 Monocycloalkyl groups: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein R 5 for or .

25. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein in some embodiments, R 5 A phenyl group optionally substituted with one to six independently selected substituents from the group consisting of: halogenated, 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, Halogenated C 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 Alkoxy C(O)-, C 1-4 Alkyl C(O)O-, C 1-4 Alkyl S(O) q -、C 1-4 Alkyl S(O) q NR c -、C 1-6 Alkyl S(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-4 alkyl-.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 5 for .

27. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 5 for .

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

29. A method for treating hepatitis B (HBV) infection in a subject with this need, the method comprising: The subject is given a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27.

30. A method for treating hepatitis B (HBV) infection in a subject with this need, the method comprising: The subject is given a therapeutically effective amount of the pharmaceutical composition according to claim 28.

31. A method for treating hepatitis D (HDV) infection in a subject with this need, the method comprising: The subject is given a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27.

32. A method for treating hepatitis D (HDV) infection in a subject with this need, the method comprising: The subject is given a therapeutically effective amount of the pharmaceutical composition according to claim 28.

33. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27, used in a therapeutic manner.

34. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27, used as a medicine.

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