Bicyclic tetrahydrothiazepine derivatives

Abstract

The present invention relates to a compound represented by general formula (I) [Formula 1] TIFF2025526681000504.tif38170 (in the formula, R 1 , R 2 and R 4 The present invention provides novel bicyclic tetrahydrothiazepine derivatives having the formula:

Description

[Technical Field]

[0001] The present invention relates to bicyclic tetrahydrothiazepine compounds that inhibit diacylglycerol kinase (DGK) α and ζ and are useful as T cell activators, their preparation, and pharmaceutical compositions containing said compounds.

[0002] The compounds may be useful as immunotherapeutic agents for treating human diseases. More specifically, the compounds may be used alone or in combination with other immunotherapeutic agents to enhance anti-cancer immunity. [Background technology]

[0003] Cancer immunity is a multistep process regulated by a series of negative immune checkpoints and positive costimulatory receptors and associated intracellular signaling cascades that, when effectively elicited, can achieve antitumor responses (Mellman, I., et al. (2011) Cancer Immunotherapy Comes of Age, Nature 480(7378),480-489). Indeed, PD1 / PDL1 targeting and other immune checkpoint inhibitors have revolutionized cancer immunotherapy, yet more than 70% of patients still do not benefit from immune checkpoint blockade. Similarly, in the case of T cell bispecific antibodies, even in the most promising indication (non-Hodgkin's lymphoma), these T cell binders (TCBs) achieve complete remission in fewer than 50% of patients. T cell exhaustion appears to play a key role in many of these cases of primary or secondary resistance to cancer immunotherapy. A possible reason for this lack of efficacy is that T cell activation occurs via targeting and crosslinking of CD3 (signal 1) but without costimulation (signal 2), for example, via CD28 or 4-1BB. This hypothesis was clinically validated for CAR T-cell therapy, where it was shown that clinically relevant efficacy was only observed after incorporation of a costimulatory domain.

[0004] Diacylglycerol kinases (DGKs) are lipid kinases that catalyze the conversion of diacylglycerol (DAG) to phosphatidic acid (PA), thus limiting DAG-regulated functions and promoting PA-dependent functions (Merida, I., Avila-Flores, A., and Merino, E. 2008: Diacylglycerol kinases: at the hub of cell signaling. Biochem. J. 409(1), 1-18). The DGK family consists of 10 isoforms that can be classified into five subtypes based on the presence of distinct regulatory domains within their structure. Beyond that, the current lack of structural data still hinders a more complete understanding of the mode of action of DGKs. Furthermore, information on certain prokaryotic DGKs and other lipid kinases, such as sphingosine kinase and phosphatidylinositol-3-kinase (PI3K), has provided limited insight into the DGK catalytic mechanisms, which appear to differ from those of classical kinases (Arranz-Nicolas, J. and Merida, I., 2020. Biological regulation of diacylglycerol kinases in normal and neoplastic tissues: New opportunities for cancer immunotherapy. Advances in Biological Regulation, Volume 75; Ma, Q., Gabelli, S.B., Raben, D.M., 2019: Diacylglycerol kinases: relationship to other lipid kinases. Adv Biol Regul 71, 104-110).

[0005] Although several isoforms within the DGK family have been described to play a role in cancer, the α and ζ isoforms are the most extensively studied in this regard. As PA producers, both enzymes are involved in various processes that promote tumor growth and metastasis. On the other hand, as DAG consumers, DGKα and ζ have been widely characterized as negative regulators of T cell responses (Riese, MJ, Moon, EK, Johnson, BD, Albelda, SM, 2016. Diacylglycerol kinases (DGKs): novel targets for improving T cell activity in cancer. Front Cell Dev Biol 4, 108; Noessner, E., 2017. DGK-alpha: a checkpoint in cancer-mediated immuno-inhibition and target for immunotherapy. Front Cell Dev Biol 5, 16; Sakane, F., Mizuno, S., Komenoi, S., 2016. Diacylglycerol kinases as emerging potential drug targets for a variety of diseases: an update. Front Cell Dev Biol 4, 82; Arranz-Nicolas, J. and Merida, I., 2020. Biological regulation of diacylglycerol kinases in normal and neoplastic tissues: New opportunities for cancer immunotherapy,Advances in Biological Regulation,Volume 75).

[0006] These two isozymes, DGKα and DGKζ, are active downstream of CD28 and other costimulatory receptors as well as the T cell receptor (TCR), and their function is to limit the amount of DAG produced and ultimately T cell activation (Merida, I., Andrada, E., Gharbi, S.I., Avila-Flores, A., 2015. Redundant and specialized roles for diacylglycerol kinases alpha and zeta in the control of T cell functions. Sci. Signal. 8(374); Shulga, Y.V., Topham, M.K., Epand, R.M., 2011. Regulation and functions of diacylglycerol kinases. Chem. Rev. 111(10), 6186-6208.). An overview of representative DGK-regulated signaling pathways is shown in Figure 1 (Sim, J.A.; Kim, J.; Yang, D. Beyond Lipid Signaling: Pleiotropic Effects of Diacylglycerol Kinases in Cellular Signaling. Int. J. Mol. Sci. 2020, 21, 6861): Activated PLC1 cleaves PIP2 in the plasma membrane to generate two secondary messengers, DAG and IP3. DAG activates PKC, Ras / MEK / ERK / AP-1, and NF-kB, while IP3 is involved in activating intracellular Ca2+ flux. Upregulated Ca2+ signaling then activates the transcription factor NFAT. Briefly, the production and levels of DAG determine the duration and strength of Ras / MEK / ERK- and PKC-dependent signaling pathways, which are central to T cell activation. Therefore, DGK acts as an intracellular checkpoint, and inhibition of DGK is expected to enhance T cell signaling pathways and T cell activation.

[0007] Experimental evidence suggests that enhanced DGK function and / or expression in tumor-infiltrating T cells (TILs) limits tumor destruction. Experiments using CAR T cells against human mesothelioma tumors implanted in nude mice demonstrated that tumor-infiltrating CAR T cells express high concentrations of surface inhibitory receptors, as well as the inhibitory enzymes SHIP-1, DGKα, and DGKζ (Moon et al., 2014). Furthermore, high DGKα expression was also observed in TILs isolated from human renal tumors (Prinz et al., 2012). In murine mesoCAR T cells, double deletion of DGKα and DGKζ results in enhanced cytokine expression and cytotoxicity against tumor cells (Riese et al., 2013). Similar results have been reported for human CAR T cells in which the expression of both DGKα and DGKζ was silenced using CRISPR / Cas9 (Jung et al., 2018). All these studies support the rationale for targeting DGKα / ζ in the development of anticancer therapies (Arranz-Nicolas, J. and Merida, I., 2020. Biological regulation of diacylglycerol kinases in normal and neoplastic tissues: New opportunities for cancer immunotherapy, Advances in Biological Regulation, Volume 10, 2020). 75; Riese, MJ, Moon, EK, Johnson, BD, Albelda, SM, 2016. Diacylglycerol kinases (DGKs): novel targets for improving T cell activity in cancer. Front Cell Dev Biol 4, 108.) Knockout mouse models provide further evidence.Mice lacking either DGKα or DGKζ exhibited a hyperresponsive T cell phenotype and improved antitumor immune activity (Riese, MJ, Grewal, J., Das, J., Zou, T., Patil, V., Chakraborty, AK, Koretzky, GA, 2011. Decreased diacylglycerol metabolism enhances ERK activation and augments CD8+ T cell functional responses. J. Biol. Chem. 286(7), 5254-5265; Zha, Y., Marks, R., Ho, AW, Peterson, AC, Janardhan, S., Brown, I., Praveen, K., Stang, S., Stone, JC, Gajewski, TF, 2006. T cell energy is reversed by active Ras and is regulated by diacylglycerol kinase-alpha.Nat.Immunol.7(11),1166-1173;Olenchock,BA,Guo,R.,Carpenter,JH,Jordan,M.,Topham,MK,Koretzky,GA,Zhong,XP,2006a.Disruption of diacylglycerol metabolism impairs the induction of T cell energy.Nat.Immunol.7(11),1174-1181.).

[0008] Taken together, there is substantial evidence that DGKα and DGKζ are high-value targets for cancer immunotherapy. At the same time, there is a lack of compounds capable of potently inhibiting both DGKα and DGKζ with good selectivity over other diacylglycerol kinases, protein kinases, and / or other lipid kinases.

[0009] The present invention describes such dual DGK α / ζ inhibitors with superior selectivity over other protein kinases across a safety / off-target panel and other lipid kinases. These compounds potently activate suboptimally stimulated T cells, thereby acting as intracellular enhancers of the costimulatory signaling cascade. These DGK α / ζ inhibitors have the potential to increase the proliferation, cytotoxicity, and longevity of targeted T cells, which may result in improved anti-cancer activity of CPI, CD3-engaged T cell bispecific, and CAR T cells. Furthermore, by engaging signaling nodes central to both the TCR and costimulatory receptors, it is plausible that these molecules could enhance both signals 1 and 2, thus achieving single-agent activity, for example, in inflammatory tumors.

[0010] There remains a need for novel compounds that can activate and expand T cells, thus enabling the treatment, prevention and / or delay of cancer progression.

[0011] It is therefore an object of the present invention to provide compounds useful as DGK α / ζ inhibitors for the treatment or prevention or amelioration of such diseases, which have improved therapeutic properties, in particular improved pharmacokinetic properties. Summary of the Invention

[0012] A first object of the present invention is to provide a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is an oxadiazole, and R 1 is one or more R, which may be the same or different 10 may be substituted with R 2 is selected from hydrogen and halogen; R 4 is C 5~14-aryl and 5- to 14-membered heteroaryl; R 4 is one or more R, which may be the same or different 11 may be substituted with R 10 teeth, i) one or more of halogen, amino, hydroxy, C 1~6 -C optionally substituted with alkoxy, 3- to 10-membered cycloalkyl, phenyl, or cyano 1~10 - alkyl; ii) C optionally substituted with one or more halogen, cyano, or amino groups 3~10 -cycloalkyl; iii) one or more halogens, C 1~10 -Alkyl, Amino, Halo-C 1~6 -Alkyl, hydroxy, cyano, -C(O)O-(R 10q ), C 3~10 -3-10 membered heterocyclyl optionally substituted by cycloalkyl, 1~10 -Alkyl is one or more hydroxy, C 1~6 -3-10-membered heterocyclyl optionally substituted by alkoxy; iv)-N(R 10e R 10f ), v) one or more C 1~10 -Alkyl, heteroaryl optionally substituted with halogen is selected from R 10e and R 10f However, respectively, i) hydrogen; ii) C optionally substituted with one or more cyano, halogen, or hydroxy groups 1~6 - alkyl; iii) one or more halogens, C 1~10 -C optionally substituted with alkyl 3~10 -cycloalkyl are independently selected from R 10q But C 1~5 -alkyl, C 1~5 - alkyl may be substituted with one or more hydroxy; R 11 teeth, i) one or more C 1~6 -Alkyl, C 3~10 Cycloalkyl, halo-C 1~6 -alkyl, 1~6 -Alkoxy, Halo-C 1~6 -5-6 membered heteroaryl optionally substituted with alkoxy, 3~10 5-6 membered heteroaryl, wherein the cycloalkyl is optionally substituted with one or more halogens; ii) one or more C 1~6 -Alkoxy, -OH, Halo-C 1~6 -phenyl optionally substituted with alkyl or a pharmaceutically acceptable salt thereof.

[0013] A second object of the present invention is a process for the preparation of the compound of formula (I) above or a pharmaceutically acceptable salt thereof, which is represented by formula (IX) [ka] (In the formula, R 1 , R 2 , and R 4 is as defined herein and PG is an amino protecting group) with a suitable deprotecting agent to form said compound of formula (I).

[0014] A third object of the present invention is a pharmaceutical composition comprising a compound of formula (I) above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0015] A fourth object of the present invention is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or delay of progression of cancer.

[0016] 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 to which this invention belongs.

[0017] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below.

[0018] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0019] The nomenclature used in this application is based on IUPAC systematic nomenclature unless otherwise indicated. DETAILED DESCRIPTION OF THE INVENTION

[0020] definition "Alkoxy" refers to an alkyl group, as defined previously, attached to the parent molecular moiety through an oxygen atom. Unless otherwise specified, an alkoxy group contains 1 to 12 carbon atoms ("C 1~12 -alkoxy"), preferably 1 to 10 carbon atoms ("C 1~10 -alkoxy"), more preferably 1 to 6 carbon atoms ("C 1~6 In some preferred embodiments, the alkoxy group contains 1 to 4 carbon atoms. In still other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0021] "Alkoxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by an alkoxy group. Preferably, "alkoxyalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group, most preferably one hydrogen atom, have been replaced by an alkoxy group. Particularly preferred, but non-limiting, examples of alkoxyalkyl are methoxymethyl and 2-methoxyethyl.

[0022] "Alkyl" refers to an alkyl group having a specified number of carbon atoms (i.e., C1 to10 refers to a saturated, straight-chain (i.e., unbranched) or branched monovalent hydrocarbon chain, or combinations thereof. Particular alkyl groups are those having 1 to 20 carbon atoms ("C1 to C10"). 20 alkyl"), those having 1 to 12 carbon atoms ("C1 12 alkyl), those having 1 to 10 carbon atoms ("C1 10 alkyl"), those having 1 to 8 carbon atoms ("C1-8 alkyl"), those having 1 to 6 carbon atoms ("C1-6 alkyl"), those having 2 to 6 carbon atoms ("C2-6 alkyl"), or those having 1 to 4 carbon atoms ("C 1~4 Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl; homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0023] "Alkynyl" refers to an alkyl group having the specified number of carbon atoms (i.e., C 2~10 "C" refers to an unsaturated, linear (i.e., unbranched) or branched monovalent hydrocarbon chain having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C), or combinations thereof. Particular alkynyl groups are those having 2 to 20 carbon atoms ("C 2~20 alkynyl"), those having 2 to 8 carbon atoms ("C 2~8 alkynyl) with 2 to 6 carbon atoms ("C 2~6 alkynyl) with 2 to 4 carbon atoms ("C 2~4 Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof.

[0024] "Amino," alone or in combination with other groups, refers to NH2.

[0025] "Aminoalkyl" refers to an alkyl group in which one or more of the alkyl group's hydrogen atoms has been replaced with an amino moiety.

[0026] "Aromatic" is a well-known term in the literature, especially in the IUPAC Compendium of Chemical Terminology, 2 nd This shows the conventional concept of aromaticity as defined in "Aromaticity in Organic Compounds: A Brief Description of the Invention," Eds. Blackwell Scientific Publications, Oxford (1997).

[0027] "Aryl" means a cyclic aromatic hydrocarbon moiety having a monocyclic, bicyclic, or tricyclic aromatic ring of 5 to 14 carbon ring atoms ("C 5~14 "-aryl" refers to a fused bicycle having two fused 5-membered aryl rings (designated 5-5), a fused bicycle having a 5-membered aryl ring and a fused 6-membered aryl ring (designated 5-6 and 6-5), and a bicycle having two fused 6-membered aryl rings (designated 6-6). The aryl group may be optionally substituted as defined herein. Examples of aryl substituents include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, and the like. The term "aryl" also includes partially hydrogenated derivatives of cyclic aromatic hydrocarbon moieties, provided that at least one ring of the cyclic aromatic hydrocarbon moiety is aromatic and each may be optionally substituted.

[0028] "Cancer" refers to a disease characterized by the presence of a neoplasia or tumor, resulting from the abnormal and uncontrolled growth of cells (such cells are "cancer cells"). As used herein, the term cancer expressly includes, but is not limited to, hepatocellular carcinoma, malignant tumors and hyperproliferative disorders of the colon (colon cancer), lung cancer, breast cancer, prostate cancer, melanoma, and ovarian cancer.

[0029] The term "cyano," alone or in combination with other groups, refers to CN (ie, nitrile).

[0030] "Cyanoalkyl" refers to an alkyl group in which one or more of the alkyl group's hydrogen atoms has been replaced with a cyano moiety.

[0031] "Cycloalkyl" refers to a monocyclic, bicyclic (including bridged bicyclic and cycloalkyl spiro substituents), or tricyclic ring and a saturated or partially unsaturated carbocyclic moiety having 3 to 10 carbon atoms, i.e., (C 10 ) cycloalkyl. The cycloalkyl moiety can be optionally substituted with one or more substituents. In certain embodiments, the cycloalkyl contains 3 to 8 carbon atoms (i.e., (C3-C8)cycloalkyl). In other certain embodiments, the cycloalkyl contains 3 to 6 carbon atoms (i.e., (C3-C6)cycloalkyl). Examples of cycloalkyl substituents include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and their partially unsaturated (cycloalkenyl) derivatives (e.g., cyclopentenyl, cyclohexenyl, and cycloheptenyl), bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptanyl, bicyclo[3.1.1]heptenyl, and bicyclo[1.1.1]pentane. The cycloalkyl moiety can be attached in a "spirocycloalkyl" or "cycloalkylspiro" fashion, such as "spirocyclopropyl." [ka]

[0032] "EC x " refers to the effective concentration of a particular compound, e.g., in culture medium or plasma, required to obtain x% of the maximum of a particular effect in vitro or in vivo. xExamples of " EC ," which indicates the concentration of a particular compound in culture medium or plasma required to obtain 20%, 50%, and 100% of the maximum of a particular effect in vitro or in vivo, respectively. 20 , E.C. 50 and E.C. 100 "Haloalkoxy" refers to an alkoxy group in which at least one halogen replaces each H in the hydrocarbon comprising the alkyl portion of the alkoxy group. Examples of haloalkoxy groups are difluoromethoxy (-OCHF2) and trifluoromethoxy (-OCF3).

[0033] "Haloaryl" refers to an aryl in which at least one hydrogen is replaced with a halogen.

[0034] "Halo" or "halo" refers to fluoro, chloro, bromo, and / or iodo. If a residue is substituted with more than one halogen, it can be referred to using a prefix corresponding to the number of halogen substituents attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl, etc., refer to aryl and alkyl substituted with two ("di") or three ("tri") halogen groups, which may be the same halo, but not necessarily the same halogen. Thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which one or more hydrogens have been replaced with a halogen group is referred to as "haloalkyl," e.g., "C 1~6 A preferred haloalkyl group is trifluoroalkyl (-CF3).

[0035] "Heteroaryl" refers to an aromatic heterocyclic monocyclic, bicyclic, or tricyclic ring system of 5 to 14 ring atoms, preferably 5 to 10 ring atoms, and more preferably 5 to 6 ring atoms, containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. In some embodiments, the monocyclic heteroaryl ring can be 5 to 6-membered. Bicyclic heteroaryl ring systems include fused bicycles having two fused 5-membered heteroaryl rings (designated 5-5), fused bicycles having a 5-membered aryl ring and a fused 6-membered heteroaryl ring (designated 5-6 and 6-5), and bicycles having two fused 6-membered aryl rings (designated 6-6). Heteroaryl groups can be optionally substituted as defined herein. Examples of heteroaryl substituents include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, benzothiophenyl, indolyl, aza-indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, Examples of heteroaryl include benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl and furopyrazinyl. Most preferably, "5-membered heteroaryl" refers to the following groups: [ka]

[0036] "Heterocycle" or "heterocyclyl" refers to a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-membered monocyclic, 7-, 8-, 9-, and 10-membered bicyclic (including bridged bicyclic and cycloalkyl spiro substituents), or 10-, 11-, 12-, 13-, 14-, and 15-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from oxygen, nitrogen, and sulfur within the ring, with the remaining ring atoms being carbon. In some embodiments, a heterocycle is a heterocyclic ring. It is cycloalkyl. In certain embodiments, heterocycle or heterocyclyl refers to a 4-, 5-, 6-, or 7-membered heterocycle. When used in reference to a ring atom of a heterocycle, nitrogen or sulfur may also be in oxidized form, and the nitrogen may be substituted with one or more (C1-C6) alkyl or groups. A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Any of the heterocycle ring atoms may be substituted with one or more substituents described herein. Examples of such saturated or partially unsaturated heterocyclyls include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, pyrrolidine 1-oxide, N-hydroxypiperidine, 1-methylpropanol ... Examples of heterocyclic rings include, but are not limited to, ethyl pyrrolidine N-oxide, diazirinyl, and quinuclidinyl. The term heterocycle also includes groups in which a heterocycle is fused to one or more aryl, heteroaryl, or cycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[3.1.0]hexanyl, azabicyclo[3.1.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.

[0037] "Hydroxy", alone or in combination with other groups, refers to OH.

[0038] "Hydroxyalkyl" refers to an alkyl group in which one or more of the alkyl group's hydrogen atoms has been replaced by a hydroxy moiety. Examples include alcohols and diols.

[0039] "Moiety" and "substituent" refer to an atom or set of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds, thereby forming a part of a molecule.

[0040] When indicating the number of substituents, the term "one or more" refers to a range from one substituent to the highest possible number of substitutions, i.e., from the replacement of one hydrogen to the replacement of all hydrogens by substituents; particularly "one or more" refers to one, two, or three; most particularly "one or more" refers to one or two.

[0041] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "an aryl group optionally substituted with an alkyl group" means that the alkyl may be present but does not have to be present, and that the description includes situations where the aryl group is substituted with an alkyl group and situations where the aryl group is not substituted with an alkyl group.

[0042] "Optionally substituted" is intended to mean unsubstituted or substituted. Generally, the substituents can be the same or different.

[0043] "Oxo", alone or in combination with other groups, refers to =O.

[0044] "Pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the free base or free acid, which are not biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, especially hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like.

[0045] Particularly preferred pharmaceutically acceptable salts of compounds of formula (I) are the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and methanesulfonic acid.

[0046] A "protecting group" (PG) refers to a group that selectively blocks a reactive site in a polyfunctional compound so that a chemical reaction, in the sense conventionally associated with synthetic chemistry, can be carried out selectively at an otherwise unprotected reactive site. The protecting group can be removed at an appropriate time. Exemplary protecting groups are an amino-protecting group, a carboxy-protecting group, or a hydroxy-protecting group. Particular protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Further particular protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). An even more particular protecting group is tert-butoxycarbonyl (Boc). Exemplary protecting groups and their use in organic synthesis are described, for example, in "Protective Groups in Organic Chemistry" by T.W. Greene and P.G.M. Hutts, 5th Ed., 2014, John Wiley & Sons, NY.

[0047] "Prophylaxis," as used herein, includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition that develops in a mammal, particularly in a human suffering from or susceptible to the condition, disorder or condition, but who has not yet experienced or exhibited clinical symptoms or asymptomatic symptoms of the condition, disorder or condition.

[0048] "Substituted" refers to the replacement of at least one of the hydrogen atoms of a compound or moiety with another substituent or moiety. Examples of such substituents include, but are not limited to, halogen, -OH, -CN, oxo, alkoxy, alkyl, alkylene, aryl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl, and heterocycle. For example, the term "haloalkyl" refers to the fact that one or more hydrogen atoms of an alkyl (defined below) have been replaced with one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.). In one aspect, as used herein, substitution can refer to at least one hydrogen atom of a compound or moiety described herein being replaced with a halogen or alkyl.

[0049] A "therapeutically effective amount" refers to the amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder, (ii) reduces, ameliorate, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The therapeutically effective amount may vary depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0050] A "therapeutically inert carrier" refers to any non-toxic ingredient, such as a disintegrant, binder, filler, solvent, buffer, isotonicity agent, stabilizer, antioxidant, surfactant, or lubricant, that has no therapeutic activity and is used in formulating a pharmaceutical product.

[0051] In particular, the chemical groups defined above are those specifically exemplified in the examples.

[0052] The following abbreviations are used herein:

[0053] AIBN = 2,2-azobis(2-methylpropionitrile), BOP = benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, Brine = saturated aqueous NaCl solution, CAS = Chemical Abstracts Registry Number, CDI = 1,1'-carbonyldiimidazole, DBU = 1,8-diazabicyclo[5,4,0]undec-7-ene, DCM = dichloromethane, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DMF = N,N-dimethylformamide difluoromamide, DIPEA = N,N-diisopropylethylamine, EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, ESI = electrospray ionization, EtOAc = ethyl acetate, EtOH = ethanol, h = hour(s), HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, HBTU = O-benzotriazole-N,N,N',N'-tetramethyl- Uronium hexafluorophosphate, HFIP = hexafluoroisopropanol, HOBt = hydroxybenzotriazole, HPLC = high performance liquid chromatography, m-CPBA = meta-chloroperoxybenzoic acid, MeCN = acetonitrile, MeI = methyloid, MeOH = methanol, min = min(s), MS = mass spectrum, NBS = N-bromosuccinimide, PE = petroleum ether, PyBroP = bromo-tris-pyrrolidino-phosphonium hexafluorophosphate RT = room temperature, TBAF = tetrabutylammonium fluoride, TBAOH = tetrabutylammonium hydroxide, TBDMS = tert-butyldimethylsilyl, TEA = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TMSOTF = trifluoromethanesulfonic acid trimethylsilyl ester, TLC = thin layer chromatography, T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide.

[0054] In the description herein, if there is a discrepancy between a depicted structure and the name given to that structure, the depicted structure shall prevail. Furthermore, if the stereochemistry of a structure or portion of a structure is not indicated, for example, with a bold wedge or a dotted line, the structure or portion of the structure is intended to encompass all of its stereoisomers. However, in some cases where multiple chiral centers are present, the structure and name may be represented as a single enantiomer to aid in describing the relative stereochemistry.

[0055] Unless otherwise indicated, "a compound of the formula" or "a compound of formula" or "compounds of the formula" or "compounds of formula" refers to any compound selected from the genus of compounds defined by that formula (including any pharmaceutically acceptable salt of any such compound, unless otherwise specified).

[0056] Certain compounds may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate individual tautomers usually result in mixtures whose chemical and physical properties match those of the compound. The position of the equilibrium depends on the chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, whereas in phenols, the enol form predominates. Common protic tautomers include keto / enol (-C(=O)-CH-⇔-C(-OH)=CH-), amide / imidic acid (-C(=O)-NH-⇔-C(-OH)=N-), and amidine (-C(=NR)-NH-⇔-C(-NHR)=N-) tautomers. The latter two are particularly common in heteroaryl and heterocyclic rings, and the present invention encompasses all tautomeric forms of the compounds.

[0057] Furthermore, the present invention includes all optical isomers of the compounds of formula (I), i.e., diastereoisomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers thereof, and solvates thereof.

[0058] Compounds of Formula (I) may contain one or more asymmetric centers and therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Additional asymmetric centers may be present depending on the nature of the various substituents on the molecule. Each such asymmetric center independently produces two optical isomers, and all possible optical isomers and diastereomers, both as mixtures and as pure or partially purified compounds, are intended to be encompassed by the present invention. The present invention is meant to encompass all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations can be achieved as known in the art by appropriate modification of the methods disclosed herein. Their absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates, which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds can be separated to isolate the individual enantiomers. Resolution can be carried out by methods known in the art, such as coupling a racemic mixture of a compound to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods such as fractional recrystallization or chromatography.

[0059] In embodiments in which optically pure enantiomers are provided, optically pure enantiomer means that the compound contains greater than 90% by weight of the desired isomer, specifically greater than 95% by weight of the desired isomer, or more specifically greater than 99% by weight of the desired isomer, the weight percentages being based on the total weight of the isomer(s) of the compound. Chirally pure or chirally enriched compounds can be prepared by chirally selective synthesis or by separation of enantiomers. Separation of enantiomers can be carried out on the final product or on a suitable intermediate.

[0060] In some embodiments, compounds of formula (I) are isotopically labeled by having one or more atoms therein replaced by atoms having a different atomic mass or mass number. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds of formula (I), for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H and carbon-14, i.e., 14C are particularly useful for this purpose given their ease of incorporation and ready means of detection. For example, compounds of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0061] Heavier isotopes, such as deuterium, i.e. 2 Substitutions such as H may confer greater metabolic stability and may confer certain therapeutic advantages, for example, by increasing in vivo half-life or requiring lower dosages.

[0062] 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the Examples set forth below, substituting appropriate isotopically labeled reagents for previously employed non-isotopically labeled reagents.

[0063] Compounds of the Invention In one embodiment, a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is an oxadiazole, and R 1 is one or more R, which may be the same or different 10 may be substituted with R 2 is selected from hydrogen and halogen; R 4 is C 5~14 -aryl and 5- to 14-membered heteroaryl; R 4 is one or more R, which may be the same or different 11 may be substituted with R 10 teeth, i) one or more of halogen, amino, hydroxy, C 1~6 -C optionally substituted with alkoxy, 3- to 10-membered cycloalkyl, phenyl, or cyano 1~10 - alkyl; ii) C optionally substituted with one or more halogen, cyano, or amino groups 3~10 -cycloalkyl; iii) one or more halogens, C 1~10 -Alkyl, Amino, Halo-C 1~6 -Alkyl, hydroxy, cyano, -C(O)O-(R 10q ), C 3~10 -3-10 membered heterocyclyl optionally substituted by cycloalkyl, 1~10 -Alkyl is one or more hydroxy, C 1~6 -3-10-membered heterocyclyl optionally substituted by alkoxy; iv)-N(R 10e R 10f ), v) one or more C 1~10 -Alkyl, heteroaryl optionally substituted with halogen is selected from R 10e and R 10f However, respectively, i) hydrogen; ii) C optionally substituted with one or more cyano, halogen, or hydroxy groups 1~6 - alkyl; iii) one or more halogens, C 1~10 -C optionally substituted with alkyl 3~10 -cycloalkyl are independently selected from R 10q But C 1~5 -alkyl, C 1~5 - alkyl may be substituted with one or more hydroxy; R 11 teeth, i) one or more C 1~6 -Alkyl, C 3~10 Cycloalkyl, halo-C1~6 -alkyl, 1~6 -Alkoxy, Halo-C 1~6 -5-6 membered heteroaryl optionally substituted with alkoxy, 3~10 5-6 membered heteroaryl, wherein the cycloalkyl is optionally substituted with one or more halogens; ii) one or more C 1~6 -Alkoxy, -OH, Halo-C 1~6 -phenyl optionally substituted with alkyl The present invention provides a compound of formula (I) selected from: In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 11 teeth, iv) one or more C 1~6 -Alkyl, C 3~10 Cycloalkyl, halo-C 1~6 -5-6-membered heteroaryl optionally substituted with alkyl; v) one or more C 1~6 -Alkoxy, Halo-C 1~6 -Alkyl, Halo-C 1~6 -phenyl optionally substituted with alkoxy is selected from.

[0064] In another embodiment, R 2 is selected from hydrogen and fluorine.

[0065] In another embodiment, R 4 is selected from phenyl and pyridinyl, and R 4 is one or more R, which may be the same or different 11

[0013] Provided are compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, optionally substituted with:

[0066] In another embodiment, R 10but tert-butyl, pyrrolidinyl, tetrafluoro-methoxy-ethyl, methyl-propanenitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, aminocyclohexyl, cyclopropanecarbonitrile, difluoro-piperidyl, ethoxy-tetrafluoro-ethyl, (hydroxymethyl)tetrahydrofuranyl, azabicyclo[3.1.1]heptane-methylcarboxylate, amino-trifluoromethyl-ethyl, difluoro-piperidine-methylcarboxylate, fluoro-methyl-piperidyl, aminooxetanyl, (difluoro-methyl-cyclobutyl)aminoyl, cyclopropyltetrahydrofuranyl, amino-dimethyl-propyl, propanenitrile, isopropylaminoyl, fluoro-methyl-pyridyl, methyl-pyridyl, chloro-pyridyl, tetrafluoroethyl, trifluoro-dihydroxy-ethyl, hydroxy-(trifluoromethyl)propyl, pentafluoroethyl, trifluoro-dimethyl-ethyl, trifluoro Oro-phenyl-ethyl, benzyl-trifluoroethyl, (trifluoromethyl)oxetanyl, trifluoro(hydroxymethyl)ethyl, amino-cyclopropyl-trifluoro-ethyl, trifluoro-hydroxy-methyl-ethyl, trifluoroethyl, morpholino, hexahydro-2H-pyrano[4,3-b]pyrrolyl, hexahydro-2H-cyclopenta[b][1,4]oxazinyl, dioxazabicyclo[3.3.1]nonanyl, morpholinyl-carbonitrile, (methoxymethyl)morpholinyl yl, (hydroxymethyl)morpholinyl, (hydroxyethyl)morpholinyl, oxazepanyl, difluoro-(methoxyethyl)-piperidyl, aminocyclohexyl, amino-trifluoro-methyl-ethyl, methyloxetanyl, trifluoro-hydroxy-(trifluoromethyl)ethyl, (trifluoromethyl)oxetan-3-yl, trifluoro-(hydroxymethyl)ethyl, amino-trifluoro-methyl-ethyl, hexahydrofuro[3,2-b]pyrrolyl, difluoro-azabicyclo[4.1.

[0010] Heptanyl, hexahydrofuro[2,3-b][1,4]oxazinyl, hexahydro-2H-cyclopenta[b][1,4]oxazinyl, hexahydro-2H-pyrano[4,3-b][1,4]oxazinyl, hexahydro-2H-cyclopenta[b][1,4]oxazinyl, oxa-azabicyclo[3.2.1]octanyl, cyclopropyl-difluoro-tetrahydrofuranyl, difluorocyclohexyl, amino-trifluoro-ethyl, difluoroethyl(hydroxyethyl)amino, difluoroethyl-aminoyl-acetonitrile, cyclopropyl(difluoroethyl)amino, difluoropyrrolidinyl, (trifluoro-methyl-ethyl)amino, trifluoroethylamino, methyl(trifluoroethyl)amino, ethyl-difluoro-piperidyl, dimethyl-pyridyl, trifluoro-methoxy-ethyl.

[0067] In another embodiment, R 10 is tert-butyl, tetrafluoro-methoxy-ethyl, methyl-propanenitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, cyclopropanecarbonitrile, difluoro-piperidyl, (hydroxymethyl)tetrahydrofuranyl, amino-trifluoromethyl-ethyl, aminooxetanyl, cyclopropyltetrahydrofuranyl, propanenitrile, aminocyclohexyl, or a pharmaceutically acceptable salt thereof.

[0068] In another embodiment, R 11is selected from (hydroxymethyl)phenyl, (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridyl, (trifluoromethyl)phenyl, methoxyphenyl, (trifluoromethyl)pyridyl, dimethylpyrazolyl, tert-butyl-oxadiazolyl, methyl-oxadiazolyl, methylpyrazolyl, (difluoromethyl)-oxadiazolyl, (trifluoromethyl)oxazolyl, methyl-(trifluoromethyl)pyrazolyl, (trifluoromethyl)pyrazolyl, (trifluoromethyl)isoxazolyl, (trifluoromethyl-ethyl)oxadiazolyl, (trifluoroethyl)oxadiazolyl, (trifluoromethoxy)phenyl, cyclopropyl-triazolyl, (trifluoromethoxy)pyridyl, (trifluoromethoxy)pyrimidinyl, (pentafluoroethoxy)pyridyl, (trifluoromethoxy), pyridyl, methyl-(trifluoromethoxy)pyrazolyl, or a pharmaceutically acceptable salt thereof.

[0069] In another embodiment, R 11 is selected from (hydroxymethyl)phenyl, (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridyl, (trifluoromethyl)phenyl, methoxyphenyl, (trifluoromethyl)pyridyl, dimethylpyrazolyl, tert-butyl-oxadiazolyl, methyl-oxadiazolyl, methylpyrazolyl, (difluoromethyl)-oxadiazolyl, (trifluoromethyl)oxazolyl, methyl-(trifluoromethyl)pyrazolyl, (trifluoromethyl)pyrazolyl, (trifluoromethyl)isoxazolyl, (trifluoromethyl-ethyl)oxadiazolyl, (trifluoroethyl)oxadiazolyl, (trifluoromethoxy)phenyl, cyclopropyl-triazolyl.

[0070] In another embodiment, R 11is selected from (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridyl, methoxyphenyl, (trifluoromethoxy)pyridyl, (trifluoromethoxy)pyrimidinyl, (pentafluoroethoxy)pyridyl, (trifluoromethoxy), pyridyl, methyl-(trifluoromethoxy)pyrazolyl, or a pharmaceutically acceptable salt thereof.

[0071] In another embodiment, R 11 is selected from (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridyl, methoxyphenyl, or a pharmaceutically acceptable salt thereof.

[0072] In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is an oxadiazole, and R 1 is one or more R 10 may be substituted with R 2 is selected from hydrogen and fluorine; R 4 is selected from phenyl and pyridinyl, and R 4 is one or more R 11 may be substituted with R 10 teeth, i) one or more of halogen, amino, hydroxy, C 1~6 -C optionally substituted with alkoxy, 3- to 10-membered cycloalkyl, phenyl, or cyano 1~10 - alkyl; ii) C optionally substituted with one or more halogen, cyano, or amino groups 3~10 -cycloalkyl; iii) one or more halogens, C 1~10 -Alkyl, Amino, Halo-C 1~6-Alkyl, hydroxy, cyano, -C(O)O-(R 10q ), C 3~10 -3-10 membered heterocyclyl optionally substituted by cycloalkyl, 1~10 -Alkyl is one or more hydroxy, C 1~6 -3-10-membered heterocyclyl optionally substituted by alkoxy; iv)-N(R 10e R 10f ), v) one or more C 1~10 -Alkyl, heteroaryl optionally substituted with halogen is selected from R 10e and R 10f are, respectively, i) hydrogen; ii) C optionally substituted with one or more cyano, halogen, or hydroxy groups 1~6 - alkyl; iii) one or more halogens, C 1~10 -C optionally substituted with alkyl 3~10 -cycloalkyl are independently selected from R 10q is C 1~5 -alkyl, C 1~5 - alkyl may be substituted with one or more hydroxy; R 11 teeth, iv) one or more C 1~6 -Alkyl, C 3~10 Cycloalkyl, halo-C 1~6 -5-6-membered heteroaryl optionally substituted with alkyl; v) one or more C 1~6 -Alkoxy, Halo-C 1~6 -Alkyl, Halo-C 1~6 -phenyl optionally substituted with alkoxy is selected from.

[0073] In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R1 is an oxadiazole, and R 1 is one or more R 10 may be substituted with R 2 is selected from hydrogen and fluorine; R 4 is selected from phenyl and pyridinyl, and R 4 is one or more R 11 may be substituted with R 10are tert-butyl, pyrrolidinyl, tetrafluoro-methoxy-ethyl, methyl-propanenitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, aminocyclohexyl, cyclopropanecarbonitrile, difluoro-piperidyl, ethoxy-tetrafluoro-ethyl, (hydroxymethyl)tetrahydrofuranyl, azabicyclo[3.1.1]heptane-methylcarboxylate, amino-trifluoromethyl-ethyl, difluoro-piperidine-methylcarboxylate, fluoro-methyl-piperidyl, aminooxetanyl, (difluoro-methyl-cyclobutyl)aminoyl, cyclopropyltetrahydrofuranyl, amino-dimethyl-propyl, propanenitrile, isopropylaminoyl, fluoro-methyl-pyridyl, methyl-pyridyl, chloro-pyridyl, tetrafluoroethyl, trifluoro-dihydroxy-ethyl, hydroxy-(trifluoromethyl)propyl, pentafluoroethyl, trifluoro-dimethyl-ethyl, trifluoro Oro-phenyl-ethyl, benzyl-trifluoroethyl, (trifluoromethyl)oxetanyl, trifluoro(hydroxymethyl)ethyl, amino-cyclopropyl-trifluoro-ethyl, trifluoro-hydroxy-methyl-ethyl, trifluoroethyl, morpholino, hexahydro-2H-pyrano[4,3-b]pyrrolyl, hexahydro-2H-cyclopenta[b][1,4]oxazinyl, dioxazabicyclo[3.3.1]nonanyl, morpholinyl-carbonitrile, (methoxymethyl)morpholinyl yl, (hydroxymethyl)morpholinyl, (hydroxyethyl)morpholinyl, oxazepanyl, difluoro-(methoxyethyl)-piperidyl, aminocyclohexyl, amino-trifluoro-methyl-ethyl, methyloxetanyl, trifluoro-hydroxy-(trifluoromethyl)ethyl, (trifluoromethyl)oxetan-3-yl, trifluoro-(hydroxymethyl)ethyl, amino-trifluoro-methyl-ethyl, hexahydrofuro[3,2-b]pyrrolyl, difluoro-azabicyclo[4.1.0]heptanyl, hexahydrofuro[2,3-b][1,4]oxazinyl, hexahydro-2H-cyclopenta[b][1,4]oxazinyl, hexahydro-2H-pyrano[4,3-b][1,4]oxazinyl, hexahydro-2H-cyclopenta[b][1,4]oxazinyl, oxa-azabicyclo[3.2.1]octanyl, cyclopropyl-difluoro-tetrahydrofuranyl, difluorocyclohexyl, amino-trifluoro-ethyl, difluoroethyl(hydroxyethyl)amino, difluoroethyl-aminoyl-acetonitrile, cyclopropyl(difluoroethyl)amino, difluoropyrrolidinyl, (trifluoro-methyl-ethyl)amino, trifluoroethylamino, methyl(trifluoroethyl)amino, ethyl-difluoro-piperidyl, dimethyl-pyridyl, trifluoro-methoxy-ethyl. R 11 is selected from (hydroxymethyl)phenyl, (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridyl, (trifluoromethyl)phenyl, methoxyphenyl, (trifluoromethyl)pyridyl, dimethylpyrazolyl, tert-butyl-oxadiazolyl, methyl-oxadiazolyl, methylpyrazolyl, (difluoromethyl)-oxadiazolyl, (trifluoromethyl)oxazolyl, methyl-(trifluoromethyl)pyrazolyl, (trifluoromethyl)pyrazolyl, (trifluoromethyl)isoxazolyl, (trifluoromethyl-ethyl)oxadiazolyl, (trifluoroethyl)oxadiazolyl, (trifluoromethoxy)phenyl, cyclopropyl-triazolyl.

[0074] In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is an oxadiazole, and R 1 is one or more R 10 may be substituted with R 2 is selected from hydrogen and fluorine; R4 is selected from phenyl and pyridinyl, and R 4 is one or more R 11 may be substituted with R 10 is tert-butyl, tetrafluoro-methoxy-ethyl, methyl-propanenitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, cyclopropanecarbonitrile, difluoro-piperidyl, (hydroxymethyl)tetrahydrofuranyl, amino-trifluoromethyl-ethyl, aminooxetanyl, cyclopropyltetrahydrofuranyl, propanenitrile, aminocyclohexyl; R 11 is selected from (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridyl, methoxyphenyl. In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is an oxadiazole, and R 1 is one or more R 10 may be substituted with R 2 is selected from hydrogen and fluorine; R 4 is selected from phenyl and pyridinyl, and R 4 is one or more R 11 may be substituted with R 10are tert-butyl, pyrrolidinyl, tetrafluoro-methoxy-ethyl, methyl-propanenitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, aminocyclohexyl, cyclopropanecarbonitrile, difluoro-piperidyl, ethoxy-tetrafluoro-ethyl, (hydroxymethyl)tetrahydrofuranyl, azabicyclo[3.1.1]heptane-methylcarboxylate, amino-trifluoromethyl-ethyl, difluoro-piperidine-methylcarboxylate, fluoro-methyl-piperidyl, aminooxetanyl, (difluoro-methyl-cyclobutyl)aminoyl, cyclopropyltetrahydrofuranyl, amino-dimethyl-propyl, propanenitrile, isopropylaminoyl, fluoro-methyl-pyridyl, methyl-pyridyl, chloro-pyridyl, tetrafluoroethyl, trifluoro-dihydroxy-ethyl, hydroxy-(trifluoromethyl)propyl, pentafluoroethyl, trifluoro-dimethyl-ethyl, trifluoro Oro-phenyl-ethyl, benzyl-trifluoroethyl, (trifluoromethyl)oxetanyl, trifluoro(hydroxymethyl)ethyl, amino-cyclopropyl-trifluoro-ethyl, trifluoro-hydroxy-methyl-ethyl, trifluoroethyl, morpholino, hexahydro-2H-pyrano[4,3-b]pyrrolyl, hexahydro-2H-cyclopenta[b][1,4]oxazinyl, dioxazabicyclo[3.3.1]nonanyl, morpholinyl-carbonitrile, (methoxymethyl)morpholinyl yl, (hydroxymethyl)morpholinyl, (hydroxyethyl)morpholinyl, oxazepanyl, difluoro-(methoxyethyl)-piperidyl, aminocyclohexyl, amino-trifluoro-methyl-ethyl, methyloxetanyl, trifluoro-hydroxy-(trifluoromethyl)ethyl, (trifluoromethyl)oxetan-3-yl, trifluoro-(hydroxymethyl)ethyl, amino-trifluoro-methyl-ethyl, hexahydrofuro[3,2-b]pyrrolyl, difluoro-azabicyclo[4.1.0]heptanyl, hexahydrofuro[2,3-b][1,4]oxazinyl, hexahydro-2H-cyclopenta[b][1,4]oxazinyl, hexahydro-2H-pyrano[4,3-b][1,4]oxazinyl, hexahydro-2H-cyclopenta[b][1,4]oxazinyl, oxa-azabicyclo[3.2.1]octanyl, cyclopropyl-difluoro-tetrahydrofuranyl, difluorocyclohexyl, amino-trifluoro-ethyl, difluoroethyl(hydroxyethyl)amino, difluoroethyl-aminoyl-acetonitrile, cyclopropyl(difluoroethyl)amino, difluoropyrrolidinyl, (trifluoro-methyl-ethyl)amino, trifluoroethylamino, methyl(trifluoroethyl)amino, ethyl-difluoro-piperidyl, dimethyl-pyridyl, trifluoro-methoxy-ethyl. R 11 is selected from (hydroxymethyl)phenyl, (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridyl, (trifluoromethyl)phenyl, methoxyphenyl, (trifluoromethyl)pyridyl, dimethylpyrazolyl, tert-butyl-oxadiazolyl, methyl-oxadiazolyl, methylpyrazolyl, (difluoromethyl)-oxadiazolyl, (trifluoromethyl)oxazolyl, methyl-(trifluoromethyl)pyrazolyl, (trifluoromethyl)pyrazolyl, (trifluoromethyl)isoxazolyl, (trifluoromethyl-ethyl)oxadiazolyl, (trifluoroethyl)oxadiazolyl, (trifluoromethoxy)phenyl, cyclopropyl-triazolyl, (trifluoromethoxy)pyridyl, (trifluoromethoxy)pyrimidinyl, (pentafluoroethoxy)pyridyl, (trifluoromethoxy), pyridyl, methyl-(trifluoromethoxy)pyrazolyl.

[0075] In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is an oxadiazole, and R 1is one or more R 10 may be substituted with R 2 is selected from hydrogen and fluorine; R 4 is selected from phenyl and pyridinyl, and R 4 is one or more R 11 may be substituted with R 10 is tert-butyl, tetrafluoro-methoxy-ethyl, methyl-propanenitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, cyclopropanecarbonitrile, difluoro-piperidyl, (hydroxymethyl)tetrahydrofuranyl, amino-trifluoromethyl-ethyl, aminooxetanyl, cyclopropyltetrahydrofuranyl, propanenitrile, aminocyclohexyl; R 11 is selected from (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridyl, methoxyphenyl, (trifluoromethoxy)pyridyl, (trifluoromethoxy)pyrimidinyl, (pentafluoroethoxy)pyridyl, (trifluoromethoxy), pyridyl, methyl-(trifluoromethoxy)pyrazolyl.

[0076] In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from:

[0077] (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-[[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-7-[5-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-8-fluoro-7-[5-(isopropylamino)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-[[6-[4-(hydroxymethyl)phenyl]-3-pyridyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-aminooxetan-3-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-aminooxetan-3-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-aminooxetan-3-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2,2-difluoromorpholin-4-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2,2-difluoromorpholin-4-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-8-fluoro-1,1-dioxo-7-(5-pyrrolidin-1-yl-1,2,4-oxadiazol-3-yl)-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 1-[3-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile 1-[3-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(5-tert-butyl-1,3,4-oxadiazol-2-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(3,5-dimethylpyrazol-1-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[4-(trifluoromethyl)imidazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[5-(trifluoromethyl)isoxazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[3-(trifluoromethyl)isoxazol-5-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[4-(trifluoromethyl)oxazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[5-(trifluoromethyl)oxazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-amino-2,2,2-trifluoro-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-amino-2,2,2-trifluoro-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-amino-2,2,2-trifluoro-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-7-[5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2-cyclopropyltetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one(*) (3R)-3-amino-7-[5-(1-amino-2,2-dimethyl-propyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]propanenitrile (3R)-3-amino-7-[5-(2-cyclopropyltetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-5-[[4-[5-(difluoromethyl)-2-pyridyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(3,3-difluorocyclopentyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(2,2,2-trifluoro-1-methyl-ethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-[5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-[5-(4,4-difluoro-1-piperidyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)oxazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile(*) 2-[5-[(3R)-3-amino-5-[[4-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-[5-(difluoromethoxy)-2-pyridyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-[5-(1,1-difluoroethyl)-2-pyridyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-[4-(difluoromethoxy)-2-pyridyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[2-(trifluoromethyl)-4-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)pyrazin-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[6-(trifluoromethyl)-3-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-[6-methyl-5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[1-(trifluoromethyl)pyrazol-4-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)pyrimidin-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-(5-cyclopropyl-2-pyridyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethoxy)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)oxazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-(5-methoxy-2-pyridyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)pyrimidin-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(1,1,2,2,2-pentafluoroethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[6-(trifluoromethoxy)-3-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-[4-methyl-5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)triazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-[2-methyl-5-(trifluoromethoxy)pyrazol-3-yl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-Amino-7-[5-(2-methyloxetan-2-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1lambda 6,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-methyloxetan-3-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-methyloxetan-3-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-amino-2,2,2-trifluoro-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-7-[5-[3-(difluoromethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-fluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-fluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-fluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(1S)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one Methyl 3,3-difluoro-5-[5-[(3R)-3-amino-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate Methyl 3,3-difluoro-5-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate Methyl 1-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]cyclopropanecarbonitrile Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (3R)-3-Amino-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-ethoxy-1,2,2,2-tetrafluoro-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one ((3R)-3-amino-5-[[4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl]methyl]-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(1-cyclopropyl-1,2,4-triazol-3-yl)phenyl]methyl]-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6 ,5-benzothiazepin-4-one (3R)-3-amino-5-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 4-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]morpholine-2-carbonitrile (3R)-3-amino-7-[5-[2-(methoxymethyl)morpholin-4-yl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-1,1-dioxo-7-[5-[2-(trifluoromethyl)morpholin-4-yl]-1,3,4-oxadiazol-2-yl]-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-1,1-dioxo-7-[5-[2-(trifluoromethyl)morpholin-4-yl]-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-1,1-dioxo-7-[5-[2-(trifluoromethyl)morpholin-4-yl]-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-[methyl(2,2,2-trifluoroethyl)amino]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-5-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(6-methoxy-3-pyridyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1-dioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoroethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1-dioxo-7-[5-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-amino-1-cyclopropyl-2,2,2-trifluoro-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]cyclobutanecarbonitrile 4-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]tetrahydropyran-4-carbonitrile 3-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2,2-dimethyl-propanenitrile 3-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-methyl-butanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-ethyl-butanenitrile 3-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]tetrahydrofuran-3-carbonitrile (3R)-3-amino-7-[5-(1-amino-4,4-difluoro-cyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-amino-3,3-difluoro-cyclobutyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 4-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-1-methyl-piperidine-4-carbonitrile (3R)-3-amino-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-7-[5-[5,5-difluoro-1-(2-methoxyethyl)-3-piperidyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-[5,5-difluoro-1-(2-methoxyethyl)-3-piperidyl]-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-aminooxetan-3-yl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1lambda 6,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2-chloro-3-pyridyl)-1,2,4-oxadiazol-3-yl]-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-(6-fluoro-2-methyl-3-pyridyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1-dioxo-7-[5-[2-(trifluoromethyl)-3-pyridyl]-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one

[0078] In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from:

[0079] (3R)-3-Amino-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-aminooxetan-3-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 1-[3-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile 1-[3-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile (3R)-3-amino-8-fluoro-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-amino-2,2,2-trifluoro-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]propanenitrile (3R)-3-amino-7-[5-(2-cyclopropyltetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(1S)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one Methyl 1-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (3R)-3-amino-7-[5-(1-ethoxy-1,2,2,2-tetrafluoro-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-1,1-dioxo-7-[5-[2-(trifluoromethyl)morpholin-4-yl]-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-[methyl(2,2,2-trifluoroethyl)amino]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-Amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)pyrimidin-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(1,1,2,2,2-pentafluoroethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-ethyl-butanenitrile 2-[5-[(3R)-3-amino-5-[[4-[2-methyl-5-(trifluoromethoxy)pyrazol-3-yl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile.

[0080] In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from:

[0081] (3R)-3-Amino-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 1-[3-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile 1-[3-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2-cyclopropyltetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-Amino-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one Methyl 1-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (3R)-3-amino-7-[5-(1-ethoxy-1,2,2,2-tetrafluoro-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-Amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)pyrimidin-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(1,1,2,2,2-pentafluoroethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-ethyl-butanenitrile 2-[5-[(3R)-3-amino-5-[[4-[2-methyl-5-(trifluoromethoxy)pyrazol-3-yl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile

[0082] In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from:

[0083] (3R)-3-amino-7-[5-(2-cyclopropyltetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-7-[5-(1-ethoxy-1,2,2,2-tetrafluoro-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6,5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(1,1,2,2,2-pentafluoroethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-ethyl-butanenitrile 2-[5-[(3R)-3-amino-5-[[4-[2-methyl-5-(trifluoromethoxy)pyrazol-3-yl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile.

[0084] Manufacturing Process Processes for the preparation of compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, are also an object of the present invention.

[0085] The present invention provides a process for the preparation of a compound of formula (I) above or a pharmaceutically acceptable salt thereof, comprising the steps of: [ka] (In the formula, R 1 , R 2 , and R 4 is as defined herein and PG is an amino protecting group) with a suitable deprotecting agent to form said compound of formula (I).

[0086] The preparation of the compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following process descriptions have the meanings given herein unless indicated to the contrary.

[0087] If one of the starting materials, intermediates, or compounds of formula (I) contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, suitable protecting groups (such as those described in "Protective Groups in Organic Chemistry," by T.W. Greene and P.G.M. Hutts, 5th Edition, 2014, John Wiley & Sons, NY) can be introduced prior to a critical step by applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0088] When the starting material or intermediate contains a stereocenter, the compound of formula (I) can be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as chiral HPLC, chiral SFC, or chiral crystallization. Racemates can be separated into their antipodes via diastereomeric salts, for example, by crystallization with an optically pure acid, or by separating the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. Starting materials and intermediates containing a stereocenter can also be separated to obtain diastereomerically / enantiomerically enriched starting materials and intermediates. The use of such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of the compound of formula (I) generally results in the respective diastereomerically / enantiomerically enriched compounds of formula (I).

[0089] Those skilled in the art will recognize that in the synthesis of compounds of formula (I), unless otherwise desired, an "orthogonal protecting group strategy" can be applied to cleave some protecting groups one at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has been described in the literature (e.g., Barany and R.B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0090] Those skilled in the art will recognize that the reaction sequence may vary depending on the reactivity and nature of the intermediates.

[0091] More specifically, compounds of formula (I) can be prepared by the methods described below, the methods described in the Examples, or similar methods. Suitable reaction conditions for the individual reaction steps are known to those skilled in the art. For literature-described reaction conditions affecting the described reactions, see, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock, John Wiley & Sons, New York, NY, 1999. The reactions could be easily carried out with or without a solvent. There are no particular restrictions on the nature of the solvent used, so long as it does not adversely affect the reaction or the reagents involved and is capable of dissolving the reagents to at least some extent. The described reactions can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. It is convenient to carry out the described reactions at temperatures ranging from -78°C to reflux. The reaction time required for the reaction can also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain the intermediates and compounds described. The reaction sequence is not limited to the sequence shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities.

[0092] If the starting materials or intermediates are not commercially available or their synthesis is not described in the literature, they can be prepared analogously to existing procedures for similar analogs or as outlined in the experimental section.

[0093] The present compounds of formula (I) or pharmaceutically acceptable salts thereof may be prepared by the process described below (Scheme 1), together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations familiar to those skilled in the art. [ka]

[0094] Suitable starting materials for the preparation of compounds of formula (I) are compounds of formula (II) 2 is F or Cl, and X 1 is already R 1 or later R 1 The nitro compound of formula (II) is a nitro compound of formula (IV) (wherein the nitro group is a group such as Br, CN, or -CO alkyl, which can be synthesized in the following manner: Compounds of formula (II) can be reacted with an appropriately protected cysteine derivative (III) in a solvent such as 1,2-dichloroethane in the presence of a base such as DIPEA at elevated temperature to give compounds of formula (IV). A preferred protecting group (PG) for cysteine derivatives (III) is Boc. The nitro group in compounds of formula (IV) can be reduced using iron in the presence of either hydrogen chloride or ammonium chloride in a solvent mixture of water and ethanol at elevated temperature to give compounds of formula (V). Alternatively, this conversion can be achieved by catalytic hydrogenation. Compounds of formula (V) can be cyclized to compounds of formula (VI) using standard amide coupling conditions. Preferably, this cyclization is carried out using 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in EtOAc) and a base such as DIPEA in a solvent such as DMF at room temperature. A compound of formula (VI) and Y 1 is Cl, Br, I or a sulfonate group in the presence of a base such as potassium carbonate, optionally with an additive such as potassium iodide, in a solvent such as DMSO or DMF at room temperature to give a compound of formula (VIII). Alternatively, a compound of formula (VI) can be reacted with a compound of formula (VII) in which Y is Cl, Br, I or a sulfonate group in a solvent such as toluene at elevated temperature to give a compound of formula (VIII). 1 The compound of formula (VIII) can be obtained by reacting the compound of formula (VII) in which X is OH with an additive such as DIAD in the presence of PPh3. 1 In the case of compounds of formula (VIII) where is Br, CN or -CO2 alkyl, these groups can be converted at this stage into the substituent R 1The compound of formula (VIII) can then be converted to a compound of formula (IX) by reaction with an appropriate amount of an oxidizing agent such as m-CPBA in a solvent such as DCM at room temperature. Final deprotection provides a compound of formula (I). When the N-protecting group (PG) is Boc, typical conditions for this deprotection step include TFA in a solvent such as DCM or hexafluoroisopropanol at room temperature, hydrogen chloride in a solvent such as dioxane, diethyl ether or ethyl acetate at room temperature, or hexafluoroisopropanol at reflux temperature. Additionally, the substituent R 1 and R 4 may contain functional groups that may be modified before removal of the N-protecting group (PG) or that require the use of appropriate protecting groups during synthesis. These protecting groups may be removed before removal of the N-protecting group (PG) or may be removed simultaneously using appropriate methods [Peter G.M.Wuts, Greene's Protective Groups in Organic Synthesis, 5th Edition, Hoboken, NJ: Wiley-Interscience].

[0095] Alternatively, compounds of formula (I) can be prepared as shown in Scheme 2. [ka]

[0096] Compounds of formula (VI) can be converted to compounds of formula (X) upon reaction with an oxidizing agent such as m-CPBA in a solvent such as DCM at room temperature. The reaction of compounds of formula (X) with compounds of formula (VII) to give compounds of formula (XI) and their subsequent conversion to compounds of formula (I) can be achieved using the reaction conditions described for the similar steps in Scheme 1. 1 is Br, CN or -CO2 alkyl, these groups can be replaced by substituent R at any stage of the synthesis (for compounds of formula (VI), (X) or (XI)) using the methods described for the following schemes: 1 can be synthesized into

[0097] 5-membered heteroaryl R 1 Compounds of formula (I) where is a 1,3,4-oxadiazolyl group may be prepared as shown in Scheme 3. [ka]

[0098] X 1 Compounds of formula (VIII), where is COMe, can be converted to compounds of formula (XII) by reaction with an alkali hydroxide, such as LiOH, NaOH, or KOH, in a mixture of solvents, such as MeOH, THF, and water, at room temperature. Compounds of formula (XII) can be reacted with hydrazine hydrate, after activation with a suitable reagent, such as CDI, in a solvent, such as THF, at room temperature, to give compounds of formula (XIII). Compounds of formula (XIII) can be converted to carboxylic acids R using standard amide coupling conditions, such as HATU, in the presence of a base, such as DIPEA, in a solvent, such as THF, at room temperature. 10 The coupling product of formula (XIV) can be cyclized to a compound of formula (XV) using a dehydrating reagent such as Burgess's reagent, or can be reacted with tosyl chloride at room temperature in the presence of a base such as DIPEA. The conversion of a compound of formula (XV) to a compound of formula (XVI) and then to a compound of formula (I) can be achieved using the reaction conditions described for the similar steps in Scheme 1.

[0099] 5-membered heteroaryl R 1 is a 1,3,4-oxadiazolyl group, and R 10 is N(R 10e R 10f Compounds of formula (I), wherein R 1 is 1 or 2, can be prepared as shown in Scheme 4. [ka]

[0100] Compounds of formula (XIII) can be reacted with CDI in THF in the presence of a base such as TEA at room temperature to give compounds of formula (XVII). Compounds of formula (XVII) can be oxidized with an oxidizing agent such as m-CPBA in a solvent such as DCM at room temperature to give compounds of formula (XVIII). Compounds of formula (XVIII) can be oxidized with an amine HN(R) in the presence of DIPEA and BOP or PyBroP in a solvent such as DMF or dioxane at room temperature or elevated temperature to give compounds of formula (XVII). 10e R 10f ) to give the compound of formula (XIX) [Org. Lett., 2008, Vol. 10, 1755-1758]. Cleavage of the N-protecting group (PG) gives the compound of formula (I).

[0101] 5-membered heteroaryl R 1 Compounds of formula (I) where is a 1,2,4-oxadiazolyl group may be prepared as shown in Scheme 5. [ka]

[0102] X 1 Compounds of formula (VIII), where R is CN, can be reacted with hydroxylamine hydrochloride in the presence of a base such as potassium carbonate in a solvent such as ethanol at elevated temperatures to give amide oxime compounds of formula (XX, where R is H). Compounds of formula (XX, where R is H) can be coupled to carboxylic acids R using standard amide coupling conditions such as CDI, HATU or EDCI and HOBt in the presence of a base such as DIPEA in a solvent such as acetonitrile, DMF or THF. 10 The coupling intermediate (XX, where R is —C(O)R) undergoes reaction with COH, which upon heating cyclizes to the corresponding compound of formula (XXI). 10 Alternatively, a coupling intermediate (XX, where R is —C(O)R 10) can be isolated and the cyclization step can be carried out either by heating in a solvent such as toluene or by reaction with TBAOH in a solvent such as THF. Conversion of compounds of formula (XXI) to compounds of formula (XXII) and then to compounds of formula (I) can be achieved using the reaction conditions described for the similar steps in Scheme 1.

[0103] 5-membered heteroaryl R 1 is a 1,2,4-oxadiazolyl group, and R 10 is N(R 10e R 10f Compounds of formula (I), wherein R 1 is methyl, R 2 is methyl, R 3 is methyl, R 4 is methyl, R 5 is methyl, R 6 is methyl, R 7 is methyl, R 8 is methyl, R 9 is methyl, R 10 is methyl, R 11 is methyl, R 12 is methyl, R 13 is methyl, R 14 is methyl, R 15 is methyl, R 16 is methyl, [ka]

[0104] Compounds of formula (XX) can be reacted with CDI in THF in the presence of a base such as TEA at room temperature or elevated temperature to give compounds of formula (XXIII). Compounds of formula (XXIII) can be converted to amines HN(R 10e R 10f The compound of formula (XXIV) can be converted to a compound of formula (XXIV) by reaction with m-CPBA. Oxidation of the compound of formula (XXIV) with an oxidizing agent such as m-CPBA in a solvent such as DCM at room temperature provides a compound of formula (XXV). Cleavage of the N-protecting group (PG) provides a compound of formula (I).

[0105] Alternatively, a five-membered heteroaryl R 1 is a 1,2,4-oxadiazolyl group, and R 4 is N(R 4b R 4c Compounds of formula (I), wherein: may be prepared as shown in Scheme 7. [ka]

[0106] X 1A compound of formula (VIII), wherein is CN, can be reacted with an oxidizing agent such as m-CPBA in a solvent such as DCM at room temperature to provide a compound of formula (XXVI). The compound of formula (XXVI) can be converted to a compound of formula (XXVII) by reaction with hydroxylamine hydrochloride in the presence of a base such as sodium bicarbonate in a solvent such as methanol at elevated temperature. Subsequent conversion of the compound of formula (XXVII) to a compound of formula (I) can be achieved using the reaction conditions described for the similar step in Scheme 6.

[0107] Pharmaceutical Compositions and Administration Another object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt excipient.

[0108] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicines in the form of pharmaceutical preparations.The pharmaceutical preparations can be administered to the body orally (for example, in the form of tablets, coated tablets, sugar-coated tablets, hard and soft gelatin capsules, solutions, emulsions, or suspensions), nasally (for example, in the form of nasal drops), or rectally (for example, in the form of suppositories).However, administration can also be carried out parenterally, such as intramuscularly or intravenously (for example, in the form of injections).Administration can also be carried out topically, for example, transdermally, or in the form of eye drops or ear drops.

[0109] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic carriers for the manufacture of pharmaceutical preparations such as tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injectable solutions or topical preparations, etc. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such carriers for tablets, coated tablets, sugar-coated tablets and hard gelatin capsules, for example.

[0110] Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. However, depending on the nature of the active substance, no carrier is usually required for soft gelatin capsules.

[0111] Suitable carriers for the production of solutions and syrups are, for example, water, alcohols, polyols, saccharose, glucose, invert sugar, vegetable oil and the like.

[0112] Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0113] Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

[0114] Suitable carriers for topical ophthalmic formulations are, for example, cyclodextrin, mannitol, or many other carriers and excipients known in the art.

[0115] Furthermore, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical formulations of the present invention may further contain other therapeutically valuable substances.

[0116] Medicaments comprising compounds of formula (I) or pharmaceutically acceptable salts thereof and therapeutically inactive excipients are also an object of the present invention, as are processes for their preparation, which involve bringing one or more compounds of formula (I) and / or their pharmaceutically acceptable salts, and, if desired, one or more other therapeutically valuable substances, together with one or more pharmaceutically acceptable salt excipients, into a galenical dosage form.

[0117] The dosage can vary within a wide range and, of course, must be adjusted to the individual requirements in each specific case. Generally, for oral administration, a daily dosage of about 0.1 mg to 20 mg / kg body weight, preferably 0.5 mg to 4 mg / kg body weight (e.g., about 300 mg / person), preferably divided into 1 to 3 individual doses, each of which may consist of the same amount, would be appropriate. For topical administration, the formulation may contain 0.001% to 15% by weight of the drug, and the required dose, which may be between 0.1 and 25 mg, may be administered as a single dose per day, a single dose per week, multiple doses (2 to 4 times per day), or multiple doses per week. However, it is clear that, where indicated, the upper or lower limits set forth herein may be exceeded.

[0118] The pharmaceutical composition of the present invention can be prepared as follows. Preparation of Pharmaceutical Compositions Containing Compounds of the Invention [Table 1] Manufacturing Procedure: 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50°C. 3. Pass the granules through suitable grinding equipment. 4. Add ingredient 5, mix for 3 minutes and compress in a suitable press. [Table 2] Manufacturing Procedure: 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into suitable capsules. [Table 3] Manufacturing Procedure: A portion of a compound of formula (I) is dissolved in a mixture of polyethylene glycol 400 and water for injection. The pH is adjusted to 5.0 with acetic acid. The remaining amount of water is added to adjust the volume to 1.0 ml. The solution is filtered, filled into vials using an appropriate overage, and sterilized.

[0119] Indications The compounds of formula (I) can be used in an effective amount to treat subjects, particularly humans, suffering from cancer.

[0120] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0121] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or delay of progression of cancer.

[0122] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment, prevention and / or delay of progression of cancer.

[0123] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment, prevention and / or delay of progression of cancer.

[0124] In a further aspect, the present invention provides a method for the treatment, prevention and / or delay of progression of cancer, comprising administering a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0125] As used herein, the terms "treatment" or "treating" and grammatical variations thereof refer to therapeutic therapy. With respect to a particular condition, treating means: (1) ameliorating the condition or one or more biological manifestations of the condition; (2) (a) interfering with one or more points in the biological cascade that leads to or causes the condition, or (b) one or more biological manifestations of the condition; (3) alleviating one or more symptoms, effects, or side effects associated with the condition or its treatment; or (4) slowing the progression of the condition or one or more biological manifestations of the condition. Prophylactic therapy using the methods and / or compositions of the present invention is also contemplated. Those skilled in the art will understand that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition or its biological manifestations, or to delay the onset of such a condition or its biological manifestations. Prophylactic therapy is appropriate when a subject is considered to be at high risk for developing cancer, for example, when the subject has a strong family history of cancer or when the subject has been exposed to a carcinogen.

[0126] As immunotherapeutic agents that act on immune cells rather than directly on cancer cells, the present disclosure may also be envisioned for use as anti-cancer vaccines, including approaches in which immune cells are cultured and engineered ex vivo, and the molecules disclosed herein are used as a means of costimulating the ex vivo engineered cells.

[0127] In one embodiment, the cancer is a blood cancer, such as lymphoma, leukemia, or myeloma. Blood cancers contemplated herein include one or more leukemias, such as B-cell acute lymphoblastic leukemia ("BALL"), T-cell acute lymphoblastic leukemia ("TALL", acute lymphoblastic leukemia (ALL); one or more chronic leukemias, including but not limited to, chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL); B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, These include, but are not limited to, small cell or large cell follicular lymphoma, malignant lymphoproliferative conditions, mucosa-associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, and "preleukemia," which are a diverse collection of hematological conditions united by the ineffective production (or dysplasia) of myeloid blood cells.

[0128] In further embodiments, the cancer is a non-hematological cancer, such as a sarcoma, carcinoma, or melanoma. Non-hematological cancers contemplated herein include, but are not limited to, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell carcinoma, melanoma, gastric cancer, brain cancer, lung cancer (e.g., non-small cell lung cancer - NSCLC), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.

[0129] Co-administration of Compounds of Formula (I) and Other Agents The compound of formula (I) or its salt, or the compound disclosed herein or its pharmaceutically acceptable salt, can be used alone or in combination with other drugs for treatment. For example, the second drug in a combined pharmaceutical formulation or administration regimen may have complementary activity to the compound of formula (I) so that they do not adversely affect each other. The compounds can be administered together in a single pharmaceutical composition or separately. In one embodiment, the compound or its pharmaceutically acceptable salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancer.

[0130] The term "co-administering" refers to simultaneous administration or separate, sequential administration in any manner of a compound of formula (I) or a salt thereof, or a compound disclosed herein or a pharmaceutically acceptable salt thereof, and additional active pharmaceutical ingredient(s), including cytotoxic agents and radiation therapy. If not administered simultaneously, the compounds are administered in close temporal proximity to each other. Furthermore, it does not matter whether the compounds are administered in the same dosage form; for example, one compound may be administered topically and the other compound may be administered orally.

[0131] Typically, any drug with anti-cancer activity can be co-administered.Examples of such drugs can be found in Cancer Principles and Practice of Oncology by V.T.Devita and S.Heilman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers.Those skilled in the art will be able to identify which combination of drugs is useful based on the specific characteristics of the drug and the disease involved.

[0132] In one aspect, the present invention provides a pharmaceutical composition as described herein, further comprising an additional therapeutic agent.

[0133] In one embodiment, the additional therapeutic agent is a chemotherapeutic agent.

[0134] In one embodiment, the additional therapeutic agent is a cytotoxic agent.

[0135] In one embodiment, the additional therapeutic agent is a cancer immunotherapeutic agent.

[0136] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents the function of cells and / or causes cell death or destruction. Cytotoxic agents include radioisotopes (AT 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 , and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof, such as nucleases; and toxins (including fragments and / or variants thereof), such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin.

[0137] Exemplary cytotoxic agents may be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, LDH-A inhibitors, fatty acid biosynthesis inhibitors, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism.

[0138] "Chemotherapeutic agents" include chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer / Sugen), letrozole (FEMARA®, Novartis), and rivaroxaban. is), imatinib mesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYT Oxa N® cyclophosphamide, alkylsulfonates such as busulfan, improsulfan, and piposulfan, aziridines such as benzodopa, carboquone, methyledopa, and uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramine ethylenimines and methylameramines, including methylameramine, acetogenins (especially bullatacin and bullatacinone), camptothecins (including topotecan and irinotecan), bryostatin, kallistatin, CC-1065 (including its azozelesin, carzelesin, and bizelesin synthetic analogs), cryptophycins (especially cryptophycin 1 and cryptophycin 8), corticosteroids (including prednisone and prednisolone),cyproterone acetate, finasteride, and dutasteride (5a-reductase inhibitors), vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat, dolastatins, aldesleukin, talc, duocarmycin (synthetic analogs KW-2189 and CBI-TM I), eleutherobin, pancratistatin, sarcodictyin, spongistatin, nitrogen mustards such as chlorambucil, chromafazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicine, fenesterine, prednimustine, trofosfamide, uracil mustard, nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine, antibiotics such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin γII and calicheamicin chol (Angew Chem. Inti. Ed. Engl. 1994) 33:183-186); dynemicins, e.g., dynemicin A, bisphosphonates, e.g., clodronate, esperamicin, and neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxo rubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rhodolubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, antimetabolites such as methotrexate and 5-fluorouracil (5-FU), folic acid analogues such as denopterin, methotrexate,Pteropterin, trimetrexate, purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone, antiadrenal agents such as aminoglutethimide, mitotane, trilostane, folic acid replacement solutions such as furoic acid, aceglatone, aldophosphamide glycosides , aminolevulinic acid, eniluracil, amsacrine, bestravcil, bisantrene, edatrexate, defofamine, demecolcine, diaziquone, elfomitin, elliptinium acetate, epothilone, etoglucide, gallium nitrate, hydroxyurea, lentinan, lonidynin, maytansinoids such as maytansine and ansamitocins, mitoguazone, mitoxantrone, mopidamol, nitraelin, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllic acid, 2-ethylhydrazide, procarbazine, PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.), razoxane, rhizoxin, schizofuran, spirogermanium, tenuazonic acid, triaziquone, 2,2',2"-trichlorotriethylamine, trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidine), urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside ("Ara-C"), cyclophosphamide, thiotepa, taxoids such as TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE® (docetaxel; Sanofi-Aventis), chlorambucil, GEMZAR® (gemcitabine),6-thioguanine, mercaptopurine, methotrexate, platinum analogs such as cisplatin and carboplatin, vinblastine, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, NAVELBINE® (vinorelbine), novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine (XELODA®), ibandronate, CPT-II, topoisomerase inhibitor RFS2000, difluoromethylornithine (DMFO), retinoids such as retinoic acid, and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0139] Chemotherapeutic agents also include: (i) antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), for example, tamoxifen (including NOLVADEX (registered trademark) and tamoxifen citrate), raloxifene, droxifene, iodoxifene, 4-hydroxytamoxifen, trihydroxyphene, ketoxifene, LY1; 17018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megstrol acetate), AROMASIN® (exemestane; Pfizer), formestany, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, Premarin, fluoxymesterone, all-trans-lethiol, (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly agents that inhibit the expression of genes in signal transduction pathways involved in abnormal cell growth, such as PKC-alpha, Ralf, and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®), HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, VAXID®; PROLEUKIN®, rIL-2; topoisomerase I inhibitors such as LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0140] Chemotherapeutic agents also include antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody-drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, celizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, nat ... tuzumab, nimotuzumab, norobizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pexelizumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, reslizumab, reslivizumab, rovelizumab, lupizumab, sibrotuzumab, siplizumab, sontuzumab, tacatatuzumab tetraxetan, tadoxizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoreukin, tuxituuzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and interleukin-12 and anti-interleukin-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), an all-human sequence, full-length IgGi lambda antibody engineered to recognize the p40 protein.

[0141] Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or otherwise directly interact with EGFR and inhibit or reduce the signaling activity of EGFR, alternatively referred to as "EGFR antagonists." Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include MAb579 (ATCC CRL HB8506), MAb455 (ATCC CRL HB8507), MAb225 (ATCC CRL8508), MAb528 (ATCC CRL8509) (see U.S. Pat. No. 4,943,533, Mendelsohn et al.), and variants thereof, such as chimerized 225 (C225 or cetuximab, ERBUTIX®) and reconstituted human 225 (H225) (see WO 96 / 40210, Imclone Systems, Inc.). Inc.), IMC-11F8, a fully human EGFR-targeting antibody (Imclone), antibodies that bind to type II mutant EGFR (U.S. Pat. No. 5,212,290), humanized and chimeric antibodies that bind to EGFR as described in U.S. Pat. No. 5,891,996, and human antibodies that bind to EGFR, such as ABX-EGF or panitumumab (WO 98 / 50433, Abgenix / Amgen), EMD55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)), EMD7200 (matuzumab) (a humanized EGFR antibody against EGFR that competes for EGFR binding of both EGF and TGF-alpha (EMD / Merck)), the human EGFR antibody, HuMax-EGFR (GenMab), the fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, and E7.6.3, and described in U.S. Pat. No. 6,235,883, MDX-447 (Medarex Inc), and mAb806 or humanized mAb806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)).Anti-EGFR antibodies can be conjugated to a cytotoxic agent to generate an immunoconjugate (see, e.g., European Patent Application Publication No. 659,439A2, Merck Patent GmbH). EGFR antagonists can be conjugated to a cytotoxic agent, such as those described in U.S. Patent Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, and 5,866,573. Nos. 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, and the following PCT publications: WO 98 / 14451, WO 98 / 50038, WO 99 / 09016, and WO 99 / 24037.Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA®, Genentech / OSI Pharmaceuticals), PD183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.), ZD1839, gefitinib (IRESSA®) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca), ZM105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca), BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim), Ingelheim), PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide), EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7 -ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butynamide) (Wyeth), AG1478 (Pfizer); AG1571 (SU5271, Pfizer), and dual EGFR / HER2 tyrosine kinase inhibitors, such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

[0142] Chemotherapeutic agents include "tyrosine kinase inhibitors," such as the EGFR-targeted drugs described in the previous paragraph; small molecule HER2 tyrosine kinase inhibitors, such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors, such as EKB-569 (available from Wyeth), which preferentially binds to EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016, available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors, such as canertinib (CI-1033, Pharmacia); Raf-1 inhibitors, such as ISIS, which inhibits Raf-1 signaling. antisense drug ISIS-5132 available from GlaxoSmithKline Pharmaceuticals; non-HER-targeted TK inhibitors such as imatinib mesylate (GLEEVEC®, available from GlaxoSmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787 / ZK222584, available from Novartis / Schering AG); the MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines such as PD 153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP 59326, CGP 60261, and CGP 62706; pyrazolopyrimidine, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide); tyrphostins containing a nitrothiophene moiety; PD-0183805 (Warner-Lamber); antisense molecules (e.g., those that bind to HER-encoding nucleic acids); quinoxalines (U.S. Patent No. 5,804,396); tryphostins (U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca);PTK-787 (Novartis / Schering AG); pan-HER inhibitors, such as CI-1033 (Pfizer); Affinitac (ISIS 3521, Isis / Lilly); imatinib mesylate (GLEEVEC®); PKI 166 (Novartis); GW2016 (GlaxoSmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); INC-ICl I (Imclone), rapamycin (sirolimus, RAPAMUNE®); or the following patent publications: U.S. Pat. No. 5,804,396, WO 1999 / 09016 (American Cyanamid), WO 1998 / 43960 (American Cyanamid), 1997 / 38983 (Warner Lambert), 1999 / 06378 (Warner Lambert), 1999 / 06396 (Warner Lambert), 1996 / 30347 (Pfizer, Inc.), 1996 / 33978 (Zeneca), 1996 / 3397 (Zeneca), and 1996 / 33980 (Zeneca).

[0143] Chemotherapeutic agents include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG (raw), bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, erlotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, and interferon alfa- 2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.

[0144] Chemotherapeutic agents include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, and hydrocortisone-17- butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasone-17-propionate, fluocortolone caproate, fluocortolone pivalate, and fluprednidene acetate; phenylalanine-glutamine-glycine (PEG) and its D-form (feG) (IMULAN) Immunoselective anti-inflammatory peptides (ImSAIDs) such as BioTherapeutics, LLC; antirheumatic drugs such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, and sulfasalazine; etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), cetolithumab pegol (Cimzia), and golimumab (Symptoms); tumor necrosis factor alpha (TNFα) blockers such as lebrikizumab (Kineret); interleukin 1 (IL-1) blockers such as anakinra (Kineret); T-cell costimulation blockers such as abatacept (Orencia); interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) blockers such as rontalizumab; beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as anti-M1 prime; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa1 / β2 blockers such as anti-lymphotoxin alpha (LTa); radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212、P 32 、Pb 212, and radioactive isotopes of Lu); various investigational drugs such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, and farnesyltransferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavins, flavanols, procyanidins, betulinic acid and its derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicine; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin; podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); clodronate (e.g., BONEFOS®) ) or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); as well as epidermal growth factor receptor (EGF-R); vaccines such as the THERATOPE® vaccine; perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteosome inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitors such as oblimersen sodium (GENASENSE®); pixantrone; lonafarnib (SCH 6636, SARASAR™); and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing; and combinations of two or more of CHOP, which is an abbreviation for the combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, which is an abbreviation for the treatment regimen with oxaliplatin in combination with 5-FU and leucovorin (ELOXATIN™).

[0145] In another embodiment, the compound of formula (I) can be co-formulated with a cancer immunotherapeutic agent. Cancer immunotherapeutic agents include, for example, small molecule drugs, antibodies, or other biological or small molecules. Examples of biological cancer immunotherapeutic agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human. In another aspect, the antibody is a bispecific antibody.

[0146] In one aspect, the cancer immunotherapeutic agent is either (i) an agonist of a stimulatory (including costimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on T cells, both of which result in amplification of antigen-specific T cell responses (often referred to as immune checkpoint modulators).

[0147] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or coinhibitory receptors are CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTfiR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNPβ, TNFR2, TNFα, LT R, lymphotoxin α It is a TNF family molecule that binds to cognate TNF receptor family members, including 1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0148] In one aspect, a T cell response may be stimulated by a combination of a compound of Formula (I) and (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin-9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) one or more of B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0149] Other drugs that can be combined with the compound of formula (I) for the treatment of cancer include the antagonist of inhibitory receptors on NK cells or the agonist of activating receptors on NK cells.For example, the compound of formula (I) can be combined with the antagonist of KIR, such as lirilumab.

[0150] Still other agents for combination therapy include agents that inhibit or deplete macrophages or monocytes, including CSF-1R antagonists such as CSF-1R antagonist antibodies, including, but not limited to, RG7155 or FPA-008.

[0151] In another embodiment, the compounds of formula (I) can be used in conjunction with one or more agents that include agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome different immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor binding (e.g., PD-L1 / PD-1 interactions), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell anergy or exhaustion), and innate immune activation and / or inflammation at the tumor site.

[0152] In some embodiments, the cancer immunotherapeutic agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. In another aspect, the cancer immunotherapeutic agent is a PD-1 antagonist, such as an antagonist PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO 2012 / 145493). Cancer immunotherapeutic agents may also include pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned. Another approach to targeting the PD-1 receptor is a recombinant protein called AMP-224, which consists of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0153] In another embodiment, the cancer immunotherapeutic agent is a PD-L1 antagonist, such as an antagonist PD-L1 antibody. Suitable PD-L1 antibodies include, for example, TECENTRIQ (atezolizumab) (RG7446; WO 2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO 2007 / 005874), and MSB0010718C (WO 2013 / 79174).

[0154] In another embodiment, the cancer immunotherapeutic agent is a LAG-3 antagonist, for example, an antagonist LAG-3 antibody.Suitable LAG-3 antibodies include, for example, BMS-986016 (WO 2010 / 19570, WO 2014 / 08218), or IMP-731 or IMP-321 (WO 2008 / 132601, WO 2009 / 44273).

[0155] In another embodiment, the cancer immunotherapeutic agent is a CD137 (4-1BB) agonist, such as an agonist CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO 2012 / 32433).

[0156] In another embodiment, the cancer immunotherapeutic agent is a GITR agonist, for example, an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO2006 / 105021, WO2009 / 009116) and MK-4166 (WO2011 / 028683).

[0157] In another embodiment, the cancer immunotherapeutic agent is IDO antagonist.Suitable IDO antagonist includes, for example, INCB-024360 (WO2006 / 122150, WO2007 / 75598, WO2008 / 36653, WO2008 / 36642), indoximod or NLG-919 (WO2009 / 73620, WO2009 / 1156652, WO2011 / 56652, WO2012 / 142237).

[0158] In another embodiment, the cancer immunotherapeutic agent is an OX40 agonist, for example, an agonistic OX40 antibody.Suitable OX40 antibody includes, for example, MEDI-6383 or MEDI-6469.In another embodiment, the cancer immunotherapeutic agent is an OX40L antagonist, for example, an antagonistic OX40 antibody.Suitable OX40L antagonist includes, for example, RG-7888 (WO06 / 029879).

[0159] In another aspect, the cancer immunotherapeutic agent is a CD40 agonist, e.g., an agonist CD40 antibody. In yet another embodiment, the cancer immunotherapeutic agent is a CD40 antagonist, such as an antagonist CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0160] In another embodiment, the cancer immunotherapeutic agent is a CD27 agonist, such as an agonist CD27 antibody. Suitable CD27 antibodies include, for example, valilumab.

[0161] In another embodiment, the cancer immunotherapeutic agent is MGA271 (directed against B7H3) (WO 2011 / 109400). [Example]

[0162] The present invention will be more fully understood by reference to the following examples, which, however, should not be construed as limiting the scope of the claims to the examples.

[0163] 1) Preparation Examples Unless otherwise stated, all reactions and intermediates were prepared under an argon atmosphere.

[0164] 1.1) General Procedure Alkylation General Procedure 1a To a solution of the intermediate of formula (VI) (2.74 mmol) in DMF (10 mL) at room temperature was added potassium carbonate (1.14 g, 8.23 mmol), potassium iodide (228 mg, 1.37 mmol), and the reagent of formula (VII) (3.29 mmol). The reaction was stirred at room temperature for 2 hours, quenched with water, and extracted twice with DCM. The combined organic layers were washed with water, saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (VIII) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0165] Alkylation General Procedure 1b: To a solution of the intermediate of formula (VI) (0.2 mmol) in toluene (3 ml) under an inert atmosphere was added the reagent of formula (VII) (0.22 mmol), PPh3 (0.4 mmol), and DIAD (0.4 mmol). The mixture was then heated to 50° C. for 4 hours. After cooling to room temperature, the mixture was concentrated and diluted with EtOAc. The solution was then washed with brine (3 times), dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (VIII) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0166] Saponification: General Procedure 2: A solution of a compound of formula (VIII) (wherein X 1 To a solution of the intermediate (4 mmol) of (XII) (wherein is COMe) was added LiOH hydrate (8 mmol) and stirred at room temperature for 2 hours. 1N HCl was added, and the resulting suspension was extracted three times with EtOAc. The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XII) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0167] Hydrazide formation: General procedure 3: To a solution of the intermediate of formula (XII) (4.5 mmol) in THF (20 ml), CDI (5.7 mmol) was added and stirred at room temperature for 90 minutes. A mixture of hydrazine hydrate (13.5 mmol) in THF (3.3 ml) was then added to this solution and stirred for 1 hour. The reaction mixture was diluted with water and EtOAc. The layers were separated, and the aqueous phase was washed twice with EtOAc. The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XIII) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0168] Hydrazide Coupling: General Procedure 4a To a solution of intermediate of formula (XIII) (0.3 mmol) in THF (3 ml) was added intermediate of formula R 10 The carboxylic acid (0.45 mmol) of COH, DIPEA (0.6 mmol), and HATU (0.45 mmol) were added. The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc and water. The layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XIV) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0169] Hydrazide Coupling: General Procedure 4b To a solution of intermediate of formula (XIII) (0.5 mmol) in THF (5 ml) was added intermediate of formula R 10 The carboxylic acid COH (0.5 mmol), DIPEA (1.5 mmol), and T3P (50% in EtOAc, 1.5 mmol) were added. The resulting solution was stirred at 60° C. for 2 hours. The reaction was then cooled to room temperature and diluted with water. The mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XIV) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0170] 1,3,4-Oxadiazole Cyclization: General Procedure 5a To a solution of the intermediate of formula (XIV) (0.3 mmol) in THF (3 ml) was added Burgess reagent (0.9 mmol). The resulting solution was stirred at room temperature overnight. Water was added, and the mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XV) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0171] 1,3,4-Oxadiazole Cyclization: General Procedure 5b To a solution of the intermediate of formula (XIV) (0.1 mmol) in acetonitrile (1.3 ml) was added p-toluenesulfonyl chloride (0.3 mmol) and DIPEA (0.2 mmol). The resulting solution was stirred at room temperature for 30 minutes. The reaction was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XV) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0172] Amidoxime formation: General procedure 6: Formula (VIII, where: 1 To a solution of the intermediate (XX, where R is CN) (0.3 mmol) in EtOH (2.5 ml) was added solid NaHCO (1.5 mmol) and hydroxylamine hydrochloride (0.6 mmol). The resulting suspension was heated to 80° C. for 90 minutes and then cooled to room temperature. The suspension was filtered, and the filter cake was washed with EtOH and DCM. The filtrate was concentrated under reduced pressure, and the remaining solid was dissolved in DCM, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XX, where R is H) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0173] Direct 1,2,4-oxadiazole formation from amidoximes: general procedure 7a Formula R in DMF (5 ml) 10 To a solution of carboxylic acid (2.4 mmol) in COH was added CDI (2.64 mmol) and stirred for 60 minutes. A solution of intermediate of formula (XX, where R is H) (1.2 mmol) in DMF (5 ml) was then added, and the resulting mixture was heated to 120° C. for 4 hours. The reaction was cooled to room temperature, and water and EtOAc were added. The layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with 1N HCl, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XXI) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0174] Direct 1,2,4-oxadiazole formation from amidoximes: general procedure 7b To a solution of intermediate of formula (XX, where R is H) (0.3 mmol) in THF (5 mL) was added intermediate of formula R 10 A 50% solution of COH carboxylic acid (0.45 mmol), DIPEA (0.76 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in EtOAc (0.6 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was quenched with water, extracted twice with EtOAc, washed with 1M aqueous NaOH, 1M aqueous HCl, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The desired product (XXI) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0175] Direct 1,2,4-oxadiazole formation from amidoximes: general procedure 7c To a solution of intermediate of formula (XX, where R is H) (0.2 mmol) in DMF (1.5 ml) was added intermediate of formula R 10The COH carboxylic acid (0.24 mmol), EDC hydrochloride (0.4 mmol), DIPEA (0.6 mmol), and HOBt (0.3 mmol) were added, and the resulting mixture was heated to 80 °C for 8 h. The reaction was cooled to room temperature, and water and EtOAc were added. The layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XXI) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0176] Amide oxime coupling with RCO2H: General procedure 8a To a solution of an intermediate of formula (XX, where R is H) (1.0 mmol) in THF (8.5 ml) was added an intermediate of formula R 10 The carboxylic acid of COH (0.12 mmol), DIPEA (2.0 mmol), and HATU (0.15 mmol) were added, and the reaction was stirred at room temperature for 4 hours. Water and EtOAc were added, and the layers were separated. The aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XX, where R is -CO(R 10 ) was used crude in the next step or purified by flash column chromatography on silica gel or reverse phase preparative HPLC.

[0177] Amide oxime coupling with RCO2H: General procedure 8b To a solution of intermediate of formula (XX, where R is H) (0.2 mmol) in DMF (1.5 ml) was added intermediate of formula R 10The carboxylic acid of COH (0.24 mmol), EDC hydrochloride (0.4 mmol), DIPEA (0.6 mmol), and HOBt (0.3 mmol) were added, and the resulting mixture was stirred at room temperature for 16 hours. Water and EtOAc were added, the layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XX, where R is -CO(R 10 ) was used crude in the next step or purified by flash column chromatography on silica gel or reverse phase preparative HPLC.

[0178] Amide oxime coupling with RCO2H: General procedure 8c Formula R in acetonitrile (0.33 ml) 10 To a solution of carboxylic acid (0.11 mmol) in COH was added CDI (0.12 mmol) and stirred at room temperature for 60 minutes. Then, to this mixture was added a solution of intermediate of formula (XX, where R is H) (0.1 mmol) in acetonitrile (0.33 ml) and stirred at room temperature for 60 minutes. The reaction was diluted with DCM and water was added. The layers were separated and the aqueous phase was extracted twice with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The desired product (XX, where R is -CO(R 10 ) was used crude in the next step or purified by flash column chromatography on silica gel or reverse phase preparative HPLC.

[0179] 1,2,4-Oxadiazole Cyclization: General Procedure 9a of formula (XX, where R is -CO(R 10 A solution of the intermediate (XXI) (0.15 mmol) was heated to 120° C. for 16 h. The solvent was then evaporated under reduced pressure. The desired product (XXI) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0180] 1,2,4-Oxadiazole Cyclization: General Procedure 9b in THF (1.2 ml) 10 To a solution of the intermediate (0.12 mmol) of (III), tetrabutylammonium hydroxide (0.06 mmol) was added and stirred at room temperature for 30 minutes. The reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3. The aqueous phase was then washed twice with EtOAc, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent evaporated under reduced pressure. The desired product (XXI) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0181] Oxidation: General Procedure 10 A solution of intermediate of formula (VIII) (2.74 mmol) and m-CPBA (1.18 g, 6.85 mmol) in DCM (10 mL) was stirred at room temperature for 1 day. The reaction was diluted with EtOAc and THF, washed with 2N aqueous sodium hydroxide, 1N aqueous HCl, and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. The desired product (IX) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0182] Boc deprotection: General procedure 11a To a solution of the intermediate of formula (IX) (0.250 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (4 mL) was added HCl / dioxane or HCl / EtO (0.5 mmol, 2 equivalents) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The solvent was evaporated, and the resulting solid was dissolved in DCM and concentrated again to remove traces of 1,1,1,3,3,3-hexafluoropropan-2-ol. This process was repeated twice, followed by drying under high vacuum to give the desired product (I).

[0183] Boc Deprotection: General Procedure 11b A solution of the intermediate of formula (IX) (22.7 μmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (1.5 mL) was stirred at reflux for 5 days, the solvent was evaporated, and the remaining residue was dried under high vacuum to give the desired product (I).

[0184] Boc Deprotection: General Procedure 11c To a solution of the intermediate of formula (IX) (0.250 mmol) in EtOAc (4 mL) was added HCl / EtOAc (4.0 mL, 16 mmol, 63 equiv) at 0° C. The reaction mixture was stirred at 20° C. for 3 hours and then concentrated in vacuo. The remaining residue was purified by preparative HPLC and dried by lyophilization to give the desired product (I).

[0185] Bromination: General Procedure 12: A solution of formula (VII), wherein Y 1 To a solution of the intermediate (1.34 mmol) of (Y is H), N-bromosuccinimide (1.6 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.13 mmol) were added and stirred at 80°C for 3 hours. The reaction was quenched by adding saturated sodium thiosulfate and aqueous EtOAc, the mixture was vigorously stirred for 5 minutes, and the phases were separated. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the desired product (VII, where Y is H). 1 is Br) was used crude in the next step or purified by flash column chromatography on silica gel.

[0186] Amination: General Procedure 13: To a solution of the intermediate of formula (XVIII) (0.06 mmol) in 1,4-dioxane (0.6 ml) was added an intermediate of formula HN(R 10 eR 10The amine from f) (0.12 mmol), DIPEA (0.18 mmol), and PyBroP (0.072 mmol) were added. The mixture was heated to 50° C. for 90 min. After cooling to room temperature, EtOAc and water were added, and the reaction was stirred vigorously for 5 min. The layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The desired product (XIX) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0187] Example 1 (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylic acid [ka] The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (9.5 g, 25.65 mmol, CAS 202449-38-7) as per general procedure 2 and obtained as a brown solid (9.5 g, 26.66 mmol, 104% yield). MS (ESI): 301.0 [M-isobutene + H] +

[0188] Step b) tert-butyl N-[(3R)-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylic acid (1300 mg, 2.81 mmol) similarly to general procedure 3 and obtained as a light brown oil (1300 mg, 3.51 mmol, 95% yield). MS (ESI): 315.2 [M-isobutene + H] +

[0189] Step c) tert-butyl N-[(3R)-7-[(2,2-dimethylpropanoylamino)carbamoyl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (1287 mg, 2.66 mmol, 1 equiv.) and pivalic acid (0.31 mL, 2.68 mmol, 1.01 equiv.) analogously to general procedure 4a and obtained as a yellow solid (1240 mg, 2.73 mmol, 97% yield). MS (ESI): 399.1 [M-isobutene + H] +

[0190] Step d) tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[(2,2-dimethylpropanoylamino)carbamoyl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (2.69 g, 5.92 mmol) in analogy to general procedure 5a as a pale yellow solid (2.57 g, 5.36 mmol, 91% yield). MS (ESI): 381.1 [M-isobutene + H] +

[0191] Step e) tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (800 mg, 1.83 mmol) as in general procedure 10 and obtained as a pale yellow solid (830 mg, 1.77 mmol, 97% yield). MS (ESI): 413.1 [M-isobutene + H] +

[0192] Step f) tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ6 Prepared as per general procedure 1b from 4-(1H-benzothiazepin-3-yl)carbamate (100 mg, 0.21 mmol, 1.0 equiv.) and 4-(1H-pyrazolo-3-yl)benzenemethanol (44 mg, 0.23 mmol, 1.1 equiv., CAS 179055-20-0) as a white solid (180 mg, 0.28 mmol, 62% yield). MS (ESI): 639.2 [M+H] +

[0193] Step g) (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 Prepared similarly to general procedure 11c from 5-benzothiazepin-3-yl]carbamate (180 mg, 0.28 mmol) as a white solid (15.5 mg, 0.03 mmol, 10% yield). MS (ESI): 539.2 [M+H] +

[0194] The examples in the table below were prepared similarly to Example 1 using the benzyl alcohol building block. [Table 4]

[0195] Example 88 2-[5-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile [ka] Step a) tert-Butyl N-[(3R)-7-[[(2-cyano-2-methyl-propanoyl)amino]carbamoyl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] To a suspension of tert-butyl N-[(3R)-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (150 mg, 404.97 μmol, 1.0 eq., Example 1, step b) and 2-cyano-2-methyl-propionic acid (55 mg, 485.96 μmol, 1.2 eq.) in THF (2.85 ml), HATU (231 mg, 607.45 μmol, 1.5 eq.) and DIPEA (130.9 mg, 176.8 μL, 1.01 mmol, 2.5 eq.) were added at room temperature, and the mixture was stirred for 4 hours. The mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (twice). The combined organic layers were washed once with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow oil (331 mg) containing the title compound. The crude material was used in the next step without further purification. MS(ESI): 464.2 [MH] -

[0196] Step b) tert-Butyl N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[[(2-cyano-2-methyl-propanoyl)amino]carbamoyl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (188 mg, 403.87 μmol) in analogy to general procedure 5b and obtained as a white solid (83.4 mg, 46%). MS (ESI): 392.1 [M+H-isobutene] +

[0197] Step c) tert-butyl N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (83.4 mg, 186.38 μmol) as in general procedure 10 and obtained as a white solid (47.2 mg, 49% yield). MS (ESI): 424.1 [M+H-isobutene] + .

[0198] Step d) tert-butyl N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 Prepared analogously to general procedure 1a from 2-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)pyridine (42.94 mg, 135.9 μmol, 1.5 equiv., CAS 1056641-21-4) as a white solid (29.1 mg, 45%). MS (ESI): 715.5 [M+H] +

[0199] Step e) 2-[5-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared similarly to general procedure 11a from [5-benzothiazepin-3-yl]carbamate (29 mg, 40.58 μmol) and obtained as the hydrochloride salt as an off-white solid (21 mg, 80%). MS (ESI): 659.2 [M-H+HCO2H] -

[0200] Example 3 (3R)-3-amino-7-[5-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) Methyl (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylate [ka] The title compound was prepared analogously to general procedure 1a from methyl (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (500.0 mg, 1.35 mmol, 1.0 equiv., CAS 202449-38-7) and 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (414.51 mg, 1.35 mmol, 1.0 equiv., CAS 2093101-98-3) as a pale yellow foam (749 mg, 1.26 mmol, 93% yield. MS (ESI): 541.1 [M-isobutene-H] +

[0201] Step b) Methyl(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine-7-carboxylate [ka] The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (749 mg, 1.26 mmol) as in general procedure 10 and obtained as a white solid (780 mg, 1.24 mmol, 99% yield). MS (ESI): 572.9 [M-isobutene + H] +

[0202] Step c) (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine-7-carboxylic acid [ka] The title compound was synthesized by the method of claim 1, wherein the methyl (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared as per general procedure 2 from 5-benzothiazepine-7-carboxylate (200 mg, 0.32 mmol) and obtained as a white powder (170 mg, 0.28 mmol, 61% yield). MS (ESI): 514.8 [M-Boc+H] +

[0203] Step d) tert-butyl N-[(3R)-8-fluoro-7-(hydrazinecarbonyl)-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared similarly to general procedure 3 from 5-benzothiazepine-7-carboxylic acid (3700 mg, 6.02 mmol) and obtained as (2500 mg, 3.98 mmol, 66% yield). MS (ESI): 573.0 [M - isobutene + H] +

[0204] Step e) tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-7-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] tert-Butyl N-[(3R)-8-fluoro-7-(hydrazinecarbonyl)-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ in THF (20 mL) 6 To a solution of [5-benzothiazepin-3-yl]carbamate (1000 mg, 1.59 mmol, 1.0 equiv.) and triethylamine (0.44 mL, 3.18 mmol, 2.0 equiv.), CDI (387 mg, 2.39 mmol, 1.5 equiv.) was added at room temperature, and the mixture was stirred for 3 h. The solution was poured into water (20 mL). The aqueous phase was extracted with EtOAc (3 times). The combined organic phases were washed with brine (2 times), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The remaining crude material was purified by silica gel chromatography (30-100% EtOAc in petroleum ether) to give the title compound (80 mg, 0.14 mmol, 76% yield). MS (ESI): 598.9 [M-isobutene + H] +

[0205] Step f) tert-butyl N-[(3R)-7-[5-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-7-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (190.0 mg, 0.29 mmol, 1.0 equiv.) and 3,3-difluoro-1-methyl-cyclobutanamine hydrochloride (68.62 mg, 0.44 mmol, 1.5 equiv.) in analogy to general procedure 13, and obtained as a colorless foam (168.0 mg, 0.22 mmol, 76% yield). MS (ESI): 758.1 [M+H] +

[0206] Step g) (3R)-3-amino-7-[5-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[5-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (168 mg, 0.22 mmol) in analogy to general procedure 11c and obtained as a white solid as the hydrochloride salt (131.6 mg, 0.19 mmol, 85% yield). MS (ESI): 657.8 [M+H] +

[0207] The examples in the table below were prepared similarly to Example 3 using the appropriate amine building blocks. [Table 5]

[0208] Example 6 (3R)-3-amino-8-fluoro-7-[5-(isopropylamino)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) tert-butyl N-[(3R)-8-fluoro-7-[5-(isopropylamino)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] tert-Butyl N-[(3R)-8-fluoro-7-(hydrazinecarbonyl)-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ in DCM (5 mL) 6 To a solution of [5-benzothiazepin-3-yl]carbamate (250.0 mg, 0.4 mmol, 1.0 equiv., Example 3, step d) was added isopropyl isocyanate (0.07 mL, 0.68 mmol, 1.72 equiv.) at 0 °C. The mixture was stirred at room temperature for 3 h. Then, 4-toluenesulfonyl chloride (130.4 mg, 0.68 mmol, 1.72 equiv.) and triethylamine (0.14 mL, 1.03 mmol, 2.6 equiv.) were added. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and purified by silica gel column chromatography (25-75% EtOAc in petroleum ether) to give the title compound as a pale yellow solid (142 mg, 0.2 mmol, 51% yield). MS (ESI): 696.0 [M+H] +

[0209] Step b) (3R)-3-amino-8-fluoro-7-[5-(isopropylamino)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-8-fluoro-7-[5-(isopropylamino)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6Prepared similarly to general procedure 11c from 5-benzothiazepin-3-yl]carbamate (122 mg, 0.18 mmol) as a white solid (73.7 mg, 0.12 mmol, 70% yield). MS (ESI): 595.9 [M+H] +

[0210] Example 7 (3R)-3-amino-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-[[6-[4-(hydroxymethyl)phenyl]-3-pyridyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) (2R)-2-(tert-butoxycarbonylamino)-3-(4-cyano-5-fluoro-2-nitro-phenyl)sulfanyl-propanoic acid [ka] To a solution of 2,4-difluoro-5-nitro-benzonitrile (9.4 g, 50 mmol) and (tert-butoxycarbonyl)-L-cysteine (11.07 g, 50 mmol) in DCM (157 mL) was added DIPEA (17.48 mL, 100 mmol, equiv: 2). The reaction mixture was stirred at 22 °C for 24 h, diluted with DCM (40 mL), washed once with 1N aqueous HCl, and extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a yellow solid (23.5 g, 118% yield). MS (ESI): 286.1 [M-Boc+H] + .

[0211] Step b) (2R)-3-(2-amino-4-cyano-5-fluoro-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid [ka] To a solution of (2R)-2-(tert-butoxycarbonylamino)-3-(4-cyano-5-fluoro-2-nitro-phenyl)sulfanyl-propanoic acid (14.0 g, 36.3 mmol, 1.0 equiv) in MeOH (140 mL) was added a solution of NH4Cl (5.83 g, 109 mmol, 3.0 equiv) in water (28 mL), followed by the portionwise addition of Fe (10.71 mL, 145.31 mmol, 4.0 equiv). The mixture was then stirred at 70 °C for 2 h. The reaction was cooled to room temperature and then filtered through a Celite plug, washing with MeOH (200 mL). The filtrate was concentrated to give (2R)-3-(2-amino-4-cyano-5-fluoro-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid as a black solid (23 g, 48.1 mmol, 80% yield). MS (ESI): 300.1 [M-isobutene + H] +

[0212] Step c) tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] To a solution of (2R)-3-(2-amino-4-cyano-5-fluoro-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (15.0 g, 42.21 mmol, 1.0 equiv.) and N,N-diisopropylethylamine (14.7 mL, 84.42 mmol, 2.0 equiv.) in THF (300 mL) was added T3P (40.29 g, 63.31 mmol, 1.5 equiv.) in EtOAc at room temperature, and the mixture was stirred for 4 hours. The reaction mixture was diluted with EtOAc (300 ml) and poured into water (600 mL). The layers were separated, and the aqueous phase was washed twice with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The remaining residue was purified by reverse-phase preparative HPLC to give N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate as a pale yellow solid (8.4 g, 24.9 mmol, 48% yield). MS(ESI): 282.1 [M-isobutene + H] +

[0213] Step d) tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] To a solution of tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (2R)-3-(2-amino-4-cyano-5-fluoro-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (200 mg, 0.59 mmol) in MeOH (2 mL) was added hydroxylamine hydrochloride (63.7 mg, 0.89 mmol, equivalents: 1.5) and sodium bicarbonate (249 mg, 2.96 mmol, equivalents: 5). The mixture was stirred at 70° C. for 16 hours, cooled to room temperature, filtered, and the filter cake was washed with DCM. The combined filtrate was concentrated in vacuo. The reaction was diluted with DCM and washed with water and brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (444 mg, 1.19 mmol, 74% yield) as a yellow solid. MS (ESI): 315.1 [M-isobutene + H] + .

[0214] Step e) [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]methylene]amino]2,2-dimethyl-propanoate [ka] The title compound, prepared analogously to general procedure 8b from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (1000 mg, 2.7 mmol), was obtained as a white solid (900 mg, 1.98 mmol, 73% yield. MS(ESI): 455.1 [M+H] +

[0215] Step f) tert-butyl N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared analogously to general procedure 9a from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]methylene]amino]2,2-dimethylpropanoate (2.12 g, 4.75 mmol, 1 equiv.) and obtained as an orange solid (1.94 g, 89%). MS (ESI): 381.1 [M-isobutene + H] +

[0216] Step g) tert-butyl N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (500 mg, 1.09 mmol) in analogy to general procedure 10 and obtained as a pale yellow solid (426 mg, 84%). MS (ESI): 413.2 [M+H] +

[0217] Step h) tert-butyl N-[(3R)-5-[[6-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]-3-pyridyl]methyl]-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 Prepared analogously to general procedure 1a from [5-benzothiazepin-3-yl]carbamate (35 mg, 0.075 mmol, 1.0 equiv.) and intermediate 1 (92.27 mg, 0.075 mmol, 1.0 equiv.) as a pale yellow solid (10 mg, 17%). MS (ESI): 780.5 [M+H] +

[0218] Step i) (3R)-3-amino-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-[[6-[4-(hydroxymethyl)phenyl]-3-pyridyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-5-[[6-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]-3-pyridyl]methyl]-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-1,1,4-trioxo-2,3-dihydro-1λ 6 Prepared similarly to general procedure 11a from 5-benzothiazepin-3-yl]carbamate (10 mg, 0.013 mmol) as a white solid (4.1 mg, 57%). MS (ESI): 566.3 [M+H] +

[0219] Example 8 (3R)-3-amino-7-[5-(3-aminooxetan-3-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) tert-Butyl N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (186 mg, 0.462 mmol, Example 7, step d) and 3-(tert-butoxycarbonylamino)oxetane-3-carboxylic acid (150 mg, 0.69 mmol, equivalents: 1.5) in analogy to general procedure 7b, and obtained as a pale yellow solid (166 mg, 0.3 mmol, 60% yield). MS (ESI): 550.5 [MH]

[0220] Step b) tert-butyl N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-5-[[4-(4-methoxyphenyl)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-yl]carbamate [ka] The title compound was prepared analogously to general procedure 1a from tert-butyl N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-yl]carbamate (40 mg, 0.067 mmol, equivalents: 1) and 1-(chloromethyl)-4-(4-methoxyphenyl)benzene (CAS 93258-73-2) (23.5 mg, 0.1 mmol, equivalents: 1.5) as a white solid (45 mg, 82% yield). MS(ESI): 746.4 [MH]

[0221] Step c) tert-butyl N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-5-[[4-(4-methoxyphenyl)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-yl]carbamate (45 mg, 0.055 mmol) as in general procedure 10 and obtained as a white solid (30 mg, 69% yield). MS(ESI): 778.5 [MH]

[0222] Step d) (3R)-3-amino-7-[5-(3-aminooxetan-3-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 Prepared analogously to general procedure 11a from [1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-yl]carbamate (30 mg, 0.038 mmol) as a white solid (9 mg, 40.3% yield). MS (ESI): 580.3 [M+H] + .

[0223] Example 9 in the table below was prepared similarly to Example 8 using the appropriate benzyl bromide building block. [Table 6]

[0224] Example 10 (3R)-3-amino-7-[5-(3-aminooxetan-3-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) tert-butyl N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-yl]carbamate [ka] The title compound was prepared analogously to general procedure 10 from tert-butyl N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-yl]carbamate (Example 8, step a) (40 mg, 0.067 mmol) as a white solid (29 mg, 73% yield). MS (ESI): 472.2 [M-isobutene + H] + .

[0225] Step b) tert-butyl N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 Prepared as per general procedure 1a from [1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-yl]carbamate (29 mg, 0.050 mmol) and 2-[4-(chloromethyl)phenyl]-5-(trifluoromethyl)pyridine (20.25 mg, 0.075 mmol, equivalents: 1.5) as a white solid (10 mg, 18% yield). MS (ESI): 819.6 [M+H] + .

[0226] Step c) (3R)-3-amino-7-[5-(3-aminooxetan-3-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared similarly to general procedure 11a from [1,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-yl]carbamate (10 mg, 0.01 mmol) as a white solid (3 mg, 47% yield). MS (ESI): 619.3 [M+H] +

[0227] Example 11 (3R)-3-amino-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) tert-butyl N-[(3R)-8-fluoro-4-oxo-7-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] To a solution of tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (580 mg, 1.57 mmol, 1.0 equiv., Example 7, Step d) and DIPEA (0.82 mL, 4.7 mmol, 3.0 equiv.) in DMF (10 mL) was added N,N'-carbonyldiimidazole (380.9 mg, 2.35 mmol, 1.5 equiv.) at 0°C. The mixture was stirred at 50°C for 16 hours. The mixture was poured into water (5 mL) and the pH was adjusted to pH 4 with 2 M HCl. The aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with (5 mL, 10% EtOAc in petroleum ether) for 10 minutes, then filtered, and the filter cake was dried in vacuo to give the title compound (190 mg, 0.48 mmol, 22% yield) as a pale yellow solid. MS (ESI): 341.1 [M-isobutene + H] +

[0228] Step b) tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-7-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-(5-hydroxy-1,2,4-oxadiazol-3-yl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (20 mg, 0.05 mmol) analogously to general procedure 10 and obtained as a pale yellow solid (18 mg, 0.04 mmol, 80% yield). MS (ESI): 329.0 [M-Boc+H] +

[0229] Step c) tert-butyl N-[(3R)-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-(5-hydroxy-1,2,4-oxadiazol-3-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (84 mg, 0.2 mmol, 1.0 equiv.) and 4-oxa-7-azaspiro[2.5]octane hydrochloride (44 mg, 0.29 mmol, 1.5 equiv.) as in general procedure 13 and obtained as a white solid (79 mg, 0.15 mmol, 65% yield). MS (ESI): 468.1 [M-isobutene + H] +

[0230] Step d) tert-butyl N-[(3R)-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared analogously to procedure 1b from tert-butyl N-[(3R)-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (94 mg, 0.18 mmol, 1.0 equiv.) and [6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methanol (50 mg, 0.2 mmol, 1.1 equiv., CAS 356058-13-4) as a white solid (60 mg, 0.08 mmol, 44% yield). MS (ESI): 688.2 [M+H] +

[0231] Step e) (3R)-3-amino-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (55 mg, 0.07 mmol) in analogy to general procedure 11c and obtained as a white solid. MS (ESI): 659.2 [M+H] +

[0232] The examples in the following table were prepared analogously to Example 11 using the general procedure shown, using the appropriate amine and benzyl bromide building blocks. [Table 7]

[0233] Example 14 (3R)-3-amino-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) tert-butyl N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ] 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (3.0 g, 8.89 mmol, Example 7, step c) analogously to general procedure 10 and obtained as a white solid (3.2 g, 8.66 mmol, 88% yield). MS (ESI): 314.1 [M-isobutene + H] +

[0234] Step b) tert-butyl N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (100 mg, 0.27 mmol, 1.0 equiv.) and Intermediate 2 (166.7 mg, 0.3 mmol, 1.1 equiv.) in analogy to general procedure 1a and obtained as a white solid (100 mg, 0.17 mmol, 59% yield). MS (ESI): 597.1 [M+H] +

[0235] Step c) tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-1,1,4-trioxo-5-[[6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate and tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-1,1,4-trioxo-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (300 mg, 0.5 mmol, 1.0 equiv.) in analogy to general procedure 6 and obtained as an inseparable mixture and a pale yellow solid (200 mg, 54% yield). MS (ESI): 630.2 [M+H] +

[0236] Step d) tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-7-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-5-[[6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-3-yl]carbamate; tert-butyl and N-[(3R)-8-fluoro-1,1,4-trioxo-7-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] tert-Butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-1,1,4-trioxo-5-[[6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ in DCM (9 ml) 6 ,5-benzothiazepin-3-yl]carbamate and tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-1,1,4-trioxo-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6To a solution of a mixture of [5-benzothiazepin-3-yl]carbamate (180 mg, 0.3 mmol, 1.0 equiv.), triethylamine (0.08 mL, 0.57 mmol, 2.0 equiv.) and N,N'-carbonyldiimidazole (69.5 mg, 0.43 mmol, 1.5 equiv.) was added at room temperature, and the mixture was stirred for 3 h. The reaction mixture was concentrated under reduced pressure. The remaining residue was dissolved in EtOAc (10 mL), washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The remaining crude material was purified by column chromatography on silica gel (30-100% EtOAc in petroleum ether) to give tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-7-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-5-[[6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate and tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-7-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 An inseparable mixture of 5-benzothiazepin-3-yl]carbamate (160 mg, 79% yield) was obtained as an orange solid. MS (ESI): 656.2 [M+H] +

[0237] Step e) tert-butyl N-[(3R)-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[[6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6,5-benzothiazepin-3-yl]carbamate and tert-butyl N-[(3R)-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [Mixture A], and tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-7-(5-pyrrolidin-1-yl-1,2,4-oxadiazol-3-yl)-5-[[6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate and tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-7-(5-pyrrolidin-1-yl-1,2,4-oxadiazol-3-yl)-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [Mixture B] [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-7-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-5-[[6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-3-yl]carbamate; tert-butyl and N-[(3R)-8-fluoro-1,1,4-trioxo-7-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6,5-Benzothiazepin-3-yl]carbamate (60 mg, 0.09 mmol, 1.0 equiv.) and 4-oxa-7-azaspiro[2.5]octane (15.06 mg, 0.1 mmol, 1.1 equiv.) were prepared analogously to general procedure 13 to give an inseparable mixture and a white solid [Mixture A] (30 mg, 23%, MS(ESI): 751.2 [M+H]). + ), as an inseparable mixture and a white solid [Mixture B] (20 mg, 19%, MS(ESI): 709.3 [M+H] + ) was obtained.

[0238] Step f) (3R)-3-amino-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] tert-Butyl N-[(3R)-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[[6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ in EtOAc (1 mL) 6 ,5-benzothiazepin-3-yl]carbamate and tert-butyl N-[(3R)-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6To a solution of [5-benzothiazepin-3-yl]carbamate [Mixture A] (30 mg, 0.04 mmol, 1.0 equiv.) was added 4 N HCl in EtOAc (1.0 mL, 4.0 mmol, 100 equiv.) at 0 °C, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and the remaining residue was purified by chiral SFC (retention time 1.77 min: conditions: column Regis (S,S) Whelk-O 1, 250 mm × 25 mm ID, 10 μm; mobile phase: phase A with CO and phase B with EtOH (0.1% NH(aq)); eluent 40% EtOH (0.1% NH(aq)) in CO; flow rate 75 mL / min; detector: PDA) to give the pure title compound as a white solid (7 mg), which was dissolved in EtOAc (1 mL). To this solution was added 4N HCl in EtOAc (1.0 mL, 4 mmol) and stirred for 1 hour. The mixture was then concentrated under reduced pressure to give the title compound (7.0 mg, 86% yield) as a white solid as the hydrochloride salt. MS (ESI): 651.1 [M+H] +

[0239] Example 15 (3R)-3-amino-8-fluoro-1,1-dioxo-7-(5-pyrrolidin-1-yl-1,2,4-oxadiazol-3-yl)-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) (3R)-3-amino-8-fluoro-1,1-dioxo-7-(5-pyrrolidin-1-yl-1,2,4-oxadiazol-3-yl)-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] tert-Butyl N-[(3R)-8-fluoro-1,1,4-trioxo-7-(5-pyrrolidin-1-yl-1,2,4-oxadiazol-3-yl)-5-[[6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ in EtOAc (1 mL) 6 ,5-benzothiazepin-3-yl]carbamate and tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-7-(5-pyrrolidin-1-yl-1,2,4-oxadiazol-3-yl)-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 To a solution of [5-benzothiazepin-3-yl]carbamate [Mixture B] (20.0 mg, 0.03 mmol, 1.0 equiv.) was added 4N HCl in EtOAc (1.0 mL, 4.0 mmol, 130 equiv.) at 0° C., and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and the remaining residue was purified by chiral SFC to give a white solid (4.5 mg), which was dissolved in EtOAc (1 mL). To this solution was added 4N HCl in EtOAc (1.0 mL, 4 mmol) and stirred for 1 h. The mixture was then concentrated under reduced pressure to give the title compound (4.8 mg, 91% yield) as a hydrochloride salt as a white solid. MS (ESI): 609.2 [M+H] +

[0240] Example 16 1-[3-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile [ka] Step a) [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]methylene]amino]1-cyanocyclopropanecarboxylate [ka] The title compound was prepared analogously to general procedure 8a from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 7, step d) (1 g, 2.7 mmol, 1.0 equiv.) and 1-cyano-1-cyclopropanecarboxylic acid (300 mg, 2.7 mmol, 1.0 equiv., CAS: 6914-79-0) as a white solid (650 mg, 35% yield). MS (ESI) 408.1 [M-isobutene + H] +

[0241] Step b) tert-Butyl N-[(3R)-7-[5-(1-cyanocyclopropyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared analogously to general procedure 9a from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]methylene]amino]1-cyanocyclopropanecarboxylate (650 g, 1.4 mmol, 1.0) as a yellow solid (160 mg, 25% yield). MS (ESI) 390.1 [M-isobutene + H] +

[0242] Step c) tert-butyl N-[(3R)-7-[5-(1-cyanocyclopropyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[5-(1-cyanocyclopropyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (160 mg, 0.36 mmol) in analogy to general procedure 10 as a yellow oil (140 mg, 60% yield). MS (ESI): 378.1 [M-Boc+H] +

[0243] Step d) tert-butyl N-[(3R)-7-[5-(1-cyanocyclopropyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-(1-cyanocyclopropyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 Prepared analogously to general procedure 1a from [4-(4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (49.5 mg, 0.2 mmol, 2 equiv., CAS: 2093101-98-3) as a yellow oil (80 mg, 73% yield). MS (ESI): 604.2 [M-Boc+H] +

[0244] Step e) 1-[3-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-(1-cyanocyclopropyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared similarly to general procedure 11c from 5-benzothiazepin-3-yl]carbamate (80 mg, 0.11 mmol) and obtained as the hydrochloride salt as a white solid (24.9 mg, 34% yield). MS (ESI): 604.2 [M+H] +

[0245] Example 17 in the table below was prepared similarly to Example 16 using the appropriate benzyl bromide building block. [Table 8]

[0246] Example 18 (3R)-3-amino-8-fluoro-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared analogously to general procedure 1a from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 104, step c) (150 mg, 0.445 mmol) and 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (CAS 2093101-98-3) (204 mg, 0.67 mmol) as a white solid (216 mg, 74% yield). MS (ESI): 508.2 [M-isobutene + H] + .

[0247] Step b) tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (200 mg, 0.302 mmol) in analogy to general procedure 6 and obtained as a white solid (200 mg, 94% yield). MS (ESI): 597.4 [M+H] + .

[0248] Step c) [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]methylene]amino]2-(hydroxymethyl)tetrahydrofuran-2-carboxylate [ka] The title compound was prepared analogously to general procedure 8a from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.142 mmol) and 2-(hydroxymethyl)tetrahydrofuran-2-carboxylic acid (CAS 442877-01-2) (25 mg, 0.17 mmol) and obtained as a white powder (72.7 mg, 53% yield). MS(ESI): 723.5 [MH]

[0249] Step d) tert-butyl N-[(3R)-8-fluoro-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,2,4-oxadiazol-3-yl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared analogously to general procedure 9a from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]methylene]amino]2-(hydroxymethyl)tetrahydrofuran-2-carboxylate (72.7 mg, 0.075 mmol) as a white solid (50.3 mg, 94% yield). MS (ESI): 651.2 [M-isobutene + H] + .

[0250] Step e) tert-butyl N-[(3R)-8-fluoro-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,2,4-oxadiazol-3-yl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (50.3 mg, 0.071 mmol) as in general procedure 10 and obtained as a white powder (23.7 mg, 45% yield). MS (ESI): 683.2 [M-isobutene + H] + .

[0251] Step e) (3R)-3-amino-8-fluoro-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-8-fluoro-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared as per general procedure 11b from 5-benzothiazepin-3-yl]carbamate (23.7 mg, 0.032 mmol) and obtained as the hydrochloride salt (20.9 mg, 96% yield) as an off-white powder. MS (ESI): 639.2 [M+H] + .

[0252] Example 19 (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(5-tert-butyl-1,3,4-oxadiazol-2-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylic acid [ka] The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (2.5 g, 7.09 mmol, CAS 2089150-62-7) as in general procedure 2 and obtained as an orange amorphous solid (2.26 g, 89%). MS (ESI): 283.0 [M-isobutene + H] +

[0253] Step b) tert-Butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylic acid (1120 mg, 3.31 mmol) in analogy to general procedure 3 and obtained as a pale yellow solid (1036 mg, 80%). MS (ESI): 351.2 [MH]

[0254] Step c) tert-Butyl N-[(3R)-7-[(2,2-dimethylpropanoylamino)carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (4.5 g, 7.39 mmol, 1 equiv.) and pivalic acid (889.0 mg, 8.7 mmol, 1.18 equiv.) analogously to general procedure 4a and obtained as a pale yellow solid (2.95 g, 6.76 mmol, 84% yield). MS (ESI): 381.1 [M+H-isobutene] +

[0255] Step d) tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[(2,2-dimethylpropanoylamino)carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (2.9 g, 6.64 mmol) in analogy to general procedure 5a as a pale yellow solid (1.6 g, 3.82 mmol, 54% yield). MS (ESI): 363.1 [M+H-isobutene] +

[0256] Step e) tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (241 mg, 0.58 mmol) analogously to general procedure 10 and obtained as a white solid (270 mg, 0.6 mmol, 94.5% yield). MS (ESI): 395.2 [M+H-isobutene] +

[0257] Step f) tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(5-tert-butyl-1,3,4-oxadiazol-2-yl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 Prepared as per general procedure 1a from [5-benzothiazepin-3-yl]carbamate (100 mg, 0.22 mmol, 1.0 equiv.) and intermediate 3 (78.94 mg, 0.22 mmol, 1.0 equiv.) as a pale yellow solid (150 mg, 0.23 mmol, 77% yield). MS (ESI): 665.3 [M+H] +

[0258] Step g) (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(5-tert-butyl-1,3,4-oxadiazol-2-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(5-tert-butyl-1,3,4-oxadiazol-2-yl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 Prepared similarly to general procedure 11c from [5-benzothiazepin-3-yl]carbamate (150 mg, 0.23 mmol) and obtained as the hydrochloride salt (23.4 mg, 0.04 mmol, 17% yield) as a yellow solid. MS (ESI): 565.2 [M+H] +

[0259] The examples in the table below were prepared similarly to Example 19 using the appropriate benzyl bromide building blocks. [Table 9] TIFF2025526681000104.tif220170TIFF2025526681000105.tif255170TIFF2025526681000106.tif214170

[0260] Example 32 (3R)-3-amino-7-[5-(1-amino-2,2,2-trifluoro-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine-7-carboxylic acid [ka] NaIO (2.28 g, 10.66 mmol, 2.283 equiv.) was dissolved in water (22.37 mL) and cooled to 0 °C under an inert atmosphere. RuCl 3 3H 2 O (12.21 mg, 46.69 μmol, 0.01 equiv.) was added, and the reaction was stirred for 5 min. A solution of (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylic acid (1580 mg, 4.67 mmol, 1.0 equiv., Example 19, Step a) in acetonitrile (25 mL) was then added, and the resulting gray suspension was stirred for 3 h. The reaction was quenched by the addition of isopropanol (2 mL) and then diluted with EtOAc and 2 M HCl. The biphasic mixture was filtered through a Celite plug. The resulting filtrate was transferred to a separatory funnel, and the phases were separated. The organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated to give (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-3,5-dihydro-2H-1λ 65-Benzothiazepine-7-carboxylic acid (1287 mg, 74%) was obtained as a pale yellow solid. MS(ESI): 369.1 [MH]

[0261] Step b) tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-3,5-dihydro-2H-1λ] 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 Prepared as per general procedure 3 from 5-benzothiazepine-7-carboxylic acid (500 mg, 877.48 μmol, 1 equiv.) and obtained as a yellow solid (282 mg, 72%). MS (ESI): 383.2 [M+H] +

[0262] Step c) tert-butyl N-[(3R)-7-[[[2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-methyl-propanoyl]amino]carbamoyl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 Prepared analogously to general procedure 4a from 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-methylpropionic acid (64.91 mg, 252.36 μmol, 1.2 equiv., CAS 170462-68-7) and obtained as a white powder (63.3 mg, 45%). MS (ESI): 622.2 [M+H] +

[0263] Step d) tert-butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[[[2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-methyl-propanoyl]amino]carbamoyl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 Prepared analogously to general procedure 5b from 5-benzothiazepin-3-yl]carbamate (60 mg, 0.106 mmol, 1 equiv.) as a white solid (50.9 mg, 83%). MS (ESI): 604.2 [M+H] +

[0264] Step e) tert-butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6Prepared as per general procedure 1a from 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (57.27 mg, 0.187 mmol, 1.5 equiv., CAS 2093101-98-3) as a white solid (73.5 mg, 71%). MS(ESI): 830.4 [MH]

[0265] Step f) (3R)-3-amino-7-[5-(1-amino-2,2,2-trifluoro-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared analogously to general procedure 11a from 5-benzothiazepin-3-yl]carbamate (75.3 mg, 0.091 mmol) and obtained as the hydrochloride salt (53.8 mg, 89%) as a white solid. MS (ESI): 632.4 [M+H] +

[0266] The examples in the following table were prepared similarly to Example 32 using the appropriate benzyl bromide building blocks. [Table 10]

[0267] The examples in the following table were prepared similarly to Example 32 using the appropriate benzyl bromide or carboxylic acid building blocks. [Table 11] TIFF2025526681000116.tif95170

[0268] Example 34 (3R)-3-amino-7-[5-(1-amino-2,2-dimethyl-propyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) tert-Butyl N-[(3R)-7-[[[2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]amino]carbamoyl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.168 mmol, 1.0 equiv., Example 54, step c) and N-Boc-tert-leucine (255.05 mg, 1.1 mmol, 1.1 equiv.) in analogy to general procedure 4b, and obtained as a light brown solid (650 mg, 0.82 mmol, 82% yield). MS (ESI): 692.3 [M+H-Boc] +

[0269] Step b) tert-Butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)-2,2-dimethyl-propyl]-1,3,4-oxadiazol-2-yl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[[[2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]amino]carbamoyl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (630 mg, 0.8 mmol) in analogy to general procedure 5a as a pale yellow solid (800 mg, 1.03 mmol, 123% yield). MS (ESI): 774.4 [M+H] + .

[0270] Step c) tert-Butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)-2,2-dimethyl-propyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)-2,2-dimethyl-propyl]-1,3,4-oxadiazol-2-yl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (750 mg, 0.97 mmol) in analogy to general procedure 10 as a yellow solid (500 mg, 0.62 mmol, 64% yield). MS (ESI): 828.3 [M+H] + .

[0271] Step d) (3R)-3-amino-7-[5-(1-amino-2,2-dimethyl-propyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)-2,2-dimethyl-propyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared similarly to general procedure 11c from 5-benzothiazepin-3-yl]carbamate (150 mg, 0.19 mmol) as a pale yellow solid (111.7 mg, 0.16 mmol, 86% yield). MS (ESI): 606.0 [M+H] + .

[0272] The examples in the table below were prepared similarly to Example 34 using the appropriate carboxylic acid building blocks. [Table 12]

[0273] Example 38 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile [ka] Step a) tert-Butyl N-[(3R)-7-[[(2-cyano-2-methyl-propanoyl)amino]carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared analogously to general procedure 4a from tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.270 mmol, 1.0 equiv., Example 19, step b) and 2-cyano-2-methylpropionic acid (36.59 mg, 0.323 mmol, 1.2 equiv., CAS 22426-30-8) as a white solid (114.5 mg, 95%). MS (ESI): 446.2 [MH]

[0274] Step b) tert-Butyl N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[[(2-cyano-2-methyl-propanoyl)amino]carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (114.5 mg, 0.256 mmol) in analogy to general procedure 5b and obtained as a white solid (83.3 mg, 76%). MS (ESI): 374.1 [M-isobutene + H] + .

[0275] Step c) tert-butyl N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized as tert-butyl N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (83.3 mg, 0.194 mmol) as in general procedure 10 to give a white solid (72.7 mg, 81%). MS (ESI): 406.1 [M-isobutene + H] +

[0276] Step d) tert-butyl N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 Prepared analogously to general procedure 1a from [4-(4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (35.9 mg, 0.117 mmol, 1.5 equiv., CAS 2093101-98-3) as a white solid (33 mg, 62%). MS (ESI): 632.1 [M-isobutene + H] +

[0277] Step e) 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared analogously to general procedure 11a from [5-benzothiazepin-3-yl]carbamate (33 mg, 0.048 mmol) and obtained as the hydrochloride salt (29.5 mg, 99%) as an off-white solid. MS (ESI): 632.4 [M+H] +

[0278] The examples in the following table were prepared similarly to Example 38, using the appropriate carboxylic acid and / or benzyl bromide building blocks in the indicated synthetic antibodies. [Table 13]

[0279] Example 41 (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) tert-Butyl N-[(3R)-7-[[[1-(tert-butoxycarbonylamino)cyclohexanecarbonyl]amino]carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared analogously to general procedure 4a from tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (150 mg, 0.425 mmol, 1.0 equiv., Example 19, step b) and 1-(tert-butoxycarbonylamino)-1-cyclohexanecarboxylic acid (124.27 mg, 0.51 mmol, 1.2 equiv., CAS 115951-16-1) as a pale yellow solid (207.5 mg, 76%). MS (ESI): 576.3 [MH]

[0280] Step b) tert-Butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[[[1-(tert-butoxycarbonylamino)cyclohexanecarbonyl]amino]carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (67 mg, 0.095 mmol) in analogy to general procedure 5b and obtained as a white solid (48 mg, 80%). MS (ESI): 560.3 [M+H] +

[0281] Step c) tert-butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (48 mg, 0.076 mmol) as in general procedure 10 and obtained as a white solid (46 mg, 96%). MS (ESI): 480.1 [M-2 x isobutene + H] +

[0282] Step d) tert-butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared analogously to general procedure 1a from 2-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)pyridine (23.1 mg, 0.073 μmol, 1.0 equiv., CAS 1056641-21-4) as a white solid (49 mg, 81%). MS (ESI): 827.7 [M+H] +

[0283] Step e) (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared similarly to general procedure 11a from 5-benzothiazepin-3-yl]carbamate (49 mg, 0.059 mmol) and obtained as the hydrochloride salt (42 mg, 101%) as an off-white solid. MS (ESI): 627.3 [M+H] +

[0284] The examples in the following table were prepared similarly to Example 41 using the appropriate benzyl bromide building blocks. [Table 14]

[0285] Example 45 2-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile [ka] Step a) tert-butyl N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The solution was treated with tert-butyl N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ as in general procedure 1a. 6 ,5-Benzothiazepin-3-yl]carbamate (36 mg, 0.078 mmol, 1.0 equiv., Example 38, step c) and 4-(chloromethyl)-4'-methoxy-1,1'-biphenyl (27.2 mg, 0.12 mmol, 1.5 equiv., CAS 93258-73-2) were added to give a white solid (35.7 mg, 70%). MS (ESI): 602.2 [M-isobutene + H] +

[0286] Step b) 2-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 Prepared analogously to general procedure 11a from [5-benzothiazepin-3-yl]carbamate (35 mg, 0.053 mmol) and obtained as the hydrochloride salt (31 mg, 98%) as an off-white solid. MS (ESI): 558.3 [M-isobutene + H] +

[0287] The examples in the table below were prepared similarly to Example 45 using the appropriate benzyl bromide building blocks. [Table 15] TIFF2025526681000141.tif229170TIFF2025526681000142.tif224170TIFF2025526681000143.tif220170TIFF2025526681000144.tif255170 TIFF2025526681000145.tif242170TIFF2025526681000146.tif225170TIFF2025526681000147.tif224170TIFF2025526681000148.tif174170

[0288] Example 48 (3R)-3-Amino-7-[5-(2-methyloxetan-2-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1lambda 6,5-benzothiazepin-4-one [ka] Step a) tert-butyl N-[(3R)-7-[[(2-methyloxetane-2-carbonyl)amino]carbamoyl]-1,1,4-trioxo-3,5-dihydro-2H-1lambda 6,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 Prepared analogously to general procedure 4a from 5-benzothiazepin-3-yl]carbamate (90 mg, 0.234 mmol, 1.0 equiv., Example 32, step b) and 2-methyl-2-oxetanecarboxylic acid (32.6 mg, 0.28 mmol, 1.2 equiv., CAS 1305207-92-4) as an off-white powder (60 mg, 53%). MS (ESI): 481.2 [M+H] +

[0289] Step b) tert-butyl N-[(3R)-7-[5-(2-methyloxetan-2-yl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1lambda 6,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[[(2-methyloxetane-2-carbonyl)amino]carbamoyl]-1,1,4-trioxo-3,5-dihydro-2H-1lambda 6,5-benzothiazepin-3-yl]carbamate (60 mg, 0.106 mmol) in analogy to general procedure 5b and obtained as a white powder (25 mg, 43%). MS (ESI): 463.1 [M+H] +

[0290] Step c) tert-butyl N-[(3R)-7-[5-(2-methyloxetan-2-yl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1lambda 6,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[5-(2-methyloxetan-2-yl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1lambda 6,5-benzothiazepin-3-yl]carbamate (25 mg, 0.054 mmol, 1.0 equiv.) and 4-(bromomethyl)-4'-(trifluoromethyl)-1,1'-biphenyl (22 mg, 0.070 μmol, 1.3 equiv., CAS 613241-14-8) in analogy to general procedure 1a and obtained as a white powder (17 mg, 44%). MS (ESI): 643.2 [M-isobutene + H] +

[0291] Step d) (3R)-3-amino-7-[5-(2-methyloxetan-2-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1 lambda 6,5-benzothiazepin-4-one [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[5-(2-methyloxetan-2-yl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1lambda 6,5-benzothiazepin-3-yl]carbamate (24.8 mg, 0.035 mmol) in analogy to general procedure 11a and obtained as a white powder (8.5 mg, 40%). MS (ESI): 599.2 [M+H] +

[0292] The examples in the following table were prepared similarly to Example 48 using the appropriate benzyl bromide building blocks. [Table 16]

[0293] The examples in the table below were prepared in a similar manner to Example 48 using the appropriate carboxylic acid building blocks. [Table 17]

[0294] Example 49 (3R)-3-amino-7-[5-(3-fluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) Benzyl 3-[[[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carbonyl]amino]carbamoyl]-3-fluoro-piperidine-1-carboxylate [ka] The title compound was prepared analogously to general procedure 4a from tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (400 mg, 1.14 mmol, 1.0 equiv., Example 19, step b) and 1-(phenylmethyl)3-fluoro-1,3-piperidinedicarboxylate (351 mg, 1.25 mmol, 1.1 equiv., CAS 1363166-38-4) as a white solid (680 mg, 97%). MS (ESI): 516.2 [M-Boc+H] +

[0295] Step b) Benzyl 3-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-fluoro-piperidine-1-carboxylate [ka] The title compound was prepared analogously to general procedure 5b from benzyl 3-[[[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carbonyl]amino]carbamoyl]-3-fluoro-piperidine-1-carboxylate (680 mg, 1.1 mmol, 1.0 equiv.) as a white solid (505 mg, 77%). MS (ESI): 542.1 [M-isobutene + H] +

[0296] Step c) Benzyl 3-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-fluoro-piperidine-1-carboxylate [ka] The title compound was prepared from benzyl 3-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-fluoro-piperidine-1-carboxylate (180 mg, 0.295 mmol, 1 eq.) analogously to general procedure 10 and obtained as a white solid (180 mg, 97%). MS (ESI): 628.4 [M+H] +

[0297] Step d) benzyl 3-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-fluoro-piperidine-1-carboxylate [ka] The title compound was prepared from benzyl 3-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-fluoro-piperidine-1-carboxylate (80 mg, 0.127 mmol, 1.0 equiv.) and 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (50.7 mg, 0.165 mmol, 1.3 equiv., CAS 2093101-98-3) in analogy to general procedure 1a and obtained as a white solid (89.6 mg, 81%). MS (ESI): 800.4 [M-isobutene + H] +

[0298] Step e) tert-butyl N-[(3R)-7-[5-(3-fluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ6 ,5-benzothiazepin-3-yl]carbamate [ka] Benzyl 3-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ in MeOH (1.7 mL) and THF (0.5 mL) 6 To a solution of [(3R)-7-[5-(3-fluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-piperidine-1-carboxylate (89.6 mg, 0.103 mmol, 1.0 equiv.) under an inert atmosphere was added Pd / C (22 mg). The reaction mixture was stirred under a hydrogen atmosphere for 5 hours. The mixture was filtered through a plug of Celite and washed with THF and MeOH. The filtrate was concentrated to give tert-butyl N-[(3R)-7-[5-(3-fluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate (81.7 mg, 55%) was obtained as a pale yellow solid. MS(ESI): 722.6 [M+H] +

[0299] Step f) tert-butyl N-[(3R)-7-[5-(3-fluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] tert-Butyl N-[(3R)-7-[5-(3-fluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ in MeOH (0.57 mL) 6 To a solution of [5-benzothiazepin-3-yl]carbamate (81.7 mg, 0.057 mmol, 1.0 equiv.) was added formalin (37% aqueous solution, 56 uL, 0.57 mmol, 10 equiv.) and sodium triacetoxyborohydride (120 mg, 0.57 mmol, 10 equiv.). The mixture was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with DCM (3 times). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The remaining crude material was purified using silica gel flash column chromatography (0 to 100% EtOAc in heptane) to give tert-butyl N-[(3R)-7-[5-(3-fluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate (15.9 mg, 38%) was obtained as a white solid. MS(ESI): 736.6 [M+H] +

[0300] Step g) (3R)-3-amino-7-[5-(3-fluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-(3-fluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared similarly to general procedure 11a from [5-benzothiazepin-3-yl]carbamate (15.9 mg, 0.022 mmol) and obtained as the hydrochloride salt (9.8 mg, 68%) as an off-white solid. MS (ESI): 636.3 [M+H] +

[0301] The examples in the following table were prepared similarly to Example 49 using the appropriate benzyl bromide building blocks. [Table 18]

[0302] Example 52 (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) (2R)-2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-methyl-propanoic acid [ka] To a solution of (2R)-2-amino-3,3,3-trifluoro-2-methyl-propionic acid (1 g, 6.37 mmol, 1.0 equiv., CAS 102210-02-6) in THF (20 ml) at room temperature, DMAP (233 mg, 1.91 mmol, 0.3 equiv.) and di-tert-butyl dicarbonate (1.67 g, 7.64 mmol, 1.2 equiv.) were added, and the reaction mixture was stirred overnight. The resulting solution was poured into saturated NaHCO3 and washed twice with EtOAc. The aqueous phase was then acidified with 1N HCl and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give (2R)-2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-methyl-propanoic acid (1.32 g, 81%) as a white solid. MS(ESI):158.0[M-Boc+H] +

[0303] Step b) tert-Butyl N-[(1R)-1-[[[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carbonyl]amino]carbamoyl]-2,2,2-trifluoro-1-methyl-ethyl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (180 mg, 0.510 mmol, 1.0 equiv.) and (2R)-2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-methyl-propanoic acid (131.37 mg, 0.510 mmol, 1.0 equiv., CAS) analogously to general procedure 4b and obtained as a white solid (88 mg, 29%). MS(ESI): 590.3 [MH]

[0304] Step c) tert-Butyl N-[(1R)-1-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2,2,2-trifluoro-1-methyl-ethyl]carbamate [ka] The title compound was prepared analogously to general procedure 5a from tert-butyl N-[(1R)-1-[[[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carbonyl]amino]carbamoyl]-2,2,2-trifluoro-1-methyl-ethyl]carbamate (750 mg, 0.3 mmol, 1.0 equiv.) as a white solid (82 mg, 46%). MS(ESI): 572.3 [MH]

[0305] Step d) tert-Butyl N-[(1R)-1-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2,2,2-trifluoro-1-methyl-ethyl]carbamate [ka] The title compound was prepared analogously to general procedure 1a from tert-butyl N-[(1R)-1-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2,2,2-trifluoro-1-methyl-ethyl]carbamate (144 mg, 0.251 mmol, 1.0 equiv.) and 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (92.5 mg, 0.301 mmol, 1.2 equiv., CAS 2093101-98-3) as a white solid (153 mg, 76%). MS (ESI): 688.2 [M-Boc+H] +

[0306] Step e) tert-butyl N-[(3R)-7-[5-[(1R)-1-(tert-butoxycarbonylamino)-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(1R)-1-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2,2,2-trifluoro-1-methyl-ethyl]carbamate (153 mg, 191.31 μmol, 1.0 equiv.) as a white solid (122 mg, 77%). MS(ESI): 830.4 [MH]

[0307] Step f) (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-[(1R)-1-(tert-butoxycarbonylamino)-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared analogously to general procedure 11a from [5-benzothiazepin-3-yl]carbamate (40 mg, 0.048 mmol, 1.0 equiv.) and obtained as the hydrochloride salt (31 mg, 97%) as a white solid. MS (ESI): 632.1 [M+H] +

[0308] The examples in the table below were prepared similarly to Example 52 using the appropriate carboxylic acid building blocks. [Table 19]

[0309] Example 153 (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) tert-butyl N-[(3R)-7-[5-[(1R)-1-(tert-butoxycarbonylamino)-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(1R)-1-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2,2,2-trifluoro-1-methyl-ethyl]carbamate (142 mg, 247.6 μmol, Example 52, step c) in analogy to general procedure 10 and obtained as a white solid (135 mg, 90%). MS (ESI): 604.2 [M+H] +

[0310] Step b) tert-Butyl N-[(3R)-7-[5-[(1R)-1-(tert-butoxycarbonylamino)-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-[(1R)-1-(tert-butoxycarbonylamino)-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6,5-benzothiazepin-3-yl]carbamate (25 mg, 41.28 μmol, 1.0 equiv.) and Intermediate 38 (15.1 mg, 45.4 μmol, 1.1 equiv.) prepared analogously to general procedure 1a as a white solid (32 mg, 91%). MS (ESI): 857.5 [M+H] +

[0311] Step c) (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-[(1R)-1-(tert-butoxycarbonylamino)-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared analogously to general procedure 11a from 5-benzothiazepin-3-yl]carbamate (32 mg, 37.35 μmol) and obtained as the hydrochloride salt (24 mg, 89%) as a white solid. MS (ESI): 657.2 [M+H] +

[0312] The examples in the following table were prepared analogously to Example 153 using the appropriate benzyl bromide building block. [Table 20]

[0313] Example 54 (3R)-3-Amino-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) Methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylate [ka] The title compound was prepared analogously to general procedure 1a from methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (500 mg, 1.4 mmol, 1.0 equiv.) and 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (496 mg, 1.62 mmol, 1.15 equiv., CAS 2093101-98-3) and obtained as a white solid (784 mg, 94%). MS (ESI): 523.2 [M-isobutene + H] +

[0314] Step b) (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid [ka] The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (770 mg, 1.33 mmol) in analogy to general procedure 2 and obtained as a pale yellow solid (756 mg, 82%). MS (ESI): 509.1 [M-isobutene + H] +

[0315] Step c) tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (750 mg, 1.08 mmol) analogously to general procedure 3 and obtained as a white solid (552 mg, 86%). MS (ESI): 523.1 [M-isobutene + H] +

[0316] Step d) tert-butyl N-[(3R)-7-[[[2-(hydroxymethyl)tetrahydrofuran-2-carbonyl]amino]carbamoyl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared analogously to general procedure 4a from tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.168 mmol, 1.0 equiv.) and 2-(hydroxymethyl)tetrahydrofuran-2-carboxylic acid (49 mg, 0.335 mmol, 2.0 equiv., CAS 442877-01-2) as a white solid (97 mg, 60%). MS (ESI): 607.1 [M-Boc+H] +

[0317] Step e) tert-butyl N-[(3R)-7-[[[2-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-2-carbonyl]amino]carbamoyl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate [ka] To a solution of tert-butyl N-[(3R)-7-[[[2-(hydroxymethyl)tetrahydrofuran-2-carbonyl]amino]carbamoyl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (97 mg, 0.1 mmol, 1.0 equiv.) in DCM (1 mL), TBDMS-Cl (22.65 mg, 0.15 mmol, 1.5 equiv.) and imidazole (17.05 mg, 0.25 mmol, 2.5 equiv.) were added at room temperature overnight. The reaction mixture was directly concentrated and purified by flash column chromatography on silica gel (0-60% EtOAc in heptane) to give the title compound (66 mg, 80%) as a white solid. MS(ESI):765.3[M-isobutene+H] +

[0318] Step f) tert-Butyl N-[(3R)-7-[5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[[[2-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-2-carbonyl]amino]carbamoyl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (66 mg, 0.08 mmol) in analogy to general procedure 5b and obtained as a colorless solid (41 mg, 61%). MS (ESI): 803.5 [M+H] +

[0319] Step g) tert-butyl N-[(3R)-7-[5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (41 mg, 0.049 mmol) in analogy to general procedure 10 and obtained as a white solid (40 mg, 98%). MS (ESI): 835.3 [M+H] +

[0320] Step h) (3R)-3-amino-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared analogously to general procedure 11a from [5-benzothiazepin-3-yl]carbamate (40 mg, 0.048 mmol) and obtained as the hydrochloride salt (18 mg, 57%) as a white solid. MS (ESI): 621.1 [M+H] +

[0321] The examples in the table below were prepared analogously to Example 54 using the appropriate benzyl bromide building blocks. [Table 21]

[0322] Example 56 Methyl 3,3-difluoro-5-[5-[(3R)-3-amino-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] Step a) Benzyl 3,3-difluoro-5-[[[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine-7-carbonyl]amino]carbamoyl]piperidine-1-carboxylate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (980 mg, 3.27 mmol, Example 19, step b) and 5,5-difluoro-1-[(E)-2-vinylbut-2-eneoxy]carbonyl-piperidine-3-carboxylic acid (980 mg, 3.3 mmol, 1.2 equivalents, CAS 1356338-81-2) in analogy to general procedure 4b, and obtained as a pale yellow solid (1.08 g, 63% yield). MS (ESI): 534.1 [M+H-isobutene] +

[0323] Step b) Benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] The title compound was synthesized by the reaction of benzyl 3,3-difluoro-5-[[[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1λ 6 Prepared similarly to general procedure 5a from 5-benzothiazepine-7-carbonylaminocarbamoylpiperidine-1-carboxylate (1060 mg, 1.67 mmol) as a pale yellow foam (721 mg, 70% yield). MS (ESI): 560.1 [M+H-isobutene] +

[0324] Step c) Benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] The title compound was synthesized by the reaction of benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1λ 6 Prepared analogously to general procedure 1a from [1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (615 mg, 0.6 mmol, 1.0 equiv.) and intermediate 13 (184, 6 mg, 0.6 mmol, 1.0 equiv.) as a pale yellow foam (721 mg, 70% yield). MS (ESI): 830.3 [M+H] +

[0325] Step d) Benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] The title compound was prepared from benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (363 mg, 0.4 mmol) in analogy to general procedure 10 and obtained as a pale yellow solid (374 mg, 0.43 mmol, 99% yield). MS (ESI): 762.2 [M+H-isobutene] +

[0326] Step e) tert-butyl N-[(3R)-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] Benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ in MeOH (10 mL) under an inert atmosphere 6To a solution of tert-butyl N-[(3R)-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ] was added tert-butyl N-[(3R)-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ]. The reaction mixture was stirred under a hydrogen atmosphere for 5 hours. The mixture was filtered through a plug of Celite and washed with MeOH. The filtrate was concentrated to give tert-butyl N-[(3R)-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ]. 6 ,5-benzothiazepin-3-yl]carbamate (244 mg, 0.34 mmol, 89% yield) was obtained as a yellow foam. MS (ESI): 728.2 [M+H] +

[0327] Step f) Methyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] tert-Butyl N-[(3R)-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ in DCM (3.0 mL) 6To a solution of N,N-diisopropylethylamine (0.0876 mL, 0.5 mmol, 3.0 equiv.) and N,N-diisopropylethylamine (122 mg, 0.2 mmol, 1.0 equiv.), methoxycarbonylmethyl carbonate (0.02 mL, 0.17 mmol, 1.0 equiv., CAS 4525-33-1) was added at 0° C. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC (neutral). The eluent was concentrated in vacuo to remove some of the acetonitrile, and then lyophilized to dryness to give the desired title compound (70 mg, 0.09 mmol, 53% yield) as a white solid. MS (ESI): 786.2 [M+H] +

[0328] Step g) Methyl 3,3-difluoro-5-[5-[(3R)-3-amino-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] The title compound was synthesized by the method of claim 1, wherein the methyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 Prepared analogously to general procedure 11c from [1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (60 mg, 0.1 mmol) and obtained as the hydrochloride salt (42.3 mg, 0.06 mmol, 75% yield) as a white solid. MS (ESI): 686.3 [M+H] +

[0329] Example 57 Methyl 3,3-difluoro-5-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] Step a) Benzyl 3,3-difluoro-5-[[[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine-7-carbonyl]amino]carbamoyl]piperidine-1-carboxylate [ka] The title compound was prepared analogously to general procedure 4b from tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (980 mg, 3.27 mmol, Example 19, step b) and 5,5-difluoro-1-[(E)-2-vinylbut-2-eneoxy]carbonyl-piperidine-3-carboxylic acid (980 mg, 3.3 mmol, 1.2 equivalents, CAS 1356338-81-2) as a pale yellow foam (1.08 g, 63% yield). MS (ESI): 534.1 [M+H-isobutene] +

[0330] Step b) Benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] The title compound was synthesized by the reaction of benzyl 3,3-difluoro-5-[[[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1λ 6 Prepared analogously to general procedure 5a from 5-benzothiazepine-7-carbonylaminocarbamoylpiperidine-1-carboxylate (1060 mg, 1.67 mmol) as a pale yellow foam (721 mg, 70% yield). MS (ESI): 560.1 [M+H-isobutene] +

[0331] Step c) Benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] The title compound was synthesized by the reaction of benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1λ 6 Prepared as per general procedure 10 from [1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (300 mg, 0.49 mmol, 1.0 equiv.) as a pale yellow solid (320 mg, 0.49 mmol, 92% yield). MS (ESI): 592.1 [M+H-isobutene] +

[0332] Step d) benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] The title compound was synthesized by the reaction of benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 Prepared analogously to general procedure 1a from [5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (300 mg, 0.46 mmol, 1.0 equiv.) and 5-(chloromethyl)-2-[4-(trifluoromethyl)phenyl]pyridine hydrochloride (185.6 mg, 0.6 mmol, 1.3 equiv., CAS 851507-54-5) as a pale yellow oil (570 mg, 106% yield). MS (ESI): 883.2 [M+H] +

[0333] Step e) tert-butyl N-[(3R)-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] Benzyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ in MeOH (5 mL) 6 To a solution of [1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (50 mg, 0.06 mmol, 1.0 equiv.) under an inert atmosphere was added Pd / C (50 mg). The reaction mixture was stirred under a hydrogen atmosphere for 5 hours. The mixture was filtered through a plug of Celite and washed with MeOH. The filtrate was concentrated to give the title compound as a pale yellow oil (30 mg, 0.04 mmol, 47% yield). MS (ESI): 749.3 [M+H] +

[0334] Step f) Methyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] tert-Butyl N-[(3R)-7-[5-(5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ in DCM (2.0 mL) 6 To a solution of [45 mg, 0.06 mmol, 1.0 equiv.] carbamate and N,N-diisopropylethylamine (0.03 mL, 0.18 mmol, 3.0 equiv.) was added methoxycarbonylmethyl carbonate (16.12 mg, 0.17 mmol, 1.0 equiv., CAS 4525-33-1) at 0 °C for 30 min. After the addition was complete, the mixture was stirred at room temperature for 12 h. The reaction mixture was poured into water (10 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (3 × 10 mL). The combined extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The remaining crude product was purified by preparative HPLC (Neutral). After drying by lyophilization, the title compound was obtained as a pale yellow oil (30 mg, 0.04 mmol, 56% yield). MS (ESI): 807.3 [M+H] +

[0335] Step g) Methyl 3,3-difluoro-5-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate [ka] The title compound was synthesized by the reaction of methyl 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 Prepared analogously to general procedure 11c from [1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (14 mg, 0.02 mmol) and obtained as the hydrochloride salt (9.2 mg, 0.01 mmol, 70% yield) as a white solid. MS (ESI): 707.2 [M+H] +

[0336] Example 58 Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate [ka] Step a) Methyl(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine-7-carboxylate [ka] The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (1000 mg, 2.84 mmol, CAS 2089150-62-7) in analogy to general procedure 10 and obtained as a pale yellow solid (900 mg, 2.34 mmol, 78% yield). MS (ESI): 285.1 [M+H-Boc] +

[0337] Step b) Methyl(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine-7-carboxylate [ka] The title compound was synthesized by the method of claim 1, wherein the methyl (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 Prepared as per general procedure 1a from 5-benzothiazepine-7-carboxylate (250 mg, 0.65 mmol) and 5-(chloromethyl)-2-[4-(trifluoromethyl)phenyl]pyridine (260.5 mg, 0.85 mmol, 1.3 equiv., CAS 851507-54-5) as a white solid (480 mg, 0.77 mmol, 83% yield). MS (ESI): 620.3 [M+H] + .

[0338] Step c) (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine-7-carboxylic acid [ka] The title compound was synthesized by the method of claim 1, wherein the methyl (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 Prepared as per general procedure 2 from 5-benzothiazepine-7-carboxylate (430 mg, 0.69 mmol) and obtained as a pale yellow solid (450 mg, 0.74 mmol, 94% yield). MS (ESI): 606.3 [M+H] + .

[0339] Step d) tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 Prepared as per general procedure 3 from 5-benzothiazepine-7-carboxylic acid (560 mg, 0.9 mmol) and obtained as a pale yellow solid (310 mg, 0.5 mmol, 54% yield). MS (ESI): 620.3 [M+H] + .

[0340] Step e) tert-butyl 1-[[[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine-7-carbonyl]amino]carbamoyl]-3-azabicyclo[3.1.1]heptane-3-carboxylate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 Prepared as per general procedure 4a from 3-tert-butoxycarbonyl-3-azabicyclo[3.1.1]heptane-1-carboxylic acid (75.9 mg, 0.31 mmol, 1.3 equiv., CAS 1000931-22-5) as a pale yellow solid (310 mg, 0.39 mmol, 74% yield). MS (ESI): 843.4 [M+H] + .

[0341] Step f) tert-Butyl 1-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate [ka] The title compound was synthesized by the reaction of tert-butyl 1-[[[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 Prepared similarly to general procedure 5a from [5-benzothiazepine-7-carbonyl]amino]carbamoyl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (330 mg, 0.37 mmol) as a pale yellow solid (150 mg, 0.18 mmol, 46% yield). MS (ESI): 825.1 [M+H] + .

[0342] Step g)) (3R)-3-amino-7-[5-(3-azabicyclo[3.1.1]heptan-1-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl 1-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 Prepared analogously to general procedure 11c from [1,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (145 mg, 0.18 mmol) as a pale yellow solid (70 mg, 0.1 mmol, 54% yield). MS (ESI): 625.3 [M+H] + .

[0343] Step h) Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate [ka] (3R)-3-amino-7-[5-(3-azabicyclo[3.1.1]heptan-1-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ in DMF (1 mL) 6To a solution of ,5-benzothiazepin-4-one (60.0 mg, 0.08 mmol, 1.0 equiv.) and N,N-diisopropylethylamine (42.26 mg, 0.33 mmol, 4.0 equiv.) was added dimethyl dicarbonate (11 mg, 0.08 mmol, 1.0 equiv.) at room temperature and stirred for 2 h. The reaction mixture was poured into water (10 mL) and EtOAc (20 mL) was added. The phases were separated and the aqueous phase was extracted with EtOAc (2 times). The combined organic phases were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The remaining residue was purified by preparative HPLC (HCl) to give the title compound as a white solid as the hydrochloride salt (36.5 mg, 0.05 mmol, 60% yield). MS (ESI): 683.3 [M+H] +

[0344] The examples in the following table were prepared analogously to Example 58 using the general procedure shown, employing the appropriate carboxylic acid and benzyl halide building blocks. [Table 22] TIFF2025526681000214.tif224170

[0345] Example 63 (3R)-3-Amino-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) tert-butyl N-[(3R)-7-[[[2-(hydroxymethyl)tetrahydrofuran-2-carbonyl]amino]carbamoyl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 Prepared analogously to general procedure 4a from 5-benzothiazepine-7-carboxylic acid (Example 32, step a) (260 mg, 676.4 μmol, 1.0 equiv.) and 2-methyloltetrahydrofuran-2-carboxylic acid (CAS: 61449-65-8) as a white solid (280 mg, 53% yield). MS (ESI): 413.1 [M-Boc+H] +

[0346] Step b) tert-butyl N-[(3R)-7-[[[2-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-2-carbonyl]amino]carbamoyl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] tert-Butyl N-[(3R)-7-[[[2-(hydroxymethyl)tetrahydrofuran-2-carbonyl]amino]carbamoyl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 [5-Benzothiazepin-3-yl]carbamate (280 mg, 546.31 μmol, 1.0 equiv.) was stirred with TBDMS-Cl (123.51 mg, 819.46 μmol, 1.5 equiv.) and imidazole (92.98 mg, 1.37 mmol, 2.5 equiv.) in DCM (5.45 mL) at room temperature for 16 h. The reaction was directly concentrated and purified by silica gel column chromatography (0-80% EtOAc in heptane) to afford the title compound as a white solid (167 mg, 49%). MS (ESI): 571.2 [M-isobutene + H] +

[0347] Step c) tert-butyl N-[(3R)-7-[5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[[[2-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-2-carbonyl]amino]carbamoyl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 Prepared similarly to general procedure 5b from 5-benzothiazepin-3-yl]carbamate (160 mg, 0.255 mmol) as a white solid (135 mg, 87% yield). MS (ESI): 609.2 [M+H] +

[0348] Step d) tert-butyl N-[(3R)-7-[5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6Prepared as per general procedure 1a from [5-benzothiazepin-3-yl]carbamate (50 mg, 0.082 mmol, 1.0 equiv.) and 4-(bromomethyl)-4'-methoxy-1,1'-biphenyl (29.6 mg, 0.11 mmol, 1.3 equiv., CAS: 20854-61-9) as a white solid (57.4 mg, 86% yield). MS (ESI): 805.4 [M+H] +

[0349] Step e) (3R)-3-amino-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] tert-Butyl N-[(3R)-7-[5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6

[0044] ,5-benzothiazepin-3-yl]carbamate (57.4 mg, 71.3 μmol, 1.0 equiv.) was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (6.43 mL), and 1M HCl in EtO (165.12 mg, 221.04 μL, 221.04 μmol, 3.1 equiv.) was added at room temperature and stirred for 1 hour. TBAF (1M in THF, 18.6 mg, 0.071 mmol, 1.0 equiv.) was then added and stirring continued for 2 hours. The reaction was concentrated under reduced pressure and directly purified by reverse-phase preparative separation. HPLC afforded the title compound as a white powder (13.5 mg, 32%). MS (ESI): 591.4 [M+H] + .

[0350] Example 64 (3R)-3-amino-7-[5-(1-ethoxy-1,2,2,2-tetrafluoro-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) 2-ethoxy-2,3,3,3-tetrafluoro-propanehydrazide [ka] To a solution of 2-ethoxy-2,3,3,3-tetrafluoropropanoic acid (200 mg, 0.92 mmol, 1 equiv., CAS 10186-67-1) in EtOH (1.5 ml), hydrazine monohydrate (54.25 mg, 1.1 mmol, 1.2 equiv.) was added and the mixture was heated to 80° C. for 8 h. The resulting colorless solution was concentrated under reduced pressure and dried under high vacuum to give 2-ethoxy-2,3,3,3-tetrafluoropropanehydrazide (119 mg, 60%) as a white solid. MS (ESI): 205.1 [M+H] +

[0351] Step b) tert-butyl N-[(3R)-7-[[(2-ethoxy-2,3,3,3-tetrafluoro-propanoyl)amino]carbamoyl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared analogously to general procedure 4a from (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (145 mg, 0.257 mmol, 1 eq., Example 54, step b) and 2-ethoxy-2,3,3,3-tetrafluoro-propanehydrazide (68.16 mg, 0.334 mmol, 1.3 eq.) to give the title compound as a yellow oil (247 mg, 99%). MS (ESI): 749.3 [MH]

[0352] Step c) tert-butyl N-[(3R)-7-[5-(1-ethoxy-1,2,2,2-tetrafluoro-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared analogously to general procedure 5b from tert-butyl N-[(3R)-7-[[(2-ethoxy-2,3,3,3-tetrafluoro-propanoyl)amino]carbamoyl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (247 mg, 0.247 mmol) and obtained as a white solid (119 mg, 65%). MS (ESI): 677.3 [M-isobutene + H] +

[0353] Step d) tert-butyl N-[(3R)-7-[5-(1-ethoxy-1,2,2,2-tetrafluoro-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-[5-(1-ethoxy-1,2,2,2-tetrafluoro-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (112 mg, 0.15 mmol) in analogy to general procedure 10 as a white solid (96 mg, 83%). MS (ESI): 709.2 [M-isobutene + H] +

[0354] Step e) (3R)-3-amino-7-[5-(1-ethoxy-1,2,2,2-tetrafluoro-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-(1-ethoxy-1,2,2,2-tetrafluoro-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared analogously to general procedure 11a from 5-benzothiazepin-3-yl]carbamate (96 mg, 0.126 mmol) and obtained as a white solid as the hydrochloride salt (67.5 mg, 76%). MS (ESI): 665.5 [M+H] +

[0355] Example 65 ((3R)-3-amino-5-[[4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl]methyl]-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) tert-Butyl N-[(3R)-4-oxo-7-[[(2,3,3,3-tetrafluoro-2-methoxy-propanoyl)amino]carbamoyl]-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared analogously to general procedure 4b from (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylic acid (Example 19, Step a, 900 mg, 2.66 mmol, 1.0 equiv.) and 2,3,3,3-tetrafluoro-2-methoxy-propanehydrazide (505 mg, 2.7 mmol, 1.0 equiv., Example 64, Step a) as a pale yellow solid (1300 mg, 95% yield). MS (ESI) 509.2 [MH] -

[0356] Step b) tert-butyl N-[(3R)-4-oxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared analogously to general procedure 4b from tert-butyl N-[(3R)-4-oxo-7-[[(2,3,3,3-tetrafluoro-2-methoxy-propanoyl)amino]carbamoyl]-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (400 mg, 0.78 mmol, 1.0 equiv.) as a pale yellow oil (560 mg, 116% yield), which was used without further purification. MS (ESI) 437.1 [M-isobutene + H] +

[0357] Step c) tert-butyl N-[(3R)-1,1,4-trioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-4-oxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (280 mg, 0.57 mmol, 1 equiv.) in analogy to general procedure 10 to give a pale yellow solid (500 mg) containing the title compound. MS (ESI) 468.9 [M-isobutene + H] +

[0358] Step d) tert-butyl N-[(3R)-5-[[4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl]methyl]-1,1,4-trioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-1,1,4-trioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-3,5-dihydro-2H-1λ 6 Prepared as per general procedure 1a from [5-benzothiazepin-3-yl]carbamate (15 mg, 0.029 mmol, 1 equiv.) and intermediate 14 (10.4 mg, 0.037 mmol, 1.3 equiv.) as a white powder (11 mg, 53% yield). MS (ESI): 723.2 [M-isobutene + H] +

[0359] Step e) (3R)-3-amino-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-5-[[4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl]methyl]-1,1,4-trioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ 6 Prepared similarly to general procedure 11c from 5-benzothiazepin-3-yl]carbamate (11 mg, 0.015 mmol) and obtained as the hydrochloride salt as a white powder (8.4 mg, 84% yield). MS (ESI): 623.1 [M+H] +

[0360] Example 66 in the table below was prepared similarly to Example 65 using the appropriate benzyl bromide building block. [Table 23]

[0361] Example 68 (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka]

[0362] Step a) tert-butyl N-[(3R)-1,1,4-trioxo-7-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] tert-Butyl N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-3,5-dihydro-2H-1λ] in THF (4.16 mL) 6 To a solution of [5-benzothiazepin-3-yl]carbamate (160 mg, 0.416 mmol, 1.0 equiv., Example 7, step b) was added CDI (80.99 mg, 0.499 mmol, 1.2 equiv.) and triethylamine (69.62 uL, 0.499 mmol, 1.2 equiv.). The solution was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and 1N HCl was added to pH = 3.0. The mixture was extracted three times with EtOAc. The combined organic layers were washed once with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The remaining crude material was purified by silica gel column chromatography (10-70% EtOAc in heptane) to give the title compound as a pale yellow powder (183 mg, 87%). MS (ESI): 409.1 [MH]

[0363] Step b) tert-butyl N-[(3R)-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-1,1,4-trioxo-7-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3,5-dihydro-2H-1λ 6 Prepared as in general procedure 13 from [5-benzothiazepin-3-yl]carbamate (33 mg, 0.06 mmol) and difluoropiperidine hydrochloride (171 mg, 1.08 mmol, 2.5 equiv., CAS 144230-52-4) as a yellow solid (192 mg, 59%). MS (ESI): 514.2 [M+H] +

[0364] Step c) tert-butyl N-[(3R)-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6Prepared analogously to general procedure 1a from 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (15.94 mg, 0.052 mmol, 1.3 equiv., CAS 2093101-98-3) as a white solid (15.1 mg, 51%). MS (ESI): 740.4 [M+H] +

[0365] Step d) (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared analogously to general procedure 11a from [5-benzothiazepin-3-yl]carbamate (15.1 mg, 0.02 mmol) and obtained as the hydrochloride salt (3.3 mg, 24%) as a white solid. MS (ESI): 640.5 [M+H] +

[0366] The examples in the following table were prepared similarly to Example 68 using the appropriate benzyl halide or amine building blocks. [Table 24] TIFF2025526681000240.tif138170

[0367] Example 72 (3R)-3-amino-7-[5-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) tert-butyl N-[(3R)-7-(5-amino-1,3,4-oxadiazol-2-yl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] A suspension of tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (350 mg, 0.97 mmol, 1.0 equiv., Example 19, Step b), cyanogen bromide (318.8 mg, 2.92 mmol, 3.0 equiv.), and sodium bicarbonate (245.3 mg, 2.92 mmol, 3.0 equiv.) in 1,4-dioxane (6 mL) and water (4 mL) was stirred at room temperature overnight. The resulting yellow solution was partitioned between EtOAc-THF (1:1) and brine. The layers were separated, and the aqueous layer was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound as an orange solid (381 mg, 98%). MS(ESI):378.2[M+H] +

[0368] Step b) tert-Butyl N-[(3R)-7-(5-bromo-1,3,4-oxadiazol-2-yl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] A solution of tert-butyl N-[(3R)-7-(5-amino-1,3,4-oxadiazol-2-yl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (381 mg, 1.01 mmol, 1.0 equiv.) in acetonitrile (5 mL) was degassed with argon for 5 minutes. Copper(II) bromide (338 mg, 1.51 mmol, 1.5 equiv.) and isoamyl nitrite (141.9 mg, 163.12 µL, 1.21 mmol, 1.2 equiv.) were then added at room temperature to form a dark green suspension. The reaction mixture was stirred for 1 hour. The reaction mixture was diluted with EtOAc (100 mL) and 1N HCl (100 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (2 × 150 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The remaining solid was purified by column chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (102 mg, 23%) as an orange solid. MS(ESI): 439.1 [MH]

[0369] Step c) tert-butyl N-[(3R)-7-(5-bromo-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-7-(5-bromo-1,3,4-oxadiazol-2-yl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (905 mg, 2.05 mmol) analogously to general procedure 10 and obtained as a white solid (524 mg, 53%). MS (ESI): 417.0 [M-isobutene + H] +

[0370] Step d) tert-butyl N-[(3R)-7-[5-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-(5-bromo-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 Prepared as per general procedure 13 from (3,5-benzothiazepin-3-yl)carbamate (25 mg, 0.052 mmol, 1.0 equiv.) and (3,3-difluoro-1-methyl-cyclobutyl)amine hydrochloride (9.8 mg, 0.061 mmol, 1.2 equiv.) as a yellow amorphous solid (30.5 mg, 43%). MS (ESI): 514.2 [M+H] +

[0371] Step e) tert-butyl N-[(3R)-7-[5-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6Prepared analogously to general procedure 1a from 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (10.1 mg, 0.033 mmol, 1.5 equiv., CAS 2093101-98-3) as a white solid (5.7 mg, 32%). MS (ESI): 740.2 [M+H] +

[0372] Step f) (3R)-3-amino-7-[5-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-7-[5-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared analogously to general procedure 11a from 5-benzothiazepin-3-yl]carbamate (5.7 mg, 0.007 mmol) as a white solid (3.2 mg, 66%). MS (ESI): 640.3 [M+H] +

[0373] The examples in the following table were prepared analogously to Example 72 using the general procedure shown, employing the appropriate amine and benzyl halide building blocks. [Table 25] TIFF2025526681000249.tif224170TIFF2025526681000250.tif112170

[0374] Example 83 (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(6-methoxy-3-pyridyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) Methyl (3R)-3-(benzyloxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate [ka] To a solution of methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (300 mg, 0.851 mmol, 1 equiv., CAS 2089150-62-7) in 1,4-dioxane (1.5 mL) was added 4 M HCl in dioxane (2.36 g, 1.97 mL, 7.88 mmol, 9.2 equiv.) at room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (40 mL) and 0.5 M NaOH (40 mL). The layers were separated, and the aqueous layer was extracted twice with 40 mL portions of EtOAc. The combined organic layers were washed once with 40 mL portions of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude yellow solid (141.7 mg). The crude solid was suspended in DCM (3 mL). DIEA (165 mg, 223 μL, 1.28 mmol, 1.5 equiv.) and benzyl chloroformate (95.3 mg, 79.8 μL, 0.56 mmol, 0.65 equiv.) were added at room temperature to give a dark yellow solution, which was stirred for 2 h. The reaction mixture was concentrated and purified by column chromatography on silica gel (0-40% EtOAc in heptane) to give methyl (3R)-3-(benzyloxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (196 mg, 59%) as a white solid. MS (ESI): 387.2 [M+H] +

[0375] Step b) (3R)-3-(benzyloxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylic acid [ka] The title compound was prepared from methyl (3R)-3-(benzyloxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (320 mg, 0.82 mmol) in analogy to general procedure 2 and obtained as a yellow solid (364 mg, 99%). MS (ESI): 373.1 [M+H] +

[0376] Step c) Benzyl N-[(3R)-7-[(2,2-dimethylpropanoylamino)carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from (3R)-3-(benzyloxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylic acid (364 mg, 0.81 mmol, 1 equiv.) and 2,2-dimethylpropionohydrazide (131.93 mg, 1.14 mmol, 1.4 equiv.) analogously to general procedure 4a and obtained as a pale yellow solid (687 mg, 99%). MS (ESI): 471.2 [M+H] +

[0377] Step d) Benzyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from benzyl N-[(3R)-7-[(2,2-dimethylpropanoylamino)carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (687 mg, 0.803 mmol) in analogy to general procedure 5a and obtained as a yellow oil (321 mg, 85%). MS (ESI): 453.2 [M+H] +

[0378] Step e) N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-triketo-3,5-dihydro-2H-1?6,5-benzothiazepin-3-yl]carbamic acid benzyl ester [ka] The title compound was synthesized by the reaction of benzyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 Prepared as per general procedure 10 from 5-benzothiazepin-3-yl]carbamate (321 mg, 0.65 mmol) as a white solid (182 mg, 57%). MS (ESI): 485.2 [M+H] +

[0379] Step f) Benzyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(6-methoxy-3-pyridyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-triketo-3,5-dihydro-2H-1λ 6 Prepared analogously to general procedure 1a from [5-benzothiazepin-3-yl]carbamic acid benzyl ester (55 mg, 0.114 mmol, 1 equiv.) and 5-[4-(bromomethyl)phenyl]-2-methoxypyridine (47.36 mg, 0.17 mmol, 1.5 equiv., CAS 234109-32-1) as a white solid (48 mg, 31%). MS (ESI): 682.5 [M+H] +

[0380] Step g) (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(6-methoxy-3-pyridyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Benzyl N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(6-methoxy-3-pyridyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ in MeOH (1.76 mL) and THF (1.76 mL) under Ar atmosphere 6 To a solution of (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-diketo-5-[4-(6-methoxy-3-pyridyl)benzyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one (5.8 mg, 27%) was added Pd / C (0.38 mg, 0.004 mmol, 0.1 equiv.) and the mixture was stirred under a hydrogen atmosphere overnight. The mixture was filtered through a plug of Celite, which was washed with MeOH and THF. The filtrate was concentrated, and the remaining crude material was purified using preparative HPLC to give (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-diketo-5-[4-(6-methoxy-3-pyridyl)benzyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one (5.8 mg, 27%) as a white solid. MS (ESI): 548.3 [M+H] +

[0381] Example 165 (3R)-3-amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) tert-butyl N-[(3R)-4-oxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate [ka] 3,3,3 trifluoro-2,2-dimethyl-propionic acid (132.88 mg, 851.3 μmol, 1.5 equiv., CAS 889940-13-0) and tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (200 mg, 567.52 μmol, 1.0 equiv., Example 19, Step b) were suspended in THF (5 mL). DIPEA (220 mg, 297.4 μL, 1.7 mmol, 3.0 equiv.) was added to this suspension to give a clear solution. Finally, HATU (323.7 mg, 851.3 μmol, 1.5 equiv.) was added, and the reaction mixture was stirred for 2 h. The reaction was diluted with water and extracted with EtOAc (3×). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining crude material was suspended in acetonitrile (5 mL), and DIPEA (146.7 mg, 198 uL, 1.14 mmol, 2.0 equiv.) and p-TsCl (324.6 mg, 1.7 mmol, 3.0 equiv.) were added. The resulting solution was stirred at room temperature for 90 minutes. The reaction mixture was partitioned between EtOAc and 1 M NaOH. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel (0–35% EtOAc in heptane) to afford the title compound (207.9 mg, 74%) as a white crystalline solid. MS (ESI): 471.2 [M+H] +

[0382] Step b) tert-butyl N-[(3R)-1,1,4-trioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,5-dihydro-2H-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was obtained as a pale yellow solid (230 mg, 0.46 mmol, 93% yield) prepared from tert-butyl N-[(3R)-4-oxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (210 mg, 0.44 mmol, 1.0 equiv.) in analogy to general procedure 10. MS (ESI): 449.1 [M+H] +

[0383] Step c) tert-butyl N-[(3R)-1,1,4-trioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-1,1,4-trioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,5-dihydro-2H-1λ 6 Prepared similarly to general procedure 1a from [5-benzothiazepin-3-yl]carbamate (100 mg, 0.2 mmol, 1.0 equiv.) using intermediate 38 (13.5 mg, 0.04 mmol, 1.05 equiv.) as a pale yellow oil (100 mg, 0.13 mmol, 65%). MS (ESI): 756.3 [M+H] +

[0384] Step d) (3R)-3-amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction of tert-butyl N-[(3R)-1,1,4-trioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ 6 Prepared similarly to general procedure 11c from 5-benzothiazepin-3-yl]carbamate (98 mg, 0.13 mmol) as a pale yellow solid (76.8 mg, 0.11 mmol, 83% yield). MS (ESI): 656.1 [M+H] +

[0385] The examples in the following table were prepared analogously to Example 165 using the appropriate benzyl bromide building blocks. [Table 26]

[0386] Example 168 (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoroethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] Step a) Methyl (3R)-3-(tert-butoxycarbonylamino)-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylate [ka] The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (939.3 mg, 2.67 mmol, 1.0 equiv., CAS 2089150-62-7) using intermediate 16 (800 mg, 2.67 mmol, 1.0 equiv.) in analogy to general procedure 1a, and obtained as a pale yellow solid (1.88 g, 99%). MS (ESI): 451.3 [M+H-Boc] +

[0387] Step b) (3R)-3-(tert-butoxycarbonylamino)-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid [ka] The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (1.04 g, 1.88 mmol) in analogy to general procedure 2 and obtained as a pale yellow foam (1.62 g, 99%). MS (ESI): 437.2 [M+H-Boc] +

[0388] Step c) tert-butyl N-[(3R)-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from (3R)-3-(tert-butoxycarbonylamino)-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (1.62 g, 3.01 mmol) in analogy to general procedure 3 and obtained as a pale yellow viscous oil (0.997 g, 60%). MS (ESI): 495.2 [M+H-isobutene] +

[0389] Step d) tert-butyl N-[(3R)-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-4-oxo-7-[5-(1,2,2,2-tetrafluoroethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate [ka] To a solution of tert-butyl N-[(3R)-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (80 mg, 145.3 μmol, 1.0 equiv.) in THF (969 μL) was added 2,3,3,3-tetrafluoropropionic acid (42.4 mg, 290.6 μmol, 2.0 equiv., CAS 359-49-9), DIPEA (37.6 mg, 50.8 μL, 290.6 μmol, 2.0 equiv.), and HATU (82.9 mg, 217.9 μmol, 1.5 equiv.). The resulting solution was stirred at room temperature for 2 h. The reaction was directly concentrated under reduced pressure until all volatiles were removed. The remaining residue was dissolved in THF (969 uL), and Burgess reagent (173 mg, 726 μmol, 5.0 equiv) was added in one portion at room temperature and stirred for 2 hours. The reaction was diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining crude material was purified by column chromatography on silica gel (0-50% EtOAc in heptane) to afford the title compound (27 mg, 29%) as a white solid. MS (ESI): 605.2 [M+H-isobutene] +

[0390] Step e) tert-butyl N-[(3R)-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1,4-trioxo-7-[5-(1,2,2,2-tetrafluoroethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-3-yl]carbamate [ka] The title compound was prepared from tert-butyl N-[(3R)-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-4-oxo-7-[5-(1,2,2,2-tetrafluoroethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (22.4 mg, 33.9 μmol) in analogy to general procedure 10 and obtained as a colorless solid (13 mg, 53%). MS(ESI): 691.3 [MH] -

[0391] Step 6: (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoroethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ 6 ,5-benzothiazepin-4-one [ka] The title compound was synthesized by the reaction...

Claims

1. Formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein R １ is oxadiazole, and R １ represents one or more R １０ may be substituted with R ２ is selected from hydrogen and halogen; R ４ is C ５～１４ -aryl and 5- to 14-membered heteroaryl; R ４ represents one or more R １１ may be substituted with R １０ teeth, i) one or more of halogen, amino, hydroxy, C １～６ -C optionally substituted with alkoxy, 3- to 10-membered cycloalkyl, phenyl, or cyano １～１０ - alkyl; ii) C optionally substituted with one or more halogen, cyano, or amino groups ３～１０ -cycloalkyl; iii) one or more halogens, C １～１０ -Alkyl, amino, halo-C １～６ -Alkyl, hydroxy, cyano, C(O)O—(R １０ｑ ), C ３～１０ -3- to 10-membered heterocyclyl optionally substituted by cycloalkyl, １～１０ - alkyl is one or more hydroxy, C １～６ -3-10 membered heterocyclyl optionally substituted by alkoxy; iv-N(R １０ｅ R １０ｆ ); v) one or more C １～１０ -Alkyl, heteroaryl optionally substituted with halogen is selected from R １０ｅ and R １０ｆ are, respectively, i) hydrogen; ii) C optionally substituted with one or more cyano, halogen, or hydroxy groups １～６ - alkyl; iii) one or more halogens, C １～１０ -C optionally substituted with alkyl ３～１０ -cycloalkyl are independently selected from R １０ｑ is C １～５ - alkyl, C １～５ - alkyl may be substituted with one or more hydroxy; R １１ teeth, i) one or more C １～６ -Alkyl, C ３～１０ Cycloalkyl, halo-C １～６ - alkyl, １～６ -alkoxy, halo-C １～６ 5-6 membered heteroaryl optionally substituted with -alkoxy, ３～１０ 5-6 membered heteroaryl, wherein the cycloalkyl is optionally substituted with one or more halogens; ii) one or more C １～６ -alkoxy, -OH, halo-C １～６ -phenyl optionally substituted with alkyl 1. A compound of formula (I) selected from:

2. R １１ but, (i) one or more C １～６ -Alkyl, C ３～１０ Cycloalkyl, halo-C １～６ -5-6 membered heteroaryl optionally substituted with alkyl; (ii) one or more C １～６ -alkoxy, halo-C １～６ -Alkyl, halo-C １～６ -phenyl optionally substituted with alkoxy 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

3. R ２ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen and fluorine.

4. R ４ is selected from phenyl and pyridinyl, and R ４ is one or more R １１ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, optionally substituted by:

5. R １０ tert-butyl, pyrrolidinyl, tetrafluoro-methoxy-ethyl, methyl-propanenitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, aminocyclohexyl, cyclopropanecarbonitrile, difluoro-piperidyl, ethoxy-tetrafluoro-ethyl, (hydroxymethyl)tetrahydrofuranyl, azabicyclo[3.1.1]heptane-methylcarboxylate, amino-trifluoromethyl-ethyl, difluoro-piperidine-methylcarboxylate fluoro-methyl-piperidyl, aminooxetanyl, (difluoro-methyl-cyclobutyl)aminoyl, cyclopropyltetrahydrofuranyl, amino-dimethyl-propyl, propanenitrile, isopropylaminoyl, fluoro-methyl-pyridyl, methyl-pyridyl, chloro-pyridyl, tetrafluoroethyl, trifluoro-dihydroxy-ethyl, hydroxy-(trifluoromethyl)propyl, pentafluoroethyl, trifluoro-dimethyl-ethyl, trifluoro-phenyl-ethyl, benzyl-trifluoroethyl, (trifluoroethyl) (trifluoromethyl)oxetanyl, trifluoro(hydroxymethyl)ethyl, amino-cyclopropyl-trifluoro-ethyl, trifluoro-hydroxy-methyl-ethyl, trifluoroethyl, morpholino, hexahydro-2H-pyrano[4,3-b]pyrrolyl, hexahydro-2H-cyclopenta[b][1,4]oxazinyl, dioxazabicyclo[3.3.1]nonanyl, morpholinyl-carbonitrile, (methoxymethyl)morpholinyl, (hydroxymethyl)morpholinyl, (hydroxyethyl)morpholinyl, oxazepanyl , difluoro-(methoxyethyl)-piperidyl, aminocyclohexyl, amino-trifluoro-methyl-ethyl, methyloxetanyl, trifluoro-hydroxy-(trifluoromethyl)ethyl, (trifluoromethyl)oxetan-3-yl, trifluoro-(hydroxymethyl)ethyl, amino-trifluoro-methyl-ethyl, hexahydrofuro[3,2-b]pyrrolyl, difluoro-azabicyclo[4.1.0]heptanyl, hexahydrofuro[2,3-b][1,4]oxazinyl, hexahydro-2H-cyclopenta[b][1,The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of 2H-pyrano[4,3-b][1,4]oxazinyl, hexahydro-2H-cyclopenta[b][1,4]oxazinyl, oxa-azabicyclo[3.2.1]octanyl, cyclopropyl-difluoro-tetrahydrofuranyl, difluorocyclohexyl, amino-trifluoro-ethyl, difluoroethyl(hydroxyethyl)amino, difluoroethyl-aminoyl-acetonitrile, cyclopropyl(difluoroethyl)amino, difluoropyrrolidinyl, (trifluoro-methyl-ethyl)amino, trifluoroethylamino, methyl(trifluoroethyl)amino, ethyl-difluoro-piperidyl, dimethyl-pyridyl, and trifluoro-methoxy-ethyl.

6. R １０ is tert-butyl, tetrafluoro-methoxy-ethyl, methyl-propanenitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, cyclopropanecarbonitrile, difluoro-piperidyl, (hydroxymethyl)tetrahydrofuranyl, amino-trifluoromethyl-ethyl, aminooxetanyl, cyclopropyltetrahydrofuranyl, propanenitrile, aminocyclohexyl, or a pharmaceutically acceptable salt thereof.

7. R １１ is selected from (hydroxymethyl)phenyl, (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridyl, (trifluoromethyl)phenyl, methoxyphenyl, (trifluoromethyl)pyridyl, dimethylpyrazolyl, tert-butyl-oxadiazolyl, methyl-oxadiazolyl, methylpyrazolyl, (difluoromethyl)-oxadiazolyl, (trifluoromethyl)oxazolyl, methyl-(trifluoromethyl)pyrazolyl, (trifluoromethyl)pyrazolyl, (trifluoromethyl)isoxazolyl, (trifluoromethyl-ethyl)oxadiazolyl, (trifluoroethyl)oxadiazolyl, (trifluoromethoxy)phenyl, cyclopropyl-triazolyl, (trifluoromethoxy)pyridyl, (trifluoromethoxy)pyrimidinyl, (pentafluoroethoxy)pyridyl, (trifluoromethoxy),pyridyl, methyl-(trifluoromethoxy)pyrazolyl, or a pharmaceutically acceptable salt thereof.

8. R １１ is selected from (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridyl, methoxyphenyl, (trifluoromethoxy)pyridyl, (trifluoromethoxy)pyrimidinyl, (pentafluoroethoxy)pyridyl, (trifluoromethoxy), pyridyl, methyl-(trifluoromethoxy)pyrazolyl, or a pharmaceutically acceptable salt thereof.

9. R １ is oxadiazole, and R １ is one or more R １０ may be substituted with R ２ is selected from hydrogen and fluorine; R ４ is selected from phenyl and pyridinyl, and R ４ is one or more R １１ may be substituted with R １０ but, i) one or more of halogen, amino, hydroxy, C １～６ -C optionally substituted with alkoxy, 3- to 10-membered cycloalkyl, phenyl, or cyano １～１０ - alkyl; ii) C optionally substituted with one or more halogen, cyano, or amino groups ３～１０ -cycloalkyl; iii) one or more halogens, C １～１０ -Alkyl, amino, halo-C １～６ -Alkyl, hydroxy, cyano, C(O)O—(R １０ｑ ), C ３～１０ -3- to 10-membered heterocyclyl optionally substituted by cycloalkyl, １～１０ - alkyl is one or more hydroxy, C １～６ -3- to 10-membered heterocyclyl optionally substituted by alkoxy; iv-N(R １０ｅ R １０ｆ ); v) one or more C １～１０ -Alkyl, heteroaryl optionally substituted with halogen is selected from R １０ｅ and R １０ｆ However, respectively, i) hydrogen; ii) C optionally substituted with one or more cyano, halogen, or hydroxy groups １～６ - alkyl; iii) one or more halogens, C １～１０ -C optionally substituted with alkyl ３～１０ -cycloalkyl are independently selected from R １０ｑ But C １～５ - alkyl, C １～５ - alkyl optionally substituted with one or more hydroxy; R １１ but, iv) one or more C １～６ -Alkyl, C ３～１０ Cycloalkyl, halo-C １～６ -5-6 membered heteroaryl optionally substituted with alkyl; v) one or more C １～６ -alkoxy, halo-C １～６ -Alkyl, halo-C １～６ -phenyl optionally substituted with alkoxy 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

10. R １ is oxadiazole, and R １ is one or more R １０ may be substituted with R ２ is selected from hydrogen and fluorine; R ４ is selected from phenyl and pyridinyl, and R ４ is one or more R １１ may be substituted with R １０ tert-butyl, pyrrolidinyl, tetrafluoro-methoxy-ethyl, methyl-propanenitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, aminocyclohexyl, cyclopropanecarbonitrile, difluoro-piperidyl, ethoxy-tetrafluoro-ethyl, (hydroxymethyl)tetrahydrofuranyl, azabicyclo[3.1.1]heptane-methylcarboxylate, amino-trifluoromethyl-ethyl, difluoro-piperidine-methylcarboxylate fluoro-methyl-piperidyl, aminooxetanyl, (difluoro-methyl-cyclobutyl)aminoyl, cyclopropyltetrahydrofuranyl, amino-dimethyl-propyl, propanenitrile, isopropylaminoyl, fluoro-methyl-pyridyl, methyl-pyridyl, chloro-pyridyl, tetrafluoroethyl, trifluoro-dihydroxy-ethyl, hydroxy-(trifluoromethyl)propyl, pentafluoroethyl, trifluoro-dimethyl-ethyl, trifluoro-phenyl-ethyl, benzyl-trifluoroethyl, (trifluoroethyl) (trifluoromethyl)oxetanyl, trifluoro(hydroxymethyl)ethyl, amino-cyclopropyl-trifluoro-ethyl, trifluoro-hydroxy-methyl-ethyl, trifluoroethyl, morpholino, hexahydro-2H-pyrano[4,3-b]pyrrolyl, hexahydro-2H-cyclopenta[b][1,4]oxazinyl, dioxazabicyclo[3.3.1]nonanyl, morpholinyl-carbonitrile, (methoxymethyl)morpholinyl, (hydroxymethyl)morpholinyl, (hydroxyethyl)morpholinyl, oxazepanyl , difluoro-(methoxyethyl)-piperidyl, aminocyclohexyl, amino-trifluoro-methyl-ethyl, methyloxetanyl, trifluoro-hydroxy-(trifluoromethyl)ethyl, (trifluoromethyl)oxetan-3-yl, trifluoro-(hydroxymethyl)ethyl, amino-trifluoro-methyl-ethyl, hexahydrofuro[3,2-b]pyrrolyl, difluoro-azabicyclo[4.1.0]heptanyl, hexahydrofuro[2,3-b][1,4]oxazinyl, hexahydro-2H-cyclopenta[b][1,4]oxazinyl, hexahydro-2H-pyrano[4,3-b][1,4]oxazinyl, hexahydro-2H-cyclopenta[b][1,4]oxazinyl, oxa-azabicyclo[3.2.1]octanyl, cyclopropyl-difluoro-tetrahydrofuranyl, difluorocyclohexyl, amino-trifluoro-ethyl, difluoroethyl(hydroxyethyl)amino, difluoroethyl-aminoyl-acetonitrile, cyclopropyl(difluoroethyl)amino, difluoropyrrolidinyl, (trifluoro-methyl-ethyl)amino, trifluoroethylamino, methyl(trifluoroethyl)amino, ethyl-difluoro-piperidyl, dimethyl-pyridyl, trifluoro-methoxy-ethyl, R １１ is selected from (hydroxymethyl)phenyl, (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridyl, (trifluoromethyl)phenyl, methoxyphenyl, (trifluoromethyl)pyridyl, dimethylpyrazolyl, tert-butyl-oxadiazolyl, methyl-oxadiazolyl, methylpyrazolyl, (difluoromethyl)-oxadiazolyl, (trifluoromethyl)oxazolyl, methyl-(trifluoromethyl)pyrazolyl, (trifluoromethyl)pyrazolyl, (trifluoromethyl)isoxazolyl, (trifluoromethyl-ethyl)oxadiazolyl, (trifluoroethyl)oxadiazolyl, (trifluoromethoxy)phenyl, cyclopropyl-triazolyl, (trifluoromethoxy)pyridyl, (trifluoromethoxy)pyrimidinyl, (pentafluoroethoxy)pyridyl, (trifluoromethoxy),pyridyl, methyl-(trifluoromethoxy)pyrazolyl, or a pharmaceutically acceptable salt thereof.

11. R １ is oxadiazole, and R １ is one or more R １０ may be substituted with R ２ is selected from hydrogen and fluorine; R ４ is selected from phenyl and pyridinyl, and R ４ is one or more R １１ may be substituted with R １０ is tert-butyl, tetrafluoro-methoxy-ethyl, methyl-propanenitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, cyclopropanecarbonitrile, difluoro-piperidyl, (hydroxymethyl)tetrahydrofuranyl, amino-trifluoromethyl-ethyl, aminooxetanyl, cyclopropyltetrahydrofuranyl, propanenitrile, aminocyclohexyl; R １１ is selected from (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridyl, methoxyphenyl, (trifluoromethoxy)pyridyl, (trifluoromethoxy)pyrimidinyl, (pentafluoroethoxy)pyridyl, (trifluoromethoxy), pyridyl, methyl-(trifluoromethoxy)pyrazolyl, or a pharmaceutically acceptable salt thereof.

12. (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-[[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-7-[5-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-8-fluoro-7-[5-(isopropylamino)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-[[6-[4-(hydroxymethyl)phenyl]-3-pyridyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-aminooxetan-3-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-aminooxetan-3-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-aminooxetan-3-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2,2-difluoromorpholin-4-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2,2-difluoromorpholin-4-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-8-fluoro-1,1-dioxo-7-(5-pyrrolidin-1-yl-1,2,4-oxadiazol-3-yl)-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 1-[3-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile 1-[3-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(5-tert-butyl-1,3,4-oxadiazol-2-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(3,5-dimethylpyrazol-1-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[4-(trifluoromethyl)imidazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[5-(trifluoromethyl)isoxazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[3-(trifluoromethyl)isoxazol-5-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[4-(trifluoromethyl)oxazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[5-(trifluoromethyl)oxazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-amino-2,2,2-trifluoro-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-amino-2,2,2-trifluoro-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-amino-2,2,2-trifluoro-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2-cyclopropyltetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (*) (3R)-3-amino-7-[5-(1-amino-2,2-dimethyl-propyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]propanenitrile (3R)-3-amino-7-[5-(2-cyclopropyltetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-5-[[4-[5-(difluoromethyl)-2-pyridyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(3,3-difluorocyclopentyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(2,2,2-trifluoro-1-methyl-ethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-[5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-[5-(4,4-difluoro-1-piperidyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)oxazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (*) 2-[5-[(3R)-3-amino-5-[[4-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-[5-(difluoromethoxy)-2-pyridyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-[5-(1,1-difluoroethyl)-2-pyridyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-[4-(difluoromethoxy)-2-pyridyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[2-(trifluoromethyl)-4-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)pyrazin-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[6-(trifluoromethyl)-3-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-[6-methyl-5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[1-(trifluoromethyl)pyrazol-4-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)pyrimidin-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-(5-cyclopropyl-2-pyridyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethoxy)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)oxazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-(5-methoxy-2-pyridyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)pyrimidin-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(1,1,2,2,2-pentafluoroethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[6-(trifluoromethoxy)-3-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-[4-methyl-5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)triazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-5-[[4-[2-methyl-5-(trifluoromethoxy)pyrazol-3-yl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-7-[5-(2-methyloxetan-2-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1lambda 6,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-methyloxetan-3-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-methyloxetan-3-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-amino-2,2,2-trifluoro-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-[3-(difluoromethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-fluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-fluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-fluoro-1-methyl-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(1S)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one Methyl 3,3-difluoro-5-[5-[(3R)-3-amino-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate Methyl 3,3-difluoro-5-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate Methyl 1-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]cyclopropanecarbonitrile Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (3R)-3-amino-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-ethoxy-1,2,2,2-tetrafluoro-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one ((3R)-3-amino-5-[[4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl]methyl]-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(1-cyclopropyl-1,2,4-triazol-3-yl)phenyl]methyl]-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-5-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 4-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]morpholine-2-carbonitrile (3R)-3-amino-7-[5-[2-(methoxymethyl)morpholin-4-yl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-[2-(trifluoromethyl)morpholin-4-yl]-1,3,4-oxadiazol-2-yl]-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-[2-(trifluoromethyl)morpholin-4-yl]-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-[2-(trifluoromethyl)morpholin-4-yl]-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-[methyl(2,2,2-trifluoroethyl)amino]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-5-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(6-methoxy-3-pyridyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1-dioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoroethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1-dioxo-7-[5-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-amino-1-cyclopropyl-2,2,2-trifluoro-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]cyclobutanecarbonitrile 4-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]tetrahydropyran-4-carbonitrile 3-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2,2-dimethyl-propanenitrile 3-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-methyl-butanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-ethyl-butanenitrile 3-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]tetrahydrofuran-3-carbonitrile (3R)-3-amino-7-[5-(1-amino-4,4-difluoro-cyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-amino-3,3-difluoro-cyclobutyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 4-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-1-methyl-piperidine-4-carbonitrile (3R)-3-amino-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-[5,5-difluoro-1-(2-methoxyethyl)-3-piperidyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-[5,5-difluoro-1-(2-methoxyethyl)-3-piperidyl]-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-aminooxetan-3-yl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1lambda 6,5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2-chloro-3-pyridyl)-1,2,4-oxadiazol-3-yl]-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-(6-fluoro-2-methyl-3-pyridyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1-dioxo-7-[5-[2-(trifluoromethyl)-3-pyridyl]-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from:

13. (3R)-3-amino-8-fluoro-7-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(3-aminooxetan-3-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 1-[3-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile 1-[3-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile (3R)-3-amino-8-fluoro-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-5-[[4-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(1-amino-2,2,2-trifluoro-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]propanenitrile (3R)-3-amino-7-[5-(2-cyclopropyltetrahydrofuran-2-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-7-[5-[(1R)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(1S)-1-amino-2,2,2-trifluoro-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-[2-(hydroxymethyl)tetrahydrofuran-2-yl]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one Methyl 1-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate Methyl 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate (3R)-3-amino-7-[5-(1-ethoxy-1,2,2,2-tetrafluoro-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-[2-(trifluoromethyl)morpholin-4-yl]-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-7-[5-(2,2-difluoromorpholin-4-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-[methyl(2,2,2-trifluoroethyl)amino]-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one (3R)-3-amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile (3R)-3-amino-1,1-dioxo-7-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ , 5-benzothiazepin-4-one 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)pyrimidin-2-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(1,1,2,2,2-pentafluoroethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-ethyl-butanenitrile, and 2-[5-[(3R)-3-amino-5-[[4-[2-methyl-5-(trifluoromethoxy)pyrazol-3-yl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ ６ ,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, selected from:

14. A process for the preparation of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, comprising the step of: 【Chemistry 2】 (In the formula, R １ , R ２ , and R ４ is as defined in any one of claims 1 to 13, and PG is an amino protecting group) with a suitable deprotecting agent to form said compound of formula (I).

15. 15. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, when produced according to the process of claim 14.

16. 14. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

18. 18. The pharmaceutical composition of claim 17, further comprising an additional therapeutic agent.

19. 14. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or delay of progression of cancer.

20. 20. The compound for use according to claim 19, wherein the cancer is associated with aberrant diacylglycerol kinase signaling, and the diacylglycerol kinase is selected from DGKα and / or DGKζ.

21. The cancer is selected from the group consisting of B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin's lymphoma, 21. The compound for use according to claim 19 or 20, wherein the compound is selected from the group consisting of leukemia, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, preleukemia, sarcoma, carcinoma, melanoma, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell carcinoma, melanoma, gastric cancer, brain cancer, lung cancer (e.g., NSCLC), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.

22. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for the treatment, prevention and / or delay of progression of cancer.

23. 14. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment, prevention and / or delay of progression of cancer.

24. 14. A method for treating, preventing and / or delaying the progression of cancer, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

25. Use of the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for inhibiting the activity of at least one diacylglycerol kinase selected from DGKα and DGKζ.

26. 14. A method for inhibiting the activity of at least one diacylglycerol kinase selected from DGKα and DGKζ, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

27. The invention as hereinbefore described.

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