Bicyclic tetrahydrothiaza derivatives

Abstract

The present invention provides novel bicyclic tetrahydrothiaza # imgabs0 # derivatives having the general formula (I), # imgabs1 # wherein R1, R2 and R4 are as defined herein; comprising the compound; methods of making the compounds; and methods of using the compounds.

Description

Technical Field

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

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

[0003] Cancer immunity is a multi-step process regulated by a series of negative immune checkpoints and positive co-stimulatory receptors and related intracellular signal cascades, which can achieve anti-tumor responses when effectively triggered (Mellman, I. et al. (2011) Cancer Immunotherapy Comes of Age, Nature 480 (7378), 480-489). In fact, PD1 / PDL1 targeting and other immune checkpoint inhibitors have revolutionized cancer immunotherapy, but more than 70% of patients still cannot benefit from immune checkpoint inhibition. Similarly, for T cell bispecific antibodies, even in the most promising indications (non-Hodgkin's lymphoma), these T cell binders (TCBs) achieve complete remission in less than 50% of patients. T cell exhaustion seems to play an important role in these examples of primary or secondary resistance to cancer immunotherapy. One possible reason for the lack of efficacy is that T cell activation occurs via targeting and cross-linking of CD3 (signal 1), but lacks costimulation such as via CD28 or 4-1BB (signal 2). This hypothesis was clinically validated in CAR T-cell therapy, where results showed that clinically relevant efficacy was only observed after the addition of the co-stimulatory domain.

[0004] Diacylglycerol kinase (DGK) is a lipid kinase that catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA), thereby limiting DAG-regulated functions and promoting PA-dependent functions (Merida, I., Avila-Flores, A., and Merino, E. 2008: Diacylglycerol kinases: at the hub of cells ignalling. Biochem. J. 409 (1), 1–18). The DGK family consists of ten isoforms, which can be divided into five subtypes based on the presence of different regulatory domains in their structures. In addition, the lack of structural data still hinders a more thorough understanding of the mode of action of DGK. Furthermore, information on some prokaryotic DGKs and other lipid kinases, such as sphingosine kinase and phosphatidylinositol 3-kinase (PI3K), provides only limited insights into the catalytic mechanisms of DGKs that appear to differ from those of typical kinases (Arranz-Nicolás, J. and Mérida, I., 2020. Biological regulation of diacylglycerol kinases in normal and neoplastic tissues: New opportunities for cancer immunotherapy, Advances in Biological Regulation, Vol. 75; Ma, Q., Gabelli, SB, Raben, DM, 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 intensively studied isoforms at this point. As PA generators, both enzymes are involved in various processes that promote tumor growth and metastasis. On the other hand, as DAG-consuming agents, DGKα and DGKζ have been extensively 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 drugtargets for a variety of diseases: an update. Front Cell Dev Biol 4, 82; Arranz-Nicolás, J. and Merida, I., 2020. Biological regulation of diacylglycerol kinases abnormal 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 co-stimulatory receptors and the T cell receptor (TCR), and their function is to limit the amount of DAG produced and ultimately limit T cell activation (Merida, I., Andrada, E., Gharbi, SI, 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, YV, Topham, MK, Epand, RM, 2011. Regulation and functions of diacylglycerol kinases. Chem. Rev. 111(10), 6186–6208). The signal transduction pathways regulated by representative DGKs are summarized as shown in Figure 1 (Sim, JA; 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. In short, DAG production and levels determine the duration and intensity of Ras / MEK / ERK and PKC-dependent signaling pathways, and they are at the core of T cell activation. Therefore, DGK is used as an intracellular checkpoint, and it is expected that inhibition of DGK can 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. CAR T cell experiments on human mesothelioma transplanted into nude mice showed that tumor-infiltrating CAR T cells expressed elevated concentrations of surface inhibitory receptors and inhibitory enzymes SHIP-1, DGKα, and DGKζ (Moon et al., 2014). In addition, high levels of DGKα expression were also observed in TILs isolated from human renal tumors (Prinz et al., 2012). In mouse mesoCAR T cells, dual deletion of DGKα and DGKζ resulted in enhanced cytokine expression and cytotoxicity to tumor cells (Riese et al., 2013). Similar results have been reported for human CAR T cells, where CRISPR / Cas9 was used to silence DGKα and DGKζ expression (Jung et al., 2018). All these studies provide a basis for targeting DGKα / ζ in the development of anti-cancer therapies (Arranz-Nicolás, J. and Mérida, I., 2020. Biological regulation of diacylglycerolkinases in normal and neoplastic tissues: New opportunities for cancer immunotherapy, Advances in Biological Regulation, Vol. 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 DGKα or DGKζ exhibit a highly responsive 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 anergy is reversed by active Ras and isregulated 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 theinduction of T cell anergy.Nat.Immunol.7(11),1174–1181).

[0008] In summary, there is a wealth of evidence that DGKα and DGKζ are high-value targets for cancer immunotherapy. At the same time, there is a lack of compounds that can effectively inhibit DGKα and DGKζ and have good selectivity for them over other diacylglycerol kinases, protein kinases, and / or other lipid kinases.

[0009] The present invention describes such dual DGKα / ζ inhibitors, which have excellent selectivity over other protein kinases in terms of safety / off-target groups and relative to other lipid kinases. These compounds effectively activate suboptimally stimulated T cells, and thus act as intracellular enhancers of costimulatory signal cascades. These DGKα / ζ inhibitors are likely to increase the proliferation, cytotoxicity and lifespan of targeted T cells, which can lead to improved CPI, CD3 engaging T cell bispecific sites, and anticancer activity of CAR T cells. In addition, by engaging signaling nodes that are important to both TCR and costimulatory receptors, these molecules may enhance signals 1 and 2, and thus single agent activity can be achieved, for example, in inflammatory tumors.

[0010] There continues to be a need for compounds that can activate and proliferate T cells and thereby treat, prevent and / or delay the progression of cancer.

[0011] Therefore, one object of the present invention is to provide compounds useful as DGKα / ζ inhibitors for the treatment or prevention or amelioration of such diseases with improved therapeutic properties, in particular improved pharmacokinetic properties. Summary of the invention

[0012] The first object of the present invention is a compound of formula (I)

[0013]

[0014] or a pharmaceutically acceptable salt thereof, wherein:

[0015] R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace;

[0016] R 2 is selected from hydrogen and halogen;

[0017] R 4 Selected from C 5-14 -aryl and 5- to 14-membered heteroaryl, wherein R 4 Optionally, one or more R 11 replace;

[0018] R 10 Selected from:

[0019] i)C 1-10 -alkyl, which is optionally substituted with one or more halogen, amino, hydroxyl, C 1-6 - substituted with alkoxy, 3- to 10-membered cycloalkyl, phenyl, or cyano;

[0020] ii) C 3-10- cycloalkyl, which is optionally substituted by one or more halogen, cyano, amino;

[0021] iii) a 3- to 10-membered heterocyclic group, which is optionally substituted with one or more halogens, C 1-10 -alkyl, amino, halo-C 1-6 -alkyl, hydroxyl, cyano, -C(O)O-(R 10q ), C 3-10 -cycloalkyl substituted, wherein C 1-10 -alkyl is optionally substituted with one or more hydroxyl groups, C 1-6 - alkoxy substitution;

[0022] iv)-N(R 10e R 10f );

[0023] v) heteroaryl, which is optionally substituted with one or more C 1-10 -Alkyl, halogen substituted;

[0024] R 10e and R 10f Each independently selected from:

[0025] i) Hydrogen;

[0026] ii) C 1-6 - alkyl, which is optionally substituted with one or more cyano, halogen, hydroxyl;

[0027] iii) C 3-10 -cycloalkyl, which is optionally substituted with one or more halogen, C 1-10 - alkyl substitution;

[0028] R 10q C 1-5 -alkyl, where C 1-5 - alkyl is optionally substituted with one or more hydroxyl groups;

[0029] R 11 Selected from:

[0030] i) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more C 1-6 -alkyl, C 3-10 Cycloalkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkoxy substituted, where C 3-10 Cycloalkyl is optionally substituted with one or more halogens;

[0031] ii) phenyl, which is optionally substituted with one or more C 1-6 -alkoxy, -OH, halo-C 1-6 -alkyl substitution.

[0032] The second object of the present invention is a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as described above, the method comprising:

[0033]

[0034] react with a suitable deprotecting agent to form the compound of formula (I), wherein R 1 , R 2 and R 4 As defined herein and PG is an amino protecting group.

[0035] The third object of the present invention is a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as described above, and a pharmaceutically acceptable excipient.

[0036] The fourth object of the present invention is a compound of formula (I) as described above or a pharmaceutically acceptable salt thereof for use in treating, preventing cancer and / or delaying cancer progression.

[0037] Unless defined otherwise, 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.

[0038] 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.

[0039] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0040] Unless otherwise indicated, the nomenclature used in this application is based on the IUPAC systematic nomenclature. DETAILED DESCRIPTION

[0041] definition

[0042] "Alkoxy" refers to an alkyl group, as previously defined, 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 containing 1 to 10 carbon atoms (“C 1-10 -alkoxy”), more preferably containing 1 to 6 carbon atoms (“C 1-6 -alkoxy"). In some preferred embodiments, the alkoxy group contains 1 to 4 carbon atoms. In 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.

[0043] "Alkoxyalkyl" refers to an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group. Preferably, "alkoxyalkyl" refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably one hydrogen atom, of the alkyl group has been replaced by an alkoxy group. A preferred but non-limiting example of alkoxyalkyl is methoxymethyl and 2-methoxyethyl.

[0044] "Alkyl" refers to a group having a specified number of carbon atoms (i.e., C 1-10 alkyl groups are saturated straight (i.e., unbranched) or branched monovalent hydrocarbon chains of one to ten carbon atoms (“C”). 1-20 alkyl”), having 1 to 12 carbon atoms (“C 1-12 alkyl”), having 1 to 10 carbon atoms (“C 1-10 alkyl”), having 1 to 8 carbon atoms (“C 1-8 alkyl”), having 1 to 6 carbon atoms (“C 1-6 alkyl”), having 2 to 6 carbon atoms (“C 2-6 alkyl") or 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, tert-butyl, isobutyl, sec-butyl, homologs and isomers thereof, such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0045] "Alkynyl" refers to a moiety having at least one site of acetylenic unsaturation (ie, having at least one moiety of the formula C≡C), having a specified number of carbon atoms (ie, C 2-10 The term "alkynyl" refers to an unsaturated straight chain (ie, unbranched) or branched monovalent hydrocarbon chain or combinations thereof having from two to ten carbon atoms. Specific alkynyl groups are those having from 2 to 20 carbon atoms ("C 2-20 Alkynyl”), having 2 to 8 carbon atoms (“C 2-8 Alkynyl”), having 2 to 6 carbon atoms (“C 2-6 Alkynyl”), having 2 to 4 carbon atoms (“C 2-4 Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (ethynyl or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.

[0046] "Amino", alone or in combination with other groups, means NH 2 .

[0047] "Aminoalkyl" refers to an alkyl group in which one or more of the hydrogen atoms of the alkyl group have been replaced by an amino moiety.

[0048] "Aromatic" means the conventional concept of aromaticity as defined in the literature, in particular in IUPAC-Compendium of Chemical Terminology, 2nd edition, AD McNaught and A. Wilkinson (eds.). Blackwell Scientific Publications, Oxford (1997).

[0049] "Aryl" refers to a cyclic aromatic hydrocarbon moiety having a monocyclic, bicyclic or tricyclic aromatic ring of 5 to 14 carbon ring atoms ("C 5-14 -aryl"). Bicyclic aryl ring systems include fused bicyclic rings having two fused five-membered aryl rings (denoted 5-5), fused bicyclic rings having one five-membered aryl ring and one fused six-membered aryl ring (denoted 5-6 and 6-5), and fused bicyclic rings having two fused six-membered aryl rings (denoted 6-6). Aryl groups may be optionally substituted as described above. Examples of aryl substituents include, but are not limited to, phenyl, naphthyl, phenanthrenyl, 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, each of which is optionally substituted.

[0050] "Cancer" refers to a disease characterized by the presence of a neoplasm or tumor resulting from the abnormal, uncontrolled growth of cells (these cells are "cancer cells"). As used herein, the term cancer specifically includes, but is not limited to, hepatocellular carcinoma, malignant tumors and hyperproliferative diseases of the colon (colon cancer), lung cancer, breast cancer, prostate cancer, melanoma, and ovarian cancer.

[0051] "Cyano", alone or in combination with other groups, means CN (ie, nitrile).

[0052] "Cyanoalkyl" refers to an alkyl group in which one or more of the hydrogen atoms of the alkyl group has been replaced with cyano moieties.

[0053] "Cycloalkyl" refers to a saturated or partially unsaturated carbocyclic moiety having a monocyclic, bicyclic (including bridged bicyclic and cycloalkyl spiro substituents) or tricyclic ring and 3 to 10 carbon atoms (i.e., (C 3 -C 10 ) cycloalkyl). The cycloalkyl moiety may be optionally substituted with one or more substituents. In certain aspects, the cycloalkyl contains 3 to 8 carbon atoms (i.e., (C 3 -C 8In other specific aspects, the cycloalkyl group contains 3 to 6 carbon atoms (ie, (C 3 -C 6 )cycloalkyl). Examples of cycloalkyl substituents include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and partially unsaturated (cycloalkenyl) derivatives thereof (e.g., cyclopentenyl, cyclohexenyl and cycloheptenyl), bicyclo[3.1.0]hexyl, bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptyl, bicyclo[3.1.1]heptenyl and bicyclo[1.1.1]pentane. The cycloalkyl moiety may be attached in a "spiro-cycloalkyl" or "cycloalkylspiro" manner, such as a "spirocyclopropyl"

[0054]

[0055] “EC x "EC" refers to the effective concentration of a specific compound in culture medium or plasma, for example, required to achieve x% of a maximum specific effect in vitro or in vivo. x An example of this is EC 20 ,EC 50 and EC 100 , respectively, represent the concentration of a specific compound in culture medium or plasma required to obtain 20%, 50% and 100% of the maximum specific effect in vitro or in vivo. "Haloalkoxy" refers to an alkoxy group in which at least one halogen replaces each H in the hydrocarbon constituting the alkyl portion of the alkoxy group. An example of a haloalkoxy group is difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ).

[0056] "Haloaryl" refers to an aryl group in which at least one hydrogen has been replaced by a halogen.

[0057] "Halogen" or "halo" refers to fluorine, chlorine, bromine and / or iodine. When a residue is substituted with more than one halogen, it may be indicated using a prefix corresponding to the number of halogen moieties attached, for example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halogen groups, which may be, but need not be, the same halogen; thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. Alkyl groups in which one or more hydrogens are replaced with halogen groups are termed "haloalkyl", for example, "C 1-6 A preferred haloalkyl group is trifluoroalkyl (-CF 3 ).

[0058] "Heteroaryl" refers to an aromatic heterocyclic monocyclic, bicyclic or tricyclic ring system of 5 to 14 ring atoms, preferably 5 to 10 ring atoms, more preferably 5 to 6 ring atoms, containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. In some aspects, the monocyclic heteroaryl ring can be a 5- to 6-membered ring. Bicyclic heteroaryl ring systems include fused bicyclic rings having two fused five-membered heteroaryl rings (denoted 5-5), fused bicyclic rings having one five-membered heteroaryl ring and one fused six-membered heteroaryl ring (denoted 5-6 and 6-5), and fused bicyclic rings having two fused six-membered heteroaryl rings (denoted 6-6). The heteroaryl group can be optionally substituted as described above. Examples of heteroaryl substituents include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothiophenyl, benzothiophenyl, indolyl, aza-indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, oxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridinyl, thienopyrimidinyl, thienopyrazinyl, furanopyridazinyl, furanopyrimidinyl and furanopyrazinyl. More preferably, "5-membered heteroaryl" refers to the following groups:

[0059]

[0060] "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, which is saturated or partially unsaturated and has one or more (e.g., 1, 2, 3 or 4) heteroatoms selected from oxygen, nitrogen and sulfur in the ring, the remaining ring atoms being carbon. In some aspects, the heterocycle is a heterocycloalkyl. In specific aspects, the heterocycle or heterocyclyl refers to a 4, 5, 6 or 7-membered heterocycle. When used to refer to the ring atoms of a heterocycle, the nitrogen or sulfur may also be in oxidized form, and the nitrogen may be substituted with one or more (C 1 -C 6) alkyl or group. The heterocycle can be attached to its side group at any heteroatom or carbon atom, resulting in a stable structure. Any ring atom of the heterocycle can be optionally substituted with one or more substituents described herein. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine Oxazepine Thiazepine The term heterocycle also includes groups in which the 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.

[0061] "Hydroxyl", alone or in combination with other groups, refers to OH.

[0062] "Hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms of the alkyl group has been replaced with a hydroxy moiety. Examples include alcohols and diols.

[0063] "Moiety" and "substituent" refer to an atom or group of chemically bonded atoms attached to another atom or molecule by one or more chemical bonds to form a part of a molecule.

[0064] When indicating the number of substituents, the term "one or more" refers to the range from one substituent to the highest possible number of substituents, i.e., replacement of one hydrogen up to replacement of all hydrogens by substituents, particularly where "one or more" refers to one, two or three, most particularly "one or more" refers to one or two.

[0065] "Optional" or "optionally" means that the subsequently described event or circumstance may occur but need not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, "an aryl group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the aryl group is substituted with an alkyl group and instances where the aryl group is not substituted with an alkyl group.

[0066] "Optionally substituted" means unsubstituted or substituted. Typically, these substituents may be the same or different.

[0067] "Oxo", alone or in combination with other groups, means =0.

[0068] "Pharmaceutically acceptable salts" refer to those salts which retain the biological effects and properties of the free bases or free acids and which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and with 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, benzylformic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine.

[0069] Particularly preferably, the pharmaceutically acceptable salts of the compounds of formula (I) are salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.

[0070] "Protecting group" (PG) means a group that selectively blocks a reactive site in a multifunctional compound so that a chemical reaction can be selectively carried out at another unprotected reactive site in synthetic chemistry in the sense in which it is customary. The protecting group can be removed at an appropriate point. Exemplary protecting groups are amino protecting groups, carboxyl protecting groups, or hydroxy protecting groups. Specific protecting groups are tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Further specific protecting groups are tert-butyloxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more specific protecting group is tert-butyloxycarbonyl (Boc). Exemplary protecting groups and their use in organic synthesis are described, for example, in TW Greene and PGM Wutts, Protective Groups in Organic Chemistry, 5th edition, 2014, John Wiley & Sons, NY.

[0071] As used herein, "prevention" includes preventing or delaying the appearance of clinical symptoms of a state, disorder or condition that develops in a mammal, especially a human, that may have or is susceptible to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.

[0072] "Substituted" refers to at least one hydrogen atom in a compound or moiety being replaced by 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 group (as defined below) are replaced by one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.). On the one hand, as used herein, substituted may refer to the replacement of at least one hydrogen atom of a compound or moiety described herein with a halogen or alkyl group.

[0073] "Therapeutically effective amount" refers to an amount of a compound or molecule of the invention that, when administered to a subject, achieves the following effects: (i) treating or preventing a specific disease, condition or disorder described herein, (ii) alleviating, ameliorating or eliminating one or more symptoms of a specific disease, condition or disorder described herein, or (iii) preventing or delaying the onset of one or more symptoms of a specific disease, condition or disorder described herein. The therapeutically effective amount depends 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 medical or veterinary doctor and other factors.

[0074] "Therapeutically inert carrier" refers to any ingredient that is not therapeutically active and non-toxic, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant or lubricant used to formulate a pharmaceutical product.

[0075] In particular, the chemical groups given definitions above are those specifically exemplified in the examples.

[0076] The following abbreviations are used in this text:

[0077] 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-dicyanoacetate =1,4-benzoquinone, DMF = N,N-dimethylformamide, DIPEA = N,N-diisopropylethylamine, EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, ESI = electrospray ionization, EtOAc = ethyl acetate, EtOH = ethanol, h = hour, 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-hexafluoro-phosphate, HFIP = hexafluoroisopropanol, HOBt = hydroxybenzotriazole, HPLC = high performance liquid chromatography, m-CPBA = meta-chloroperbenzoic acid, MeCN = acetonitrile, MeI = iodomethane, MeOH = methanol, min = minute, MS = mass spectrometry, NBS = N-bromosuccinimide, PE = petroleum ether, PyBroP = bromo-tris-pyrrolidino-phosphorus hexafluorophosphate, RT = room temperature, RP = reverse phase, TBAF = tetrabutylammonium fluoride, TBAOH = tetrabutylammonium hydroxide, TBDMS = tert-butyldimethylsilyl, TEA = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TMSOTF = trimethylsilyl trifluoromethanesulfonate, TLC = thin layer chromatography, T 3 P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide.

[0078] In the descriptions herein, if there is a discrepancy between a depicted structure and the name given to the structure, the depicted structure controls. In addition, if the stereochemistry of a structure or portion of a structure is not indicated, for example, by a thick wedge or dashed line, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers thereof. However, in some cases where more than one chiral center is present, the structure and name may be represented as a single enantiomer to aid in describing the relative stereochemistry.

[0079] Unless otherwise indicated, the term "the compound of formula..." or "the compound of formula..." or "the compounds of formula..." or "compounds of formula..." refers to any compound selected from the group of compounds defined by the formula (including any pharmaceutically acceptable salt of any such compound if not otherwise specified).

[0080] 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 separate individual tautomers generally produce a mixture with chemical and physical properties consistent with the compound mixture. The position of equilibrium depends on the chemical features within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. Common prototropic tautomers include keto / enol Amide / Imidic Acid and amidine The latter two are particularly common in heteroaryls and heterocycles, and the present invention encompasses all tautomeric forms of the compounds.

[0081] Furthermore, the present invention includes all optical isomers, ie diastereomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers thereof and their solvates of the compounds of formula (I).

[0082] Compounds of formula (I) may contain one or more asymmetric centers and may therefore exist as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Depending on the nature of the various substituents on the molecule, additional asymmetric centers may be present. Each such asymmetric center will independently produce two optical isomers, and it is intended that all possible optical isomers and diastereomers in the form of mixtures and as pure compounds or partially purified compounds are included in the present invention. The present invention is intended to cover all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their chromatographic separation can be achieved by making appropriate changes to the methods disclosed herein as known in the art. The absolute stereochemistry of the crystalline product or crystalline intermediate can be determined by x-ray crystallography, and if necessary, these products or intermediates can be derivatized using reagents containing asymmetric centers of known absolute configuration. If necessary, the racemic mixture of the compound can be separated so that the individual enantiomers are separated. Separation can be carried out by methods well known in the art, such as coupling a racemic mixture of the compounds to an enantiomerically pure compound to form a diastereomeric mixture followed by separation of the individual diastereomers by standard methods such as fractional crystallization or chromatography.

[0083] In embodiments where an optically pure enantiomer is provided, an optically pure enantiomer means that the compound contains >90% by weight of the desired isomer, particularly >95% by weight of the desired isomer, or more particularly >99% by weight of the desired isomer, the weight percentages being based on the total weight of the isomers of the compound. Chirally pure compounds or chirally enriched compounds can be prepared by chiral selective synthesis or by enantiomer separation. Separation of enantiomers can be performed on the final product, or alternatively on a suitable intermediate.

[0084] In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more atoms with 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, such as but not limited to 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 I. Certain isotopically-labeled compounds of formula (I) (e.g., those containing a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and detection means are readily available. For example, compounds of formula (I) may be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95 or 99% of a given isotope.

[0085] Using heavier isotopes (such as deuterium, 2 H) substitutions may provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0086] Using positron-emitting isotopes such as 11 C. 18 F. 15 O and 13N) substitution can be used to examine positron emission tomography (PET) studies of 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 methods analogous to those described in the Examples set forth below using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used.

[0087] Compounds of the present invention

[0088] In one embodiment, a compound of formula (I) is provided,

[0089]

[0090] or a pharmaceutically acceptable salt thereof, wherein:

[0091] R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace;

[0092] R 2 is selected from hydrogen and halogen;

[0093] R 4 Selected from C 5-14 -aryl and 5- to 14-membered heteroaryl, wherein R 4 Optionally, one or more R 11 replace;

[0094] R 10 Selected from:

[0095] i)C 1-10 -alkyl, which is optionally substituted with one or more halogen, amino, hydroxyl, C 1-6 - substituted with alkoxy, 3- to 10-membered cycloalkyl, phenyl, or cyano;

[0096] ii) C 3-10 - cycloalkyl, which is optionally substituted by one or more halogen, cyano, amino;

[0097] iii) a 3- to 10-membered heterocyclic group, which is optionally substituted with one or more halogens, C 1-10 -alkyl, amino, halo-C 1-6 -alkyl, hydroxyl, cyano, -C(O)O-(R 10q ), C 3-10 -cycloalkyl substituted, wherein C 1-10 -alkyl is optionally substituted with one or more hydroxyl groups, C 1-6 - alkoxy substitution;

[0098] iv)-N(R 10e R10f );

[0099] v) heteroaryl, which is optionally substituted with one or more C 1-10 -Alkyl, halogen substituted;

[0100] R 10e and R 10f Each independently selected from:

[0101] i) Hydrogen;

[0102] ii) C 1-6 - alkyl, which is optionally substituted with one or more cyano, halogen, hydroxyl;

[0103] iii) C 3-10 -cycloalkyl, which is optionally substituted with one or more halogen, C 1-10 - alkyl substitution;

[0104] R 10q C 1-5 -alkyl, where C 1-5 - alkyl is optionally substituted with one or more hydroxyl groups;

[0105] R 11 Selected from:

[0106] i) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more C 1-6 -alkyl, C 3-10 Cycloalkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkoxy substituted, where C 3-10 Cycloalkyl is optionally substituted with one or more halogens;

[0107] ii) phenyl, which is optionally substituted with one or more C 1-6 -alkoxy, -OH, halo-C 1-6 -alkyl substitution.

[0108] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 11 Selected from:

[0109] (i) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more C 1-6 -alkyl, C 3-10 Cycloalkane

[0110] C 1-6 - alkyl substitution;

[0111] (ii) phenyl, optionally substituted with one or more C 1-6 -alkoxy, halo-C1-6 -alkyl, halo-C 1-6 -Alkoxy substitution.

[0112] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 2 Selected from hydrogen and fluorine.

[0113] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 4 is selected from phenyl and pyridyl, wherein R 4 Optionally, one or more R 11 replace.

[0114] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 10is tert-butyl, pyrrolidinyl, tetrafluoro-methoxy-ethyl, methyl-propionitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, aminocyclohexyl, cyclopropanecarbonitrile, difluoro-piperidinyl, ethoxy-tetrafluoro-ethyl, (hydroxymethyl)tetrahydrofuranyl, azabicyclo[3.1.1]heptane-methylformate, amino-trifluoromethyl-ethyl, difluoro-piperidinyl-methylformate, fluoro-methyl-piperidinyl, aminooxetanyl, (difluoro-methyl-cyclobutyl)aminoacyl, cyclopropyltetrahydrofuranyl, amino-dimethyl-propyl, propionitrile, isopropylaminoacyl, Fluoro-methyl-pyridyl, methyl-pyridyl, chloro-pyridyl, tetrafluoroethyl, trifluoro-dihydroxy-ethyl, hydroxy-(trifluoromethyl)propyl, pentafluoroethyl, trifluoro-dimethyl-ethyl, trifluoro-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, dioxaazabicyclo[3.3.1]nonanyl, morpholino-carbonitrile , (methoxymethyl)morpholinyl, (hydroxymethyl)morpholinyl, (hydroxyethyl)morpholinyl, oxazepanyl, difluoro-(methoxyethyl)-piperidinyl, 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-aminoacyl-acetonitrile, cyclopropyl(difluoroethyl)amino, difluoropyrrolidinyl, (trifluoro-methyl-ethyl)amino, trifluoroethylamino, methyl(trifluoroethyl)amino, ethyl-difluoro-piperidinyl, dimethyl-pyridinyl, trifluoro-methoxy-ethyl.

[0115] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 10is tert-butyl, tetrafluoro-methoxy-ethyl, methyl-propionitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, cyclopropanecarbonitrile, difluoro-piperidinyl, (hydroxymethyl)tetrahydrofuranyl, amino-trifluoromethyl-ethyl, aminooxetanyl, cyclopropyltetrahydrofuranyl, propionitrile, aminocyclohexyl.

[0116] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 11 Selected from (hydroxymethyl)phenyl, (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridinyl, (trifluoromethyl)phenyl, methoxyphenyl, (trifluoromethyl)pyridinyl, dimethylpyrazolyl, tert-butyl-oxadiazolyl, methyl-oxadiazolyl, methylpyrazolyl, (difluoromethyl)-oxadiazolyl, (trifluoromethyl)oxadiazolyl, methyl-(trifluoromethyl)pyrazolyl, (trifluoromethyl)pyrazolyl, (trifluoromethyl)isoxazolyl, (trifluoromethyl-ethyl)oxadiazolyl, (trifluoroethyl)oxadiazolyl, (trifluoromethoxy)phenyl, cyclopropyl-triazolyl, (trifluoromethoxy)pyridinyl, (trifluoromethoxy)pyrimidinyl, (pentafluoroethoxy)pyridinyl, (trifluoromethoxy)pyridinyl, methyl-(trifluoromethoxy)pyrazolyl.

[0117] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 11 Selected from (hydroxymethyl)phenyl, (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridinyl, (trifluoromethyl)phenyl, methoxyphenyl, (trifluoromethyl)pyridinyl, dimethylpyrazolyl, tert-butyl-oxadiazolyl, methyl-oxadiazolyl, methylpyrazolyl, (difluoromethyl)-oxadiazolyl, (trifluoromethyl)oxadiazolyl, methyl-(trifluoromethyl)pyrazolyl, (trifluoromethyl)pyrazolyl, (trifluoromethyl)isoxazolyl, (trifluoromethyl-ethyl)oxadiazolyl, (trifluoroethyl)oxadiazolyl, (trifluoromethoxy)phenyl, cyclopropyl-triazolyl.

[0118] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 11 Selected from (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridinyl, methoxyphenyl, (trifluoromethoxy)pyridinyl, (trifluoromethoxy)pyrimidinyl, (pentafluoroethoxy)pyridinyl, (trifluoromethoxy)pyridinyl, methyl-(trifluoromethoxy)pyrazolyl.

[0119] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 11 Selected from (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridinyl, methoxyphenyl.

[0120] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein:

[0121] R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace;

[0122] R 2 is selected from hydrogen and fluorine;

[0123] R 4 is selected from phenyl and pyridyl, wherein R 4 Optionally, one or more R 11 replace;

[0124] R 10 Selected from:

[0125] i)C 1-10 -alkyl, which is optionally substituted with one or more halogen, amino, hydroxyl, C 1-6 - substituted with alkoxy, 3- to 10-membered cycloalkyl, phenyl, or cyano;

[0126] ii) C 3-10 - cycloalkyl, which is optionally substituted by one or more halogen, cyano, amino;

[0127] iii) a 3- to 10-membered heterocyclic group, which is optionally substituted with one or more halogens, C 1-10 -alkyl, amino, halo-C 1-6 -alkyl, hydroxyl, cyano, -C(O)O-(R 10q ), C 3-10 -cycloalkyl substituted, wherein C 1-10 -alkyl is optionally substituted with one or more hydroxyl groups, C 1-6 - alkoxy substitution;

[0128] iv)-N(R 10e R 10f );

[0129] v) heteroaryl, which is optionally substituted with one or more C 1-10 -Alkyl, halogen substituted;

[0130] R 10e and R 10f Each independently selected from:

[0131] i) Hydrogen;

[0132] ii) C 1-6 - alkyl, which is optionally substituted with one or more cyano, halogen, hydroxyl;

[0133] iii) C 3-10 -cycloalkyl, which is optionally substituted with one or more halogen, C 1-10 - alkyl substitution;

[0134] R 10q C 1-5 -alkyl, where C 1-5 - alkyl is optionally substituted with one or more hydroxyl groups;

[0135] R 11 Selected from:

[0136] i) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more C 1-6 -alkyl, C 3-10 Cycloalkyl, halo-C 1-6 - alkyl substitution;

[0137] ii) phenyl, which is optionally substituted with one or more C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -Alkoxy substitution.

[0138] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided,

[0139] in:

[0140] R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace;

[0141] R 2 is selected from hydrogen and fluorine;

[0142] R 4 is selected from phenyl and pyridine, wherein R 4 Optionally, one or more R 11 replace;

[0143] R 10is tert-butyl, pyrrolidinyl, tetrafluoro-methoxy-ethyl, methyl-propionitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, aminocyclohexyl, cyclopropanecarbonitrile, difluoro-piperidinyl, ethoxy-tetrafluoro-ethyl, (hydroxymethyl)tetrahydrofuranyl, azabicyclo[3.1.1]heptane-methylformate, amino-trifluoromethyl-ethyl, difluoro-piperidinyl-methylformate, fluoro-methyl-piperidinyl, aminooxetanyl, (difluoro-methyl-cyclobutyl)aminoacyl, cyclopropyltetrahydrofuranyl, amino-dimethyl-propyl, propionitrile, isopropylaminoacyl, Fluoro-methyl-pyridyl, methyl-pyridyl, chloro-pyridyl, tetrafluoroethyl, trifluoro-dihydroxy-ethyl, hydroxy-(trifluoromethyl)propyl, pentafluoroethyl, trifluoro-dimethyl-ethyl, trifluoro-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, dioxaazabicyclo[3.3.1]nonanyl, morpholino-carbonitrile , (methoxymethyl)morpholinyl, (hydroxymethyl)morpholinyl, (hydroxyethyl)morpholinyl, oxazepanyl, difluoro-(methoxyethyl)-piperidinyl, 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-aminoacyl-acetonitrile, cyclopropyl(difluoroethyl)amino, difluoropyrrolidinyl, (trifluoro-methyl-ethyl)amino, trifluoroethylamino, methyl(trifluoroethyl)amino, ethyl-difluoro-piperidinyl, dimethyl-pyridinyl, trifluoro-methoxy-ethyl;

[0144] R 11Selected from (hydroxymethyl)phenyl, (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridinyl, (trifluoromethyl)phenyl, methoxyphenyl, (trifluoromethyl)pyridinyl, dimethylpyrazolyl, tert-butyl-oxadiazolyl, methyl-oxadiazolyl, methylpyrazolyl, (difluoromethyl)-oxadiazolyl, (trifluoromethyl)oxadiazolyl, methyl-(trifluoromethyl)pyrazolyl, (trifluoromethyl)pyrazolyl, (trifluoromethyl)isoxazolyl, (trifluoromethyl-ethyl)oxadiazolyl, (trifluoroethyl)oxadiazolyl, (trifluoromethoxy)phenyl, cyclopropyl-triazolyl.

[0145] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein:

[0146] R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace;

[0147] R 2 is selected from hydrogen and fluorine;

[0148] R 4 is selected from phenyl and pyridine, wherein R 4 Optionally, one or more R 11 replace;

[0149] R 10 is tert-butyl, tetrafluoro-methoxy-ethyl, methyl-propionitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, cyclopropanecarbonitrile, difluoro-piperidinyl, (hydroxymethyl)tetrahydrofuranyl, amino-trifluoromethyl-ethyl, aminooxetanyl, cyclopropyltetrahydrofuranyl, propionitrile, aminocyclohexyl;

[0150] R 11 Selected from (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridinyl, methoxyphenyl.

[0151] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein:

[0152] R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace;

[0153] R 2 is selected from hydrogen and fluorine;

[0154] R 4 is selected from phenyl and pyridyl, wherein R 4Optionally, one or more R 11 replace;

[0155] R 10 is tert-butyl, pyrrolidinyl, tetrafluoro-methoxy-ethyl, methyl-propionitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, aminocyclohexyl, cyclopropanecarbonitrile, difluoro-piperidinyl, ethoxy-tetrafluoro-ethyl, (hydroxymethyl)tetrahydrofuranyl, azabicyclo[3.1.1]heptane-methylformate, amino-trifluoromethyl-ethyl, difluoro-piperidinyl-methylformate, fluoro-methyl-piperidinyl, aminooxetanyl, (difluoro-methyl-cyclobutyl)aminoacyl, cyclopropyltetrahydrofuranyl, amino-dimethyl-propyl, propionitrile, isopropylaminoacyl, Fluoro-methyl-pyridyl, methyl-pyridyl, chloro-pyridyl, tetrafluoroethyl, trifluoro-dihydroxy-ethyl, hydroxy-(trifluoromethyl)propyl, pentafluoroethyl, trifluoro-dimethyl-ethyl, trifluoro-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, dioxaazabicyclo[3.3.1]nonanyl, morpholino-carbonitrile , (methoxymethyl)morpholinyl, (hydroxymethyl)morpholinyl, (hydroxyethyl)morpholinyl, oxazepanyl, difluoro-(methoxyethyl)-piperidinyl, 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-aminoacyl-acetonitrile, cyclopropyl(difluoroethyl)amino, difluoropyrrolidinyl, (trifluoro-methyl-ethyl)amino, trifluoroethylamino, methyl(trifluoroethyl)amino, ethyl-difluoro-piperidinyl, dimethyl-pyridinyl, trifluoro-methoxy-ethyl;

[0156] R 11Selected from (hydroxymethyl)phenyl, (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridinyl, (trifluoromethyl)phenyl, methoxyphenyl, (trifluoromethyl)pyridinyl, dimethylpyrazolyl, tert-butyl-oxadiazolyl, methyl-oxadiazolyl, methylpyrazolyl, (difluoromethyl)-oxadiazolyl, (trifluoromethyl)oxadiazolyl, methyl-(trifluoromethyl)pyrazolyl, (trifluoromethyl)pyrazolyl, (trifluoromethyl)isoxazolyl, (trifluoromethyl-ethyl)oxadiazolyl, (trifluoroethyl)oxadiazolyl, (trifluoromethoxy)phenyl, cyclopropyl-triazolyl, (trifluoromethoxy)pyridinyl, (trifluoromethoxy)pyrimidinyl, (pentafluoroethoxy)pyridinyl, (trifluoromethoxy)pyridinyl, methyl-(trifluoromethoxy)pyrazolyl.

[0157] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein:

[0158] R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace;

[0159] R 2 is selected from hydrogen and fluorine;

[0160] R 4 is selected from phenyl and pyridyl, wherein R 4 Optionally, one or more R 11 replace;

[0161] R 10 is tert-butyl, tetrafluoro-methoxy-ethyl, methyl-propionitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, cyclopropanecarbonitrile, difluoro-piperidinyl, (hydroxymethyl)tetrahydrofuranyl, amino-trifluoromethyl-ethyl, aminooxetanyl, cyclopropyltetrahydrofuranyl, propionitrile, aminocyclohexyl;

[0162] R 11 Selected from (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridinyl, methoxyphenyl, (trifluoromethoxy)pyridinyl, (trifluoromethoxy)pyrimidinyl, (pentafluoroethoxy)pyridinyl, (trifluoromethoxy)pyridinyl, methyl-(trifluoromethoxy)pyrazolyl.

[0163] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, which is selected from:

[0164] (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-Benzothiazepine (Benzothiazepin)-4-ketone

[0165] (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-Benzothiazepine -4-Keto

[0166] 2-[5-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0167] (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-Benzothiazepine -4-Keto

[0168] (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-Benzothiazepine -4-Keto

[0169] (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-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-Benzothiazepine -4-Keto

[0170] (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-Benzothiazepine -4-Keto

[0171] (3R)-3-amino-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-[[6-[4-(hydroxymethyl)phenyl]-3-pyridinyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0172] (3R)-3-amino-7-[5-(3-aminooxetane-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-Benzothiazepine -4-Keto

[0173] (3R)-3-amino-7-[5-(3-aminooxetane-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-Benzothiazepine -4-Keto

[0174] (3R)-3-amino-7-[5-(3-aminooxetane-3-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0175] (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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0176] (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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0177] (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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0178] (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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0179] (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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0180] 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-Benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile

[0181] 1-[3-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile

[0182] (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-Benzothiazepine -4-Keto

[0183] (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-Benzothiazepine -4-Keto

[0184] (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-Benzothiazepine -4-Keto

[0185] (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-Benzothiazepine -4-Keto

[0186] (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-Benzothiazepine -4-Keto

[0187] (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-Benzothiazepine -4-Keto

[0188] (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-Benzothiazepine -4-Keto

[0189] (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-Benzothiazepine -4-Keto

[0190] (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-Benzothiazepine -4-Keto

[0191] (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-Benzothiazepine -4-Keto

[0192] (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-Benzothiazepine -4-Keto

[0193] (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-Benzothiazepine -4-Keto

[0194] (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-Benzothiazepine -4-Keto

[0195] (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-Benzothiazepine -4-Keto

[0196] (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-Benzothiazepine -4-Keto

[0197] (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-Benzothiazepine -4-Keto

[0198] (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-Benzothiazepine -4-Keto

[0199] (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-Benzothiazepine -4-Keto

[0200] (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-Benzothiazepine -4-Keto

[0201] (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-Benzothiazepine -4-Keto

[0202] (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-Benzothiazepine -4-Keto

[0203] (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-Benzothiazepine -4-Keto

[0204] (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-Benzothiazepine -4-Keto

[0205] (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-Benzothiazepine -4-Keto(*)

[0206] (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-Benzothiazepine -4-Keto

[0207] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[0208] (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-Benzothiazepine -4-Keto

[0209] (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-Benzothiazepine -4-Keto

[0210] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0211] (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-Benzothiazepine -4-Keto

[0212] 2-[5-[(3R)-3-amino-5-[[4-[5-(difluoromethyl)-2-pyridyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0213] (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0214] (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-Benzothiazepine -4-Keto

[0215] (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-Benzothiazepine -4-Keto

[0216] (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-Benzothiazepine -4-Keto

[0217] (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-Benzothiazepine -4-Keto

[0218] 2-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0219] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0220] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0221] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0222] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0223] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0224] 2-[5-[(3R)-3-amino-5-[[4-[5-(4,4-difluoro-1-piperidinyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0225] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)oxazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0226] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile(*)

[0227] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0228] 2-[5-[(3R)-3-amino-5-[[4-[5-(difluoromethoxy)-2-pyridinyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0229] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0230] 2-[5-[(3R)-3-amino-5-[[4-[4-(difluoromethoxy)-2-pyridinyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0231] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[2-(trifluoromethyl)-4-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0232] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)pyrazin-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0233] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[6-(trifluoromethyl)-3-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0234] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0235] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[1-(trifluoromethyl)pyrazol-4-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0236] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0237] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)pyrimidin-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0238] 2-[5-[(3R)-3-amino-5-[[4-(5-cyclopropyl-2-pyridyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0239] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethoxy)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0240] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0241] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0242] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)oxazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0243] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0244] 2-[5-[(3R)-3-amino-5-[[4-(5-methoxy-2-pyridyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0245] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0246] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)pyrimidin-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0247] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(1,1,2,2,2-pentafluoroethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0248] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(2,2,2-trifluoroethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0249] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[6-(trifluoromethoxy)-3-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0250] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0251] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0252] 2-[5-[(3R)-3-amino-5-[[4-[4-methyl-5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0253] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)triazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0254] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0255] (3R)-3-amino-7-[5-(2-methyloxetane-2-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0256] (3R)-3-amino-7-[5-(3-methyloxetane-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-Benzothiazepine -4-Keto

[0257] (3R)-3-amino-7-[5-(3-methyloxetan-3-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0258] (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-Benzothiazepine -4-Keto

[0259] (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-Benzothiazepine -4-Keto

[0260] (3R)-3-amino-7-[5-(3-fluoro-1-methyl-3-piperidinyl)-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-Benzothiazepine -4-Keto

[0261] (3R)-3-amino-7-[5-(3-fluoro-1-methyl-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0262] (3R)-3-amino-7-[5-(3-fluoro-1-methyl-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0263] (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-Benzothiazepine -4-Keto

[0264] (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-Benzothiazepine -4-Keto

[0265] (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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0266] (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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0267] (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-Benzothiazepine -4-Keto

[0268] (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-Benzothiazepine -4-Keto

[0269] (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-Benzothiazepine -4-Keto

[0270] (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-Benzothiazepine -4-Keto

[0271] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid methyl ester

[0272] 3,3-Difluoro-5-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid methyl ester

[0273] 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester

[0274] 1-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester

[0275] 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester

[0276] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester

[0277] 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]cyclopropanecarbonitrile

[0278] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester

[0279] 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester

[0280] (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-Benzothiazepine -4-Keto

[0281] (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-Benzothiazepine -4-keto((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-Benzothiazepine -4-Keto

[0282] (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-Benzothiazepine -4-Keto

[0283] (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-Benzothiazepine -4-Keto

[0284] (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-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-Benzothiazepine -4-Keto

[0285] (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0286] (3R)-3-amino-5-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-7-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0287] (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-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-Benzothiazepine -4-Keto

[0288] (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0289] (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-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-Benzothiazepine -4-Keto

[0290] (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0291] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]morpholine-2-carbonitrile

[0292] (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-Benzothiazepine -4-Keto

[0293] (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-Benzothiazepine -4-Keto

[0294] (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-Benzothiazepine -4-Keto

[0295] (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-Benzothiazepine -4-Keto

[0296] (3R)-3-amino-1,1-dioxo-7-[5-[2-(trifluoromethyl)morpholin-4-yl]-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0297] (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-Benzothiazepine -4-Keto

[0298] (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-Benzothiazepine -4-Keto

[0299] (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-Benzothiazepine -4-Keto

[0300] (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-Benzothiazepine -4-Keto

[0301] (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-Benzothiazepine -4-Keto

[0302] (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-Benzothiazepine -4-Keto

[0303] (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-Benzothiazepine -4-Keto

[0304] (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-Benzothiazepine -4-Keto

[0305] (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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0306] (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-Benzothiazepine -4-Keto

[0307] (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-dimethylethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0308] (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-Benzothiazepine -4-Keto

[0309] (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-Benzothiazepine -4-Keto

[0310] (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-Benzothiazepine -4-Keto

[0311] (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-Benzothiazepine -4-Keto

[0312] 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]cyclobutanecarbonitrile

[0313] 4-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]tetrahydropyran-4-carbonitrile

[0314] 3-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2,2-dimethyl-propionitrile

[0315] 3-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-methyl-butyronitrile

[0316] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-ethyl-butyronitrile

[0317] 3-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]tetrahydrofuran-3-carbonitrile

[0318] (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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0319] (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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0320] 4-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-1-methyl-piperidine-4-carbonitrile

[0321] (3R)-3-amino-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0322] (3R)-3-amino-7-[5-[5,5-difluoro-1-(2-methoxyethyl)-3-piperidinyl]-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-Benzothiazepine -4-Keto

[0323] (3R)-3-amino-7-[5-[5,5-difluoro-1-(2-methoxyethyl)-3-piperidinyl]-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0324] (3R)-3-amino-7-[5-(3-aminooxetane-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-1λ 6 ,5-Benzothiazepine -4-Keto

[0325] (3R)-3-amino-7-[5-(2-chloro-3-pyridinyl)-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-Benzothiazepine -4-Keto

[0326] (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-Benzothiazepine -4-Keto

[0327] (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1-dioxo-7-[5-[2-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0328] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, which is selected from:

[0329] (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-Benzothiazepine -4-Keto

[0330] (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-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-Benzothiazepine -4-Keto

[0331] (3R)-3-amino-7-[5-(3-aminooxetane-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-Benzothiazepine -4-Keto

[0332] 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-Benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile

[0333] 1-[3-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile

[0334] (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-Benzothiazepine -4-Keto

[0335] (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-Benzothiazepine -4-Keto

[0336] (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-Benzothiazepine -4-Keto

[0337] (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-Benzothiazepine -4-Keto

[0338] (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-Benzothiazepine -4-Keto

[0339] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]propionitrile (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-Benzothiazepine -4-Keto

[0340] (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-Benzothiazepine -4-Keto

[0341] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0342] (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-Benzothiazepine -4-Keto

[0343] 2-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0344] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0345] (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-Benzothiazepine -4-Keto

[0346] (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-Benzothiazepine -4-Keto

[0347] (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-Benzothiazepine -4-Keto

[0348] 1-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester

[0349] 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester

[0350] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester

[0351] (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-Benzothiazepine -4-Keto

[0352] (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-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-Benzothiazepine -4-Keto

[0353] (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-Benzothiazepine -4-Keto

[0354] (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-Benzothiazepine -4-Keto

[0355] (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-Benzothiazepine -4-Keto

[0356] (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-Benzothiazepine -4-Keto

[0357] (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-Benzothiazepine -4-Keto

[0358] (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-Benzothiazepine -4-Keto

[0359] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0360] (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-Benzothiazepine -4-Keto

[0361] 2-[5-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile (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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0362] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)pyrimidin-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0363] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(1,1,2,2,2-pentafluoroethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-ethyl-butyronitrile 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile.

[0364] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, which is selected from:

[0365] (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-Benzothiazepine -4-keto(3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-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-Benzothiazepine -4-Keto

[0366] 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-Benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile

[0367] 1-[3-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -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-Benzothiazepine -4-Keto

[0368] (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-Benzothiazepine -4-Keto

[0369] (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-Benzothiazepine -4-Keto

[0370] 2-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0371] (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-Benzothiazepine -4-Keto

[0372] 1-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester

[0373] 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester

[0374] (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-Benzothiazepine -4-Keto

[0375] (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-Benzothiazepine -4-Keto

[0376] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0377] (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-Benzothiazepine -4-Keto

[0378] 2-[5-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0379] (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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0380] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)pyrimidin-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0381] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(1,1,2,2,2-pentafluoroethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0382] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0383] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-ethyl-butyronitrile

[0384] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0385] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, which is selected from:

[0386] (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-Benzothiazepine -4-Keto

[0387] 2-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0388] (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-Benzothiazepine -4-Keto

[0389] (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-Benzothiazepine -4-Keto

[0390] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0391] 2-[5-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0392] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(1,1,2,2,2-pentafluoroethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0393] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0394] 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-ethyl-butyronitrile

[0395] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile.

[0396] Manufacturing method

[0397] Processes for the manufacture of compounds of formula (I) or pharmaceutically acceptable salts thereof as described herein are also an object of the present invention.

[0398] The present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0399]

[0400] react with a suitable deprotecting agent to form the compound of formula (I), wherein R 1 , R 2 and R 4 As defined herein and PG is an amino protecting group.

[0401] The preparation of the compound of formula (I) of the present invention can be carried out according to sequential or concurrent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required for performing the reaction and purifying the resulting product are known to those skilled in the art. Unless otherwise indicated, the substituents and indices used in the following method descriptions have the meanings provided herein.

[0402] If one of the starting materials, intermediates or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups may be introduced before the key steps of the methods well known in the art (such as "Protective Groups in Organic Chemistry" by TW Greene and PGM Wutts, 5th edition, 2014, John Wiley & Sons, NY). Such protecting groups may be removed at a later stage of the synthesis using standard methods described in the literature.

[0403] If the starting material or intermediate contains a stereogenic center, the compound of formula (I) can be obtained in the form of a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art (e.g., chiral HPLC, chiral SFC or chiral crystallization). Racemic compounds can be separated into corresponding enantiomers, for example, by diastereomeric salts, which are crystallized with optically pure acids, or by specific chromatography separations of enantiomers using chiral adsorbents or chiral eluents. Starting materials and intermediates containing stereogenic centers can also be separated to provide starting materials and intermediates enriched in diastereomers / enantiomers. Using such diastereomer / enantiomer-enriched starting materials and intermediates in the synthesis of compounds of formula (I) will generally produce diastereomers / enantiomer-enriched compounds of the corresponding formula (I).

[0404] Those skilled in the art will recognize that in the synthesis of compounds of formula (I) (if not desired), an "orthogonal protecting group strategy" will be applied, which allows multiple protecting groups to be cleaved each time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has also been reported in the literature (e.g., Barany and RB Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0405] Those skilled in the art will recognize that the order of reactions may vary depending on the reactivity and nature of the intermediates.

[0406] In more detail, the compound of formula (I) can be manufactured by the method given below, by the method given in the examples or by similar methods. The appropriate reaction conditions for each reaction step are known to those skilled in the art. Similarly, the reaction conditions affecting the reaction reported in the relevant literature are described, for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999. It is convenient to react in the presence or absence of a solvent. There are no particular restrictions on the nature of the solvent used, as long as it has no adverse effect on the reaction or the reagents involved and can dissolve the reagents at least to a certain extent. The described reaction can occur over a wide temperature range, and the precise reaction temperature is not critical to the present invention. The above reaction can be conveniently performed in a temperature range of -78°C to reflux. The time required for the reaction can also vary over a wide range, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, it usually takes 0.5 hours to several days to obtain the intermediates and compounds. The reaction sequence is not limited to the one shown in the schemes, but, depending on the starting materials and their respective reactivity, the order of the reaction steps can be freely varied.

[0407] If starting materials or intermediates were not commercially available or their synthesis was not reported in the literature, they could be prepared by analogy to existing preparations of close analogs or as outlined in the experimental section.

[0408] The compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention can be prepared by the following method (Scheme 1) and synthetic methods known in the field of organic chemistry or those modifications and derivatization methods familiar to those skilled in the art.

[0409]

[0410] Solution 1

[0411] Suitable starting materials for preparing compounds of formula (I) are nitro compounds of formula (II) wherein X 2 is F or Cl, and X 1 Already R 1 or can be later refined to R 1 groups such as Br, CN or -CO 2Alkyl. The compound of formula (II) can be reacted with a suitably protected cysteine ​​derivative (III) in the presence of a base such as DIPEA at elevated temperature in a solvent such as 1,2-dichloroethane to obtain a compound of formula (IV). The preferred protecting group (PG) of the cysteine ​​derivative (III) is Boc. The nitro group in the compound of formula (IV) can be reduced using iron in the presence of hydrogen chloride or ammonium chloride at elevated temperature in a solvent mixture of water and ethanol to obtain a compound of formula (V). Alternatively, the conversion can be achieved by catalytic hydrogenation. Standard amide coupling conditions can be used to cyclize the compound of formula (V) to the compound of formula (VI). Preferably, the cyclization is carried out at room temperature using 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphocyclohexane 2,4,6-trioxide (50% solution in EtOAc) and using a base such as DIPEA in a solvent such as DMF. The compound of formula (VI) and the compound of formula (VII) (wherein Y 1 is Cl, Br, I or sulfonate) at room temperature in the presence of a base such as potassium carbonate, and if necessary with an additive such as potassium iodide in a solvent such as DMSO or DMF to obtain a compound of formula (VIII). Alternatively, a compound of formula (VI) can be reacted with a compound of formula (VII) (wherein Y 1 for OH) in PPh 3 In the presence of with additives such as DIAD in a solvent such as toluene at elevated temperature to give a compound of formula (VIII). 1 Br, CN or -CO 2 Compounds of formula (VIII) containing alkyl groups, these groups can be purified at this stage to form substituents R 1 , as described in the following scheme. The compound of formula (VIII) can then be converted to the compound of formula (IX) by reaction with an appropriate amount of an oxidant such as m-CPBA at room temperature in a solvent such as DCM. Final deprotection is performed to obtain the compound of formula (I). If the N-protecting group (PG) is Boc, typical conditions for the deprotection step include TFA in a solvent such as DCM or hexafluoroisopropanol at room temperature, hydrogen chloride in a solvent such as dioxane, ether or ethyl acetate at room temperature, or hexafluoroisopropanol at reflux temperature. In addition, the substituent R 1 and R 4May contain functional groups that can be modified prior to removal of the N-protecting group (PG), or may require the use of appropriate protecting groups during the synthesis. These protecting groups can be removed prior to removal of the N-protecting group (PG), or they can be removed simultaneously using appropriate methods [Peter GMWuts, Greene's protective groups in organic synthesis, 5th edition, Hoboken, NJ: Wiley-Interscience].

[0412] Alternatively, compounds of formula (I) can be prepared as shown in Scheme 2.

[0413]

[0414] Solution 2

[0415] The compound of formula (VI) can be reacted with an oxidizing agent such as m-CPBA at room temperature in a solvent such as DCM to be converted to the compound of formula (X). The reaction of the compound of formula (X) with the compound of formula (VII) to obtain the compound of formula (XI) and the subsequent conversion to the compound of formula (I) can be achieved using the reaction conditions described for the analogous steps in Scheme 1. If X 1 Br, CN or -CO 2 alkyl, these groups can be refined at any stage of the synthesis (for compounds of formula (VI), (X) or (XI), using the methods described for the following schemes) to the substituent R 1 .

[0416] The 5-membered heteroaryl group R 1 Compounds of formula (I) which are 1,3,4-oxadiazolyl groups can be prepared as shown in Scheme 3.

[0417]

[0418] Solution 3

[0419] Where X 1 For CO 2 The compound of formula (VIII) can be converted to the compound of formula (XII) by reacting with an alkali metal hydroxide such as LiOH, NaOH or KOH at room temperature in a solvent such as a mixture of MeOH, THF and water. The compound of formula (XII) can be reacted with hydrazine hydrate activated with a suitable reagent such as CDI at room temperature in a solvent such as THF to obtain the compound of formula (XIII). The compound of formula (XIII) can be reacted with a carboxylic acid R using standard amide coupling conditions such as HATU. 10 CO 2H is reacted at room temperature in the presence of a base such as DIPEA in a solvent such as THF. The coupling product of formula (XIV) can be cyclized to a compound of formula (XV) using a dehydrating agent such as Burgess reagent, or can be reacted with tosyl chloride in the presence of a base such as DIPEA at room temperature. The conversion of the 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.

[0420] The compound of formula (I) (wherein the 5-membered heteroaryl group R 1 is a 1,3,4-oxadiazolyl group, R 10 N(R 10e R 10f )) can be prepared as shown in Scheme 4.

[0421]

[0422] Solution 4

[0423] The compound of formula (XIII) can be reacted with CDI in THF at room temperature in the presence of a base such as TEA to obtain the compound of formula (XVII). The compound of formula (XVII) can be oxidized with an oxidizing agent such as m-CPBA in a solvent such as DCM at room temperature to obtain the compound of formula (XVIII). The compound of formula (XVIII) can be oxidized by reacting with an amine HN(R 10e R 10f ) is reacted in the presence of DIPEA and BOP or PyBroP in a solvent such as DMF at room temperature or at elevated temperature to convert into a compound of formula (XIX) [Org. Lett., 2008, Vol. 10, 1755-1758]. The N-protecting group (PG) is cleaved to obtain a compound of formula (I).

[0424] The 5-membered heteroaryl group R 1 Compounds of formula (I) which are 1,2,4-oxadiazolyl groups can be prepared as shown in Scheme 5.

[0425]

[0426] Solution 5

[0427] The compound of formula (VIII) (wherein X 1 CN) can be reacted with hydroxylamine hydrochloride at elevated temperature in the presence of a base such as potassium carbonate in a solvent such as ethanol to obtain an amide oxime of formula (XX, wherein R is H). Compounds of formula (XX, wherein R is H) are reacted with a carboxylic acid R 10 CO 2Reaction of H in the presence of a base such as DIPEA using standard amide coupling conditions such as CDI, HATU or EDCI and HOBt in a solvent such as acetonitrile, DMF or THF provides a coupling intermediate (XX, wherein R is -C(O)R 10 ), which upon heating cyclizes to the corresponding compound of formula (XXI). Alternatively, the coupling intermediate (XX, wherein R is -C(O)R 10 ), and the cyclization step can be performed by heating in a solvent such as toluene or reacting with TBAOH in a solvent such as THF. The conversion of the compound of formula (XXI) to the compound of formula (XXII) and then to the compound of formula (I) can be achieved using the reaction conditions described for the similar steps in Scheme 1.

[0428] The compound of formula (I) (wherein the 5-membered heteroaryl group R 1 is a 1,2,4-oxadiazolyl group, R 10 N(R 10e R 10f )) can be prepared as shown in Scheme 6.

[0429]

[0430] Solution 6

[0431] Compounds of formula (XX) can be reacted with CDI in THF at room temperature or elevated temperature in the presence of a base such as TEA to obtain compounds of formula (XXIII). Compounds of formula (XXIII) can be reacted with an amine HN(R 10e R 10f ) is reacted at elevated temperature in the presence of DIPEA and PyBroP in a solvent such as dioxane to convert to a compound of formula (XXIV). Oxidation of the compound of formula (XXIV) with an oxidant such as m-CPBA in a solvent such as DCM at room temperature affords a compound of formula (XXV). Cleavage of the N-protecting group (PG) affords a compound of formula (I).

[0432] Alternatively, the compound of formula (I) (wherein the 5-membered heteroaryl R 1 is a 1,2,4-oxadiazolyl group, R 4 N(R 4b R 4c )) can be prepared as shown in Scheme 7.

[0433]

[0434] Solution 7

[0435] The compound of formula (VIII) (wherein X 1(CN) can be reacted with an oxidant 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 reacting with hydroxylamine hydrochloride at elevated temperature in the presence of a base such as sodium bicarbonate in a solvent such as methanol. The conversion of the compound of formula (XXVII) to a compound of formula (I) can be achieved using the reaction conditions described for the similar steps in Scheme 6.

[0436] Pharmaceutical compositions and administration

[0437] Another object of the present invention is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein and a pharmaceutically acceptable excipient.

[0438] The compound of formula (I) and its pharmaceutical salt can be used as a medicine in the form of a pharmaceutical preparation. The pharmaceutical preparation can be administered internally, such as orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays) or rectally (e.g., in the form of suppositories). However, administration can also be implemented parenterally such as intramuscularly or intravenously (e.g., in the form of injections). Administration can also be implemented topically, such as percutaneously, or in the form of eye drops or ear drops.

[0439] The compound of formula (I) and its pharmaceutically acceptable salt can be processed with a pharmaceutically inert inorganic or organic carrier to prepare a pharmaceutical preparation such as a tablet, a coated tablet, a dragee, a hard gelatin capsule, an injection or a topical preparation. For example, lactose, corn starch or its derivatives, talcum powder, stearic acid or its salts etc. can be used as such carriers for tablets, coated tablets, dragees and hard gelatin capsules.

[0440] 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, carriers are often not required in soft gelatin capsules.

[0441] Suitable carriers for the preparation of solutions and syrups are, for example, water, alcohols, polyols, sucrose, glucose, invert sugar, vegetable oils and the like.

[0442] Suitable carriers for injection solutions are, for example, water, alcohol, polyol, glycerol, vegetable oil and the like.

[0443] Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

[0444] Suitable liquids for topical ophthalmic formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.

[0445] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

[0446] Medicaments containing compounds of formula (I) or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients and a process for their production are also objects of the present invention, the process comprising bringing one or more compounds of formula (I) and / or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances together with one or more pharmaceutically acceptable excipients into a galenical administration form.

[0447] Dosage is variable over a wide range, but will certainly have to be adjusted according to the individual needs of each particular case. Generally speaking, in the case of oral administration, the daily dose is about 0.1 mg to 20 mg per kg body weight, preferably 0.5 mg to 4 mg per kg body weight (e.g., about 300 mg per person), preferably divided into 1-3 separate doses (which may be composed of, for example, the same amount) should be suitable. In the case of topical administration, the preparation may contain 0.001% to 15% of the drug by weight, and the desired dose may be between 0.1 mg and 25 mg, and may be administered in a single dose every day or every week, or in multiple doses every day (2 to 4 times), or in multiple doses every week. However, it is apparent that if the upper or lower limit given herein is indicated, the upper or lower limit may be exceeded.

[0448] The pharmaceutical composition according to the present invention can be prepared as follows.

[0449] Preparation of pharmaceutical compositions containing the compounds of the present invention Tablet preparation (wet granulation)

[0450]

[0451] Manufacturing process:

[0452] 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

[0453] 2. Dry the granules at 50°C.

[0454] 3. Pass the particles through suitable grinding equipment.

[0455] 4. Add ingredient 5 and mix for three minutes; press on a suitable press.

[0456] Capsule preparation

[0457]

[0458] Manufacturing process:

[0459] 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

[0460] 2. Add ingredients 4 and 5 and mix for 3 minutes.

[0461] 3. Fill into suitable capsules.

[0462] Injection

[0463] Element mg / injection Compounds of formula I 3 Polyethylene glycol 400 150 Acetic acid Adjust pH to 5.0 Water for injection Add to 1.0ml

[0464] Manufacturing process:

[0465] The compound of formula (I) is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by adding the remainder of water. The solution is filtered, filled into a vial with an appropriate excess and sterilized.

[0466] Indications

[0467] The compounds of formula (I) may be used in an effective amount for treating a subject, particularly a human, affected by cancer.

[0468] 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.

[0469] In yet another aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in treating, preventing and / or delaying progression of cancer.

[0470] In yet another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for treating, preventing and / or delaying the progression of cancer.

[0471] In yet another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for the preparation of a medicament for treating, preventing and / or delaying the progression of cancer.

[0472] In yet another aspect, the present invention provides a method for treating, preventing and / or delaying the progression of cancer, which method comprises administering a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0473] As used herein, the terms "treatment" or "treating" and grammatical variations thereof refer to therapeutic therapy. With respect to a particular condition, treatment means: (1) ameliorating the condition or one or more of the biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that causes or leads to the condition, or (b) one or more of the biological manifestations of the condition, (3) alleviating one or more of the symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more of the 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 appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to significantly 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 treatment is appropriate, for example, when a subject is considered to be at high risk for developing cancer, such as when the subject has a significant family history of cancer or when the subject has been exposed to a carcinogen.

[0474] As an immunotherapeutic agent that acts on immune cells rather than directly on cancer cells, the present disclosure is also envisioned to be used as an anti-cancer vaccine. Also included are methods in which immune cells are cultured and manipulated ex vivo and the molecules disclosed herein are used as a means of conferring co-stimulation to the ex vivo manipulated cells.

[0475] In one embodiment, the cancer is a hematologic cancer, such as a lymphoma, leukemia, or myeloma. Hematologic cancers contemplated herein include, but are not limited to, 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); additional hematologic cancers or hematologic disorders, including but not limited to B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse The term "preleukemia" refers to a group of hematologic disorders that consists of ineffective production (or dysplasia) of blood cells in the bone marrow.

[0476] In yet another embodiment, the cancer is a non-hematologic cancer, such as a sarcoma, an epithelial cancer, or a melanoma. Non-hematologic 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.

[0477] Co-administration of compounds of formula (I) with other pharmaceutical agents

[0478] The compound of formula (I) or its salt, or the compound disclosed herein or its pharmaceutical salt, can be used alone or in combination with other agents for treatment. For example, the second agent of the drug combination formulation or dosing regimen may have an activity complementary to the compound of formula (I) so that they do not adversely affect each other. The compounds can be administered together or separately in a single pharmaceutical composition. In one embodiment, the compound or pharmaceutical salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancer.

[0479] The term "co-administration" refers to the simultaneous administration of a compound of formula (I) or a salt thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof with one or more other active pharmaceutical ingredients (including cytotoxic agents and radiotherapy) or administered separately and sequentially in any manner. If the administration is not simultaneous, the compounds should be administered at a time close to each other. In addition, it is irrelevant whether the compounds are administered in the same dosage form, for example, one compound may be administered topically and another compound may be administered orally.

[0480] Generally, any agent with anticancer activity may be co-administered. Examples of such agents can be found in Cancer Principles and Practice of Oncology (V.T. Devita and S. Heilman, eds.), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. Based on the specific characteristics of the drugs and diseases involved, one of ordinary skill in the art will be able to discern which combination of agents will be useful.

[0481] In one aspect, the present invention provides a pharmaceutical composition as described herein, further comprising an additional therapeutic agent.

[0482] In one embodiment, the additional therapeutic agent is a chemotherapeutic agent.

[0483] In one embodiment, the additional therapeutic agent is a cytotoxic agent.

[0484] In one embodiment, the additional therapeutic agent is an immuno-oncology agent.

[0485] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cellular function and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (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 nucleolytic enzymes; and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof.

[0486] Exemplary cytotoxic agents can 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 cancer metabolism inhibitors.

[0487] "Chemotherapeutic agents" include chemical compounds that can be used to treat cancer. Examples of chemotherapeutic agents include erlotinib ( Genentech / OSI Pharm.), bortezomib ( Millennium Pharm.), disulfiram, epigallocatechin gallate, salisosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant ( AstraZeneca), sunitinib ( Pfizer / Sugen), letrozole ( Novartis), imatinib mesylate ( Novartis), phenaxate ( Novartis), oxaliplatin ( Sanofi), 5-FU (5-fluorouracil), folinic acid, rapamycin (sirolimus, Wyeth), Lapatinib ( GSK572016, Glaxo Smith Kline), Rhonafarmib (SCH 66336), Sorafenib ( Bayer Labs), gefitinib ( AstraZeneca), AG1478; alkylating agents such as thiotepa and Cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquinone, meturedopa, and uredopa; ethylimines and methylmelamines including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; annona lactones (especially bullatacin and bullatacinone); camptothecins (including topotecan and irinotecan); bryostatin; callystatin; CC-106 5 (including its synthetic analogs of adozelesin, carzelesin and bizelesin); cryptophycin (particularly cryptophycin I and cryptophycin 8); adrenocortical steroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductase (including finasteride and dutasteride); vorinostat, romidepsin, panbicistat, valproic acid, mocetinostat, dolastatin; aldesleukin, talc, dukamycin (including synthetic analogs of KW-2189 and CBI-TM I); eleutherobin; sarcodictine; sarcodictyin; spongestatin; nitrogen mustards such as chlorambucil, chlorpheniramine, clofosamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine hydrochloride, melphalan, novembichin, phenambucil, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and lanimustine; antibiotics such as enediyne antibiotics (e.g. calicheamicin, especially calicheamicin and calicheamicin coll (Angew Chem. Inti. Ed. Engl. 1994 33:183-186); dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicin; and the neocarcinogen chromophores and related chromoprotein enediyne antibiotic chromophores, aclacinomycins, actinomycins, authramycins, azaserine, bleomycin, cactinomycin, carabicin, carminomicin, carzinophilin, chromomycin, dactinomycin, daunomycin, detopicin, 6-diazo-5-oxo-L-norleucine, (doxorubicin) (morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogamycin, olive mycins, peplomycin, potfiromycin, puromycin, quelamycin, rhodorubicin, streptomycin, streptozotocin, tuberculin, ubenimex, zorubicin, antimetabolites such as methotrexate and 5-fluorouracil (5 -FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiopurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calosterone, drostanolone propionate, cyclothiodine, melastane, testolactone; antiadrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid (frolinic acid) acid; aceglucuronide; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; colcemid; diaziquone; elfornithine; elliptonium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan Sugar; lonidainine; maytansinoids, such as maytansine and ansamitocin; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazine; procarbazine; polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizoran; germanium spiroamine; tenuazonic acid; triazoquinone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, baculocin A, and anguidine); urethane; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dibromodulanol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, for example, TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), (without Cremophor), albumin-engineered paclitaxel nanoparticle formulation (American Pharmaceutical Partners, Schaumberg, 111.) and (docetaxel, docetaxel; Sanofi-Aventis); chloranbucil; (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (Changchunorelbine); Novantrone; Teniposide; Edatrexed; Daunorubicin; Aminopterin; Capecitabine 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.

[0488] Chemotherapeutic agents also include: (i) antihormonal agents that act to modulate or inhibit the effects of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including tamoxifen (including Tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and (toremifine citrate); (ii) aromatase inhibitors that inhibit aromatase, an enzyme that regulates estrogen production by the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, (Megestrol acetate), (exemestane; Pfizer), formestanie, fadrozole, (vorozole), (letrozole; Novartis) and (anastrozole; AstraZeneca); (iii) antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, triptorelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all trans-retinoic acid, fenretinide, and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, such as PKC-α, Ralf, and H-Ras; (vii) ribozymes, such as inhibitors of VEGF expression (e.g. ) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, such as and rIL-2; topoisomerase I inhibitors, e.g. rmRH; and (ix) any of the pharmaceutically acceptable salts, acids and derivatives of the foregoing.

[0489] Chemotherapeutic agents also include antibodies such as alemtuzumab (Campath), bevacizumab ( Genentech; Cetuximab ( Imclone; Panitumumab ( Amgen), rituximab ( Genentech / Biogen Idee), Pertuzumab ( 2C4, Genentech), trastuzumab ( Genentech), tositumomab (Bexxar, Corixia) and antibody-drug conjugates, gemtuzumab ozogamicin ( Wyeth). Additional humanized monoclonal antibodies with therapeutic potential for use as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumabmertansine, cantuzumab mertansine, cedilizumab, certolizumab pegol-conjugated pegol), cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin), ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumabThe antibodies include celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and anti-IL-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), a recombinant, fully human sequence-specific IgGiλ antibody that has been genetically modified to recognize the IL-12p40 protein.

[0490] Chemotherapeutic agents also include "EGFR inhibitors", which refer to compounds that bind to or directly interact with EGFR and prevent or reduce its signaling activity, and are 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 MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Pat. No. 4,943,533, Mendelsohn et al.) and variants thereof, such as chimeric 225 (C225 or cetuximab; ) and reshaped human 225 (H225) (see, WO 96 / 40210, Imclone Systems Inc.); IMC-11F8, a fully human antibody targeting EGFR (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 (see 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 with EGF and TGF-α for binding to EGFR (EMD / Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies, referred to as E1.1, E2.4, E2.5, E6.2, E6.4, E2.ll, E6.3 and E7.6.3, and described in US 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)). Anti-EGFR antibodies can be conjugated to cytotoxic agents to generate immunoconjugates (see, e.g., EP 659,439 A2, Merck Patent GmbH). EGFR antagonists include small molecules such as U.S. Pat. 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, 6,140,3 32, 5,866,572, 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: WO98 / 14451, WO98 / 50038, WO99 / 09016 and WO99 / 24037. Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, Genentech / OSI Pharmaceuticals); PD183805 (Cl 1033, 2-acrylamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer); ZD1839, gefitinib 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 (6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(l-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-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR / HER2 tyrosine kinase inhibitors such as lapatinib ( GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[(2-methylsulfonyl)ethyl]amino]methyl]-2-furyl]-4-quinazolinamine).

[0491] Chemotherapeutic agents also include "tyrosine kinase inhibitors", including the EGFR targeted drugs described in the previous paragraph; small molecule FIER2 tyrosine kinase inhibitors, such as TAK165 available from Takeda Pharmaceuticals; 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 simultaneously inhibits cells overexpressing HER2 and EGFR; lapatinib (GSK572016; available from GlaxoSmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors, such as canertinib (CI-1033; Pharmacia); Raf-I inhibitors, such as ISIS-5132, an antisense agent that inhibits Raf-I signaling, available from ISIS Pharmaceuticals; non-HER targeted TK inhibitors, such as imatinib mesylate ( available from GlaxoSmithKline); multitargeted tyrosine kinase inhibitors such as sunitinib ( VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787 / ZK222584, available from Novartis / Schering AG); MAPK extracellular regulated kinase I inhibitor Cl-1040 (available from Pharmacia); quinazolines such as PD 153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP 59326, CGP60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (difluoroformylmethane, 4,5-bis(4-fluoroanilino)phthalimide); tyrosine containing a nitrothiophene moiety; PD-0183805 (Wamer-Lamber); antisense molecules (e.g., molecules that bind to HER encoding nucleic acids); quinoxalines (U.S. Pat. No. 5,804,396); tyrosine phosphorylation inhibitors (U.S. Pat. No. 5,804,396); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); pan-HER inhibitors, such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis / Lilly); imatinib mesylate PKI 166 (Novartis); GW2016 (GlaxoSmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); seramatinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering); INC-ICl I (Imclone), rapamycin (sirolimus, ); or any of the following patent publications: U.S. Pat. No. 5,804,396, WO 1999 / 09016 (American Cyanamid), WO 1998 / 43960 (American Cyanamid), WO 1997 / 38983 (Warner Lambert), WO 1999 / 06378 (Warner Lambert), WO 1999 / 06396 (Warner Lambert), WO 1996 / 30347 (Pfizer, Inc), WO 1996 / 33978 (Zeneca), WO 1996 / 3397 (Zeneca), and WO 1996 / 33980 (Zeneca).

[0492] Chemotherapeutic agents also include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, live BCG, bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, alfa), erlotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium sodium), quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate and zoledronic acid and pharmaceutically acceptable salts thereof.

[0493] Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, thiocortisone pivalate, triamcinolone acetonide, triamcinolone acetonide alcohol, mometasone, amcinonide, budesonide, desonide, fluocinolone acetate, fluocinolone, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, and phenoxyethanol. dipropionate), betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, flucortolone hexanoate, flucortolone valerate, and fluprednidine acetate; immunoselective anti-inflammatory peptides (ImSAIDs), such as phenylalanine-glutamine-glycine (PEG) and its D-isomer form (feG) (IMULAN Biotherapeutics Ltd. BioTherapeutics, LLC); antirheumatic drugs such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, sulfasalazine; tumor necrosis factor alpha (TNFa) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi); interleukin I (IL-I) blockers such as anakinra (Kineret); T-cell costimulation blockers such as abatacept (Orencia); interleukin 6 (IL-6) blockers such as tocilizumab Interleukin 13 (IL-13) blockers, such as lebrikizumab; interferon alpha (IFN) blockers, such as lonavirin; β7 integrin blockers, such as rhuMAb β7; IgE pathway blockers, such as anti-M1 primers; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa I / β2 blockers, such as anti-lymphotoxin α (LTa); radioisotopes (e.g., At 211 ,I 131 ,I 125 , Y 90 、Re 186 、Re 188 、Sm 153 、Bi 212 , P 32 , Pb 212and radioisotopes of Lu); various experimental agents such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3 or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, picrophenol, epigallocatechin gallate, theaflavins, flavanols, proanthocyanidins, betulinic acid and its derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, ); β-lapachone; lapaol; colchicine; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur Bexarotene Bisphosphonates, such as clodronate (e.g. or ), etidronate NE-58095, Zoledronic Acid / Zoledronate Alendronate Pamidronate Tirodronate Risedronate and epidermal growth factor receptor (EGF-R); vaccines such as Vaccines; 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 Pixantrone; farnesyl transferase inhibitors such as lonafamib (SCH 6636, SARASAR TM ); and pharmaceutically acceptable salts, acids or derivatives of any of the above; and combinations of two or more of the above, such as CHOP (an abbreviation for the combination therapy of cyclophosphamide, doxorubicin, vincristine and prednisolone); and FOLFOX (oxaliplatin (ELOXATIN TM ) is an abbreviation for the combination therapy with 5-FU and folinate).

[0494] In another embodiment, the compound of formula (I) can be co-formulated with an immuno-oncology agent. Immuno-oncology agents include, for example, small molecule drugs, antibodies or other biological or small molecules. Examples of biological immuno-oncology 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.

[0495] In one aspect, the immuno-oncology agent is either (i) an agonist of a stimulatory (including co-stimulatory) 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 (commonly referred to as immune checkpoint modulators).

[0496] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory 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 co-stimulatory or co-inhibitory receptors is the family of TNF molecules that bind to cognate TNF receptor family members, which include 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 alpha / TNP beta, TNFR2, TNF alpha, LTR, lymphotoxin alpha 1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0497] In one aspect, T cell responses can be stimulated by a combination of a compound of Formula (I) with one or more of: (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, Galectin9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; and (ii) an agonist of a protein that stimulates T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0498] Other agents that can be combined with compounds of formula (I) for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, compounds of formula (I) can be combined with antagonists of KIR such as lirilumab.

[0499] Other agents for combination therapy include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists, such as CSF-1R antagonist antibodies (including RG7155 or FPA-008).

[0500] In another aspect, the compounds of formula (I) may be used with one or more of the following agents: agonists that bind to positive co-stimulatory receptors; blockers that attenuate signals 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 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by in vitro anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell anergy or exhaustion); and agents that trigger innate immune activation and / or inflammation at the tumor site.

[0501] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonist CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. On the other hand, the immuno-oncology 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; WO2012 / 145493). Immuno-oncology agents may also include pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned. Another method of targeting the PD-1 receptor is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, which is called AMP-224.

[0502] In another aspect, the immuno-oncology agent is a PD-L1 antagonist, such as an antagonist PD-L1 antibody. Suitable PD-L1 antibodies include, for example, TECENTRIQ (atezolizumab) (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0503] In another aspect, the immuno-oncology agent is a LAG-3 antagonist, such as an antagonist LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO2010 / 19570, WO2014 / 08218), or IMP-731 or IMP-321 (WO2008 / 132601, WO2009 / 44273).

[0504] In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonist CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO2012 / 32433).

[0505] In another aspect, the immuno-oncology agent is a GITR agonist, such as an agonist GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO2006 / 105021, WO2009 / 009116) and MK-4166 (WO2011 / 028683).

[0506] In another aspect, the immuno-oncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO2006 / 122150, WO2007 / 75598, WO2008 / 36653, WO2008 / 36642), indoximod or NLG-919 (WO2009 / 73620, WO2009 / 1156652, WO2011 / 56652, WO2012 / 142237).

[0507] In another aspect, the immuno-oncology agent is an OX40 agonist, such as an agonist OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469. In another aspect, the immuno-oncology agent is an OX40L antagonist, such as an antagonist OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0508] In another aspect, the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the immuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, Lucatumumab or Dacetuzumab.

[0509] In another aspect, the immuno-oncology agent is a CD27 agonist, such as an agonist CD27 antibody. Suitable CD27 antibodies include, for example, Varlilumab.

[0510] In another aspect, the immuno-oncology agent is MGA271 (to B7H3) (WO2011 / 109400).

[0511] Examples

[0512] The present invention will be more fully understood by reference to the following examples. However, the claims should not be interpreted as being limited to the scope of the examples.

[0513] 1) Preparation Example

[0514] If not stated otherwise, all reaction examples and intermediates were prepared under argon atmosphere.

[0515] 1.1) General Procedure

[0516] ● Alkylation: General Procedure 1a

[0517] To a solution of the intermediate of formula (VI) (2.74 mmol) in DMF (10 mL) was added potassium carbonate (1.14 g, 8.23 ​​mmol), potassium iodide (228 mg, 1.37 mmol) and a reagent of formula (VII) (3.29 mmol) at RT. The reaction mixture was stirred at RT for 2 hours, quenched with water, and extracted twice with DCM. The combined organic layers were washed with water, saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (VIII) was used crude for the next step or purified by silica gel flash column chromatography or by reverse phase preparative HPLC.

[0518] · Alkylation: General Procedure 1b

[0519] To a solution of the intermediate of formula (VI) (0.2 mmol) in toluene (3 ml) under an inert atmosphere were added the reagent of formula (VII) (0.22 mmol), PPh 3To the mixture was added 4-nitropropene (0.4 mmol) and 4-nitropropene (0.4 mmol). The mixture was then heated to 50 °C and kept for 4 hours. After cooling to RT, the mixture was concentrated and diluted with EtOAc. The solution was then washed with saline (3x), dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The desired product (VIII) was used in the next step as a crude product or purified by silica gel flash column chromatography or by reverse phase preparative HPLC.

[0520] ● Saponification: General Procedure 2

[0521] To formula (VIII, where X 1 For CO 2 To a solution of the intermediate (4 mmol) of 1-(4-hydroxy-1-yl)-2-nitropropene (Me) in THF (18 ml), MeOH (3 ml) and water (6 ml) was added LiOH hydrate (8 mmol) and stirred for 2 hours at RT. 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 by reverse phase preparative HPLC.

[0522] ● Hydrazide formation: general procedure 3

[0523] To the solution of the intermediate (4.5mmol) of formula (XII) in THF (20ml), CDI (5.7mmol) is added, and stirred for 90 minutes at RT. Then a mixture of hydrazine hydrate (13.5mmol) in THF (3.3ml) is added to the solution and stirred for 1 hour. The reaction mixture is diluted with water and EtOAc. Each layer is separated, and the aqueous phase is washed twice with EtOAc. The combined organic layer is washed with brine, then dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure. The desired product (XIII) is used in the next step as a crude product or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.

[0524] ● Hydrazide coupling: General procedure 4a

[0525] To a solution of the intermediate of formula (XIII) (0.3 mmol) in THF (3 ml) was added a 10 CO 2The product (XIV) was added to the reaction mixture with 1,4-dihydro-2-nitropropane (2-nitropropane-1-yl)-2-nitropropane (2-nitropropane-1-yl)-2-nitropropane (3-nitropropane-1-yl)-2-nitropropane (4-nitropropane-1-yl)-2-nitropropane (5-nitropropane-1-yl)-2-nitropropane (6-nitropropane-1-yl)-2-nitropropane (7-nitropropane-1-yl)-2-nitropropane (8-nitropropane-1-yl)-2-nitropropane (9-nitropropane-1-yl)-2-nitropropane (1-nitropropane-1-yl)-2-nitropropane (2-nitropropane-1-yl)-2-nitropropane (5-nitropropane-1-yl)-2-nitropropane (6-nitropropane-1-yl)-2-nitropropane (7-nitropropane-1-yl)-2-nitropropane (8-nitropropane-1-yl)-2-nitropropane (9-nitropropane-1-yl)-2-nitropropane (1-nitropropane-1-yl)-2-nitropropane (

[0526] ● Hydrazide coupling: General procedure 4b

[0527] To a solution of the intermediate of formula (XIII) (0.5 mmol) in THF (5 ml) was added a 10 CO 2 H carboxylic acid (0.5 mmol), DIPEA (1.5 mmol) and T 3 P (50%, in EtOAc, 1.5 mmol). The resulting solution was stirred at 60 ° C for 2 hours. The reaction mixture was then cooled to RT 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 by reverse phase preparative HPLC.

[0528] ● 1,3,4-Oxadiazole cyclization: General procedure 5a

[0529] To a solution of the intermediate of formula (XIV) (0.3mmol) in THF (3ml) is added Burgess reagent (0.9mmol). The resulting solution is stirred overnight at RT. Water is added and the mixture is extracted three times with EtOAc. The combined organic layers are washed with brine, then dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure. The desired product (XV) is used crude for the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.

[0530] ● 1,3,4-Oxadiazole Cyclization: General Procedure 5b

[0531] To the solution of the intermediate (0.1mmol) of formula (XIV) in acetonitrile (1.3ml) p-Toluenesulfonyl chloride (0.3mmol) and DIPEA (0.2mmol) are added. The resulting solution is stirred for 30 minutes at RT. The reaction is diluted with water and extracted three times with EtOAc. The combined organic layer is washed with brine, then dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure. The desired product (XV) is used in the next step as a crude product or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.

[0532] ● Amide oxime formation: general procedure 6

[0533] To formula (VIII, where X 1 To a solution of the intermediate (0.3 mmol) of (CN) in EtOH (2.5 ml) was added solid NaHCO 3 The mixture was stirred for 2 hours at 4 ℃ for 1 h.Then the mixture was stirred for 2 hours at 4 ℃ for 3 hours at 5 ℃ for 4 hours at 8 ℃ for 8 hours.Then the mixture was stirred for 2 hours at 5 ℃ for 3 hours at 8 ... at 8 ℃ for 9 hours at 8 ℃ for 8 hours at 8 ℃ for 9 hours at 8 ℃ for 8 hours at 8 ℃ for 9 hours at 8 ℃ for 8 hours at 8 ℃ for 8 hours at 8 ℃ for 8 hours at 8 ℃ for 8 hours at 8 ℃ for 8 hours at 8 ℃ for 8 hours at 8 ℃ for 8 hours at 8 ℃ for 8 hours at 8 ℃ for 8 hours at 8 ℃ for 8 hours at 8 ℃ for 8 hours at 8 ℃ for 8 hours at 8 ℃ for 8 hours at 8 ℃ for 8 hours at 8 ℃ for 8 hours at 8 ℃ for 8 hours at

[0534] ● Direct formation of 1,2,4-oxadiazoles from amide oximes: General Procedure 7a

[0535] Direction R 10 CO 2 To a solution of the carboxylic acid (2.4mmol) of H in DMF (5ml) was added CDI (2.64mmol) and stirred for 60 minutes. Then, a solution of the intermediate (1.2mmol) of formula (XX, wherein R is H) in DMF (5ml) was added, and the resulting mixture was heated to 120°C and kept for 4 hours. The reaction mixture was cooled to RT, 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 in the next step as a crude product or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.

[0536] ● Direct formation of 1,2,4-oxadiazoles from amide oximes: General Procedure 7b

[0537] To a solution of the intermediate of formula (XX, wherein R is H) (0.3 mmol) in THF (5 mL) was added a 10 CO 2H's carboxylic acid (0.45 mmol), DIPEA (0.76 mmol) and 50% solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine 2,4,6-trioxide in EtOAc (0.6 mmol) were added and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was quenched with water and extracted twice with EtOAc, washed with 1 M aqueous NaOH, 1 M 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 by reverse phase preparative HPLC.

[0538] ● Direct formation of 1,2,4-oxadiazoles from amide oximes: General Procedure 7c

[0539] To a solution of the intermediate of formula (XX, wherein R is H) (0.2 mmol) in DMF (1.5 ml) was added a 10 CO 2 H'-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 and maintained for 8 hours. The reaction mixture was cooled to RT 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 by reverse phase preparative HPLC.

[0540] ● With RCO 2 H for amide oxime coupling: General Procedure 8a

[0541] To a solution of the intermediate of formula (XX, wherein R is H) (1.0 mmol) in THF (8.5 ml) was added a 10 CO 2 H-carboxylic acid (0.12 mmol), DIPEA (2.0 mmol) and HATU (0.15 mmol) were added and the reaction mixture was stirred at RT for 4 hours. Water and EtOAc were added and the layers were separated. The aqueous layer 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, wherein R is -CO(R 10 )) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.

[0542] ● With RCO 2 H for amide oxime coupling: General Procedure 8b

[0543] To a solution of the intermediate of formula (XX, wherein R is H) (0.2 mmol) in DMF (1.5 ml) was added a 10 CO 2 H-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 stirred at RT 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, wherein R is -CO(R 10 )) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.

[0544] ● With RCO 2 H for amide oxime coupling: General Procedure 8c

[0545] Direction R 10 CO 2 To a solution of H's carboxylic acid (0.11mmol) in acetonitrile (0.33ml) was added CDI (0.12mmol) and stirred at RT for 60 minutes. Then to the mixture was added a solution of the intermediate of formula (XX, wherein R is H) (0.1mmol) in acetonitrile (0.33ml) and stirred at RT for 60 minutes. The reaction mixture was diluted with DCM and water was added thereto. The layers were separated and the aqueous phase was extracted twice with DCM. 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, wherein R is -CO(R 10 )) was used crude in the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.

[0546] ● 1,2,4-Oxadiazole Cyclization: General Procedure 9a

[0547] Formula (XX, wherein R is -CO(R 10 A solution of the intermediate (0.15 mmol) of (XIII) in toluene (1 ml) was heated to 120° C. for 16 hours. 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 by reverse phase preparative HPLC.

[0548] ● 1,2,4-Oxadiazole Cyclization: General Procedure 9b

[0549] Formula (XX, wherein R is -CO(R 10)) in THF (1.2 ml) was added tetrabutylammonium hydroxide (0.06 mmol) and stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3. The aqueous phase was then washed twice with EtOAc, the combined organic layers were 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 by reverse phase preparative HPLC.

[0550] ● Oxidation: General Procedure 10

[0551] A solution of the intermediate of formula (VIII) (2.74 mmol) and m-CPBA (1.18 g, 6.85 mmol) in DCM (10 mL) was stirred at RT for 1 day. The reaction was diluted with EtOAc and THF, washed with 2N aqueous sodium hydroxide solution, 1N aqueous HCl solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The desired product (IX) was used as a crude product in the next step or purified by silica gel flash column chromatography or by reverse phase preparative HPLC.

[0552] ● Boc deprotection: General procedure 11a

[0553] To a solution of the intermediate of formula (IX) (0.250 mmol) in 1,1,1,3,3,3-hexafluoropropane-2-ol (4 mL) was added HCl / dioxane or HCl / Et 2 O (0.5 mmol, 2 eq.). The reaction mixture was stirred at 20 °C for 2 hours. The solvent was evaporated and the resulting solid was taken up in DCM and then concentrated again to remove traces of 1,1,1,3,3,3-hexafluoropropane-2-ol. The process was repeated twice and then dried under high vacuum to obtain the desired product (I).

[0554] ● Boc deprotection: General procedure 11b

[0555] A solution of the intermediate of formula (IX) (22.7 μmol) in 1,1,1,3,3,3-hexafluoropropane-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).

[0556] ● Boc deprotection: General procedure 11c

[0557] 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 freeze drying to obtain the desired product (I).

[0558] ● Bromination: General Procedure 12

[0559] Formula (VII, wherein Y 1 To a solution of the intermediate (1.34 mmol) of (VII) (H) in acetonitrile (5.3 mL) was added N-bromosuccinimide (1.6 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.13 mmol) and stirred at 80 ° C for 3 hours. The reaction was quenched after adding saturated aqueous sodium thiosulfate solution and EtOAc, the mixture was vigorously stirred for 5 minutes, and the phases were separated. The aqueous layer was extracted twice with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The desired product (VII, wherein Y 1 Br) was used crude in the next step or purified by flash column chromatography on silica gel.

[0560] ● Amination: General Procedure 13

[0561] To a solution of the intermediate of formula (XVIII) (0.06 mmol) in 1,4-dioxane (0.6 ml) was added a mixture of formula HN(R 10 eR 10 f) amine (0.12mmol), DIPEA (0.18mmol) and PyBroP (0.072mmol). The mixture was heated to 50°C for 90 minutes. After cooling to RT, EtOAc and water were added and the reaction mixture was stirred vigorously for 5 minutes. 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 for the next step or purified by flash column chromatography on silica gel or by reverse phase preparative HPLC.

[0562] Example 1

[0563] (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-Benzothiazepine -4-Keto

[0564]

[0565] Step a) (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-Formic acid

[0566]

[0567] Analogously to General Procedure 2, (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-Methyl formate (9.5 g, 25.65 mmol, CAS 202449-38-7) was prepared and the title compound (9.5 g, 26.66 mmol, 104% yield) was obtained as a brown solid. MS (ESI): 301.0 [M-isobutylene + H] +

[0568] Step b) N-[(3R)-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0569]

[0570] Analogously to General Procedure 3, (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-carboxylic acid (1300 mg, 2.81 mmol) was used to prepare the title compound (1300 mg, 3.51 mmol, 95% yield) as a light brown oil. MS (ESI): 315.2 [M-isobutylene + H] +

[0571] Step c) N-[(3R)-7-[(2,2-dimethylpropionylamino)carbamoyl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0572]

[0573] Analogously to general procedure 4a, N-[(3R)-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl] tert-butyl carbamate (1287 mg, 2.66 mmol, 1 eq.) and trimethylacetic acid (0.31 mL, 2.68 mmol, 1.01 eq.) were used to prepare the title compound (1240 mg, 2.73 mmol, 97% yield) as a yellow solid. MS (ESI): 399.1 [M-isobutylene + H] +

[0574] Step d) N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0575]

[0576] Analogously to General Procedure 5a, N-[(3R)-7-[(2,2-dimethylpropionylamino)carbamoyl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine was used. -3-yl] tert-butyl carbamate (2.69 g, 5.92 mmol) was prepared and the title compound (2.57 g, 5.36 mmol, 91% yield) was obtained as a light yellow solid. MS (ESI): 381.1 [M-isobutylene + H] +

[0577] Step e) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0578]

[0579] Analogous to General Procedure 10, N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl] tert-butyl carbamate (800 mg, 1.83 mmol) was prepared and the title compound (830 mg, 1.77 mmol, 97% yield) was obtained as a light yellow solid. MS (ESI): 413.1 [M-isobutylene + H] +

[0580] Step f) 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-1λ6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0581]

[0582] Analogously to General Procedure 1b, 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-Benzothiazepine -3-yl] tert-butyl carbamate (100 mg, 0.21 mmol, 1.0 equiv) and 4-(1-methyl-1H-pyrazol-3-yl)benzyl alcohol (44 mg, 0.23 mmol, 1.1 equiv, CAS 179055-20-0) were prepared and the title compound (180 mg, 0.28 mmol, 62% yield) was obtained as a white solid. MS (ESI): 639.2 [M+H] +

[0583] 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-Benzothiazepine -4-Keto

[0584]

[0585] Analogously to General Procedure 11c, 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 was prepared. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (180 mg, 0.28 mmol) was prepared and the title compound (15.5 mg, 0.03 mmol, 10% yield) was obtained as a white solid. MS (ESI): 539.2 [M+H] +

[0586] The examples in the following table were prepared analogously to Example 1 using the benzyl alcohol building block.

[0587]

[0588] * Hydrochloride

[0589] Example 88

[0590] 2-[5-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0591]

[0592] Step a) N-[(3R)-7-[[(2-cyano-2-methyl-propionyl)amino]carbamoyl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0593]

[0594] N-[(3R)-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] To a suspension of tert-butyl]-3-yl]carbamate (150 mg, 404.97 μmol, 1.0 equiv., Example 1, step b) and 2-cyano-2-methyl-propionic acid (55 mg, 485.96 μmol, 1.2 equiv.) in THF (2.85 ml) was added HATU (231 mg, 607.45 μmol, 1.5 equiv.) and DIPEA (130.9 mg, 176.8 uL, 1.01 mmol, 2.5 equiv.), and the mixture was stirred for 4 hours. The mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed once with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a light 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] -

[0595] Step b) 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0596]

[0597] Analogously to General Procedure 5b, N-[(3R)-7-[[(2-cyano-2-methyl-propionyl)amino]carbamoyl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine was used. -3-yl] tert-butyl carbamate (188 mg, 403.87 μmol) was prepared and the title compound (83.4 mg, 46%) was obtained as a white solid. MS (ESI): 392.1 [M+H-isobutylene] +

[0598] Step c) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0599]

[0600] Analogous to General Procedure 10, 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-benzothiazepine was used. -3-yl] tert-butyl carbamate (83.4 mg, 186.38 μmol) and the title compound was obtained as a white solid (47.2 mg, 49% yield). MS (ESI): 424.1 [M+H-isobutylene] + .

[0601] Step d) 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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0602]

[0603] Analogously to General Procedure 1a, 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 was used. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (47.2 mg, 0.091 mmol) and 2-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)pyridine (42.94 mg, 135.9 μmol, 1.5 equivalents, CAS 1056641-21-4) were used to prepare the title compound (29.1 mg, 45%) as a white solid. MS (ESI): 715.5 [M+H]+

[0604] Step e) 2-[5-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0605]

[0606] Analogous to General Procedure 11a, the reaction mixture was prepared from 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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (29 mg, 40.58 μmol) was prepared and the title compound (21 mg, 80%) was obtained as an off-white solid as a hydrochloride salt. MS (ESI): 659.2 [M-H+HCO 2 H] -

[0607] Example 3

[0608] (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-Benzothiazepine -4-Keto

[0609]

[0610] Step a) (3R)-3-(tert-Butyloxycarbonylamino)-8-fluoro-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine -7-Methyl formate

[0611]

[0612] Analogously to General Procedure 1a, (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-formic acid methyl ester (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) were prepared and the title compound (749 mg, 1.26 mmol, 93% yield) was obtained as a light yellow foam. MS (ESI): 541.1 [M-isobutylene-H] +

[0613] Step b) (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-Methyl formate

[0614]

[0615] Analogously to General Procedure 10, (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 was used. -7-Methyl formate (749 mg, 1.26 mmol) was prepared and the title compound (780 mg, 1.24 mmol, 99% yield) was obtained as a white solid. MS (ESI): 572.9 [M-isobutylene + H] +

[0616] 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-Formic acid

[0617]

[0618] Analogously to General Procedure 2, (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 was prepared. 6 ,5-Benzothiazepine -7-Methyl carboxylate (200 mg, 0.32 mmol) was prepared and the title compound (170 mg, 0.28 mmol, 61% yield) was obtained as a white powder. MS (ESI): 514.8 [M-Boc+H] +

[0619] Step d) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0620]

[0621] Analogously to General Procedure 3, (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 was prepared. 6 ,5-Benzothiazepine -7-carboxylic acid (3700 mg, 6.02 mmol) was used to prepare the title compound (2500 mg, 3.98 mmol, 66% yield). MS (ESI): 573.0 [M-isobutylene + H] +

[0622] Step e) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0623]

[0624] At RT, 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-Benzothiazepine -3-yl] tert-butyl carbamate (1000 mg, 1.59 mmol, 1.0 equiv) and triethylamine (0.44 mL, 3.18 mmol, 2.0 equiv) in THF (20 mL) were added CDI (387 mg, 2.39 mmol, 1.5 equiv), and the mixture was stirred for 3 hours. The solution was poured into water (20 mL). The aqueous phase was extracted with EtOAc (3x). The combined organic phases were washed with brine (2x), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The remaining crude material was purified by silica gel chromatography on silica gel (30% to 100% EtOAc in petroleum ether) to give the title compound (80 mg, 0.14 mmol, 76% yield). MS (ESI): 598.9 [M-isobutylene + H] +

[0625] Step f) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0626]

[0627] Analogous to General Procedure 13, 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-benzothiazepine was used. -3-yl]carbamic acid tert-butyl ester (190.0 mg, 0.29 mmol, 1.0 equiv) and 3,3-difluoro-1-methyl-cyclobutylamine hydrochloride (68.62 mg, 0.44 mmol, 1.5 equiv) were used to prepare the title compound (168.0 mg, 0.22 mmol, 76% yield) as a colorless foam. MS (ESI): 758.1 [M+H] +

[0628] 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-Benzothiazepine -4-Keto

[0629]

[0630] Analogous to General Procedure 11c, the reaction mixture was prepared from 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-Benzothiazepine -3-yl] tert-butyl carbamate (168 mg, 0.22 mmol) was prepared and the title compound (131.6 mg, 0.19 mmol, 85% yield) was obtained as a white solid as a hydrochloride salt. MS (ESI): 657.8 [M+H] +

[0631] The examples in the following table were prepared analogously to Example 3 using the appropriate amine building blocks.

[0632]

[0633] (*) is hydrochloride

[0634] Example 6

[0635] (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-Benzothiazepine -4-Keto

[0636]

[0637] Step a) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0638]

[0639] At 0°C, 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 was added.6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (250.0 mg, 0.4 mmol, 1.0 equiv., Example 3, step d) was added to a solution of isopropyl isocyanate (0.07 mL, 0.68 mmol, 1.72 equiv.) in DCM (5 mL). The mixture was stirred at RT for 3 hours. 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 RT for 1 hour. The reaction mixture was concentrated and purified by column chromatography on silica gel (25% to 75% EtOAc in petroleum ether) to give the title compound (142 mg, 0.2 mmol, 51% yield) as a light yellow solid. MS (ESI): 696.0 [M+H] +

[0640] 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-Benzothiazepine -4-Keto

[0641]

[0642] Analogous to General Procedure 11c, 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 was used. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (122 mg, 0.18 mmol) was prepared and the title compound (73.7 mg, 0.12 mmol, 70% yield) was obtained as a white solid. MS (ESI): 595.9 [M+H] +

[0643] Example 7

[0644] (3R)-3-amino-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-[[6-[4-(hydroxymethyl)phenyl]-3-pyridinyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0645]

[0646] Step a) (2R)-2-(tert-Butyloxycarbonylamino)-3-(4-cyano-5-fluoro-2-nitro-phenyl)thio-propionic acid

[0647]

[0648] 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, eq: 2). The reaction mixture was stirred at 22 °C for 24 h, diluted with DCM (40 mL), and washed once with 1 N 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 (23.5 g, 118% yield) as a yellow solid. MS (ESI): 286.1 [M-Boc+H] + .

[0649] Step b) (2R)-3-(2-amino-4-cyano-5-fluoro-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid

[0650]

[0651] To a solution of (2R)-2-(tert-butoxycarbonylamino)-3-(4-cyano-5-fluoro-2-nitro-phenyl)sulfanyl-propionic acid (14.0 g, 36.3 mmol, 1.0 equiv) in MeOH (140 mL) was added NH 4 Cl (5.83g, 109mmol, 3.0 equiv) in water (28mL) solution, then Fe (10.71mL, 145.31mmol, 4.0 equiv) was added in batches. The mixture was then stirred at 70 ° C for 2 hours. The reaction was cooled to RT and then filtered through a celite plug and washed with MeOH (200mL). The filtrate was concentrated to give (2R) -3- (2-amino-4-cyano-5-fluoro-phenyl) sulfenyl -2- (tert-butoxycarbonylamino) propionic acid (23g, 48.1mmol, 80% yield) as a black solid. MS (ESI): 300.1 [M-isobutylene + H] +

[0652] Step c) N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0653]

[0654] 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 THF at RT. 3 P in EtOAc solution (40.29g, 63.31mmol, 1.5 equivalents), and the mixture was stirred for 4 hours. The reaction mixture was diluted with EtOAc (300ml) and poured into water (600ml). The layers were separated, and the aqueous phase was washed twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The remaining residue was purified by reverse phase preparative HPLC to obtain N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine as a light yellow solid. -3-yl] tert-butyl carbamate (8.4 g, 24.9 mmol, 48% yield). MS (ESI): 282.1 [M-isobutylene + H] +

[0655] Step d) N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0656]

[0657] To tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine To a solution of tert-butyl (2R)-3-(2-amino-4-cyano-5-fluoro-phenyl)thio-2-(tert-butoxycarbonylamino)propanoic acid (200 mg, 0.59 mmol) in MeOH (2 mL) was added hydroxylamine hydrochloride (63.7 mg, 0.89 mmol, eq.: 1.5) and sodium bicarbonate (249 mg, 2.96 mmol, eq.: 5). The mixture was stirred at 70 °C for 16 hours, cooled to RT, filtered, and the filter cake was washed with DCM. The combined filtrate was concentrated in vacuo. The reaction mixture was diluted with DCM and washed with water and brine. The organic phase 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-isobutylene + H] +.

[0658] Step e) 2,2-dimethylpropanoic acid [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-yl]methylene]amino]ester

[0659]

[0660] Analogous to general procedure 8b, N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine was used. -3-yl] tert-butyl carbamate (1000 mg, 2.7 mmol) was prepared and the title compound (900 mg, 1.98 mmol, 73% yield) was obtained as a white solid. MS (ESI): 455.1 [M+H] +

[0661] Step f) N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0662]

[0663] Analogously to General Procedure 9a, 2,2-dimethylpropanoic acid [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -7-yl]methylene]amino]ester (2.12 g, 4.75 mmol, 1 equiv) and the title compound (1.94 g, 89%) was obtained as an orange solid. MS (ESI): 381.1 [M-isobutylene + H] +

[0664] Step g) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0665]

[0666] Analogously to General Procedure 10, N-[(3R)-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl] tert-butyl carbamate (500 mg, 1.09 mmol) was prepared and the title compound (426 mg, 84%) was obtained as a light yellow solid. MS (ESI): 413.2 [M+H] +

[0667] Step h) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0668]

[0669] Analogously to General Procedure 1a, 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (35 mg, 0.075 mmol, 1.0 equiv) and intermediate 1 (92.27 mg, 0.075 mmol, 1.0 equiv) were used to prepare the title compound (10 mg, 17%) as a light yellow solid. MS (ESI): 780.5 [M+H] +

[0670] Step i) (3R)-3-amino-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-[[6-[4-(hydroxymethyl)phenyl]-3-pyridinyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0671]

[0672] Analogously to General Procedure 11a, N-[(3R)-5-[[6-[4-[[tert-butyl(dimethyl)silanyl]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 was used. 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (10 mg, 0.013 mmol) was prepared and the title compound (4.1 mg, 57%) was obtained as a white solid. MS (ESI): 566.3 [M+H]+

[0673] Example 8

[0674] (3R)-3-amino-7-[5-(3-aminooxetane-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-Benzothiazepine -4-Keto

[0675]

[0676] Step a) N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-yl]carbamic acid tert-butyl ester

[0677]

[0678] Analogous to general procedure 7b, N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine was used. -3-yl] tert-butyl carbamate (186 mg, 0.462 mmol, Example 7, step d) and 3-(tert-butoxycarbonylamino)oxetane-3-carboxylic acid (150 mg, 0.69 mmol, equivalent: 1.5) were prepared and the title compound (166 mg, 0.3 mmol, 60% yield) was obtained as a light yellow solid. MS (ESI): 550.5 [MH]

[0679] Step b) N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-5-[[4-(4-methoxyphenyl)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-yl]carbamic acid tert-butyl ester

[0680]

[0681] Analogously to General Procedure 1a, N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]oxetane-3-yl]carbamic acid tert-butyl ester (40 mg, 0.067 mmol, eq: 1) and 1-(chloromethyl)-4-(4-methoxyphenyl)benzene (CAS 93258-73-2) (23.5 mg, 0.1 mmol, eq: 1.5) were prepared and the title compound (45 mg, 82% yield) was obtained as a white solid. MS (ESI): 746.4 [MH]

[0682] Step c) 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-Benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-yl]carbamic acid tert-butyl ester

[0683]

[0684] Analogous to General Procedure 10, N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-5-[[4-(4-methoxyphenyl)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine was used. -7-yl]-1,2,4-oxadiazol-5-yl]oxetane-3-yl]carbamic acid tert-butyl ester (45 mg, 0.055 mmol) was prepared and the title compound (30 mg, 69% yield) was obtained as a white solid. MS (ESI): 778.5 [MH]

[0685] Step d) (3R)-3-amino-7-[5-(3-aminooxetane-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-Benzothiazepine -4-Keto

[0686]

[0687] Analogous to General Procedure 11a, 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-Benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]oxetane-3-yl]carbamic acid tert-butyl ester (30 mg, 0.038 mmol) was prepared and the title compound (9 mg, 40.3% yield) was obtained as a white solid. MS (ESI): 580.3 [M+H] + .

[0688] The preparation of Example 9 in the following table was prepared analogously to Example 8 using the appropriate benzyl bromide building blocks.

[0689]

[0690] Example 10

[0691] (3R)-3-amino-7-[5-(3-aminooxetane-3-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0692]

[0693] Step a) N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-yl]carbamic acid tert-butyl ester

[0694]

[0695] Analogous to General Procedure 10, N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]oxetane-3-yl]carbamic acid tert-butyl ester (Example 8, step a) (40 mg, 0.067 mmol) was prepared and the title compound was obtained as a white solid (29 mg, 73% yield). MS (ESI): 472.2 [M-isobutylene + H] + .

[0696] Step b) 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-Benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-yl]carbamic acid tert-butyl ester

[0697]

[0698] Analogously to General Procedure 1a, N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]oxetane-3-yl]carbamic acid tert-butyl ester (29 mg, 0.050 mmol) and 2-[4-(chloromethyl)phenyl]-5-(trifluoromethyl)pyridine (20.25 mg, 0.075 mmol, equivalent: 1.5) were prepared and the title compound (10 mg, 18% yield) was obtained as a white solid. MS (ESI): 819.6 [M+H] + .

[0699] Step c) (3R)-3-amino-7-[5-(3-aminooxetane-3-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0700]

[0701] Analogous to General Procedure 11a, N-[3-[3-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]oxetane-3-yl]carbamic acid tert-butyl ester (10 mg, 0.01 mmol) was prepared and the title compound was obtained as a white solid (3 mg, 47% yield) MS (ESI): 619.3 [M+H] + .

[0702] Example 11

[0703] (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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0704]

[0705] Step a) N-[(3R)-8-fluoro-4-oxo-7-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0706]

[0707] At 0°C, add N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl] tert-butyl 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) were added N, N'-carbonyldiimidazole (380.9 mg, 2.35 mmol, 1.5 equiv.). 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 2M HCl. The aqueous phase was extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was ground 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 light yellow solid. MS (ESI): 341.1 [M-isobutylene + H] +

[0708] Step b) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0709]

[0710] Analogously to General Procedure 10, N-[(3R)-8-fluoro-7-(5-hydroxy-1,2,4-oxadiazol-3-yl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl] tert-butyl carbamate (20 mg, 0.05 mmol) was prepared and the title compound (18 mg, 0.04 mmol, 80% yield) was obtained as a light yellow solid. MS (ESI): 329.0 [M-Boc+H] +

[0711] Step c) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0712]

[0713] Analogous to General Procedure 13, N-[(3R)-8-fluoro-7-(5-hydroxy-1,2,4-oxadiazol-3-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl methyl ester (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) were used to prepare the title compound (79 mg, 0.15 mmol, 65% yield) as a white solid. MS (ESI): 468.1 [M-isobutylene + H] +

[0714] Step d) 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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0715]

[0716] Analogously to General Procedure 1b, 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 was used. 6,5-Benzothiazepine -3-yl] tert-butyl carbamate (94 mg, 0.18 mmol, 1.0 equiv) and [6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methanol (50 mg, 0.2 mmol, 1.1 equiv, CAS 356058-13-4) were prepared and the title compound (60 mg, 0.08 mmol, 44% yield) was obtained as a white solid. MS (ESI): 688.2 [M+H] +

[0717] 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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0718]

[0719] Analogous to General Procedure 11c, the reaction mixture was prepared from 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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (55 mg, 0.07 mmol) was prepared and the title compound was obtained as a white solid. MS (ESI): 659.2 [M+H] +

[0720] The examples in the following table were prepared analogously to Example 11 using the appropriate amine and benzyl bromide building blocks using the general procedures indicated.

[0721]

[0722] (*) is hydrochloride

[0723] Example 14

[0724] (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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0725]

[0726] Step a) N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0727]

[0728] Analogously to General Procedure 10, N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl] tert-butyl carbamate (3.0 g, 8.89 mmol, Example 7, step c) was prepared and the title compound was obtained as a white solid (3.2 g, 8.66 mmol, 88% yield). MS (ESI): 314.1 [M-isobutylene + H] +

[0729] Step b) N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0730]

[0731] Analogously to general procedure 1a, N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (100 mg, 0.27 mmol, 1.0 equiv) and intermediate 2 (166.7 mg, 0.3 mmol, 1.1 equiv) were used to prepare the title compound (100 mg, 0.17 mmol, 59% yield) as a white solid. MS (ESI): 597.1 [M+H] +

[0732] Step c) N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-1,1,4-trioxo-5-[[6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl] carbamic acid tert-butyl ester and N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-1,1,4-trioxo-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0733]

[0734] Analogously to General Procedure 6, N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridinyl]methyl]-2,3-dihydro-1λ was used. 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (300 mg, 0.5 mmol, 1.0 equiv) was prepared and an inseparable mixture and the title compound (200 mg, 54% yield) were obtained as a light yellow solid. MS (ESI): 630.2 [M+H] +

[0735] Step d) 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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester 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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0736]

[0737] N-[(3R)-8-fluoro-7-[(Z)-N′-hydroxycarbamimidoyl]-1,1,4-trioxo-5-[[6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-3-pyridinyl]methyl]-2,3-dihydro-1λ was added at RT. 6 ,5-Benzothiazepine -3-yl] carbamic acid tert-butyl ester and N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-1,1,4-trioxo-5-[[6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine To a solution of a mixture of tert-butyl]-3-yl]carbamate (180 mg, 0.3 mmol, 1.0 equiv) in DCM (9 ml) was added triethylamine (0.08 mL, 0.57 mmol, 2.0 equiv) and N,N'-carbonyldiimidazole (69.5 mg, 0.43 mmol, 1.5 equiv), and the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. The remaining residue was dissolved in EtOAc (10 mL) and washed with brine (2 x 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% to 100% EtOAc in petroleum ether) to give 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-pyridinyl]methyl]-2,3-dihydro-1λ as an orange solid. 6 ,5-Benzothiazepine -3-yl] carbamic acid tert-butyl ester 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-Benzothiazepine Inseparable mixture of tert-butyl 3-yl]carbamate (160 mg, 79% yield). MS (ESI): 656.2 [M+H] +

[0738] Step e) 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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine 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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate [Mixture A] and 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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester and 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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester [Mixture B]

[0739]

[0740]

[0741] Analogous to General Procedure 13, 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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester 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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl] tert-butyl 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 used to prepare and obtain the title mixture as an inseparable mixture and as a white solid [Mixture A] (30 mg, 23%, MS (ESI): 751.2 [M+H] + ) and an inseparable mixture and a white solid [Mixture B] (20 mg, 19%, MS (ESI): 709.3 [M+H] + ).

[0742] 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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0743]

[0744] At 0°C, 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-pyridinyl]methyl]-2,3-dihydro-1λ was added. 6 ,5-Benzothiazepine 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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine To a solution of tert-butyl 1-(2-(4-(4-(2-nitrophenyl)-3-yl)carbamate [Mixture A] (30 mg, 0.04 mmol, 1.0 equiv) in EtOAc (1 mL) was added a solution of 4N HCl in EtOAc (1.0 mL, 4.0 mmol, 100 equiv), and the mixture was stirred at RT for 1 hour. The mixture was concentrated under reduced pressure, and the remaining residue was purified by chiral SFC (retention time 1.77 minutes; conditions: column: Regis (S,S) Whelk-O 1, 250 mm*25 mm ID, 10 μm, mobile phase: phase A is CO 2Phase B is EtOH (0.1% NH 3 (aq)), the eluent was CO 2 40% EtOH (0.1% NH 3 (aq)), flow rate of 75 mL / min, detector: PDA) to give the pure title compound (7 mg) as a white solid, which was dissolved in EtOAc (1 ml). To the solution was added a solution of 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 a hydrochloride salt. MS (ESI): 651.1 [M+H] +

[0745] Example 15

[0746] (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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0747]

[0748] 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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0749]

[0750] At 0°C, 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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester and 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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine To a solution of tert-butyl]-3-yl]carbamate [Mixture B] (20.0 mg, 0.03 mmol, 1.0 equiv) in EtOAc (1 mL) was added 4N HCl in EtOAc (1.0 mL, 4.0 mmol, 130 equiv) and the mixture was stirred at RT for 1 hour. 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 hour. The mixture was then concentrated under reduced pressure to give the title compound (4.8 mg, 91% yield) as a white solid as the hydrochloride salt. MS (ESI): 609.2 [M+H] +

[0751] Example 16

[0752] 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-Benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile

[0753]

[0754] Step a) 1-Cyanocyclopropanecarboxylic acid [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-yl]methylene]amino]ester

[0755]

[0756] Analogously to General Procedure 8a, N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine was used. -3-yl] tert-butyl 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) were prepared and the title compound (650 mg, 35% yield) was obtained as a white solid. MS (ESI) 408.1 [M-isobutylene + H] +

[0757] Step b) N-[(3R)-7-[5-(1-cyanocyclopropyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0758]

[0759] Analogously to General Procedure 9a, 1-cyanocyclopropanecarboxylic acid [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] was prepared. -7-yl]methylene]amino]ester (650 g, 1.4 mmol, 1.0) and the title compound (160 mg, 25% yield) was obtained as a yellow solid. MS (ESI) 390.1 [M-isobutylene + H] +

[0760] Step c) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0761]

[0762] Analogous to General Procedure 10, N-[(3R)-7-[5-(1-cyanocyclopropyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine was used. -3-yl] tert-butyl carbamate (160 mg, 0.36 mmol) was prepared and the title compound (140 mg, 60% yield) was obtained as a yellow oil. MS (ESI): 378.1 [M-Boc+H] +

[0763] Step d) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0764]

[0765] Analogously to General Procedure 1a, N-[(3R)-7-[5-(1-cyanocyclopropyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1,4-trioxo-3,5-dihydro-2H-1λ was used. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (70 mg, 0.15 mmol, 1.0 equiv) and 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (49.5 mg, 0.2 mmol, 2 equiv, CAS: 2093101-98-3) were prepared and the title compound (80 mg, 73% yield) was obtained as a yellow oil. MS (ESI): 604.2 [M-Boc+H] +

[0766] 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-Benzothiazepine -7-yl]-1,2,4-oxadiazol-5-yl]cyclopropanecarbonitrile

[0767]

[0768] Analogous to General Procedure 11c, 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 was prepared. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (80 mg, 0.11 mmol) was prepared and the title compound (24.9 mg, 34% yield) was obtained as a white solid as a hydrochloride salt. MS (ESI): 604.2 [M+H] +

[0769] The preparation of Example 17 in the following table was prepared analogously to Example 16 using the appropriate benzyl bromide building blocks.

[0770]

[0771]

[0772] (*) is hydrochloride

[0773] Example 18

[0774] (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-Benzothiazepine -4-Keto

[0775]

[0776] Step a) 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0777]

[0778] Analogously to General Procedure 1a, N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl] tert-butyl 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) were prepared and the title compound (216 mg, 74% yield) was obtained as a white solid. MS (ESI): 508.2 [M-isobutylene + H] + .

[0779] Step b) 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0780]

[0781] Analogously to General Procedure 6, 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-benzothiazepine was used. -3-yl] tert-butyl carbamate (200 mg, 0.302 mmol) was prepared and the title compound (200 mg, 94% yield) was obtained as a white solid. MS (ESI): 597.4 [M+H] + .

[0782] Step c) 2-(Hydroxymethyl)tetrahydrofuran-2-carboxylic acid [(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-benzothiazepine -7-yl]methylene]amino]ester

[0783]

[0784] Analogously to General Procedure 8a, 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-benzothiazepine was used. -3-yl]carbamic acid tert-butyl ester (100 mg, 0.142 mmol) and 2-(hydroxymethyl)tetrahydrofuran-2-carboxylic acid (CAS 442877-01-2) (25 mg, 0.17 mmol) were prepared and the title compound (72.7 mg, 53% yield) was obtained as a white powder. MS (ESI): 723.5 [MH]

[0785] Step d) 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0786]

[0787] Analogously to General Procedure 9a, [(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-benzothiazepine] was prepared from 2-(hydroxymethyl)tetrahydrofuran-2-carboxylic acid. -7-yl]methylene]amino]ester (72.7 mg, 0.075 mmol) and the title compound was obtained as a white solid (50.3 mg, 94% yield). MS (ESI): 651.2 [M-isobutylene + H] + .

[0788] Step e) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0789]

[0790] Analogous to General Procedure 10, the reaction mixture was prepared from 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-benzothiazepine. -3-yl] tert-butyl carbamate (50.3 mg, 0.071 mmol) was prepared and the title compound was obtained as a white powder (23.7 mg, 45% yield). MS (ESI): 683.2 [M-isobutylene + H] + .

[0791] 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-Benzothiazepine -4-Keto

[0792]

[0793] Analogous to General Procedure 11b, the reaction mixture was prepared from 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-Benzothiazepine -3-yl] tert-butyl carbamate (23.7 mg, 0.032 mmol) was prepared and the title compound (20.9 mg, 96% yield) was obtained as an off-white powder as a hydrochloride salt. MS (ESI): 639.2 [M+H] + .

[0794] Example 19

[0795] (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-Benzothiazepine -4-Keto

[0796]

[0797] Step a) (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-Formic acid

[0798]

[0799] Analogously to General Procedure 2, (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-Methyl formate (2.5 g, 7.09 mmol, CAS 2089150-62-7) was prepared and the title compound (2.26 g, 89%) was obtained as an orange amorphous solid. MS (ESI): 283.0 [M-isobutylene + H] +

[0800] Step b) N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0801]

[0802] Analogously to General Procedure 3, (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-carboxylic acid (1120 mg, 3.31 mmol) was used to prepare the title compound (1036 mg, 80%) as a light yellow solid. MS (ESI): 351.2 [MH]

[0803] Step c) N-[(3R)-7-[(2,2-dimethylpropionylamino)carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0804]

[0805] Analogously to general procedure 4a, N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl] tert-butyl carbamate (4.5 g, 7.39 mmol, 1 equivalent) and trimethylacetic acid (889.0 mg, 8.7 mmol, 1.18 equivalent) were used to prepare the title compound, and the title compound was obtained as a light yellow solid (2.95 g, 6.76 mmol, yield 84%). MS (ESI): 381.1 [M+H-isobutylene] +

[0806] Step d) N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0807]

[0808] Analogously to General Procedure 5a, N-[(3R)-7-[(2,2-dimethylpropionylamino)carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine was used. -3-yl] tert-butyl carbamate (2.9 g, 6.64 mmol) was used to prepare the title compound, and the title compound was obtained as a light yellow solid (1.6 g, 3.82 mmol, yield 54%). MS (ESI): 363.1 [M+H-isobutylene] +

[0809] Step e) N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0810]

[0811] Analogously to General Procedure 10, N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl] tert-butyl carbamate (241 mg, 0.58 mmol) was prepared and the title compound (270 mg, 0.6 mmol, 94.5% yield) was obtained as a white solid. MS (ESI): 395.2 [M+H-isobutylene] +

[0812] Step f) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0813]

[0814] Analogously to General Procedure 1a, N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (100 mg, 0.22 mmol, 1.0 equiv) and intermediate 3 (78.94 mg, 0.22 mmol, 1.0 equiv) were prepared and the title compound (150 mg, 0.23 mmol, 77% yield) was obtained as a light yellow solid. MS (ESI): 665.3 [M+H] +

[0815] 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-Benzothiazepine -4-Keto

[0816]

[0817] Analogously to General Procedure 11c, 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 was used. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (150 mg, 0.23 mmol) was prepared and the title compound (23.4 mg, 0.04 mmol, 17% yield) was obtained as a yellow solid as a hydrochloride salt. MS (ESI): 565.2 [M+H] +

[0818] The examples in the following table were prepared analogously to Example 19 using the appropriate benzyl bromide building blocks.

[0819]

[0820]

[0821]

[0822]

[0823]

[0824] (*) is hydrochloride

[0825] Example 32

[0826] (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-Benzothiazepine -4-Keto

[0827]

[0828] Step a) (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -7-Formic acid

[0829]

[0830] NaIO 4(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 was added 3 ·3H 2 O (12.21 mg, 46.69 μmol, 0.01 equiv) and the reaction was stirred for 5 minutes. Then, (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine was added -7-formic acid (1580mg, 4.67mmol, 1.0 equivalent, Example 19, step a) in acetonitrile (25mL) solution, and the resulting gray suspension was stirred for 3 hours. The reaction was quenched by adding isopropanol (2ml), then diluted with EtOAc and 2M HCl. The biphasic mixture was filtered through a diatomaceous earth plug. The resulting filtrate was transferred to a separatory funnel and the layers 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 as a light yellow solid. 6 ,5-Benzothiazepine -7-Formic acid (1287 mg, 74%). MS (ESI): 369.1 [MH]

[0831] Step b) N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0832]

[0833] Analogously to General Procedure 3, (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -7-carboxylic acid (500 mg, 877.48 μmol, 1 eq.) was used to prepare the title compound (282 mg, 72%) as a yellow solid. MS (ESI): 383.2 [M+H] +

[0834] Step c) N-[(3R)-7-[[[2-(tert-butoxyamino)-3,3,3-trifluoro-2-methyl-propionyl]amino]carbamoyl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0835]

[0836] Analogously to general procedure 4a, N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (94 mg, 210.3 μmol) and 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-methyl-propionic acid (64.91 mg, 252.36 μmol, 1.2 equivalents, CAS170462-68-7) were prepared and the title compound (63.3 mg, 45%) was obtained as a white powder. MS (ESI): 622.2 [M+H] +

[0837] Step d) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0838]

[0839] Analogously to General Procedure 5b, N-[(3R)-7-[[[2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-methyl-propionyl]amino]carbamoyl]-1,1,4-trioxo-3,5-dihydro-2H-1λ was used. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (60 mg, 0.106 mmol, 1 eq.) was prepared and the title compound (50.9 mg, 83%) was obtained as a white solid. MS (ESI): 604.2 [M+H] +

[0840] Step e) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0841]

[0842] Analogously to General Procedure 1a, 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 was used. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (75.3 mg, 0.124 mmol, 1.0 equiv.) and 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (57.27 mg, 0.187 mmol, 1.5 equiv., CAS 2093101-98-3) were used to prepare the title compound (73.5 mg, 71%) as a white solid. MS (ESI): 830.4 [MH]

[0843] 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-Benzothiazepine -4-Keto

[0844]

[0845] Analogous to General Procedure 11a, 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 was prepared. 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (75.3 mg, 0.091 mmol) was prepared and the title compound (53.8 mg, 89%) was obtained as a white solid as a hydrochloride salt. MS (ESI): 632.4 [M+H] +

[0846] The examples in the following table were prepared analogously to Example 32 using the appropriate benzyl bromide building blocks.

[0847]

[0848] (*) is hydrochloride

[0849] The examples in the following table were prepared analogously to Example 32 using the appropriate benzyl bromide or carboxylic acid building blocks.

[0850]

[0851]

[0852] (*) is hydrochloride

[0853] Example 34

[0854] (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-Benzothiazepine -4-Keto

[0855]

[0856] Step a) N-[(3R)-7-[[[2-(tert-Butoxycarbonylamino)-3,3-dimethyl-butyryl]amino]carbamoyl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0857]

[0858] Analogously to General Procedure 4b, N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine was used. -3-yl] tert-butyl 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.) were prepared to give the title compound (650 mg, 0.82 mmol, 82% yield) as a light brown solid. MS (ESI): 692.3 [M+H-Boc] +

[0859] Step b) 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0860]

[0861] Analogously to General Procedure 5a, 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-benzothiazepine was used. -3-yl] tert-butyl carbamate (630 mg, 0.8 mmol) was prepared and the title compound (800 mg, 1.03 mmol, 123% yield) was obtained as a light yellow solid. MS (ESI): 774.4 [M+H] + .

[0862] Step c) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0863]

[0864] Analogous to General Procedure 10, 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-benzothiazepine was used. -3-yl] tert-butyl carbamate (750 mg, 0.97 mmol) was prepared and the title compound (500 mg, 0.62 mmol, 64% yield) was obtained as a yellow solid. MS (ESI): 828.3 [M+H] + .

[0865] 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-Benzothiazepine -4-Keto

[0866]

[0867] Analogous to General Procedure 11c, 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 was used. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (150 mg, 0.19 mmol) was prepared and the title compound (111.7 mg, 0.16 mmol, 86% yield) was obtained as a light yellow solid. MS (ESI): 606.0 [M+H] + .

[0868] The examples in the following table were prepared analogously to Example 34 using the appropriate carboxylic acid building blocks.

[0869]

[0870]

[0871] (*) is hydrochloride

[0872] Example 38

[0873] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0874]

[0875] Step a) N-[(3R)-7-[[(2-cyano-2-methyl-propionyl)amino]carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0876]

[0877] Analogously to general procedure 4a, N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl] tert-butyl carbamate (100 mg, 0.270 mmol, 1.0 equiv., Example 19, step b) and 2-cyano-2-methylpropanoic acid (36.59 mg, 0.323 mmol, 1.2 equiv., CAS 22426-30-8) were prepared to obtain the title compound (114.5 mg, 95%) as a white solid. MS (ESI): 446.2 [MH]

[0878] Step b) N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0879]

[0880] Analogously to General Procedure 5b, N-[(3R)-7-[[(2-cyano-2-methyl-propionyl)amino]carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine was used. -3-yl] tert-butyl carbamate (114.5 mg, 0.256 mmol) was prepared and the title compound (83.3 mg, 76%) was obtained as a white solid. MS (ESI): 374.1 [M-isobutylene + H] + .

[0881] Step c) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0882]

[0883] Analogous to general procedure 10, N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine was used. -3-yl] tert-butyl carbamate (83.3 mg, 0.194 mmol) was prepared and the title compound (72.7 mg, 81%) was obtained as a white solid. MS (ESI): 406.1 [M-isobutylene + H] +

[0884] Step d) 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-Benzothiazepine tert-butyl 3-amino-4-nitropropane

[0885]

[0886] Analogously to General Procedure 1a, N-[(3R)-7-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ was prepared. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (36 mg, 0.078 mmol, 1.0) and 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (35.9 mg, 0.117 mmol, 1.5 equiv., CAS 2093101-98-3) were used to prepare the title compound (33 mg, 62%) as a white solid. MS (ESI): 632.1 [M-isobutylene + H] +

[0887] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0888]

[0889] Analogously to General Procedure 11a, 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 was prepared. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (33 mg, 0.048 mmol) was prepared and the title compound (29.5 mg, 99%) was obtained as an off-white solid as a hydrochloride salt. MS (ESI): 632.4 [M+H] +

[0890] The examples in the following table were prepared analogously to Example 38 using the appropriate carboxylic acid and / or benzyl bromide building blocks in the indicated synthetic steps.

[0891]

[0892] (*) is hydrochloride

[0893] Example 41

[0894] (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0895]

[0896] Step a) N-[(3R)-7-[[[1-(tert-butoxycarbonylamino)cyclohexanecarbonyl]amino]carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0897]

[0898] Analogously to general procedure 4a, N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl] tert-butyl 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) were prepared to obtain the title compound (207.5 mg, 76%) as a light yellow solid. MS (ESI): 576.3 [MH]

[0899] Step b) N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0900]

[0901] Analogously to General Procedure 5b, N-[(3R)-7-[[[1-(tert-butoxycarbonylamino)cyclohexanecarbonyl]amino]carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine was used. -3-yl]carbamic acid tert-butyl ester (67 mg, 0.095 mmol) was prepared and the title compound (48 mg, 80%) was obtained as a white solid. MS (ESI): 560.3 [M+H] +

[0902] Step c) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0903]

[0904] Analogous to General Procedure 10, N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine was used. -3-yl] tert-butyl carbamate (48 mg, 0.076 mmol) was prepared and the title compound (46 mg, 96%) was obtained as a white solid. MS (ESI): 480.1 [M-2xisobutylene + H] +

[0905] Step d) N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0906]

[0907] Analogously to General Procedure 1a, N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ was prepared from 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (46 mg, 0.073 mmol, 1.0 equiv.) and 2-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)pyridine (23.1 mg, 0.073 μmol, 1.0 equiv., CAS 1056641-21-4) were used to prepare the title compound (49 mg, 81%) as a white solid. MS (ESI): 827.7 [M+H] +

[0908] Step e) (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0909]

[0910] Analogous to General Procedure 11a, the reaction mixture was prepared from N-[(3R)-7-[5-[1-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (49 mg, 0.059 mmol) was prepared and the title compound (42 mg, 101%) was obtained as an off-white solid as a hydrochloride salt. MS (ESI): 627.3 [M+H] +

[0911] The examples in the following table were prepared analogously to Example 41 using the appropriate benzyl bromide building blocks.

[0912]

[0913] (*) is hydrochloride

[0914] Example 45

[0915] 2-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0916]

[0917] Step a) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0918]

[0919] 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (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 a solution of tert-butyl ester (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) and a white solid (35.7 mg, 70%) was obtained similarly to general procedure 1a. MS (ESI): 602.2 [M-isobutylene + H] +

[0920] Step b) 2-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0921]

[0922] Analogously to General Procedure 11a, 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 was prepared. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (35 mg, 0.053 mmol) was prepared and the title compound (31 mg, 98%) was obtained as an off-white solid as a hydrochloride salt. MS (ESI): 558.3 ​​[M-isobutylene + H] +

[0923] The examples in the following table were prepared analogously to Example 45 using the appropriate benzyl bromide building blocks.

[0924]

[0925]

[0926]

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934] (*) is hydrochloride

[0935] Example 48

[0936] (3R)-3-amino-7-[5-(2-methyloxetane-2-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[0937]

[0938] Step a) N-[(3R)-7-[[(2-methyloxetane-2-carbonyl)amino]carbamoyl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0939]

[0940] Analogously to general procedure 4a, N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl] tert-butyl 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) were prepared to obtain the title compound (60 mg, 53%) as an off-white powder. MS (ESI): 481.2 [M+H] +

[0941] Step b) N-[(3R)-7-[5-(2-methyloxetane-2-yl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0942]

[0943] Analogously to General Procedure 5b, N-[(3R)-7-[[(2-methyloxetane-2-carbonyl)amino]carbamoyl]-1,1,4-trioxo-3,5-dihydro-2H-1λ was used. 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (60 mg, 0.106 mmol) was prepared and the title compound (25 mg, 43%) was obtained as a white powder. MS (ESI): 463.1 [M+H] +

[0944] Step c) N-[(3R)-7-[5-(2-methyloxetane-2-yl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0945]

[0946] Analogously to General Procedure 1a, N-[(3R)-7-[5-(2-methyloxetane-2-yl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ was prepared. 6 ,5-Benzothiazepine -3-yl] tert-butyl 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) were used to prepare the title compound (17 mg, 44%) as a white powder. MS (ESI): 643.2 [M-isobutylene + H] +

[0947] Step d) (3R)-3-amino-7-[5-(2-methyloxetane-2-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto

[0948]

[0949] Analogous to General Procedure 11a, the reaction mixture was prepared from 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-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (24.8 mg, 0.035 mmol) was prepared and the title compound (8.5 mg, 40%) was obtained as a white powder. MS (ESI): 599.2 [M+H] + The examples in the following table were prepared analogously to Example 48 using the appropriate benzyl bromide building blocks.

[0950]

[0951] The examples in the following table were prepared analogously to Example 48 using the appropriate carboxylic acid building blocks.

[0952]

[0953]

[0954] (*) is hydrochloride

[0955] Example 49

[0956] (3R)-3-amino-7-[5-(3-fluoro-1-methyl-3-piperidinyl)-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-Benzothiazepine -4-Keto

[0957]

[0958] Step a) 3-[[[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine [7-Carbonyl]amino]carbamoyl]-3-fluoro-piperidine-1-carboxylic acid benzyl ester

[0959]

[0960] Analogously to general procedure 4a, N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl] tert-butyl 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) were prepared to obtain the title compound (680 mg, 97%) as a white solid. MS (ESI): 516.2 [M-Boc+H] +

[0961] Step b) 3-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-fluoro-piperidine-1-carboxylic acid benzyl ester

[0962]

[0963] Analogously to General Procedure 5b, 3-[[[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-Carboxyl]amino]carbamoyl]-3-fluoro-piperidine-1-carboxylic acid benzyl ester (680 mg, 1.1 mmol, 1.0 equiv) was prepared and the title compound (505 mg, 77%) was obtained as a white solid. MS (ESI): 542.1 [M-isobutylene + H] +

[0964] Step c) 3-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-fluoro-piperidine-1-carboxylic acid benzyl ester

[0965]

[0966] Analogous to General Procedure 10, 3-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-fluoro-piperidine-1-carboxylic acid benzyl ester (180 mg, 0.295 mmol, 1 equiv) was prepared and the title compound (180 mg, 97%) was obtained as a white solid. MS (ESI): 628.4 [M+H] +

[0967] Step d) 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-fluoro-piperidine-1-carboxylic acid benzyl ester

[0968]

[0969] Analogously to General Procedure 1a, 3-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-fluoro-piperidine-1-carboxylic acid benzyl ester (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) were used to prepare and obtain the title compound (89.6 mg, 81%) as a white solid. MS (ESI): 800.4 [M-isobutylene + H] +

[0970] Step e) N-[(3R)-7-[5-(3-fluoro-3-piperidinyl)-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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0971]

[0972] Under an inert atmosphere, 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-Benzothiazepine -7-yl] -1,3,4-oxadiazole-2-yl] -3-fluoro-piperidin-1-carboxylic acid benzyl ester (89.6mg, 0.103mmol, 1.0 equivalent) was added to a solution of MeOH (1.7mL) and THF (0.5mL) with Pd / C (22mg). The reaction mixture was stirred for 5 hours under a hydrogen atmosphere. The mixture was filtered through a celite plug and washed with THF and MeOH. The filtrate was concentrated to give a light yellow solid N-[(3R) -7-[5-(3-fluoro-3-piperidinyl) -1,3,4-oxadiazole-2-yl] -1,1,4-trioxo-5-[[4-[5-(trifluoromethyl) -1,2,4-oxadiazole-3-yl] phenyl] methyl] -2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (81.7 mg, 55%). MS (ESI): 722.6 [M+H] +

[0973] Step f) N-[(3R)-7-[5-(3-fluoro-1-methyl-3-piperidinyl)-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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0974]

[0975] To N-[(3R)-7-[5-(3-fluoro-3-piperidinyl)-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-Benzothiazepine To a solution of tert-butyl]-3-yl]carbamate (81.7 mg, 0.057 mmol, 1.0 equiv) in MeOH (0.57 mL) 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 RT for two hours. The reaction was poured onto water and extracted with DCM (3x). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The remaining crude material was purified using column chromatography on silica gel (0% to 100% EtOAc in heptane) to give N-[(3R)-7-[5-(3-difluoro-1-methyl-3-piperidinyl)-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 as a white solid. 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (15.9 mg, 38%). MS (ESI): 736.6 [M+H] +

[0976] Step g) (3R)-3-amino-7-[5-(3-fluoro-1-methyl-3-piperidinyl)-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-Benzothiazepine -4-Keto

[0977]

[0978] Analogous to General Procedure 11a, the reaction mixture was prepared from N-[(3R)-7-[5-(3-fluoro-1-methyl-3-piperidinyl)-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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (15.9 mg, 0.022 mmol) was prepared and the title compound (9.8 mg, 68%) was obtained as an off-white solid as a hydrochloride salt. MS (ESI): 636.3 [M+H] +

[0979] The examples in the following table were prepared analogously to Example 49 using the appropriate benzyl bromide building blocks.

[0980]

[0981] (*) is hydrochloride

[0982] Example 52

[0983] (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-Benzothiazepine -4-Keto

[0984]

[0985] Step a) (2R)-2-(tert-Butyloxycarbonylamino)-3,3,3-trifluoro-2-methyl-propionic acid

[0986]

[0987] To a solution of (2R)-2-amino-3,3,3-trifluoro-2-methyl-propionic acid (1 g, 6.37 mmol, 1.0 eq., CAS 102210-02-6) in THF (20 ml) was added DMAP (233 mg, 1.91 mmol, 0.3 eq.) and di-tert-butyl dicarbonate (1.67 g, 7.64 mmol, 1.2 eq.) at RT, and the reaction mixture was stirred overnight. The resulting solution was poured into saturated NaHCO 3 The solution was decanted and washed twice with EtOAc. The aqueous phase was then acidified with 1N HCl and extracted with EtOAc (3x). The combined organic phases were dried over sodium sulfate, filtered and concentrated to give (2R)-2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-methyl-propionic acid (1.32 g, 81%) as a white solid. MS (ESI): 158.0 [M-Boc+H] +

[0988] Step b) 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]carbamic acid tert-butyl ester

[0989]

[0990] Analogous to general procedure 4b, N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl]carbamic acid tert-butyl ester (180 mg, 0.510 mmol, 1.0 equiv.) and (2R)-2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-methyl-propionic acid (131.37 mg, 0.510 mmol, 1.0 equiv., CAS) were used to prepare the title compound (88 mg, 29%) as a white solid. MS (ESI): 590.3 [MH]

[0991] Step c) N-[(1R)-1-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2,2,2-trifluoro-1-methyl-ethyl]carbamic acid tert-butyl ester

[0992]

[0993] Analogously to general procedure 5a, 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]carbamic acid tert-butyl ester (750 mg, 0.3 mmol, 1.0 equiv) was prepared and the title compound (82 mg, 46%) was obtained as a white solid. MS (ESI): 572.3 [MH]

[0994] Step d) 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-benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2,2,2-trifluoro-1-methyl-ethyl]carbamic acid tert-butyl ester

[0995]

[0996] Analogously to General Procedure 1a, N-[(1R)-1-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2,2,2-trifluoro-1-methyl-ethyl]carbamic acid tert-butyl ester (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) were used to prepare the title compound (153 mg, 76%) as a white solid. MS (ESI): 688.2 [M-Boc+H] +

[0997] Step e) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0998]

[0999] Analogous to General Procedure 10, 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-benzothiazepine was used. -7-yl]-1,3,4-oxadiazol-2-yl]-2,2,2-trifluoro-1-methyl-ethyl]carbamic acid tert-butyl ester (153 mg, 191.31 μmol, 1.0 equiv) was prepared and the title compound (122 mg, 77%) was obtained as a white solid. MS (ESI): 830.4 [MH]

[1000] 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-Benzothiazepine -4-Keto

[1001]

[1002] Analogously to General Procedure 11a, 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 was prepared. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (40 mg, 0.048 mmol, 1.0 equiv) was prepared and the title compound (31 mg, 97%) was obtained as a white solid as a hydrochloride salt. MS (ESI): 632.1 [M+H] +

[1003] The examples in the following table were prepared analogously to Example 52 using the appropriate carboxylic acid building blocks.

[1004]

[1005] (*) is hydrochloride

[1006] Example 153

[1007] (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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[1008]

[1009] Step a) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1010]

[1011] Analogous to General Procedure 10, N-[(1R)-1-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2,2,2-trifluoro-1-methyl-ethyl]carbamic acid tert-butyl ester (142 mg, 247.6 μmol, Example 52, step c) was prepared and the title compound (135 mg, 90%) was obtained as a white solid. MS (ESI): 604.2 [M+H] +

[1012] Step b) 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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1013]

[1014] Analogously to General Procedure 1a, 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 was used. 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (25 mg, 41.28 μmol, 1.0 equiv) and intermediate 38 (15.1 mg, 45.4 μmol, 1.1 equiv) were used to prepare the title compound (32 mg, 91%) as a white solid. MS (ESI): 857.5 [M+H] +

[1015] 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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[1016]

[1017] Analogous to General Procedure 11a, the reaction mixture was prepared from 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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (32 mg, 37.35 μmol) was prepared and the title compound (24 mg, 89%) was obtained as a white solid as a hydrochloride salt. MS (ESI): 657.2 [M+H] +

[1018] The examples in the following table were prepared analogously to Example 153 using the appropriate benzyl bromide building blocks.

[1019]

[1020]

[1021] (*) is hydrochloride

[1022] Example 54

[1023] (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-Benzothiazepine -4-Keto

[1024]

[1025] Step a) (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-Methyl formate

[1026]

[1027] Analogously to General Procedure 1a, (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-formic acid methyl ester (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) were prepared and the title compound (784 mg, 94%) was obtained as a white solid. MS (ESI): 523.2 [M-isobutylene + H] +

[1028] Step b) (3R)-3-(tert-Butyloxycarbonylamino)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine -7-Formic acid

[1029]

[1030] Analogously to General Procedure 2, (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine was used. -7-Methyl formate (770 mg, 1.33 mmol) was prepared and the title compound (756 mg, 82%) was obtained as a light yellow solid. MS (ESI): 509.1 [M-isobutylene + H] +

[1031] Step c) N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1032]

[1033] Analogously to General Procedure 3, (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine was used. -7-carboxylic acid (750 mg, 1.08 mmol) was used to prepare the title compound (552 mg, 86%) as a white solid. MS (ESI): 523.1 [M-isobutylene + H] +

[1034] Step d) 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1035]

[1036] Analogously to General Procedure 4a, N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine was used. -3-yl] tert-butyl 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) were prepared to obtain the title compound (97 mg, 60%) as a white solid. MS (ESI): 607.1 [M-Boc+H] +

[1037] Step e) 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1038]

[1039] 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-benzothiazepine was added at RT. To a solution of tert-butyl]-3-yl]carbamate (97 mg, 0.1 mmol, 1.0 equiv) in DCM (1. ml) was added TBDMS-Cl (22.65 mg, 0.15 mmol, 1.5 equiv) and imidazole (17.05 mg, 0.25 mmol, 2.5 equiv) overnight. The reaction mixture was directly concentrated and purified by flash column chromatography on silica gel (0% to 60% EtOAc in heptane) to give the title compound (66 mg, 80%) as a white solid. MS (ESI): 765.3 [M-isobutylene + H]+

[1040] Step f) 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1041]

[1042] Analogously to General Procedure 5b, the product was prepared from 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-benzothiazepine. -3-yl]carbamic acid tert-butyl ester (66 mg, 0.08 mmol) was prepared and the title compound (41 mg, 61%) was obtained as a colorless solid. MS (ESI): 803.5 [M+H] +

[1043] Step g) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1044]

[1045] Analogously to General Procedure 10, the reaction mixture was prepared from N-[(3R)-7-[5-[2-[[tert-butyl(dimethyl)silanyl]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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (41 mg, 0.049 mmol) was prepared and the title compound (40 mg, 98%) was obtained as a white solid. MS (ESI): 835.3 [M+H] +

[1046] 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-Benzothiazepine -4-Keto

[1047]

[1048] Analogously to General Procedure 11a, the reaction mixture was prepared from 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-Benzothiazepine -3-yl] tert-butyl carbamate (40 mg, 0.048 mmol) was prepared and the title compound (18 mg, 57%) was obtained as a white solid as a hydrochloride salt. MS (ESI): 621.1 [M+H] +

[1049] The examples in the following table were prepared analogously to Example 54 using the appropriate benzyl bromide building blocks.

[1050]

[1051] Example 56

[1052] 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidin-1-

[1053] Methyl formate

[1054]

[1055] Step a) 3,3-difluoro-5-[[[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine [7-Carboxyl]amino]carbamoyl]piperidine-1-carboxylic acid benzyl ester

[1056]

[1057] Analogous to general procedure 4b, N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl] tert-butyl carbamate (980 mg, 3.27 mmol, Example 19, step b) and 5,5-difluoro-1-[(E)-2-vinylbut-2-enyloxy]carbonyl-piperidine-3-carboxylic acid (980 mg, 3.3 mmol, 1.2 equivalents CAS1356338-81-2) were prepared and the title compound (1.08 g, 63% yield) was obtained as a light yellow solid. MS (ESI): 534.1 [M+H-isobutylene] +

[1058] Step b) 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid benzyl ester

[1059]

[1060] Analogously to general procedure 5a, 3,3-difluoro-5-[[[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine [-7-carbonyl]amino]carbamoyl]piperidine-1-carboxylic acid benzyl ester (1060 mg, 1.67 mmol) was prepared and the title compound (721 mg, 70% yield) was obtained as a light yellow foam. MS (ESI): 560.1 [M+H-isobutylene] +

[1061] Step c) 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-benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid benzyl ester

[1062]

[1063] Analogously to General Procedure 1a, 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid benzyl ester (615 mg, 0.6 mmol, 1.0 equiv) and intermediate 13 (184.6 mg, 0.6 mmol, 1.1 equiv) were used to prepare the title compound (721 mg, 70% yield) as a light yellow foam. MS (ESI): 830.3 [M+H] +

[1064] Step d) 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid benzyl ester

[1065]

[1066] Analogously to General Procedure 10, 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-benzothiazepine was used. -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid benzyl ester (363 mg, 0.4 mmol) and obtain the title compound as a light yellow solid (374 mg, 0.43 mmol, 99% yield). MS (ESI): 762.2 [M+H-isobutylene] +

[1067] Step e) N-[(3R)-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-(5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1068]

[1069] Under an inert atmosphere, 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-Benzothiazepine -7-yl]-1,3,4-oxadiazole-2-yl] piperidine-1-carboxylic acid benzyl ester (324mg, 0.4mmol, 1.0 equivalent) in MeOH (10mL). The reaction mixture was stirred under a hydrogen atmosphere for 5 hours. The mixture was filtered through a diatomaceous earth plug and washed with MeOH. The filtrate was concentrated to give yellow foamy N-[(3R)-5-[[4-(5-tert-butyl-1,2,4-oxadiazole-3-yl)phenyl]methyl]-7-[5-(5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazole-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (244 mg, 0.34 mmol, 89% yield). MS (ESI): 728.2 [M+H] +

[1070] Step f) 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid methyl ester

[1071]

[1072] At 0°C, N-[(3R)-5-[[4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-(5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ was added. 6 ,5-Benzothiazepine To a solution of tert-butyl]carbamate (122 mg, 0.2 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.0876 mL, 0.5 mmol, 3.0 equiv) in DCM (3.0 mL) was added methyl carbonate (0.02 mL, 0.17 mmol, 1.0 equiv CAS 4525-33-1). The mixture was stirred at RT for 30 minutes. The reaction mixture was concentrated in vacuo to give a crude product. The crude product was purified by preparative HPLC (neutral), the eluent was concentrated in vacuo to remove part of the acetonitrile, and then dried by lyophilization to give the desired title compound (70 mg, 0.09 mmol, 53% yield) as a white solid. MS (ESI): 786.2 [M + H] +

[1073] Step g) 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid methyl ester

[1074]

[1075] Analogously to General Procedure 11c, 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 was prepared. 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid methyl ester (60 mg, 0.1 mmol) and obtained the title compound (42.3 mg, 0.06 mmol, 75% yield) as a white solid as a hydrochloride salt. MS (ESI): 686.3 [M+H] +

[1076] Example 57

[1077] 3,3-Difluoro-5-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid methyl ester

[1078]

[1079] Step a) 3,3-difluoro-5-[[[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine [7-Carboxyl]amino]carbamoyl]piperidine-1-carboxylic acid benzyl ester

[1080]

[1081] Analogous to general procedure 4b, N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl] tert-butyl carbamate (980 mg, 3.27 mmol, Example 19, step b) and 5,5-difluoro-1-[(E)-2-vinylbut-2-enyloxy]carbonyl-piperidine-3-carboxylic acid (980 mg, 3.3 mmol, 1.2 equivalents CAS 1356338-81-2) were prepared and the title compound (1.08 g, 63% yield) was obtained as a light yellow foam. MS (ESI): 534.1 [M+H-isobutylene] +

[1082] Step b) 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid benzyl ester

[1083]

[1084] Analogously to general procedure 5a, 3,3-difluoro-5-[[[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine [-7-carbonyl]amino]carbamoyl]piperidine-1-carboxylic acid benzyl ester (1060 mg, 1.67 mmol) was prepared and the title compound (721 mg, 70% yield) was obtained as a light yellow foam. MS (ESI): 560.1 [M+H-isobutylene] +

[1085] Step c) 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid benzyl ester

[1086]

[1087] Analogous to General Procedure 10, 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid benzyl ester (300 mg, 0.49 mmol, 1.0 equiv) was prepared and the title compound (320 mg, 0.49 mmol, 92% yield) was obtained as a light yellow solid. MS (ESI): 592.1 [M+H-isobutylene]+

[1088] Step d) 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid benzyl ester

[1089]

[1090] Analogously to General Procedure 1a, 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid benzyl ester (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) were prepared and the title compound (570 mg, 106% yield) was obtained as a light yellow oil. MS (ESI): 883.2 [M+H] +

[1091] Step e) N-[(3R)-7-[5-(5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1092]

[1093] Under an inert atmosphere, 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 was added. 6 ,5-Benzothiazepine To a solution of [7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid benzyl ester (50 mg, 0.06 mmol, 1.0 equiv) in MeOH (5 mL) was added Pd / C (50 mg). The reaction mixture was stirred under a hydrogen atmosphere for 5 hours. The mixture was filtered through a celite plug and washed with MeOH. The filtrate was concentrated to give the title compound (30 mg, 0.04 mmol, 47% yield) as a light yellow oil. MS (ESI): 749.3 [M+H] +

[1094] Step f) 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid methyl ester

[1095]

[1096] At 0°C, N-[(3R)-7-[5-(5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ was added. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (45mg, 0.06mmol, 1.0 equivalent) and N, N-diisopropylethylamine (0.03mL, 0.18mmol, 3.0 equivalent) in DCM (2.0mL) solution add methyl carbonate methoxycarbonyl ester (16.12mg, 0.17mmol, 1.0 equivalent CAS4525-33-1) for 30 minutes. After the addition is complete, the mixture is stirred at RT for 12 hours. The reaction mixture is poured into water (10mL) and the layers are separated. The aqueous phase is extracted with EtOAc (3x 10mL). The combined extracts are washed with brine (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The remaining crude product is purified by preparative HPLC (neutral). After being dried by lyophilization, a light yellow oily title compound (30mg, 0.04mmol, 56% yield) is obtained. MS (ESI): 807.3 [M+H] +

[1097] Step g) 3,3-difluoro-5-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid methyl ester

[1098]

[1099] Analogous to General Procedure 11c, 3,3-difluoro-5-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ was prepared. 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid methyl ester (14 mg, 0.02 mmol) was prepared and the title compound (9.2 mg, 0.01 mmol, 70% yield) was obtained as a white solid as a hydrochloride salt. MS (ESI): 707.2 [M+H] +

[1100] Example 58

[1101] 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester

[1102]

[1103] Step a) (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -7-Methyl formate

[1104]

[1105] Analogously to General Procedure 10, (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-Methyl formate (1000 mg, 2.84 mmol, CAS 2089150-62-7) was prepared and the title compound (900 mg, 2.34 mmol, 78% yield) was obtained as a light yellow solid. MS (ESI): 285.1 [M+H-Boc] +

[1106] Step b) (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-Methyl formate

[1107]

[1108] Analogously to General Procedure 1a, (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -7-formic acid methyl ester (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) were prepared and the title compound (480 mg, 0.77 mmol, 83% yield) was obtained as a white solid. MS (ESI): 620.3 [M+H] + .

[1109] Step c) (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-Formic acid

[1110]

[1111] Analogously to General Procedure 2, (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ was prepared. 6 ,5-Benzothiazepine -7-Methyl formate (430 mg, 0.69 mmol) was prepared and the title compound (450 mg, 0.74 mmol, 94% yield) was obtained as a light yellow solid. MS (ESI): 606.3 [M+H] + .

[1112] Step d) N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1113]

[1114] Analogously to General Procedure 3, (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ was prepared. 6 ,5-Benzothiazepine -7-carboxylic acid (560 mg, 0.9 mmol) was used to prepare the title compound (310 mg, 0.5 mmol, 54% yield) as a light yellow solid. MS (ESI): 620.3 [M+H] + .

[1115] Step e) 1-[[[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-Carbonyl]amino]carbamoyl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester

[1116]

[1117] Analogously to General Procedure 4a, N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ was used. 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (150 mg, 0.24 mmol) and 3-tert-butoxycarbonyl-3-azabicyclo[3.1.1]heptane-1-carboxylic acid (75.9 mg, 0.31 mmol, 1.3 equivalents CAS1000931-22-5) were prepared and the title compound (310 mg, 0.39 mmol, 74% yield) was obtained as a light yellow solid. MS (ESI): 843.4 [M+H] + .

[1118] Step f) 1-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester

[1119]

[1120] Analogously to General Procedure 5a, 1-[[[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-carbonyl]amino]carbamoyl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (330 mg, 0.37 mmol) was prepared and the title compound (150 mg, 0.18 mmol, 46% yield) was obtained as a light yellow solid. MS (ESI): 825.1 [M+H] + .

[1121] Step g) (3R)-3-amino-7-[5-(3-azabicyclo[3.1.1]heptane-1-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[1122]

[1123] Analogous to General Procedure 11c, 1-[5-[(3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (145 mg, 0.18 mmol) was prepared and the title compound (70 mg, 0.1 mmol, 54% yield) was obtained as a light yellow solid. MS (ESI): 625.3 [M+H] + .

[1124] Step h) 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester

[1125]

[1126] To (3R)-3-amino-7-[5-(3-azabicyclo[3.1.1]heptane-1-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ at RT 6 ,5-Benzothiazepine -4-ketone (60.0mg, 0.08mmol, 1.0 equivalent) and N, N-diisopropylethylamine (42.26mg, 0.33mmol, 4.0 equivalent) in DMF (1mL) solution was added dimethyl dicarbonate (11mg, 0.08mmol, 1.0 equivalent) and stirred for 2 hours. The reaction mixture was poured into water (10mL) and EtOAc (20ml) was added. The phases were separated and the aqueous phase was extracted with EtOAc (2x). The combined organic phases were washed with brine (5mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The remaining residue was purified by preparative HPLC (HCl) to obtain the title compound (36.5mg, 0.05mmol, 60% yield) as a white solid, which was the hydrochloride salt. MS (ESI): 683.3 [M + H] +

[1127] The examples in the following table were prepared analogously to Example 58 using the appropriate carboxylic acid and benzyl halide building blocks using the general procedures indicated.

[1128]

[1129]

[1130]

[1131] (*) is hydrochloride

[1132] Example 63

[1133] (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-Benzothiazepine -4-Keto

[1134]

[1135] Step a) N-[(3R)-7-[[[2-(Hydroxymethyl)tetrahydrofuran-2-carbonyl]amino]carbamoyl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1136]

[1137] Analogously to general procedure 4a, (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -7-carboxylic acid (Example 32, step a) (260 mg, 676.4 μmol, 1.0 equiv) and 2-hydroxymethyltetrahydrofuran-2-carboxylic acid (CAS: 61449-65-8) were used to prepare the title compound (280 mg, 53% yield) as a white solid. MS (ESI): 413.1 [M-Boc+H] +

[1138] Step b) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1139]

[1140] N-[(3R)-7-[[[2-(Hydroxymethyl)tetrahydrofuran-2-carbonyl]amino]carbamoyl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl] tert-butyl 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 RT for 16 h. The reaction was directly concentrated and purified by column chromatography on silica gel (0% to 80% EtOAc in heptane) to give the title compound (167 mg, 49%) as a white solid. MS (ESI): 571.2 [M-isobutylene + H] +

[1141] Step c) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1142]

[1143] Analogously to General Procedure 5b, N-[(3R)-7-[[[2-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-2-carbonyl]amino]carbamoyl]-1,1,4-trioxo-3,5-dihydro-2H-1λ was used. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (160 mg, 0.255 mmol) was prepared and the title compound (135 mg, 87% yield) was obtained as a white solid. MS (ESI): 609.2 [M+H] +

[1144] Step d) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1145]

[1146] Analogously to General Procedure 1a, 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 was prepared. 6 ,5-Benzothiazepine -3-yl] tert-butyl 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) were used to prepare the title compound as a white solid (57.4 mg, 86% yield). MS (ESI): 805.4 [M+H] +

[1147] 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-Benzothiazepine -4-Keto

[1148]

[1149] 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-Benzothiazepine tert-Butyl-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 1 M HCl in Et 2 O solution (165.12 mg, 221.04 uL, 221.04 μmol, 3.1 eq) and stirred for 1 hour. Then TBAF (1 M solution in THF, 18.6 mg, 0.071 mmol, 1.0 eq) was added and stirring continued for 2 hours. The reaction was concentrated under reduced pressure and directly purified by reverse phase preparative HPLC to give the title compound as a white powder (13.5 mg, 32%). MS (ESI): 591.4 [M+H] + .

[1150] Example 64

[1151] (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-Benzothiazepine -4-Keto

[1152]

[1153] Step a) 2-ethoxy-2,3,3,3-tetrafluoro-propionyl hydrazide

[1154]

[1155] To a solution of 2-ethoxy-2,3,3,3-tetrafluoropropionic acid (200 mg, 0.92 mmol, 1 eq., CAS 10186-67-1) in EtOH (1.5 ml) was added hydrazine monohydrate (54.25 mg, 1.1 mmol, 1.2 eq.) and the mixture was heated to 80 °C for 8 hours. The resulting colorless solution was concentrated under reduced pressure and dried under high vacuum to give 2-ethoxy-2,3,3,3-tetrafluoro-propanoic acid hydrazide (119 mg, 60%) as a white solid. MS (ESI): 205.1 [M+H] +

[1156] Step b) N-[(3R)-7-[[(2-ethoxy-2,3,3,3-tetrafluoro-propionyl)amino]carbamoyl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1157]

[1158] Analogously to General Procedure 4a, (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine was used. -7-carboxylic acid (145 mg, 0.257 mmol, 1 eq., Example 54, step b) and 2-ethoxy-2,3,3,3-tetrafluoro-propionyl hydrazide (68.16 mg, 0.334 mmol, 1.3 eq.) were used to prepare the title compound (247 mg, 99%) as a yellow oil. MS (ESI): 749.3 [MH]

[1159] Step c) 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1160]

[1161] Analogously to General Procedure 5b, N-[(3R)-7-[[(2-ethoxy-2,3,3,3-tetrafluoro-propionyl)amino]carbamoyl]-4-oxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine was used. -3-yl] tert-butyl carbamate (247 mg, 0.247 mmol) was prepared and the white title compound (119 mg, 65%) was obtained. MS (ESI): 677.3 [M-isobutylene + H] +

[1162] Step d) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1163]

[1164] Analogous to General Procedure 10, 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-benzothiazepine was used. -3-yl] tert-butyl carbamate (112 mg, 0.15 mmol) was prepared and the title compound (96 mg, 83%) was obtained as a white solid. MS (ESI): 709.2 [M-isobutylene + H] +

[1165] 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-Benzothiazepine -4-Keto

[1166]

[1167] Analogous to General Procedure 11a, 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 was prepared. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (96 mg, 0.126 mmol) was prepared and the title compound (67.5 mg, 76%) was obtained as a white solid as a hydrochloride salt. MS (ESI): 665.5 [M+H] +

[1168] 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-methoxyethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine

[1169] -4-Keto

[1170]

[1171] Step a) N-[(3R)-4-oxo-7-[[(2,3,3,3-tetrafluoro-2-methoxy-propionyl)amino]carbamoyl]-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1172]

[1173] Analogously to General Procedure 4b, (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-propionyl hydrazide (505 mg, 2.7 mmol, 1.0 equiv, Example 64, step a) were used to prepare and obtain the title compound as a light yellow solid (1300 mg, 95% yield). MS (ESI) 509.2 [MH] -

[1174] Step b) 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1175]

[1176] Analogously to General Procedure 4b, N-[(3R)-4-oxo-7-[[(2,3,3,3-tetrafluoro-2-methoxy-propionyl)amino]carbamoyl]-3,5-dihydro-2H-1,5-benzothiazepine was used. -3-yl] tert-butyl carbamate (400 mg, 0.78 mmol, 1.0 equiv) was prepared and the title compound (560 mg, 116% equiv) was obtained as a light yellow oil, which was used without further purification. MS (ESI) 437.1 [M-isobutylene + H] +

[1177] Step c) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1178]

[1179] Analogous to General Procedure 10, 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-benzothiazepine was used. -3-yl] tert-butyl carbamate (280 mg, 0.57 mmol, 1. equivalent) was used to prepare the title compound, and a light yellow solid (500 mg) containing the title compound was obtained. MS (ESI) 468.9 [M-isobutylene + H] +

[1180] Step d) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1181]

[1182] Analogously to General Procedure 1a, 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 was used. 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (15 mg, 0.029 mmol, 1 eq.) and intermediate 14 (10.4 mg, 0.037 mmol, 1.3 eq.) were used to prepare the title compound (11 mg, 53% yield) as a white powder. MS (ESI): 723.2 [M-isobutylene + H] +

[1183] 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-Benzothiazepine -4-Keto

[1184]

[1185] Analogously to General Procedure 11c, 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 was prepared. 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (11 mg, 0.015 mmol) was prepared and the title compound (8.4 mg, 84% yield) was obtained as a white powder as a hydrochloride salt. MS (ESI): 623.1 [M+H] +

[1186] The preparation of Example 66 in the following table was prepared analogously to Example 65 using the appropriate benzyl bromide building blocks.

[1187]

[1188] * Hydrochloride

[1189] Example 68 (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-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-Benzothiazepine -

[1190] 4-Keto

[1191]

[1192] Step a) N-[(3R)-1,1,4-trioxo-7-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1193]

[1194] To N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (160 mg, 0.416 mmol, 1.0 equiv., Example 7, step b) in THF (4.16 mL) 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 RT for 3 hours. The reaction mixture was poured onto water and 1N HCl was added to reach 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 was purified by column chromatography on silica gel (10% to 70% EtOAc in heptane) to give the title compound (183 mg, 87%) as a light yellow powder. MS (ESI): 409.1 [MH]

[1195] Step b) N-[(3R)-7-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1196]

[1197] Analogous to General Procedure 13, N-[(3R)-1,1,4-trioxo-7-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (33 mg, 0.06 mmol) and difluoropiperidin hydrochloride (171 mg, 1.08 mmol, 2.5 equivalents, CAS 144230-52-4) were used to prepare the title compound (192 mg, 59%) as a yellow solid. MS (ESI): 514.2 [M+H] +

[1198] Step c) N-[(3R)-7-[5-(4,4-difluoro-1-piperidinyl)-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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1199]

[1200] Analogously to General Procedure 1a, N-[(3R)-7-[5-(4,4-difluoro-1-methyl-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ was used. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (20.5 mg, 0.04 mmol, 1.0 equiv) and 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (15.94 mg, 0.052 mmol, 1.3 equiv, CAS 2093101-98-3) were used to prepare the title compound (15.1 mg, 51%) as a white solid. MS (ESI): 740.4 [M+H] +

[1201] Step d) (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-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-Benzothiazepine -4-Keto

[1202]

[1203] Analogously to General Procedure 11a, N-[(3R)-7-[5-(4,4-difluoro-1-piperidinyl)-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 was prepared. 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (15.1 mg, 0.02 mmol) was prepared and the title compound (3.3 mg, 24%) was obtained as a white solid as a hydrochloride salt. MS (ESI): 640.5 [M+H] +

[1204] The examples in the following table were prepared analogously to Example 68 using the appropriate benzyl halide or amine building blocks.

[1205]

[1206]

[1207]

[1208] (*) is hydrochloride

[1209] Example 72

[1210] (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-Benzothiazepine -4-Keto

[1211]

[1212] Step a) N-[(3R)-7-(5-amino-1,3,4-oxadiazol-2-yl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1213]

[1214] N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl] tert-butyl 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) were stirred overnight at RT. 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 (3x). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (381 mg, 98%) as an orange solid. MS (ESI): 378.2 [M+H] +

[1215] Step b) N-[(3R)-7-(5-bromo-1,3,4-oxadiazol-2-yl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1216]

[1217] N-[(3R)-7-(5-amino-1,3,4-oxadiazol-2-yl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl] tert-butyl carbamate (381mg, 1.01mmol, 1.0 equivalent) in acetonitrile (5mL) was degassed with argon for 5 minutes. Copper (II) bromide (338mg, 1.51mmol, 1.5 equivalent) and isoamyl nitrite (141.9mg, 163.12uL, 1.21mmol, 1.2 equivalent) were then added at RT to form a dark green suspension. The reaction mixture was stirred for 1 hour. The reaction mixture was diluted with EtOAc (100ml) and 1N HCl (100ml). Each phase was separated, and the aqueous phase was extracted with EtOAc (2x 150ml). 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% to 100% EtOAc in heptane) to obtain the title compound (102mg, 23%) as an orange solid. MS (ESI): 439.1 [MH]

[1218] Step c) N-[(3R)-7-(5-bromo-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1219]

[1220] Analogous to general procedure 10, N-[(3R)-7-(5-bromo-1,3,4-oxadiazol-2-yl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl] tert-butyl carbamate (905 mg, 2.05 mmol) was prepared and the title compound (524 mg, 53%) was obtained as a white solid. MS (ESI): 417.0 [M-isobutylene + H] +

[1221] Step d) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1222]

[1223] Analogous to general procedure 13, N-[(3R)-7-(5-bromo-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (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) were used to prepare and obtain the title compound (30.5 mg, 43%) as a yellow amorphous solid. MS (ESI): 514.2 [M+H] +

[1224] Step e) 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-Benzothiazepine -3-yl]carbamic acid tert-butyl ester

[1225]

[1226] Analogously to General Procedure 1a, 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 was used. 6 ,5-Benzothiazepine -3-yl] tert-butyl carbamate (30.5 mg, 0.023 mmol, 1.0 equiv) and 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (10.1 mg, 0.033 mmol, 1.5 equiv, CAS 2093101-98-3) were used to prepare the title compound (5.7 mg, 32%) as a white solid. MS (ESI): 740.2 [M+H] +

[1227] 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-Benzothiazepine -4-Keto

[1228]

[1229] Analogously to General Procedure 11a, 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 was prepared. 6 ,5-Benzothiazepine -3-yl]carbamic acid tert-butyl ester (5.7 mg, 0.007 mmol) was prepared and the title compound (3.2 mg, 66%) was obtained as a white solid. MS (ESI): 640.3 [M+H] +

[1230] The examples in the following table were prepared analogously to Example 72 using the appropriate amine and benzyl halide building blocks using the general procedures indicated.

[1231]

[1232]

[1233]

[1234] (*) is hydrochloride

[1235] Example 83

[1236] (3R)-3-amino-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-[[4-(6-methoxy-3-pyridyl)phenyl]

[1237] methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto

[1238]

[1239] Step a) (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-Methyl formate

[1240]

[1241] To (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine at RT To a solution of methyl 7-formate (300 mg, 0.851 mmol, 1 eq., CAS 2089150 -62-7) in 1,4-dioxane (1.5 mL) was added a solution of 4M HCl in dioxane (2.36 g, 1.97 mL, 7.88 mmol, 9.2 eq.) 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 with two 40 ml portions of EtOAc. The combined organic layers were washed with a 40 ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude yellow solid (141.7 mg). The crude solid was suspended in DCM (3 mL). DIEA (165 mg, 223 uL, 1.28 mmol, 1.5 equiv) and benzyl chloroformate (95.3 mg, 79.8 uL, 0.56 mmol, 0.65 equiv) were added at RT 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% to 40% EtOAc in heptane) to give (3R)-3-(benzyloxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine as a white solid -7-Methyl formate (196 mg, 59%). MS (ESI): 387.2 [M+H] +

[1242] Step b) (3R)-3-(Benzyloxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-Formic acid

[1243]

[1244] Analogously to General Procedure 2, (3R)-3-(benzyloxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-Methyl formate (320 mg, 0.82 mmol) was prepared and the title compound (364 mg, 99%) was obtained as a yellow solid. MS (ESI): 373.1 [M+H] +

[1245] Step c) N-[(3R)-7-[(2,2-dimethylpropionylamino)carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]benzyl carbamate

[1246]

[1247] Analogously to General Procedure 4a, (3R)-3-(benzyloxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-carboxylic acid (364 mg, 0.81 mmol, 1 eq.) and 2,2-dimethylpropanoic acid hydrazide (131.93 mg, 1.14 mmol, 1.4 eq.) were used to prepare the title compound (687 mg, 99%) as a light yellow solid. MS (ESI): 471.2 [M+H] +

[1248] Step d) N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl]benzyl carbamate

[1249]

[1250] Analogously to General Procedure 5a, N-[(3R)-7-[(2,2-dimethylpropionylamino)carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine was used. -3-yl] benzyl carbamate (687 mg, 0.803 mmol) was prepared and the title compound (321 mg, 85%) was obtained as a yellow oil. MS (ESI): 453.2 [M+H] +

[1251] Step e) N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-trione-3,5-dihydro-2H-1?6,5-benzothiazepine -3-yl]benzyl carbamate

[1252]

[1253] Analogous to general procedure 10, N-[(3R)-7-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1,1,4-trioxo-3,5-dihydro-2H-1λ 6 ,5-Benzothiazepine -3-yl] benzyl carbamate (321 mg, 0.65 mmol) was prepared and the title compound (182 mg, 57%) was obtained as a white solid. MS (ESI): 485.2 [M+H] +

[1254] Step f) 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-Benzothiazepine -3-yl]benzyl carbamate [12...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace; R 2 is selected from hydrogen and halogen; R 4 Selected from C 5-14 -aryl and 5- to 14-membered heteroaryl, wherein R 4 Optionally, one or more R 11 replace; R 10 Selected from: i)C 1-10 -alkyl, which is optionally substituted with one or more halogen, amino, hydroxyl, C 1-6 - substituted with alkoxy, 3- to 10-membered cycloalkyl, phenyl, or cyano; ii) C 3-10 - cycloalkyl, which is optionally substituted by one or more halogen, cyano, amino; iii) a 3- to 10-membered heterocyclic group, which is optionally substituted with one or more halogens, C 1-10 -alkyl, amino, halo-C 1-6 -alkyl, hydroxyl, cyano, -C(O)O-(R 10q ), C 3-10 -cycloalkyl substituted, wherein C 1-10 -alkyl is optionally substituted with one or more hydroxyl groups, C 1-6 - alkoxy substitution; iv)-N(R 10e R 10f ); v) heteroaryl, which is optionally substituted with one or more C 1-10 -Alkyl, halogen substituted; R 10e and R 10f Each independently selected from: i) Hydrogen; ii) C 1-6 - alkyl, which is optionally substituted with one or more cyano, halogen, hydroxyl; iii) C 3-10 -cycloalkyl, which is optionally substituted with one or more halogen, C 1-10 - alkyl substitution; R 10q C 1-5 -alkyl, where C 1-5 - alkyl is optionally substituted with one or more hydroxyl groups; R 11 Selected from: i) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more C 1-6 -alkyl, C 3-10 Cycloalkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkoxy substituted, where C 3-10 Cycloalkyl is optionally substituted with one or more halogens; ii) phenyl, which is optionally substituted with one or more C 1-6 -alkoxy, -OH, halo-C 1-6 -alkyl substitution.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from: (i) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more C 1-6 -alkyl, C 3-10 Cycloalkyl, halo-C 1-6 - alkyl substitution; (ii) phenyl, optionally substituted with one or more C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -Alkoxy substitution.

3. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, wherein R 2 Selected from hydrogen and fluorine.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 4 is selected from phenyl and pyridyl, wherein R 4 Optionally, one or more R 11 replace.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 10 is tert-butyl, pyrrolidinyl, tetrafluoro-methoxy-ethyl, methyl-propionitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, aminocyclohexyl, cyclopropanecarbonitrile, difluoro-piperidinyl, ethoxy-tetrafluoro-ethyl, (hydroxymethyl)tetrahydrofuranyl, azabicyclo[3.1.1]heptane-methylformate, amino-trifluoromethyl-ethyl, difluoro-piperidinyl-methylformate, fluoro-methyl-piperidinyl, aminooxetanyl, (difluoro-methyl-cyclobutyl)aminoacyl, cyclopropyltetrahydrofuranyl, amino-dimethyl-propyl, propionitrile, isopropylaminoacyl, Fluoro-methyl-pyridyl, methyl-pyridyl, chloro-pyridyl, tetrafluoroethyl, trifluoro-dihydroxy-ethyl, hydroxy-(trifluoromethyl)propyl, pentafluoroethyl, trifluoro-dimethyl-ethyl, trifluoro-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, dioxaazabicyclo[3.3.1]nonanyl, morpholino-carbonitrile , (methoxymethyl)morpholinyl, (hydroxymethyl)morpholinyl, (hydroxyethyl)morpholinyl, oxazepanyl, difluoro-(methoxyethyl)-piperidinyl, 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-aminoacyl-acetonitrile, cyclopropyl(difluoroethyl)amino, difluoropyrrolidinyl, (trifluoro-methyl-ethyl)amino, trifluoroethylamino, methyl(trifluoroethyl)amino, ethyl-difluoro-piperidinyl, dimethyl-pyridinyl, trifluoro-methoxy-ethyl.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 10 is tert-butyl, tetrafluoro-methoxy-ethyl, methyl-propionitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, cyclopropanecarbonitrile, difluoro-piperidinyl, (hydroxymethyl)tetrahydrofuranyl, amino-trifluoromethyl-ethyl, aminooxetanyl, cyclopropyltetrahydrofuranyl, propionitrile, aminocyclohexyl.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 11 Selected from (hydroxymethyl)phenyl, (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridinyl, (trifluoromethyl)phenyl, methoxyphenyl, (trifluoromethyl)pyridinyl, dimethylpyrazolyl, tert-butyl-oxadiazolyl, methyl-oxadiazolyl, methylpyrazolyl, (difluoromethyl)-oxadiazolyl, (trifluoromethyl)oxadiazolyl, methyl-(trifluoromethyl)pyrazolyl, (trifluoromethyl)pyrazolyl, (trifluoromethyl)isoxazolyl, (trifluoromethyl-ethyl)oxadiazolyl, (trifluoroethyl)oxadiazolyl, (trifluoromethoxy)phenyl, cyclopropyl-triazolyl, (trifluoromethoxy)pyridinyl, (trifluoromethoxy)pyrimidinyl, (pentafluoroethoxy)pyridinyl, (trifluoromethoxy)pyridinyl, methyl-(trifluoromethoxy)pyrazolyl.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 11 Selected from (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridinyl, methoxyphenyl, (trifluoromethoxy)pyridinyl, (trifluoromethoxy)pyrimidinyl, (pentafluoroethoxy)pyridinyl, (trifluoromethoxy)pyridinyl, methyl-(trifluoromethoxy)pyrazolyl.

9. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace; R 2 is selected from hydrogen and fluorine; R 4 is selected from phenyl and pyridyl, wherein R 4 Optionally, one or more R 11 replace; R 10 Selected from: i)C 1-10 -alkyl, which is optionally substituted with one or more halogen, amino, hydroxyl, C 1-6 - substituted with alkoxy, 3- to 10-membered cycloalkyl, phenyl, or cyano; ii) C 3-10 - cycloalkyl, which is optionally substituted by one or more halogen, cyano, amino; iii) a 3- to 10-membered heterocyclic group, which is optionally substituted with one or more halogens, C 1-10 -alkyl, amino, halo-C 1-6 -alkyl, hydroxyl, cyano, -C(O)O-(R 10q ), C 3-10 -cycloalkyl substituted, wherein C 1-10 -alkyl is optionally substituted with one or more hydroxyl groups, C 1-6 - alkoxy substitution; iv)-N(R 10e R 10f ); v) heteroaryl, which is optionally substituted with one or more C 1-10 -Alkyl, halogen substituted; R 10e and R 10f Each independently selected from: i) Hydrogen; ii) C 1-6 - alkyl, which is optionally substituted with one or more cyano, halogen, hydroxyl; iii) C 3-10 -cycloalkyl, which is optionally substituted with one or more halogen, C 1-10 - alkyl substitution; R 10q C 1-5 -alkyl, where C 1-5 - alkyl is optionally substituted with one or more hydroxyl groups; R 11 Selected from: iv) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more C 1-6 -alkyl, C 3-10 Cycloalkyl, halo-C 1-6 - alkyl substitution; v) phenyl, which is optionally substituted with one or more C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -Alkoxy substitution.

10. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace; R 2 is selected from hydrogen and fluorine; R 4 is selected from phenyl and pyridyl, wherein R 4 Optionally, one or more R 11 replace; R 10 is tert-butyl, pyrrolidinyl, tetrafluoro-methoxy-ethyl, methyl-propionitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, aminocyclohexyl, cyclopropanecarbonitrile, difluoro-piperidinyl, ethoxy-tetrafluoro-ethyl, (hydroxymethyl)tetrahydrofuranyl, azabicyclo[3.1.1]heptane-methylformate, amino-trifluoromethyl-ethyl, difluoro-piperidinyl-methylformate, fluoro-methyl-piperidinyl, aminooxetanyl, (difluoro-methyl-cyclobutyl)aminoacyl, cyclopropyltetrahydrofuranyl, amino-dimethyl-propyl, propionitrile, isopropylaminoacyl, Fluoro-methyl-pyridyl, methyl-pyridyl, chloro-pyridyl, tetrafluoroethyl, trifluoro-dihydroxy-ethyl, hydroxy-(trifluoromethyl)propyl, pentafluoroethyl, trifluoro-dimethyl-ethyl, trifluoro-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, dioxaazabicyclo[3.3.1]nonanyl, morpholino-carbonitrile , (methoxymethyl)morpholinyl, (hydroxymethyl)morpholinyl, (hydroxyethyl)morpholinyl, oxazepanyl, difluoro-(methoxyethyl)-piperidinyl, 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-aminoacyl-acetonitrile, cyclopropyl(difluoroethyl)amino, difluoropyrrolidinyl, (trifluoro-methyl-ethyl)amino, trifluoroethylamino, methyl(trifluoroethyl)amino, ethyl-difluoro-piperidinyl, dimethyl-pyridinyl, trifluoro-methoxy-ethyl; R 11 Selected from (hydroxymethyl)phenyl, (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridinyl, (trifluoromethyl)phenyl, methoxyphenyl, (trifluoromethyl)pyridinyl, dimethylpyrazolyl, tert-butyl-oxadiazolyl, methyl-oxadiazolyl, methylpyrazolyl, (difluoromethyl)-oxadiazolyl, (trifluoromethyl)oxadiazolyl, methyl-(trifluoromethyl)pyrazolyl, (trifluoromethyl)pyrazolyl, (trifluoromethyl)isoxazolyl, (trifluoromethyl-ethyl)oxadiazolyl, (trifluoroethyl)oxadiazolyl, (trifluoromethoxy)phenyl, cyclopropyl-triazolyl, (trifluoromethoxy)pyridinyl, (trifluoromethoxy)pyrimidinyl, (pentafluoroethoxy)pyridinyl, (trifluoromethoxy)pyridinyl, methyl-(trifluoromethoxy)pyrazolyl.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace; R 2 is selected from hydrogen and fluorine; R 4 is selected from phenyl and pyridyl, wherein R 4 Optionally, one or more R 11 replace; R 10 is tert-butyl, tetrafluoro-methoxy-ethyl, methyl-propionitrile, difluoromorpholinyl, oxa-azaspiro[2.5]octan-yl, (trifluoromethyl)morpholinyl, cyclopropanecarbonitrile, difluoro-piperidinyl, (hydroxymethyl)tetrahydrofuranyl, amino-trifluoromethyl-ethyl, aminooxetanyl, cyclopropyltetrahydrofuranyl, propionitrile, aminocyclohexyl; R 11 Selected from (trifluoromethyl)oxadiazolyl, cyclopropyl-oxadiazolyl, (trifluoromethyl)pyridinyl, methoxyphenyl, (trifluoromethoxy)pyridinyl, (trifluoromethoxy)pyrimidinyl, (pentafluoroethoxy)pyridinyl, (trifluoromethoxy)pyridinyl, methyl-(trifluoromethoxy)pyrazolyl.

12. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, selected from: (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto 2-[5-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (3R)-3-amino-7-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-[[6-[4-(hydroxymethyl)phenyl]-3-pyridinyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-(3-aminooxetane-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-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-(3-aminooxetane-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-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-(3-aminooxetane-3-yl)-1,2,4-oxadiazol-3-yl]-8-fluoro-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (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-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto 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-Benzothiazepine -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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto(*) (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-Benzothiazepine -4-Keto 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]propionitrile (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile (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-Benzothiazepine -4-Keto 2-[5-[(3R)-3-amino-5-[[4-[5-(difluoromethyl)-2-pyridyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile (3R)-3-amino-7-[5-(1-aminocyclohexyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto 2-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-5-[[4-[5-(4,4-difluoro-1-piperidinyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)oxazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile(*) 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-5-[[4-[5-(difluoromethoxy)-2-pyridinyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-5-[[4-[4-(difluoromethoxy)-2-pyridinyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[2-(trifluoromethyl)-4-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)pyrazin-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[6-(trifluoromethyl)-3-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[1-(trifluoromethyl)pyrazol-4-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)pyrimidin-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-5-[[4-(5-cyclopropyl-2-pyridyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethoxy)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)oxazol-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-5-[[4-(5-methoxy-2-pyridyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)pyrimidin-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(1,1,2,2,2-pentafluoroethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(2,2,2-trifluoroethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[6-(trifluoromethoxy)-3-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-5-[[4-[4-methyl-5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)triazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile (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-1λ6,5-benzothiazepine -4-Keto (3R)-3-amino-7-[5-(3-methyloxetane-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-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-(3-methyloxetan-3-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-(3-fluoro-1-methyl-3-piperidinyl)-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-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-(3-fluoro-1-methyl-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-(3-fluoro-1-methyl-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid methyl ester 3,3-Difluoro-5-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylic acid methyl ester 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester 1-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl heptane-3-carboxylate 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl heptane-3-carboxylate 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl heptane-3-carboxylate 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]cyclopropanecarbonitrile 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl heptane-3-carboxylate 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl 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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto ((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-methoxyethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-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-Benzothiazepine -4-Keto (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-7-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (3R)-3-amino-5-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-7-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-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-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-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-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto 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-Benzothiazepine -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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (3R)-3-amino-1,1-dioxo-7-[5-[2-(trifluoromethyl)morpholin-4-yl]-1,3,4-oxadiazol-2-yl]-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-dimethylethyl)-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]cyclobutanecarbonitrile 4-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2,2-dimethyl-propionitrile 3-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-methyl-butyronitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-ethyl-butyronitrile 3-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto 4-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -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-piperidinyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-[5,5-difluoro-1-(2-methoxyethyl)-3-piperidinyl]-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-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-[5,5-difluoro-1-(2-methoxyethyl)-3-piperidinyl]-1,3,4-oxadiazol-2-yl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto (3R)-3-Amino-7-[5-(3-aminooxetane-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-1λ6,5-benzothiazepine -4-Keto (3R)-3-amino-7-[5-(2-chloro-3-pyridinyl)-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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-1,1-dioxo-7-[5-[2-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto.

13. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, selected from: (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-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-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-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-(3-aminooxetane-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-Benzothiazepine -4-Keto 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-Benzothiazepine -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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]propionitrile (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile (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-Benzothiazepine -4-Keto 2-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto 1-[5-[(3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl heptane-3-carboxylate 1-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl heptane-3-carboxylate 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl 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-Benzothiazepine -4-Keto (3R)-3-amino-7-[5-(4,4-difluoro-1-piperidinyl)-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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto (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-Benzothiazepine -4-Keto 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile (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-Benzothiazepine -4-Keto 2-[5-[(3R)-3-amino-8-fluoro-1,1,4-trioxo-5-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile (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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -4-Keto 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)pyrimidin-2-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(1,1,2,2,2-pentafluoroethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ 6 ,5-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-ethyl-butyronitrile, 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-Benzothiazepine -7-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile.

14. A method for preparing a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, the method comprising: Where R 1 , R 2 and R 4 As defined in any one of claims 1 to 13 and PG is an amino protecting group, reacted with a suitable deprotecting agent to form the compound of formula (I).

15. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, which is prepared according to the method according to claim 14.

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

19. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use in treating, preventing and / or delaying the progression of cancer.

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

21. The compound for use according to claim 19 or 20, wherein the cancer is selected from the group consisting of: B-cell acute lymphoid leukemia, T-cell acute lymphoid leukemia, acute lymphoid 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 disorders, MALT lymphoma, mantle cell Lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, 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 treating, preventing and / or delaying the progression of cancer.

23. 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 treating, preventing and / or delaying the progression of cancer.

24. A method for treating, preventing and / or delaying the progression of cancer, the method 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. A method for inhibiting the activity of at least one diacylglycerol kinase selected from DGKα and DGKζ, the method 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 herein described.

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