Bicyclic tetrahydrothiazepine derivatives

Abstract

The present invention relates to novel bicyclic tetrahydrothiazepine derivatives having the general formula (I): TIFF2025526727000187.tif44170 (in the formula, Y, R 1 , R 2 and R 4 is as defined herein), compositions comprising the compounds, methods of making the compounds, and methods of using the compounds are provided.

Description

[Technical Field]

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

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

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

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

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

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

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

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

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

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

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

[0012] A first object of the present invention is to provide a compound of formula (I) TIFF2025526727000002.tif38170 (in the formula, Y is S(O), S(O)2 and S(O)N(R y ) and R 1 is a 5-membered heteroaryl, and R 1 is one or more R which may be the same or different 10 may be substituted with R 2 is selected from hydrogen and halogen; R 4 is C 5-14-aryl and 5- to 14-membered heteroaryl; R 4 is one or more R which may be the same or different 11 may be substituted with R 10 is -C(R 10a R 10b )2-S(O)2(R 10c ) and R 10a and R 10b are each independently hydrogen or C 1-6 -alkyl, or R 10a and R 10b together with the carbon atoms to which they are attached, form C 3-6 - forming a cycloalkyl, R 10c is hydrogen, C 1-6 -Alkyl, C 3-6 -cycloalkyl, -N(C 1-6 -alkyl), halo-C 1-6 -alkyl, and phenyl, wherein phenyl is selected from one or more halogens, or C 1-6 - optionally substituted with alkyl, or R 10a and R 10c together with the carbon and sulfur atoms to which they are attached form a 3- to 10-membered heterocyclyl; R 11 teeth, i) halogens, ii) one or more halo-C 1-6 -Alkyl, C 3-10 -3-10 membered heterocyclyl optionally substituted by cycloalkyl; iii) one or more halogens, C 1-6 -Alkyl, Halo-C 1-6 -Alkyl, C 3-10 -cycloalkyl, C 1-6 -5-6 membered heteroaryl optionally substituted with haloalkoxy; iv) one or more halogens, cyano, C 1-6 -alkoxy, C 1-6 -haloalkyl, C 1-6-phenyl, optionally substituted with alkyl; v)-O(R 11a ), vi)-N(R 11g R 11h ), and vii)-S(R 11k ) is selected from R 11a is C 1-12 -Alkyl, Halo-C 1-6 -Alkyl, C 3-7 -cycloalkyl, 3-10 membered -(C 1-6 -alkyl)heterocyclyl, phenyl and -C 1-6 -alkyl-phenyl, wherein C 1-12 -Alkyl, C 3-7 -cycloalkyl, phenyl and -C 1-6 -Alkyl-phenyl is substituted with one or more halogens, C 1-6 -Alkyl, Halo-C 1-6 -Alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, R 11g and R 11h are each independently hydrogen, C 1-6 -alkyl, -(C 1-6 -alkyl)phenyl; R 11k is hydrogen and halo-C 1-6 -alkyl, R y is hydrogen and C 1-6 -alkyl) or a pharmaceutically acceptable salt thereof.

[0013] A second object of the present invention is a process for preparing a compound of formula (I) above, or a pharmaceutically acceptable salt thereof, comprising the steps of: TIFF2025526727000003.tif39170 (in the formula, Y, R 1 , R 2 and R 4is as defined above and PG is an amino protecting group) with a suitable deprotecting agent to form said compound of formula (I).

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

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

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. 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.

[0017] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0018] The nomenclature used in this application is based on IUPAC systematic nomenclature unless otherwise indicated. DETAILED DESCRIPTION OF THE INVENTION

[0019] definition "Alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Unless otherwise specified, an alkoxy group contains 1 to 12 carbon atoms ("C 1-12 -alkoxy"), preferably 1 to 10 carbon atoms ("C 1-10 -alkoxy"), more preferably 1 to 6 carbon atoms ("C 1-6In some preferred embodiments, alkoxy groups contain 1 to 4 carbon atoms. In still other embodiments, alkoxy groups contain 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0020] "Alkoxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced with an alkoxy group. Preferably, "alkoxyalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group, most preferably one hydrogen atom, have been replaced with an alkoxy group. Particularly preferred, but non-limiting, examples of alkoxyalkyl are methoxymethyl and 2-methoxyethyl.

[0021] "Alkyl" refers to an alkyl group having a specified number of carbon atoms (i.e., C1- 10 "C1-" refers to a saturated, linear (i.e., unbranched) or branched monovalent hydrocarbon chain having from 1 to 10 carbon atoms, or a combination thereof. Particular alkyl groups are those having from 1 to 20 carbon atoms ("C1- 20 alkyl"), those having 1 to 12 carbon atoms ("C1- 12 alkyl"), those having 1 to 10 carbon atoms ("C1- 10 alkyl"), those having 1 to 8 carbon atoms ("C1-8 alkyl"), those having 1 to 6 carbon atoms ("C1-6 alkyl"), those having 2 to 6 carbon atoms ("C2-6 alkyl"), or those having 1 to 4 carbon atoms ("C 1-4 Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl; homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0022] "Alkynyl" refers to an alkyl group having the specified number of carbon atoms (i.e., C2-10 "C" refers to an unsaturated, linear (i.e., unbranched) or branched monovalent hydrocarbon chain having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C), or combinations thereof. Particular alkynyl groups are those having 2 to 20 carbon atoms ("C 2-20 alkynyl"), those having 2 to 8 carbon atoms ("C 2-8 alkynyl) with 2 to 6 carbon atoms ("C 2-6 alkynyl) with 2 to 4 carbon atoms ("C 2-4 Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof.

[0023] "Amino," alone or in combination with other groups, refers to NH2.

[0024] "Aminoalkyl" refers to an alkyl group in which one or more of the alkyl group's hydrogen atoms has been replaced with an amino moiety.

[0025] "Aromatic" is a well-known term in the literature, especially in the IUPAC Compendium of Chemical Terminology, 2 nd This shows the conventional concept of aromaticity as defined in "Aromaticity in Organic Compounds: A Brief Description of the Invention," Eds. Blackwell Scientific Publications, Oxford (1997).

[0026] "Aryl" means a cyclic aromatic hydrocarbon moiety having a monocyclic, bicyclic, or tricyclic aromatic ring of 5 to 14 carbon ring atoms ("C 5-14"-aryl"). Bicyclic aryl ring systems include fused bicycles having two fused 5-membered aryl rings (designated 5-5), fused bicycles having a 5-membered aryl ring and a fused 6-membered aryl ring (designated 5-6 and 6-5), and bicycles having two fused 6-membered aryl rings (designated 6-6). Aryl groups can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, and the like. The term "aryl" also includes partially hydrogenated derivatives of cyclic aromatic hydrocarbon moieties, provided that at least one ring of the cyclic aromatic hydrocarbon moiety is aromatic and each is optionally substituted.

[0027] "Cancer" refers to a disease characterized by the presence of a neoplasia or tumor, resulting from the abnormal and uncontrolled growth of cells (such cells are "cancer cells"). As used herein, the term cancer expressly includes, but is not limited to, hepatocellular carcinoma, malignant tumors and hyperproliferative disorders of the colon (colon cancer), lung cancer, breast cancer, prostate cancer, melanoma, and ovarian cancer.

[0028] "Cyano," alone or in combination with other groups, refers to CN (ie, nitrile).

[0029] "Cyanoalkyl" refers to an alkyl group in which one or more of the alkyl group's hydrogen atoms has been replaced with a cyano moiety.

[0030] "Cycloalkyl" refers to monocyclic, bicyclic (including bridged bicyclic and cycloalkyl spiro moieties), or tricyclic rings and 3 to 10 carbon atoms (i.e., (C3-C4) 10(C-C)cycloalkyl) refers to a saturated or partially unsaturated carbocyclic moiety having an alkyl group. The cycloalkyl moiety can be optionally substituted with one or more substituents. In certain embodiments, the cycloalkyl contains 3 to 8 carbon atoms (i.e., (C-C)cycloalkyl). In other certain embodiments, the cycloalkyl contains 3 to 6 carbon atoms (i.e., (C-C)cycloalkyl). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and their partially unsaturated (cycloalkenyl) derivatives (e.g., cyclopentenyl, cyclohexenyl, and cycloheptenyl), bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptanyl, bicyclo[3.1.1]heptenyl, and bicyclo[1.1.1]pentane. The cycloalkyl moieties may be attached in a "spirocycloalkyl" or "cycloalkylspiro" fashion, such as "spirocyclopropyl." TIFF2025526727000004.tif21170

[0031] "EC x " refers to the effective concentration of a particular compound, e.g., in culture medium or plasma, required to obtain x% of the maximum of a particular effect in vitro or in vivo. x Examples of compounds that may be used in the present invention include EC values, which indicate the concentrations in culture medium or plasma of a particular compound required to achieve 20%, 50%, and 100% of the maximum of a particular effect in vitro or in vivo, respectively. 20 , E.C. 50 and E.C. 100"Halo" or "halogen" refers to fluoro, chloro, bromo, and / or iodo. If a residue is substituted with more than one halogen, it may be referred to using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl, etc., refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may, but need not, be the same halo. Thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. Alkyl groups in which one or more hydrogens have been replaced with halo groups are referred to as "haloalkyl," e.g., "C 1-6 A preferred haloalkyl group is trifluoroalkyl (-CF3).

[0032] "Haloalkoxy" refers to an alkoxy group in which at least one halogen replaces each H in the hydrocarbon that makes up the alkyl portion of the alkoxy group. Examples of haloalkoxy groups are difluoromethoxy (-OCHF2) and trifluoromethoxy (-OCF3).

[0033] "Haloalkyl" refers to an alkyl group, as defined above, containing at least one carbon atom substituted with at least one halo group, where halo is as defined herein. Examples of "haloalkyl" groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, and n-butyl, each independently substituted with one or more halo groups, such as fluoro, chloro, bromo, and iodo.

[0034] "Haloaryl" refers to an aryl in which at least one hydrogen is replaced with a halogen.

[0035] "Heteroatom" refers to an atom other than carbon or hydrogen.

[0036] "Heteroaryl" refers to an aromatic heterocyclic monocyclic, bicyclic, or tricyclic ring system of 5 to 14 ring atoms, preferably 5 to 10 ring atoms, and more preferably 5 to 6 ring atoms, containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. In some embodiments, a monocyclic heteroaryl ring may be 5 to 6-membered. Bicyclic heteroaryl ring systems include fused bicycles having two fused 5-membered heteroaryl rings (designated 5-5), fused bicycles having a 5-membered aryl ring and a fused 6-membered heteroaryl ring (designated 5-6 and 6-5), and bicycles having two fused 6-membered aryl rings (designated 6-6). Heteroaryl groups may be optionally substituted as defined herein. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, benzothiophenyl, indolyl, aza-indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, Examples of heteroaryl include benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl and furopyrazinyl. Most preferably, "5-membered heteroaryl" refers to the following groups: TIFF2025526727000005.tif42170

[0037] "Heterocycle" or "heterocyclyl" refers to a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered monocyclic, 7-, 8-, 9-, and 10-membered bicyclic (including bridged bicyclic and cycloalkyl spiro moieties), or 10-, 11-, 12-, 13-, 14-, and 15-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from oxygen, nitrogen, and sulfur within the ring, with the remaining ring atoms being carbon. In some embodiments, the heterocycle is a heterocycloalkyl. In certain embodiments, heterocycle or heterocyclyl refers to a 4-, 5-, 6-, or 7-membered heterocycle. When used in reference to a ring atom of a heterocycle, nitrogen or sulfur may also be in an oxidized form, and the nitrogen may be substituted with one or more (C-C) alkyl or groups. A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Any heterocyclic ring atom can be optionally substituted with one or more substituents as described herein.The example of such saturated or partially unsaturated heterocycle includes but is not limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, pyrrolidine 1-oxide, N-hydroxypiperidine, 1-methylpyrrolidine N-oxide, diazirinyl and quinuclidinyl. The term heterocycle also includes groups in which a heterocycle is fused to one or more aryl, heteroaryl, or cycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[3.1.0]hexanyl, azabicyclo[3.1.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.

[0038] "Hydroxy", alone or in combination with other groups, refers to OH.

[0039] "Hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group have been replaced with a hydroxy moiety. Examples include alcohols and diols.

[0040] "Moiety" and "substituent" refer to an atom or a group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds, thereby forming a part of the molecule.

[0041] When indicating the number of substituents, the term "one or more" refers to a range from one substituent to the highest possible number of substitutions, i.e., replacement of one hydrogen to replacement of all hydrogens by substituents; particularly "one or more" refers to one, two, or three; most particularly "one or more" refers to one or two.

[0042] "Optional" or "optionally" means that the subsequently described event or circumstance may occur but need not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "an aryl group optionally substituted with an alkyl group" means that the alkyl may be present but need not be present, and that the description includes situations where the aryl group is substituted with an alkyl group and situations where the aryl group is not substituted with an alkyl group.

[0043] "Optionally substituted" means unsubstituted or substituted. In general, the substituents can be the same or different.

[0044] "Oxo", alone or in combination with other groups, refers to =O.

[0045] "Pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the free base or free acid, which are not biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, especially hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like.

[0046] Particularly preferred pharmaceutically acceptable salts of compounds of formula (I) are the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and methanesulfonic acid.

[0047] A "protecting group" (PG) refers to a group that selectively blocks a reactive site in a polyfunctional compound so that a chemical reaction, in the sense conventionally associated with synthetic chemistry, can be carried out selectively at an otherwise unprotected reactive site. The protecting group can be removed at an appropriate time. Exemplary protecting groups are amino-protecting, carboxy-protecting, or hydroxy-protecting groups. Particular protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Further particular protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). An even more particular protecting group is tert-butoxycarbonyl (Boc). Exemplary protecting groups and their use in organic synthesis are described, for example, in "Protective Groups in Organic Chemistry" by T.W. Greene and P.G.M. Hutts, 5th Ed., 2014, John Wiley & Sons, NY.

[0048] "Prophylaxis," as used herein, includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition that develops in a mammal, particularly in a human suffering from or susceptible to the condition, disorder or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder or condition.

[0049] "Substituted" refers to the replacement of at least one hydrogen atom of a compound or moiety with another substituent or moiety. Examples of such substituents include, but are not limited to, halogen, -OH, -CN, oxo, alkoxy, alkyl, alkylene, aryl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl, and heterocycle. For example, the term "haloalkyl" refers to the fact that one or more hydrogen atoms of an alkyl (defined below) are replaced with one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.). In one aspect, as used herein, substitution can refer to the replacement of at least one hydrogen atom of a compound or moiety described herein with a halogen or alkyl.

[0050] A "therapeutically effective amount" refers to the amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The therapeutically effective amount will vary depending on the compound, the condition being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0051] "Therapeutically inert carrier" refers to any non-toxic ingredient, such as a disintegrant, binder, filler, solvent, buffer, isotonicity agent, stabilizer, antioxidant, surfactant, or lubricant, that has no therapeutic activity and is used in formulating a pharmaceutical product.

[0052] In particular, the chemical groups defined above are those specifically exemplified in the examples.

[0053] The following abbreviations are used herein:

[0054] BOP = benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, Brine = saturated aqueous NaCl solution, CAS = Chemical Abstracts Registry Number, CDI = 1,1'-carbonyldiimidazole, DBU = 1,8-diazabicyclo[5,4,0]undec-7-ene, DCM = dichloromethane, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DMF = N,N-dimethylformamide, 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 m-uronium hexafluorophosphate, HFIP = hexafluoroisopropanol, HOBt = hydroxybenzotriazole, HPLC = high performance liquid chromatography, m-CPBA = meta-chloroperoxybenzoic acid, MeCN = acetonitrile, MeI = methyl iodide, MeOH = methanol, min = minute, MS = mass spectrum, NBS = N-bromosuccinimide, PE = petroleum ether, PyBroP = bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, RT = room temperature, T3P = propylphosphonic anhydride, TBAF = tetrabutylammonium fluoride, TBAOH = tetrabutylammonium hydroxide, TBDMS = tert-butyldimethylsilyl, TEA = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TMSOTF = trifluoromethanesulfonic acid trimethylsilyl ester, TLC = thin layer chromatography.

[0055] In the description herein, if there is a discrepancy between a depicted structure and the name given to that structure, the depicted structure shall prevail. Furthermore, if the stereochemistry of a structure or portion of a structure is not indicated, for example, by a bold wedge or a dotted line, that structure or portion of a structure should be interpreted as encompassing all of its stereoisomers. However, in some cases where multiple chiral centers are present, the structure and name may be represented as a single enantiomer to aid in describing the relative stereochemistry.

[0056] Unless otherwise indicated, "a compound of the formula" or "a compound of formula" or "compounds of the formula" or "compounds of formula" refers to any compound selected from the genus of compounds defined by that formula (including any pharmaceutically acceptable salts of any such compound unless otherwise specified).

[0057] Certain compounds may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate individual tautomers usually produce mixtures whose chemical and physical properties match the compound's mixture. The position of the equilibrium depends on the chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, whereas in phenols, the enol form predominates. Common prototropic tautomers include keto / enol (-C(=O)-CH-⇔-C(-OH)=CH-), amide / imidic acid (-C(=O)-NH-⇔-C(-OH)=N-), and amidine (-C(=NR)-NH-⇔-C(-NHR)=N-) tautomers. The latter two are particularly common in heteroaryl and heterocyclic rings, and the present invention encompasses all tautomeric forms of the compounds.

[0058] Furthermore, the present invention includes all optical isomers of the compounds of formula (I), i.e., diastereoisomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers thereof, and solvates thereof.

[0059] The compounds of Formula (I) may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Additional asymmetric centers may be present depending on the nature of the various substituents on the molecule. Each such asymmetric center independently produces two optical isomers, and all possible optical isomers and diastereomers, both as mixtures and as pure or partially purified compounds, are intended to be encompassed by the present invention. The present invention is meant to encompass all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methods disclosed herein. Their absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates, which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated to isolate the individual enantiomers. Resolution can be carried out by methods well known in the art, such as coupling a racemic mixture of a compound to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods such as fractional crystallization or chromatography.

[0060] In embodiments where an optically pure enantiomer is provided, optically pure enantiomer means that the compound contains greater than 90% by weight of the desired isomer, specifically greater than 95% by weight of the desired isomer, or more specifically greater than 99% by weight of the desired isomer, said weight percentages being based on the total weight of the isomers of the compound. Chirally pure or chirally enriched compounds can be prepared by chirally selective synthesis or by separation of enantiomers. Separation of enantiomers can be carried out on the final product or on a suitable intermediate.

[0061] In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more atoms therein with atoms having different atomic masses or mass numbers. 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, such as: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. For example, compounds of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0062] Heavier isotopes, such as deuterium, i.e. 2 Substitutions such as H may confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0063] 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples set forth below, substituting the appropriate isotopically labeled reagent for the previously employed unlabeled reagent.

[0064] Compounds of the Invention In one embodiment, the compound of formula (I) TIFF2025526727000006.tif37170 (in the formula, Y is S(O), S(O)2 and S(O)N(R y ) and R 1 is a 5-membered heteroaryl, and R 1 is one or more R which may be the same or different 10 may be substituted with R 2 is selected from hydrogen and halogen; R 4 is C 5-14 -aryl and 5- to 14-membered heteroaryl; R 4 is one or more R which may be the same or different 11 may be substituted with R 10 is -C(R 10a R 10b )2-S(O)2(R 10c ) and R10a and R 10b are each independently hydrogen and C 1-6 -alkyl, or R 10a and R 10b together with the carbon atoms to which they are attached, form C 3-6 - forming a cycloalkyl, R 10c is hydrogen, C 1-6 -Alkyl, C 3-6 -cycloalkyl, -N(C 1-6 -alkyl), halo-C 1-6 -alkyl, and phenyl, wherein phenyl is selected from one or more halogens, or C 1-6 - optionally substituted with alkyl, or R 10a and R 10c together with the carbon and sulfur atoms to which they are attached form a 3- to 10-membered heterocyclyl; R 11 teeth, i) halogens, ii) one or more halo-C 1-6 -Alkyl, C 3-10 -3-10 membered heterocyclyl optionally substituted by cycloalkyl; iii) one or more halogens, C 1-6 -Alkyl, Halo-C 1-6 -Alkyl, C 3-10 -cycloalkyl, C 1-6 -5-6 membered heteroaryl optionally substituted with haloalkoxy; iv) one or more halogens, cyano, C 1-6 -alkoxy, C 1-6 -haloalkyl, C 1-6 -phenyl, optionally substituted with alkyl; v)-O(R 11a ), vi)-N(R 11g R 11h ), and vii)-S(R 11k ) is selected from R 11a is C1-12 -Alkyl, Halo-C 1-6 -Alkyl, C 3-7 -cycloalkyl, 3-10 membered -(C 1-6 -alkyl)heterocyclyl, phenyl and -C 1-6 -alkyl-phenyl, wherein C 1-12 -Alkyl, C 3-7 -cycloalkyl, phenyl and -C 1-6 -Alkyl-phenyl is substituted with one or more halogens, C 1-6 -Alkyl, Halo-C 1-6 -Alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, R 11g and R 11h are each independently hydrogen, C 1-6 -alkyl, -(C 1-6 -alkyl)phenyl; R 11k is hydrogen and halo-C 1-6 -alkyl, R y is hydrogen and C 1-6 -alkyl) or a pharmaceutically acceptable salt thereof is provided.

[0065] In another embodiment, R 1 may be the same or different, but 10 Provided are compounds of formula (I) as described herein, optionally substituted with:

[0066] In another embodiment, R 2 is selected from hydrogen and fluorine, or a pharmaceutically acceptable salt thereof.

[0067] In another embodiment, R 4 is phenyl, or a pharmaceutically acceptable salt thereof.

[0068] In another embodiment, R 10a and R 10b are each independently hydrogen or C 1-6 -alkyl, or R 10a and R 10b together with the carbon atoms to which they are attached, C 3-6

[0023] Provided are compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, which form -cycloalkyl.

[0069] In another embodiment, R 10 But one -S(O)2(C 1-6 -alkyl) substituted C 3-6 -cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0070] In another embodiment, R 10 is a 3- to 6-membered heterocyclyl, the heteroatom is sulfur, and one or more C 1-10 -alkyl, oxo, wherein the oxo substitution is on the sulfur atom; or a pharmaceutically acceptable salt thereof.

[0071] In another embodiment, R 10 is selected from 1-methyl-methylsulfonyl-ethyl.

[0072] In another embodiment, R 11 But -O(R 11a ) and R 11a is C 1-12 -Alkyl, Halo-C 1-6 -Alkyl, C 3-7 -cycloalkyl, 3-10 membered -(C 1-6 -alkyl)heterocyclyl, phenyl, -C 1-6 -alkyl-phenyl, wherein C 1-12 -Alkyl, C 3-7 -cycloalkyl, phenyl and -C1-6 -Alkyl-phenyl is substituted with one or more halogens, C 1-6 -Alkyl, Halo-C 1-6 -Alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxyl-substituted compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, are provided.

[0073] In one embodiment, R 11 but, viii) halogens, ix) 3- to 10-membered heterocyclyl, x) one or more halogens, halo-C 1-6 -Alkyl, C 3-10 -cycloalkyl, C 1-6 -5-6 membered heteroaryl optionally substituted with haloalkoxy; xi) one or more cyano, C 1-6 -alkoxy, C 1-6 -haloalkyl, C 1-6 -phenyl, optionally substituted with alkyl; xii)-O(R 11a )(R 11a is C 1-12 -Alkyl, Halo-C 1-6 -Alkyl, C 3-7 -cycloalkyl, 5-6 membered -(C 1-6 -alkyl)heteroaryl, phenyl and -C 1-6 -alkyl-phenyl, wherein C 1-12 -Alkyl, phenyl, 5-6 membered -(C 1-6 -alkyl)heteroaryl and -C 1-6 -Alkyl-phenyl is substituted with one or more halogens, C 1-6 -Alkyl, Halo-C 1-6 -Alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy), xiii)-N(R 11g R 11h )(R 11g and R 11h are each independently1-6 -alkyl, -(C 1-6 -alkyl)phenyl), xiv)-S(Halo-C 1-6 -alkyl), xv) CH2-O-phenyl

[0013] Provided is a compound of formula (I) as described herein, selected from:

[0074] In another embodiment, R 11 but, i)-O(R 11a )(wherein, R 11a is Halo-C 1-6 - selected from alkyl and phenyl, said phenyl being optionally substituted with one or more halogens, or ii) one or more C 1-6 -alkoxy, C 1-6 phenyl, optionally substituted by haloalkyl; iii) halogens, iv) one or more halo-C 1-6 -Alkyl, C 3-10 -cycloalkyl, C 1-6 -5-6 membered heteroaryl optionally substituted with haloalkoxy, chloro, trifluoromethoxy-2-pyridyl

[0013] Provided is a compound of formula (I) as described herein, selected from:

[0075] In another embodiment, R 11 is selected from (trifluoromethyl)phenyl, (trifluoromethyl)-oxadiazolyl, cyclopropyl-oxadiazolyl, phenoxyl, methoxyphenyl, tetrafluoroethoxyl, dichlorophenoxyl, or a pharmaceutically acceptable salt thereof.

[0076] In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein Y is S(O)2.

[0077] In another embodiment, Y is S(O), S(O)2 and S(O)N(R y ) and R 1 is a 5-membered heteroaryl, and R 1 is one or more R which may be the same or different 10 may be substituted with R 2 is selected from hydrogen and fluorine; R 4 is selected from C-aryl and 6-membered heteroaryl, and R 4 is one or more R which may be the same or different 11 may be substituted with R 10 But one -S(O)2(C 1-6 -alkyl) substituted C 3-6 -cycloalkyl, R 11 but, i) halogens, ii) 3- to 10-membered heterocyclyl, iii) one or more halogens, halo-C 1-6 -Alkyl, C 3-10 -cycloalkyl, C 1-6 -5-6 membered heteroaryl optionally substituted with haloalkoxy; iv) one or more cyano, C 1-6 -alkoxy, C 1-6 -haloalkyl, C 1-6 -phenyl, optionally substituted with alkyl; v)-O(R 11a )(R 11a is C 1-12 -Alkyl, Halo-C 1-6 -Alkyl, C 3-7 -cycloalkyl, 5-6 membered -(C 1-6 -alkyl)heteroaryl, phenyl and -C 1-6 -alkyl-phenyl, wherein C 1-12 -Alkyl, phenyl, 5-6 membered -(C 1-6 -alkyl)heteroaryl and -C 1-6-Alkyl-phenyl is substituted with one or more halogens, C 1-6 -Alkyl, Halo-C 1-6 -Alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy), vi)-N(R 11g R 11h )(R 11g and R 11h are each independently 1-6 -alkyl, -(C 1-6 -alkyl)phenyl), vii)-S(Halo-C 1-6 -alkyl), viii) CH2-O-phenyl

[0013] Provided is a compound of formula (I) as described herein, wherein:

[0078] In another embodiment, Y is S(O), S(O)2 and S(O)N(R y ) and R 1 is oxadiazole, and R 1 is one or more R which may be the same or different 10 may be substituted with R 2 is selected from hydrogen and fluorine; R 4 is phenyl, R 10 is selected from methyl-methylsulfonyl-ethyl, cyclopropylsulfonyl-methyl-ethyl, methyl-dioxo-thiolanyl, methylsulfonylmethyl, methylsulfonylcyclobutyl; R 11 but, i)-O(R 11a )(wherein, R 11a is Halo-C 1-6 -alkyl, phenyl, wherein the phenyl is optionally substituted with one or more halogens; ii) one or more C 1-6 -alkoxy, C 1-6phenyl, optionally substituted by haloalkyl; iii) halogens, and iv) one or more halo-C 1-6 -Alkyl, C 3-10 -cycloalkyl, C 1-6 -5-6 membered heteroaryl optionally substituted with haloalkoxy

[0013] Provided is a compound of formula (I) as described herein, selected from:

[0079] In another embodiment, Y is S(O), S(O)2 and S(O)N(R y ) and R 1 is oxadiazole, and R 1 is one or more R which may be the same or different 10 may be substituted with R 2 is selected from hydrogen and fluorine; R 4 is phenyl, R 10 is methyl-methylsulfonyl-ethyl, R 11 is selected from (trifluoromethyl)phenyl, (trifluoromethyl)-oxadiazolyl, cyclopropyl-oxadiazolyl, phenoxyl, methoxyphenyl, tetrafluoroethoxyl, dichlorophenoxyl, chloro, and trifluoromethoxy-2-pyridyl, or a pharmaceutically acceptable salt thereof.

[0080] In another embodiment, Y is S(O), S(O)2 and S(O)N(R y ) and R 1 is a 5-membered heteroaryl, and R 1 is one or more R which may be the same or different 10 may be substituted with R 2 is selected from hydrogen and fluorine; R 4 is selected from C-aryl and 6-membered heteroaryl, and R 4 is one or more R which may be the same or different 11 may be substituted with R 10 But one -S(O)2(C 1-6 -alkyl) substituted C 3-6 -cycloalkyl, R 11 But -O(R 11a ) and R 11a is C 1-12 -Alkyl, Halo-C 1-6 -Alkyl, C 3-7 -cycloalkyl, 3-10 membered -(C 1-6 -alkyl)heterocyclyl, phenyl, -C 1-6 -alkyl-phenyl, wherein C 1-12 -Alkyl, C 3-7 -cycloalkyl, phenyl and -C 1-6 -Alkyl-phenyl is substituted with one or more halogens, C 1-6 -Alkyl, Halo-C 1-6 -Alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxyl-substituted compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, are provided.

[0081] In another embodiment, Y is S(O), S(O)2 and S(O)N(R y ) and R 1 is oxadiazole, and R 1 is one or more R which may be the same or different 10 may be substituted with R 2 is selected from hydrogen and fluorine; R 4 is phenyl, R 10is selected from methyl-methylsulfonyl-ethyl, cyclopropylsulfonyl-methyl-ethyl, methyl-dioxo-thiolanyl, methylsulfonylmethyl, methylsulfonylcyclobutyl; R 11 However, 2-methoxy-1,1-dimethyl-ethoxy, phenoxyl, bromophenoxyl, (trifluoromethyl)-oxadiazolyl]methoxyl, (trifluoromethyl)phenyl, tetrahydropyranyl, methoxyphenyl, methoxy-methyl-phenyl, (difluoromethoxy)phenoxyl, (trifluoromethyl)-oxadiazolyl, cyclopropyl-oxadiazolyl, trifluoromethoxy, chloro, methoxyphenoxyl, chloro-methoxy-phenoxyl, trifluoromethoxy)phenoxyl, fluoro-(trifluoromethyl)phenoxyl, chloro-fluoro

[0013] Provided is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from chloro-phenoxyl, trifluoromethyl-pyridyl, chlorophenoxyl, fluorophenoxyl, dichlorophenoxyl, methylphenoxyl, tetrafluoroethoxyl, trifluoroethoxyl, trifluoropropoxyl, benzonitrileyl, ethylpropoxyl, isopropyl(methyl)aminoyl, cyclopentoxyl, benzyl(methyl)aminoyl, (fluorophenyl)methoxyl, benzyloxyl, fluoro-pyridyl, trifluoromethylsulfanyl.

[0082] In another embodiment, Y is S(O), S(O)2 and S(O)N(R y ) and R 1 is oxadiazole, and R 1 is one or more R which may be the same or different 10 may be substituted with R 2 is selected from hydrogen and fluorine; R 4 is phenyl, R 10 is selected from methyl-methylsulfonyl-ethyl; R11 is selected from (trifluoromethyl)phenyl, (trifluoromethyl)-oxadiazolyl, cyclopropyl-oxadiazolyl, phenoxyl, methoxyphenyl, tetrafluoroethoxyl, dichlorophenoxyl, or a pharmaceutically acceptable salt thereof.

[0083] In another embodiment, (3R)-3-amino-5-[[4-(1-ethylpropoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-(cyclopentoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[(4-(benzyloxyphenyl)methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-[(4-fluorophenyl)methoxy]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-[(2-fluorophenyl)methoxy]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-(3,3,3-trifluoropropoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-(trifluoromethylsulfanyl)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-(phenoxymethyl)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-[3-(difluoromethoxy)phenoxy]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[[4-(3-methylphenoxy)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-(2,3-dichlorophenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-(3-fluorophenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-(3-chlorophenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-(3-chloro-4-fluoro-phenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[3-(trifluoromethyl)phenoxy]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-[3-fluoro-5-(trifluoromethyl)phenoxy]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[3-(trifluoromethoxy)phenoxy]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-(3-chloro-5-methoxy-phenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-(3-chloro-5-methoxy-phenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, 4-[4-[[(3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-5-yl]methyl]phenyl]benzonitrile, (3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-(3-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-(4-methoxy-2-methyl-phenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-(3-bromophenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-1,1-diketo-7-[5-(1-mesyl-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[4-[5-(trifluoromethoxy)-2-pyridyl]benzyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-[benzyl(methyl)amino]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-[isopropyl(methyl)amino]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-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-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-(5-fluoro-2-pyridyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[(6-phenoxy-3-pyridyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-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-benzothiazepin-4-one, (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methylsulfonylcyclopropyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-5-[[4-(2-methoxy-1,1-dimethyl-ethoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-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-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[6-(trifluoromethyl)-3-pyridyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[4-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methoxy]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ4,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methylsulfonylcyclobutyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methylsulfonylcyclopropyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-cyclopropylsulfonyl-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-7-[5-(2-methyl-1,1-dioxo-thiolan-2-yl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-N,N-dimethyl-propane-2-sulfonamide, (3R)-3-amino-7-[5-(1-methyl-1-pyrrolidin-1-ylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[2-(methylsulfonylmethyl)tetrazol-5-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-Amino-8-fluoro-7-[1-(methylsulfonylmethyl)tetrazol-5-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one

[0013] Provided is a compound of formula (I) as described herein, selected from:

[0084] In a preferred embodiment, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-(2,3-dichlorophenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-(3-chlorophenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-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-benzothiazepin-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one, (3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one, and (3R)-3-Amino-1,1-diketo-7-[5-(1-mesyl-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[4-[5-(trifluoromethoxy)-2-pyridyl]benzyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one

[0013] Provided is a compound of formula (I) as described herein, selected from:

[0085] Manufacturing method Processes for preparing the compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, are also an object of the present invention.

[0086] The present invention provides a process for preparing a compound described herein or a pharmaceutically acceptable salt thereof, comprising the steps of: TIFF2025526727000007.tif34170 (in the formula, Y, R 1 , R 2 and R 4 is as defined herein and PG is an amino protecting group) with a suitable deprotecting agent to form said compound of formula (I).

[0087] The preparation of the compounds of formula (I) of the present invention may be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following method descriptions have the meanings indicated herein unless otherwise indicated.

[0088] If one of the starting materials, intermediates or compounds of formula (I) contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, suitable protecting groups (such as those described in "Protective Groups in Organic Chemistry" by T.W. Greene and P.G.M. Hutts, 5th Ed., 2014, John Wiley & Sons, NY) can be introduced prior to a critical step by applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0089] When the starting material or intermediate contains a stereocenter, the compound of formula (I) is obtained as a mixture of diastereomers or enantiomers, which can be separated by methods known in the art, such as chiral HPLC, chiral SFC, or chiral crystallization. Racemates can be separated into their antipodes via diastereomeric salts, for example, by crystallization with an optically pure acid, or by separating the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. Starting materials and intermediates containing a stereocenter can also be separated to obtain diastereomerically / enantiomerically enriched starting materials and intermediates. The use of such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of the compound of formula (I) generally results in the respective diastereomerically / enantiomerically enriched compounds of formula (I).

[0090] Those skilled in the art will recognize that in the synthesis of compounds of formula (I), unless otherwise desired, an "orthogonal protecting group strategy" may be applied to cleave several protecting groups one at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has been described in the literature (e.g., Barany and R.B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0091] Those skilled in the art will recognize that the reaction sequence may vary depending on the reactivity and nature of the intermediates.

[0092] More specifically, compounds of formula (I) can be prepared by the methods described below, the methods shown in the Examples, or similar methods. Suitable reaction conditions for the individual reaction steps are known to those skilled in the art. For literature-described reaction conditions affecting the described reactions, see, for example, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999." It has been found convenient to carry out the reaction in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent used, so long as it does not adversely affect the reaction or the reagents involved and is capable of dissolving the reagents to at least some extent. The described reactions can occur over a wide range of temperatures, and the precise reaction temperature is not critical to the present invention. It is convenient to carry out the described reactions at temperatures ranging from -78°C to reflux. The time required for the reaction can also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain the intermediates and compounds described. The reaction sequence is not limited to the sequence shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities.

[0093] If the starting materials or intermediates are not commercially available or their synthesis is not described in the literature, they can be prepared analogously to existing procedures for close analogs or as outlined in the experimental section.

[0094] The present compounds of formula (I), or pharmaceutically acceptable salts thereof, can be prepared by the methods described below (Scheme 1), together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations familiar to those skilled in the art. TIFF2025526727000008.tif125170

[0095] Suitable starting materials for the preparation of compounds of formula (I) are nitro compounds of formula (II) 2 is F or Cl, and X 1 is already R 1 or later R 1 (The protective group is a group such as Br, CN, or -CO alkyl, which can be synthesized in a suitable manner.) Compounds of formula (II) can be reacted with an appropriately protected cysteine derivative (III) in the presence of a base such as DIPEA at elevated temperatures in a solvent such as 1,2-dichloroethane to give compounds of formula (IV). A preferred protecting group (PG) for cysteine derivatives (III) is Boc. The nitro group in compounds of formula (IV) can be reduced using iron in the presence of either hydrogen chloride or ammonium chloride in a solvent mixture of water and ethanol at elevated temperatures to give compounds of formula (V). Alternatively, this conversion can be achieved by catalytic hydrogenation. Compounds of formula (V) can be cyclized to compounds of formula (VI) using standard amide coupling conditions. Preferably, this cyclization is carried out using 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in EtOAc) and a base such as DIPEA in a solvent such as DMF at room temperature. A compound of formula (VI) and Y 1 is Cl, Br, I or a sulfonate group in the presence of a base such as potassium carbonate, optionally with an additive such as potassium iodide, in a solvent such as DMSO or DMF at room temperature to give a compound of formula (VIII). 1 Compounds of formula (VII) in which X is OH can be reacted with PPh3 in the presence of an additive such as DIAD in a solvent such as toluene at elevated temperatures to give compounds of formula (VIII). 1 In the case of compounds of formula (VIII) where is Br or -CO2 alkyl, these groups can be converted at this stage into the substituent R 1The compound of formula (VIII) can then be converted to a compound of formula (IX) where Y is S(O) or S(O)2 by reaction with an appropriate amount of an oxidizing agent such as m-CPBA in a solvent such as DCM at room temperature. Final deprotection provides a compound of formula (I). When the N-protecting group (PG) is Boc, typical conditions for this deprotection step include TFA in a solvent such as DCM at room temperature, hydrogen chloride in a solvent such as dioxane, diethyl ether or ethyl acetate at room temperature, or hexafluoroisopropanol at reflux temperature. Additionally, the substituent R 1 and R 4 may contain functional groups that may be modified before removal of the N-protecting group (PG) or that require the use of appropriate protecting groups during synthesis. These protecting groups may be removed before removal of the N-protecting group (PG) or may be removed simultaneously using appropriate methods [Peter G.M.Wuts, Greene's Protective Groups in Organic Synthesis, 5th Edition, Hoboken, NJ: Wiley-Interscience].

[0096] Alternatively, compounds of formula (I) where Y is (O) 2 can be prepared as shown in Scheme 2. TIFF2025526727000009.tif79170

[0097] Compounds of formula (VI) can be converted to compounds of formula (X) upon reaction with an oxidizing agent such as m-CPBA in a solvent such as DCM at room temperature. Reaction of compounds of formula (X) with compounds of formula (VII) to give compounds of formula (XI) and subsequent conversion to compounds of formula (I) (where Y is S(O)2) can be achieved using the reaction conditions described for the similar steps in Scheme 1. X 1 is Br, -CO2 alkyl, or CN, these groups can be replaced by substituent R at any stage of the synthesis (for compounds of formula (VI), (X) or (XI)) using the methods described for the following schemes: 1 can be synthesized into

[0098] 5-membered heteroaryl R 1 Compounds of formula (I) where is a 1,3,4-oxadiazolyl group may be prepared as shown in Scheme 3. TIFF2025526727000010.tif111170

[0099] X 1 Compounds of formula (VIII), where is COMe, can be converted to compounds of formula (XII) by reaction with an alkali hydroxide, such as LiOH, NaOH, or KOH, in a mixture of solvents, such as MeOH, THF, and water, at room temperature. Compounds of formula (XII) can be reacted with hydrazine hydrate, after activation with a suitable reagent, such as CDI, in a solvent, such as THF, at room temperature, to give compounds of formula (XIII). Compounds of formula (XIII) can be coupled to carboxylic acids R using standard amide coupling conditions, such as HATU, in the presence of a base, such as DIPEA, in a solvent, such as THF, at room temperature. 10 The coupling product of formula (XIV) can be cyclized to a compound of formula (XV) using a dehydrating reagent such as Burgess's reagent, or can be reacted with tosyl chloride at room temperature in the presence of a base such as DIPEA. The conversion of a compound of formula (XV) to a compound of formula (XVI) and then to a compound of formula (I) can be achieved using the reaction conditions described for the similar steps in Scheme 1.

[0100] 5-membered heteroaryl R 1 Compounds of formula (I) where is a 1,2,4-oxadiazolyl group may be prepared as shown in Scheme 4. TIFF2025526727000011.tif75170

[0101] X 1Compounds of formula (VIII), where R is CN, can be reacted with hydroxylamine hydrochloride in the presence of a base such as potassium carbonate in a solvent such as ethanol at elevated temperatures to give amide oxime compounds of formula (XVII, where R is H). Standard amide coupling conditions, such as CDI, HATU, or EDCI and HOBt, can be used to couple compounds of formula (XVII, where R is H) with carboxylic acids R in the presence of a base such as DIPEA in a solvent such as acetonitrile, DMF, or THF. 10 COH to form a coupling intermediate (XVII, where R is —C(O)R) that cyclizes upon heating to the corresponding compound of formula (XVIII). 10 Alternatively, the coupling intermediate (XVII, where R is —C(O)R 10 (wherein X is a methyl group, and X is a methyl group) can be isolated and the cyclization step can be carried out either by heating in a solvent such as toluene or by reaction with TBAOH in a solvent such as THF. Conversion of compounds of formula (XVIII) to compounds of formula (XIX) and then to compounds of formula (I) can be achieved using the reaction conditions described for the similar steps in Scheme 1.

[0102] 5-membered heteroaryl R 1 Compounds of formula (I) where is a tetrazolyl group can be prepared as shown in Scheme 5. TIFF2025526727000012.tif75170

[0103] X 1 Compounds of formula (VIII) where is CN can be converted to compounds of formula (XX) by reaction with an azide reagent such as azidotrimethylsilane in the presence of tetra-N-butylammonium fluoride trihydrate in toluene at elevated temperature. To obtain compounds of formula (XXI) from compounds of formula (XX), the reaction can be carried out with the reagent R in the presence of a base such as potassium carbonate in a solvent such as DMF at room temperature. 10 The substituent R can be converted by various methods, such as by reaction with Y (wherein Y is Cl, Br, or I). 10 Alternatively, the compound of formula (XX) can be introduced with a reagent R 10Reaction with Y (where Y is OH) in the presence of PPh3 with an additive such as DIAD in a solvent such as toluene at elevated temperature can provide a compound of formula (XXI). Conversion of a compound of formula (XXI) to a compound of formula (XXII) and then to a compound of formula (I) can be achieved using the reaction conditions described for the similar steps in Scheme 1.

[0104] Pharmaceutical Compositions and Administration Another object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0105] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicines in the form of pharmaceutical preparations.The pharmaceutical preparations can be administered orally (for example, in the form of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules and soft gelatin capsules, solutions, emulsions, or suspensions), nasally (for example, in the form of nasal drops), or rectally (for example, in the form of suppositories), etc.However, administration can also be carried out parenterally, such as intramuscularly or intravenously (for example, in the form of injections).Administration can also be carried out topically, for example, transdermally, or in the form of eye drops or ear drops.

[0106] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic carriers for the manufacture of pharmaceutical preparations such as tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injections or topical preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such carriers for tablets, coated tablets, sugar-coated tablets and hard gelatin capsules.

[0107] Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. However, depending on the nature of the active substance, no carrier is usually required for soft gelatin capsules.

[0108] Suitable carriers for the production of solutions and syrups are, for example, water, alcohols, polyols, saccharose, glucose, invert sugar, vegetable oil and the like.

[0109] Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0110] Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

[0111] Suitable carriers for topical ophthalmic formulations are, for example, cyclodextrin, mannitol, or many other carriers and additives known in the art.

[0112] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying osmotic pressure, buffers, masking agents or antioxidants. Pharmaceutical preparations may also contain other therapeutically valuable substances.

[0113] Medicaments comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient are also an object of the present invention, as are processes for their preparation, which comprise bringing one or more compounds of formula (I) and / or a pharmaceutically acceptable salt thereof, and, if desired, one or more other therapeutically valuable substances, together with one or more pharmaceutically acceptable excipients, into a galenical dosage form.

[0114] Dosages may vary within wide limits and, of course, must be adjusted to the individual requirements of each particular case. Generally, for oral administration, a daily dose of about 0.1 mg to 20 mg per kg of body weight, preferably 0.5 mg to 4 mg per kg of body weight (e.g., about 300 mg per person), preferably divided into 1 to 3 individual doses, each of which may consist of the same amount, would be appropriate. For topical administration, the formulation may contain 0.001% to 15% by weight of the drug, and the required dose, which may be between 0.1 and 25 mg, may be administered either in a single dose per day or a single dose per week, or in multiple doses (2 to 4 times) per day or multiple doses per week. However, it is clear that the upper or lower limits indicated herein may be exceeded, if indicated.

[0115] The pharmaceutical composition of the present invention can be prepared as follows. Preparation of Pharmaceutical Compositions Containing Compounds of the Invention TIFF2025526727000013.tif77170Manufacturing Instructions: 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50°C. 3. Pass the granules through suitable grinding equipment. 4. Add ingredient 5, mix for 3 minutes and compress in a suitable press. TIFF2025526727000014.tif77170Manufacturing Instructions: 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into suitable capsules. TIFF2025526727000015.tif51170Manufacturing Instructions: A compound of formula (I) is dissolved (in part) in a mixture of polyethylene glycol 400 and water for injection. The pH is adjusted to 5.0 with acetic acid. The remaining amount of water is added to adjust the volume to 1.0 ml. The solution is filtered, filled into vials using an appropriate overage, and sterilized.

[0116] Indications The compounds of formula (I) may be used in an amount effective to treat subjects, particularly humans, suffering from cancer.

[0117] 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.

[0118] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or delay of progression of cancer.

[0119] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment, prevention and / or delay of progression of cancer.

[0120] In a further aspect, the present invention provides the use of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment, prevention and / or delay of progression of cancer.

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

[0122] As used herein, the terms "treatment" or "treating" and grammatical variations thereof refer to therapeutic therapy. With respect to a particular condition, treating means (1) ameliorating the condition or one or more biological manifestations of the condition; (2) (a) interfering with one or more points in the biological cascade that leads to or causes the condition, or (b) one or more biological manifestations of the condition; (3) alleviating one or more symptoms, effects, or side effects associated with the condition or its treatment; or (4) slowing the progression of the condition or one or more biological manifestations of the condition. Preventive therapy using the methods and / or compositions of the present invention is also contemplated. Those skilled in the art will understand that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition or its biological manifestations, or to delay the onset of such a condition or its biological manifestations. Preventive therapy is appropriate when a subject is considered to be at high risk for developing cancer, for example, when the subject has a strong family history of cancer or has been exposed to a carcinogen.

[0123] As immunotherapeutics that act on immune cells rather than directly on cancer cells, the present disclosure may also be envisioned for use as an anti-cancer vaccine, including approaches in which immune cells are cultured and engineered ex vivo and the molecules disclosed herein are used as a means of costimulating the ex vivo engineered cells.

[0124] In one embodiment, the cancer is a blood cancer, such as lymphoma, leukemia, or myeloma. Blood cancers contemplated herein include one or more leukemias, such as B-cell acute lymphoblastic leukemia ("BALL"), T-cell acute lymphoblastic leukemia ("TALL"), acute lymphoblastic leukemia (ALL); one or more chronic leukemias, including but not limited to chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL); B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant tumors, and the like. These include, but are not limited to, additional blood cancers or conditions including, but not limited to, myeloid lymphoproliferative conditions, mucosa-associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, and "preleukemia," which are a diverse collection of hematological conditions united by the ineffective production (or dysplasia) of myeloid blood cells.

[0125] In further embodiments, the cancer is a non-hematological cancer such as a sarcoma, carcinoma, or melanoma. Non-hematological cancers contemplated herein include, but are not limited to, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, 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.

[0126] Co-administration of Compounds of Formula (I) and Other Agents The compound of formula (I) or its salt or the compound disclosed herein or its pharmaceutically acceptable salt can be used alone or in combination with other drugs for treatment.For example, the second drug of the combined pharmaceutical preparation or administration regimen can have complementary activity to the compound of formula (I), so that they do not adversely affect each other.The compounds can be administered together in a single pharmaceutical composition or separately.In one embodiment, the compound or its pharmaceutically acceptable salt can be administered together with a cytotoxic agent to treat proliferative diseases and cancer.

[0127] The term "co-administering" refers to simultaneous administration or separate sequential administration in any manner of a compound of formula (I) or its salt, or a compound disclosed herein or its pharmaceutically acceptable salt, and one or more additional active pharmaceutical ingredients, including cytotoxic agents and radiation treatment.If administration is not simultaneous, the compounds are administered close in time to each other.Furthermore, it is not important 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.

[0128] Typically, any drug with anti-cancer activity can be co-administered.Examples of such drugs can be found in Cancer Principles and Practice of Oncology by VTDevita and S.Heilman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers.Those skilled in the art will be able to identify which drug combination is useful based on the specific characteristics of the drug and the disease involved.

[0129] In one aspect, the present invention provides a pharmaceutical composition as described herein, further comprising an additional therapeutic agent.

[0130] In one embodiment, the additional therapeutic agent is a chemotherapeutic agent.

[0131] In one embodiment, the additional therapeutic agent is a cytotoxic agent.

[0132] In one embodiment, the additional therapeutic agent is a cancer immunotherapeutic agent.

[0133] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents the function of cells and / or causes cell death or destruction. Cytotoxic agents include radioisotopes (AT 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 , and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof, such as nucleolytic enzymes; and toxins (including fragments and / or variants thereof), such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin.

[0134] Exemplary cytotoxic agents may be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism.

[0135] "Chemotherapeutic agents" include chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitinib (SUTENT®, Pfizer / Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate, and fluticasone. nib (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Alkylating agents such as cyclophosphamide (IRESSA®, AstraZeneca), AG1478, thiotepa, and CYTOXAN®; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including topotecan and irinotecan); bryostatin; kallistatin; CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogs); cryptophycins (especially cryptophycin I and cryptophycin 8);Corticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductase inhibitors (including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat; dolastatins; aldesleukin, talc; duocarmycin (synthetic analogs, KW-2189, and CBI-TM) I); eleutherobin; pancratistatin; sarcodictine; spongistatin; chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, nitrogen mustards such as uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ1I and calicheamicin coll (Angew Chem. Inti. Ed. Engl. 1994) 33:183-186); dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicin;and neocarzinostatin chromophores and related chromoproteins (enediyne antibiotic chromophores), aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo- L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, queramycin (que antibiotics such as lamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; and steroids such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine. Purine analogues; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; anti-adrenals such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziconazole;Elfomithine; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oregon; razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triazicon; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, New Jersey), ABRAXANE® (Cremophor-free), an albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE® (docetaxel; Sanofi-Aventis; chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-II; topoisomerase inhibitor RFS 2000;Difluoromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0136] Chemotherapeutic agents also include: (i) antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen (including NOLVADEX®, tamoxifen citrate), raloxifene, droxifene, iodoxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) estrogens that inhibit the growth of adrenal glands. aromatase inhibitors, which inhibit the enzyme aromatase, which regulates strogen production, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestany, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) flutamide, nilutamide, bicalutamide, leuconazole ... antiandrogens such as prolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all-trans retionic acid, fenretinide and troxacitabine (1,3-dioxolane nucleoside cytosine analogue); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, especially agents that inhibit the expression of genes in signal transduction pathways involved in abnormal cell growth, e.g., PKC-alpha, Ralf and H -Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®), HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, e.g., ALLOVECTIN®, LEUVECTIN®, and VAXID®; topoisomerase I inhibitors such as PROLEUKIN®, rIL-2; LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0137] Chemotherapeutic agents also include antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody-drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, natalizumab, natalizumab ... tuzumab, nimotuzumab, norobizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, reslizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatatuzumab tetraxetan, tadoxizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoreukin, tuxituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and interleukin-12 and anti-interleukin-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), an all-human sequence, full-length IgG1λ antibody engineered to recognize the p40 protein.

[0138] Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or otherwise directly interact with EGFR and inhibit or reduce the signaling activity of EGFR, alternatively referred to as "EGFR antagonists." Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include MAb579 (ATCC CRL HB 8506), MAb455 (ATCC CRL HB8507), MAb225 (ATCC CRL8508), MAb528 (ATCC CRL8509) (see U.S. Pat. No. 4,943,533, Mendelsohn et al.), and variants thereof, such as chimerized 225 (C225 or cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see WO 96 / 40210, Imclone Systems, Inc.). Inc.), IMC-11F8, a fully human, EGFR-targeting antibody (Imclone), antibodies that bind type II mutant EGFR (U.S. Pat. No. 5,212,290), humanized and chimeric antibodies that bind EGFR as described in U.S. Pat. No. 5,891,996, and human antibodies that bind EGFR, such as ABX-EGF or panitumumab (WO 98 / 50433, Abgenix / Amgen), EMD55900 (Stragliotto et al. al. Eur. J. Cancer 32A:636-640 (1996)), EMD7200 (matuzumab), a humanized EGFR antibody against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD / Merck), the human EGFR antibody, HuMax-EGFR (GenMab), the fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, and E7.6.3 and described in U.S. Pat. No. 6,235,883, MDX-447 (Medarex Inc), and mAb806 or humanized mAb806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)).Anti-EGFR antibodies can be conjugated to cytotoxic agents to form immunoconjugates (see, for example, European Patent Application Publication No. 659,439, Merck Patent GmbH). EGFR antagonists include those described in U.S. Patent Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, and small molecules such as the compounds described in PCT Publications WO 98 / 14451, WO 98 / 50038, WO 99 / 09016, and WO 99 / 24037.Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA®, Genentech / OSI Pharmaceuticals), PD183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.), ZD1839, gefitinib (IRESSA®) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca), ZM105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca), BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim), Ingelheim), PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol; (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine), CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide), EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano -7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth), AG1478 (Pfizer); AG1571 (SU5271, Pfizer), dual EGFR / HER2 tyrosine kinase inhibitors, such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

[0139] Chemotherapeutic agents include "tyrosine kinase inhibitors," such as the EGFR-targeted drugs described in the previous paragraph; small molecule HER2 tyrosine kinase inhibitors, such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors, such as EKB-569 (available from Wyeth), which preferentially binds to EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016, available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors, such as canertinib (CI-1033, Pharmacia); Raf-1 inhibitors, such as ISIS, which inhibits Raf-1 signaling. non-HER-targeted TK inhibitors, such as imatinib mesylate (GLEEVEC®, available from GlaxoSmithKline); multi-targeted tyrosine kinase inhibitors, such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors, such as vatalanib (PTK787 / ZK222584, available from Novartis / Schering AG); the MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, such as PD153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP60261, and CGP62706; pyrazolopyrimidine, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide); tyrphostins containing a nitrothiophene moiety; PD-0183805 (Warner-Lamber); antisense molecules (e.g., those that bind to HER-encoding nucleic acids); quinoxalines (U.S. Patent No. 5,804,396); tryphostins (U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca);PTK-787 (Novartis / Schering AG); pan-HER inhibitors, such as CI-1033 (Pfizer); Affinitac (ISIS3521, Isis / Lilly); imatinib mesylate (GLEEVEC®); PKI166 (Novartis); GW2016 (GlaxoSmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®); or the following patent publications: U.S. Pat. No. 5,804,396; WO 1999 / 09016 (American Cyanamid); WO 1998 / 43960 (American Cyanamid; 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);

[0140] Chemotherapeutic agents include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG (raw), bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, erlotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, and interferon alfa- 2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.

[0141] Chemotherapeutic agents include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, and hydrocortisone-17-butyrate. late, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, and fluprednidene acetate; phenylalanine-glutamine-glycine (PEG) and its D-isomer form (feG) (IMULAN) Immunoselective anti-inflammatory peptides (ImSAIDs) such as those from BioTherapeutics, LLC; antirheumatic drugs such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, and sulfasalazine; etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simpson) tumor necrosis factor alpha (TNFα) blockers such as anakinra (Kineret), interleukin 1 (IL-1) blockers such as anakinra (Kineret), T-cell costimulation blockers such as abatacept (Orencia), interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) blockers such as rontalizumab; beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as anti-M1 prime; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa1 / β2 blockers such as anti-lymphotoxin alpha (LTa); radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi212 、P 32 、Pb 212, and radioactive isotopes of Lu); various investigational drugs such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, or farnesyltransferase inhibitors (L-739749, L-744832); polyphenols, such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavins, flavanols, procyanidins, betulinic acid and its derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicine; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin; podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); clodronate (e.g., BONEFOS®) or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); as well as epidermal growth factor receptor (EGF-R); vaccines such as the THERATOPE® vaccine; perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteosome inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitors such as oblimersen sodium (GENASENSE®); pixantrone; lonafarnib (SCH 6636, SARASAR™); and pharmaceutically acceptable salts, acids, or derivatives of any of the above;and combinations of two or more of the above, such as CHOP, which is an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, which is an abbreviation for a treatment regimen using oxaliplatin in combination with 5-FU and leucovorin (ELOXATIN™);

[0142] In another embodiment, the compound of formula (I) can be co-formulated with a cancer immunotherapeutic agent. Cancer immunotherapeutic agents include, for example, small molecule drugs, antibodies, or other biological or small molecules. Examples of biological cancer immunotherapeutic agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human. In another aspect, the antibody is a bispecific antibody.

[0143] In one aspect, the cancer immunotherapeutic agent is either (i) an agonist of a stimulatory (including costimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on T cells, both of which result in amplification of antigen-specific T cell responses (often referred to as immune checkpoint modulators).

[0144] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or coinhibitory receptors are CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTfiR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNPβ, TNFR2, TNFα, LT R, and lymphotoxin a The TNF family of molecules binds to cognate TNF receptor family members, including 1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0145] In one aspect, T cell responses may be stimulated by a combination of a compound of Formula (I) and one or more of: (i) antagonists of proteins that inhibit T cell activation (e.g., immune checkpoint inhibitors), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin-9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; and (ii) agonists of proteins that stimulate 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.

[0146] Other drugs that can be combined with the compound of formula (I) for the treatment of cancer include the antagonist of the inhibitory receptor on NK cell or the agonist of the activating receptor on NK cell.For example, the compound of formula (I) can be combined with the antagonist of KIR, such as lirilumab.

[0147] Still other agents for combination therapy include agents that inhibit or deplete macrophages or monocytes, including CSF-1R antagonists such as CSF-1R antagonist antibodies, including, but not limited to, RG7155 or FPA-008.

[0148] In another embodiment, the compounds of formula (I) can be used in combination with one or more of agonist agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome different immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor binding (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell anergy or exhaustion), and agents that cause innate immune activation and / or inflammation at the tumor site.

[0149] In some embodiments, the cancer immunotherapeutic agent is a CTLA-4 antagonist, e.g., an antagonist CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. In another aspect, the cancer immunotherapeutic agent is a PD-1 antagonist, e.g., an antagonist PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO 2012 / 145493). Cancer immunotherapeutic agents may also include pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned. Another approach to targeting the PD-1 receptor is a recombinant protein called AMP-224, which consists of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0150] In another embodiment, the cancer immunotherapeutic agent is a PD-L1 antagonist, such as an antagonist PD-L1 antibody. Suitable PD-L1 antibodies include, for example, TECENTRIQ (atezolizumab) (RG7446; WO 2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO 2007 / 005874), and MSB0010718C (WO 2013 / 79174).

[0151] In another embodiment, the cancer immunotherapeutic agent is a LAG-3 antagonist, for example, 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).

[0152] In another embodiment, the cancer immunotherapeutic agent is a CD137 (4-1BB) agonist, such as an agonist CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO 2012 / 32433).

[0153] In another embodiment, the cancer immunotherapeutic agent is a GITR agonist, for example, 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).

[0154] In another embodiment, cancer immunotherapeutic agent is IDO antagonist.Suitable IDO antagonist includes, for example, INCB-024360 (WO2006 / 122150, WO2007 / 75598, WO2008 / 36653, WO2008 / 36642), indoximod or NLG-919 (WO2009 / 73620, WO2009 / 1156652, WO2011 / 56652, WO2012 / 142237).

[0155] In another embodiment, the cancer immunotherapeutic agent is an OX40 agonist, for example, an agonist OX40 antibody.Suitable OX40 antibody includes, for example, MEDI-6383 or MEDI-6469.In another embodiment, the cancer immunotherapeutic agent is an OX40L antagonist, for example, an antagonist OX40 antibody.Suitable OX40L antagonist includes, for example, RG-7888 (WO06 / 029879).

[0156] In another aspect, the cancer immunotherapeutic agent is a CD40 agonist, for example, an agonist CD40 antibody. In yet another embodiment, the cancer immunotherapeutic agent is a CD40 antagonist, for example, an antagonist CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0157] In another embodiment, the cancer immunotherapeutic agent is a CD27 agonist, such as an agonist CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0158] In another embodiment, the cancer immunotherapeutic agent is MGA271 (against B7H3) (WO 2011 / 109400). [Example]

[0159] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the claims to the examples.

[0160] 1) Preparation example Unless otherwise noted, all reactions and intermediates were prepared under an argon atmosphere.

[0161] 1.1) General Procedure Reduction of the nitro group: General procedure 2 To a solution of the intermediate of formula (IV) (23 mmol) in EtOH (112 mL) and water (18.7 mL) was added 1N aqueous hydrogen chloride solution (2.3 mL). The reaction mixture was heated to 50° C. and iron (8.99 g, 161 mmol) was added to the hot, stirred solution. The temperature was raised to 80° C. and stirred for 3.5 hours. The reaction mixture was cooled to room temperature, filtered through Celite, washed with ethyl acetate, and concentrated under reduced pressure. The desired product (V) was used crude in the next step. Cyclization: General Procedure 3 To a solution of intermediate (V) (5.74 mmol) in DMF (15 mL) was added DIPEA (1.85 g, 2.51 mL, 14.4 mmol, 2.5 equiv.) and a 50% solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in EtOAc (7.31 g, 6.76 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water, extracted twice with DCM, washed with 1 M aqueous NaOH, 1 M aqueous HCl, and saturated aqueous NaCl, dried over NaSO, filtered, and concentrated in vacuo. The desired product (VI) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC. Alkylation: General Procedure 4 To a solution of the intermediate of formula (VI) (2.74 mmol) in DMSO (10 mL) at room temperature was added potassium carbonate (1.14 g, 8.23 mmol), potassium iodide (228 mg, 1.37 mmol), and the reagent of formula (VII) (3.29 mmol). The reaction was stirred at room temperature for 2 hours, quenched with water, and extracted twice with DCM. The combined organic layers were washed with water, saturated aqueous NaCl, dried over NaSO, filtered, and the solvent was evaporated under reduced pressure. The desired product (VIII) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC. Oxidation: General Procedure 5 A solution of intermediate of formula (VIII) (2.74 mmol) and m-CPBA (1.18 g, 6.85 mmol) in DCM (10 mL) was stirred at room temperature for 1 day. The reaction was diluted with ethyl acetate and THF, washed with 2 N aqueous sodium hydroxide, 1 N aqueous HCl, and saturated aqueous NaCl, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The desired product (IX) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC. Boc deprotection: General procedure 6a To a solution of the intermediate of formula (IX) (0.250 mmol) in EtOAc (4 mL) was added HCl / EtOAc (4.0 mL, 16 mmol, 63 equiv) at 0° C. The reaction mixture was stirred at 20° C. for 3 hours and then concentrated in vacuo. The remaining residue was purified by preparative HPLC and dried by lyophilization to give the desired product (I). Boc deprotection: General procedure 6b A solution of the intermediate of formula (IX) (22.7 μmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (1.5 mL) was stirred at reflux for 5 days, the solvent was evaporated, and the remaining residue was dried under high vacuum to give the desired product (I). Boc deprotection: General procedure 6c To a solution of the intermediate of formula (IX) (0.250 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (4 mL) was added HCl / dioxane or HCl / EtO (0.5 mmol, 2 equivalents) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The solvent was evaporated, and the resulting solid was dissolved in DCM and concentrated again to remove traces of 1,1,1,3,3,3-hexafluoropropan-2-ol. This process was repeated twice, followed by drying under high vacuum to give the desired product (I). Hydrazide Coupling: General Procedure 7 To a solution of the intermediate of formula (XIII) (0.5 mmol) in THF (5 ml) was added a carboxylic acid of formula R10CO2H (0.5 mmol), DIPEA (1.5 mmol), and T3P (50% in EtOAc, 1.5 mmol). The resulting solution was stirred at 60 °C for 2 h. The reaction was then cooled to room temperature and diluted with water. The mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XIV) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC. 1,3,4-Oxadiazole Cyclization: General Procedure 8 To a solution of the intermediate of formula (XIV) (0.3 mmol) in THF (3 ml) was added Burgess reagent (0.9 mmol). The resulting solution was stirred at room temperature overnight. Water was added, and the mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XV) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC. Amide oxime coupling with RCO2H: General procedure 10a To a solution of the intermediate of formula (XVII, where R is H) (1.0 mmol) in THF (8.5 ml) was added a carboxylic acid of formula RCOH (0.12 mmol), DIPEA (2.0 mmol), and HATU (0.15 mmol), and the reaction was stirred at room temperature for 4 hours. Water and EtOAc were added, and the layers were separated. The aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XVII, where R is —CO(R)) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC. Amide oxime coupling with RCO2H: General procedure 10b To a solution of the intermediate of formula (XVII, where R is H) (0.2 mmol) in DMF (1.5 ml) was added a carboxylic acid of formula RCOH (0.24 mmol), EDC hydrochloride (0.4 mmol), DIPEA (0.6 mmol), and HOBt (0.3 mmol), and the resulting mixture was stirred at room temperature for 16 hours. Water and EtOAc were added, the layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XVII, where R is —CO(R)) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC. 1,2,4-Oxadiazole Cyclization: General Procedure 11 A solution of the intermediate of formula (XVII, where R is -CO(R10)) (0.15 mmol) in toluene (1 ml) was heated to 120°C for 16 hours. The solvent was then evaporated under reduced pressure. The desired product (XVIII) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC. Amidoxime formation: General procedure 12 To a solution of the intermediate of formula (VIII) (0.3 mmol) in EtOH (2.5 ml) was added solid NaHCO (1.5 mmol) and hydroxylamine hydrochloride (0.6 mmol). The resulting suspension was heated to 80° C. for 90 minutes and then cooled to room temperature. The suspension was filtered, and the filter cake was washed with EtOH and DCM. The filtrate was concentrated under reduced pressure, and the remaining solid was dissolved in DCM, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XVII) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC. Saponification: General Procedure 13 To a solution of the intermediate of formula (VIII) (4 mmol) in THF (18 ml), MeOH (3 ml), and water (6 ml) was added LiOH hydrate (8 mmol) and stirred at room temperature for 2 hours. 1N aqueous HCl was added, and the resulting suspension was extracted three times with EtOAc. The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XII) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC. Hydrazide formation: General procedure 14 To a solution of the intermediate of formula (XII) (4.5 mmol) in THF (20 ml), CDI (5.7 mmol) was added and stirred at room temperature for 90 minutes. A mixture of hydrazine hydrate (13.5 mmol) in THF (3.3 ml) was then added to this solution and stirred for 1 hour. The reaction mixture was diluted with water and EtOAc. The layers were separated, and the aqueous phase was washed twice with EtOAc. The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The desired product (XIII) was used crude in the next step or purified by flash column chromatography on silica gel or reverse-phase preparative HPLC.

[0162] Example 19 (3R)-3-Amino-5-[[4-(1-ethylpropoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one TIFF2025526727000016.tif47170

[0163] Step a) (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylic acid To a solution of methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (30.0 g, 85.1 mmol, 1 equiv.) (CAS: 2089150-62-7) in THF (300 mL) was added a solution of NaOH (5.11 g, 127.7 mmol, 1.5 equiv.) in water (300 mL) at 0° C. The mixture was stirred at room temperature for 7 h. At 0° C., 0.5 M aqueous HCl was added to the reaction mixture, which was then warmed to room temperature. EtOAc was added, and the layers were separated. The aqueous phase was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (29.4 g, 86.8 mmol, 91% yield) as a yellow solid. MS (ESI): 283.0 [M+H-isobutene] + .

[0164] Step b) tert-Butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate To a solution of (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylic acid (29.4 g, 86.8 mmol, 1 equiv.) and DIPEA (45.4 mL, 260.6 mmol, 3 equiv.) in DCM (400 mL), T3P (50 wt.% in EtOAc, 66.8 mL, 130.3 mmol, 1.5 equiv.) was added at room temperature, and the reaction was stirred for 30 minutes. The reaction mixture was then transferred via a dropping funnel to a solution of hydrazine hydrate (17.2 mL, 347.5 mmol, 4 equiv.) in DCM (190 mL). The reaction mixture was stirred at room temperature for 3 hours, during which time a yellow precipitate formed. The mixture was concentrated and the crude material was purified by preparative HPLC to give the title compound (6 g, 17.0 mmol, 19% yield) as a white solid. MS (ESI): 297.1 [M+H-isobutene] + .

[0165] Step c) tert-butyl N-[(3R)-7-[[(2-methyl-2-methylsulfonyl-propanoyl)amino]carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (5.0 g, 14.2 mmol, 1 equiv.), 2-methyl-2-methylsulfonyl-propanoic acid (3.3 g, 19.8 mmol, 1.4 equiv.), and DIPEA (12.5 mL, 71.7 mmol, 5.06 equiv.) in THF (100 mL) was added T3P (50 wt.% in EtOAc, 19.0 g, 29.8 mmol, 2.1 equiv.). The mixture was stirred at 60 °C for 3 h. The solution was poured into water (300 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, and concentrated. The crude residue was purified by preparative HPLC to give the title compound (5.6 g, 11.1 mmol, 77% yield) as an orange solid. MS (ESI): 445.1 [M+H-isobutene] + .

[0166] Step d) tert-butyl N-[(3R)-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-7-[[(2-methyl-2-methylsulfonyl-propanoyl)amino]carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (1.8 g, 3.6 mmol) in analogy to general procedure 8 in TIFF2025526727000020.tif36170 as a yellow solid (1.6 g, 89% yield). MS (ESI): 427.0 [M+H-isobutene] + .

[0167] Step e) tert-butyl N-[(3R)-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (800.0 mg, 1.66 mmol) in analogy to TIFF2025526727000021.tif36170 General Procedure 5 as a yellow solid (690 mg, 1.34 mmol, 78% yield). MS (ESI): 459.1 [M+H-isobutene] + .

[0168] Step f) tert-Butyl N-[(3R)-5-[[4-(1-ethylpropoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate TIFF2025526727000022.tif48170 tert-Butyl N-[(3R)-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (50.0 mg, 0.1 mmol) in DMF (1.5 mL) To a suspension of 1-(chloromethyl)-4-(1-ethylpropoxy)benzene (27.0 mg, 0.13 mmol, 1.31 equiv., CAS 248262-55-7) (1.1, 1 equiv.), potassium iodide (10.0 mg, 0.06 mmol, 0.62 equiv.), and potassium carbonate (40.0 mg, 0.29 mmol, 2.98 equiv.), 1-(chloromethyl)-4-(1-ethylpropoxy)benzene (27.0 mg, 0.13 mmol, 1.31 equiv., CAS 248262-55-7) was added and stirred at room temperature for 12 hours. The mixture was then poured into water (40 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The remaining residue was purified by preparative TLC (PE / EtOAc = 1:1) to afford the desired title compound (50 mg, 0.07 mmol, 75% yield) as a colorless oil. MS (ESI): 635.3 [M+H-isobutene] + .

[0169] Step g) (3R)-3-amino-5-[[4-(1-ethylpropoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one The title compound was prepared from tert-butyl N-[(3R)-5-[[4-(1-ethylpropoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50.0 mg, 0.07 mmol) in analogy to TIFF2025526727000023.tif47170 General Procedure 6a, and obtained as the hydrochloride salt (23.8 mg, 0.04 mmol, 52% yield) as a white solid. MS (ESI): 591.1 [M+H] + .

[0170] The examples in the table below were prepared similarly to Example 19 using the appropriate benzyl halide building blocks. TIFF2025526727000024.tif233170TIFF2025526727000025.tif223170TIFF2025526727000026.tif218170TIFF2025526727000027.tif223170 TIFF2025526727000028.tif239170TIFF2025526727000029.tif225170TIFF2025526727000030.tif228170TIFF2025526727000031.tif115170

[0171] Example 15 (3R)-3-Amino-5-[[4-[benzyl(methyl)amino]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one TIFF2025526727000032.tif47170

[0172] Step a) tert-butyl N-[(3R)-5-[[4-[benzyl(methyl)amino]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (50 mg, 0.1 mmol, 1 equiv., Example 19, step e) in toluene (1.5 mL) was added [4-[benzyl(methyl)amino]phenyl]methanol (55.2 mg, 0.24 mmol, 2.5 equiv., CAS 131719-59-0), Ph3P (0.05 mL, 0.19 mmol, 2 equiv.), and di-tert-butyl azodicarboxylate (44.7 mg, 0.19 mmol, 2 equiv.). The mixture was degassed with nitrogen and stirred at 50°C for 3 hours. The reaction was diluted with water (5 mL) and EtOAc (5 ml). The layers were separated and the aqueous phase was extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The remaining crude material was purified using column chromatography on silica gel (60% EtOAc in PE) to afford the title compound (36 mg, 0.05 mmol, 51% yield) as a pale yellow solid. MS (ESI): 724.0 [M+H-isobutene] + .

[0173] Step b) (3R)-3-amino-5-[[4-[benzyl(methyl)amino]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one The title compound was prepared from tert-butyl N-[(3R)-5-[[4-[benzyl(methyl)amino]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (36 mg, 0.05 mmol) in analogy to TIFF2025526727000034.tif47170 General Procedure 6a as a pale yellow solid (7.4 mg, 0.01 mmol, 23% yield). MS (ESI): 624.1 [M+H] + .

[0174] Example 18 in the table below was prepared similarly to Example 15 using the appropriate benzylic alcohol building block. TIFF2025526727000035.tif71170

[0175] Example 17 (3R)-3-Amino-7-[5-(1-methyl-1-methylsulfonyl-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-1λ6,5-benzothiazepin-4-one TIFF2025526727000036.tif56170

[0176] Step a) tert-butyl N-[(3R)-7-[5-(1-methyl-1-methylsulfonyl-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-1λ6,5-benzothiazepin-3-yl]carbamate TIFF2025526727000037.tif57170 tert-Butyl N-[(3R)-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (40 mg, 0.08 mmol, 1 equiv., actual) in DMF (1 mL) Example 19, step e), to a solution of KI (6.45 mg, 0.04 mmol, 0.5 equiv.) and potassium carbonate (32.23 mg, 0.23 mmol, 3 equiv.) was added a solution of 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (28.6 mg, 0.09 mmol, 1.2 equiv.) in DMF (0.5 mL) at 20° C. The reaction mixture was stirred at that temperature for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (8 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The remaining residue was purified by preparative TLC (60% EtOAc in PE) to give the title compound (45 mg, 0.06 mmol, 78% yield) as a white solid. MS (ESI): 685.2 [M+H-isobutene] + .

[0177] Step b) (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-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-1λ6,5-benzothiazepin-4-one The title compound was prepared from tert-butyl N-[(3R)-7-[5-(1-methyl-1-methylsulfonyl-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-1λ6,5-benzothiazepin-3-yl]carbamate (40 mg, 0.05 mmol) in analogy to TIFF2025526727000038.tif56170 general procedure 6a, and obtained as the hydrochloride salt (34.3 mg, 0.05 mmol, 93% yield) as a white solid. MS (ESI): 641.2 [M+H] + .

[0178] The examples in the table below were prepared similarly to Example 17 using the appropriate carboxylic acid building blocks. TIFF2025526727000039.tif184170

[0179] Example 48 (3R)-3-Amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[(6-phenoxy-3-pyridyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one TIFF2025526727000040.tif38170

[0180] Step a) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 43, step c), 54 mg, 0.108 mmol) in analogy to TIFF2025526727000041.tif31170 General Procedure 5, and obtained as a white powder (28.5 mg, 50% yield). MS (ESI): 477.2 [M-isobutene + H] + .

[0181] Step b) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[(6-phenoxy-3-pyridyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (9 mg, 0.017 mmol, 1 equiv.) using 5-(chloromethyl)-2-phenoxy-pyridine (CAS 5795855-1, 5.57 mg, 0.025 mmol, 1.5 equiv.) as a white powder (4.4 mg, 36% yield). MS (ESI): 716.4 [M+H] + .

[0182] Step c) (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[(6-phenoxy-3-pyridyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[(6-phenoxy-3-pyridyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (4.4 mg, 0.006 mmol) in analogy to TIFF2025526727000043.tif38170 general procedure 6c, and obtained as a white powder as the hydrochloride salt (4 mg, 94% yield). MS(ESI): 660.4 [M+HCOO] - .

[0183] Example 50 in the table below was prepared analogously to steps a-c) of Example 48 using the appropriate building blocks. TIFF2025526727000044.tif82170

[0184] Example 43 (3R)-3-Amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one TIFF2025526727000045.tif37170

[0185] Step a) tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (2R)-3-(2-amino-4-cyano-5-fluoro-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (200 mg, 0.59 mmol) in MeOH (2 mL) was added hydroxylamine hydrochloride (63.7 mg, 0.89 mmol, 1.5 equiv.) and sodium bicarbonate (249 mg, 2.96 mmol, 5 equiv.). The mixture was stirred at 70 °C for 16 hours, cooled to room temperature, filtered, and the filter cake was washed with DCM. The combined filtrate was concentrated in vacuo. The reaction was diluted with DCM and washed with water and brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (444 mg, 1.19 mmol, 74% yield) as a yellow solid. MS (ESI): 315.1 [M-isobutene + H] + .

[0186] Step b) [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]methylene]amino]2-methyl-2-methylsulfonyl-propanoate The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (440 mg, 1.03 mmol) similarly to general procedure 10a in TIFF2025526727000047.tif42170 as a pale yellow solid (520 mg, 97% yield). MS (ESI): 463.2 [M-isobutene + H] + .

[0187] Step c) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-(1-methyl-1-methylsulfonyl-ethoxy)carbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (520 mg, 1 mmol, 1 equiv.) analogously to TIFF2025526727000048.tif31170 General Procedure 11 as a pale yellow solid (250 mg, 47% yield). MS (ESI): 445.2 [M-isobutene + H] + .

[0188] Step d) tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (30 mg, 0.057 mmol, 1 equiv.) using 1-(bromomethyl)-4-chloro-benzene (17.55 mg, 0.085 mmol, 1.5 equiv.) as in general procedure 4 in TIFF2025526727000049.tif41170 as an off-white powder (18 mg, 49% yield). MS (ESI): 569.3 [M-isobutene + H] + .

[0189] Step e) tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (18 mg, 0.028 mmol, 1 equiv.) in analogy to TIFF2025526727000050.tif41170 General Procedure 5 as an off-white powder (20.4 mg, 108% yield). MS (ESI): 601.2 [M-isobutene + H] + .

[0190] Step f) (3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (20.4 mg, 0.031 mmol) in analogy to TIFF2025526727000051.tif37170 general procedure 6c, and obtained as the hydrochloride salt (15 mg, 80% yield) as a white solid. MS (ESI): 557.3 [M+H] + .

[0191] The examples in the table below were prepared analogously to steps d-f) of Example 43 using the appropriate building blocks. TIFF2025526727000052.tif148170

[0192] Example 30 (3R)-3-Amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one TIFF2025526727000053.tif38170

[0193] Step a) tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 53, step d) 200 mg, 0.593 mmol) using 1-(bromomethyl)-4-phenoxy-benzene (CAS 36881-42-2, 156 mg, 0.593 mmol) in analogy to TIFF2025526727000054.tif41170 General Procedure 4, as a white solid (210 mg, 67% yield). MS (ESI): 542.0 [M+Na] + .

[0194] Step b) tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (210 mg, 0.404 mmol) in analogy to TIFF2025526727000055.tif41170 General Procedure 12 as a pale yellow solid (125 mg, 49% yield). MS (ESI): 553.0 [M+H] + .

[0195] Step c) [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]methylene]amino]2-methyl-2-methylsulfonyl-propanoate The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (125 mg, 0.226 mmol) analogously to TIFF2025526727000056.tif41170 general procedure 10b as a pale yellow gum (154 mg, 93% yield). MS (ESI): 644.9 [M-isobutene + H] + .

[0196] Step d) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]methylene]amino]2-methyl-2-methylsulfonyl-propanoate (154 mg, 0.220 mmol) analogously to TIFF2025526727000057.tif41170 General Procedure 11 as a light brown gum (140 mg, 73% yield). MS (ESI): 627.0 [M-isobutene + H] + .

[0197] Step e) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(2-methyl-2-methylsulfonyl-propyl)-1,2,4-oxadiazol-3-yl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (140 mg, 0.205 mmol) in analogy to TIFF2025526727000058.tif41170 General Procedure 5 as a white solid (130 mg, 74% yield). MS (ESI): 659.1 [M-isobutene + H] + .

[0198] Step f) (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (130 mg, 0.182 mmol) in analogy to TIFF2025526727000059.tif38170 general procedure 6a and obtained as the hydrochloride salt (45.9 mg, 38% yield) as a white solid. MS (ESI): 615.0 [M+H] + .

[0199] Example 44 (3R)-3-Amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one TIFF2025526727000060.tif47170

[0200] Step a) [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]methylene]amino]2-methyl-2-methylsulfonyl-propanoate The title compound was prepared analogously to TIFF2025526727000061.tif37170 General Procedure 10a from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 43, step a)) (440 mg, 1.03 mmol, 1 equiv.) and 2-methyl-2-methylsulfonyl-propanoic acid (CAS 25841-43-4) as a pale yellow solid (520 mg, 97% yield). MS (ESI): 463.2 [M-isobutene + H] + .

[0201] Step b) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-7-yl]methylene]amino]2-methyl-2-methylsulfonyl-propanoate (520 mg, 1 mmol, 1 equiv.) analogously to TIFF2025526727000062.tif38170 General Procedure 11 as a white solid (250 mg, 47% yield). MS(ESI): 499.3 [MH] - .

[0202] Step c) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (30 mg, 0.057 mmol, 1 equiv.) and 1-(bromomethyl)-4-(trifluoromethoxy)benzene (CAS 50824-05-0) in analogy to general procedure 4 of TIFF2025526727000063.tif48170 as an off-white solid (31 mg, 79% yield). MS (ESI): 619.3 [M-isobutene + H] + .

[0203] Step d) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-4-oxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (31 mg, 0.046 mmol, 1 equiv.) in analogy to TIFF2025526727000064.tif48170 General Procedure 5 as an off-white solid (22 mg, 68% yield). MS(ESI): 651.4 [MH] - .

[0204] Step e) (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (22 mg, 0.031 mmol, 1 equiv.) in analogy to TIFF2025526727000065.tif47170 general procedure 6c, and obtained as the hydrochloride salt as a white solid (9.9 mg, 48% yield). MS (ESI): 607.3 [M+H] + .

[0205] Example 2 (3R)-3-Amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one TIFF2025526727000066.tif33170

[0206] Step a) Methyl (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylate The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (CAS: 2002449-38-7) (5.67 g, 13.77 mmol, 1 equiv.) in analogy to general procedure 4 in TIFF2025526727000067.tif37170 as a pale yellow solid (2699 mg, 36% yield). MS (ESI): 439.3 [M-isobutene + H] + .

[0207] Step b) (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (300 mg, 606 μmol, 1 equiv.) analogously to TIFF2025526727000068.tif37170 General Procedure 13 as a yellow oil (280 mg, 512 μmol, 85% yield). MS (ESI): 425.2 [M-isobutene + H] + .

[0208] Step c) tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (2.9 g, 6.03 mmol, 1 equiv.) analogously to general procedure 14 in TIFF2025526727000069.tif37170 as a pale yellow solid (1.9 g, 64% yield). MS (ESI): 439.3 [M-isobutene + H] + .

[0209] Step d) tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate TIFF2025526727000070.tif37170 tert-Butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (100 mg, 0.20 mmol, 1.0 equiv.) was dissolved in THF (2 mL), and 2-mesyl-2-methyl-propionic acid (36.9 mg, 0.22 mmol, 1.1 equiv.), HATU (84.5 mg, 0.22 mmol, 1.1 equiv.), and DIEA (52.2 mg, 70.6 µL, 0.40 mmol, 2.0 equiv.) were added to give a yellow solution. The mixture was stirred at room temperature for 45 min. Burgess reagent (240.7 mg, 1.01 mmol, 5 equiv) was added, and the reaction mixture was stirred at room temperature for 60 min. The crude material was concentrated under reduced pressure, and the remaining solid was purified by flash chromatography on silica gel (0-50% EtOAc in heptane) to afford the title compound (44 mg, 31% yield) as a pale yellow solid. MS (ESI): 569.2 [M-isobutene + H] + .

[0210] Step e) (3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one The title compound was prepared from tert-butyl N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (49 mg, 0.075 mmol, 1 equiv.) in analogy to TIFF2025526727000071.tif36170 general procedure 6a, and obtained as the hydrochloride salt (12 mg, 26% yield) as a pale yellow solid. MS (ESI): 557.2 [M+H] + .

[0211] The examples in the table below were prepared similarly to Example 2 using the appropriate carboxylic acid building blocks. TIFF2025526727000072.tif71170

[0212] Example 53 (3R)-3-Amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one TIFF2025526727000073.tif46170

[0213] Step a) 4-[4-(chloromethyl)phenyl]tetrahydropyran To a solution of (4-tetrahydropyran-4-ylphenyl)methanol (CAS: 1276024) (300 mg, 1.56 mmol, 1 equiv.) in DCM (10 mL) was added thionyl chloride (0.4 mL, 5.65 mmol, 3.6 equiv.) via syringe at room temperature. The solution was stirred at room temperature for 12 hours. The mixture was poured into water (50 mL), and the pH was adjusted to approximately pH 9 by the slow addition of solid NaHCO3. The solution was extracted with DCM (100 mL). The organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (330 mg, 1.57 mmol, 95% yield) as a pale yellow oil. MS (ESI): 211.2 [M+H] + .

[0214] Step b) (2R)-2-(tert-butoxycarbonylamino)-3-(4-cyano-5-fluoro-2-nitro-phenyl)sulfanyl-propanoic acid TIFF2025526727000075.tif41170 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, 2 equiv.). The reaction mixture was stirred at 22 °C for 24 h, diluted with DCM (40 mL), washed once with 1N aqueous HCl, and extracted twice with DCM. The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered, and concentrated in vacuo to give a yellow solid (23.5 g) containing the title compound. MS (ESI): 286.1 [M-isobutene + H] + .

[0215] Step c) (2R)-3-(2-amino-4-cyano-5-fluoro-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid The title compound was prepared from (2R)-2-(tert-butoxycarbonylamino)-3-(4-cyano-5-fluoro-2-nitro-phenyl)sulfanyl-propanoic acid (23 g, 57.9 mmol) analogously to general procedure 2 in TIFF2025526727000076.tif42170 and obtained as a black solid (23 g, 48.1 mmol, 80% yield). MS (ESI): 300.1 [M-isobutene + H] + .

[0216] Step d) tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from (2R)-3-(2-amino-4-cyano-5-fluoro-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (23 g, 48.1 mmol) in analogy to general procedure 3 in TIFF2025526727000077.tif25170 as a pale yellow solid (8.4 g, 24.9 mmol, 48% yield). MS (ESI): 282.1 [M-isobutene + H] + .

[0217] Step e) tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate To a solution of 4-[4-(chloromethyl)phenyl]tetrahydropyran (Example 53, Step a) (224.83 mg, 1.07 mmol, 1.2 equiv.), KCO (245.8 mg, 1.78 mmol, 2.0 equiv.), and KI (73.8 mg, 0.44 mmol, 0.5 equiv.) in DMF (6 mL) was added dropwise a solution of tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (300.0 mg, 0.89 mmol, 1.0 equiv.) in DMF (3 mL) at room temperature, and the mixture was stirred for 12 hours. The reaction mixture was poured into water and extracted with EtOAc (3×). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to give the title compound (500 mg, 0.97 mmol, 100% yield) as a pale yellow oil. MS (ESI): 412.2 [M-isobutene + H] + .

[0218] Step f) tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate TIFF2025526727000079.tif47170 To a solution of tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (400 mg, 0.78 mmol, 1 equiv.) and DIPEA (0.53 mL, 3.13 mmol, 4.0 equiv.) in EtOH (5 mL), hydroxylamine hydrochloride (165.3 mg, 2.35 mmol, 3 equiv.) was added and stirred at 50° C. for 3 h. The reaction mixture was concentrated under reduced pressure. EtOAc and water were added, and the layers were separated. The aqueous phase was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (400 mg, 0.73 mmol, 83% yield) as a white solid. MS (ESI): 545.3 [M+H] + .

[0219] Step g) [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]methylene]amino]2-methyl-2-methylsulfonyl-propanoate The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[(4-(tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (350 mg, 0.6 mmol) analogously to TIFF2025526727000080.tif47170 General Procedure 10a as a pale yellow solid (481 mg, 92% yield). MS (ESI): 693.2 [M+H] + .

[0220] Step h) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-4-oxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]methylene]amino]2-methyl-2-methylsulfonyl-propanoate (500 mg, 0.7 mmol, 1 equiv.) analogously to TIFF2025526727000081.tif47170 General Procedure 11 as a pale yellow solid (136 mg, 28% yield). MS (ESI): 575.4 [M+H] + .

[0221] Step i) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-4-oxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (130 mg, 0.2 mmol, 1 equiv.) in analogy to TIFF2025526727000082.tif47170 General Procedure 5 as an off-white solid (120 mg, 88% yield). MS (ESI): 607.3 [M-isobutene + H] + .

[0222] Step j) (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50.0 mg, 0.1 mmol) in analogy to TIFF2025526727000083.tif46170 General Procedure 6a, and obtained as the hydrochloride salt (30.6 mg, 0.05 mmol, 70% yield) as a white solid. MS (ESI): 607.3 [M+H] + .

[0223] The examples in the table below were prepared similarly to Example 53 using the appropriate benzyl halide building blocks. TIFF2025526727000084.tif76170

[0224] Example 35 (3R)-3-Amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one TIFF2025526727000085.tif53170

[0225] Step a) (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylic acid To a solution of methyl (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (CAS: 2002449-38-7) (8.5 g, 22.9 mmol, 1 equiv.) in THF (150 mL) was added a solution of NaOH (1220 mg, 30.5 mmol, 1.33 equiv.) in water (150 mL) at 0° C. The mixture was then stirred at room temperature for 9 hours. The reaction mixture was added dropwise to 0.5 M aqueous HCl (70 mL). The mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (5700 mg, 15.99 mmol, 57% yield) as a white solid. MS (ESI): 301.0 [M+H] + .

[0226] Step b) tert-butyl N-[(3R)-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate TIFF2025526727000087.tif26170 (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylic acid (202.6 mg, 0.55 mmol, 1 equiv.) and CDI (116.2 mg, 0.72 mmol, 1.3 equiv.) were dissolved in THF (2.4 mL) and stirred at room temperature for 30 minutes. This solution was then added dropwise to a solution of hydrazine monohydrate (53.0 mg, 51.5 µL, 1.65 mmol, 3 equiv.) in THF (0.8 mL) and stirred for 30 minutes. The reaction mixture was partially concentrated under reduced pressure and diluted with EtOAc. The solution was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound (214.7 mg, 100%) as a pale yellow solid. MS(ESI): 369.3 [MH].

[0227] Step c) tert-butyl N-[(3R)-8-fluoro-7-[[(2-methyl-2-methylsulfonyl-propanoyl)amino]carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate To a mixture of 2-methyl-2-methylsulfonylpropanoic acid (0.27 g, 1.62 mmol, 1.2 equiv.), tert-butyl N-[(3R)-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (0.5 g, 1.35 mmol, 1.0 equiv.), and N,N-diisopropylethylamine (0.59 mL, 3.37 mmol, 2.5 equiv.) in THF (10 mL), T3P (1.81 g, 2.84 mmol, 2.1 equiv.) in EtOAc was added at room temperature and stirred for 16 h. The solution was poured into water (10 mL) and extracted with EtOAc (10 mL). The organic phase was washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (570 mg, 1.1 mmol, 80% yield) as a white solid. MS (ESI): 445.1 [M-isobutene + H] + .

[0228] Step d) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[[(2-methyl-2-methylsulfonyl-propanoyl)amino]carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (1800 mg, 3.5 mmol) in 1,4-dioxane analogously to TIFF2025526727000089.tif31170 General Procedure 8 as a yellow solid (1000 mg, 2 mmol, 54% yield). MS (ESI): 445.1 [M-isobutene + H] + .

[0229] Step e) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (1000 mg, 2 mmol) in analogy to TIFF2025526727000090.tif28170 General Procedure 5 as a white solid (1000 mg, 1.88 mmol, 85% yield). MS (ESI): 477.0 [M-isobutene + H] + .

[0230] Step f) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-3,5-dihydro-2H-1λ6,5-benzothiazepin-3-yl]carbamate (50 mg, 0.1 mmol) in analogy to TIFF2025526727000091.tif52170 General Procedure 4 as a white solid (50 mg, 0.07 mmol, 63% yield). MS (ESI): 710.8 [M - isobutene + H] + .

[0231] Step g) (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (45 mg, 0.1 mmol) in analogy to TIFF2025526727000092.tif53170 general procedure 6a, and obtained as the hydrochloride salt (14.9 mg, 0.02 mmol, 35% yield) as a white solid. MS (ESI): 667.2 [M+H] + .

[0232] The examples in the table below were prepared similarly to Example 35 using the appropriate benzyl halide building blocks. TIFF2025526727000093.tif233170TIFF2025526727000094.tif184170

[0233] Example 59 (3R)-3-Amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[4-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methoxy]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one TIFF2025526727000095.tif51170

[0234] Step a) tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-triisopropylsilyloxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 53, step d) (100 mg, 0.3 mmol) in analogy to TIFF2025526727000096.tif52170 General Procedure 4 as a colorless oil (100 mg, 0.17 mmol, 52% yield). MS (ESI): 622.2 [M+Na] + .

[0235] Step b) tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[(4-triisopropylsilyloxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-triisopropylsilyloxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (470 mg, 0.8 mmol) in analogy to TIFF2025526727000097.tif51170 General Procedure 12 as a colorless oil (390 mg, 0.62 mmol, 71% yield). MS (ESI): 633.3 [M+H] + .

[0236] Step c) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-4-oxo-5-[(4-triisopropylsilyloxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[(4-triisopropylsilyloxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (390 mg, 0.62 mmol, 1.0 equiv), DIEA (106.4 mg, 0.92 mmol, 1.5 equiv) and 2-methyl-2-methylsulfonyl-propanoic acid (112.6 mg, 0.68 mmol, 1.1 equiv) in toluene (5 mL) was added T3P (784.0 mg, 1.23 mmol, 2.0 equiv) in EtOAc at 100°C and stirred for 12 h. The reaction was concentrated under reduced pressure and the remaining crude material was purified by silica gel chromatography (20% EtOAc in petroleum ether) to give the title compound (320 mg, 0.42 mmol, 54% yield) as a colorless oil. MS (ESI): 785.2 [M+Na] + .

[0237] Step c) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[(4-triisopropylsilyloxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-4-oxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (200 mg, 0.3 mmol) in analogy to TIFF2025526727000099.tif47170 General Procedure 5 as a colorless oil (180 mg, 0.23 mmol, 81% yield). MS (ESI): 817.1 [M+Na] + .

[0238] Step d) tert-butyl N-[(3R)-8-fluoro-5-[(4-hydroxyphenyl)methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate To a mixture of tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[(4-triisopropylsilyloxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (175 mg, 0.22 mmol, 1.0 equiv.) in DMF (2 mL) was added CsF (100.3 mg, 0.66 mmol, 3.0 equiv.) at room temperature and stirred for 12 h. The reaction was quenched by the addition of water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (120 mg, 0.19 mmol, 85% yield) as a colorless oil. MS (ESI): 639.2 [M+H] + .

[0239] Step e) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[[4-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methoxy]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate TIFF2025526727000101.tif61170 tert-Butyl N-[(3R)-8-fluoro-5-[(4-hydroxyphenyl)methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate ( To a mixture of 5-(chloromethyl)-3-(trifluoromethyl)-1,2,4-oxadiazole (CAS: 1000442-49-7) (20.4 mg, 0.11 mmol, 1.0 equiv.) and K2CO3 (30.2 mg, 0.22 mmol, 2.0 equiv.) was added 5-(chloromethyl)-3-(trifluoromethyl)-1,2,4-oxadiazole (CAS: 1000442-49-7) (20.4 mg, 0.11 mmol, 1.0 equiv.) and KI (18.2 mg, 0.11 mmol, 1.0 equiv.) at 50 °C and stirred for 1 h. The reaction was quenched by the addition of water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining residue was purified by preparative HPLC to afford the title compound (20 mg, 0.03 mmol, 23% yield) as a colorless oil upon lyophilization. MS (ESI): 789.2 [M+H] + .

[0240] Step f) (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-5-[[4-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methoxy]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-5-[[4-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methoxy]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (12 mg, 0.02 mmol) in analogy to TIFF2025526727000102.tif61170 general procedure 6a, and obtained as the hydrochloride salt (6 mg, 0.01 mmol, 51.2% yield) as a white solid. MS (ESI): 689.2 [M+H] + .

[0241] Examples 51 and 52 (3R)-3-Amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ4,5-benzothiazepin-4-one [Epimer A] and (3R)-3-Amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ4,5-benzothiazepin-4-one [Epimer B] TIFF2025526727000103.tif42170

[0242] Step a) tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (Example 53, step d) (500 mg, 1.5 mmol) in analogy to TIFF2025526727000104.tif43170 General Procedure 4 as a white solid (570 mg, 1.1 mmol, 73% yield). MS (ESI): 542.2 [M+Na] + .

[0243] Step b) tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (200 mg, 0.34 mmol) in analogy to TIFF2025526727000105.tif43170 General Procedure 12 as a white solid (210 mg, 95% yield). MS (ESI): 553.4 [M+H] + .

[0244] Step c) [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]methylene]amino]2-methyl-2-methylsulfonyl-propanoate The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[(4-(tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (112.3 mg, 0.17 mmol) analogously to TIFF2025526727000106.tif43170 General Procedure 10a as a white powder (119.5 mg, 91% yield). MS (ESI): 559.3 [M-isobutene + H] + .

[0245] Step d) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-7-yl]methylene]amino]2-methyl-2-methylsulfonyl-propanoate (119.5 mg, 0.16 mmol) analogously to TIFF2025526727000107.tif43170 General Procedure 11 and obtained as a white powder (89 mg, 81% yield). MS (ESI): 627.3 [M-isobutene + H] + .

[0246] Step e) tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,4-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (epimer A) and tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,4-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate (epimer B) The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (89 mg, 0.13 mmol) using m-CPBA (28.6 mg, 0.13 mmol, 1 equiv.) as per TIFF2025526727000108.tif43170 General Procedure 5. The two epimers were separated as white powders (45.9 mg, 50% yield, epimer A) and white powders (21.9 mg, 24% yield, epimer B). For both products, MS(ESI): 643.2 [M+H-isobutene] + .

[0247] Step f1) (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ4,5-benzothiazepin-4-one [epimer A] The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,4-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate [epimer A] (45.9 mg, 0.07 mmol) in analogy to TIFF2025526727000109.tif42170 general procedure 6c, and obtained as a white powder as the hydrochloride salt (39.7 mg, 88% yield). MS (ESI): 599.2 [M+H] + .

[0248] Step f2) (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ4,5-benzothiazepin-4-one [epimer B] The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,4-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ4,5-benzothiazepin-3-yl]carbamate [epimer B] (21.9 mg, 0.03 mmol) in analogy to general procedure 6c in TIFF2025526727000110.tif42170, and obtained as a white powder as the hydrochloride salt (20.2 mg, 94% yield). MS (ESI): 599.2 [M+H] + .

[0249] Example 63 (3R)-3-Amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one TIFF2025526727000111.tif52170

[0250] Step a) (2R)-2-(tert-butoxycarbonylamino)-3-(4-cyano-2-nitro-phenyl)sulfanyl-propanoic acid To a solution of 4-fluoro-3-nitrobenzonitrile (10.0 g, 60.2 mmol) in DCM (200 mL) was added (2R)-2-(tert-butoxycarbonylamino)-3-sulfanyl-propanoic acid (14.6 g, 66.2 mmol, 1.1 equiv.) and DIPEA (20.5 mL, 120.4 mmol, 2 equiv.), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the remaining residue was dissolved in 200 mL of EtOAc and washed with 1N aqueous HCl (50 mL), water (100 mL), and brine (50 mL × 2). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (24 g, 65.3 mmol, 77% yield) as a yellow solid. MS(ESI):390.1[M+Na] + .

[0251] Step b) (2R)-3-(2-amino-4-cyano-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid The title compound was prepared from (2R)-2-(tert-butoxycarbonylamino)-3-(4-cyano-2-nitrophenyl)sulfanyl-propanoic acid (10.0 g, 27.2 mmol) in analogy to TIFF2025526727000113.tif22170 General Procedure 2 and obtained as a brown solid (10 g, 87% yield). MS (ESI): 338.2 [M+H] + .

[0252] Step c) tert-Butyl N-[(3R)-7-cyano-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate The title compound was prepared from (2R)-3-(2-amino-4-cyano-phenyl)sulfanyl-2-(tert-butoxycarbonylamino)propanoic acid (11.3 g, 33.5 mmol) analogously to general procedure 3 in TIFF2025526727000114.tif25170 as a white solid (5 g, 45% yield). MS (ESI): 263.9 [M-isobutene + H] + .

[0253] Step d) tert-butyl N-[(3R)-7-cyano-5-[[4-(4-methoxyphenyl)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-7-cyano-4-oxo-3,5-dihydro-2H-1,5-benzothiazepin-3-yl]carbamate (300.0 mg, 0.89 mmol, 1.0 equiv.), potassium iodide (0.01 g, 0.18 mmol, 0.2 equiv.), and sodium carbonate (237 mg, 2.24 mmol, 2.5 equiv.) in DMF (2 mL) was added a solution of 1-(chloromethyl)-4-(4-methoxyphenyl)benzene (218.5 mg, 0.94 mmol, 1.05 equiv.) in DMF (2 mL) at room temperature, and the mixture was stirred at 40° C. for 12 h. The solution was poured into water and extracted with EtOAc (3×). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel (0-50% EtOAc in heptane) to give the title compound (460 mg, 0.89 mmol, 69% yield) as a yellow solid. MS (ESI): 460.0 [M-isobutene + H] + .

[0254] Step e) tert-butyl N-[(3R)-7-cyano-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-7-cyano-5-[[4-(4-methoxyphenyl)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (450 mg, 0.9 mmol) in analogy to TIFF2025526727000116.tif52170 General Procedure 5 as a yellow solid (360 mg, 0.66 mmol, 44.4% yield). MS (ESI): 548.1 [M+H] + .

[0255] Step f) tert-Butyl N-[(3R)-7-[(Z)-N'-hydroxycarbamimidoyl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate A solution of tert-butyl N-[(3R)-7-cyano-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (350 mg, 0.64 mmol, 1.0 equiv.), sodium acetate (157.2 mg, 1.92 mmol, 3.0 equiv.), and hydroxylamine hydrochloride (66.6 mg, 0.96 mmol, 1.5 equiv.) in EtOH (5 mL) was stirred at 50° C. for 12 h. The reaction was concentrated in vacuo to give a suspension, which was poured into water. The aqueous phase was extracted with EtOAc (3×). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (360 mg, 0.62 mmol, 97% yield) as a yellow solid. MS (ESI): 581.4 [M+H] + .

[0256] Step g) [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]methylene]amino]2-methyl-2-methylsulfonyl-propanoate The title compound was prepared from tert-butyl N-[(3R)-7-[(Z)-N'-hydroxycarbamimidoyl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (10 mg, 0.02 mmol, 1 equiv.) analogously to TIFF2025526727000118.tif53170 General Procedure 10a as a yellow oil (10 mg, 0.01 mmol, 80% yield). MS (ESI): 729.0 [M+H] + .

[0257] Step h) tert-butyl N-[(3R)-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]methylene]amino]2-methyl-2-methylsulfonyl-propanoate (280 mg, 0.4 mmol, 1 equiv.) analogously to TIFF2025526727000119.tif56170 General Procedure 11 as a yellow solid (100 mg, 0.14 mmol, 37% yield). MS (ESI): 733.2 [M+Na] + .

[0258] Step i) (3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepin-4-one The title compound was prepared from tert-butyl N-[(3R)-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (95 mg, 0.13 mmol, 1 equiv.) in analogy to TIFF2025526727000120.tif53170 general procedure 6a, and obtained as the hydrochloride salt (85.6 mg, 0.13 mmol, 96% yield) as a yellow solid. MS (ESI): 611.3 [M+H] + .

[0259] Example 68 (3R)-3-Amino-7-[5-(1-methylsulfonylcyclobutyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one TIFF2025526727000121.tif41170

[0260] Step a) Methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylate The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (1.0 g, 2.84 mmol, 1.0 equiv.) similarly to general procedure 4 in TIFF2025526727000122.tif42170 as a white solid (1.38 g, 87% yield). MS (ESI): 479.2 [M-isobutene + H] + .

[0261] Step b) (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (1.38 g, 2.58 mmol, 1.0 equiv.) analogously to TIFF2025526727000123.tif43170 General Procedure 13 as a yellow foam (1.54 g, 97% yield). MS (ESI): 465.1 [M-isobutene + H] + .

[0262] Step c) (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine-7-carboxylic acid Sodium periodate (1.11 g, 5.19 mmol, 2.34 equiv.) was dissolved in water (8.5 mL) and the mixture was cooled to 0 °C under Ar. RuCl3.3HO (5.81 mg, 0.022 mmol, 0.01 equiv.) was added and the reaction was stirred for 5 min. Then, a solution of (3R)-3-(tert-butoxycarbonylamino)-4-keto-5-(4-phenoxybenzyl)-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (1.36 g, 2.22 mmol, 1.0 equiv.) in acetonitrile (8.54 mL) was added in one portion and stirred for 3 h. The reaction was quenched by the addition of iPrOH (2 mL), EtOAc, and 2 M aqueous HCl. The gray suspension was filtered through a plug of Celite and the filtrate was extracted with EtOAc. The combined organic phases were washed with saturated aqueous NaSO, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (1.3 g, 99%) as a yellow solid. MS (ESI): 497.1 [M-isobutene + H] + .

[0263] Step d) tert-Butyl N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine-7-carboxylic acid (1.3 g, 2.19 mmol, 1.0 equiv.) analogously to TIFF2025526727000125.tif42170 General Procedure 14 as a white solid (980 mg, 79% yield). MS (ESI): 511.1 [M-isobutene + H] + .

[0264] Step d) tert-Butyl N-[(3R)-7-[[(1-methylsulfonylcyclobutanecarbonyl)amino]carbamoyl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (500 mg, 0.88 mmol, 1.0 equiv.) as in TIFF2025526727000126.tif42170 General Procedure 7 (CAS 1250528-75-6) as a yellow solid (260 mg, 41% yield). MS (ESI): 727.1 [M+H] + .

[0265] Step e) tert-butyl N-[(3R)-7-[5-(1-methylsulfonylcyclobutyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-7-[[(1-methylsulfonylcyclobutanecarbonyl)amino]carbamoyl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (260 mg, 0.36 mmol) analogously to TIFF2025526727000127.tif42170 General Procedure 8 as a yellow oil (120 mg, 0.17 mmol, 45% yield). MS (ESI): 653.1 [M-isobutene + H] + .

[0266] Step e) (3R)-3-amino-7-[5-(1-methylsulfonylcyclobutyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one The title compound was prepared from tert-butyl N-[(3R)-7-[5-(1-methylsulfonylcyclobutyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50 mg, 0.07 mmol) in analogy to TIFF2025526727000128.tif41170 general procedure 6a, and obtained as the hydrochloride salt (35 mg, 0.05 mmol, 64% yield) as an off-white solid. MS (ESI): 609.2 [M+H] + .

[0267] The examples in the following table can be prepared in a similar manner to Example 68 using the appropriate carboxylic acid building blocks. TIFF2025526727000129.tif179170

[0268] Example 65 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-7-yl]-1,3,4-oxadiazol-2-yl]-N,N-dimethyl-propane-2-sulfonamide TIFF2025526727000130.tif52170

[0269] Step a) Methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylate The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine-7-carboxylate (CAS: 2089150-62-7) (400 mg, 1.14 mmol) in analogy to general procedure 4 in TIFF2025526727000131.tif57170 as a pale brown oil (420 mg, 0.72 mmol, 60% yield). MS (ESI): 587.3 [M+H] + .

[0270] Step b) (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid The title compound was prepared from methyl (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylate (400 mg, 0.68 mmol, 1.0 equiv.) analogously to TIFF2025526727000132.tif58170 General Procedure 13 as a yellow solid (350 mg, 0.61 mmol, 86% yield). MS (ESI): 517.2 [M-isobutene + H] + .

[0271] Step c) (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-7-carboxylic acid To a solution of sodium periodate (821.8 mg, 3.84 mmol, 2.0 equiv.) in water (8 mL) was added RuCl (3.98 mg, 0.02 mmol, 0.01 equiv.) at 0 °C and stirred for 10 min. A solution of (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine-7-carboxylic acid (1100 mg, 1.92 mmol, 1.0 equiv.) in acetonitrile (12 mL) was added to the mixture at 0 °C and stirred at room temperature for 2 h. The reaction mixture was quenched by the slow addition of isopropanol (4 mL) under stirring. EtOAc (50 mL) was then added to the mixture, which was then carefully acidified with 0.5 N aqueous HCl to pH = 4-5. The gray suspension was filtered through a plug of Celite, and the filtrate was extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1150 mg, 1.9 mmol, 87% yield) as a pale green solid. MS (ESI): 603.1 [MH].

[0272] Step d) tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-7-carboxylic acid (2.3 g, 3.8 mmol) analogously to general procedure 14 as a light brown solid (2.2 g, 3.56 mmol, 76% yield). MS (ESI): 563.2 [M-isobutene + H] + .

[0273] Step e) tert-butyl N-[(3R)-7-[[[2-(dimethylsulfamoyl)-2-methyl-propanoyl]amino]carbamoyl]-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate TIFF2025526727000135.tif57170To a solution of 2-(dimethylsulfamoyl)-2-methyl-propanoic acid (132.55 mg, 0.68 mmol, 2.1 equiv) and N,N-diisopropylethylamine (83.57 mg, 0.65 mmol, 2.0 equiv) in DMF (2 mL) was added HATU (91.3 mg, 0.39 mmol, 1.2 equiv) at room temperature. The mixture was stirred for 25 minutes, then a solution of tert-butyl N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (200 mg, 0.32 mmol, 1.0 equiv.) in DMF (2 mL) was added and stirred at room temperature for 5 hours. The reaction mixture was poured into water, EtOAc was added, and the layers were separated. The aqueous phase was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining residue was purified by preparative TLC (100% EtOAc) to give the title compound (110 mg, 0.14 mmol, 36% yield) as a pale yellow oil. MS (ESI): 740.2 [M-isobutene + H] + .

[0274] Step f) tert-Butyl N-[(3R)-7-[5-[1-(dimethylsulfamoyl)-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-7-[[[2-(dimethylsulfamoyl)-2-methyl-propanoyl]amino]carbamoyl]-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (100 mg, 0.13 mmol) in toluene analogously to General Procedure 8 as a pale yellow oil (55 mg, 0.07 mmol, 56%). MS (ESI): 722.2 [M-isobutene + H] + .

[0275] Step f) tert-Butyl N-[(3R)-7-[5-[1-(dimethylsulfamoyl)-1-methyl-ethyl]-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-7-[5-(1-(dimethylsulfamoyl)-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (50.0 mg, 0.06 mmol) in analogy to TIFF2025526727000137.tif57170 general procedure 6a as a white solid (19.2 mg, 0.03 mmol, 41% yield). MS (ESI): 678.2 [M+H] + .

[0276] The examples in the following table can be prepared in a similar manner to Example 65 using the appropriate carboxylic acid building blocks. TIFF2025526727000138.tif69170

[0277] Example 54 (3R)-3-Amino-8-fluoro-7-[2-(methylsulfonylmethyl)tetrazol-5-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one TIFF2025526727000139.tif38170

[0278] Step a) tert-butyl N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-3-yl]carbamate (Examples 51 and 52, step a) (0.57 g, 1.1 mmol) in analogy to TIFF2025526727000140.tif42170 General Procedure 5 as a white solid (600 mg, 1.09 mmol, 98% yield). MS (ESI): 574.3 [M+Na] + .

[0279] Step b) tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-7-(2H-tetrazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (500.0 mg, 0.91 mmol, 1.0 equiv.) in toluene (10 mL) was added azido(trimethyl)silane (0.48 mL, 3.63 mmol, 4.0 equiv.) and dibutyltin oxide (50 mg, 0.2 mmol, 0.22 equiv., CAS 818-08-6). The mixture was degassed with N (3×) and then stirred at 100 °C for 3 h. After cooling to room temperature, the mixture was filtered and the filter cake was washed with toluene (5 mL) and petroleum ether (5 mL). The filtrate was concentrated under reduced pressure to give the title compound (530 mg, 0.89 mmol, 90% yield) as a gray solid. MS (ESI): 617.3 [M+Na] + .

[0280] Step c) tert-butyl N-[(3R)-8-fluoro-7-[2-(methylsulfanylmethyl)tetrazol-5-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate and tert-butyl N-[(3R)-8-fluoro-7-[1-(methylsulfanylmethyl)tetrazol-5-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-8-fluoro-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-7-(2H-tetrazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (200 mg, 0.34 mmol, 1.0 equiv), K2CO3 (92.8 mg, 0.67 mmol, 2.0 equiv), and KI (40.0 mg, 0.24 mmol, 0.71 equiv) in DMF (4 mL), chloromethyl methyl sulfide (0.03 mL, 0.37 mmol, 1.1 equiv) was added at room temperature, and the mixture was stirred for 16 h. The mixture was diluted with EtOAc (5 mL), washed with brine (5 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel (50% EtOAc in petroleum ether) to give tert-butyl N-[(3R)-8-fluoro-7-[2-(methylsulfanylmethyl)tetrazol-5-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (90 mg, 0.14 mmol, 41% yield) as a white solid, and tert-butyl N-[(3R)-8-fluoro-7-[1-(methylsulfanylmethyl)tetrazol-5-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (16 mg, 0.02 mmol, 7% yield) as a white solid. For both products, MS(ESI): 699.2 [M-isobutene+H] + .

[0281] Step d) tert-butyl N-[(3R)-8-fluoro-7-[2-(methylsulfonylmethyl)tetrazol-5-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[2-(methylsulfanylmethyl)tetrazol-5-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (80 mg, 0.15 mmol, 1.0 equiv.) analogously to TIFF2025526727000143.tif42170 General Procedure 5 as a white solid (90 mg, 0.13 mmol, 78% yield). MS (ESI): 631.2 [M-isobutene + H] + .

[0282] Step e) (3R)-3-amino-8-fluoro-7-[2-(methylsulfonylmethyl)tetrazol-5-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-4-one The title compound was prepared from tert-butyl N-[(3R)-8-fluoro-7-[2-(methylsulfanylmethyl)tetrazol-5-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepin-3-yl]carbamate (90 mg, 0.13 mmol, 1.0 equiv.) in analogy to TIFF2025526727000144.tif41170 general procedure 6a, and obtained as the hydrochloride salt (40.2 mg, 0.06 mmol, 49% yield) as a white solid. MS (ESI): 587.3 [M+H] + .

[0283] The examples in the following table were prepared from the indicated starting materials in a manner similar to Example 54 (steps d and e). TIFF2025526727000145.tif97170

[0284] Intermediate 1 1-(Bromomethyl)-4-(2-methoxy-1,1-dimethyl-ethoxy)benzene TIFF2025526727000146.tif41170

[0285] Step a) Ethyl 2-methyl-2-(4-methylphenoxy)propanoate A mixture of p-cresol (3.5 g, 32.3 mmol, 1.26 equiv.), ethyl 2-bromoisobutyrate (5 g, 25.6 mmol, 1.0 equiv.), and potassium carbonate (10 g, 72.3 mmol, 2.8 equiv.) in DMF (20 mL) was stirred at room temperature for 12 h. The mixture was poured into water (100 mL) and extracted with EtOAc (200 mL). The organic phase was washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The remaining residue was purified by column chromatography (2–20% EtOAc in petroleum ether) to afford the title compound (2.5 g, 11.2 mmol, 42% yield) as a colorless oil. MS (ESI): 223.1 [M+H] + .

[0286] Step b) 2-methyl-2-(4-methylphenoxy)propan-1-ol To a solution of ethyl 2-methyl-2-(4-methylphenoxy)propanoate (1.0 g, 4.5 mmol, 1.0 equiv.) in THF (10 mL) was added LiAlH (550.0 mg, 14.5 mmol, 3.2 equiv.) slowly under argon at 0 °C. Upon completion of the addition, the solution was warmed to room temperature and stirred for 2 h. The solution was poured into water (100 mL) and extracted with EtOAc (300 mL). The organic phase was washed with brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (680 mg, 3.77 mmol, 80% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ = 7.07 (d, 2H), 6.88 (d, 2H), 4.85 (s, 1H), 2.25 (s, 3H), 1.15 (s, 6H).

[0287] Step c) 1-(2-Methoxy-1,1-dimethyl-ethoxy)-4-methyl-benzene To a solution of 2-methyl-2-(4-methylphenoxy)propan-1-ol (1500 mg, 8.32 mmol, 1.0 equiv) in THF (15 mL) was slowly added NaH (900 mg, 22.5 mmol, 2.7 equiv) under a nitrogen atmosphere at 0° C. The solution was stirred at room temperature for 30 minutes. Iodomethane (1.1 mL, 17.6 mmol, 2.12 equiv) was then added to the mixture, which was stirred at room temperature for 4 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.5 g, 7.72 mmol, 91% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ=7.07(d,2H),6.91(d,2H),4.13(q,J=7.1Hz,1H),3.44(s,3H),3.36(s,2H),2.32(s,3H),1.28(s,6H).

[0288] Step d) 1-(bromomethyl)-4-(2-methoxy-1,1-dimethyl-ethoxy)benzene A solution of N-bromosuccinimide (1400 mg, 7.87 mmol, 1.02 equiv.), 1-(2-methoxy-1,1-dimethyl-ethoxy)-4-methyl-benzene (1500 mg, 7.72 mmol, 1.0 equiv.), and AIBN (170.0 mg, 1.04 mmol, 0.13 equiv.) in CCl4 (15 mL) was stirred at 80 °C for 3 h. The mixture was poured into saturated aqueous NaHCO3 (30 mL) and extracted with DCM (100 mL). The organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining crude material was purified by preparative TLC (0-10% EtOAc in petroleum ether) to afford the title compound (1.8 g, 6.59 mmol, 85% yield) as a brown oil. 1 H NMR (400MHz, CDCl3) δ=7.22(d,2H),6.92(d,2H),4.42(s,2H),3.35(s,3H),3.28(s,2H),1.23(s,6H).

[0289] Intermediate 6 1-(chloromethyl)-4-[3-(difluoromethoxy)phenoxy]benzene TIFF2025526727000151.tif26170

[0290] Step a) 4-[3-(difluoromethoxy)phenoxy]benzaldehyde To a mixture of 3-(difluoromethoxy)phenylboronic acid (461.69 mg, 2.46 mmol, 1.5 equiv.) and 4-hydroxybenzaldehyde (200 mg, 1.64 mmol, 1 equiv.) in 1,4-dioxane (15 mL) was added pyridine (0.53 mL, 6.55 mmol, 4 equiv.) and copper diacetate (735.69 mg, 3.68 mmol, 2.25 equiv.) at room temperature. The mixture was then heated to 80 °C for 12 h. The reaction was cooled to room temperature and diluted with water (3 mL). The resulting solution was extracted with EtOAc (3 × 5 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel (4-40% EtOAc in petroleum ether) to give the title compound (90 mg, 0.34 mmol, 15% yield) as a yellow oil. MS (ESI): 264.9 [M+H] + .

[0291] Step b) [4-[3-(difluoromethoxy)phenoxy]phenyl]methanol To a mixture of 4-[3-(difluoromethoxy)phenoxy]benzaldehyde (140 mg, 0.5 mmol, 1 equiv.) in THF (4 mL) was added LiAlH (27.75 mg, 0.7 mmol, 1.38 equiv.) under a nitrogen atmosphere at 0° C. The reaction was stirred at 0° C. for 1 h. The mixture was quenched by the addition of water (0.24 mL), 1 M aqueous NaOH (0.04 mL), and water (0.12 mL). The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil (110 mg) containing the title product, which was used in the next step without further purification. MS (ESI): 248.9 [M-OH] + .

[0292] Step c) 1-(chloromethyl)-4-[3-(difluoromethoxy)phenoxy]benzene To a solution of [4-[3-(difluoromethoxy)phenoxy]phenyl]methanol (110 mg, 0.410 mmol, 1 equiv.) in DCM (10 mL) was added thionyl chloride (0.18 mL, 2.48 mmol, 6 equiv.) and stirred at room temperature for 16 h. The mixture was concentrated, and the remaining residue was dissolved in THF (2 mL) and again concentrated under reduced pressure. This process was repeated twice to afford the title compound (110 mg, 0.39 mmol, 69% yield) as a yellow oil. MS (ESI): 334.0 [M+H+Piperidine] + .

[0293] Intermediate 7 1-(chloromethyl)-4-[3-(trifluoromethoxy)phenoxy]benzene TIFF2025526727000155.tif26170Step a) 4-[3-(trifluoromethoxy)phenoxy]benzaldehyde To a mixture of 3-(trifluoromethoxy)phenol (1.44 g, 8.06 mmol, 1 equiv.) and 4-fluorobenzaldehyde (0.86 mL, 8.06 mmol, 1 equiv.) in DMF (50 mL) was added cesium carbonate (3.94 g, 12.09 mmol, 1.5 equiv.) at room temperature. The reaction was heated to 100 °C for 12 h. The mixture was quenched by the addition of water (150 mL) and extracted with EtOAc (4 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel (5–90% EtOAc in PE) to afford the title compound (2 g, 7.09 mmol, 87% yield) as a yellow oil. MS(ESI):282.9[M+H] + .

[0294] Step b) [4-[3-(trifluoromethoxy)phenoxy]phenyl]methanol To a mixture of 4-[3-(trifluoromethoxy)phenoxy]benzaldehyde (1.0 g, 3.54 mmol, 1 equiv.) in THF (15 mL) was added LiAlH (185.57 mg, 4.89 mmol, 1.38 equiv.) under nitrogen at 0° C. and stirred for 1 h. The mixture was quenched by the addition of water (0.05 mL) and 1 M aqueous NaOH (0.05 mL) and water (0.15 mL). The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil (1 g) containing the title product, which was used in the next step without further purification. MS (ESI): 266.9 [M-OH] + .

[0295] Step c) 1-(chloromethyl)-4-[3-(trifluoromethoxy)phenoxy]benzene To a solution of [4-[3-(trifluoromethoxy)phenoxy]phenyl]methanol (800.0 mg, 2.81 mmol, 1 equiv.) in DCM (15 mL) was added thionyl chloride (1.23 mL, 16.89 mmol, 6 equiv.), and the mixture was stirred at 20 °C for 16 h. The mixture was concentrated, and the remaining residue was dissolved in THF (2 mL) and again concentrated under reduced pressure. This process was repeated twice to afford the title compound (780 mg, 2.58 mmol, 68% yield) as a yellow oil. MS (ESI): 352.0 [M+H+Piperidine] + .

[0296] Intermediate 10 1-[4-(chloromethyl)phenyl]-4-methoxy-2-methyl-benzene TIFF2025526727000159.tif31170

[0297] Step a) 4-(4-methoxy-2-methyl-phenyl)benzaldehyde To a mixture of 4-formylphenylboronic acid (1.64 g, 10.9 mmol, 1.1 equiv.) and 4-bromo-3-methylanisole (2 g, 9.95 mmol, 1 equiv.) in toluene (15 mL), 2 M aqueous NaCO (4.97 mL, 9.95 mmol, 1 equiv.) and Pd(PPh) (344.85 mg, 0.3 mmol, 0.03 equiv.) in EtOH (25 mL) were added at room temperature under nitrogen. The mixture was then stirred for 16 h. The reaction was diluted with water (15 mL). The resulting solution was extracted with EtOAc (3 × 15 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The remaining residue was purified by column chromatography on silica gel (5-60% EtOAc in PE) to give the title compound (1.6 g, 7.07 mmol, 65% yield) as a yellow oil. MS (ESI): 226.9 [M+H] + .

[0298] Step b) [4-(4-methoxy-2-methyl-phenyl)phenyl]methanol To a mixture of 4-(4-methoxy-2-methyl-phenyl)benzaldehyde (600 mg, 2.27 mmol, 1 equiv.) in THF (10 mL) was added LiAlH (118.93 mg, 3.13 mmol, 1.38 equiv.) under a nitrogen atmosphere at 0° C. The reaction was stirred at 0° C. for 1 h. The mixture was quenched by the addition of water (0.24 mL) and 1 M aqueous NaOH (0.24 mL) and water (0.75 mL). The mixture was filtered, and the filtrate was concentrated in vacuo to give a yellow oil (640 mg) containing the title product, which was used in the next step without further purification. MS (ESI): 211.0 [M-OH] + .

[0299] Step c) 1-[4-(chloromethyl)phenyl]-4-methoxy-2-methyl-benzene TIFF2025526727000162.tif31170 To a solution of [4-(4-methoxy-2-methyl-phenyl)phenyl]methanol (640 mg, 2.8 mmol, 1 equiv.) in DCM (10 mL) was added thionyl chloride (1.22 mL, 16.8 mmol, 6 equiv.) and stirred at room temperature for 16 h. The mixture was concentrated, and the remaining residue was dissolved in THF (2 mL) and concentrated again. This process was repeated twice to afford the title compound (600 mg, 2.43 mmol, 78% yield) as a yellow oil. MS (ESI): 296.0 [M+H+Piperidine] + .

[0300] Intermediates 8 and 9 in the table below were prepared similarly to Intermediate 10 using the appropriate benzyl halide building block. TIFF2025526727000163.tif76170

[0301] Intermediate 11 2-[4-(bromomethyl)phenyl]-5-(trifluoromethoxy)pyridine TIFF2025526727000164.tif33170

[0302] Step a) 2-(p-tolyl)-5-(trifluoromethoxy)pyridine A mixture of p-tolylboronic acid (9.4 g, 69.1 mmol, 1 equiv.) and K2CO3 (28.6 g, 207 mmol, 3 equiv.) in 1,4-dioxane (244 mL) and water (24.4 mL) was degassed with argon for 10 minutes. 1,1-bis(diphenylphosphino)ferrocenedichloropalladium(II) (1.02 g, 1.38 mmol, 0.02 equiv.) was then added at room temperature. The reaction mixture was heated to 80 °C, stirred for 7 hours, partitioned between ethyl acetate (450 mL) and water (225 mL), and the layers were separated. The aqueous layer was extracted with 150 mL portions of ethyl acetate. The combined organic layers were washed with 150 mL portions of brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (SiO2, 330 g, 0-10% EtOAc in heptane) to give the title compound as a white solid (13 g, 68%, 92% purity). MS (ESI): 254.1 [M+H] + .

[0303] Step b) 2-[4-(bromomethyl)phenyl]-5-(trifluoromethoxy)pyridine TIFF2025526727000166.tif33170 To a solution of 2-(p-tolyl)-5-(trifluoromethoxy)pyridine (1015 mg, 4 mmol, 1 equiv.) in excess dry acetonitrile (17 mL) was added N-bromosuccinimide (749 mg, 4.21 mmol, 1.05 equiv.) and AIBN (197 mg, 1.2 mmol, 0.3 equiv.). The reaction mixture was stirred overnight at 80 °C, poured into brine, and extracted three times with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude product was purified using flash chromatography (SiO2, 40 g, 0–10% EtOAc in heptane) to afford the title compound as a white solid (971 mg, 62%, 86% purity). MS (ESI): 332.0 [M+H]+ .

[0304] 2) Biological Examples 2.1) In vitro DGK inhibition assay DGKα and ζ kinases use ATP to phosphorylate the substrate 1,2-dilauroyl-sn-glycerol (DLG incorporated into liposomes). This enzymatic reaction results in the conversion of ATP to ADP. After the kinase reaction, an ATP depletion reagent is added to stop the kinase reaction and deplete the remaining ATP, leaving only ADP. Second, a detection reagent is added to simultaneously convert ADP to ATP and convert the newly synthesized ATP to light using a coupled luciferase / luciferin reaction.

[0305] Reagents and materials JPEG2025526727000167.jpg58170JPEG2025526727000168.jpg94170

[0306] Full-length DGKA and Z were expressed in Sf21 insect cells by infecting the cells with baculovirus stocks at an MOI of 2. Purification of both enzymes was performed as previously described by Takahashi et al., PeerJ, 2018 (Takahashi, D.; Sakane, F. Expression and purification of human diacylglycerol kinase alpha from baculovirus-infected insect cells for structural studies. PeerJ 2018, 6, No. e5449).

[0307] JPEG2025526727000169.jpg60170JPEG2025526727000170.jpg72170

[0308] Assay procedure Concentrated liposome solutions were prepared in assay buffer without DTT and BSA: 2 mM DLG in 21 mM total liposomes (2 mM DLG / 8 mM PS / 11 mM PC). The reaction mixtures contained assay buffer with a final DLG concentration of 25 μM (for the DGKA assay) or 50 μM (for the DGKZ assay) for a 125 μM ATP concentration. The reaction was initiated by the addition of DGKα and ζ kinases at final concentrations of 4 nM and 2 nM, respectively. After 1 h of reaction, the amount of ADP formed was detected using the ADP-Glo kinase assay (Promega) according to the manufacturer's instructions. Compounds were added in an 11-point dose response, starting at 10 mM, 1:3 dilution, with a final DMSO concentration of 2%. A Multidrop Combi was used as the liquid handler, and luminescence was read in 0.5 seconds using an Envision Reader (PE).

[0309] TIFF2025526727000171.tif252170TIFF2025526727000172.tif231170

[0310] In vitro DGK inhibition assay (ADP Glo) DGKα and ζ kinases use ATP to phosphorylate the substrate 1,2-dilauroyl-sn-glycerol (DLG), which results in the conversion of ATP to ADP.

[0311] After the kinase reaction, an ATP depletion reagent is added to stop the kinase reaction and deplete the remaining ATP, leaving only ADP. Second, a detection reagent is added to simultaneously convert ADP to ATP and convert the newly synthesized ATP to light using a coupled luciferase / luciferin reaction.

[0312] Experimental procedures, reagents and materials The DGKα and ζ kinase ADP Glo assay was performed by Reaction Biology Corp., 1 Great Valley Parkway, Suite 2, Malvern, PA 19355, USA. The information provided by the service provider is as follows: DGKα and ζ kinase were used at a final concentration of 2 nM. Reactions were performed with 50 μM ATP. 500 μM of the substrate DLG (dilauroyl-sn-glycerol) was used. Compounds were received at 10 mM DMSO stock solutions and tested at 10 doses of IC50 replicates using 3-fold serial dilutions starting at 1 μM. The control compound, calphostin C, was tested at 10 doses of IC50 replicates using 3-fold serial dilutions starting at 100 μM.

[0313] TIFF2025526727000173.tif48170

[0314] 2.2) IL2 secretion measurement As a readout of T cell activation, IL2 secretion after 24 hours and proliferation after 5 days were measured. The increase in IL2 secretion and proliferation upon compound treatment was evaluated as % of the maximum value of reference compound A1. WO 2016 / 139181 discloses reference compound A1 as Example 70. As a counterscreen and to ensure that undesired TCR-independent activation was not caused, PBS conditions were performed for all compounds. JPEG2025526727000174.jpg253170JPEG2025526727000175.jpg138170

[0315] cell culture Expanded primary human T cells were thawed and cultured at a density of 2 μl / ml in RPMI 1640 (Gibco, #61870-010) + 5% human serum (HS, Sigma, #H3667) + 1 mM sodium pyruvate (Gibco, #11360-039) + 50 μM 2-mercaptoethanol (Gibco, #31350-010) and 1x Pen-Strep (Life Technologies, #15140122) medium at 5% CO2, 37°C, and 95% humidity for 3 hours. For plate coating, 100 μl / well of PBS++ and PBS-- or PBS++ and CD3 antibody (donor-dependent concentration determined by CD3 titration) was added to a poly-D-lysine-coated 96-well plate. The plate was sealed and incubated at room temperature for 3 hours on a tabletop rocking platform. After incubation, plates were washed once with PBS and filled with 40 μl / well of culture medium alone. Compounds were then added to the medium-only plates (see next section). After 3 hours of T cell culture, cells were filtered through a cell strainer (Miltenyi Biotech, #130-041-407), counted again, and the concentration was adjusted to 1.25 Mio / ml.

[0316] Cells were then seeded with 80 μl / well to 40 μl / well of compound dispensed according to the plate layout. Compounds were further diluted 1:3 by adding cells, resulting in 100k cells / 120 μl / well. After 24 hours, 40 μl of supernatant was carefully collected from the top without disturbing the cells and transferred to a round-bottom 96-well plate. The collected and frozen supernatant was used for IL-2 detection using the IL-2 Human ProQuantum Immunoassay Kit (Invitrogen) or the Human IL-2 ELISA Kit (Thermo Fisher).

[0317] Compound treatment Compounds were added in a 5- or 6-point dose response using a Tecan D300e digital dispenser. All conditions were 3x concentrated to the final concentration (80 μl cells to 40 μl treated conditioned medium) before cells were added. DRs started at a final top concentration of 20 μM or 10 μM and a dilution factor of 3.333. The positive control was reference compound A1, added in a similar dose response, plus three wells at only 20 μM to represent a positive stimulator control. All wells were normalized to a final concentration of 0.6% with DMSO (0.2% final concentration).

[0318] IL2 ProQuantum Immunoassay The immunoassay is performed according to the manufacturer's manual (Invitrogen, #A35603).

[0319] Additional Information: For immunoassays, use MicroAmp™ EnduraPlate™ Optical 384-well plates. Thaw the frozen supernatant and centrifuge at 1000 x g for 5 minutes, both steps performed at 4°C. After centrifugation, collect the required sample volume from the top and dilute it in a separate LightCycler V-bottom plate (working plate) with assay dilution buffer, PBS, or CD3 buffer, depending on the condition, at a dilution factor of at least 1:3. Prepare IL-2 standards and blanks in the same V-bottom plate (extended version) with standards ranging from 0.0128 to 5000 pg / ml. After preparation, transfer 5 μl of sample dilutions or standards / blanks to the optical 384-well plate (assay plate) and follow the 10 μl reaction protocol. Use a QuantStudio 12K Flex system for measurements. Extract raw data and calculate IL-2 concentrations using the Thermo Fisher online app (apps.thermofisher.com / apps / proquantum).

[0320] IL2 Elisa The ELISA is performed according to the manufacturer's manual (Thermo Fisher Scientific, #88-7025-88). Additional information: For ELISA, Nunc MaxiSorp 96-well plates are used. Frozen supernatants are thawed and centrifuged at 1000 x g for 5 minutes, both steps being carried out at 4°C. The required sample volume is then collected from the top and placed in a separate V-bottom plate, diluted with ELISA diluent, PBS, or a dilution factor depending on the CD3 condition. IL-2 standards and blanks are prepared in the same V-bottom plate. After preparation, 50 μl of sample diluent and 100 μl of standard or blank are transferred to the Nunc plate.

[0321] Calculations and Data Reporting CD3 and PBS plates were analyzed separately in Genedata Screener using Roche Normalization PCT_POS_CTRL, DMSO was set as neutral control and 20 μM of reference compound A1 was set as stimulator control / 100%. For CD3 conditions, the EC50 and Emax of the fitted sigmoidal curve were reported. If a curve could not be fitted, the EC50 was reported as a blank field, and Emax was based on individual data points. Emax did not necessarily correspond to the highest concentration tested. Compounds that activated unstimulated cells or had a negative effect on viability (see proliferation assay) were flagged.

[0322] TIFF2025526727000176.tif254170TIFF2025526727000177.tif253170

[0323] 2.4) Proliferation Assay JPEG2025526727000178.jpg251170JPEG2025526727000179.jpg26170

[0324] Thaw expanded primary human T cells and culture them at a density of 2 μl / ml in RPMI 1640 (Gibco, #61870-010) + 5% human serum (HS, Sigma, #H3667) + 1 mM sodium pyruvate (Gibco, #11360-039) + 50 μM 2-mercaptoethanol (Gibco, #31350-010) and 1x Pen-Strep (Life Technologies, #15140122) medium at 5% CO2, 37°C, and 95% humidity for 3 hours. For plate coating, add 100 μl / well of PBS++ alone or PBS++ with CD3 antibody (donor-dependent concentration determined by CD3 titration) to a poly-D-lysine-coated 96-well plate. Seal the plate and incubate it at room temperature for 3 hours on a tabletop rocking platform. After incubation, the plates are washed once with PBS and filled with 40 μl / well of culture medium alone. Compounds are then added to the medium-only plates (see next section). After 3 hours of culturing the T cells, the cells are filtered through a cell strainer (Miltenyi Biotech, #130-041-407), counted again, and the concentration is adjusted to 1.25 Mio / ml.

[0325] Cells are then seeded in 80 μl / well to 40 μl / well containing compounds dispensed according to the plate layout. Compounds are further diluted 1:3 by adding cells to obtain 100k cells / 120 μl / well. After 48 hours, 40 μl of supernatant is carefully removed from the top without disturbing the cells. Cells are assessed for proliferation after 5 days by measuring ATP consumption using CellTiterGlo (Promega).

[0326] Compound treatment Compounds were added in a 5- or 6-point dose response using a Tecan D300e digital dispenser. All conditions were 3x concentrated to the final concentration (80 μl cells to 40 μl treated conditioned medium) before cells were added. DRs started at a final top concentration of 20 μM or 10 μM and a dilution factor of 3.333. The positive control was reference compound A1, added in a similar dose response, plus three wells at only 20 μM to represent a positive stimulator control. All wells were normalized to a final concentration of 0.6% with DMSO (0.2% final concentration).

[0327] Cell titer Glo measurement After 5 days, CellTiter-Glo® 2.0 reagent is used to detect ATP, which is directly proportional to the number of cells present per well. After visually controlling for toxicity or precipitation of the tested compounds, the plate is equilibrated to room temperature for 45 minutes. The CellTiter-Glo® 2.0 reagent is also equilibrated to room temperature. After equilibration, an equal volume of CellTiter-Glo reagent is added to the cells (80 μl / well) using an electronic multichannel pipette. The plate is placed on a rocking platform for 15 minutes at room temperature. After incubation, the bottom of the plate is sealed with backing tape. Luminescence is measured on a PHERAstar FSX (interval time 0.5 seconds, gain 3000, focal height 15 mm) and exported as a CSV file for analysis on the Genedata screener.

[0328] Calculations and Data Reporting CD3 and PBS plates were analyzed separately in Genedata Screener using Roche Normalization PCT_POS_CTRL, DMSO was set as neutral control and 20 μM of reference compound A1 was set as stimulator control / 100%. For CD3 conditions, the EC50 and Emax of the fitted sigmoidal curve were reported. If a curve could not be fitted, the EC50 was reported as a blank field, and Emax was based on individual data points. Emax did not necessarily correspond to the highest concentration tested. Compounds that activated unstimulated cells (see IL2 measurements) or had a negative effect on viability were flagged.

[0329] TIFF2025526727000180.tif254170TIFF2025526727000181.tif249170

[0330] 2.4) T cell-TCB-MV3 killing assay JPEG2025526727000182.jpg253170JPEG2025526727000183.jpg58170

[0331] cell culture All culture steps are carried out at 5% CO2, 37°C and 95% humidity.

[0332] MV-3 RFP cells were cultured in MV-3 medium (DMEM + 10% FBS, 1x PenStrep, and 0.5 μg / mL puromycin) for at least 3 weeks. 80% confluent cultured MV-3 cells were washed once with PBS and trypsinized until detached. Cells were then counted and resuspended at 1x105 cells / mL in T cell medium (RPMI1640 + 5% human serum + 1 mM sodium pyruvate + 50 μM 2-mercaptoethanol and 1x PenStrep). Cells were seeded at 100 μL / well into a 96-well plate (TTP, #92696) and left undisturbed at room temperature for 40 minutes to achieve uniformly distributed cell attachment. The plate was then incubated until further use.

[0333] The next day, thaw the expanded primary human T cells and resuspend them in T cell medium to 4 x 106 cells / mL. Culture them in a 6-well plate for 3 hours, up to 6 mL per well. After culturing the T cells, filter them through a cell strainer (Miltenyi Biotech, #130-041-407), count them again, and adjust the cell concentration to 2 x 106 cells / mL.

[0334] Compound treatment MCSP-TCB or PBS was prediluted in T cell medium (concentration dependent on T cell donor) at 4x the final concentration. 60 μL / well of the predilution was then dispensed into a round-bottom plate (Costar, #3799) according to the plate layout. Compounds were added in a 9-point dose response using a Tecan D300e digital dispenser, also at 4x the final concentration. DMSO concentration in all wells was adjusted to 0.8% to obtain a final concentration of 0.2%.

[0335] Add 60 μL / well of the T cell suspension to the prepared round-bottom plate and resuspend using a manual multichannel filter. Then, carefully transfer 100 μL / well of the resuspended T cell suspension containing the treatment to the overnight-cultured MV-3 cells according to the plate layout. Add 100 μL of T cell medium only to the outer MV-3 wells only. The final compound DR starts at 20 μM, with a dilution factor of 3.333. The final TCB concentration ranged from 1.5 pM to 5 pM and was determined individually for each T cell donor by performing a TCB titration. For each donor, a TCB concentration corresponding to 10-20% of the MV3 baseline cell killing in the absence of compound treatment was selected. Positive controls were reference compound A1 added at the DR, and only 20 μM of the compound was added to additional wells. 20 μM reference compound A1 represented a positive stimulator control, while TCB alone (DMSO wells) served as a neutral control.

[0336] calculation After transfer of T cells with pretreatment diluent, MV-3 cells were imaged by time-lapse microscopy using IncucyteZOOM™ (Essen BioScience, Michigan, USA). Images were acquired every 3 hours for a total of 120 hours (10x objective, phase and red imaging channels, 400 ms acquisition time, green / red 4614 optical module). RFP object counts per well were analyzed using IncucyteZOOM™ software (version 2019B Rev2) using a mask previously created and optimized for MV-3 cells. Raw data were exported as object counts / well, and values were normalized as %TCL compared to MV-3-only wells, with 100% proliferation and therefore 0% TCL.

[0337] RFP measurement The calculated %TCL values are analyzed in Genedata Screener using Roche Normalization PCT_POS_CTRL, with MCSP-TCB alone set as neutral control and 20 μM reference compound A1 set as stimulator control / 100%.

[0338] The EC50 and Emax values are shown in the table below.

[0339] TCLs induced by compounds without TCB treatment or toxicity (observed in PBS conditions) were flagged.

[0340] TIFF2025526727000184.tif94170

Claims

1. Compound of formula (I) (In the formula, Y is S(O), S(O) ２ and S(O)N(R) ｙ ) and R １ It is a 5-membered heteroaryl, R １ R may be one or more R which are the same or different １０ It may also be replaced with R ２ It is selected from hydrogen and halogens. R ４ is selected from C ５－１４ -aryl and 5- to 14-membered heteroaryl, and R ４ may be substituted with one or more R １１ which may be the same or different, R １０ is -C(R １０ａ R １０ｂ ) ２ -S(O) ２ (R １０ｃ ) and R １０ａ and R １０ｂ These are, independently, hydrogen and C １－６ - Selected from alkyl groups, or R １０ａ and R １０ｂ Together with the carbon atoms to which they are bonded, C ３－６ - Forms a cycloalkyl group, R １０ｃ is hydrogen, C １－６ - Alkyl, C ３－６ -Cycloalkyl, -N(C) １－６ -Alkyl), Halo-C １－６ - Selected from alkyl and phenyl, where phenyl is one or more halogens or C １－６ - May be substituted with alkyl, or R １０ａ and R １０ｃ These, together with the carbon and sulfur atoms to which they are bonded, form a 3- to 10-membered heterocycline. R １１ teeth, i) Halogen, ii) One or more Halo-C １－６ - Alkyl, C ３－１０ - A 3- to 10-membered heterocycline, which may be substituted with a cycloalkyl group. iii) One or more halogens, C １－６ -Alkyl, Halo-C １－６ - Alkyl, C ３－１０ - Cycloalkyl, C １－６ - A 5-6 member heteroaryl, which may be substituted with a haloalkoxy, iv) One or more halogens, cyanoacrylates, C10 １－６ - Alkoxy, C １－６ - Haloalkyl, C １－６ - Phenyl, which may be substituted with alkyl v)-O(R １１ａ )、 vi) - N(R １１ｇ R １１ｈ ), and v))) ｳ() １１ｋ ) Selected from, R １１ａ C １－１２ -Alkyl, Halo-C １－６ - Alkyl, C ３－７ -Cycloalkyl, 3-10 member-(C １－６ -Alkyl) heterocyclyl, phenyl and -C １－６ - Selected from alkylphenyl, the C １－１２ - Alkyl, C ３－７ -Cycloalkyl, phenyl and -C １－６ -Alkylphenyl is a compound containing one or more halogens, C １－６ -Alkyl, Halo-C １－６ - Alkyl, C １－６ - Alkoxy, C １－６ - May be substituted with a haloalkoxy, R １１ｇ and R １１ｈ These are, independently, hydrogen and C １－６ -Alkyl, -(C １－６ - Selected from alkyl)phenyl, R １１ｋ This is hydrogen and halo-C １－６ - Selected from alkyl groups, R ｙ is hydrogen and C １－６ (Selected from alkyl groups) or a pharmaceutically acceptable salt thereof.

2. R １ However, it is oxadiazole or tetrazole, R １ R may be one or more R which are the same or different １０ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with.

3. R １ However, it is an oxadiazole, and R １ R may be one or more R which are the same or different １０ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with.

4. R ２ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from hydrogen and fluorine.

5. R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is phenyl.

6. R １０ａ and R １０ｂ However, each independently, hydrogen and C １－６ - Selected from alkyl groups, or R １０ａ and R １０ｂ However, together with the carbon atoms to which they are bonded, C ３－６ - A compound according to claim 1 or a pharmaceutically acceptable salt thereof that forms a cycloalkyl group.

7. R １０ However, one -S(O) ２ (C １－６ C substituted with -alkyl ３－６ - A cycloalkyl compound or a pharmaceutically acceptable salt thereof according to claim 1.

8. R １０ However, it is a 3-6 member heterocycline, where the heteroatom is sulfur and there is one or more C １－１０ - A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with an alkyl or oxo molecule, the oxo substitution being located on the sulfur atom.

9. R １０ The compound according to claim 1, selected from 1-methylmethylsulfonylethyl, or a pharmaceutically acceptable salt thereof.

10. R １１ but, i) Halogen, ii) 3-10 member heterocyclines, iii) one or more halogens, halo-C １－６ -alkyl, C ３－１０ -cycloalkyl, C １－６ -heteroaryl having 5 to 6 members which may be substituted with -haloalkoxy, iv) One or more cyanoacrylates, C １－６ - Alkoxy, C １－６ - Haloalkyl, C １－６ - Phenyl, which may be substituted with alkyl v) -O(R １１ａ ); R １１ａ is selected from C １－１２ -alkyl, halo-C １－６ -alkyl, C ３－７ -cycloalkyl, 5- to 6-membered -(C １－６ -alkyl) heteroaryl, phenyl and -C １－６ -alkyl-phenyl, and the C １－１２ -alkyl, phenyl, 5- to 6-membered -(C １－６ -alkyl) heteroaryl and -C １－６ -alkyl-phenyl may be substituted with one or more halogen, C １－６ -alkyl, halo-C １－６ -alkyl, C １－６ -alkoxy, C １－６ -haloalkoxy., vi) - N(R １１ｇ R １１ｈ ); R １１ｇ and R １１ｈ Each of them is independent of C １－６ -Alkyl, -(C １－６ - Selected from alkyl)phenyl, vii)-S (Hello-C １－６ -Alkyl), viiii)CH ２ -O-phenyl The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. R １１ but, i) - O(R １１ａ ) (wherein, R １１ａ Hello-C １－６ - Selected from alkyl and phenyl, wherein the phenyl may be substituted with one or more halogens), or ii) One or more C １－６ - Alkoxy, C １－６ - Phenyl, which may be substituted with a haloalkyl group. iii) Halogen, iv) One or more Halo-C １－６ - Alkyl, C ３－１０ - Cycloalkyl, C １－６ - 5-6 member heteroaryls, which may be substituted with haloalkoxys. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

12. R １１ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from (trifluoromethyl)phenyl, (trifluoromethyl)-oxadiazolyl, cyclopropyl-oxadiazolyl, phenoxyl, methoxyphenyl, tetrafluoroethoxyl, dichlorophenoxyl, chloro, and trifluoromethoxy-2-pyridyl.

13. Y is S(O) ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. Y is S(O), S(O) ２ and S(O)N(R) ｙ ) and R １ However, it is a 5-membered heteroaryl, R １ R may be one or more R which are the same or different １０ It may also be replaced with R ２ However, hydrogen and fluorine are selected, R ４ However, C ６ - Selected from aryls and 6-membered heteroaryls, R ４ R may be one or more R which are the same or different １１ It may also be replaced with R １０ However, one -S(O) ２ (C １－６ C substituted with -alkyl ３－６ - It is a cycloalkyl, R １１ but, i) Halogen, ii) 3-10 member heterocyclines, iii) One or more halogens, halo-C １－６ - Alkyl, C ３－１０ - Cycloalkyl, C １－６ - A 5-6 member heteroaryl, which may be substituted with a haloalkoxy, iv) One or more cyanoacrylates, C １－６ - Alkoxy, C １－６ - Haloalkyl, C １－６ - Phenyl, which may be substituted with alkyl v) - O(R １１ａ ); R １１ａ C １－１２ -Alkyl, Halo-C １－６ - Alkyl, C ３－７ -Cycloalkyl, 5-6 member-(C) １－６ -Alkyl) heteroaryl, phenyl and -C １－６ - Selected from alkylphenyl, the C １－１２ -Alkyl, phenyl, 5-6 member-(C) １－６ -Alkyl)heteroaryl and -C １－６ -Alkylphenyl is a compound containing one or more halogens, C １－６ -Alkyl, Halo-C １－６ - Alkyl, C １－６ - Alkoxy, C １－６ - May be substituted with a haloalkoxy, vi) - N(R １１ｇ R １１ｈ ); R １１ｇ and R １１ｈ Each of them is independent of C １－６ -Alkyl, -(C １－６ - Selected from alkyl)phenyl, vii)-S (Hello-C １－６ -Alkyl), viiii)CH ２ -O-phenyl The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15. Y is S(O), S(O) ２ and S(O)N(R) ｙ ) and R １ However, it is an oxadiazole, and R １ R may be one or more R which are the same or different １０ It may also be replaced with R ２ However, hydrogen and fluorine are selected, R ４ However, it is phenyl, R １０ However, it is selected from methyl-methylsulfonyl-ethyl, cyclopropylsulfonyl-methyl-ethyl, methyl-dioxothiolanyl, methylsulfonylmethyl, and methylsulfonylcyclobutyl. R １１ but, i) - O(R １１ａ ) (wherein, R １１ａ Hello-C １－６ - Selected from alkyl and phenyl, wherein the phenyl may be substituted with one or more halogens.) ii) One or more C １－６ - Alkoxy, C １－６ - Phenyl, which may be substituted with a haloalkyl group. iii) Halogens, and iv) One or more Halo-C １－６ - Alkyl, C ３－１０ - Cycloalkyl, C １－６ - 5-6 member heteroaryls, which may be substituted with haloalkoxys. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

16. Y is S(O), S(O) ２ and S(O)N(R) ｙ ) and R １ However, it is an oxadiazole, and R １ R may be one or more R which are the same or different １０ It may also be replaced with R ２ However, hydrogen and fluorine are selected, R ４ However, it is phenyl, R １０ However, it is methyl-methylsulfonyl-ethyl, R １１ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from (trifluoromethyl)phenyl, (trifluoromethyl)-oxadiazolyl, cyclopropyl-oxadiazolyl, phenoxyl, methoxyphenyl, tetrafluoroethoxyl, dichlorophenoxyl, chloro, and trifluoromethoxy-2-pyridyl.

17. (3R)-3-amino-5-[[4-(1-ethylpropoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-(cyclopentoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[(4-benzyloxyphenyl)methyl]-7-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-[(4-fluorophenyl)methoxy]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-[(2-fluorophenyl)methoxy]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-(3,3,3-trifluoropropoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-(trifluoromethylsulfanyl)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-(phenoxymethyl)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-[3-(difluoromethoxy)phenoxy]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-5-[[4-(3-methylphenoxy)phenyl]methyl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-(2,3-dichlorophenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-(3-fluorophenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-(3-chlorophenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-(3-chloro-4-fluorophenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-[3-(trifluoromethyl)phenoxy]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-[3-fluoro-5-(trifluoromethyl)phenoxy]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-[3-(trifluoromethoxy)phenoxy]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-(3-chloro-5-methoxyphenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-(3-chloro-5-methoxyphenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, 4-[4-[[(3R)-3-amino-7-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepine-5-yl]methyl]phenyl]benzonitrile, (3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-(3-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-(4-methoxy-2-methylphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-(3-bromophenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-1,1-diketo-7-[5-(1-mesyl-1-methyl-ethyl)-1,3,4-oxadiazole-2-yl]-5-[4-[5-(trifluoromethoxy)-2-pyridyl]benzyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-[benzyl(methyl)amino]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-[isopropyl(methyl)amino]phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]phenyl]methyl]2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-(5-fluoro-2-pyridyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazole-3-yl]-1,1-dioxo-5-[(6-phenoxy-3-pyridyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazole-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonylethyl)-1,2,4-oxadiazole-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonylethyl)-1,2,4-oxadiazole-3-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]phenyl]methyl]2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)phenyl]methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonylethyl)-1,2,4-oxadiazole-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazole-3-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazole-3-yl]-1,1-dioxo-5-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methylsulfonylcyclopropyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazole-3-yl]-1,1-dioxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-5-[[4-(2-methoxy-1,1-dimethyl-ethoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazole-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-[6-(trifluoromethyl)-3-pyridyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazole-3-yl]-1,1-dioxo-5-[[4-[[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methoxy]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazole-3-yl]-1-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ4,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazole-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methylsulfonylcyclobutyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methylsulfonylcyclopropyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-cyclopropylsulfonyl-1-methyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(2-methyl-1,1-dioxothiolan-2-yl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, 2-[5-[(3R)-3-amino-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-7-yl]-1,3,4-oxadiazole-2-yl]-N,N-dimethylpropane-2-sulfonamide, (3R)-3-amino-7-[5-(1-methyl-1-pyrrolidine-1-ylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[2-(methylsulfonylmethyl)tetrazole-5-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, and (3R)-3-amino-8-fluoro-7-[1-(methylsulfonylmethyl)tetrazole-5-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

18. (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazole-3-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-(2,3-dichlorophenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-(3-chlorophenoxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonylethyl)-1,2,4-oxadiazole-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonylethyl)-1,2,4-oxadiazole-3-yl]-1,1-dioxo-5-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]phenyl]methyl]2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-1,1-dioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one, (3R)-3-amino-5-[[4-(4-methoxyphenyl)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazole-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine-4-one, and (3R)-3-amino-1,1-diketo-7-[5-(1-mesyl-1-methyl-ethyl)-1,3,4-oxadiazole-2-yl]-5-[4-[5-(trifluoromethoxy)-2-pyridyl]benzyl]-2,3-dihydro-1λ6,5-benzothiazepine-4-one A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

19. A method for preparing a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, comprising the compound of formula (IX). (In the formula, Y, R １ , R ２ and R ４ A method comprising reacting a compound of formula (I) with a suitable deprotecting agent, wherein the compound is as defined in any one of claims 1 to 16, and PG is an amino protecting group.

20. A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, as produced according to the method of claim 19.

21. A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

23. The pharmaceutical composition according to claim 22, further comprising an additional therapeutic agent.

24. A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or delay of the progression of cancer.

25. The compound for use according to claim 24 or a pharmaceutically acceptable salt thereof, wherein the cancer is associated with abnormal diacylglycerol kinase signaling, and the diacylglycerol kinase is selected from DGKα and / or DGKζ.

26. The aforementioned cancers include B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative conditions, A compound for use according to claim 24, selected from the group consisting of MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenström macroglobulinemia, preleukemia, sarcoma, carcinoma, melanoma, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, squamous cell carcinoma (e.g., NSCLC), 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.

27. Use of any compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18 for the treatment, prevention and / or delay of the progression of cancer.

28. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18 for the preparation of a medicament for the treatment, prevention and / or delay of the progression of cancer.

29. A method for treating, preventing and / or delaying the progression of cancer, comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of claims 1 to 18.

30. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof to inhibit the activity of at least one diacylglycerol kinase selected from DGKα and DGKζ.

31. A method for inhibiting the activity of at least one diacylglycerol kinase selected from DGKα and DGKζ, comprising administering a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt thereof described in any one of claims 1 to 18 to a subject in need thereof.

32. The invention is as described above.

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