Bicyclic tetrahydrothiaza derivatives

Abstract

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

Description

Technical Field

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

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

[0003] Cancer immunity is a multi-step process, which is regulated by a series of negative immune checkpoints and positive co-stimulatory receptors and related intracellular signaling cascades, and anti-tumor responses can be achieved when effectively triggered (Mellman, I., et al. (2011) Cancer Immunotherapy Comes of Age, Nature 480 (7378), 480-489). In fact, inhibitors targeting PD1 / PDL1 and other immune checkpoint inhibitors have revolutionized cancer immunotherapy, but more than 70% of patients still do not benefit from immune checkpoint inhibition. Similarly, for T cell bispecific antibodies, even in the most promising indications (non-Hodgkin's lymphoma), these T cell binders (TCBs) can achieve complete remission in less than 50% of patients. T cell exhaustion seems to play an important role in many examples of primary or secondary resistance to these cancer immunotherapies. The possible reason for this lack of efficacy is that T cell activation occurs via targeting and cross-linking of CD3 (signal 1), but lacks costimulation such as via CD28 or 4-1BB (signal 2). This hypothesis has been clinically validated in CAR T-cell therapy, where results have shown that clinically relevant efficacy is 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), thereby limiting DAG-regulated functions and promoting PA-dependent functions (Merida, I., Avila-Flores, A., and Merino, E. 2008: Diacylglycerol kinases: at the hub of cell signalling. Biochem. J. 409(1), 1–18). The DGK family consists of ten isoforms, which can be divided into five subtypes based on the presence of different regulatory domains in their structures. In addition, the lack of structural data still hinders a more thorough understanding of the mode of action of DGKs. Furthermore, information on some prokaryotic DGKs and other lipid kinases, such as sphingosine kinase and phosphatidylinositol 3-kinase (PI3K), provides only limited insight into the DGK catalytic mechanism, which appears to be distinct from classical kinases (Arranz-Nicolás, J. and Mérida, I., 2020. Biological regulation of diacylglycerol kinases in normal and neoplastic tissues: New opportunities for cancer immunotherapy, Advances in Biological Regulation, Vol. 75; Ma, Q., Gabelli, SB, Raben, DM, 2019: Diacylglycerol kinases: relationship to other lipid kinases. Adv Biol Regul 71, 104–110).

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

[0006] These two isozymes, DGKα and DGKζ, are active downstream of CD28 and other co-stimulatory receptors and the T cell receptor (TCR), and their function is to limit the amount of DAG produced and ultimately limit T cell activation (Merida, I., Andrada, E., Gharbi, SI, Avila-Flores, A., 2015. Redundant and specialized roles for diacylglycerol kinases alpha and zeta in the control of T cell functions. Sci. Signal. 8(374); Shulga, YV, Topham, MK, Epand, RM, 2011. Regulation and functions of diacylglycerol kinases. Chem. Rev. 111(10), 6186–6208). A summary of representative DGK-regulated signal transduction pathways is shown in Figure 1 (Sim, JA; Kim, J.; Yang, D. Beyond Lipid Signaling: Pleiotropic Effects of Diacylglycerol Kinases in Cellular Signaling. Int. J. Mol. Sci. 2020, 21, 6861): Activated PLC1 cleaves PIP2 in the plasma membrane to produce two second messengers: DAG and IP3. DAG activates PKC, Ras / MEK / ERK / AP-1, and NF-kB, while IP3 is involved in the activation of intracellular Ca2+ flux. Upregulated Ca2+ signaling then activates the transcription factor NFAT. In short, DAG production and levels determine the duration and intensity of Ras / MEK / ERK and PKC-dependent signaling pathways, and they are essential for 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 in which CAR T cells targeting human mesothelioma were transplanted into nude mice demonstrated that tumor-infiltrating CAR T cells expressed elevated concentrations of surface inhibitory receptors and the inhibitory enzymes SHIP-1, DGKα, and DGKζ (Moon et al., 2014). In addition, high DGKα expression was also observed in TILs isolated from human renal tumors (Prinz et al., 2012). In mouse mesoCAR T cells, dual deletion of DGKα and DGKζ resulted in enhanced cytokine expression and cytotoxicity against tumor cells (Riese et al., 2013). Similar results have been reported for human CAR T cells, in which both DGKα and DGKζ expression was abrogated using CRISPR /

[0008] Cas9 to silence (Jung et al., 2018). All these studies support the basic principle of targeting DGKα / ζ in the development of anticancer therapy (Arranz-Nicolás, J. and Merida, I., 2020. Biological regulation of diacylglycerol kinases in normal and neoplastic tissues: New opportunities for cancer immunotherapy, Advances in Biological Regulation, Vol. 75; Riese, MJ, Moon, EK, Johnson, BD, Albelda, SM, 2016. Diacylglycerol kinases (DGKs): novel targets for improving T cell activity in cancer. Front Cell Dev Biol 4, 108).Knockout mouse models provide additional evidence: mice lacking DGKα or DGKζ display 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 anergy 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 anergy.Nat.Immunol.7(11),1174–1181).

[0009] In summary, there is a lot of evidence that DGKα and DGKζ are high-value targets for cancer immunotherapy. At the same time, there is a lack of compounds that have the ability to effectively inhibit DGKα and DGKζ and have good selectivity compared with other diacylglycerol kinases, protein kinases and / or other lipid kinases.

[0010] The present invention describes such dual DGKα / ζ inhibitors, which have excellent selectivity in the safety / off-target group compared to other protein kinases and compared to other lipid kinases. These compounds effectively activate suboptimally stimulated T cells and thereby act as intracellular enhancers of the co-stimulatory signaling cascade. These DGKα / ζ inhibitors have the potential to increase the proliferation, cytotoxicity, and lifespan of targeted T cells, thereby potentially improving the anti-cancer activity of CPI, CD3-engaged T cell bispecific cells, and CAR T cells. In addition, by engaging the central signaling node of TCR and co-stimulatory receptors, these molecules appear to enhance signals 1 and 2, thereby achieving single-agent activity, such as in inflamed tumors.

[0011] There is a continuing need for new compounds that can activate and proliferate T cells, thereby being able to treat, prevent and / or delay the progression of cancer.

[0012] Therefore, the object of the present invention is to provide compounds useful as DGKα / ζ inhibitors for the treatment or prevention or alleviation of such diseases, which compounds have improved therapeutic properties, in particular improved pharmacokinetic properties. Summary of the invention

[0013] The first object of the present invention is a compound of formula (I)

[0014]

[0015] or a pharmaceutically acceptable salt thereof, wherein:

[0016] Y is S(O), S(O)2 and S(O)N(R y );

[0017] R 1 is a 5-membered heteroaryl group, wherein R 1 Optionally, one or more R 10 replace;

[0018] R 2 is selected from hydrogen and halogen;

[0019] R 4 Selected from C 5-14 -aryl and 5- to 14-membered heteroaryl, wherein R 4 Optionally, one or more R 11 replace;

[0020] R 10 -C(R 10a R 10b )2-S(O)2(R 10c );

[0021] R 10a and R10b are each independently selected from hydrogen or C 1-6 -alkyl, or R 10a and R 10b Together with the carbon atom to which they are attached, they form C 3-6 - cycloalkyl;

[0022] R 10c Selected from hydrogen, C 1-6 -alkyl, C 3-6 -cycloalkyl, -N(C 1-6 -alkyl), halo-C 1-6 -alkyl and phenyl, wherein the phenyl group is optionally substituted with one or more halogen or C 1-6 - alkyl substitution;

[0023] or R 10a and R 10c Together with the carbon atom and the sulfur atom to which they are attached, they form a 3- to 10-membered heterocyclic group;

[0024] R 11 Selected from:

[0025] i) Halogen

[0026] ii) a 3- to 10-membered heterocyclic group, which is optionally substituted with one or more halogenated -C 1-6 -alkyl, C 3-10 - Cycloalkyl substitution;

[0027] iii) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more halogens, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 3-10 -Cycloalkyl, C 1-6 -Haloalkoxy substitution;

[0028] iv) phenyl, which is optionally substituted with one or more halogen, cyano, C 1-6 -alkoxy, C 1-6 -haloalkyl, C 1-6 - alkyl substitution;

[0029] v)-O(R 11a );

[0030] vi)-N(R 11g R 11h );as well as

[0031] vii)–S(R 11k );

[0032] R 11a Selected from C 1-12 -alkyl, halo-C 1-6 -alkyl, C3-7 -cycloalkyl, 3- to 10-membered-(C 1-6 -alkyl) heterocyclic group, phenyl and -C 1-6 -alkyl-phenyl, wherein the C 1-12 -alkyl, C 3-7 -cycloalkyl, phenyl and -C 1-6 -alkyl-phenyl is optionally substituted with one or more halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -Haloalkoxy substitution;

[0033] R 11g and R 11h are each independently selected from hydrogen, C 1-6 -alkyl, -(C 1-6 -alkyl)phenyl;

[0034] R 11k Selected from hydrogen and halo-C 1-6 -alkyl;

[0035] R y Selected from hydrogen and C 1-6 -alkyl.

[0036] The second object of the present invention is a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as described above, the method comprising:

[0037]

[0038] Among them, Y, R 1 , R 2 and R 4 As defined above, and PG is an amino protecting group, reacted with a suitable deprotecting agent to form the compound of formula (I).

[0039] The third object of the present invention is a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as described above, and a pharmaceutically acceptable excipient.

[0040] A fourth object of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for use in treating, preventing and / or delaying the progression of cancer.

[0041] 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 the 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.

[0042] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0043] Unless otherwise indicated, the nomenclature used in this application is based on the IUPAC systematic nomenclature. DETAILED DESCRIPTION

[0044] definition

[0045] "Alkoxy" refers to an alkyl group as previously defined attached to the parent molecular moiety through an oxygen atom. Unless otherwise specified, alkoxy groups contain 1 to 12 carbon atoms ("C 1-12 -alkoxy”), preferably 1 to 10 carbon atoms (“C 1-10 -alkoxy”), more preferably 1 to 6 carbon atoms (“C 1-6 -alkoxy"). In some preferred embodiments, the alkoxy group contains 1 to 4 carbon atoms. In yet other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0046] "Alkoxyalkyl" refers to an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced by an alkoxy group. Preferably, "alkoxyalkyl" refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably one hydrogen atom, of the alkyl group has been replaced by an alkoxy group. A particularly preferred but non-limiting example of alkoxyalkyl is methoxymethyl and 2-methoxyethyl.

[0047] "Alkyl" refers to a group having a specified number of carbon atoms (i.e., C 1-10 alkyl groups are saturated linear (i.e., unbranched) or branched monovalent hydrocarbon chains of one to ten carbon atoms (“C”). 1-20 alkyl”), having 1 to 12 carbon atoms (“C 1-12 alkyl”), having 1 to 10 carbon atoms (“C 1-10 alkyl”), having 1 to 8 carbon atoms (“C 1-8 alkyl”), having 1 to 6 carbon atoms (“C 1-6 alkyl”), having 2 to 6 carbon atoms (“C 2-6 alkyl") or having 1 to 4 carbon atoms ("C 1-4 Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, and homologs and isomers such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0048] "Alkynyl" refers to a moiety having at least one site of acetylenic unsaturation (ie, having at least one moiety of the formula C≡C) and having a specified number of carbon atoms (ie, C 2-10 means an unsaturated linear (ie, unbranched) or branched monovalent hydrocarbon chain or combinations thereof of two to ten carbon atoms). Specific alkynyl groups are those having 2 to 20 carbon atoms (“C 2-20 Alkynyl”), having 2 to 8 carbon atoms (“C 2-8 Alkynyl”), having 2 to 6 carbon atoms (“C 2-6 Alkynyl”), having 2 to 4 carbon atoms (“C 2-4 Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (ethynyl / acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.

[0049] "Amino", alone or in combination with other groups, refers to NH2.

[0050] "Aminoalkyl" refers to an alkyl group wherein one or more of the hydrogen atoms of the alkyl group has been replaced with an amino moiety.

[0051] "Aromatic" means the conventional concept of aromatic as defined in the literature, in particular in IUPAC-Compendium of Chemical Terminology, 2nd edition, AD McNaught & A. Wilkinson (eds). Blackwell Scientific Publications, Oxford (1997).

[0052] "Aryl" refers to a cyclic aromatic hydrocarbon moiety having a monocyclic, bicyclic or tricyclic aromatic ring of 5 to 14 carbon ring atoms ("C 5-14 -aryl"). Bicyclic aryl ring systems include fused bicyclic rings having two fused five-membered aryl rings (denoted 5-5), fused bicyclic rings having one five-membered aryl ring and one fused six-membered aryl ring (denoted 5-6 and 6-5), and fused bicyclic rings having two fused six-membered aryl rings (denoted 6-6). The aryl group may be optionally substituted as defined above. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, and the like. The term "aryl" also includes partially hydrogenated derivatives of cyclic aromatic hydrocarbon moieties, provided that at least one ring of the cyclic aromatic hydrocarbon moiety is aromatic, each optionally substituted.

[0053] "Cancer" refers to a disease characterized by the presence of a neoplasm or tumor due to abnormal, uncontrolled growth of cells (such cells are "cancer cells"). As used herein, the term cancer specifically 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.

[0054] "Cyano", alone or in combination with other groups, means CN (ie, nitrile).

[0055] "Cyanoalkyl" refers to an alkyl group wherein one or more of the hydrogen atoms of the alkyl group has been replaced with a cyano moiety.

[0056] "Cycloalkyl" refers to a monocyclic, bicyclic (including bridged bicyclic and cycloalkyl spiro moieties) or tricyclic ring having 3 to 10 carbon atoms (i.e., (C3-C 10 The saturated or partially unsaturated carbocyclic moiety of (C3-C8) cycloalkyl). The cycloalkyl moiety can be optionally substituted with one or more substituents. In a particular aspect, the cycloalkyl contains 3 to 8 carbon atoms (i.e., (C3-C8) cycloalkyl). In other particular aspects, the cycloalkyl contains 3 to 6 carbon atoms (i.e., (C3-C6) cycloalkyl). The example of the cycloalkyl moiety includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and its partially unsaturated derivatives (cycloalkenyl) (e.g., cyclopentenyl, cyclohexenyl and cycloheptenyl), bicyclo [3.1.0] hexyl, bicyclo [3.1.0] hexenyl, bicyclo [3.1.1] heptyl, bicyclo [3.1.1] heptenyl and bicyclo [1.1.1] pentane. The cycloalkyl moiety can be connected in a "spiro-cycloalkyl" or "cycloalkyl spiral" manner, such as "spirocyclopropyl".

[0057]

[0058] “EC x ” refers to the effective concentration, e.g., in culture medium or plasma, of a particular compound required to obtain x% of a maximal specific effect in vitro or in vivo. “EC x An example of this is EC 20 ,EC 50 and EC 100, respectively, represent the concentration of a specific compound in culture medium or plasma required to obtain 20%, 50% and 100% of the maximum specific effect in vitro or in vivo. "Halo" or "halogen" refers to fluorine, chlorine, bromine and / or iodine. When a residue is substituted with more than one halogen, this can be referred to by using a prefix corresponding to the number of halogen moieties attached, for example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which can be, but are not necessarily, the same halo; thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which one or more hydrogens are replaced by a halo group is called a "haloalkyl", for example "C 1-6 A preferred haloalkyl group is trifluoroalkyl (-CF3).

[0059] "Haloalkoxy" refers to an alkoxy group in which at least one halogen replaces each H in the hydrocarbon constituting the alkyl portion of the alkoxy group. Examples of haloalkoxy groups are difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3).

[0060] "Haloalkyl" refers to an alkyl group as defined above containing at least one carbon atom substituted with at least one halo group, halo being 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 independently substituted with one or more halo groups such as fluorine, chlorine, bromine and iodine.

[0061] "Haloaryl" refers to an aryl group in which at least one hydrogen has been replaced by a halogen.

[0062] "Heteroatom" refers to atoms other than carbon or hydrogen.

[0063] "Heteroaryl" refers to an aromatic heterocyclic monocyclic, bicyclic or tricyclic ring system of 5 to 14 ring atoms, preferably 5 to 10 ring atoms, more preferably 5 to 6 ring atoms, containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. In some aspects, the monocyclic heteroaryl ring may be 5-membered to 6-membered. Bicyclic heteroaryl ring systems include fused bicyclic rings having two fused five-membered heteroaryl rings (denoted 5-5), fused bicyclic rings having one five-membered heteroaryl ring and one fused six-membered heteroaryl ring (denoted 5-6 and 6-5), and fused bicyclic rings having two fused six-membered heteroaryl rings (denoted 6-6). The heteroaryl group may be optionally substituted as defined above. 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, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furanopyridazinyl, furanopyrimidinyl and furanopyrazinyl. Most preferably, "5-membered heteroaryl" refers to the following groups:

[0064]

[0065] "Heterocycle" or "heterocyclyl" refers to a 3, 4, 5, 6, 7, 8, 9, 10-membered monocyclic, 7, 8, 9 and 10-membered bicyclic (including bridged bicyclic and cycloalkyl spiro moieties) or 10, 11, 12, 13, 14 and 15-membered bicyclic heterocyclic moieties, which are saturated or partially unsaturated and have one or more (e.g., 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur) in the ring, wherein the remaining ring atoms are carbon. In some aspects, the heterocycle is a heterocycloalkyl. In particular aspects, the heterocycle or heterocyclyl refers to a 4, 5, 6 or 7-membered heterocycle. When used to refer to the ring atoms of the heterocycle, the nitrogen or sulfur may also be in an oxidized form, and the nitrogen may be substituted with one or more (C1-C6) alkyl or groups. The heterocycle may be attached to its side group at any heteroatom or carbon atom to produce a stable structure. Any ring atom of the heterocycle may be optionally substituted with one or more substituents described herein. Examples of such saturated or partially unsaturated heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine, Oxazepine Thiazepine The term heterocycle also includes groups in which the heterocycle is fused to one or more aryl, heteroaryl or cycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl, azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, azabicyclo[3.1.1]heptyl, octahydroindolyl or tetrahydroquinolinyl.

[0066] "Hydroxyl", alone or in combination with other groups, refers to OH.

[0067] "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.

[0068] "Moiety" and "substituent" refer to an atom or group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds to form a part of a molecule.

[0069] When indicating the number of substituents, the term "one or more" refers to the range from one substituent to the highest possible number of substituents, i.e., replacement of one hydrogen up to replacement of all hydrogens by substituents, particularly where "one or more" refers to one, two or three, most particularly "one or more" refers to one or two.

[0070] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, "an aryl group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the aryl group is substituted with an alkyl group and instances where the aryl group is not substituted with an alkyl group.

[0071] "Optionally substituted" means unsubstituted or substituted. Typically these substituents may be the same or different.

[0072] "Oxo", alone or in combination with other groups, means =0.

[0073] "Pharmaceutically acceptable salts" refer to those salts which retain the biological effects and properties of the free bases or free acids and which are not biologically or otherwise undesirable. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid (particularly 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.

[0074] Particularly preferably, the pharmaceutically acceptable salts of the compounds of formula (I) are salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.

[0075] "Protecting group" (PG) means a group that selectively blocks a reactive site in a multifunctional compound so that another unprotected reactive site that is usually associated therewith in synthetic chemistry selectively reacts chemically. The protecting group can be removed at an appropriate point. Exemplary protecting groups are amino protecting groups, carboxyl protecting groups, or hydroxyl protecting groups. Specific protecting groups are tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Further specific protecting groups are tert-butyloxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more specific protecting group is tert-butyloxycarbonyl (Boc). Exemplary protecting groups and their use in organic synthesis are described in, for example, TW Greene and PGM Wutts, "Protective Groups in Organic Chemistry", 5th edition, 2014, John Wiley & Sons, NY.

[0076] As used herein, "preventing" includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition that develops in a mammal, and particularly in a human, that may be suffering from or susceptible to the condition, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the condition, disorder or condition.

[0077] "Substituted" refers to at least one hydrogen atom of a compound or part being replaced by another substituent or part. Examples of such substituents include, but are not limited to, halogen, -OH, -CN, oxo, alkoxy, alkyl, alkylene, aryl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl, and heterocycle. For example, the term "haloalkyl" refers to the fact that one or more hydrogen atoms of an alkyl group (as defined below) are replaced by one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.). In one aspect, substituted as used herein may refer to at least one hydrogen atom of a compound or part described herein being replaced by a halogen or alkyl.

[0078] "Therapeutically effective amount" refers to an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, disorder or condition, (ii) reduces, ameliorates or eliminates one or more symptoms of a particular disease, disorder or condition, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, disorder or condition as described herein. The therapeutically effective amount will depend on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0079] "Therapeutically inert carrier" refers to any ingredient that is not therapeutically active and non-toxic, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant or lubricant used to formulate a drug product.

[0080] In particular, the chemical groups given definitions above are those specifically exemplified in the Examples.

[0081] The following abbreviations are used in this text:

[0082] 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-uronium-hexafluorophosphate, HFIP = hexafluoroisopropanol, HOBt = hydroxybenzotriazole, HPLC = high performance liquid chromatography, m-CPBA = meta-chloroperbenzoic acid, MeCN = acetonitrile, MeI = iodomethane, MeOH = methanol, min = minute, MS = mass spectrometry, NBS = N-bromosuccinimide, PE = petroleum ether, PyBroP = bromo-tris-pyrrolidine-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 = trimethylsilyl trifluoromethanesulfonate, TLC = thin layer chromatography.

[0083] In the descriptions herein, if there is a discrepancy between a depicted structure and the name given to that structure, the depicted structure controls. Additionally, if the stereochemistry of a structure or portion of a structure is not indicated, for example, by a bold wedge or dashed line, that structure or portion of a structure is interpreted as encompassing all stereoisomers thereof. However, in some cases where there is more than one chiral center, the structure and name may be represented as a single enantiomer to aid in describing the relative stereochemistry.

[0084] Unless otherwise stated, the term "a compound of the formula" or "compounds of the formula" refers to any compound selected from the class of compounds defined by the formula (including any pharmaceutically acceptable salts of any such compound, if not stated otherwise).

[0085] Certain compounds may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate individual tautomers generally produce a mixture with chemical and physical properties consistent with the compound mixture. The position of equilibrium depends on the chemical features within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. Common prototropic tautomers include keto / enol Amide / Imidic Acid and amidine The latter two are particularly common in heteroaryls and heterocycles, and the present invention encompasses all tautomeric forms of the compounds.

[0086] Furthermore, the present invention includes all optical isomers of the compounds of formula (I), ie diastereomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers thereof and solvates thereof.

[0087] Compounds of formula (I) may contain one or more asymmetric centers and may therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Depending on the nature of the various substituents on the molecule, additional asymmetric centers may be present. Each such asymmetric center will independently produce two optical isomers, and it is intended that all possible optical isomers and diastereomers of the compound in the form of a mixture and as a pure compound or partially purified compound are included in the present invention. The present invention is intended to encompass all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their chromatographic separation can be achieved by appropriate modifications to the methods disclosed herein as known in the art. Their absolute stereochemistry can be determined by x-ray crystallography of crystalline products or crystalline intermediates, which, if desired, are derivatized with reagents containing asymmetric centers of known absolute configuration. If desired, the racemic mixture of the separable compound can be separated so that individual enantiomers are separated. Separation can be carried out by methods well known in the art, such as coupling a racemic mixture of the compounds to an enantiomerically pure compound to form a diastereomeric mixture followed by separation of the individual diastereomers by standard methods such as fractional crystallization or chromatography.

[0088] In embodiments where an optically pure enantiomer is provided, an optically pure enantiomer means that the compound contains >90% by weight of the desired isomer, specifically >95% by weight of the desired isomer, or more specifically >99% by weight of the desired isomer, the weight percentages being based on the total weight of the isomers of the compound. Chirally pure or chirally enriched compounds can be prepared by chiral selective synthesis or by separation of enantiomers. Separation of enantiomers can be performed on the final product, or alternatively on a suitable intermediate.

[0089] In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more atoms with atoms having a different atomic mass or mass number. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, such as but not limited to 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Certain isotopically-labeled compounds of formula (I) (e.g., those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and detection means are readily available. For example, compounds of formula (I) may be enriched with 1%, 2%, 5%, 10%, 25%, 50%, 75%, 90%, 95% or 99% of a given isotope.

[0090] Using heavier isotopes (such as deuterium, 2 H) substitutions may provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0091] Using positron-emitting isotopes such as 11 C. 18 F. 15 O and 13N) substitution can be used to examine positron emission tomography (PET) studies of substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the Examples set forth below using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.

[0092] Compounds of the present invention

[0093] In one embodiment, a compound of formula (I) is provided,

[0094]

[0095] or a pharmaceutically acceptable salt thereof, wherein:

[0096] Y is S(O), S(O)2 and S(O)N(R y );

[0097] R 1 is a 5-membered heteroaryl group, wherein R 1 Optionally, one or more R 10 replace;

[0098] R 2 is selected from hydrogen and halogen;

[0099] R 4 Selected from C 5-14 -aryl and 5- to 14-membered heteroaryl, wherein R 4 Optionally, one or more R 11 replace;

[0100] R 10 -C(R 10a R 10b )2-S(O)2(R 10c );

[0101] R 10a and R 10b are each independently selected from hydrogen and C 1-6 -alkyl, or R 10a and R 10b Together with the carbon atom to which they are attached, they form C 3-6 - cycloalkyl;

[0102] R 10c Selected from hydrogen, C 1-6 -alkyl, C 3-6 -cycloalkyl, -N(C 1-6 -alkyl), halo-C 1-6 -alkyl and phenyl, wherein the phenyl group is optionally substituted with one or more halogen or C 1-6- alkyl substitution;

[0103] or R 10a and R 10c Together with the carbon atom and the sulfur atom to which they are attached, they form a 3- to 10-membered heterocyclic group;

[0104] R 11 Selected from:

[0105] i) halogen;

[0106] ii) a 3- to 10-membered heterocyclic group, which is optionally substituted with one or more halogenated -C 1-6 -alkyl, C 3-10 - Cycloalkyl substitution;

[0107] iii) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more halogens, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 3-10 -Cycloalkyl, C 1-6 -Haloalkoxy substitution;

[0108] iv) phenyl, which is optionally substituted with one or more halogen, cyano, C 1-6 -alkoxy, C 1-6 -haloalkyl, C 1-6 - alkyl substitution;

[0109] v)-O(R 11a );

[0110] vi)-N(R 11g R 11h );as well as

[0111] vii)–S(R 11k );

[0112] R 11a Selected from C 1-12 -alkyl, halo-C 1-6 -alkyl, C 3-7 -cycloalkyl, 3- to 10-membered-(C 1-6 -alkyl) heterocyclic group, phenyl and -C 1-6 -alkyl-phenyl, wherein the C 1-12 -alkyl, C 3-7 -cycloalkyl, phenyl and -C 1-6 -alkyl-phenyl is optionally substituted with one or more halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -Haloalkoxy substitution;

[0113] R11g and R 11h are each independently selected from hydrogen, C 1-6 -alkyl, -(C 1-6 -alkyl)phenyl;

[0114] R 11k Selected from hydrogen and halo-C 1-6 -alkyl;

[0115] R y Selected from hydrogen and C 1-6 -alkyl.

[0116] In another embodiment, a compound of formula (I) as described herein is provided, wherein R 1 Optionally, one or more R 10 replace.

[0117] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 2 Selected from hydrogen and fluorine.

[0118] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 4 It is phenyl.

[0119] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 10a and R 10b are each independently selected from hydrogen or C 1-6 -alkyl, or R 10a and R 10b Together with the carbon atom to which they are attached, they form C 3-6 -cycloalkyl.

[0120] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 10 Selected from C 3-6 -cycloalkyl, through a -S(O)2(C 1-6 -alkyl) substituted.

[0121] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 10 is a 3- to 6-membered heterocyclic group, wherein the heteroatom is sulfur, and one or more C 1-10 -alkyl, oxo-substituted, wherein the oxo-substituted is on the sulfur atom.

[0122] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 10 Selected from 1-methyl-methylsulfonyl-ethyl.

[0123] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 11 Selected from -O(R 11a ), where R 11a Selected from C 1-12 -alkyl, halo-C 1-6 -alkyl, C 3-7 -cycloalkyl, 3- to 10-membered-(C 1-6 -alkyl) heterocyclic group, phenyl, -C 1-6 -alkyl-phenyl, wherein the C 1-12 -alkyl, C 3-7 -cycloalkyl, phenyl and -C 1-6 -alkyl-phenyl is optionally substituted with one or more halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy substitution.

[0124] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 11 Selected from

[0125] viii) halogen;

[0126] ix) a 3- to 10-membered heterocyclic group;

[0127] x) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more halogens, halo-C 1-6 -alkyl, C 3-10 -Cycloalkyl, C 1-6 -Haloalkoxy substitution;

[0128] xi) phenyl, which is optionally substituted with one or more cyano, C 1-6 -alkoxy, C 1-6 -haloalkyl, C 1-6 - alkyl substitution;

[0129] xii)-O(R 11a );R 11a 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, wherein the C 1-12 -alkyl, phenyl, 5- to 6-membered-(C 1-6 -alkyl)heteroaryl and -C 1-6-alkyl-phenyl is optionally substituted with one or more halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -Haloalkoxy substitution;

[0130] xiii)-N(R 11g R 11h );R 11g and R 11h Each independently selected from C 1-6 -alkyl, -(C 1-6 -alkyl)

[0131] Phenyl;

[0132] xiv)–S(halogenated-C 1-6 -alkyl);

[0133] xv) CH2-O-phenyl.

[0134] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 11 Selected from

[0135] i)-O(R 11a ), where R 11a Selected from halogenated-C 1-6 - alkyl and phenyl, wherein the phenyl is optionally substituted with one or more halogens; or

[0136] ii) phenyl, which is optionally substituted with one or more C 1-6 -alkoxy, C 1-6 -Haloalkyl substitution;

[0137] iii) Halogen

[0138] iv) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more halogenated -C 1-6 -alkyl, C 3-10 -Cycloalkyl, C 1-6 -haloalkoxy, chloro, trifluoromethoxy-2-pyridyl substituted.

[0139] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein is provided, wherein R 11 Selected from (trifluoromethyl)phenyl, (trifluoromethyl)-oxadiazolyl, cyclopropyl-oxadiazolyl, phenoxy, methoxyphenyl, tetrafluoroethoxy, dichlorophenoxy.

[0140] In another embodiment, provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein Y is S(O)2.

[0141] In another embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0142] Y is S(O), S(O)2 and S(O)N(R y );

[0143] R 1 is a 5-membered heteroaryl group, wherein R 1 Optionally, one or more R 10 replace;

[0144] R 2 is selected from hydrogen and fluorine;

[0145] R 4 is selected from C6-aryl and 6-membered heteroaryl, wherein R 4 Optionally, one or more R 11 replace;

[0146] R 10 For a -S(O)2(C 1-6 -alkyl) substituted C 3-6 - cycloalkyl;

[0147] R 11 for

[0148] i) halogen;

[0149] ii) a 3- to 10-membered heterocyclic group;

[0150] iii) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more halogens, halo-C 1-6 -alkyl, C 3-10 -Cycloalkyl, C 1-6 -Haloalkoxy substitution;

[0151] iv) phenyl, which is optionally substituted with one or more cyano, C 1-6 -alkoxy, C 1-6 -haloalkyl, C 1-6 - alkyl substitution;

[0152] v)-O(R 11a );R 11a 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, wherein the C 1-12 -alkyl, phenyl, 5- to 6-membered-(C 1-6-alkyl)heteroaryl and -C 1-6 -alkyl-phenyl is optionally substituted with one or more halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -Haloalkoxy substitution;

[0153] vi)-N(R 11g R 11h );R 11g and R 11h Each independently selected from C 1-6 -alkyl, -(C 1-6 -alkyl)

[0154] Phenyl;

[0155] vii) –S(halogenated-C 1-6 -alkyl);

[0156] viii) CH2-O-phenyl.

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

[0158] Y is S(O), S(O)2 and S(O)N(R y );

[0159] R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace;

[0160] R 2 is selected from hydrogen and fluorine;

[0161] R 4 is phenyl;

[0162] R 10 Selected from methyl-methylsulfonyl-ethyl, cyclopropylsulfonyl-methyl-ethyl, methyl-dioxo-thiolanyl, methylsulfonylmethyl, methylsulfonylcyclobutyl;

[0163] R 11 Selected from:

[0164] i)-O(R 11a ), where R 11a Selected from halogenated-C 1-6 -alkyl, phenyl, wherein the phenyl is optionally substituted with one or more halogens;

[0165] ii) phenyl, which is optionally substituted with one or more C 1-6 -alkoxy, C1-6 -Haloalkyl substitution;

[0166] iii) halogen; and

[0167] iv) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more halogenated -C 1-6 -alkyl, C 3-10 -cycloalkyl, C 1-6 -haloalkoxy substitution.

[0168] In another embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0169] Y is S(O), S(O)2 and S(O)N(R y );

[0170] R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace;

[0171] R 2 is selected from hydrogen and fluorine;

[0172] R 4 is phenyl;

[0173] R 10 is methyl-methylsulfonyl-ethyl;

[0174] R 11 is selected from (trifluoromethyl)phenyl, (trifluoromethyl)-oxadiazolyl, cyclopropyl-oxadiazolyl, phenoxy, methoxyphenyl, tetrafluoroethoxy, dichlorophenoxy, chloro and trifluoromethoxy)-2-pyridinyl.

[0175] In another embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0176] Y is S(O), S(O)2 and S(O)N(R y );

[0177] R 1 is a 5-membered heteroaryl group, wherein R 1 Optionally, one or more R 10 replace;

[0178] R 2 is selected from hydrogen and fluorine;

[0179] R 4 is selected from C6-aryl and 6-membered heteroaryl, wherein R 4 Optionally, one or more R 11replace;

[0180] R 10 Selected from C 3-6 -cycloalkyl, through a -S(O)2(C 1-6 -alkyl) substituted;

[0181] R 11 Selected from -O(R 11a ), where R 11a Selected from C 1-12 -alkyl, halo-C 1-6 -alkyl, C 3-7 -cycloalkyl, 3- to 10-membered-(C 1-6 -alkyl) heterocyclic group, phenyl, -C 1-6 -alkyl-phenyl, wherein the C 1-12 -alkyl, C 3-7 -cycloalkyl, phenyl and -C 1-6 -alkyl-phenyl is optionally substituted with one or more halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy substitution.

[0182] In another embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0183] Y is S(O), S(O)2 and S(O)N(R y );

[0184] R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace;

[0185] R 2 is selected from hydrogen and fluorine;

[0186] R 4 is phenyl;

[0187] R 10 Selected from methyl-methylsulfonyl-ethyl, cyclopropylsulfonyl-methyl-ethyl, methyl-dioxo-thiolanyl, methylsulfonylmethyl, methylsulfonylcyclobutyl;

[0188] R 11Selected from 2-methoxy-1,1-dimethyl-ethoxy, phenoxy, bromophenoxy, (trifluoromethyl)-oxadiazolyl]methoxy, (trifluoromethyl)phenyl, tetrahydropyranyl, methoxyphenyl, methoxy-methyl-phenyl, (difluoromethoxy)phenoxy, (trifluoromethyl)-oxadiazolyl, cyclopropyl-oxadiazolyl, trifluoromethoxy, chloro, methoxyphenoxy, chloro-methoxy-phenoxy, trifluoromethoxy)phenoxy, fluoro-(trifluoromethyl)phenoxy, chloro-fluoro-phenoxy, trifluoromethyl-pyridyl, chlorophenoxy, fluorophenoxy, dichlorophenoxy, methylphenoxy, tetrafluoroethoxy, trifluoroethoxy, trifluoropropoxy, benzonitrile, ethylpropoxy, isopropyl(methyl)aminoacyl, cyclopentyloxy, benzyl(methyl)aminoacyl, (fluorophenyl)methoxy, benzyloxy, fluoro-pyridyl, trifluoromethylsulfhydryl.

[0189] In another embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0190] Y is S(O), S(O)2 and S(O)N(R y );

[0191] R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace;

[0192] R 2 is selected from hydrogen and fluorine;

[0193] R 4 is phenyl;

[0194] R 10 Selected from methyl-methylsulfonyl-ethyl;

[0195] R 11 Selected from (trifluoromethyl)phenyl, (trifluoromethyl)-oxadiazolyl, cyclopropyl-oxadiazolyl, phenoxy, methoxyphenyl, tetrafluoroethoxy, dichlorophenoxy.

[0196] In another embodiment, there is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, which is selected from:

[0197] (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-benzothiazepine -4-Keto;

[0198] (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-benzothiazepine -4-Keto;

[0199] (3R)-3-Amino-5-[[4-(cyclopentyloxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto;

[0200] (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-benzothiazepine -4-Keto;

[0201] (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-benzothiazepine -4-Keto;

[0202] (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-benzothiazepine -4-Keto;

[0203] (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-benzothiazepine -4-Keto;

[0204] (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-benzothiazepine -4-Keto;

[0205] (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-benzothiazepine -4-Keto;

[0206] (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-benzothiazepine -4-Keto;

[0207] (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-benzothiazepine -4-Keto;

[0208] (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-benzothiazepine -4-Keto;

[0209] (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-benzothiazepine -4-Keto;

[0210] (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-benzothiazepine -4-Keto;

[0211] (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-benzothiazepine -4-Keto;

[0212] (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-benzothiazepine -4-Keto;

[0213] (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-benzothiazepine -4-Keto;

[0214] (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-benzothiazepine -4-Keto;

[0215] (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-benzothiazepine -4-Keto;

[0216] (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-benzothiazepine -4-Keto;

[0217] (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-benzothiazepine -4-Keto;

[0218] (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-benzothiazepine -4-Keto;

[0219] 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-benzothiazepine -5-yl]methyl]phenyl]benzonitrile;

[0220] (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-benzothiazepine -4-Keto;

[0221] (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-benzothiazepine -4-Keto;

[0222] (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-benzothiazepine -4-Keto;

[0223] (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-benzothiazepine -4-Keto;

[0224] (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-benzothiazepine -4-Keto;

[0225] (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-benzothiazepine -4-Keto;

[0226] (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-benzothiazepine -4-Keto;

[0227] (3R)-3-Amino-1,1-dioxo-7-[5-(1-methylsulfonyl-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[4-[5-(trifluoromethoxy)-2-pyridyl]benzyl]-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto;

[0228] (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-benzothiazepine -4-Keto;

[0229] (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-benzothiazepine -4-Keto;

[0230] (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-benzothiazepine -4-Keto;

[0231] (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-benzothiazepine -4-Keto;

[0232] (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-benzothiazepine -4-Keto;

[0233] (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-pyridinyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto;

[0234] (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-benzothiazepine -4-Keto;

[0235] (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-benzothiazepine -4-Keto;

[0236] (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-benzothiazepine -4-Keto;

[0237] (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-benzothiazepine -4-Keto;

[0238] (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-benzothiazepine -4-Keto;

[0239] (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-benzothiazepine -4-Keto;

[0240] (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-benzothiazepine -4-Keto;

[0241] (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-benzothiazepine -4-Keto;

[0242] (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-benzothiazepine -4-Keto;

[0243] (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-benzothiazepine -4-Keto;

[0244] (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-benzothiazepine -4-Keto;

[0245] (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-benzothiazepine -4-Keto;

[0246] (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-benzothiazepine -4-Keto;

[0247] (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-benzothiazepine -4-Keto;

[0248] (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-benzothiazepine -4-Keto;

[0249] (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-benzothiazepine -4-Keto;

[0250] (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-benzothiazepine -4-Keto;

[0251] (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-benzothiazepine -4-Keto;

[0252] (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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto;

[0253] (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-benzothiazepine -4-Keto;

[0254] (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-benzothiazepine -4-Keto;

[0255] (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-benzothiazepine -4-Keto;

[0256] (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-benzothiazepine -4-Keto;

[0257] (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-benzothiazepine -4-Keto;

[0258] (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-benzothiazepine -4-Keto;

[0259] (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-benzothiazepine -4-Keto;

[0260] 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-oxadiazol-2-yl]-N,N-dimethyl-propane-2-sulfonamide;

[0261] (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-benzothiazepine -4-Keto;

[0262] (3R)-3-Amino-8-fluoro-7-[2-(methylsulfonylmethyl)tetrazol-5-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto;

[0263] (3R)-3-Amino-8-fluoro-7-[1-(methylsulfonylmethyl)tetrazol-5-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto.

[0264] In a preferred embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, which is selected from

[0265] (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-benzothiazepine -4-Keto;

[0266] (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-benzothiazepine -4-Keto;

[0267] (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-benzothiazepine -4-Keto;

[0268] (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-benzothiazepine -4-Keto;

[0269] (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-benzothiazepine -4-Keto;

[0270] (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-benzothiazepine -4-Keto;

[0271] (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-benzothiazepine -4-Keto;

[0272] (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-benzothiazepine -4-Keto;

[0273] (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-benzothiazepine -4-Keto;

[0274] (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-benzothiazepine -4-ketone; and

[0275] (3R)-3-Amino-1,1-dioxo-7-[5-(1-methylsulfonyl-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[4-[5-(trifluoromethoxy)-2-pyridyl]benzyl]-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto.

[0276] Manufacturing Process

[0277] Processes for the manufacture of compounds of formula (I) or pharmaceutically acceptable salts thereof as described herein are also an object of the present invention.

[0278] The present invention provides a method for preparing a compound as described herein or a pharmaceutically acceptable salt thereof, the method comprising:

[0279]

[0280] Among them, Y, R 1 , R 2 and R 4 As defined herein, and PG is an amino protecting group, reacted with a suitable deprotecting agent to form the compound of formula (I).

[0281] The preparation of the compound of formula (I) of the present invention can be carried out according to sequential or concurrent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required for performing the reaction and purifying the resulting product are known to those skilled in the art. Unless otherwise indicated, the substituents and labels used in the following description of the process have the meanings given herein.

[0282] If one of the starting materials, intermediates or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, appropriate protective groups may be introduced before applying key steps of methods well known in the art (such as "Protective Groups in Organic Chemistry" by TW Greene and PGM Wutts, 5th edition, 2014, John Wiley & Sons, NY). Such protective groups may be removed at a later stage of the synthesis using standard methods described in the literature.

[0283] If the starting material or intermediate contains a stereogenic center, the compound of formula (I) can be obtained in the form of a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art (e.g., chiral HPLC, chiral SFC or chiral crystallization). Racemic compounds can be separated into corresponding enantiomers, for example, by diastereomeric salts, which are crystallized with optically pure acids, or by specific chromatography separations of enantiomers using chiral adsorbents or chiral eluents. Starting materials and intermediates containing stereogenic centers can also be separated to obtain starting materials and intermediates enriched in diastereomers / enantiomers. Using such diastereomer / enantiomer-enriched starting materials and intermediates in the synthesis of compounds of formula (I) will generally produce diastereomers / enantiomer-enriched compounds of the corresponding formula (I).

[0284] Those skilled in the art will recognize that in the synthesis of compounds of formula (I) (if not desired), an "orthogonal protecting group strategy" will be applied, which allows multiple protecting groups to be cleaved each time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has also been reported in the literature (e.g., Barany and RB Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0285] Those skilled in the art will recognize that the order of reactions may vary depending on the reactivity and nature of the intermediates.

[0286] In more detail, the compound of formula (I) can be manufactured by the method given below, by the method given in the example or by a similar method. The appropriate reaction conditions for each reaction step are known to those skilled in the art. In addition, the reaction conditions of the reaction described in the relevant literature are reported, for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999. It is convenient to react in the presence or absence of a solvent. There are no particular restrictions on the nature of the solvent used, provided that it has no adverse effect on the reaction or the reagent involved and can dissolve the reagent at least to a certain extent. The described reaction can occur over a wide temperature range, and the precise reaction temperature is not critical for the present invention. The described reaction can be conveniently performed in a temperature range of -78 ° C to reflux. The time required for the reaction can also vary over a wide range, depending on many factors, particularly the nature of the reaction temperature and the reagent. However, it usually takes 0.5 hours to several days to obtain the described intermediates and compounds. The reaction sequence is not limited to the one shown in the schemes, however, depending on the starting materials and their respective reactivities, the order of the reaction steps can be freely varied.

[0287] If starting materials or intermediates were not commercially available or their synthesis was not reported in the literature, they were prepared analogously to existing preparations of close analogs or as outlined in the experimental section.

[0288] The compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention can be prepared by the following process (Scheme 1) together with synthetic methods known in the field of organic chemistry or modifications and derivatizations familiar to those skilled in the art.

[0289]

[0290] Solution 1

[0291] Suitable starting materials for preparing compounds of formula (I) are nitro compounds of formula (II) wherein X 2 is F or Cl and X 1 Already R 1 or groups such as Br, CN or -CO2 alkyl, which may be elaborated later as R 1. The compound of formula (II) can be reacted with a suitably protected cysteine ​​derivative (III) in the presence of a base such as DIPEA at elevated temperature in a solvent such as 1,2-dichloroethane to obtain a compound of formula (IV). The preferred protecting group (PG) of the cysteine ​​derivative (III) is Boc. The nitro group in the compound of formula (IV) can be reduced using iron in the presence of hydrogen chloride or ammonium chloride in a solvent mixture of water and ethanol at elevated temperature to obtain a compound of formula (V). Alternatively, the conversion can be achieved by catalytic hydrogenation. The compound of formula (V) can be cyclized to a compound of formula (VI) using standard amide coupling conditions. Preferably, the cyclization is carried out using 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine 2,4,6-trioxide (50% solution in EtOAc) in a solvent such as DMF at room temperature and using a base such as DIPEA. The compound of formula (VI) and the compound of formula (VII) (wherein Y 1 is Cl, Br, I or a sulfonate group) in the presence of a base such as potassium carbonate and, if necessary, with an additive such as potassium iodide in a solvent such as DMSO or DMF at room temperature to obtain a compound of formula (VIII). Alternatively, a compound of formula (VI) can be reacted with a compound of formula (VII) (wherein Y 1 is OH) in the presence of PPh3 with an additive such as DIAD in a solvent such as toluene at an elevated temperature to obtain a compound of formula (VIII). For compounds of formula (VIII), wherein X 1 is Br or -CO2 alkyl, which groups can be elaborated at this stage as substituents R as shown in the following schemes 1 The compound of formula (VIII) can then be converted to a compound of formula (IX), wherein 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). If the N-protecting group (PG) is Boc, typical conditions for the 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. In addition, the substituent R 1 and R 4May contain functional groups that may be modified prior to removal of the N-protecting group (PG), or may require the use of suitable protecting groups during the synthesis. These protecting groups may be removed prior to removal of the N-protecting group (PG), or they may be removed simultaneously using suitable methods [Peter GMWuts, Greene's protective groups in organic synthesis, 5th edition, Hoboken, NJ: Wiley-Interscience].

[0292] Alternatively, compounds of formula (I) wherein Y is S(O)2 can be prepared as shown in Scheme 2.

[0293]

[0294] (l) Where Y is S(O)2

[0295] Solution 2

[0296] The compound of formula (VI) can be converted to the compound of formula (X) after reaction with an oxidant such as m-CPBA in a solvent such as DCM at room temperature. The compound of formula (X) is reacted with a compound of formula (VII) to give a compound of formula (XI), and then converted to a compound of formula (I), wherein Y is S(O)2, using reaction conditions similar to those described in Scheme 1. If X 1 is Br, -CO2 alkyl or CN, these groups can be elaborated as substituents R at any stage of the synthesis 1 (The method described in the following schemes is used for compounds of formula (VI), (X) or (XI).

[0297] The 5-membered heteroaryl group R 1 Compounds of formula (I) which are 1,3,4-oxadiazolyl can be prepared as shown in Scheme 3.

[0298]

[0299] Solution 3

[0300] The compound of formula (VIII) (wherein X 1The compound of formula (XIII) can be converted to the compound of formula (XII) by reaction with an alkali metal hydroxide such as LiOH, NaOH or KOH in a solvent such as a mixture of MeOH, THF and water at room temperature. The compound 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 obtain the compound of formula (XIII). The compound of formula (XIII) can be reacted with a carboxylic acid R using standard amide coupling conditions such as HATU in the presence of a base such as DIPEA in a solvent such as THF at room temperature. 10 CO2H reaction. The coupling product of formula (XIV) can be cyclized to a compound of formula (XV) using a dehydrating agent such as Burgess reagent, or can be reacted with tosyl chloride in the presence of a base such as DIPEA at room temperature. The conversion of a compound of formula (XV) to a compound of formula (XVI) and subsequently to a compound of formula (I) can be achieved using reaction conditions as described in the analogous steps in Scheme 1.

[0301] The 5-membered heteroaryl group R 1 Compounds of formula (I) which are 1,2,4-oxadiazolyl may be prepared as shown in Scheme 4.

[0302]

[0303] Solution 4

[0304] The compound of formula (VIII) (wherein X 1 The compound of formula (XVII) (wherein R is H) can be reacted with hydroxylamine hydrochloride in the presence of a base such as potassium carbonate in a solvent such as ethanol at an elevated temperature to obtain an amidoxime compound of formula (XVII) (wherein R is H). 10 CO2H is reacted using standard amide coupling conditions such as CDI, HATU or EDCI and HOBt in the presence of a base such as DIPEA in a solvent such as acetonitrile, DMF or THF to provide the coupling intermediate (XVII, wherein R is -C(O)R 10 ), which upon heating cyclizes to the corresponding compound of formula (XVIII). Alternatively, the coupled intermediate (XVII) (wherein R is -C(O)R 10 ), and the cyclization step can be carried out by heating in a solvent such as toluene or reacting with TBAOH in a solvent such as THF. The conversion of the compound of formula (XVIII) to the compound of formula (XIX) and then to the compound of formula (I) can be achieved using the reaction conditions described in the analogous steps in Scheme 1.

[0305] The compound of formula (I) (wherein the 5-membered heteroaryl group R 1 is a tetrazolyl group) can be prepared as shown in Scheme 5.

[0306]

[0307] Solution 5

[0308] The compound of formula (VIII) (wherein X 1 (CN) can be converted to compounds of formula (XX) by reaction with an azide reagent such as trimethylsilyl azide 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 substituent R 10 This can be done by various methods (such as with reagent R 10 Y (wherein Y is Cl, Br or I) is introduced in the presence of a base such as potassium carbonate in a solvent such as DMF at room temperature. Alternatively, the compound of formula (XX) can be reacted with a reagent R 10 Y (wherein Y is OH) is reacted in the presence of PPh with an additive such as DIAD in a solvent such as toluene at elevated temperature to obtain a compound of formula (XXI). The conversion of a compound of formula (XXI) to a compound of formula (XXII) and subsequently to a compound of formula (I) can be achieved using reaction conditions as described in the analogous steps in Scheme 1.

[0309] Pharmaceutical compositions and administration

[0310] Another object of the present invention is to provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, and a pharmaceutically acceptable excipient.

[0311] Formula (I) compound and its pharmaceutical salt can be used as medicine in the form of pharmaceutical preparation. Pharmaceutical preparation can be internally administered, such as oral (for example, in the form of tablets, coated tablets, dragees, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions), nasal (for example, in the form of nasal sprays) or rectal (for example, in the form of suppositories). However, administration can also be implemented parenterally such as intramuscular or intravenous (for example, in the form of injection solutions). Administration can also be implemented locally, for example, percutaneous administration, or in the form of eye drops or ear drops.

[0312] The compound of formula (I) and its pharmaceutically acceptable salt can be processed with a pharmaceutically inert inorganic or organic carrier to produce a pharmaceutical preparation such as a tablet, a coated tablet, a dragee, a hard gelatin capsule, an injection or a topical formulation. For example, lactose, corn starch or its derivatives, talcum powder, stearic acid or its salts etc. can be used as such carriers for tablets, coated tablets, dragees and hard gelatin capsules.

[0313] Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols, etc. However, depending on the nature of the active substance, no carriers are usually required in the case of soft gelatin capsules.

[0314] Suitable carriers for the production of solutions and syrups are, for example, water, alcohols, polyols, sucrose, glucose, invert sugar, vegetable oils and the like.

[0315] Suitable carriers for injection solutions are, for example, water, alcohol, polyol, glycerol, vegetable oil and the like.

[0316] Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

[0317] Suitable carriers for topical ophthalmic formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.

[0318] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

[0319] Medicaments containing compounds of formula (I) or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients and processes for their production are also objects of the present invention, which process comprises bringing one or more compounds of formula (I) and / or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances together with one or more pharmaceutically acceptable excipients into a galenical administration form.

[0320] Dosage is variable over a wide range, but will certainly have to be adjusted according to the individual needs of each particular case. Generally speaking, in the case of oral administration, the daily dose is about 0.1 mg to 20 mg per kg body weight, preferably 0.5 mg to 4 mg per kg body weight (e.g., about 300 mg per person), preferably divided into 1-3 separate doses (which may be composed of, for example, the same amount) should be appropriate. In the case of topical administration, the formulation may contain 0.001% to 15% of the drug by weight, and the desired dose may be between 0.1 mg and 25 mg, and may be administered in a single dose every day or every week, or in multiple doses every day (2 to 4 times), or in multiple doses every week. However, it is apparent that if the upper or lower limit given herein is indicated, the upper or lower limit may be exceeded.

[0321] The pharmaceutical composition according to the present invention can be prepared as follows.

[0322] Preparation of pharmaceutical compositions containing the compounds of the present invention Tablet formulation (wet granulation)

[0323]

[0324]

[0325] Manufacturing process:

[0326] 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

[0327] 2. Dry the granules at 50°C.

[0328] 3. Pass the granules through suitable grinding equipment.

[0329] 4. Add ingredient 5 and mix for three minutes; press on a suitable press.

[0330] Capsule formulations

[0331]

[0332] Manufacturing process:

[0333] 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

[0334] 2. Add ingredients 4 and 5 and mix for 3 minutes.

[0335] 3. Fill into suitable capsules.

[0336] Injection

[0337]

[0338]

[0339] Manufacturing process:

[0340] The compound of formula (I) is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by adding the remainder of water. The solution is filtered, filled into a vial with an appropriate excess and sterilized.

[0341] Indications

[0342] The compounds of formula (I) may be used in an effective amount for treating a subject, particularly a human, affected by cancer.

[0343] 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.

[0344] In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for use in treating, preventing and / or delaying the progression of cancer.

[0345] In another aspect, the present invention provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for treating, preventing and / or delaying the progression of cancer.

[0346] In another aspect, the present invention provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for preparing a medicament for treating, preventing and / or delaying the progression of cancer.

[0347] In another aspect, the present invention provides a method for treating, preventing and / or delaying the progression of cancer, which method comprises administering a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0348] As used herein, the term "treatment" or "treating" and its grammatical variants mean therapeutic therapy. With reference to a particular disorder, treatment means: (1) ameliorating the disorder or one or more biological manifestations of the disorder, (2) interfering with (a) one or more points in the biological cascade that lead to or cause the disorder, or (b) one or more biological manifestations of the disorder, (3) alleviating one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder. Prophylactic therapy using the methods and / or compositions of the present invention is also contemplated. Those skilled in the art will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to significantly reduce the likelihood or severity of a disorder or its biological manifestations, or to delay the onset of such a disorder or its biological manifestations. For example, when a subject is considered to be at high risk for developing cancer, such as when the subject has a strong family history of cancer or when the subject has been exposed to a carcinogen, prophylactic therapy is appropriate.

[0349] As an immunotherapeutic agent that acts on immune cells rather than directly on cancer cells, the present disclosure also foresees use as an anti-cancer vaccine. This also includes methods in which immune cells are cultured and manipulated ex vivo, and the molecules disclosed herein are used as a means of conferring co-stimulation to the manipulated cells ex vivo.

[0350] In one embodiment, the cancer is a blood cancer, such as lymphoma, leukemia, or myeloma. Hematological cancers contemplated herein include, but are not limited to, one or more leukemias, such as B-cell acute lymphoid leukemia ("BALL"), T-cell acute lymphoid leukemia ("TALL"), acute lymphoid leukemia (ALL); one or more chronic leukemias, including, but not limited to, chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL); additional hematological cancers or disorders, including, but not limited to, B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative disorders, mucosa-associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, The term "leukemia" refers to a group of blood disorders that result from ineffective production (or maldevelopment) of myeloid blood cells.

[0351] In another embodiment, the cancer is a non-hematological cancer, such as a sarcoma, carcinoma, or melanoma. Non-hematological cancers contemplated herein include, but are not limited to, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell carcinoma, melanoma, gastric cancer, brain cancer, lung cancer (e.g., non-small cell lung cancer-NSCLC), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.

[0352] Co-administration of compounds of formula (I) and other agents

[0353] 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 agents for treatment. For example, the second agent of the drug combination formulation or dosing regimen may have an activity complementary to the compound of formula (I) so that they do not adversely affect each other. The compounds can be administered together or separately in a single pharmaceutical composition. In one embodiment, the compound or pharmaceutically acceptable salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancer.

[0354] The term "co-administration" refers to the simultaneous administration of a compound of formula (I) or a salt thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof with one or more other active pharmaceutical ingredients (including cytotoxic agents and radiotherapy) or in any manner, respectively, in sequence. If the administration is not simultaneous, the compounds should be administered at a time close to each other. In addition, it does not matter 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.

[0355] Generally, any agent with anticancer activity can be co-administered. Examples of such agents can be found in Cancer Principles and Practice of Oncology (V.T. Devita and S. Heilman, eds.), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. Based on the specific characteristics of the drugs and diseases involved, one of ordinary skill in the art will be able to discern which combination of agents will be useful.

[0356] In one aspect, the present invention provides a pharmaceutical composition as described herein, further comprising an additional therapeutic agent.

[0357] In one embodiment, the additional therapeutic agent is a chemotherapeutic agent.

[0358] In one embodiment, the additional therapeutic agent is a cytotoxic agent.

[0359] In one embodiment, the additional therapeutic agent is an immuno-oncology agent.

[0360] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cellular function and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (At 211 ,I 131 ,I 125 , Y 90 、Re 186 、Re 188 、Sm 153 、Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof, such as nucleolytic enzymes; and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof.

[0361] Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, LDH-A inhibitors; fatty acid biosynthesis inhibitors; cell cycle signaling inhibitors; HDAC inhibitors, proteasome inhibitors; and cancer metabolism inhibitors.

[0362] "Chemotherapeutic agents" include chemical compounds that can be used to treat cancer. Examples of chemotherapeutic agents include erlotinib ( Genentech / OSI Pharm.), bortezomib ( Millennium Pharm.), disulfiram, epigallocatechin gallate, salisosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant ( AstraZeneca), sunitinib ( Pfizer / Sugen), letrozole ( Novartis), imatinib mesylate ( Novartis), phenaxate ( Novartis), oxaliplatin ( Sanofi), 5-FU (5-fluorouracil), folinic acid, rapamycin (sirolimus, Wyeth), Lapatinib ( GSK572016, Glaxo Smith Kline), Rhonafarmib (SCH 66336), Sorafenib ( Bayer Labs), gefitinib ( AstraZeneca), AG1478; alkylating agents such as thiotepa and Cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquinone, meturedopa, and uredopa; ethylimines and methylmelamines including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; annona lactones (especially bullatacin and bullatacinone); camptothecins (including topotecan and irinotecan); bryostatin; callystatin; CC-106 5 (including its synthetic analogs of adozelesin, carzelesin and bizelesin); cryptophycin (particularly cryptophycin I and cryptophycin 8); adrenocortical steroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductase (including finasteride and dutasteride); vorinostat, romidepsin, panbicistat, valproic acid, mocetinostat, dolastatin; aldesleukin, talc, dukamycin (including synthetic analogs of KW-2189 and CBI-TM I); eleutherobin; sarcodictine; sarcodictyin; spongestatin; nitrogen mustards such as chlorambucil, chlorpheniramine, clofosamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine hydrochloride, melphalan, novembichin, phenambucil, prednimustine, trofosfamide, uracilmustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and lanimustine; antibiotics such as enediyne antibiotics (e.g. calicheamicin, especially calicheamicin and calicheamicin coll (Angew Chem. Inti. Ed. Engl. 1994 33:183-186); dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicin; and the neocarcinogen chromophores and related chromoprotein enediyne antibiotic chromophores, aclacinomycins, actinomycins, authramycins, azaserine, bleomycin, cactinomycin, carabicin, carminomicin, carzinophilin, chromomycin, dactinomycin, daunomycin, detopicin, 6-diazo-5-oxo-L-norleucine, (doxorubicin) (morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogamycin, olive mycins, peplomycin, potfiromycin, puromycin, quelamycin, rhodorubicin, streptomycin, streptozotocin, tuberculin, ubenimex, zoloft, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5- FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiopurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calosterone, drostanolone propionate, cyclothiodine, melastosane, testolactone; antiadrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid (frolinic acid), leucovorin, doxycycline, cyclopentolone, cytarabine, cytarabine, doxorubicin, cyclopentolone, cytarabine ... acid; aceglucuronide; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; colcemid; diaziquone; elfornithine; elliptonium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan Sugar; lonidainine; maytansinoids, such as maytansine and ansamitocin; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazine; procarbazine; polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizoran; germanium spiroamine; tenuazonic acid; triazoquinone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, baculocin A, and anguidine); urethane; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dibromodulanol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, for example, TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), (without Cremophor), albumin-engineered paclitaxel nanoparticle formulation (American Pharmaceutical Partners, Schaumberg, 111.), and (docetaxel, docetaxel; Sanofi-Aventis); chloranbucil; (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (Changchunorelbine); Novantrone; Teniposide; Edatrexed; Daunorubicin; Aminopterin; Capecitabine ( ); ibandronate; CPT-II; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0363] Chemotherapeutic agents also include: (i) antihormonal agents that regulate or inhibit the effects of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including tamoxifen (including Tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and (toremifine citrate); (ii) aromatase inhibitors that inhibit aromatase, an enzyme that regulates estrogen production by the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, (Megestrol acetate), (exemestane; Pfizer), formestanie, fadrozole, (vorozole), (letrozole; Novartis) and (anastrozole; AstraZeneca); (iii) antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, triptorelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all trans-retinoic acid, fenretinide, and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways involved in abnormal cell proliferation, such as PKC-α, Ralf, and H-Ras; (vii) ribozymes, such as inhibitors of VEGF expression (e.g. ) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, such as and rIL-2; topoisomerase I inhibitors, e.g. and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0364] Chemotherapeutic agents also include antibodies such as alemtuzumab (Campath), bevacizumab ( Genentech; Cetuximab ( Imclone; Panitumumab ( Amgen), rituximab ( Genentech / Biogen Idee), Pertuzumab ( 2C4,Genentech), trastuzumab ( Genentech), tositumomab (Bexxar, Corixia) and antibody-drug conjugates, gemtuzumab ozogamicin ( Wyeth). Additional humanized monoclonal antibodies with therapeutic potential for use as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumabmertansine, cantuzumab mertansine, cedilizumab, certolizumab pegol-conjugated pegol), cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin), ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumabThe drugs include anti-interleukin 12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), a recombinant, fully human sequence-specific IgGiλ antibody that has been genetically modified to recognize the interleukin 12p40 protein.

[0365] Chemotherapeutic agents also include "EGFR inhibitors", which refer to compounds that bind to or directly interact with EGFR and prevent or reduce its signaling activity, and are alternatively referred to as "EGFR antagonists". Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Pat. No. 4,943,533, Mendelsohn et al.) and variants thereof, such as chimeric 225 (C225 or cetuximab; ) and reshaped human 225 (H225) (see, WO 96 / 40210, Imclone Systems Inc.); IMC-11F8, a fully human antibody targeting EGFR (Imclone); antibodies that bind to type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind to EGFR as described in U.S. Pat. No. 5,891,996; and human antibodies that bind to EGFR, such as ABX-EGF or panitumumab (see WO 98 / 50433, Abgenix / Amgen); EMD55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab), a humanized EGFR antibody against EGFR that competes with EGF and TGF-α for binding to EGFR (EMD / Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies, referred to as E1.1, E2.4, E2.5, E6.2, E6.4, E2.ll, E6.3 and E7.6.3, and described in US 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)). Anti-EGFR antibodies can be conjugated to cytotoxic agents to generate immunoconjugates (see, e.g., EP 659,439 A2, Merck Patent GmbH). EGFR antagonists include small molecules such as U.S. Pat. Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5 ,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008 and 5,747,498, and the following PCT publications: compounds described in WO98 / 14451, WO98 / 50038, WO99 / 09016 and WO99 / 24037. Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, Genentech / OSI Pharmaceuticals); PD 183805 (Cl1033, 2-acrylamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib ( )4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(l-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR / HER2 tyrosine kinase inhibitors such as lapatinib ( GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[(2-methylsulfonyl)ethyl]amino]methyl]-2-furyl]-4-quinazolinamine).

[0366] Chemotherapeutic agents also include "tyrosine kinase inhibitors", including the EGFR targeted drugs described in the previous paragraph; small molecule FIER2 tyrosine kinase inhibitors, such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors, such as EKB-569 (available from Wyeth), which preferentially binds to EGFR but simultaneously inhibits cells overexpressing HER2 and EGFR; lapatinib (GSK572016; available from 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-I inhibitors, such as ISIS-5132, an antisense agent that inhibits Raf-I signaling, available from ISIS Pharmaceuticals; non-HER targeted TK inhibitors, such as imatinib mesylate ( available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib ( available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787 / ZK222584, available from Novartis / Schering AG); MAPK extracellular regulated kinase I inhibitor Cl-1040 (available from Pharmacia); quinazolines such as PD 153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (difluoroformylmethane, 4,5-bis(4-fluoroanilino)phthalimide); tyrosine containing a nitrothiophene moiety; PD-0183805 (Wamer-Lamber); antisense molecules (e.g., molecules that bind to HER encoding nucleic acids); quinoxalines (U.S. Pat. No. 5,804,396); tyrosine phosphorylation inhibitors (U.S. Pat. No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis / Schering AG); pan-HER inhibitors, such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis / Lilly); imatinib mesylate ( ); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); seramatinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / ScheringAG); INC-ICl I (Imclone), rapamycin (sirolimus, ); or as described in any of the following patent publications: U.S. Patent 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).

[0367] Chemotherapeutic agents also include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, live BCG, bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, and leukopenia. alfa), erlotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium sodium), quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate and zoledronic acid and pharmaceutically acceptable salts thereof.

[0368] Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, thiocortisone pivalate, triamcinolone acetonide, triamcinolone acetonide alcohol, mometasone, amcinonide, budesonide, desonide, fluocinolone acetate, fluocinolone, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, and phenoxyethanol. dipropionate), betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, flucortolone hexanoate, flucortolone valerate, and fluprednidine acetate; immunoselective anti-inflammatory peptides (ImSAIDs), such as phenylalanine-glutamine-glycine (PEG) and its D-isomer form (feG) (IMULAN Biotherapeutics Ltd. BioTherapeutics, LLC); antirheumatic drugs such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, sulfasalazine; tumor necrosis factor alpha (TNFa) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi); interleukin I (IL-I) blockers such as anakinra (Kineret); T-cell costimulation blockers such as abatacept (Orencia); interleukin 6 (IL-6) blockers such as tocilizumab ( ); interleukin 13 (IL-13) blockers, such as lebrikizumab; interferon alpha (IFN) blockers, such as lonavirin; β7 integrin blockers, such as rhuMAb β7; IgE pathway blockers, such as anti-M1 primers; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa I / β2 blockers, such as anti-lymphotoxin alpha (LTa); radioisotopes (e.g. At 211 ,I 131 ,I 125 , Y 90 、Re 186 、Re 188 、Sm 153 、Bi 212 , P 32 , Pb 212and radioisotopes of Lu); various experimental agents such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3 or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, picrophenol, epigallocatechin gallate, theaflavins, flavanols, proanthocyanidins, betulinic acid and its derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, ); β-lapachone; lapaol; colchicine; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur ( ); Bexarotene ( ); bisphosphonates, such as clodronate (e.g., or ), etidronate ( ), NE-58095, zoledronic acid / zoledronic acid salt ( ), alendronate ( ), Pamidronate ( ), tirodronate ( ) or risedronate ( ); and epidermal growth factor receptor (EGF-R); vaccines, such as vaccines; perifosine; COX-2 inhibitors (e.g., celecoxib or etoricoxib); proteosome inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitors such as oblimersen sodium ( ); pixantrone; farnesyl transferase inhibitors such as lonafamib (SCH 6636, SARASAR TM ); and pharmaceutically acceptable salts, acids or derivatives of any of the above; and combinations of two or more of the above, such as CHOP (abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine and prednisolone); and FOLFOX (oxaliplatin (ELOXATIN TM ) is an abbreviation for the combination therapy with 5-FU and folinate).

[0369] In another embodiment, the compound of formula (I) can be co-formulated with an immuno-oncology agent. Immuno-oncology agents include, for example, small molecule drugs, antibodies or other biological or small molecules. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies and cytokines. In one aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human. In another aspect, the antibody is a bispecific antibody.

[0370] In one aspect, the immuno-oncology agent is (i) a stimulatory (including co-stimulatory) receptor agonist or (ii) an antagonist of T cell inhibitory (including co-inhibitory) signals, both of which result in potentiation of antigen-specific T cell responses (often referred to as immune checkpoint modulators).

[0371] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA) and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the family of TNF molecules that bind to cognate TNF receptor family members, including 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 / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTfiR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin alpha / TNP beta, TNFR2, TNF alpha, LTR, lymphotoxin alpha 1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0372] In one aspect, T cell responses can be stimulated by a combination of a compound of formula (I) with one or more of the following: (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, galactin-9, CEACAM-1, BTLA, CD69, galactin-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.

[0373] Other agents that can be combined with compounds of formula (I) for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors of NK cells. For example, compounds of formula (I) can be combined with antagonists of KIR such as lirilumab.

[0374] Still other agents for use in combination therapy include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists, such as CSF-1R antagonist antibodies, including RG7155 or FPA-008.

[0375] In another aspect, the compounds of Formula (I) can be used with one or more of the following: agonists that engage positive co-stimulatory receptors, blockers 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 immune suppression pathways within the tumor microenvironment (e.g., blocking inhibitory receptor engagement (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 trigger innate immune activation and / or inflammation at the tumor site.

[0376] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonist CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. In another aspect, the immuno-oncology agent is a PD-1 antagonist, such as an antagonist PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab) or MEDI-0680 (AMP-514; WO2012 / 145493). Immuno-oncology agents may also include pidilizumab (CT-011), although its specificity for binding to PD-1 is questioned. Another method for targeting the PD-1 receptor is a recombinant protein composed of a fusion of the extracellular domain of PD-L2 (B7-DC) with the Fc portion of IgG1, called AMP-224.

[0377] In another aspect, the immuno-oncology agent is a PD-L1 antagonist, such as an antagonist PD-L1 antibody. Suitable PD-L1 antibodies include, for example, TECENTRIQ (atezolizumab) (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0378] In another aspect, the immuno-oncology agent is a LAG-3 antagonist, such as an antagonist LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO2010 / 19570, WO2014 / 08218), or IMP-731 or IMP-321 (WO2008 / 132601, WO2009 / 44273).

[0379] In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO2012 / 32433).

[0380] In another aspect, the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO2006 / 105021, WO2009 / 009116) and MK-4166 (WO2011 / 028683).

[0381] In another aspect, the immuno-oncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO2006 / 122150, WO2007 / 75598, WO2008 / 36653, WO2008 / 36642), indoximod or NLG-919 (WO2009 / 73620, WO2009 / 1156652, WO2011 / 56652, WO2012 / 142237).

[0382] In another aspect, the immuno-oncology agent is an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469. In another aspect, the immuno-oncology agent is an OX40L antagonist, such as an antagonist OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0383] In another aspect, the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the immuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0384] In another aspect, the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0385] In another aspect, the immuno-oncology agent is MGA271 (to B7H3) (WO2011 / 109400).

[0386] Examples

[0387] The present invention will be more fully understood by reference to the following examples. However, the claims should not be interpreted as being limited to the scope of the examples.

[0388] 1) Preparation Example

[0389] If not stated otherwise, all reaction examples and intermediates were prepared under argon atmosphere.

[0390] 1.1) General Procedure

[0391] ● Reduction of the nitro group: General procedure 2

[0392] 1N aqueous hydrogen chloride solution (2.3mL) is added to the solution of formula (IV) intermediate (23mmol) in EtOH (112mL) and water (18.7mL). The reaction mixture is heated to 50 ° C and iron (8.99g, 161mmol) is added to the hot and stirred solution. The temperature is raised to 80 ° C and stirred for 3.5h. The reaction mixture is cooled to RT and filtered through diatomaceous earth, washed with ethyl acetate and concentrated under reduced pressure. The desired product (V) is used in the next step as a crude substance.

[0393] ● Cyclization: General Procedure 3

[0394] DIPEA (1.85 g, 2.51 mL, 14.4 mmol, 2.5 eq) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine 2,4,6-trioxide 50% EtOAc solution (7.31 g, 6.76 mL) are added to the solution of the intermediate (5.74 mmol) of formula (V) in DMF (15 mL). The reaction mixture is stirred for 3 h at RT. The reaction mixture is quenched with water and extracted twice with DCM, washed with 1 M NaOH aqueous solution, 1 M HCl aqueous solution and saturated NaCl solution, dried over Na2SO4, filtered and concentrated in vacuo. The desired product (VI) is used in the next step as a crude material or purified by silica gel flash column chromatography or by reverse phase preparative HPLC.

[0395] ● Alkylation: General Procedure 4

[0396] Potassium carbonate (1.14 g, 8.23 ​​mmol), potassium iodide (228 mg, 1.37 mmol) and formula (VII) reagent (3.29 mmol) were added to a solution of the intermediate (2.74 mmol) of formula (VI) in DMSO (10 mL) at RT. The reaction was stirred for 2 h at RT, quenched with water and extracted twice with DCM. The combined organic layer was washed with water, saturated NaCl aqueous solution, dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The desired product (VIII) was used in the next step as a crude substance or purified by silica gel flash column chromatography or by reverse phase preparative HPLC.

[0397] ● Oxidation: General Procedure 5

[0398] The solution of formula (VIII) intermediate (2.74mmol) and m-CPBA (1.18g, 6.85mmol) in DCM (10mL) was stirred at RT for 1 day. The reaction was diluted with ethyl acetate and THF, washed with 2N sodium hydroxide aqueous solution, 1N HCl aqueous solution and saturated NaCl aqueous solution, dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The required product (IX) was used in the next step in the form of crude material or purified by silica gel flash column chromatography or by reverse phase preparative HPLC.

[0399] ● Boc deprotection: General procedure 6a

[0400] 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 eq) at 0°C. The reaction mixture was stirred at 20°C for 3 h and then concentrated in vacuo. The remaining residue was purified by preparative HPLC and dried by lyophilization to obtain the desired product (I).

[0401] ● Boc deprotection: General procedure 6b

[0402] 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).

[0403] ● Boc deprotection: General procedure 6c

[0404] HCl / dioxane or HCl / EtO (0.5mmol, 2eq) was added to a solution of the intermediate of formula (IX) (0.250mmol) in 1,1,1,3,3,3-hexafluoropropane-2-ol (4mL) at 0°C. The reaction mixture was stirred for 2h at 20°C. 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-hexafluoropropane-2-ol. The process was repeated twice and then dried under high vacuum to obtain the desired product (I).

[0405] ● Hydrazide Coupling: General Procedure 7

[0406] To the solution of formula (XIII) intermediate (0.5mmol) in THF (5ml), add carboxylic acid (0.5mmol), DIPEA (1.5mmol) and T3P (50% in EtOAc, 1.5mmol) of formula R10CO2H. The resulting solution is stirred at 60°C for 2h. The reaction is then cooled to RT and diluted with water. The mixture is extracted three times with EtOAc. The combined organic layers are washed with brine, and then dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure. The desired product (XIV) is used in the next step as a crude material or purified by silica gel flash column chromatography or by reverse phase preparative HPLC.

[0407] ● 1,3,4-Oxadiazole Cyclization: General Procedure 8

[0408] Burgess reagent (0.9mmol) is added to a solution of formula (XIV) intermediate (0.3mmol) in THF (3ml). The resulting solution is stirred overnight at RT. Water is added and the mixture is extracted three times with EtOAc. The combined organic layers are washed with brine, and then dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure. The desired product (XV) is used in the next step in the form of crude material or purified by silica gel flash column chromatography or by reverse phase preparative HPLC.

[0409] ● Coupling of amidoximes with RCO2H: General Procedure 10a

[0410] To the solution of formula (XVII) intermediate (wherein R is H) (1.0mmol) in THF (8.5ml), add formula R10CO2H carboxylic acid (0.12mmol), DIPEA (2.0mmol) and HATU (0.15mmol), and the reaction is stirred at RT for 4h. Add water and EtOAc and separate each layer. The aqueous phase is extracted twice with EtOAc. The combined organic layer is washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent is evaporated under reduced pressure. The desired product (XVII, wherein R is-CO(R10)) is used in the next step or purified by silica gel flash column chromatography or by reverse phase preparative HPLC in the form of crude material.

[0411] ● Coupling of Amidoximes with RCO2H: General Procedure 10b

[0412] Formula R is added to the solution of formula (XVII) intermediate (wherein R is H) (0.2mmol) in DMF (1.5ml) carboxylic acid (0.24mmol), EDC hydrochloride (0.4mmol), DIPEA (0.6mmol) and HOBt (0.3mmol), and the resulting mixture is stirred at RT for 16h. Water and EtOAc are added, each layer is separated and the aqueous phase is extracted twice with EtOAc. The combined organic layer is washed with salt water, dried over anhydrous sodium sulfate, filtered and the solvent is evaporated under reduced pressure. The required product (XVII, wherein R is-CO (R10)) is used in the next step or purified by silica gel flash column chromatography or by reverse phase preparative HPLC in the form of crude material.

[0413] ● 1,2,4-Oxadiazole Cyclization: General Procedure 11

[0414] A solution of the intermediate of formula (XVII) wherein R is -CO(R10) (0.15 mmol) in toluene (1 ml) was heated to 120°C for 16 h. The solvent was then evaporated under reduced pressure. The desired product (XVIII) was used in the next step as crude material or purified by silica gel flash column chromatography or by reverse phase preparative HPLC.

[0415] ● Amidoxime Formation: General Procedure 12

[0416] Solid NaHCO is added to the solution of formula (VIII) intermediate (0.3mmol) in EtOH (2.5ml) (1.5mmol) and hydroxylamine hydrochloride (0.6mmol). The obtained suspension is heated to 80 ° C for 90min, and then cooled to RT. The suspension is filtered and the filter cake is washed with EtOH and DCM. The filtrate is concentrated under reduced pressure and the remaining solid is dissolved in DCM, and washed with water and brine, dried over anhydrous sodium sulfate, filtered and the solvent is evaporated under reduced pressure. Required product (XVII) is used for the next step in the form of crude material or by silica gel flash column chromatography or by reverse phase preparative HPLC purification.

[0417] ● Saponification: General Procedure 13

[0418] To the solution of formula (VIII) intermediate (4mmol) in THF (18ml), MeOH (3ml) and water (6ml), LiOH hydrate (8mmol) is added and stirred for 2h at RT. The 1N HCl aqueous solution is added and the obtained suspension is extracted three times with EtOAc. The organic layer merged is washed with salt water, and then dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure. Required product (XII) is used for the next step or purified by silica gel flash column chromatography or by reverse phase preparative HPLC in the form of crude material.

[0419] ● Hydrazide Formation: General Procedure 14

[0420] To the solution of formula (XII) intermediate (4.5mmol) in THF (20ml), CDI (5.7mmol) is added and stirred for 90min at RT. Then the mixture of hydrazine hydrate (13.5mmol) in THF (3.3ml) is added to the solution and stirred for 1h. The reaction mixture is diluted with water and EtOAc. Each layer is separated and the aqueous phase is washed twice with EtOAc. The organic layer merged is washed with salt water, and then dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure. Required product (XIII) is used for the next step or purified by silica gel flash column chromatography or by reverse phase preparative HPLC in the form of crude material.

[0421] Example 19

[0422] (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-benzothiazepine -4-Keto

[0423]

[0424] Step a) (3R)-3-(tert-Butyloxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine 7-Formic acid

[0425]

[0426] To (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine at 0°C To a solution of methyl-7-formate (30.0 g, 85.1 mmol, 1 eq) (CAS: 2089150-62-7) in THF (300 mL) was added a solution of NaOH (5.11 g, 127.7 mmol, 1.5 eq) in water (300 mL). The mixture was stirred at RT for 7 h. At 0 ° C, 0.5 M aqueous HCl was added to the reaction mixture, which was then warmed to RT. EtOAc was added and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 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-isobutylene] + .

[0427] Step b) N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0428]

[0429] To (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine at RT -7-formic acid (29.4g, 86.8mmol, 1eq) and DIPEA (45.4mL, 260.6mmol, 3eq) in DCM (400mL) solution was added T3P (50wt% in EtOAc, 66.8mL, 130.3mmol, 1.5eq) and the reaction was stirred for 30min. The reaction mixture was then transferred to a solution of hydrazine hydrate (17.2mL, 347.5mmol, 4eq) in DCM (190mL) by a dropping funnel. The reaction mixture was stirred at RT for 3h and a yellow precipitate was formed. The mixture was concentrated and the crude material was purified by preparative HPLC to give the title compound (6g, 17.0mmol, 19% yield) as a white solid. MS (ESI): 297.1 [M+H-isobutylene]+ .

[0430] Step c) N-[(3R)-7-[[(2-methyl-2-methylsulfonyl-propionyl)amino]carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0431]

[0432] N-[(3R)-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine To a solution of tert-butyl]carbamate (5.0 g, 14.2 mmol, 1 eq), 2-methyl-2-methylsulfonyl-propionic acid (3.3 g, 19.8 mmol, 1.4 eq), and DIPEA (12.5 mL, 71.7 mmol, 5.06 eq) in THF (100 mL) was added T3P (50 wt% in EtOAc, 19.0 g, 29.8 mmol, 2.1 eq). The mixture was stirred at 60 ° C for 3 h. The solution was poured into water (300 mL) and extracted with EtOAc (2 x 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-isobutylene] + .

[0433] Step d) N-[(3R)-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0434]

[0435] The title compound is prepared from N-[(3R)-7-[[(2-methyl-2-methylsulfonyl-propionyl)amino]carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester (1.8 g, 3.6 mmol) was prepared in analogy to general procedure 8 and obtained as a yellow solid (1.6 g, 89% yield). MS (ESI): 427.0 [M+H-isobutylene] + .

[0436] Step e) N-[(3R)-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0437]

[0438] The title compound is prepared from N-[(3R)-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester (800.0 mg, 1.66 mmol) was prepared similarly to general procedure 5 and obtained as a yellow solid (690 mg, 1.34 mmol, 78% yield). MS (ESI): 459.1 [M+H-isobutylene] + .

[0439] Step f) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0440]

[0441] N-[(3R)-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine To a suspension of tert-butyl]carbamate (50.0 mg, 0.1 mmol, 1 eq), potassium iodide (10.0 mg, 0.06 mmol, 0.62 eq), and potassium carbonate (40.0 mg, 0.29 mmol, 2.98 eq) in DMF (1.5 mL) was added 1-(chloromethyl)-4-(1-ethylpropoxy)benzene (27.0 mg, 0.13 mmol, 1.31 eq, CAS 248262-55-7) and stirred at RT for 12 h. The mixture was then poured into water (40 mL) and extracted with EtOAc (2 x 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 give the desired title compound (50 mg, 0.07 mmol, 75% yield) as a colorless oil. MS (ESI): 635.3 [M+H-isobutylene]+ .

[0442] 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-benzothiazepine 4-Keto

[0443]

[0444] The title compound is prepared from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (50.0 mg, 0.07 mmol) was prepared in analogy to general procedure 6a and obtained as a white solid as the hydrochloride salt (23.8 mg, 0.04 mmol, 52% yield). MS (ESI): 591.1 [M+H] + .

[0445] The examples in the following table were prepared analogously to Example 19 using the appropriate benzyl halide building blocks.

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454] (*) As hydrochloride

[0455] Example 15

[0456] (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-benzothiazepine -4-Keto

[0457]

[0458] Step a) 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0459]

[0460] N-[(3R)-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine To a solution of [4-[benzyl(methyl)amino]phenyl]methanol (55.2 mg, 0.24 mmol, 2.5 eq, CAS 131719-59-0), Ph3P (0.05 mL, 0.19 mmol, 2 eq) and di-tert-butyl azodicarboxylate (44.7 mg, 0.19 mmol, 2 eq) was added tert-butyl [3-yl]carbamate (50 mg, 0.1 mmol, 1 eq, Example 19, step e) in toluene (1.5 mL). The mixture was degassed with nitrogen and stirred at 50 ° C for 3 h. The reaction was diluted with water (5 mL) and EtOAc (5 ml). The layers were separated and the aqueous phase was extracted with EtOAc (3×5 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The remaining crude material was purified using silica gel column chromatography (60% EtOAc / PE) to obtain the title compound (36 mg, 0.05 mmol, 51% yield) as a light yellow solid. MS (ESI): 724.0 [M+H-isobutylene] + .

[0461] 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-benzothiazepine 4-Keto

[0462]

[0463] The title compound is prepared from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (36 mg, 0.05 mmol) was prepared in analogy to general procedure 6a and obtained as a light yellow solid (7.4 mg, 0.01 mmol, 23% yield). MS (ESI): 624.1 [M+H] + .

[0464] Example 18 in the table below was prepared similarly to Example 15 using the appropriate benzyl alcohol building blocks.

[0465]

[0466] Example 17

[0467] (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-benzothiazepine -4-Keto

[0468]

[0469] Step a) 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-benzothiazepine tert-butyl 3-amino-4-nitropropane

[0470]

[0471] N-[(3R)-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine was added at 20°C. To a solution of 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (28.6 mg, 0.09 mmol, 1.2 eq) in DMF (0.5 mL) was added tert-butyl]carbamate (40 mg, 0.08 mmol, 1 eq, Example 19, step e), KI (6.45 mg, 0.04 mmol, 0.5 eq) and potassium carbonate (32.23 mg, 0.23 mmol, 3 eq) in DMF (1 mL). The reaction mixture was stirred at this temperature for 2 h. The reaction was diluted with water (5 ml) and extracted with EtOAc (8 ml x 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 / PE) to give the title compound (45 mg, 0.06 mmol, 78% yield) as a white solid. MS (ESI): 685.2 [M+H-isobutylene] + .

[0472] 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-benzothiazepine 4-Keto

[0473]

[0474] The title compound is prepared from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (40 mg, 0.05 mmol) was prepared in analogy to general procedure 6a and obtained as a white solid as the hydrochloride salt (34.3 mg, 0.05 mmol, 93% yield). MS (ESI): 641.2 [M+H] + .

[0475] The examples in the following table were prepared analogously to Example 17 using the appropriate carboxylic acid building blocks.

[0476]

[0477] (*) As hydrochloride

[0478] Example 48

[0479] (3R)-3-amino-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,2,4-oxadiazol-3-yl]-1,1-

[0480] Dioxo-5-[(6-phenoxy-3-pyridyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto

[0481]

[0482] Step a) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0483]

[0484] The title compound was prepared analogously to General Procedure 5 from 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-benzothiazepine -3-yl] tert-butyl carbamate (Example 43, step c, 54 mg, 0.108 mmol) was prepared and obtained as a white powder (28.5 mg, 50% yield). MS (ESI): 477.2 [M-isobutylene + H] + .

[0485] Step b) 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester

[0486]

[0487] The title compound was prepared analogously to General Procedure 4 from 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-benzothiazepine 3-yl]carbamic acid tert-butyl ester (9 mg, 0.017 mmol, 1 eq) was prepared using 5-(chloromethyl)-2-phenoxy-pyridine (CAS 5795855-1, 5.57 mg, 0.025 mmol, 1.5 eq) and obtained as a white powder (4.4 mg, 36% yield). MS (ESI): 716.4 [M+H] + .

[0488] 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-benzothiazepine 4-Keto

[0489]

[0490] The title compound was prepared analogously to the general procedure 6c from 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-pyridinyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine 3-yl] tert-butyl carbamate (4.4 mg, 0.006 mmol) was prepared and obtained as a white powder in the form of hydrochloride (4 mg, 94% yield). MS (ESI): 660.4 [M+HCOO] - .

[0491] Example 50 in the table below was prepared analogously to Example 48, steps ac) using the appropriate building blocks.

[0492]

[0493] *As 2,2,2,-trifluoroacetate

[0494] Example 43

[0495] (3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-

[0496] 1,2,4-oxadiazol-3-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto

[0497]

[0498] Step a) N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0499]

[0500] N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine To a solution of (2R)-3-(2-amino-4-cyano-5-fluoro-phenyl)thio-2-(tert-butoxycarbonylamino)propanoic acid (200 mg, 0.59 mmol) in MeOH (2 mL) was added hydroxylamine hydrochloride (63.7 mg, 0.89 mmol, 1.5 eq) and sodium bicarbonate (249 mg, 2.96 mmol, 5 eq). The mixture was stirred at 70 ° C for 16 h, cooled to RT, 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-isobutylene + H] + .

[0501] Step b) [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine 7-yl]methylene]amino]-2-methyl-2-methylsulfonyl-propionate

[0502]

[0503] The title compound was prepared analogously to General Procedure 10a from N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl] tert-butyl carbamate (440 mg, 1.03 mmol) was prepared and obtained as a light yellow solid (520 mg, 97% yield). MS (ESI): 463.2 [M-isobutylene + H] + .

[0504] Step c) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0505]

[0506] The title compound was prepared analogously to General Procedure 11 from N-[(3R)-8-fluoro-7-[(Z)-N'-(1-methyl-1-methylsulfonyl-ethoxy)carbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine 3-yl] tert-butyl carbamate (520 mg, 1 mmol, 1 eq) was prepared and obtained as a light yellow solid (250 mg, 47% yield). MS (ESI): 445.2 [M-isobutylene + H] + .

[0507] Step d) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0508]

[0509] The title compound was prepared analogously to General Procedure 4 from 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-benzothiazepine -3-yl] tert-butyl carbamate (30 mg, 0.057 mmol, 1 eq) was obtained using 1-(bromomethyl)-4-chloro-benzene (17.55 mg, 0.085 mmol, Eq: 1.5) as a white powder (18 mg, 49% yield). MS (ESI): 569.3 [M-isobutylene + H] + .

[0510] Step e) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0511]

[0512] The title compound was prepared analogously to General Procedure 5 from 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-benzothiazepine -3-yl] tert-butyl carbamate (18 mg, 0.028 mmol, Eq: 1) was prepared and obtained as an off-white powder (20.4 mg, 108% yield). MS (ESI): 601.2 [M-isobutylene + H] + .

[0513] 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-benzothiazepine 4-Keto

[0514]

[0515] The title compound was prepared analogously to general procedure 6c from 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-benzothiazepine 3-yl] tert-butyl carbamate (20.4 mg, 0.031 mmol) was prepared and obtained as a white solid in the form of hydrochloride (15 mg, 80% yield). MS (ESI): 557.3 [M+H] + .

[0516] The examples in the following table were prepared analogously to Example 43, steps df, using the appropriate building blocks.

[0517]

[0518]

[0519] *As hydrochloride

[0520] Example 30

[0521] (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-benzothiazepine -4-Keto

[0522]

[0523] Step a) N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0524]

[0525] The title compound was prepared analogously to General Procedure 4 from N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl] tert-butyl carbamate (Example 53 step d) 200 mg, 0.593 mmol) was prepared using 1-(bromomethyl)-4-phenoxy-benzene (CAS 36881-42-2, 156 mg, 0.593 mmol) and obtained as a white solid (210 mg, 67% yield) MS (ESI): 542.0 [M+Na] + .

[0526] Step b) N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine tert-butyl 3-amino-4-nitropropane

[0527] The title compound was prepared analogously to General Procedure 12 from N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine 3-yl] tert-butyl carbamate (210 mg, 0.404 mmol) was prepared and obtained as a light yellow solid (125 mg, 49% yield) MS (ESI): 553.0 [M+H] + .

[0528] Step c) [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine 7-yl]methylene]amino]-2-methyl-2-methylsulfonyl-propionate

[0529]

[0530] The title compound was prepared analogously to General Procedure 10b from N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine 3-yl] tert-butyl carbamate (125 mg, 0.226 mmol) was prepared and obtained as a light yellow gum (154 mg, 93% yield) MS (ESI): 644.9 [M-isobutylene + H] + .

[0531] Step d) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0532]

[0533] The title compound was prepared analogously to General Procedure 11 from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine 7-yl]methylene]amino]-2-methyl-2-methylsulfonyl-propionate (154 mg, 0.220 mmol) was prepared and obtained as a light brown gum (140 mg, 73% yield) MS (ESI): 627.0 [M-isobutylene + H] + .

[0534] Step e) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0535]

[0536] The title compound was prepared analogously to General Procedure 5 from 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-benzothiazepine 3-yl] tert-butyl carbamate (140 mg, 0.205 mmol) was prepared and obtained as a white solid (130 mg, 74% yield) MS (ESI): 659.1 [M-isobutylene + H] + .

[0537] 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-benzothiazepine 4-Keto

[0538]

[0539] The title compound was prepared analogously to General Procedure 6a from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (130 mg, 0.182 mmol) was prepared and obtained as a white solid in the form of hydrochloric acid (45.9 mg, 38% yield) MS (ESI): 615.0 [M+H] + .

[0540] Example 44

[0541] (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-benzothiazepine -4-Keto

[0542]

[0543] Step a) [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine 7-yl]methylene]amino]-2-methyl-2-methylsulfonyl-propionate

[0544]

[0545] The title compound was prepared analogously to General Procedure 10a from N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl] tert-butyl carbamate (Example 43, step a) (440 mg, 1.03 mmol, 1 eq) and 2-methyl-2-methylsulfonyl-propionic acid (CAS 25841-43-4) were prepared and obtained as a light yellow solid (520 mg, 97% yield). MS (ESI): 463.2 [M-isobutylene + H] + .

[0546] Step b) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0547]

[0548] The title compound was prepared analogously to General Procedure 11 from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-yl]methylene]amino]-2-methyl-2-methylsulfonyl-propionate (520 mg, 1 mmol, 1 eq) was prepared and obtained as a white solid (250 mg, 47% yield). MS (ESI): 499.3 [MH] - .

[0549] Step c) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0550]

[0551] The title compound was prepared analogously to General Procedure 4 from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (30 mg, 0.057 mmol, 1 eq) and 1-(bromomethyl)-4-(trifluoromethoxy)benzene (CAS 50824-05-0) were prepared and obtained as an off-white solid (31 mg, 79% yield). MS (ESI): 619.3 [M-isobutylene + H] + .

[0552] Step d) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0553]

[0554] The title compound was prepared analogously to General Procedure 5 from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (31 mg, 0.046 mmol, 1 eq) was prepared and obtained as an off-white solid (22 mg, 68% yield). MS (ESI): 651.4 [MH] - .

[0555] 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-benzothiazepine 4-Keto

[0556]

[0557] The title compound was prepared analogously to general procedure 6c from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (22 mg, 0.031 mmol, 1 eq) was prepared and obtained as a white solid in the form of hydrochloride (9.9 mg, 48% yield). MS (ESI): 607.3 [M+H] + .

[0558] Example 2

[0559] (3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-

[0560] 1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto

[0561]

[0562] Step a) (3R)-3-(tert-Butyloxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine 7-Methyl formate

[0563]

[0564] The title compound was prepared analogously to General Procedure 4 from (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-Methyl formate (CAS: 2002449-38-7) (5.67 g, 13.77 mmol, 1 eq) was prepared and obtained as a light yellow solid (2699 mg, 36%). MS (ESI): 439.3 [M-isobutylene + H] + .

[0565] Step b) (3R)-3-(tert-Butyloxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine 7-Formic acid

[0566]

[0567] The title compound was prepared analogously to General Procedure 13 from (3R)-3-(tert-butoxycarbonylamino)-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3-dihydro-1,5-benzothiazepine -7-Methyl carboxylate (300 mg, 606 μmol, Eq: 1) was prepared and obtained as a yellow oil (280 mg, 512 μmol, 85% yield). MS (ESI): 425.2 [M-isobutylene + H] + .

[0568] Step c) N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0569]

[0570] The title compound was prepared analogously to General Procedure 14 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, Eq: 1) was prepared and obtained as a light yellow solid (1.9 g, 64%). MS (ESI): 439.3 [M-isobutylene + H] + .

[0571] Step d) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0572]

[0573] N-[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-2,3-dihydro-1,5-benzothiazepine -3-yl] tert-butyl carbamate (100 mg, 0.20 mmol, 1.0 eq) was dissolved in THF (2. mL) and 2-methylsulfonyl-2-methyl-propionic acid (36.9 mg, 0.22 mmol, 1.1 eq), HATU (84.5 mg, 0.22 mmol, 1.1 eq) and DIEA (52.2 mg, 70.6 uL, 0.40 mmol, 2.0 eq) were added to give a yellow solution. The mixture was stirred at RT for 45 minutes. Burgess reagent (240.7 mg, 1.01 mmol, 5 eq) was added and the reaction mixture was stirred at RT for 60 min. The crude material was concentrated under reduced pressure and the remaining solid was purified by silica gel flash chromatography (0-50% EtOAc / heptane) to give the title compound (44 mg, 31%) as a light yellow solid. MS (ESI): 569.2 [M-isobutylene + H] + .

[0574] 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-benzothiazepine 4-Keto

[0575]

[0576] The title compound was prepared analogously to general procedure 6a from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (49.mg, 0.075mmol, 1eq) was prepared and obtained as a light yellow solid in the form of hydrochloride (12mg, 26%). MS (ESI): 557.2 [M+H] +

[0577] The examples in the following table were prepared analogously to Example 2 using the appropriate carboxylic acid building blocks.

[0578]

[0579] *As hydrochloride

[0580] Example 53

[0581] (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-benzothiazepine -4-Keto

[0582]

[0583] Step a) 4-[4-(Chloromethyl)phenyl]tetrahydropyran

[0584]

[0585] To a solution of (4-tetrahydropyran-4-ylphenyl)methanol (CAS: 1276024) (300 mg, 1.56 mmol, 1 eq) in DCM (10 mL) was added thionyl chloride (0.4 mL, 5.65 mmol, 3.6 eq) by syringe at RT. The solution was stirred for 12 h at RT. The mixture was poured into water (50 mL) and the pH was adjusted to about pH 9 by gradually adding 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 light yellow oil. MS (ESI): 211.2 [M+H] +

[0586] Step b) (2R)-2-(tert-Butyloxycarbonylamino)-3-(4-cyano-5-fluoro-2-nitrophenyl)sulfhydryl-propionic acid

[0587]

[0588] To a solution of 2,4-difluoro-5-nitro-benzonitrile (9.4 g, 50 mmol) and (tert-butoxycarbonyl)-L-cysteine ​​(11.07 g, 50 mmol) in DCM (157 mL) was added DIPEA (17.48 mL, 100 mmol, Eq: 2). The reaction mixture was stirred at 22 °C for 24 h, diluted with DCM (40 mL) and washed once with 1N HCl aqueous solution 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-isobutylene + H] + .

[0589] Step c) (2R)-3-(2-amino-4-cyano-5-fluoro-phenyl)sulfhydryl-2-(tert-butoxycarbonylamino)propanoic acid

[0590]

[0591] The title compound was prepared in analogy to General Procedure 2 from (2R)-2-(tert-butoxycarbonylamino)-3-(4-cyano-5-fluoro-2-nitro-phenyl)sulfhydryl-propionic acid (23 g, 57.9 mmol) and obtained as a black solid (23 g, 48.1 mmol, 80% yield). MS (ESI): 300.1 [M-isobutylene + H] + .

[0592] Step d) N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0593]

[0594] The title compound was prepared in analogy to General Procedure 3 from (2R)-3-(2-amino-4-cyano-5-fluoro-phenyl)sulfhydryl-2-(tert-butoxycarbonylamino)propanoic acid (23 g, 48.1 mmol) and obtained as a light yellow solid (8.4 g, 24.9 mmol, 48% yield). MS (ESI): 282.1 [M-isobutylene + H] + .

[0595] Step e) N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0596]

[0597] To a solution of 4-[4-(chloromethyl)phenyl]tetrahydropyran (Example 53, step a) (224.83 mg, 1.07 mmol, 1.2 eq), KCO (245.8 mg, 1.78 mmol, 2.0 eq) and KI (73.8 mg, 0.44 mmol, 0.5 eq) in DMF (6 mL) was added N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] dropwise at RT. -3-yl] tert-butyl carbamate (300.0 mg, 0.89 mmol, 1.0 eq) in DMF (3 mL) was added and the mixture was stirred for 12 h. The reaction mixture was poured into water and extracted with EtOAc (3x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (20% EtOAc / petroleum ether) to give the title compound (500 mg, 0.97 mmol, 100% yield) as a light yellow oil. MS (ESI): 412.2 [M-isobutylene + H] +

[0598] Step f) N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0599]

[0600] N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine To a solution of tert-butyl]carbamate (400 mg, 0.78 mmol, 1 eq) and DIPEA (0.53 mL, 3.13 mmol, 4.0 eq) in EtOH (5 mL) was added hydroxylamine hydrochloride (165.3 mg, 2.35 mmol, 3 eq) 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 (2x). 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] +

[0601] Step g) [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine 7-yl]methylene]amino]2-methyl-2-methylsulfonyl-propionate

[0602]

[0603] The title compound was prepared analogously to General Procedure 10a from N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester (350 mg, 0.6 mmol) was prepared and obtained as a light yellow solid (481 mg, 92% yield). MS (ESI): 693.2 [M+H] + .

[0604] Step h) 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-benzothiazepine tert-butyl 3-amino-4-nitropropane

[0605]

[0606] The title compound was prepared analogously to General Procedure 11 from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine -7-yl]methylene]amino]2-methyl-2-methylsulfonyl-propionate (500 mg, 0.7 mmol, 1 eq) was prepared and obtained as a light yellow solid (136 mg, 28% yield). MS (ESI): 575.4 [M+H] + .

[0607] Step i) 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-benzothiazepine tert-butyl 3-amino-4-nitropropane

[0608]

[0609] The title compound was prepared analogously to General Procedure 5 from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (130 mg, 0.2 mmol, 1 eq) was prepared and obtained as an off-white solid (120 mg, 88% yield). MS (ESI): 607.3 [M-isobutylene + H] + .

[0610] 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-benzothiazepine 4-Keto

[0611]

[0612] The title compound is prepared from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (50.0 mg, 0.1 mmol) was prepared in analogy to general procedure 6a and obtained as a white solid as a hydrochloride salt (30.6 mg, 0.05 mmol, 70% yield). MS (ESI): 607.3 [M+H] + .

[0613] The examples in the following table were prepared analogously to Example 53 using the appropriate benzyl halide building blocks.

[0614]

[0615] Example 35

[0616] (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-benzothiazepine -4-Keto

[0617]

[0618] Step a) (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine 7-Formic acid

[0619]

[0620] To (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine at 0°C -7-Methyl formate (CAS: 2002449-38-7) (8.5g, 22.9mmol, 1eq) in THF (150mL) was added to a solution of NaOH (1220mg, 30.5mmol, 1.33eq) in water (150mL). The mixture was then stirred at RT for 9h. The reaction mixture was added dropwise to a 0.5M aqueous HCl solution (70mL). The mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (5700mg, 15.99mmol, 57% yield) as a white solid. MS (ESI): 301.0 [M+H] + .

[0621] Step b) N-[(3R)-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0622]

[0623] (3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-Formic acid (202.6 mg, 0.55 mmol, 1 eq) and CDI (116.2 mg, 0.72 mmol, 1.3 eq) were dissolved in THF (2.4 mL) and stirred at RT for 30 min. The solution was added dropwise to a solution of hydrazine monohydrate (53.0 mg, 51.5 uL, 1.65 mmol, 3 eq) in THF (0.8 mL) and stirred for 30 min. 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 yellow solid. MS (ESI): 369.3 [MH]

[0624] Step c) N-[(3R)-8-Fluoro-7-[[(2-methyl-2-methylsulfonyl-propionyl)amino]carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0625]

[0626] 2-Methyl-2-methylsulfonyl-propionic acid (0.27 g, 1.62 mmol, 1.2 eq), N-[(3R)-8-fluoro-7-(hydrazinecarbonyl)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] To a mixture of tert-butyl]carbamate (0.5 g, 1.35 mmol, 1.0 eq) and N,N-diisopropylethylamine (0.59 mL, 3.37 mmol, 2.5 eq) in THF (10 mL) was added T3P (1.81 g, 2.84 mmol, 2.1 eq) in EtOAc 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 silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (570 mg, 1.1 mmol, 80% yield) as a white solid. MS (ESI): 445.1 [M-isobutylene + H] + .

[0627] Step d) 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-benzothiazepine tert-butyl 3-amino-4-nitropropane

[0628]

[0629] The title compound is prepared from N-[(3R)-8-fluoro-7-[[(2-methyl-2-methylsulfonyl-propionyl)amino]carbamoyl]-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -3-yl]butyl carbamate (1800 mg, 3.5 mmol) was prepared in analogy to general procedure 8 in 1,4-dioxane and obtained as a yellow solid (1000 mg, 2 mmol, 54% yield). MS (ESI): 445.1 [M-isobutylene + H] + .

[0630] Step e) 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-benzothiazepine tert-butyl 3-amino-4-nitropropane

[0631]

[0632] The title compound is prepared from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (1000 mg, 2 mmol) was prepared similar to general procedure 5 and obtained as a white solid (1000 mg, 1.88 mmol, 85% yield). MS (ESI): 477.0 [M-isobutylene + H] + .

[0633] Step f) 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-benzothiazepine tert-butyl 3-amino-4-nitropropane

[0634]

[0635] The title compound is prepared from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (50 mg, 0.1 mmol) was prepared similarly to general procedure 4 and obtained as a white solid (50 mg, 0.07 mmol, 63% yield). MS (ESI): 710.8 [M-isobutylene + H] + .

[0636] 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-benzothiazepine 4-Keto

[0637]

[0638] The title compound is prepared from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (45 mg, 0.1 mmol) was prepared in analogy to general procedure 6a and obtained as a white solid as the hydrochloride salt (14.9 mg, 0.02 mmol, 35% yield). MS (ESI): 667.2 [M+H] + .

[0639] The examples in the following table were prepared analogously to Example 35 using the appropriate benzyl halide building blocks.

[0640]

[0641]

[0642] *As hydrochloride Example 59

[0643] (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-benzothiazepine -4-Keto

[0644]

[0645] Step a) N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-triisopropylsilyloxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine tert-butyl 3-amino-4-nitropropane

[0646]

[0647] The title compound was prepared analogously to General Procedure 4 from N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl]carbamic acid tert-butyl ester (Example 53 step d) (100 mg, 0.3 mmol) was prepared and obtained as a colorless oil (100 mg, 0.17 mmol, 52% yield). MS (ESI): 622.2 [M+Na] + .

[0648] Step b) N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[(4-triisopropylsilyloxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine tert-butyl 3-amino-4-nitropropane

[0649]

[0650] The title compound was prepared analogously to General Procedure 12 from N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-triisopropylsilyloxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester (470 mg, 0.8 mmol) was prepared and obtained as a colorless oil (390 mg, 0.62 mmol, 71% yield). MS (ESI): 633.3 [M+H] + .

[0651] Step c) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0652]

[0653] At 100 °C, N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[(4-triisopropylsilyloxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine was added. To a solution of tert-butyl]carbamate (390 mg, 0.62 mmol, 1.0 eq), DIEA (106.4 mg, 0.92 mmol, 1.5 eq) and 2-methyl-2-methylsulfonyl-propionic acid (112.6 mg, 0.68 mmol, 1.1 eq) in toluene (5 mL) was added T3P (784.0 mg, 1.23 mmol, 2.0 eq) in EtOAc 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 / petroleum ether) to give the title compound (320 mg, 0.42 mmol, 54% yield) as a colorless oil. MS (ESI): 785.2 [M+Na] + .

[0654] Step c) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0655]

[0656] The title compound was prepared analogously to General Procedure 5 from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (200 mg, 0.3 mmol) was prepared and obtained as a colorless oil (180 mg, 0.23 mmol, 81% yield). MS (ESI): 817.1 [M+Na] + .

[0657] Step d) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0658]

[0659] 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-benzothiazepine was added at RT. To a mixture of tert-butyl]-3-yl]carbamate (175 mg, 0.22 mmol, 1.0 eq) in DMF (2 mL) was added CsF (100.3 mg, 0.66 mmol, 3.0 eq) and stirred for 12 h. The reaction was quenched by adding water and extracted with EtOAc (3x). 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] + .

[0660] Step e) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0661]

[0662] At 50 °C, 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-benzothiazepine was added. -3-yl] tert-butyl carbamate (70.0 mg, 0.11 mmol, 1.0 eq) and K2CO3 (30.2 mg, 0.22 mmol, 2.0 eq) in acetonitrile (1 mL) were added 5-(chloromethyl)-3-(trifluoromethyl)-1,2,4-oxadiazole (CAS: 1000442-49-7) (20.4 mg, 0.11 mmol, 1.0 eq) and KI (18.2 mg, 0.11 mmol, 1.0 eq) and stirred for 1 h. The reaction was quenched after adding 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 give the title compound (20 mg, 0.03 mmol, 23% yield) as a colorless oil after lyophilization. MS (ESI): 789.2 [M+H] + .

[0663] 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-benzothiazepine 4-Keto

[0664]

[0665] The title compound was prepared analogously to General Procedure 6a from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (12 mg, 0.02 mmol) was prepared and obtained as a white solid in the form of hydrochloride (6 mg, 0.01 mmol, 51.2% yield). MS (ESI): 689.2 [M+H] +

[0666] Examples 51 and 52

[0667] (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-benzothiazepine -4-Keto[Dimer A]

[0669] 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-benzothiazepine -4-Keto[Dimer B]

[0671]

[0672] Step a) N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0673]

[0674] The title compound was prepared analogously to General Procedure 4 from N-[(3R)-7-cyano-8-fluoro-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] -3-yl]carbamic acid tert-butyl ester (Example 53 step d) (500 mg, 1.5 mmol) was prepared and obtained as a white solid (570 mg, 1.1 mmol, 73% yield). MS (ESI): 542.2 [M+Na] + .

[0675] Step b) N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0676]

[0677] The title compound was prepared analogously to General Procedure 12 from N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester (200 mg, 0.34 mmol) was prepared and obtained as a white solid (210 mg, 95% yield). MS (ESI): 553.4 [M+H] + .

[0678] Step c) [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine 7-yl]methylene]amino]-2-methyl-2-methylsulfonyl-propionate

[0679]

[0680] The title compound was prepared analogously to General Procedure 10a from N-[(3R)-8-fluoro-7-[(Z)-N'-hydroxycarbamimidoyl]-4-oxo-5-[(4-tetrahydropyran-4-ylphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester (112.3 mg, 0.17 mmol) was prepared and obtained as a white powder (119.5 mg, 91% yield). MS (ESI): 559.3 [M-isobutylene + H] + .

[0681] Step d) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0682]

[0683] The title compound was prepared analogously to General Procedure 11 from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine -7-yl]methylene]amino]2-methyl-2-methylsulfonyl-propionate (119.5 mg, 0.16 mmol) and obtained as a white powder (89 mg, 81% yield). MS (ESI): 627.3 [M-isobutylene + H] + .

[0684] Step e) 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-benzothiazepine 3-yl] carbamic acid tert-butyl ester (dimer A) and 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-benzothiazepine 3-yl]carbamic acid tert-butyl ester (dimer B)

[0685]

[0686] The title compound is prepared from 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-benzothiazepine -3-yl] tert-butyl carbamate (89 mg, 0.13 mmol) was prepared similarly to general procedure 5 using m-CPBA (28.6 mg, 0.13 mmol, 1 eq). The two diastereomers were separated and obtained as white powder (45.9 mg, 50% yield, diastereomer A) and white powder (21.9 mg, 24% yield, diastereomer B). For both products MS (ESI): 643.2 [M+H-isobutylene] + .

[0687] 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-benzothiazepine 4-Keto[Dimer A]

[0688]

[0689] The title compound is prepared from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester [Dimer A] (45.9 mg, 0.07 mmol) was prepared in analogy to general procedure 6c and obtained as a white powder as a hydrochloride salt (39.7 mg, 88% yield). MS (ESI): 599.2 [M+H] + .

[0690] 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-benzothiazepine 4-Keto[Dimer B]

[0691]

[0692] The title compound is prepared from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester [Dimer B] (21.9 mg, 0.03 mmol) was prepared in analogy to general procedure 6c and obtained as a white powder as a hydrochloride salt (20.2 mg, 94% yield). MS (ESI): 599.2 [M+H] + .

[0693] Example 63

[0694] (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-benzothiazepine -4-Keto

[0695]

[0696] Step a) (2R)-2-(tert-Butyloxycarbonylamino)-3-(4-cyano-2-nitro-phenyl)sulfhydryl-propionic acid

[0697]

[0698] 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-mercapto-propionic acid (14.6 g, 66.2 mmol, 1.1 eq) and DIPEA (20.5 mL, 120.4 mmol, 2 eq) and the mixture was stirred at RT for 16 h. The mixture was concentrated under reduced pressure, and the remaining residue was dissolved in EtOAc (200 mL), washed with 1N HCl aqueous solution (50 mL), water (100 mL) and brine (50 mL x 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] + .

[0699] Step b) (2R)-3-(2-amino-4-cyano-phenyl)sulfhydryl-2-(tert-butoxycarbonylamino)propionic acid

[0700]

[0701] The title compound was prepared from (2R)-2-(tert-butoxycarbonylamino)-3-(4-cyano-2-nitro-phenyl)sulfhydryl-propionic acid (10.0 g, 27.2 mmol) in analogy to General Procedure 2 and obtained as a brown solid (10 g, 87% yield). MS (ESI): 338.2 [M+H] + .

[0702] Step c) N-[(3R)-7-cyano-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0703]

[0704] The title compound was prepared from (2R)-3-(2-amino-4-cyano-phenyl)sulfhydryl-2-(tert-butoxycarbonylamino)propanoic acid (11.3 g, 33.5 mmol) in analogy to General Procedure 3 and obtained as a white solid (5 g, 45% yield). MS (ESI): 263.9 [M-isobutylene + H] + .

[0705] Step d) N-[(3R)-7-cyano-5-[[4-(4-methoxyphenyl)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0706]

[0707] At RT, tert-butyl N-[(3R)-7-cyano-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine] To a solution of 1-(chloromethyl)-4-(4-methoxyphenyl)benzene (218.5 mg, 0.94 mmol, 1.05 eq) in DMF (2 mL), potassium iodide (0.01 g, 0.18 mmol, 0.2 eq), sodium carbonate (237 mg, 2.24 mmol, 2.5 eq) was added tert-butyl carbamate (300.0 mg, 0.89 mmol, 1.0 eq), potassium iodide (0.01 g, 0.18 mmol, 0.2 eq), sodium carbonate (237 mg, 2.24 mmol, 2.5 eq) was added and the mixture was stirred at 40 ° C for 12 h. The solution was poured into water and extracted with EtOAc (3x). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (0-50% EtOAc / heptane) to give the title compound (460 mg, 0.89 mmol, 69% yield) as a yellow solid. MS (ESI): 460.0 [M-isobutylene + H] + .

[0708] Step e) N-[(3R)-7-cyano-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepine tert-butyl 3-amino-4-nitropropane

[0709]

[0710] The title compound is prepared from N-[(3R)-7-cyano-5-[[4-(4-methoxyphenyl)phenyl]methyl]-4-oxo-2,3-dihydro-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester (450 mg, 0.9 mmol) was prepared similarly to general procedure 5 and obtained as a yellow solid (360 mg, 0.66 mmol, 44.4% yield). MS (ESI): 548.1 [M+H] + .

[0711] Step f) N-[(3R)-7-[(Z)-N'-hydroxycarbamimidoyl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepine tert-butyl 3-amino-4-nitropropane

[0712]

[0713] N-[(3R)-7-cyano-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepine A solution of tert-butyl]carbamate (350 mg, 0.64 mmol, 1.0 eq), sodium acetate (157.2 mg, 1.92 mmol, 3.0 eq) and hydroxylamine hydrochloride (66.6 mg, 0.96 mmol, 1.5 eq) 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 (3x). 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] + .

[0714] Step g) [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepine 7-yl]methylene]amino]2-methyl-2-methylsulfonyl-propionate

[0715]

[0716] The title compound is prepared from N-[(3R)-7-[(Z)-N'-hydroxycarbamimidoyl]-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester (10 mg, 0.02 mmol, 1 eq.) was prepared in analogy to general procedure 10a and obtained as a yellow oil (10 mg, 0.01 mmol, 80% yield). MS (ESI): 729.0 [M+H] + .

[0717] Step h) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0718]

[0719] The title compound is prepared from [(Z)-[amino-[(3R)-3-(tert-butoxycarbonylamino)-5-[[4-(4-methoxyphenyl)phenyl]methyl]-1,1,4-trioxo-2,3-dihydro-1λ6,5-benzothiazepine -7-yl]methylene]amino]2-methyl-2-methylsulfonyl-propionate (280 mg, 0.4 mmol, 1 eq.) was prepared similarly to general procedure 11 and obtained as a yellow solid (100 mg, 0.14 mmol, 37% yield). MS (ESI): 733.2 [M+Na] + .

[0720] 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-benzothiazepine 4-Keto

[0721]

[0722] The title compound is prepared from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (95 mg, 0.13 mmol, 1 eq.) was prepared in analogy to general procedure 6a and obtained as a yellow solid in the form of the hydrochloride salt (85.6 mg, 0.13 mmol, 96% yield). MS (ESI): 611.3 [M+H] + .

[0723] Example 68

[0724] (3R)-3-amino-7-[5-(1-methylsulfonylcyclobutyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-5-

[0725] [(4-Phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto

[0726]

[0727] Step a) (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine 7-Methyl formate

[0728]

[0729] The title compound is prepared from (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-Methyl carboxylate (1.0 g, 2.84 mmol, 1.0 eq) was prepared similarly to general procedure 4 and obtained as a white solid (1.38 g, 87% yield). MS (ESI): 479.2 [M-isobutylene + H] + .

[0730] Step b) (3R)-3-(tert-Butyloxycarbonylamino)-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine 7-Formic acid

[0731]

[0732] The title compound is prepared from (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine -7-Methyl carboxylate (1.38 g, 2.58 mmol, 1.0 eq) was prepared in analogy to general procedure 13 and obtained as a yellow foam (1.54 g, 97% yield). MS (ESI): 465.1 [M-isobutylene + H] + .

[0733] Step c) (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine 7-Formic acid

[0734]

[0735] Sodium periodate (1.11 g, 5.19 mmol, 2.34 eq) was dissolved in water (8.5 mL) and the mixture was cooled to 0°C under Ar. RuCl3.3H2O (5.81 mg, 0.022 mmol, 0.01 eq) was added and the reaction was stirred for 5 min. (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-(4-phenoxybenzyl)-2,3-dihydro-1,5-benzothiazepine was then added in one portion. -7-formic acid (1.36 g, 2.22 mmol, 1.0 eq) in acetonitrile (8.54 mL) was added and stirred for 3 h. The reaction was quenched by adding iPrOH (2 ml), EtOAc and 2M HCl aqueous solution. The gray suspension was filtered through a celite plug and the filtrate was extracted with EtOAc. The combined organic phases were washed with saturated Na2S2O3 aqueous solution, 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-isobutylene + H] + .

[0736] Step d) N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine tert-butyl 3-amino-4-nitropropane

[0737]

[0738] The title compound is 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 eq) was prepared in analogy to general procedure 14 and obtained as a white solid (980 mg, 79% yield). MS (ESI): 511.1 [M-isobutylene + H] + .

[0739] Step d) N-[(3R)-7-[[(1-methylsulfonylcyclobutanecarbonyl)amino]carbamoyl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine tert-butyl 3-amino-4-nitropropane

[0740]

[0741] The title compound is prepared from N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester (500 mg, 0.88 mmol, 1.0 eq) was prepared in analogy to general procedure 7 (CAS 1250528-75-6) and obtained as a yellow solid (260 mg, 41% yield). MS (ESI): 727.1 [M+H] + .

[0742] Step e) 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-benzothiazepine tert-butyl 3-amino-4-nitropropane

[0743]

[0744] The title compound is prepared from N-[(3R)-7-[[(1-methylsulfonylcyclobutanecarbonyl)amino]carbamoyl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester (260 mg, 0.36 mmol) was prepared in analogy to general procedure 8 and obtained as a yellow oil (120 mg, 0.17 mmol, 45% yield). MS (ESI): 653.1 [M-isobutylene + H] + .

[0745] 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-benzothiazepine 4-Keto

[0746]

[0747] The title compound is prepared from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (50 mg, 0.07 mmol) was prepared in analogy to general procedure 6a and obtained as an off-white solid as the hydrochloride salt (35 mg, 0.05 mmol, 64% yield). MS (ESI): 609.2 [M+H] + .

[0748] The examples in the following table can be prepared in a manner similar to Example 68 using the appropriate carboxylic acid building blocks.

[0749]

[0750]

[0751] *As hydrochloride salt

[0752] Example 65

[0753] 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-oxadiazol-2-yl]-N,N-dimethyl-propane-2-sulfonyl

[0754]

[0755] Step a) (3R)-3-(tert-Butyloxycarbonylamino)-4-oxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine 7-Methyl formate

[0756]

[0757] The title compound is prepared from (3R)-3-(tert-butoxycarbonylamino)-4-oxo-3,5-dihydro-2H-1,5-benzothiazepine -7-Methyl carboxylate (CAS: 2089150-62-7) (400 mg, 1.14 mmol) was prepared similarly to general procedure 4 and obtained as a light brown oil (420 mg, 0.72 mmol, 60% yield). MS (ESI): 587.3 [M+H] + .

[0758] Step b) (3R)-3-(tert-Butyloxycarbonylamino)-4-oxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine 7-Formic acid

[0759]

[0760] The title compound is prepared from (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine -7-Methyl carboxylate (400 mg, 0.68 mmol, 1.0 eq) was prepared similarly to general procedure 13 and obtained as a yellow solid (350 mg, 0.61 mmol, 86% yield). MS (ESI): 517.2 [M-isobutylene + H] + .

[0761] Step c) (3R)-3-(tert-butoxycarbonylamino)-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine 7-Formic acid

[0762]

[0763] To a solution of sodium periodate (821.8 mg, 3.84 mmol, 2.0 eq) in water (8 mL) was added RuCl3 (3.98 mg, 0.02 mmol, 0.01 eq) at 0°C and stirred for 10 min. (3R)-3-(tert-butoxycarbonylamino)-4-oxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1,5-benzothiazepine was added at 0°C. -7-formic acid (1100mg, 1.92mmol, 1.0eq) in acetonitrile (12mL) was added to the mixture and stirred for 2h at RT. Isopropanol (4mL) was slowly added under stirring to quench the reaction mixture. EtOAc (50mL) was then added to the mixture, which was then carefully acidified to pH=4-5 with 0.5N HCl aqueous solution. The gray suspension was filtered through a diatomaceous earth plug 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 (1150mg, 1.9mmol, 87% yield) as a light green solid. MS (ESI): 603.1 [MH]

[0764] Step d) N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine tert-butyl 3-amino-4-nitropropane

[0765]

[0766] The title compound is 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) was prepared in analogy to general procedure 14 and obtained as a light brown solid (2.2 g, 3.56 mmol, 76% yield). MS (ESI): 563.2 [M-isobutylene + H] + .

[0767] Step e) N-[(3R)-7-[[[2-(dimethylsulfamoyl)-2-methyl-propionyl]amino]carbamoyl]-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0768]

[0769] To a solution of 2-(dimethylsulfamoyl)-2-methyl-propionic acid (132.55 mg, 0.68 mmol, 2.1 eq) and N,N-diisopropylethylamine (83.57 mg, 0.65 mmol, 2.0 eq) in DMF (2 mL) was added HATU (91.3 mg, 0.39 mmol, 1.2 eq) at RT. The mixture was stirred for 25 min, then N-[(3R)-7-(hydrazinecarbonyl)-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine was added. -3-yl] tert-butyl carbamate (200 mg, 0.32 mmol, 1.0 eq) in DMF (2 mL) was stirred at RT for 5 h. The reaction mixture was poured into water, EtOAc was added and the layers were separated. The aqueous phase was extracted with EtOAc (3x). 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 light yellow oil. MS (ESI): 740.2 [M-isobutylene + H] + .

[0770] Step f) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0771]

[0772] The title compound is prepared from N-[(3R)-7-[[[2-(dimethylsulfamoyl)-2-methyl-propionyl]amino]carbamoyl]-1,1,4-trioxo-5-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester (100 mg, 0.13 mmol) was prepared in toluene in analogy to general procedure 8 and obtained as a light yellow oil (55 mg, 0.07 mmol, 56%). MS (ESI): 722.2 [M-isobutylene + H] + .

[0773] Step f) 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-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0774]

[0775] The title compound is prepared from 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-benzothiazepine -3-yl]carbamic acid tert-butyl ester (50.0 mg, 0.06 mmol) was prepared in analogy to general procedure 6a and obtained as a white solid (19.2 mg, 0.03 mmol, 41% yield). MS (ESI): 678.2 [M+H] + .

[0776] The examples in the following table can be prepared in a manner similar to Example 65 using the appropriate carboxylic acid building blocks.

[0777]

[0778] Example 54

[0779] (3R)-3-Amino-8-fluoro-7-[2-(methylsulfonylmethyl)tetrazol-5-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto

[0780]

[0781] Step a) N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0782]

[0783] The title compound is prepared from N-[(3R)-7-cyano-8-fluoro-4-oxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester (Examples 51 and 52, step a) (0.57 g, 1.1 mmol) was prepared in analogy to General Procedure 5 and obtained as a yellow solid (600 mg, 1.09 mmol, 98% yield). MS (ESI): 574.3 [M+Na] + .

[0784] Step b) N-[(3R)-8-fluoro-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-7-(2H-tetrazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0785]

[0786] N-[(3R)-7-cyano-8-fluoro-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine -3-yl] tert-butyl carbamate (500.0 mg, 0.91 mmol, 1.0 eq) in toluene (10 mL) was added azido (trimethyl) silane (0.48 mL, 3.63 mmol, 4.0 eq) and dibutyltin oxide (50 mg, 0.2 mmol, 0.22 eq, CAS 818-08-6). The mixture was degassed with N2 (3x) and then stirred at 100 ° C for 3 h. After cooling to RT, 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 obtain the title compound (530 mg, 0.89 mmol, 90% yield) as a gray solid. MS (ESI): 617.3 [M + Na] + .

[0787] Step c) N-[(3R)-8-fluoro-7-[2-(methylthiomethyl)tetrazol-5-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine tert-butyl 3-yl]carbamate and N-[(3R)-8-fluoro-7-[1-(methylthiothiomethyl)tetrazol-5-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine tert-butyl 3-aminophenyl carbamate

[0788]

[0789] N-[(3R)-8-fluoro-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-7-(2H-tetrazol-5-yl)-2,3-dihydro-1λ6,5-benzothiazepine was added at RT. To a solution of tert-butyl-3-yl]carbamate (200 mg, 0.34 mmol, 1.0 eq), K2CO3 (92.8 mg, 0.67 mmol, 2.0 eq) and KI (40.0 mg, 0.24 mmol, 0.71 eq) in DMF (4 mL) was added chloromethyl methyl sulfide (0.03 mL, 0.37 mmol, 1.1 eq) and the mixture was stirred for 16 h. The mixture was diluted with EtOAc (5 mL) and washed with brine (5 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (50% EtOAc / petroleum ether) to give N-[(3R)-8-fluoro-7-[2-(methylthiomethyl)tetrazol-5-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine as a white solid. -3-yl]carbamic acid tert-butyl ester (90 mg, 0.14 mmol, 41% yield) and N-[(3R)-8-fluoro-7-[1-(methylthiothiomethyl)tetrazol-5-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine as a white solid -3-yl] tert-butyl carbamate (16 mg, 0.02 mmol, 7% yield). For both products MS (ESI): 699.2 [M-isobutylene + H] + .

[0790] Step d) N-[(3R)-8-fluoro-7-[2-(methylsulfonylmethyl)tetrazol-5-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine tert-butyl 3-amino-4-nitropropane

[0791]

[0792] The title compound is prepared from N-[(3R)-8-fluoro-7-[2-(methylthiothiomethyl)tetrazol-5-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester (80 mg, 0.15 mmol, 1.0 eq) was prepared similarly to general procedure 5 and obtained as a white solid (90 mg, 0.13 mmol, 78% yield). MS (ESI): 631.2 [M-isobutylene + H] + .

[0793] 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-benzothiazepine 4-Keto

[0794]

[0795] The title compound is prepared from N-[(3R)-8-fluoro-7-[2-(methylthiothiomethyl)tetrazol-5-yl]-1,1,4-trioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine -3-yl]carbamic acid tert-butyl ester (90 mg, 0.13 mmol, 1.0 eq) was prepared in analogy to general procedure 6a and obtained as a white solid as a hydrochloride salt (40.2 mg, 0.06 mmol, 49% yield). MS (ESI): 587.3 [M+H] + .

[0796] The examples in the following table were prepared in a manner analogous to Example 54 (steps d and e) from the indicated starting materials.

[0797]

[0798] *As hydrochloride

[0799] Intermediate 1

[0800] 1-(Bromomethyl)-4-(2-methoxy-1,1-dimethyl-ethoxy)benzene

[0801]

[0802] Step a) Ethyl 2-methyl-2-(4-methylphenoxy)propionate

[0803]

[0804] A mixture of p-cresol (3.5 g, 32.3 mmol, 1.26 eq), ethyl 2-bromoisobutyrate (5 g, 25.6 mmol, 1.0 eq) and potassium carbonate (10 g, 72.3 mmol, 2.8 eq) in DMF (20 mL) was stirred at RT 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 / petroleum ether) to give the title compound (2.5 g, 11.2 mmol, 42% yield) as a colorless oil. MS (ESI): 223.1 [M+H] +

[0805] Step b) 2-methyl-2-(4-methylphenoxy)propan-1-ol

[0806]

[0807] To a solution of ethyl 2-methyl-2-(4-methylphenoxy)propanoate (1.0 g, 4.5 mmol, 1.0 eq) in THF (10 mL) was slowly added LiAlH4 (550.0 mg, 14.5 mmol, 3.2 eq) at 0 ° C and argon. After the addition was complete, the solution was warmed to RT 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 give 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).

[0808] Step c) 1-(2-methoxy-1,1-dimethyl-ethoxy)-4-methyl-benzene

[0809]

[0810] To a solution of 2-methyl-2-(4-methylphenoxy)propan-1-ol (1500mg, 8.32mmol, 1.0eq) in THF (15mL) was slowly added NaH (900mg, 22.5mmol, 2.7eq) at 0°C and under a nitrogen atmosphere. The solution was stirred for 30min at RT. Then iodomethane (1.1mL, 17.6mmol, 2.12eq) was added to the mixture and stirred for 4h at RT. The mixture was poured into water (20mL) and extracted with EtOAc (50mL). The organic phase was washed with brine (50mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (1.5g, 7.72mmol, 91% yield) as a yellow oil. 1 HNMR (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).

[0811] Step d) 1-(Bromomethyl)-4-(2-methoxy-1,1-dimethyl-ethoxy)benzene

[0812]

[0813] A solution of N-bromosuccinimide (1400 mg, 7.87 mmol, 1.02 eq), 1-(2-methoxy-1,1-dimethyl-ethoxy)-4-methyl-benzene (1500 mg, 7.72 mmol, 1.0 eq) and AIBN (170.0 mg, 1.04 mmol, 0.13 eq) in CCl4 (15 mL) was stirred at 80 ° C for 3 h. The mixture was poured into a saturated NaHCO3 aqueous solution (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 / petroleum ether) to give 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).

[0814] Intermediate 6

[0815] 1-(Chloromethyl)-4-[3-(difluoromethoxy)phenoxy]benzene

[0816]

[0817] Step a) 4-[3-(difluoromethoxy)phenoxy]benzaldehyde

[0818]

[0819] Pyridine (0.53 mL, 6.55 mmol, 4 eq) and cupric acetate (735.69 mg, 3.68 mmol, 2.25 eq) were added to a mixture of 3-(difluoromethoxy)phenylboronic acid (461.69 mg, 2.46 mmol, 1.5 eq) and 4-hydroxybenzaldehyde (200 mg, 1.64 mmol, 1 eq) in 1,4-dioxane (15 mL) at RT. The mixture was then heated to 80 ° C for 12 h. The reaction was cooled to RT and diluted with water (3 mL). The resulting solution was extracted with EtOAc (3x5 mL) and the combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (4-40% EtOAc / petroleum ether) to give the title compound (90 mg, 0.34 mmol, 15% yield) as a yellow oil. MS (ESI): 264.9 [M+H] + .

[0820] Step b) [4-[3-(difluoromethoxy)phenoxy]phenyl]methanol

[0821]

[0822] To a mixture of 4-[3-(difluoromethoxy)phenoxy]benzaldehyde (140 mg, 0.5 mmol, 1 eq) in THF (4 mL) was added LiAlH4 (27.75 mg, 0.7 mmol, 1.38 eq) at 0 ° C and nitrogen atmosphere. The reaction was stirred at 0 ° C for 1 h. The mixture was quenched by adding water (0.24 mL), 1M NaOH aqueous solution (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 containing the title compound (110 mg), which was used in the next step without further purification. MS (ESI): 248.9 [M-OH] + .

[0823] Step c) 1-(Chloromethyl)-4-[3-(difluoromethoxy)phenoxy]benzene

[0824]

[0825] To a solution of [4-[3-(difluoromethoxy)phenoxy]phenyl]methanol (110 mg, 0.410 mmol, 1 eq) in DCM (10 mL) was added thionyl chloride (0.18 mL, 2.48 mmol, 6 eq) and stirred at RT for 16 h. The mixture was concentrated and the remaining residue was dissolved in THF (2 mL) and concentrated again under reduced pressure. The process was repeated twice to give the title compound (110 mg, 0.39 mmol, 69% yield) as a yellow oil. MS (ESI): 334.0 [M+H+piperidine] + .

[0826] Intermediate 7

[0827] 1-(Chloromethyl)-4-[3-(trifluoromethoxy)phenoxy]benzene

[0828]

[0829] Step a) 4-[3-(trifluoromethoxy)phenoxy]benzaldehyde

[0830]

[0831] Cesium carbonate (3.94 g, 12.09 mmol, 1.5 eq) was added to a mixture of 3- (trifluoromethoxy) phenol (1.44 g, 8.06 mmol, 1 eq) and 4- fluoro-benzaldehyde (0.86 mL, 8.06 mmol, 1 eq) in DMF (50 mL) at RT. The reaction was heated to 100 ° C for 12 h. The mixture was quenched by adding water (150 mL) and extracted with EtOAc (4x50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (5-90% EtOAc / PE) to obtain the title compound (2 g, 7.09 mmol, 87% yield) as a yellow oil. MS (ESI): 282.9 [M+H] + .

[0832] Step b) [4-[3-(trifluoromethoxy)phenoxy]phenyl]methanol

[0833]

[0834] To a mixture of 4-[3-(trifluoromethoxy)phenoxy]benzaldehyde (1.0 g, 3.54 mmol, 1 eq) in THF (15 mL) was added LiAlH4 (185.57 mg, 4.89 mmol, 1.38 eq) at 0 ° C and nitrogen and stirred for 1 h. The mixture was quenched by adding water (0.05 mL) and 1 M NaOH aqueous solution (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 compound, which was used in the next step without further purification. MS (ESI): 266.9 [M-OH] + .

[0835] Step c) 1-(Chloromethyl)-4-[3-(trifluoromethoxy)phenoxy]benzene

[0836]

[0837] To a solution of [4-[3-(trifluoromethoxy)phenoxy]phenyl]methanol (800.0 mg, 2.81 mmol, 1 eq) in DCM (15 mL) was added thionyl chloride (1.23 mL, 16.89 mmol, 6 eq) 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 concentrated again under reduced pressure. This process was repeated twice to give the title compound (780 mg, 2.58 mmol, 68% yield) as a yellow oil. MS (ESI): 352.0 [M + H + piperidine] + .

[0838] Intermediate 10

[0839] 1-[4-(Chloromethyl)phenyl]-4-methoxy-2-methyl-benzene

[0840]

[0841] Step a) 4-(4-methoxy-2-methyl-phenyl)benzaldehyde

[0842]

[0843] To a mixture of 4-formylphenylboronic acid (1.64 g, 10.9 mmol, 1.1 eq) and 4-bromo-3-methylanisole (2 g, 9.95 mmol, 1 eq) in toluene (15 mL) was added 2M Na2CO3 aqueous solution (4.97 ml, 9.95 mmol, 1 eq) and Pd(PPh3)4 (344.85 mg, 0.3 mmol, 0.03 eq) in EtOH (25 ml) at RT and nitrogen. The mixture was then stirred for 16 h. The reactant was diluted with water (15 mL). The resulting solution was extracted with EtOAc (3 x 15 mL) and the combined organic extracts were dried over sodium sulfate, filtered and concentrated. The remaining residue was purified by silica gel column chromatography (5-60% EtOAc / PE) to give the title compound (1.6 g, 7.07 mmol, 65% yield) as a yellow oil. MS (ESI): 226.9 [M+H] + .

[0844] Step b) [4-(4-methoxy-2-methyl-phenyl)phenyl]methanol

[0845]

[0846] To a mixture of 4-(4-methoxy-2-methyl-phenyl)benzaldehyde (600 mg, 2.27 mmol, 1 eq) in THF (10 mL) was added LiAlH4 (118.93 mg, 3.13 mmol, 1.38 eq) at 0 ° C and nitrogen atmosphere. The reaction was stirred at 0 ° C for 1 h. The mixture was quenched by adding water (0.24 mL) and 1M NaOH aqueous solution (0.24 mL) and water (0.75 ml). The mixture was filtered and the filtrate was concentrated under vacuum to give a yellow oil containing the title compound (640 mg), which was used in the next step without further purification. MS (ESI): 211.0 [M-OH] + .

[0847] Step c) 1-[4-(Chloromethyl)phenyl]-4-methoxy-2-methyl-benzene

[0848]

[0849] To a solution of [4-(4-methoxy-2-methyl-phenyl)phenyl]methanol (640 mg, 2.8 mmol, 1 eq) in DCM (10 mL) was added thionyl chloride (1.22 mL, 16.8 mmol, 6 eq) and stirred at RT for 16 h. The mixture was concentrated and the remaining residue was dissolved in THF (2 mL) and concentrated again. The process was repeated twice to give the title compound (600 mg, 2.43 mmol, 78% yield) as a yellow oil. MS (ESI): 296.0 [M + H + piperidine] + .

[0850] Intermediates 8 and 9 in the table below were prepared analogously to Intermediate 10 using the appropriate benzyl halide building blocks.

[0851]

[0852] Intermediate 11

[0853] 2-[4-(Bromomethyl)phenyl]-5-(trifluoromethoxy)pyridine

[0854]

[0855] Step a) 2-(p-tolyl)-5-(trifluoromethoxy)pyridine

[0856]

[0857] A mixture of p-tolylboronic acid (9.4 g, 69.1 mmol, 1 eq) and K2CO3 (28.6 g, 207 mmol, 3 eq) in 1,4-dioxane (244 mL) and water (24.4 mL) was degassed with argon for 10 minutes. 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (1.02 g, 1.38 mmol, 0.02 eq) was then added at room temperature. The reaction mixture was heated to 80 ° C and stirred for 7 hours, distributed between ethyl acetate (450 ml) and water (225 ml) and the layers were separated. The aqueous layer was extracted with 150 ml of ethyl acetate. The combined organic layers were washed with 150 ml of brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (SiO2, 330 g, 0-10% EtOAc / heptane) to generate the title compound (13 g, 68%, 92% purity) as a white solid. MS (ESI): 254.1 [M+H] + .

[0858] Step b) 2-[4-(bromomethyl)phenyl]-5-(trifluoromethoxy)pyridine

[0859]

[0860] To a solution of 2-(p-tolyl)-5-(trifluoromethoxy)pyridine (1015 mg, 4 mmol, 1 eq) in super anhydrous acetonitrile (17 mL) was added N-bromosuccinimide (749 mg, 4.21 mmol, 1.05 eq) and AIBN (197 mg, 1.2 mmol, 0.3 eq). The reaction mixture was stirred at 80 ° C overnight, poured into brine and extracted 3 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 / heptane) to generate the title compound (971 mg, 62%, 86% purity) as a white solid. MS (ESI): 332.0 [M+H] + .

[0861] 2) Biological Examples

[0862] 2.1) In vitro DGK inhibition assay

[0863] DGKα and ζ kinases use ATP to phosphorylate the substrate 1,2-dilauroyl-sn-glycerol (DLG, incorporated into liposomes). As a result of this enzymatic reaction, ATP is converted to ADP.

[0864] After the kinase reaction, an ATP depletion reagent is added to terminate the kinase reaction and deplete any remaining ATP, leaving only ADP. Next, a detection reagent is added to simultaneously convert ADP to ATP and convert the newly synthesized ATP into light using a coupled luciferase / luciferin reaction.

[0865] Reagents and materials

[0866] Buffer components (solvents and salts)

[0867] Chemicals supplier Catalog Number: DTT AppliChem Catalog Number A3668 BSA Sigma-Aldrich Catalog Number A2153-10G MOPS Sigma-Aldrich Catalog No. M1254 Sodium chloride (NaCl) Sigma-Aldrich Catalog No. S7663-1KG <![CDATA[Magnesium chloride (MgCl2)]]> MERCK Catalog number 1.05833.0250 <![CDATA[Calcium chloride (CaCl2)]]> Sigma-Aldrich Catalog Number C4901-500G

[0868] Protein / Substrate / Tracer

[0869] Protein / Substrate / Tracer supplier Batch number; probe number DGKA In-house production hDGKalpha(1-735)-N-His DZD In-house production hDGKζ(1-928)-N-His 18:1PS(DOPS) Sigma-Aldrich Catalog No. 840035C 16:0-18:1PC Sigma-Aldrich Catalog No. 850457C 1,2-Dilauroyl-sn-glycerol (DLG) Sigma-Aldrich Catalog No. 800812C Ultrapure ATP Promega Catalog No. V9101 Part No. V915A ADP-Glo ​​Reagent Promega Catalog No. V9101 Part No. V912A Kinase Assay Substrates Promega Catalog No. V9101 Part No. V914A Kinase Assay Buffer Promega Catalog No. V9101 Part No. V913A

[0870] Full-length DGKA and Z were expressed in Sf21 insect cells by infecting them with baculovirus stocks at an MOI of 2. Purification of both enzymes was performed as previously described by Takahashi et al., Peer J, 2018 (Takahashi, D.; Sakane, F. Expression and purification of human diacylglycerol kinase alpha from baculovirus-infected insect cells for structural studies. Peer J 2018, 6, No. e5449).

[0871] hardware

[0872] Material supplier Catalog Number / Volume Range 384 multiwell plate, white Greiner Catalog No. 781904 384 multiwell plate, white Corning Catalog Number CLS3574 Matrix Multichannel Pipette Thermo Fisher SCIENTIFIC 2-125μl Multidrop Combi Thermo Fisher SCIENTIFIC 0.5–50 μl / well Envision Microplate Reader PerkinElmer

[0873] Assay buffer (30 ml)

[0874]

[0875] Determination procedure

[0876] Concentrated liposome solutions were prepared in assay buffer without DTT and BSA: 2mM DLG in 21mM total liposomes (2mM DLG / 8mM PS / 11mM PC). The reaction mixture contained assay buffer with a final DLG concentration of 125uM and an ATP concentration of 25μM (for DGKA assay) or 50μM (for DGKZ assay). The reaction was initiated by adding DGKα and ζ kinases at final concentrations of 4nM and 2nM, respectively. After 1 hour of reaction, the amount of ADP formed was measured using the ADP-Glo ​​kinase assay (Promega) according to the manufacturer's instructions. Compounds were added in an 11-point dose response, starting from 10mM, with a 1:3 dilution, with a final DMSO concentration of 2%. A multidrop combi was used as a liquid handler, and luminescence was read within 0.5s by an envision reader (PE).

[0877] result

[0878]

[0879]

[0880]

[0881]

[0882] In vitro DGK inhibition assay (ADP Glo)

[0883] DGKα and ζ kinases use ATP to phosphorylate the substrate 1,2-dilauroyl-sn-glycerol (DLG). As a result of this enzymatic reaction, ATP is converted to ADP.

[0884] After the kinase reaction, an ATP depletion reagent is added to terminate the kinase reaction and deplete any remaining ATP, leaving only ADP. Next, a detection reagent is added to simultaneously convert ADP to ATP and convert the newly synthesized ATP into light using a coupled luciferase / luciferin reaction.

[0885] Experimental procedures, reagents, and materials

[0886] DGKα and ζ kinase ADP Glo assays were performed by Reaction Biology Corp., 1 Great Valley Parkway, Suite 2, Malvern, 19355, PA, USA. Information provided by the service provider is as follows: The final concentration of DGKα and ζ kinase was 2 nM. Reactions were performed at 50 μM ATP. 500 uM substrate DLG (dilauroyl-sn-glycerol) was used. Compounds were received as 10 mM DMSO stock solutions and tested in 10 doses of IC50 replicates, starting with 3-fold serial dilutions from 1 μM. The control compound Calphostin C was tested in 10 doses of IC50, starting with 3-fold serial dilutions from 100 μM.

[0887] result:

[0888]

[0889] 2.2) IL2 secretion measurement

[0890] 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 after compound treatment was assessed as % of the maximum value of reference compound A1. WO 2016 / 139181 discloses reference compound A1 as Example 70. As a counter screen and to ensure that unwanted TCR-independent activation is not triggered, PBS conditions are run for all compounds.

[0891] Reagents and materials

[0892]

[0893]

[0894]

[0895] Cell culture

[0896] The expanded primary human T cells were thawed and cultured at a density of 2 Mio / 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 penicillin-streptomycin (Life Technologies, #15140122) medium for 3 hours at 5% CO2, 37°C and 95% humidity. To coat the plates, PBS++ with PBS-- or PBS++ with CD3 antibody (concentration depends on the donor and determined by CD3 titration) was added to a poly-D-lysine coated 96-well plate at 100 μl / well. The plates were sealed and incubated at room temperature for 3 hours on a tabletop rocking platform. After incubation, the plates were washed once with PBS-- and filled with medium only at 40 μl / well. Compounds were then added to the plates in medium only (see next section).After culturing T cells for 3 hours, cells were filtered through a cell strainer (Miltenyi Biotech, #130-041-407), counted again and the concentration adjusted to 1.25 Mio / ml.

[0897] The cells were then inoculated at 80 μl / well to 40 μl / well, which included the compounds assigned according to the plate layout. By adding cells, the compounds were further diluted 1:3 and 100k cells / 120 μl / well were generated. 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 to detect IL2 using the IL-2 Human ProQuantum Immunoassay Kit (Invitrogen) or using the Human IL-2 ELISA Kit (Thermo Fisher).

[0898] Compound treatment

[0899] Compounds were added in 5 or 6 pt dose responses using a Tecan D300e digital dispenser, with concentrations in all conditions being 3 times the final concentration since cells were added later (80 μl of cells added to 40 μl of prep media after treatment). DR starting concentration was 20 μM or final maximum concentration was 10 μM, and the dilution factor was 3.333. The positive control was the reference compound A1, which was also added in the dose response, and was also added to 3 wells at only 20 μM, representing a positive stimulator control. All wells were normalized to a final concentration of 0.6% with DMSO (0.2% final concentration).

[0900] IL2ProQuantum Immunoassay

[0901] Immunoassay was performed according to the manufacturer's manual (Invitrogen, #A35603).

[0902] Additional Information: For immunoassays, use MicroAmp TM EnduraPlate TM Optical 384-well plates. Frozen supernatants were thawed and centrifuged at 1000 x g for 5 min, both steps were performed at 4°C. After centrifugation, the required sample volume was removed from the top and diluted with assay dilution buffer in a separate LightCycler V-bottom plate (working plate), the dilution factor depending on the PBS or CD3 condition, but at least 1:3. IL-2 standards and blanks were prepared in the same V-bottom plate, with standards ranging from 0.0128-5000 pg / ml (extended version). After preparation, 5 μl of sample dilution or standards / blanks were transferred to an optical 384-well plate (assay plate) and a 10 μl reaction protocol was followed. Measurements were performed using a QuantStudio 12K Flex system. Raw data were extracted and IL-2 concentrations were calculated using the ThermoFisher online application (apps.thermofisher.com / apps / proquantum).

[0903] IL2Elisa

[0904] ELISA was performed according to the manufacturer's manual (Thermo Fisher Scientific, #88-7025-88).

[0905] Additional information: ELISA was performed using Nunc MaxiSorp 96-well plates. Frozen supernatants were thawed and centrifuged at 1000xg for 5 minutes, both steps were performed at 4°C. Afterwards, the required sample volume was taken from the top and diluted with ELISA diluent in a separate V-bottom plate, the dilution factor depending on the PBS or CD3 conditions. IL-2 standards and blanks were prepared in the same V-bottom plate. After preparation, 50 μl of sample diluent and 100 μl of standard or blank were transferred to the Nunc plate.

[0906] Calculations and data reporting

[0907] CD3 and PBS plates were analyzed separately in Genedata Screener using Roche normalized PCT_POS_CTRL, with DMSO set as neutral control and reference compound A1 at 20 μM set as stimulator control / 100%.

[0908] For CD3 conditions, EC50 and Emax are reported for the fitted sigmoidal curve. If a curve could not be fitted, EC50 is reported as a blank field and Emax is based on individual data points. Emax does not always correspond to the highest concentration tested. Compounds that activate unstimulated cells or compounds that negatively affect viability are flagged (see Proliferation Assay).

[0909] result

[0910]

[0911]

[0912]

[0913] 2.4) Proliferation assay

[0914] Reagents and materials

[0915]

[0916]

[0917]

[0918] The expanded primary human T cells were thawed and cultured at a density of 2 Mio / 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 penicillin-streptomycin (Life Technologies, #15140122) medium for 3 hours at 5% CO2, 37°C and 95% humidity. To coat the plates, PBS++ alone or PBS++ with CD3 antibody (concentration depends on the donor and determined by CD3 titration) was added to a poly-D-lysine coated 96-well plate at 100 μl / well. The plates were sealed and incubated at room temperature for 3 hours on a tabletop rocking platform. After incubation, the plates were washed once with PBS-- and filled with medium only at 40 μl / well. Compounds were then added to the plates in medium only (see next section).After culturing T cells for 3 hours, cells were filtered through a cell strainer (Miltenyi Biotech, #130-041-407), counted again and the concentration adjusted to 1.25 Mio / ml.

[0919] The cells were then inoculated at 80 μl / well to 40 μl / well, which included the compounds assigned according to the plate layout. The compounds were further diluted 1:3 by adding cells and yielded 100k cells / 120 μl / well. After 48 hours, 40 μl of supernatant was carefully collected from the top without disturbing the cells. Cell proliferation was assessed 5 days later by measuring ATP consumption using CellTiterGlo (Promega).

[0920] Compound treatment

[0921] Compounds were added in 5 or 6 pt dose responses using a Tecan D300e digital dispenser, with concentrations in all conditions being 3 times the final concentration since cells were added later (80 μl of cells added to 40 μl of prep media after treatment). DR starting concentration was 20 μM or final maximum concentration was 10 μM, and the dilution factor was 3.333. The positive control was the reference compound A1, which was also added in the dose response, and was also added to 3 wells at only 20 μM, representing a positive stimulator control. All wells were normalized to a final concentration of 0.6% with DMSO (0.2% final concentration).

[0922] Cell Titer Glo Measurement

[0923] After 5 days, in order to detect ATP which is proportional to the number of cells present in each well, 2.0 reagents. After visual control of the toxicity or precipitation of the tested compounds, the plates were equilibrated to room temperature for 45 minutes. 2.0 reagents were balanced to room temperature. After equilibrium, an equal amount of CellTiter-Glo reagent was added to the cells (80 μl / well) using an electronic multichannel pipette. The plate was placed on a shaking platform at room temperature for 15 minutes. After incubation, the bottom of the plate was sealed with backing tape. Luminescence was measured using PHERAstar FSX (interval 0.5 sec, gain 3000, focal height 15 mm) and exported as a CSV file for analysis in the Genedata filter.

[0924] Calculations and data reporting

[0925] CD3 and PBS plates were analyzed separately in Genedata Screener using Roche normalized PCT_POS_CTRL, with DMSO set as neutral control and reference compound A1 at 20 μM set as stimulator control / 100%.

[0926] For CD3 conditions, EC50 and Emax are reported for the fitted sigmoidal curve. If a curve could not be fitted, EC50 is reported as a blank field and Emax is based on individual data points. Emax does not always correspond to the highest concentration tested. Compounds that activate unstimulated cells (see IL2 measurements) or that negatively affect viability are flagged.

[0927] result

[0928]

[0929]

[0930]

[0931]

[0932] 2.4) T cell-TCB-MV3 killing assay

[0933] Reagents and materials

[0934]

[0935]

[0936]

[0937] Cell culture

[0938] All incubation steps were performed under 5% CO2, 37°C and 95% humidity.

[0939] MV-3RFP cells were cultured in MV-3 ​​medium (DMEM + 10% FBS, 1x PenStrep and 0.5 μg / mL puromycin) for at least 3 weeks. The cultured MV-3 ​​cells were washed once with PBS at 80% confluence and digested with trypsin until detached. The cells were then counted and resuspended to 1 * 105 cells / mL in T cell culture medium (RPMI 1640 + 5% human serum + 1mM sodium pyruvate + 50μM 2-mercaptoethanol and 1x Pen-Strep). The cells were inoculated into a 96-well plate (TTP, #92696) at 100μL / well and placed at room temperature for 40 minutes without moving to achieve uniform distribution of cells. The plate was then incubated until further use.

[0940] The next day, the expanded primary human T cells were thawed and resuspended in T cell culture medium to 4*106 cells / mL. They were cultured in 6-well plates for 3 hours, with a maximum of 6 mL per well. After culturing the T cells, the cells were filtered through a cell strainer (Miltenyi Biotech, #130-041-407), counted again, and the concentration was adjusted to 2*106 cells / mL.

[0941] Compound treatment

[0942] MCSP-TCB or PBS was pre-diluted in T cell culture medium (concentration depends on T cell donor) at 4 times the final concentration. 60 μL / well of the pre-dilution was then dispensed into round bottom plates (Costar, #3799) according to the plate layout. Compounds were added using a Tecan D300e digital dispenser at a 9pt dose response, also at 4 times the final concentration. The DMSO concentration of all wells was adjusted to 0.8%, resulting in a final concentration of 0.2%.

[0943] 60 μL of T cell suspension per well is added to the prepared round bottom plate and resuspended using manual multichannel. Then, according to the plate layout, 100 μL / well of resuspended T cell suspension (including treatment) is carefully transferred to the MV-3 ​​cells cultured overnight. Only 100 μL T cell culture medium is added to the external MV-3 ​​well. The final compound DR starts from 20 μM, and the dilution factor is 3.333. The final TCB concentration is between 1.5 pM and 5 pM, and each T cell donor is determined individually by running TCB titration. For each donor, the TCB concentration corresponding to the MV3 baseline cell that kills 10%-20% in the absence of compound treatment is selected. The positive control is the reference compound A1 added in DR, and only 20 μM is added to other wells. 20 μM of reference compound A1 represents the positive stimulant control, and only TCB (DMSO well) represents the neutral control.

[0944] calculate

[0945] After transferring T cells with pre-treatment dilutions, use IncucyteZOOM TM MV-3 cells were imaged by time-lapse microscopy (Essen BioScience, MI, USA). Imaging was performed every 3 h for a total of 120 h (10X objective, phase and red image channels, acquisition time 400 ms, green / red 4614 optical module). Using a mask previously created and optimized for MV-3 ​​cells, the IncucyteZOOM TMRFP object counts per well were analyzed in the software (version 2019B Rev2). Raw data were exported as object counts / well and values ​​were normalized to %TCL compared to wells with MV-3 ​​alone, representing 100% growth and therefore 0% TCL.

[0946] RFP Measurement

[0947] The calculated %TCL values ​​were analyzed in Genedata Screener using Roche normalized PCT_POS_CTRL, with MCSP-TCB only set as neutral control and reference compound A1 at 20 μM set as stimulator control / 100%.

[0948] The table below provides the EC50 and Emax values.

[0949] Compound-induced TCLs without TCB treatment or toxicity (observed under PBS conditions) are marked.

[0950] result

[0951]

[0952] #imgpt544#

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: Y is S(O), S(O)2 and S(O)N(R y ); R 1 is a 5-membered heteroaryl group, wherein R 1 Optionally, one or more R 10 replace; R 2 is selected from hydrogen and halogen; R 4 Selected from C 5-14 -aryl and 5- to 14-membered heteroaryl, wherein R 4 Optionally, one or more R 11 replace; R 10 -C(R 10a R 10b )2-S(O)2(R 10c ); R 10a and R 10b are each independently selected from hydrogen and C 1-6 -alkyl, or R 10a and R 10b Together with the carbon atom to which they are attached, they form C 3-6 - cycloalkyl; R 10c Selected from hydrogen, C 1-6 -alkyl, C 3-6 -cycloalkyl, -N(C 1-6 -alkyl), halo-C 1-6 -alkyl and phenyl, wherein the phenyl group is optionally substituted with one or more halogen or C 1-6 - alkyl substituted; or R 10a and R 10c Together with the carbon atom and the sulfur atom to which they are attached, they form a 3- to 10-membered heterocyclic group; R 11 Selected from: i) halogen; ii) a 3- to 10-membered heterocyclic group, which is optionally substituted with one or more halogenated -C 1-6 -alkyl, C 3-10 - Cycloalkyl substitution; iii) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more halogens, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 3-10 -Cycloalkyl, C 1-6 -Haloalkoxy substitution; iv) phenyl, which is optionally substituted with one or more halogen, cyano, C 1-6 -alkoxy, C 1-6 -haloalkyl, C 1-6 - alkyl substitution; v)-O(R 11a ); vi)-N(R 11g R 11h );as well as vii)–S(R 11k ): R 11a Selected from C 1-12 -alkyl, halo-C 1-6 -alkyl, C 3-7 -cycloalkyl, 3- to 10-membered-(C 1-6 -alkyl) heterocyclic group, phenyl and -C 1-6 -alkyl-phenyl, wherein the C 1-12 -alkyl, C 3-7 -cycloalkyl, phenyl and -C 1-6 -alkyl-phenyl is optionally substituted with one or more halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -Haloalkoxy substitution; R 11g and R 11h are each independently selected from hydrogen, C 1-6 -alkyl, -(C 1-6 -alkyl)phenyl; R 11k Selected from hydrogen and halo-C 1-6 -alkyl; R y Selected from hydrogen and C 1-6 -alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is oxadiazole or tetrazole, wherein R 1 Optionally, one or more R 10 replace.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace.

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

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 4 It is phenyl.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 10a and R 10b are each independently selected from hydrogen and C 1-6 -alkyl, or R 10a and R 10b Together with the carbon atom to which they are attached, they form C 3-6 -cycloalkyl.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 10 For a -S(O)2(C 1-6 -alkyl) substituted C 3-6 -cycloalkyl.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 10 is a 3- to 6-membered heterocyclic group, wherein the heteroatom is sulfur, and one or more C 1-10 -alkyl, oxo-substituted, wherein the oxo-substituted is on the sulfur atom.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 10 Selected from 1-methyl-methylsulfonyl-ethyl.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 11 for i) halogen; ii) a 3- to 10-membered heterocyclic group; iii) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more halogens, halo-C 1-6 -alkyl, C 3-10 -Cycloalkyl, C 1-6 -Haloalkoxy substitution; iv) phenyl, which is optionally substituted with one or more cyano, C 1-6 -alkoxy, C 1-6 -haloalkyl, C 1-6 - alkyl substitution; v)-O(R 11a );R 11a 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, wherein the C 1-12 -alkyl, phenyl, 5- to 6-membered-(C 1-6 -alkyl)heteroaryl and -C 1-6 -alkyl-phenyl is optionally substituted with one or more halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -Haloalkoxy substitution; vi)-N(R 11g R 11h );R 11g and R 11h Each independently selected from C 1-6 -alkyl, -(C 1-6 -alkyl)phenyl; vii) –S(halogenated-C 1-6 -alkyl); viii) CH2-O-phenyl.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 11 Selected from: i)-O(R 11a ), where R 11a Selected from halogenated-C 1-6 - alkyl and phenyl, wherein the phenyl is optionally substituted with one or more halogens; or ii) phenyl, which is optionally substituted with one or more C 1-6 -alkoxy, C 1-6 -Haloalkyl substitution; iii) halogen; iv) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more halogenated -C 1-6 -alkyl, C 3-10 -Cycloalkyl, C 1-6 -haloalkoxy substitution.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 11 Selected from (trifluoromethyl)phenyl, (trifluoromethyl)-oxadiazolyl, cyclopropyl-oxadiazolyl, phenoxy, methoxyphenyl, tetrafluoroethoxy, dichlorophenoxy, chloro, trifluoromethoxy-2-pyridyl.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein Y is S(O)2.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Y is S(O), S(O)2 and S(O)N(R y ); R 1 is a 5-membered heteroaryl group, wherein R 1 Optionally, one or more R 10 replace; R 2 is selected from hydrogen and fluorine; R 4 is selected from C6-aryl and 6-membered heteroaryl, wherein R 4 Optionally, one or more R 11 replace; R 10 For a -S(O)2(C 1-6 -alkyl) substituted C 3-6 - cycloalkyl; R 11 for i) halogen; ii) a 3- to 10-membered heterocyclic group; iii) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more halogens, halo-C 1-6 -alkyl, C 3-10 -Cycloalkyl, C 1-6 -Haloalkoxy substitution; iv) phenyl, which is optionally substituted with one or more cyano, C 1-6 -alkoxy, C 1-6 -haloalkyl, C 1-6 - alkyl substitution; v)-O(R 11a );R 11a 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, wherein the C 1-12 -alkyl, phenyl, 5- to 6-membered-(C 1-6 -alkyl)heteroaryl and -C 1-6 -alkyl-phenyl is optionally substituted with one or more halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -Haloalkoxy substitution; vi)-N(R 11g R 11h );R 11g and R 11h Each independently selected from C 1-6 -alkyl, -(C 1-6 -alkyl)phenyl; vii) –S(halogenated-C 1-6 -alkyl); viii) CH2-O-phenyl.

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Y is S(O), S(O)2 and S(O)N(R y ); R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace; R 2 is selected from hydrogen and fluorine; R 4 is phenyl; R 10 Selected from methyl-methylsulfonyl-ethyl, cyclopropylsulfonyl-methyl-ethyl, methyl-dioxo-thiolanyl, methylsulfonylmethyl, methylsulfonylcyclobutyl; R 11 Selected from: i)-O(R 11a ), where R 11a Selected from halogenated-C 1-6 -alkyl, phenyl, wherein the phenyl is optionally substituted with one or more halogens; ii) phenyl, which is optionally substituted with one or more C 1-6 -alkoxy, C 1-6 -Haloalkyl substitution; iii) halogen; and iv) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more halogenated -C 1-6 -alkyl, C 3-10 -Cycloalkyl, C 1-6 -haloalkoxy substitution.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Y is S(O), S(O)2 and S(O)N(R y ); R 1 is oxadiazole, wherein R 1 Optionally, one or more R 10 replace; R 2 is selected from hydrogen and fluorine; R 4 is phenyl; R 10 is methyl-methylsulfonyl-ethyl; R 11 is selected from (trifluoromethyl)phenyl, (trifluoromethyl)-oxadiazolyl, cyclopropyl-oxadiazolyl, phenoxy, methoxyphenyl, tetrafluoroethoxy, dichlorophenoxy, chloro and trifluoromethoxy)-2-pyridinyl.

17. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, selected from: (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (3R)-3-Amino-5-[[4-(cyclopentyloxy)phenyl]methyl]-7-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1,1-dioxo-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; 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-benzothiazepine -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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (3R)-3-Amino-1,1-dioxo-7-[5-(1-methylsulfonyl-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[4-[5-(trifluoromethoxy)-2-pyridyl]benzyl]-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-pyridinyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-pyridinyl]phenyl]methyl]-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -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-benzothiazepine -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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; 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-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-benzothiazepine -4-Keto; (3R)-3-Amino-8-fluoro-7-[2-(methylsulfonylmethyl)tetrazol-5-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine -4-ketone; and (3R)-3-Amino-8-fluoro-7-[1-(methylsulfonylmethyl)tetrazol-5-yl]-1,1-dioxo-5-[(4-phenoxyphenyl)methyl]-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto.

18. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, selected from (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-Keto; (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-benzothiazepine -4-ketone; and (3R)-3-Amino-1,1-dioxo-7-[5-(1-methylsulfonyl-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5-[4-[5-(trifluoromethoxy)-2-pyridyl]benzyl]-2,3-dihydro-1λ6,5-benzothiazepine -4-Keto.

19. A method for preparing a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, the method comprising: Among them, Y, R 1 , R 2 and R 4 As defined in any one of claims 1 to 18 and PG is an amino protecting group, reacted with a suitable deprotecting agent to form the compound of formula (I).

20. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, prepared according to the method according to 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 excipient.

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

25. The compound for use according to claim 24, wherein the cancer is associated with aberrant diacylglycerol kinase signaling, wherein the diacylglycerol kinase is selected from DGKα and / or DGKζ.

26. The compound for use according to claim 24 or 25, wherein the cancer is selected from the group consisting of: B-cell acute lymphoid leukemia, T-cell acute lymphoid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative disorders, MALT lymphoma, mantle cell The invention relates to leukemia, leukemia of the kidney, sarcoma, carcinoma, melanoma, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell carcinoma, melanoma, gastric cancer, brain cancer, lung cancer (e.g., NSCLC), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.

27. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof for treating, preventing and / or delaying the progression of cancer.

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

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

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

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

32. The invention as herein described.

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