Bicyclic tetrahydroaza derivatives

Abstract

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

Description

Technical Field

[0001] The present invention relates to bicyclic tetrahydroazepines that inhibit diacylglycerol kinase (DGK) α and ζ and are useful as T cell activators Its manufacture and pharmaceutical composition containing the compound.

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

[0004] Diacylglycerol kinase (DGK) is a lipid kinase that catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA), thereby limiting DAG-regulated 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 within their structures. In addition, the lack of structural data still hinders a more thorough understanding of the mode of action of DGK. Furthermore, information on some prokaryotic DGKs and other lipid kinases, such as sphingosine kinase and phosphatidylinositol 3-kinase (PI3K), provides only limited insights into the catalytic mechanisms of DGKs that appear to differ from those of typical kinases (Arranz-Nicolás, J. and Mérida, I., 2020. Biological regulation of diacylglycerol kinases in normal and neoplastic tissues: New opportunities for cancer immunotherapy, Advances in Biological Regulation, Vol. 75; Ma, Q., Gabelli, SB, Raben, DM, 2019: Diacylglycerol kinases: relationship to other lipid kinases. Adv Biol Regul 71, 104–110).

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

[0006] These two isozymes, DGKα and DGKζ, are active downstream of CD28 and other co-stimulatory receptors and the T cell receptor (TCR), and their function is to limit the amount of DAG produced and ultimately limit T cell activation (Merida, I., Andrada, E., Gharbi, SI, Avila-Flores, A., 2015. Redundant and specialized roles for diacylglycerol kinases alpha and zeta in the control of T cell functions. Sci. Signal. 8(374); Shulga, YV, Topham, MK, Epand, RM, 2011. Regulation and functions of diacylglycerol kinases. Chem. Rev. 111(10), 6186–6208). A summary of the signal transduction pathways regulated by representative DGKs 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 generate two secondary messengers DAG and IP3. DAG activates PKC, Ras / MEK / ERK / AP-1 and NF-kB, while IP3 is involved in activating intracellular Ca2+ flux. Upregulated Ca2+ signaling then activates the transcription factor NFAT. In short, DAG production and levels determine the duration and intensity of Ras / MEK / ERK and PKC-dependent signaling pathways, and they are at the core of T cell activation. Therefore, DGK is used as an intracellular checkpoint, and it is expected that inhibition of DGK can enhance T cell signaling pathways and T cell activation.

[0007] Experimental evidence suggests that enhanced DGK function and / or expression in tumor-infiltrating T cells (TILs) limits tumor destruction. CAR T cell experiments on human mesothelioma transplanted into nude mice showed that tumor-infiltrating CAR T cells expressed elevated concentrations of surface inhibitory receptors and inhibitory enzymes SHIP-1, DGKα, and DGKζ (Moon et al., 2014). In addition, high 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 to tumor cells (Riese et al., 2013). Similar results have been reported for human CAR T cells, in which CRISPR / Cas9 was used to silence both DGKα and DGKζ expression (Jung et al., 2018). All these studies provide a basis for targeting DGKα / ζ in the development of anti-cancer therapies (Arranz-Nicolás, J. and Mérida, I., 2020. Biological regulation of 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 further evidence: mice lacking DGKα or DGKζ exhibit 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).

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

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

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

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

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

[0013]

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

[0015] R 1 is a 5-membered or 6-membered heteroaryl group, wherein R 1 Optionally, one or more R 10 replace;

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

[0017] R 4 is selected from phenyl and pyridyl, wherein R 4 Optionally, one or more R 11 replace;

[0018] R 10 Selected from:

[0019] i)C 1-6 -alkyl, which is optionally substituted with one or more halogen, amino, C 1-6 -Alkoxy, -S(O) 2 (C 1-6 -alkyl), cyano substituted;

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

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

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

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

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

[0025] i) Hydrogen;

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

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

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

[0029] R 11 Selected from:

[0030] i) halogen;

[0031] ii) C 1-6 -alkoxy, which is optionally substituted with one or more C 1-6 -alkyl, C 5-6 -Aryl, C 3-10 -cycloalkyl, halo-C 1-6 -alkyl, C 3-10 -heterocyclyl, wherein the 3- to 10-membered heterocyclyl is optionally substituted by C 1-6 - alkyl substitution;

[0032] iii) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more halogens, halo-C 1-6 -alkyl, C 1-6 -alkoxy, C 3-10 -cycloalkyl, C 1-6 -alkyl, halo-C 1-6 - alkoxy substitution;

[0033] iv) phenyl, which is optionally substituted with one or more C 1-6 -alkoxy, halo-C 1-6 - alkyl substitution;

[0034] v)-O(R 11a );

[0035] R 11a Selected from C 1-6 -alkyl, C 3-6 -cycloalkyl, phenyl and halo-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 herein, the method comprising reacting a compound of formula (XVIII),

[0037]

[0038] Where 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 said compound of formula (I).

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

[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 the treatment, prevention and / or delay of cancer progression.

[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 containing 1 to 10 carbon atoms (“C 1-10 -alkoxy”), more preferably containing 1 to 6 carbon atoms (“C 1-6 -alkoxy"). In some preferred embodiments, the alkoxy group contains 1 to 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[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 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 straight (ie, unbranched) or branched monovalent hydrocarbon chains of one to ten carbon atoms (“C”). 1-20 alkyl”), having 1 to 12 carbon atoms (“C 1-12 alkyl”), having 1 to 10 carbon atoms (“C 1-10 alkyl”), having 1 to 8 carbon atoms (“C 1-8 alkyl”), having 1 to 6 carbon atoms (“C 1-6 alkyl”), having 2 to 6 carbon atoms (“C 2-6 alkyl") or having 1 to 4 carbon atoms ("C 1-4 Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, homologs and isomers thereof, such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[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), having a specified number of carbon atoms (ie, C 2-10means an unsaturated straight chain (ie, unbranched) or branched monovalent hydrocarbon chain or combinations thereof having from two to ten carbon atoms). Specific alkynyl groups are those having from 2 to 20 carbon atoms (“C 2-20 Alkynyl”), having 2 to 8 carbon atoms (“C 2-8 Alkynyl”), having 2 to 6 carbon atoms (“C 2-6 Alkynyl”), having 2 to 4 carbon atoms (“C 2-4 Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (ethynyl or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.

[0049] "Amino", alone or in combination with other groups, means NH 2 .

[0050] "Aminoalkyl" refers to an alkyl group in which one or more of the hydrogen atoms of the alkyl group have been replaced by an amino moiety.

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

[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). Aryl groups may be optionally substituted as defined herein. 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 of which is optionally substituted.

[0053] "Cancer" refers to a disease characterized by the presence of a neoplasm or tumor resulting from the 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 diseases 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 in which one or more of the hydrogen atoms of the alkyl group has been replaced with a cyano moiety.

[0056] "Cycloalkyl" refers to a saturated or partially unsaturated carbocyclic moiety having a monocyclic, bicyclic (including bridged bicyclic and cycloalkyl spiro moieties) or tricyclic ring and 3 to 10 carbon atoms (i.e., (C 3 -C 10 ) cycloalkyl). The cycloalkyl moiety may be optionally substituted with one or more substituents. In certain aspects, the cycloalkyl contains 3 to 8 carbon atoms (i.e., (C 3 -C 8 In other specific aspects, the cycloalkyl group contains 3 to 6 carbon atoms (ie, (C 3 -C 6 )cycloalkyl). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and partially unsaturated (cycloalkenyl) derivatives thereof (e.g., cyclopentenyl, cyclohexenyl and cycloheptenyl), bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptanyl, bicyclo[3.1.1]heptenyl and bicyclo[1.1.1]pentane. Cycloalkyl moieties may be attached in a "spiro-cycloalkyl" or "cycloalkylspiro" manner, such as a "spirocyclopropyl"

[0057]

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

[0059] "Haloalkoxy" refers to an alkoxy group in which at least one halogen is substituted for each H in the hydrocarbon constituting the alkyl portion of the alkoxy group. An example of a haloalkoxy group is difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ).

[0060] "Haloaryl" refers to an aryl group in which at least one hydrogen has been replaced by a halogen.

[0061] "Heteroaryl" refers to an aromatic heterocyclic monocyclic, bicyclic or tricyclic ring system of 5 to 14 ring atoms, preferably 5 to 10 ring atoms, more preferably 5 to 6 ring atoms, containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. In some aspects, the monocyclic heteroaryl ring can be 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 herein. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothiophenyl, benzophenylthio, indolyl, aza-indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl oxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furanopyridazinyl, furanopyrimidinyl and furanopyrazinyl. More preferably, "5-membered heteroaryl" refers to the following groups:

[0062]

[0063] "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 that 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, with the remaining ring atoms being 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 a heterocycle, the nitrogen or sulfur may also be in oxidized form, and the nitrogen may be substituted with one or more (C 1 -C 6) alkyl or radicals. The heterocycle may be attached to its side group at any heteroatom or carbon atom, resulting in a stable structure. Any ring atom of the heterocycle may be optionally substituted with one or more substituents as described herein. Examples of such saturated or partially unsaturated heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepine Oxazepine Thiazepine The term "heterocycle" also includes groups in which the heterocycle is fused to one or more aryl, heteroaryl or cycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[3.1.0]hexanyl, azabicyclo[3.1.1]heptanyl, octahydroindolyl or tetrahydroquinolinyl.

[0064] "Hydroxyl", alone or in combination with other groups, refers to OH.

[0065] "Hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms of the alkyl group has been replaced with a hydroxy moiety. Examples include alcohols and diols.

[0066] "Moiety" and "substituent" refer to an atom or group of chemically bonded atoms attached to another atom or molecule by one or more chemical bonds to form a part of a molecule.

[0067] 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.

[0068] "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.

[0069] "Optionally substituted" means unsubstituted or substituted. Typically, these substituents may be the same or different.

[0070] "Oxo", alone or in combination with other groups, means =0.

[0071] "Pharmaceutically acceptable salts" are salts which retain the biological effectiveness and properties of the free bases or free acids and which are not biologically or otherwise undesirable. Such salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and with organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine.

[0072] 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.

[0073] As used herein, the term "protecting group" (PG) represents 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. The protecting group can be removed at an appropriate point. Exemplary protecting groups are amino protecting groups, carboxyl protecting groups, or hydroxy protecting groups. Specific protecting groups are tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Further specific protecting groups are tert-butyloxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more specific protecting group is tert-butyloxycarbonyl (Boc). Exemplary protecting groups and their use in organic synthesis are described in, for example, TW Greene and PGM Wutts, Protective Groups in Organic Chemistry, 5th edition, 2014, John Wiley & Sons, NY.

[0074] As used herein, "prevention" includes preventing or delaying the onset of clinical symptoms of a disease, disorder or condition in a mammal, especially a human, who may be suffering from or susceptible to the disease, disorder or condition but has not yet experienced or displayed clinical or subclinical symptoms of the disease, disorder or condition.

[0075] "Substituted" refers to at least one hydrogen atom in 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 replacing at least one hydrogen atom of a compound or part described herein with a halogen or alkyl group.

[0076] "Therapeutically effective amount" refers to an amount that, when a compound or molecule of the invention is administered to a subject, achieves the following effects: (i) treatment or prevention of a specific disease, condition or disorder described herein, (ii) alleviation, amelioration or elimination of one or more symptoms of a specific disease, condition or disorder described herein, or (iii) prevention or delay of the onset of one or more symptoms of a specific disease, condition or disorder described herein. The therapeutically effective amount depends on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary doctor and other factors.

[0077] "Therapeutically inert carrier" refers to any ingredient that is not therapeutically active and non-toxic, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant or lubricant used to formulate a pharmaceutical product.

[0078] In particular, the chemical groups whose definitions are given above are those specifically exemplified in the Examples.

[0079] The following abbreviations are used in this text:

[0080] BOP = benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, brine = saturated aqueous NaCl, CAS = Chemical Abstracts Service, CDI = 1,1'-carbonyldiimidazole, DAD = diode-array detection, 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 =amine, 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'-tetrakis Methyl-uronium-hexafluoro-phosphate, HFIP=hexafluoroisopropanol, HOBt=hydroxybenzotriazole, HPLC=high performance liquid chromatography, IPA=isopropanol, m-CPBA=m-chloroperbenzoic acid, MeCN=acetonitrile, MeI=methyl iodide, MeOH=methanol, min=minutes, MS=mass spectrometry, NBS=N-bromosuccinimide, PDA=photodiode-array detection, PE=petroleum ether, PyBroP=bromo-tris-pyrrolidine =Substituted-phosphonium hexafluorophosphate, RT = room temperature, TBAF = tetrabutylammonium fluoride, TBAOH = tetrabutylammonium hydroxide, TBDMS = tert-butyldimethylsilyl, TEA = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TMSOTF = trimethylsilyl trifluoromethanesulfonate, TLC = thin layer chromatography, T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine 2,4,6-trioxide.

[0081] In the descriptions herein, if there is a discrepancy between a depicted structure and the name given to the structure, the depicted structure controls. In addition, if the stereochemistry of a structure or portion of a structure is not indicated, for example, by a thick wedge or dashed line, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers thereof. However, in some cases where more than one chiral center is present, the structure and name may be represented as a single enantiomer to aid in describing the relative stereochemistry.

[0082] Unless otherwise stated, the term "compound of formula" or "compounds of formula" or "compounds of formula" or "compounds of formula" refers to any compound selected from the genus of compounds as defined by the formula (including any pharmaceutically acceptable salts of any such compound unless otherwise stated).

[0083] 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.

[0084] Furthermore, the present invention includes all optical isomers, ie diastereomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers and solvates thereof, of the compounds of formula (I).

[0085] Compounds of formula (I) may contain one or more asymmetric centers, and therefore racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers may exist. Depending on the nature of the various substituents on the molecule, additional asymmetric centers may exist. 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 cover all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their chromatographic separation can be achieved by making appropriate changes to the methods disclosed herein as known in the art. The absolute stereochemistry can be determined by x-ray crystallography of the crystalline product or crystalline intermediate, and if necessary, these products or intermediates can be derivatized using reagents containing asymmetric centers of known absolute configuration. If necessary, the racemic mixture of the compound can be separated so that the individual enantiomers are separated. Separation can be carried out by methods well known in the art, such as coupling a racemic mixture of the compounds to an enantiomerically pure compound to form a diastereomeric mixture followed by separation of the individual diastereomers by standard methods such as fractional crystallization or chromatography.

[0086] In embodiments where an optically pure enantiomer is provided, an optically pure enantiomer means that the compound contains >90% by weight of the desired isomer, particularly >95% by weight of the desired isomer, or more particularly >99% by weight of the desired isomer, the weight percentages being based on the total weight of the isomers of the compound. Chirally pure compounds or chirally enriched compounds can be prepared by chiral selective synthesis or by enantiomer separation. Separation of enantiomers can be performed on the final product, or alternatively on a suitable intermediate.

[0087] In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more atoms with atoms having a different atomic mass or mass number. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, such as but not limited to 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Certain isotopically-labeled compounds of formula (I) (e.g., those containing a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and detection means are readily available. For example, compounds of formula (I) may be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95 or 99% of a given isotope.

[0088] 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.

[0089] Using positron-emitting isotopes such as 11 C. 18 F. 15 O and 13N) substitution can be used to examine positron emission tomography (PET) studies of substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the Examples set forth below using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used.

[0090] Compounds of the present invention

[0091] In one embodiment, there is provided a compound of formula (I) as described herein,

[0092]

[0093] or a pharmaceutically acceptable salt thereof, wherein:

[0094] R 1 is a 5-membered or 6-membered heteroaryl group, wherein R 1 Optionally, one or more R 10 replace;

[0095] R 2 is selected from hydrogen and halogen;

[0096] R 4 is selected from phenyl and pyridyl, wherein R 4 Optionally, one or more R 11 replace;

[0097] R 10 Selected from:

[0098] i)C 1-6 -alkyl, which is optionally substituted with one or more halogen, amino, C 1-6 -Alkoxy, -S(O) 2 (C 1-6 -alkyl), cyano substituted;

[0099] ii) C 3-10 - cycloalkyl, which is optionally substituted by one or more halogen, cyano, amino;

[0100] iii) a 3- to 10-membered heterocyclic group, which is optionally substituted with one or more halogens, C 1-10 -alkyl, amino, halo-C 1-6 -alkyl, hydroxyl, cyano, -C(O)O-(R 10q ), C 3-10 -cycloalkyl substituted, wherein C 1-10 -alkyl is optionally substituted with one or more hydroxyl groups, C 1-6 - alkoxy substitution;

[0101] iv)-N(R10e R 10f );

[0102] v) heteroaryl, which is optionally substituted with one or more C 1-10 -Alkyl, halogen substituted;

[0103] R 10e and R 10f Each independently selected from:

[0104] i) Hydrogen;

[0105] ii) C 1-6 - alkyl, which is optionally substituted with one or more cyano, halogen, hydroxyl;

[0106] iii) C 3-10 -cycloalkyl, which is optionally substituted with one or more halogen, C 1-10 - alkyl substitution;

[0107] R 10q C 1-5 -alkyl, where C 1-5 - alkyl is optionally substituted with one or more hydroxyl groups;

[0108] R 11 Selected from:

[0109] i) halogen;

[0110] ii) C 1-6 -alkoxy, which is optionally substituted with one or more C 1-6 -alkyl, C 5-6 -Aryl, C 3-10 -cycloalkyl, halo-C 1-6 -alkyl, C 3-10 -heterocyclyl, wherein the 3- to 10-membered heterocyclyl is optionally substituted by C 1-6 - alkyl substitution;

[0111] iii) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more halogens, halo-C 1-6 -alkyl, C 1-6 -alkoxy, C 3-10 -cycloalkyl, C 1-6 -alkyl, halo-C 1-6 - alkoxy substitution;

[0112] iv) phenyl, which is optionally substituted with one or more C 1-6 -alkoxy, halo-C 1-6 - alkyl substitution;

[0113] v)-O(R 11a );

[0114] R 11a Selected from C 1-6 -alkyl, C 3-6 -cycloalkyl, phenyl and halo-C 1-6 -alkyl.

[0115] In another embodiment, there is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5-membered heteroaryl group, wherein R 1 Optionally, one or more R 10 replace.

[0116] In a preferred embodiment, there is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is an oxadiazole, which is optionally substituted with one or more R 10 replace.

[0117] In a more preferred embodiment, there is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is an oxadiazole, which is 10 replace.

[0118] In an even more preferred embodiment, there is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 1 is 1,3,4-oxadiazole, which is 10 replace.

[0119] In another embodiment, there is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 2 For fluorine.

[0120] In another embodiment, there is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 4 It is phenyl.

[0121] In another embodiment, there is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from methyl-methylsulfonyl-ethyl, pyrrolidine, 4-oxa-7-azaspiro[2.5]octan-7-yl, methyl-propionitrile, 1,2,2,2-tetrafluoro-methoxy-ethyl, tert-butyl, 1-ethyl-5,5-difluoro-3-piperidinyl, 4,4-difluoro-1-piperidinyl and azabicyclo[3.1.1]heptane-3-carboxylate.

[0122] In another embodiment, there is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from methyl-methylsulfonyl-ethyl, pyrrolidine, oxa-azaspiro[2.5]octanyl, methyl-propionitrile, tetrafluoro-methoxy-ethyl.

[0123] In another embodiment, there is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from 5-(trifluoromethyl)-2-pyridinyl, phenoxy, trifluoromethoxy, methoxy-pyridinyl, cyclopentyloxy, 4-methoxyphenyl, (trifluoromethyl)-1,2,4-oxadiazol-3-yl, 5-(trifluoromethoxy)-2-pyridinyl, 4-(trifluoromethyl)pyrazol-1-yl, chloro, 5-(difluoromethoxy)-2-pyridinyl, 4-[4-(trifluoromethoxy)pyrazol-1-yl, 4-[5-(trifluoromethyl)tetrazol-2-yl.

[0124] In another embodiment, there is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from (trifluoromethyl)-pyridinyl, phenoxy, trifluoromethoxy, (trifluoromethyl)-oxadiazolyl, methoxy-pyridinyl.

[0125] In another embodiment, there is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0126] R 1 is a 5-membered heteroaryl group, wherein R 1 Optionally, one or more R 10 replace;

[0127] R 2 is a halogen;

[0128] R 4 is phenyl or pyridyl;

[0129] R 10 Selected from:

[0130] iv) C 1-6 -alkyl, which is optionally substituted with one or more halogen, C 1-6 -Alkoxy, -S(O) 2 (C 1-6 -alkyl), cyano substituted;

[0131] v) a 3- to 10-membered heterocyclic group, which is optionally substituted with one or more halogens, C 1-10 -alkyl, -C(O)O-(R 10q ), C 3-10 -cycloalkyl substituted, wherein C 1-10 -alkyl is optionally substituted with one or more C 1-6 - alkoxy substitution;

[0132] vi) heteroaryl, which is optionally substituted with one or more C 1-10 - alkyl substitution;

[0133] R 11Selected from:

[0134] i) halogen;

[0135] ii) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more halogens, halo- 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 - alkoxy substitution;

[0136] iii) phenyl, optionally substituted with one or more C 1-6 -alkoxy, halo-C 1-6 - alkyl substitution;

[0137] iv)-O(R 11a );

[0138] R 11a Selected from C 1-6 -alkyl, C 3-6 -cycloalkyl, phenyl and halo-C 1-6 -alkyl.

[0139] In another embodiment, there is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0140] R 1 is a 5-membered heteroaryl group, wherein R 1 Optionally, one or more R 10 replace;

[0141] R 2 is a halogen;

[0142] R 4 is phenyl;

[0143] R 10 Selected from:

[0144] i)C 1-6 -alkyl, which is optionally substituted with one or more halogen, amino, C 1-6 -Alkoxy, -S(O) 2 (C 1-6 -alkyl), cyano substituted;

[0145] ii) C 3-10 - cycloalkyl, which is optionally substituted by one or more halogen, cyano, amino;

[0146] iii) a 3- to 10-membered heterocyclic group, which is optionally substituted by one or more -C(O)O-(R 10q )replace;

[0147] R 11 Selected from

[0148] i) halogen;

[0149] ii) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more halogens, halo- 1-6 -alkyl, C 1-6 - alkoxy substitution;

[0150] iii) phenyl, optionally substituted with one or more C 1-6 -alkoxy, halo-C 1-6 - alkyl substitution;

[0151] iv)-O(R 11a );

[0152] R 11a Selected from C 1-6 -alkyl, C 3-6 -cycloalkyl, phenyl and halo-C 1-6 -alkyl.

[0153] In another embodiment, there is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0154] R 1 is 1,3,4-oxadiazole, which is 10 replace;

[0155] R 2 For fluorine;

[0156] R 4 is phenyl;

[0157] R 10 is selected from methyl-methylsulfonyl-ethyl, pyrrolidine, 4-oxa-7-azaspiro[2.5]octan-7-yl, methyl-propionitrile, 1,2,2,2-tetrafluoro-methoxy-ethyl, tert-butyl, 1-ethyl-5,5-difluoro-3-piperidinyl, 4,4-difluoro-1-piperidinyl and azabicyclo[3.1.1]heptane-3-carboxylate;

[0158] R 11 Selected from 5-(trifluoromethyl)-2-pyridinyl, phenoxy, trifluoromethoxy, methoxy-pyridinyl, cyclopentyloxy, 4-methoxyphenyl, (trifluoromethyl)-1,2,4-oxadiazol-3-yl, 5-(trifluoromethoxy)-2-pyridinyl, 4-(trifluoromethyl)pyrazol-1-yl, chloro, 5-(difluoromethoxy)-2-pyridinyl, 4-[4-(trifluoromethoxy)pyrazol-1-yl and 4-[5-(trifluoromethyl)tetrazol-2-yl.

[0159] In another embodiment, there is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0160] R1 is a 5-membered heteroaryl group, wherein R 1 Optionally, one or more R 10 replace;

[0161] R 2 For fluorine;

[0162] R 4 is phenyl;

[0163] R 10 Selected from difluoro-(methoxyethyl)piperidinyl, azabicyclo[3.1.1]heptane-carboxylate, amino-trifluoro-methyl-ethyl, methyl-methylsulfonyl-ethyl, pyrrolidine, oxa-azaspiro[2.5]octanyl, methyl-propionitrile, tert-butyl, tetrafluoro-methoxy-ethyl, morpholino;

[0164] R 11 Selected from methoxyphenyl, (trifluoromethyl)-pyridinyl, cyclopentyloxy, phenoxy, trifluoromethoxy, (trifluoromethyl)-oxadiazolyl, chlorine, methoxy-pyridinyl.

[0165] In another embodiment, there is provided a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0166] R 1 is 1,3,4-oxadiazole, which is 10 replace;

[0167] R 2 For fluorine;

[0168] R 4 is phenyl;

[0169] R 10 Selected from methyl-methylsulfonyl-ethyl, pyrrolidine, oxa-azaspiro[2.5]octanyl, methyl-propionitrile, tetrafluoro-methoxy-ethyl;

[0170] R 11 Selected from (trifluoromethyl)-pyridinyl, phenoxy, trifluoromethoxy, (trifluoromethyl)-oxadiazolyl, methoxy-pyridinyl.

[0171] In another embodiment, there is provided a compound of formula (I) as described herein, wherein the compound is selected from:

[0172] 3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0173] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0174] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0175] (3S)-3-Amino-5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0176] (3R)-3-Amino-5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0177] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0178] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0179] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0180] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0181] (3S)-3-Amino-5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0182] (3R)-3-Amino-5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0183] (3S)-3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto;

[0184] (3R)-3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto;

[0185] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0186] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0187] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0188] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0189] (3S)-3-Amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1-benzazepine -2-Keto;

[0190] (3R)-3-Amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1-benzazepine -2-Keto;

[0191] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0192] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0193] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0194] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0195] (3S)-3-Amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0196] (3R)-3-Amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0197] (3S)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0198] (3R)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0199] (3S)-3-Amino-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0200] (3R)-3-Amino-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0201] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0202] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0203] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0204] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0205] (3S)-3-Amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto;

[0206] (3R)-3-Amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto;

[0207] 2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0208] 2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0209] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0210] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0211] (3S)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0212] (3R)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0213] (3S)-3-Amino-8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0214] (3R)-3-Amino-8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0215] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0216] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0217] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0218] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0219] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0220] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0221] 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0222] 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0223] 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0224] 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0225] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0226] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0227] 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0228] 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0229] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0230] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0231] 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0232] 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0233] (3S)-3-Amino-8-[5-[5,5-difluoro-1-(2-methoxyethyl)-3-piperidinyl]-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0234] (3R)-3-Amino-8-[5-[5,5-difluoro-1-(2-methoxyethyl)-3-piperidinyl]-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0235] 1-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester;

[0236] 1-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester;

[0237] 1-[5-[(3S)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester;

[0238] 1-[5-[(3R)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester;

[0239] 2-[5-[(3S)-3-amino-1-[[4-[5-(1,1-difluoroethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0240] 2-[5-[(3R)-3-amino-1-[[4-[5-(1,1-difluoroethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0241] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-(5-methoxy-2-pyridyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0242] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-(5-methoxy-2-pyridyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0243] (3S)-3-Amino-5,5,7-trifluoro-1-[[4-(5-methoxy-2-pyridyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1-benzazepine -2-Keto;

[0244] (3R)-3-Amino-5,5,7-trifluoro-1-[[4-(5-methoxy-2-pyridyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1-benzazepine -2-Keto;

[0245] 2-Methyl-2-[5-[(3S)-3-amino-1-[[4-[5-(difluoromethyl)-2-pyridinyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0246] 2-Methyl-2-[5-[(3R)-3-amino-1-[[4-[5-(difluoromethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0247] 2-Methyl-2-[5-[(3S)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridinyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0248] 2-Methyl-2-[5-[(3R)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridinyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0249] 1-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester;

[0250] 1-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester;

[0251] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0252] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0253] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[2-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0254] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[2-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0255] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0256] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0257] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0258] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0259] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[3-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0260] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[3-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0261] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[1-(trifluoromethyl)pyrazol-4-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; and

[0262] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[1-(trifluoromethyl)pyrazol-4-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0263] or a pharmaceutically acceptable salt thereof.

[0264] In a preferred embodiment, there is provided a compound of formula (I) as described herein, wherein the compound is selected from:

[0265] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0266] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0267] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0268] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0269] (3S)-3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto;

[0270] (3R)-3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto;

[0271] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0272] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0273] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0274] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0275] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0276] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0277] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0278] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0279] (3S)-3-Amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0280] (3R)-3-Amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0281] (3S)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0282] (3R)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0283] (3S)-3-Amino-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0284] (3R)-3-Amino-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0285] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0286] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0287] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0288] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0289] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0290] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0291] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0292] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0293] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0294] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0295] 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0296] 1-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester;

[0297] 1-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester;

[0298] 1-[5-[(3S)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester;

[0299] 1-[5-[(3R)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester;

[0300] 2-[5-[(3S)-3-amino-1-[[4-[5-(1,1-difluoroethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0301] 2-[5-[(3R)-3-amino-1-[[4-[5-(1,1-difluoroethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0302] 2-Methyl-2-[5-[(3S)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridinyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; and

[0303] 2-Methyl-2-[5-[(3R)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridinyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0304] or a pharmaceutically acceptable salt thereof.

[0305] In a more preferred embodiment, there is provided a compound of formula (I) as described herein, wherein the compound is selected from:

[0306] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0307] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0308] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0309] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0310] (3S)-3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto;

[0311] (3R)-3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto;

[0312] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0313] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0314] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0315] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0316] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0317] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0318] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0319] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0320] (3S)-3-Amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0321] (3R)-3-Amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0322] (3S)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0323] (3R)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0324] (3S)-3-Amino-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0325] (3R)-3-Amino-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0326] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0327] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0328] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0329] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile;

[0330] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0331] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto;

[0332] 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0333] 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0334] 1-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester;

[0335] 1-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester;

[0336] 1-[5-[(3S)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester;

[0337] 1-[5-[(3R)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylic acid methyl ester;

[0338] 2-[5-[(3S)-3-amino-1-[[4-[5-(1,1-difluoroethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0339] 2-[5-[(3R)-3-amino-1-[[4-[5-(1,1-difluoroethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile;

[0340] 2-Methyl-2-[5-[(3S)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridinyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; and

[0341] 2-Methyl-2-[5-[(3R)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridinyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile.

[0342] Manufacturing method

[0343] 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.

[0344] The present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, the method comprising reacting a compound of formula (XVIII),

[0345]

[0346] Where 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 said compound of formula (I).

[0347] The preparation of the compound of formula (I) of the present invention can be carried out according to sequential or concurrent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required for performing the reaction and purifying the resulting product are known to those skilled in the art. Unless otherwise indicated, the substituents and indices used in the following method descriptions have the meanings provided herein.

[0348] If one of the starting materials, intermediates or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups may be introduced before applying key steps of methods well known in the art (such as described in "Protective Groups in Organic Chemistry" by TW Greene and PGM Wutts, 5th edition, 2014, John Wiley & Sons, NY). Such protecting groups may be removed at a later stage of the synthesis using standard methods described in the literature.

[0349] If the starting material or intermediate contains a stereogenic center, the compound of formula (I) can be obtained in the form of a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art (e.g., chiral HPLC, chiral SFC or chiral crystallization). Racemic compounds can be separated into corresponding enantiomers, for example, by diastereomeric salts, which are crystallized with optically pure acids, or by specific chromatography separations of enantiomers using chiral adsorbents or chiral eluents. Starting materials and intermediates containing stereogenic centers can also be separated to provide starting materials and intermediates enriched in diastereomers / enantiomers. Using such diastereomer / enantiomer-enriched starting materials and intermediates in the synthesis of compounds of formula (I) will generally produce diastereomers / enantiomer-enriched compounds of the corresponding formula (I).

[0350] 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).

[0351] Those skilled in the art will recognize that the order of reactions may vary depending on the reactivity and nature of the intermediates.

[0352] In more detail, the compound of formula (I) can be manufactured by the method given below, by the method given in the examples or by similar methods. The appropriate reaction conditions for each reaction step are known to those skilled in the art. Similarly, the reaction conditions affecting the reaction reported in the relevant literature are described, for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999. It is convenient to react in the presence or absence of a solvent. There are no particular restrictions on the nature of the solvent used, as long as it has no adverse effect on the reaction or the reagents involved and can dissolve the reagents at least to a certain extent. The described reaction can occur over a wide temperature range, and the precise reaction temperature is not critical to the present invention. The above reaction can be conveniently performed in a temperature range of -78°C to reflux. The time required for the reaction can also vary over a wide range, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, it usually takes 0.5 hours to several days to obtain the intermediates and compounds. The reaction sequence is not limited to the one shown in the schemes, but, depending on the starting materials and their respective reactivity, the order of the reaction steps can be freely varied.

[0353] If starting materials or intermediates were not commercially available or their synthesis was not reported in the literature, they could be prepared by analogy to existing preparations of close analogs or as outlined in the experimental section.

[0354] Processes for the manufacture of compounds of formula (I) as described herein are also an object of the present invention.

[0355] The preparation of the compound of formula (I) of the present invention can be carried out according to sequential or convergent synthetic pathways. The synthesis of the present invention is shown in the following general scheme. Unless otherwise indicated, the substituents and labels used in the following description of the process have the meanings given herein before.

[0356] In more detail, formula (I) compound can be manufactured by the method given below, by the method given in the example or by a similar method. The appropriate reaction conditions of each reaction step are known to those skilled in the art. The reaction sequence is not limited to the reaction sequence shown in the scheme, however, depending on the starting material and its respective reactivity, the order of reactions steps can be freely changed. The starting material is commercially available, or can be prepared by a method similar to the method given below, by the method described in the reference cited in the specification or in the embodiment or by methods known in the art.

[0357] The compound of formula (I) of the present invention and its pharmaceutically acceptable salt can be prepared by the following method (Scheme 1).

[0358]

[0359]

[0360] Solution 1

[0361] Suitable starting materials for preparing compounds of formula (I) are aniline derivatives of formula (II). Compounds of formula (II) can be prepared by reacting AlCl 3 and BCl 3 The derivative (III) can be reacted with an aminomalonate derivative (IV) (wherein R n The compound of formula (V) can be reacted with aqueous HCl at elevated temperature to provide an amino acid derivative of formula (VI), which can then be N-protected by reaction with di-tert-butyl dicarbonate in the presence of a base such as TEA in a solvent mixture such as dioxane and water to obtain a compound of formula (VII). The derivative (VII) can be cyclized to a compound of formula (VIII) using T3P in the presence of a base such as DIPEA or TEA in a solvent such as DCM or THF. The introduction of a benzyl substituent to obtain a compound of formula (X) can be accomplished by reacting the derivative in the presence of a base such as K 2 CO 3 In the presence of a solvent such as DMF and a halide or sulfonate (X 1 Cl, Br, I or OSO 2R) reaction is completed. Optionally, potassium iodide can be added. The reaction of the compound of formula (X) with DAST will provide a derivative of formula (XI), which can be converted into a compound of formula (XII) by carbonylation using a catalyst such as Pd(OAc) 2 / dppp or Pd(dppp)Cl 2 In the presence of a base such as TEA or DIPEA, in a solvent mixture of DMF and an alcohol, at elevated temperature. Reaction of a compound of formula (XII) with an alkaline hydroxide such as LiOH in an aqueous solvent mixture such as THF and water will provide a compound of formula (XIII). Alternatively, an acid derivative (XIII) can be obtained from a compound of formula (XI) by a carbonylation reaction using a catalyst such as Pd(OAc) 2 / dppp or Pd(dppp)Cl 2 In the presence of a base such as TEA or DIPEA, in a solvent mixture of DMF and water, at elevated temperature. The conversion of the compound of formula (XIII) to the compound of formula (XIV) can be accomplished by activating the derivative (XIII) with a reagent such as T3P in the presence of DIPEA or oxalyl chloride in a solvent such as DCM in the presence of DIPEA and a catalytic amount of DMF followed by reaction with hydrazine. The compound of formula (XIV) is activated with a reagent such as HATU or T3P in the presence of a base such as DIPEA and then reacted with an acid derivative R 10 CO 2 H reaction will provide compounds of formula (XV). Alternatively, compounds of formula (XV) can be prepared by reacting a hydrazide derivative R in the presence of a base such as DIPEA in a solvent such as THF. 10 CONHNH 2 The compound of formula (XIII) can be obtained by reacting with a coupling agent such as HATU. The compound of formula (XVI) can be obtained by reacting with a dehydrating agent such as Burgess reagent in a solvent such as toluene or THF from the compound of formula (XV). The compound of formula (I) wherein R 1 is 1,3,4-oxadiazolyl, which can be obtained from compounds of formula (XVI) by reaction with HCl in EtOAc, TFA in DCM or HFIP.

[0362] Where R 1 Compounds of formula (I) which are 6-membered heteroaryl groups can be prepared as shown in Scheme 2.

[0363]

[0364] Solution 2

[0365] Compounds of formula (XI) are reacted in the presence of a palladium catalyst such as Pd(dppf)Cl 2-DCM and a base such as K 2 CO 3 Reaction with a boronic acid (R is H) or a boronate ester derivative (XVII) in the presence of an aqueous solvent mixture such as dioxane and water will provide a compound of formula (XVIII). The compound of formula (XVIII) can be converted to a compound of formula (I) wherein R 1 is a 6-membered heteroaryl group as described in Scheme 1 for the conversion of a compound of formula (XVI) to a compound of formula (I).

[0366] Pharmaceutical compositions and administration

[0367] Another object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0368] 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 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 intramuscularly or intravenously (for example, in the form of injections). Administration can also be implemented topically, for example, percutaneously, or in the form of eye drops or ear drops.

[0369] The compound of formula (I) and its pharmaceutically acceptable salt can be processed with a pharmaceutically inert inorganic or organic carrier to prepare a pharmaceutical preparation such as a tablet, a coated tablet, a dragee, a hard gelatin capsule, an injection or a topical preparation. For example, lactose, corn starch or its derivatives, talcum powder, stearic acid or its salts etc. can be used as such carriers for tablets, coated tablets, dragees and hard gelatin capsules.

[0370] Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. However, depending on the nature of the active substance, carriers are often not required in soft gelatin capsules.

[0371] Suitable carriers for the preparation of solutions and syrups are, for example, water, alcohols, polyols, sucrose, glucose, invert sugar, vegetable oils and the like.

[0372] Suitable carriers for injection solutions are, for example, water, alcohol, polyol, glycerol, vegetable oil and the like.

[0373] Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

[0374] Suitable liquids for topical ophthalmic formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.

[0375] 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.

[0376] Medicaments comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient are also an object of the present invention, as is a process for the production of such a medicament, which comprises bringing one or more compounds of formula (I) and / or a pharmaceutically acceptable salt thereof, if desired, and one or more other therapeutically valuable substances together with one or more pharmaceutically acceptable excipients into a galenical administration form.

[0377] Dosage is variable within a wide range, but will certainly have to be adjusted according to the individual needs of each particular case. Generally, in the case of oral administration, about 0.1mg to 20mg / kg body weight, preferably 0.5mg to 4mg / kg body weight (e.g., about 300mg / individual) should be appropriate for being divided into 1 to 3 independent doses (which can be composed of, for example, the same amount). In the case of topical administration, the preparation can contain 0.001% to 15% of the medicine by weight, and the desired dose can be between 0.1mg and 25mg, and can be applied by single dose every day or every week or by multiple doses every day (2 to 4 times) or by multiple doses every week. However, it is obvious that if the upper or lower limit given herein is indicated, the upper or lower limit can be exceeded.

[0378] The pharmaceutical composition according to the present invention can be prepared as follows.

[0379] Preparation of pharmaceutical compositions containing the compounds of the present invention Tablet preparation (wet granulation)

[0380]

[0381]

[0382] Manufacturing process:

[0383] 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

[0384] 2. Dry the granules at 50°C.

[0385] 3. Pass the particles through suitable grinding equipment.

[0386] 4. Add ingredient 5 and mix for three minutes; press on a suitable press.

[0387] Capsule formula

[0388]

[0389] Manufacturing process:

[0390] 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

[0391] 2. Add ingredients 4 and 5 and mix for 3 minutes.

[0392] 3. Fill into suitable capsules.

[0393] Injection

[0394]

[0395]

[0396] Manufacturing process:

[0397] 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.

[0398] Indications

[0399] The compounds of formula (I) may be used in an effective amount for treating a subject, particularly a human, affected by cancer.

[0400] 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.

[0401] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in treating, preventing and / or delaying progression of cancer.

[0402] In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for treating, preventing and / or delaying the progression of cancer.

[0403] In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for the preparation of a medicament for treating, preventing and / or delaying the progression of cancer.

[0404] In a further 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.

[0405] As used herein, the terms "treatment" or "treating" and grammatical variations thereof refer to therapeutic therapy. With respect to a particular condition, treatment means: (1) ameliorating the condition or one or more of the biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that causes or leads to the condition, or (b) one or more of the biological manifestations of the condition, (3) alleviating one or more of the symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more of the biological manifestations of the condition. Prophylactic therapy using the methods and / or compositions of the present invention is also contemplated. Those skilled in the art will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to significantly reduce the likelihood or severity of a condition or its biological manifestations or to delay the onset of such a condition or its biological manifestations. Prophylactic therapy is appropriate, for example, when a subject is considered to be at high risk for developing cancer, such as when the subject has a significant family history of cancer or when the subject has been exposed to a carcinogen.

[0406] As an immunotherapeutic agent that acts on immune cells rather than directly on cancer cells, the present disclosure is also envisioned to be used as an anti-cancer vaccine. Also included are methods in which immune cells are cultured and manipulated ex vivo and the molecules disclosed herein are used as a means of conferring co-stimulation to the ex vivo manipulated cells.

[0407] In one embodiment, the cancer is a non-hematologic cancer, such as a lymphoma, leukemia, or myeloma. Hematologic cancers contemplated herein include, but are not limited to, one or more leukemias, such as B-cell acute lymphocytic leukemia ("BALL"), T-cell acute lymphocytic leukemia ("TALL"), acute lymphocytic leukemia (ALL); one or more chronic leukemias, including, but not limited to, chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL); additional hematologic cancers or hematologic disorders, including, but not limited to, B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, Diffuse 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, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, and "preleukemia," a collection of various blood disorders consisting of ineffective production (or dysplasia) of blood cells in the bone marrow.

[0408] In a further embodiment, the cancer is a non-hematologic cancer, such as a sarcoma, carcinoma, or melanoma. Non-hematologic cancers contemplated herein include, but are not limited to, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell carcinoma, melanoma, gastric cancer, brain cancer, lung cancer (e.g., non-small cell lung cancer-NSCLC), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.

[0409] Compounds of formula (I) and other pharmaceutical agents are administered together

[0410] The compound of formula (I) or its salt, or the compound disclosed herein or its pharmaceutical salt, can be used alone or in combination with other agents for treatment. For example, the second agent of the drug combination formulation or dosing regimen may have an activity complementary to the compound of formula (I) so that they do not adversely affect each other. The compounds can be administered together or separately in a single pharmaceutical composition. In one embodiment, the compound or pharmaceutical salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancer.

[0411] The term "co-administration" refers to the simultaneous administration of a compound of formula (I) or a salt thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof with one or more other active pharmaceutical ingredients (including cytotoxic agents and radiotherapy) or administered separately and sequentially in any manner. If the administration is not simultaneous, the compounds should be administered at a time close to each other. In addition, it is irrelevant whether the compounds are administered in the same dosage form, for example, one compound may be administered topically and another compound may be administered orally.

[0412] Generally, any agent with anticancer activity may be co-administered. Examples of such agents can be found in Cancer Principles and Practice of Oncology (V.T. Devita and S. Heilman, eds.), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. Based on the specific characteristics of the drugs and diseases involved, one of ordinary skill in the art will be able to discern which combination of agents will be useful.

[0413] In one aspect, the present invention provides a pharmaceutical composition as described herein, further comprising an additional therapeutic agent.

[0414] In one embodiment, the additional therapeutic agent is a chemotherapeutic agent.

[0415] In one embodiment, the additional therapeutic agent is a cytotoxic agent.

[0416] In one embodiment, the additional therapeutic agent is an immuno-oncology agent.

[0417] 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.

[0418] 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.

[0419] "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, GlaxoSmith 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 neocarcinogen chromophores and related chromoprotein enediyne antibiotic chromophores, aclacinomysins, actinomycins, authramycins, azaserine, bleomycin, cactinomycin, carabicin, carminomicin, carzinophilin, chromomycin, dactinomycin, daunomycin, detopicin, 6-diazo-5-oxo-L-norleucine, (doxorubicin) (morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogamycin, olive mycins, peplomycin, potfiromycin, puromycin, quelamycin, rhodorubicin, streptomycin, streptozotocin, tuberculin, ubenimex, zorubicin, antimetabolites such as methotrexate and 5-fluorouracil (5 -FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiopurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calosterone, drostanolone propionate, cyclothiodine, melastane, testolactone; antiadrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid (frolinic acid) acid; aceglucuronide; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; colcemid; diaziquone; elfornithine; elliptonium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan Sugar; lonidainine; maytansinoids, such as maytansine and ansamitocin; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazine; procarbazine; polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizoran; germanium spiroamine; tenuazonic acid; triazoquinone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, baculocin A, and anguidine); urethane; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dibromodulanol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, for example, TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), (without Cremophor), albumin-engineered paclitaxel nanoparticle formulation (American Pharmaceutical Partners, Schaumberg, 111.), and (docetaxel, docetaxel; Sanofi-Aventis); chloranbucil; (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (Changchunorelbine); Novantrone; Teniposide; Edatrexed; Daunorubicin; Aminopterin; Capecitabine Ibandronate; CPT-II; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0420] Chemotherapeutic agents also include: (i) antihormonal agents that act to modulate or inhibit the effects of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including tamoxifen (including Tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and (toremifine citrate); (ii) aromatase inhibitors that inhibit aromatase, an enzyme that regulates estrogen production by the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, (Megestrol acetate), (exemestane; Pfizer), formestanie, fadrozole, (vorozole), (letrozole; Novartis) and (anastrozole; AstraZeneca); (iii) antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, triptorelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all trans-retinoic acid, fenretinide, and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, such as PKC-α, Ralf, and H-Ras; (vii) ribozymes, such as inhibitors of VEGF expression (e.g. ) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, such as and rIL-2; topoisomerase I inhibitors, e.g. rmRH; and (ix) any of the pharmaceutically acceptable salts, acids and derivatives of the foregoing.

[0421] 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.

[0422] 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, e.g., U.S. Pat. Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,3 32, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008 and 5,747,498, and the following PCT publications: WO98 / 14451, WO98 / 50038, WO99 / 09016 and WO99 / 24037. Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, Genentech / OSI Pharmaceuticals); PD 183805 (Cl 1033, 2-acrylamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer); ZD1839, gefitinib 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 (6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(l-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(l-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidine-6- [(4-( ... GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[(2-methylsulfonyl)ethyl]amino]methyl]-2-furyl]-4-quinazolinamine).

[0423] Chemotherapeutic agents also include "tyrosine kinase inhibitors", including the EGFR targeted drugs described in the previous paragraph; small molecule FIER2 tyrosine kinase inhibitors, such as TAK165 available from Takeda Pharmaceuticals; CP-724,714, an oral selective inhibitor of ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors, such as EKB-569 (available from Wyeth), which preferentially binds to EGFR but simultaneously inhibits cells overexpressing HER2 and EGFR; lapatinib (GSK572016; available from GlaxoSmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors, such as canertinib (CI-1033; Pharmacia); Raf-I inhibitors, such as ISIS-5132, an antisense agent that inhibits Raf-I signaling, available from ISIS Pharmaceuticals; non-HER targeted TK inhibitors, such as imatinib mesylate ( available from GlaxoSmithKline); multitargeted tyrosine kinase inhibitors such as sunitinib ( VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787 / ZK222584, available from Novartis / Schering AG); MAPK extracellular regulated kinase I inhibitor Cl-1040 (available from Pharmacia); quinazolines such as PD153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP59326, 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 (AstraZeneca); PTK-787 (Novartis / Schering AG); pan-HER inhibitors, such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis / Lilly); imatinib mesylate PKI 166 (Novartis); GW2016 (GlaxoSmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); seramatinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering); INC-ICl I (Imclone), rapamycin (sirolimus, ); or any of the following patent publications: U.S. Pat. No. 5,804,396, WO 1999 / 09016 (American Cyanamid), WO 1998 / 43960 (American Cyanamid), WO 1997 / 38983 (Warner Lambert), WO 1999 / 06378 (Warner Lambert), WO 1999 / 06396 (Warner Lambert), WO 1996 / 30347 (Pfizer, Inc), WO 1996 / 33978 (Zeneca), WO 1996 / 3397 (Zeneca), and WO 1996 / 33980 (Zeneca).

[0424] Chemotherapeutic agents also include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, live BCG, bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, alfa), erlotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium sodium), quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate and zoledronic acid and pharmaceutically acceptable salts thereof.

[0425] Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, thiocortisone pivalate, triamcinolone acetonide, triamcinolone acetonide alcohol, mometasone, amcinonide, budesonide, desonide, fluocinolone acetate, fluocinolone, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, and phenoxyethanol. dipropionate), betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, flucortolone hexanoate, flucortolone valerate, and fluprednidine acetate; immunoselective anti-inflammatory peptides (ImSAIDs), such as phenylalanine-glutamine-glycine (PEG) and its D-isomer form (feG) (IMULAN Biotherapeutics Ltd. BioTherapeutics, LLC); antirheumatic drugs such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, sulfasalazine; tumor necrosis factor alpha (TNFa) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi); interleukin I (IL-I) blockers such as anakinra (Kineret); T-cell costimulation blockers such as abatacept (Orencia); interleukin 6 (IL-6) blockers such as tocilizumab Interleukin 13 (IL-13) blockers, such as lebrikizumab; interferon alpha (IFN) blockers, such as lonavirin; β7 integrin blockers, such as rhuMAb β7; IgE pathway blockers, such as anti-M1 primers; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa I / β2 blockers, such as anti-lymphotoxin α (LTa); radioisotopes (e.g., At 211 ,I 131 ,I 125 , Y 90 、Re 186 、Re 188 、Sm 153 、Bi 212 , P 32 , Pb 212and radioisotopes of Lu); various experimental agents such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3 or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, picrophenol, epigallocatechin gallate, theaflavins, flavanols, proanthocyanidins, betulinic acid and its derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, ); β-lapachone; lapaol; colchicine; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur Bexarotene Bisphosphonates, such as clodronate (e.g. or ), etidronate NE-58095, Zoledronic Acid / Zoledronate Alendronate Pamidronate Tirodronate Risedronate and epidermal growth factor receptor (EGF-R); vaccines such as Vaccines; perifosine; COX-2 inhibitors (e.g., celecoxib or etoricoxib); proteosome inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitors such as oblimersen sodium Pixantrone; farnesyl transferase inhibitors such as lonafamib (SCH 6636, SARASAR TM ); and pharmaceutically acceptable salts, acids or derivatives of any of the above; and combinations of two or more of the above, such as CHOP (an abbreviation for the combination therapy of cyclophosphamide, doxorubicin, vincristine and prednisolone); and FOLFOX (oxaliplatin (ELOXATIN TM ) is an abbreviation for the combination therapy with 5-FU and folinate).

[0426] 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.

[0427] In one aspect, the immuno-oncology agent is either (i) an agonist of a stimulatory (including co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on T cells, both of which result in amplification of antigen-specific T cell responses (commonly referred to as immune checkpoint modulators).

[0428] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA) and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the family of TNF molecules that bind to cognate TNF receptor family members, which include CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTfiR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin alpha / TNP beta, TNFR2, TNF alpha, LTR, lymphotoxin alpha 1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0429] In one aspect, T cell responses can be stimulated by a combination of a compound of Formula (I) with one or more of: (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; and (ii) an agonist of a protein that stimulates T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0430] Other agents that can be combined with compounds of formula (I) for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, compounds of formula (I) can be combined with antagonists of KIR such as lirilumab.

[0431] Other agents for combination therapy include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists, such as CSF-1R antagonist antibodies (including RG7155 or FPA-008).

[0432] In another aspect, the compounds of formula (I) may be used with one or more of the following agents: agonists that bind to positive co-stimulatory receptors; blockers that attenuate signaling through inhibitory receptors; antagonists; and one or more agents that systemically increase the frequency of anti-tumor T cells; agents that overcome different immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor 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.

[0433] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonist CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. On the other hand, the immuno-oncology agent is a PD-1 antagonist, such as an antagonist PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab) or MEDI-0680 (AMP-514; WO2012 / 145493). Immuno-oncology agents may also include pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned. Another method of targeting the PD-1 receptor is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, which is called AMP-224.

[0434] 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).

[0435] 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).

[0436] 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).

[0437] 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).

[0438] 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).

[0439] 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).

[0440] 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 antagonist CD40 antibody. Suitable CD40 antibodies include, for example, Lucatumumab or Dacetuzumab.

[0441] In another aspect, the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, Varlilumab.

[0442] In another aspect, the immuno-oncology agent is MGA271 (to B7H3) (WO2011 / 109400).

[0443] Examples

[0444] 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.

[0445] 1) Preparation Example

[0446] 1.1) Intermediates

[0447] Intermediate 1

[0448] 2-Ethoxy-2,3,3,3-tetrafluoro-propionyl hydrazide

[0449]

[0450] To a solution of 2-ethoxy-2,3,3,3-tetrafluoropropionic acid [CAS10186-67-1] (200 mg, 0.92 mmol, 1 eq) in EtOH (1.5 ml) was added hydrazine monohydrate (54.25 mg, 1.1 mmol, 1.2 eq) and the mixture was heated to 80° C. for 8 h. The resulting colorless solution was concentrated under reduced pressure and dried under high vacuum to give the title compound (119 mg, 60%) as a white solid. MS (ESI): 205.1 [M+H] + .

[0451] Intermediate 2

[0452] 1-Ethyl-5,5-difluoro-piperidine-3-carboxylic acid

[0453] Step a) 1-ethyl-5,5-difluoro-piperidine-3-carboxylic acid methyl ester

[0454]

[0455] To a solution of 5,5-difluoropiperidine-3-carboxylic acid methyl ester; hydrochloride [CAS1359656-87-3] (370.0 mg, 1.72 mmol, 1.0 eq) and TEA (0.24 mL, 1.72 mmol, 1.0 eq) in MeOH (5 mL) was added acetaldehyde (0.14 mL, 2.57 mmol, 1.5 eq) at 25°C and the mixture was stirred for 1 h. Sodium cyanoborohydride (323.48 mg, 5.15 mmol, 3.0 eq) was added at 25°C, and the mixture was then stirred at 25°C for 2 h. The reaction mixture was concentrated in vacuo, and the remaining residue was purified by silica gel column chromatography (PE / EtOAc=1:0 to 5:1) to give the title compound (300.0 mg, 1.45 mmol, 84% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ=3.72(s,3H),3.19-3.15(m,1H),3.13-3.05(m,1H),2.95-2.84(m,1H),2.65-2.48(m,2H),2.47 -2.37(m,1H),2.31-2.18(m,1H),2.14(t,J=11.2Hz,1H),1.97-1.80(m,1H),1.11(t,J=7.2Hz,3H).

[0456] Step b) 1-ethyl-5,5-difluoro-piperidine-3-carboxylic acid

[0457]

[0458] To a solution of 1-ethyl-5,5-difluoro-piperidine-3-carboxylic acid methyl ester (340.0 mg, 1.64 mmol, 1.0 eq) in THF (10 mL) was added dropwise a solution of LiOH monohydrate (131.26 mg, 3.28 mmol, 2.0 eq) in water (2 mL), and the reaction mixture was stirred at 20° C. for 2 h. The mixture was poured into water (10 mL) and the pH was adjusted to 5 by adding HCl (1 M). The mixture was then lyophilized to give a white solid (300 mg) containing the title compound. 1 H NMR (400 MHz, D 2 O)δ=4.04-3.58(m,2H),3.57-2.96(m,5H),2.87-2.08(m,2H),1.35(t,J=7.2Hz,3H).

[0459] Intermediate 3

[0460] 2-[4-(Chloromethyl)phenyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0461]

[0462] Step a) [4-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]phenyl]methanol

[0463]

[0464] Under nitrogen atmosphere at 25°C, 4-(Hydroxymethyl)phenylboronic acid [CAS#59016-93-2] (1000.0 mg, 6.58 mmol, 1.0 eq), Pd(dppf)Cl 2 To a mixture of 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine [CAS#89402-29-9] (1926.66 mg, 7.9 mmol, 1.2 eq) (70.03 mg, 0.66 mmol, 0.1 eq) and potassium carbonate (2728.47 mg, 19.74 mmol, 3.0 eq) in a solvent mixture of water (3 mL) and 1,4-dioxane (24 mL) was added 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine [CAS#89402-29-9] (1926.66 mg, 7.9 mmol, 1.2 eq). The reaction mixture was stirred at 90 °C for 12 h. Water (50 mL) was then added and the mixture was extracted with EtOAc (100 mL x 3). The combined extracts were washed with brine (200 mL x 2), dried (Na 2 SO 4 ) and purified by centrifugation. 2 SO 4 ), and concentrated, and the remaining residue was purified by silica gel column chromatography (PE / EtOAc=1:0 to 3:1) to give the title compound (1650.0 mg, 6.08 mmol, 92% yield) as a yellow solid. MS (ESI): 272.1 [M+H] + .

[0465] Step b) 2-[4-(chloromethyl)phenyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0466]

[0467] To a solution of [4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]phenyl]methanol (1600.0 mg, 5.9 mmol, 1.0 eq) in DCM (10 mL) at 25°C was added thionyl chloride (1.39 mL, 19.11 mmol, 3.0 eq) and the mixture was stirred at 25°C for 1 h. Water (30 mL) was added and the mixture was extracted with EtOAc (50 mL x 3). The combined extracts were washed with brine (100 mL x 2), dried (Na 2 SO 4 ) and purified by HPLC. 2 SO 4) and concentrated to give the title compound (1600.0 mg) as a yellow solid. 1 HNMR (400 MHz, DMSO-d 6 )δ=8.96(s,1H),8.43(d,J=10.5Hz,1H),8.00–7.96(m,2H),7.63(d,J=8.3Hz,2H),4.85(s,2H).

[0468] Intermediate 4

[0469] 2-[4-(Bromomethyl)phenyl]-5-(trifluoromethyl)tetrazolyl

[0470]

[0471] A solution of 2-(p-tolyl)-5-(trifluoromethyl)tetrazole [CAS# 1817810-19-7] (300.0 mg, 1.31 mmol, 1.0 eq), N-bromosuccinimide (304.22 mg, 1.71 mmol, 1.3 eq) and AIBN (107.95 mg, 0.66 mmol, 0.5 eq) in chlorobenzene (10 mL) was stirred at 100° C. for 12 h. The mixture was concentrated and the remaining residue was purified by silica gel column chromatography (PE / EtOAc=1:0 to 50:1) to give the title compound (200.0 mg, 0.65 mmol, 50% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ=8.17(d,J=8.8Hz,2H),7.64(d,J=8.8Hz,2H),4.56(s,2H).

[0472] Intermediate 5

[0473] 1-[4-(Bromomethyl)phenyl]-3-(trifluoromethyl)-1,2,4-triazole

[0474]

[0475] The title compound was prepared similarly to Intermediate 4 from 1-(p-tolyl)-3-(trifluoromethyl)-1,2,4-triazole [CAS# 2850321-26-3] and obtained as a white solid. MS (ESI): 308.0 [M+H] + .

[0476] Intermediate 6

[0477] 2-[4-(Chloromethyl)phenyl]-4-(trifluoromethyl)pyridine; hydrochloride

[0478]

[0479] The title compound was prepared in analogy to Intermediate 3 step b from [4-[4-(trifluoromethyl)-2-pyridyl]phenyl]methanol [CAS#1185444-74-9] and obtained as a white solid. MS (ESI): 272.0 [M+H] + .

[0480] Intermediate 7

[0481] 2-[4-(Chloromethyl)phenyl]-5-(1,1-difluoroethyl)pyridine

[0482]

[0483] Step a) [4-[5-(1,1-difluoroethyl)-2-pyridyl]phenyl]methanol

[0484]

[0485] The title compound was prepared similarly to Intermediate 3 step a from 2-bromo-5-(1,1-difluoroethyl)pyridine [CAS#1211521-60-6] and 4-(hydroxymethyl)phenylboronic acid [CAS#59016-93-2] and obtained as a light yellow solid. MS (ESI): 250.3 [M+H] + .

[0486] Step b) 2-[4-(Chloromethyl)phenyl]-5-(1,1-difluoroethyl)pyridine

[0487]

[0488] The title compound was prepared in analogy to Intermediate 3, step b, from [4-[5-(1,1-difluoroethyl)-2-pyridyl]phenyl]methanol and obtained as a pale yellow solid. MS (ESI): 268.1 [M+H] + .

[0489] Intermediate 8

[0490] 2-[4-(Chloromethyl)phenyl]-5-(difluoromethyl)pyridine

[0491]

[0492] Step a) [4-[5-(difluoromethyl)-2-pyridyl]phenyl]methanol

[0493]

[0494] The title compound was prepared in analogy to Intermediate 3, step a, from 2-bromo-5-(difluoromethyl)pyridine [CAS#1221272-81-6] and 4-(hydroxymethyl)phenylboronic acid [CAS#59016-93-2] and obtained as a white solid. MS (ESI): 236.1 [M+H] + .

[0495] Step b) 2-[4-(chloromethyl)phenyl]-5-(difluoromethyl)pyridine

[0496]

[0497] The title compound was prepared in analogy to Intermediate 3, step b, from [4-[5-(difluoromethyl)-2-pyridyl]phenyl]methanol and obtained as a pale yellow solid. MS (ESI): 254.1 [M+H] + .

[0498] Intermediate 9

[0499] 2-[4-(Chloromethyl)phenyl]-5-(difluoromethoxy)pyridine

[0500]

[0501] Step a) [4-[5-(difluoromethoxy)-2-pyridyl]phenyl]methanol

[0502]

[0503] The title compound was prepared in analogy to Intermediate 3, step a, from 2-bromo-5-(difluoromethoxy)pyridine [CAS#845827-14-7] and 4-(hydroxymethyl)phenylboronic acid [CAS#59016-93-2] and obtained as a white solid. MS (ESI): 252.1 [M+H] + .

[0504] Step b) 2-[4-(chloromethyl)phenyl]-5-(difluoromethoxy)pyridine

[0505]

[0506] The title compound was prepared in analogy to Intermediate 3, step b, from [4-[5-(difluoromethoxy)-2-pyridyl]phenyl]methanol and obtained as a pale yellow solid. MS (ESI): 270.0 [M+H] + .

[0507] Intermediate 10

[0508] 1-[4-(Bromomethyl)phenyl]-4-(trifluoromethoxy)pyrazole

[0509]

[0510] Step a) O-[1-(p-Tolyl)pyrazol-4-yl]methylthiomethanethioate

[0511]

[0512] To a solution of 1-(p-tolyl)pyrazol-4-ol (2300.0 mg, 13.2 mmol, 1.0 eq) [CAS#77458-34-5] and 3-methylimidazol-3-ium-1-carboxylic acid dithiomethyl ester (3431.78 mg, 19.8 mmol, 1.5 eq) in MeCN (40 mL) at 25°C was added TEA (3.68 mL, 26.41 mmol, 2.0 eq) and the mixture was stirred at 25°C for 1 h. The reaction mixture was poured into water (40 mL) and the resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine (100 mL), dried (Na 2 SO 4 ) and purified by HPLC. 2 SO 4 ) and concentrated. The remaining residue was purified by silica gel column chromatography (PE / EtOAc=1:0 to 10:1) to give the title compound (2.7 g, 10.21 mmol, 76% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ=8.04(s,1H),7.69(s,1H),7.57(d,J=8.4Hz,2H),7.29(s,2H),2.71(s,3H),2.42(s,3H).

[0513] Step b) 3,5-dibromo-1-(p-tolyl)-4-(trifluoromethoxy)pyrazole and 5-bromo-1-(p-tolyl)-4-(trifluoromethoxy)pyrazole

[0514]

[0515] A solution of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (8652.12 mg, 30.26 mmol, 4.0 eq) and HF-pyridine (1165.27 mg, 7.57 mmol, 1.0 eq) in DCM (15 mL) was stirred at -70 °C for 0.5 h. O-[1-(p-tolyl)pyrazol-4-yl]methylthiomethanethioate (2.0 g, 7.57 mmol, 1.0 eq) in DCM (15 mL) was then added dropwise at -70 °C, and the mixture was warmed to 0 °C and stirred at 0 °C for 0.5 h. The mixture was poured into saturated NaHCO 3 (80mL) aqueous solution, and the resulting mixture is extracted with EtOAC (3x 60mL). The combined organic extracts are washed with brine (200mL), dried over anhydrous sodium sulfate, filtered and concentrated. The remaining residue is purified by silica gel column chromatography (PE / EtOAc=1:0 to 10:1) to obtain a mixture of 3,5-dibromo-1-(p-tolyl)-4-(trifluoromethoxy)pyrazole (1550.0mg, 3.88mmol, 51% yield) and 5-bromo-1-(p-tolyl)-4-(trifluoromethoxy)pyrazole (600.0mg, 1.87mmol, 25% yield) as a yellow solid. MS (ESI): 400.9[M+H] + and 323.0[M+H] + .

[0516] Step c) 1-(p-tolyl)-4-(trifluoromethoxy)pyrazole

[0517]

[0518] A solution of a mixture of 3,5-dibromo-1-(p-tolyl)-4-(trifluoromethoxy)pyrazole (1550.0 mg, 3.88 mmol, 1.0 eq) and 5-bromo-1-(p-tolyl)-4-(trifluoromethoxy)pyrazole (600.0 mg, 1.87 mmol, 0.48 eq) in MeOH (5 mL) was added to a suspension of Pd / C (500.0 mg, 18.69 mmol, 4.82 eq) in MeOH (5 mL) under a nitrogen atmosphere. The reaction mixture was degassed and filled with hydrogen three times, and the mixture was then stirred at 25 ° C under a hydrogen atmosphere for 1 h. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give the title compound (1360.0 mg, 5.62 mmol, 98% yield) as a yellow solid. MS (ESI): 243.3 [M+H] + .

[0519] Step d) 1-[4-(bromomethyl)phenyl]-4-(trifluoromethoxy)pyrazole

[0520]

[0521] The title compound was prepared in analogy to Intermediate 4 from 1-(p-tolyl)-4-(trifluoromethoxy)pyrazole and obtained as a yellow solid. MS (ESI): 323.0 [M+H] + .

[0522] Intermediate 11

[0523] 1-[4-(Chloromethyl)-3-fluoro-phenyl]-4-(trifluoromethyl)pyrazole

[0524]

[0525] Step a) Methyl 2-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]benzoate

[0526]

[0527] To a solution of methyl 4-bromo-2-fluorobenzoate [CAS#179232-29-2] (5.14 g, 22.05 mmol, 1.0 eq), 4-(trifluoromethyl)-1H-pyrazole [CAS#52222-73-8] (3.0 g, 22.05 mmol, 1.0 eq) and trans-N,N-dimethylcyclohexane-1,2-diamine (6.27 g, 44.09 mmol, 2.0 eq) in DMSO (50 mL) was added CuI (4.2 g, 22.05 mmol, 1.0 eq) at 25°C under a nitrogen atmosphere, and the mixture was stirred at 100°C for 3 h. The mixture was then filtered through celite and water (200 mL) was added to the filtrate. The mixture was extracted with EtOAc (150 mL×3), and the organic extract was washed with brine (300 mL), dried (Na 2 SO 4 ) and 4% CO 2 . 2 SO 4 ) and concentrated. The remaining residue was purified by silica gel column chromatography (PE / EtOAc=10:1) to give the title compound (4.4 g, 15.27 mmol, 69% yield) as a yellow solid. MS (ESI): 289.1 [M+H] + Step b) [2-Fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methanol

[0528]

[0529] To a solution of methyl 2-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]benzoate (3400.0 mg, 11.8 mmol, 1.0 eq) in THF (40 mL) was added diisobutylaluminum hydride (50.0 mL, 50.0 mmol, 4.24 eq) at 0°C, and the mixture was then warmed to 25°C and stirred for 12 h. The reaction mixture was poured into water (100 mL) and the resulting mixture was extracted with EtOAc (300 mL). The organic phase was washed with brine (100 mL), dried (Na 2 O) and purified by column chromatography (HPLC). 2 SO 4 ) and concentrated to give the title compound as a white solid (2500.0 mg, 9.61 mmol, 79% yield), which was used in the next step without further purification. MS (ESI): 261.1 [M+H] + .

[0530] Step c) 1-[4-(Chloromethyl)-3-fluoro-phenyl]-4-(trifluoromethyl)pyrazole

[0531]

[0532] The title compound was prepared in analogy to Intermediate 3, step b, from [2-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methanol and obtained as a brown oil. 1 H NMR (400 MHz, CDCl 3 )δ=8.00(s,1H),7.72(s,1H),7.38–7.27(m,3H),4.47(s,2H).

[0533] Intermediate 12

[0534] 3-(Chloromethyl)-2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]pyridine

[0535]

[0536] Step a) 2-Fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]pyridine-3-carboxylic acid methyl ester

[0537]

[0538] A mixture of 4-(trifluoromethyl)-1H-pyrazole (3.0 g, 22.05 mmol, 1.0 eq), potassium carbonate (9140.61 mg, 66.14 mmol, 3.0 eq) and methyl 2,6-difluoropyridine-3-carboxylate (4579.89 mg, 26.46 mmol, 1.2 eq) in DMSO (60 mL) was stirred at 20° C. for 8 h. The mixture was poured into water (300 mL) and the resulting mixture was extracted with EtOAc (500 mL). The organic extract was washed with brine (300 mL), dried (Na 2 O) and purified by HPLC. 2 SO 4 ) and concentrated. The remaining residue was purified by silica gel column chromatography (PE / EtOAc=20:1 to 5:1) to give a light yellow solid, which was further purified by reverse phase chromatography (water (containing formic acid) / MeCN=5:1 to 1:1) to give the title compound as a light yellow solid (2.1 g, 7.26 mmol, 32% yield). MS (ESI): 290.0 [M+H] + .

[0539] Step b) [2-Fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]methanol

[0540]

[0541] The title compound was prepared in analogy to Intermediate 11, step b, from methyl 2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]pyridine-3-carboxylate and obtained as a pale yellow solid. MS (ESI): 262.1 [M+H] + .

[0542] Step c) 3-(Chloromethyl)-2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]pyridine

[0543]

[0544] The title compound was prepared in analogy to Intermediate 3, step b, from [2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]methanol and obtained as a pale yellow solid. MS (ESI): 280.1 [M+H] + .

[0545] Intermediate 13

[0546] 5-(Chloromethyl)-2-[4-(trifluoromethyl)pyrazol-1-yl]pyridine

[0547]

[0548] Step a) 6-[4-(trifluoromethyl)pyrazol-1-yl]pyridine-3-carboxylic acid methyl ester

[0549]

[0550] To a mixture of 4-(trifluoromethyl)-1H-pyrazole (2.0 g, 14.7 mmol, 1.0 eq) and potassium carbonate (6.1 g, 44.1 mmol, 3.0 eq) in DMF (48 mL) at 25° C., a solution of methyl 6-chloronicotinate (2.27 g, 13.2 mmol, 0.9 eq) in DMF (24 mL) was added dropwise, and then the mixture was stirred at 100° C. for 12 h. Water (50 mL) was added and the mixture was extracted with EtOAc (30 mL×3). The organic extract was washed with brine (30 mL×5), dried (Na 2 O) and purified by HPLC. 2 SO 4 ) and concentrated. The remaining residue was purified by silica gel column chromatography (PE / EtOAc=1:0 to 10:1) to give the title compound (1650.0 mg, 6.08 mmol, 41% yield) as a white solid. MS (ESI): 272.2 [M+H] + .

[0551] Step b) 6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]methanol

[0552]

[0553] The title compound was prepared in analogy to Intermediate 11, step b, from methyl 6-[4-(trifluoromethyl)pyrazol-1-yl]pyridine-3-carboxylate and obtained as a yellow solid. MS (ESI): 244.3 [M+H] + Step c) 5-(Chloromethyl)-2-[4-(trifluoromethyl)pyrazol-1-yl]pyridine

[0554]

[0555] The title compound was prepared in analogy to Intermediate 3, step b, from 6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]methanol and obtained as a yellow oil. MS (ESI): 262.2 [M+H] + .

[0556] Intermediate 14

[0557] 1-[4-(Chloromethyl)-2-fluoro-phenyl]-4-(trifluoromethyl)pyrazole

[0558]

[0559] Step a) Methyl 3-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]benzoate

[0560]

[0561] A mixture of 4-(trifluoromethyl)-1H-pyrazole (200.0 mg, 1.47 mmol, 1.0 eq), potassium carbonate (609.37 mg, 4.41 mmol, 3.0 eq) and methyl 3,4-benzoate (379.48 mg, 2.2 mmol, 1.5 eq) in DMF (10 mL) was stirred at 100 °C for 8 h. The reaction mixture was poured into water (30 mL) and the resulting mixture was extracted with EtOAc (50 mL). The organic phase was washed with brine (50 mL), dried (Na 2 O) and purified by HPLC. 2 SO 4 ) and concentrated. The remaining residue was purified by silica gel column chromatography (PE / EtOAc=1:0 to 5:1) to give the title compound (400.0 mg, 1.39 mmol, 80% yield) as a light yellow solid. MS (ESI): 289.0 [M+H] + .

[0562] Step b) [3-Fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methanol

[0563]

[0564] The title compound was prepared in analogy to Intermediate 11, step b, from methyl 3-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]benzoate and obtained as a white solid. MS (ESI): 261.0 [M+H] + Step c) 1-[4-(Chloromethyl)-2-fluoro-phenyl]-4-(trifluoromethyl)pyrazole

[0565]

[0566] The title compound was prepared in analogy to Intermediate 3, step b, from [3-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methanol and obtained as a pale yellow solid. MS (ESI): 279.0 [M+H] + .

[0567] Intermediate 15

[0568] 4-[4-(Chloromethyl)phenyl]-1-(trifluoromethyl)pyrazole

[0569]

[0570] Step a) [4-[1-(trifluoromethyl)pyrazol-4-yl]phenyl]methanol

[0571]

[0572] A mixture of potassium carbonate (2571.19 mg, 18.6 mmol, 2.5 eq), 4-bromobenzyl alcohol [CAS#873-75-6] (1391.8 mg, 7.44 mmol, 1.0 eq), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)pyrazole [CAS#1046831-98-4] (1950.0 mg, 7.44 mmol, 1.0 eq), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (607.24 mg, 0.74 mmol, 0.1 eq) in a mixture of water (1 mL) and 1,4-dioxane (8 mL) was stirred at 90° C. under a nitrogen atmosphere for 3 h. The reaction mixture was concentrated in vacuo, and the remaining residue was purified by silica gel column chromatography to give the title compound as a yellow oil (1620.0 mg, 6.69 mmol, 90% yield). MS (ESI): 243.1 [M+H] + .

[0573] Step b) 4-[4-(chloromethyl)phenyl]-1-(trifluoromethyl)pyrazole

[0574]

[0575] To a solution of [4-[1-(trifluoromethyl)pyrazol-4-yl]phenyl]methanol (1600.0 mg, 6.61 mmol, 1.0 eq) in DCM (10 mL) at 20°C was slowly added thionyl chloride (1.4 mL, 19.82 mmol, 3.0 eq) and the solution was stirred at 20°C for 1 h. The reaction mixture was concentrated in vacuo to give the crude title compound (1710.0 mg, 6.56 mmol, 99% yield) as a yellow solid which was used without further purification. MS (ESI): 261.1 [M+H] + .

[0576] Intermediate 16

[0577] 5,5-Difluoro-1-(2-methoxyethyl)piperidine-3-carboxylic acid

[0578]

[0579] Step a) 5.5-Difluoro-1-(2-methoxyethyl)piperidine-3-carboxylic acid methyl ester

[0580]

[0581] To a mixture of 5,5-difluoropiperidine-3-carboxylic acid methyl ester hydrochloride (1100.0 mg, 5.1 mmol, 1.0 eq), 2-bromoethyl methyl ether (1.44 mL, 15.3 mmol, 3.0 eq), potassium carbonate (2115.1 mg, 15.3 mmol, 3.0 eq) in MeCN (20 mL) was added potassium iodide (0.14 mL, 2.55 mmol, 0.5 eq) at 20°C, and the mixture was stirred at 80°C for 12 h. The reaction mixture was poured into water (50 mL), and the resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with brine (100 mL), dried (Na 2 SO 4 ) and purified by HPLC. 2 SO 4 ) and concentrated in vacuo. The remaining residue was purified by silica gel column chromatography (PE / EtOAc=100:1 to 5:1) to give the title compound (1200.0 mg, 5.06 mmol, 99% yield) as a yellow oil. 1 HNMR (400MHz, CDCl 3 )δ=3.71(s,3H),3.55-3.49(m,2H),3.35(s,3H),3.22-3.09(m,2H),2.95-2.86(m ,1H),2.82-2.65(m,2H),2.48-2.35(m,2H),2.34-2.27(m,1H),1.97-1.80(m,1H).

[0582] Step b) 5.5-Difluoro-1-(2-methoxyethyl)piperidine-3-carboxylic acid

[0583]

[0584] To a solution of methyl 5,5-difluoro-1-(2-methoxyethyl)piperidine-3-carboxylate (500.0 mg, 2.11 mmol, 1.0 eq) in THF (10 mL) was added LiOH—H 2 A solution of 1,4-dihydro-2-nitropropene (2,4-dihydro-1,4-dihydro-2-nitropropene) (168.61 mg, 4.22 mmol, 2.0 eq) in water (2 mL) was added and the reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was poured into water (10 mL) and the pH of the mixture was adjusted to 5 by adding HCl (1 M). The mixture was lyophilized to give the title compound (450.0 mg) as a white solid (containing LiCl). 1 HNMR (400 MHz, DMSO-d 6)δ=3.87-3.71(m,4H),3.55-3.47(m,1H),3.38-3.34(m,2H),3.25(s,3H),3.17-3.15(m,1H),2.43-2.41(m,2H),2.29-2.08(m,1H).

[0585] 1.2) Synthesis of Examples

[0586] Example 1

[0587] 3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0588]

[0589] Step a) 1-(2-amino-4-bromo-5-fluoro-phenyl)-2-chloro-ethanone

[0590]

[0591] Chloroacetonitrile (4.6 mL, 72.63 mmol, 1.38 eq) was added dropwise to the AlCl 3 (8.84 g, 66.31 mmol, 1.26 eq) and BCl 3 (1M in DCM, 61.05mL, 61.05mmol, 1.16eq) in a mixture of toluene (200mL), and the mixture was stirred at 0°C under a nitrogen atmosphere for 0.5h. 3-bromo-4-fluoroaniline (6.33mL, 52.63mmol, 1eq) was added and the reaction mixture was stirred at 20°C for 0.5h, and then heated to 70°C for 16h. HCl (100mL) was then added at 50°C over a period of 30min. The mixture was cooled to room temperature and extracted with DCM (2x 30mL). The combined organic extracts were purified by Na 2 SO 4 Drying and removal of the solvent under reduced pressure gave a residue which was purified by preparative HPLC. The title compound was obtained as a brown solid (3.3 g, 12.38 mmol, 23% yield).

[0592] 1 H NMR (400MHz, DMSO-d6)δ=7.76-7.68(m,1H),7.34-7.20(m,2H),7.18-7.14(m,1H),5.07-4.99(m,2H)

[0593] Step b) 2-Acetylamino-2-[2-(2-amino-4-bromo-5-fluoro-phenyl)-2-oxo-ethyl]malonic acid diethyl ester

[0594]

[0595] Sodium ethoxide (21 wt.% in ethanol, 1.09 mL, 13.9 mmol, 1.61 eq) was added to a solution of diethyl 2-acetamidomalonate (1.87 g, 8.63 mmol, 1 eq) in ethanol (20 mL) at 20° C., and the mixture was stirred for 0.5 h. A solution of sodium iodide (0.26 g, 1.72 mmol, 0.200 eq) and 1-(2-amino-4-bromo-5-fluoro-phenyl)-2-chloro-ethanone (2.3 g, 8.63 mmol, 1 eq) in THF (10 mL) was added, and the resulting mixture was stirred at 50° C. for 16 h.

[0596] The reaction mixture was added to ice / water (15 mL), and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a crude product which was purified by silica gel column chromatography (5% to 40% EtOAc in PE) to give the title compound (2.5 g, 5.59 mmol, 60% yield) as a brown oil. MS (ESI): 447.0 [M+H] + .

[0597] Step c) 2-amino-4-(2-amino-4-bromo-5-fluoro-phenyl)-4-oxo-butyric acid

[0598]

[0599] A solution of 2-acetylamino-2-[2-(2-amino-4-bromo-5-fluoro-phenyl)-2-oxo-ethyl] diethyl malonate (1.95 g, 4.36 mmol, 1 eq) in hydrochloric acid (0.218 M, 20.0 mL, 4.36 mmol, 1 eq) was stirred at 110 ° C for 16 h. The mixture was concentrated under vacuum to obtain a brown solid (1.33 g), which was dissolved in water. The pH of the aqueous solution was then adjusted to 7 with NaOH (2 M), and the aqueous solution was used as is in the next reaction step.

[0600] Step d) 4-(2-amino-4-bromo-5-fluoro-phenyl)-2-(tert-butoxycarbonylamino)-4-oxo-butanoic acid

[0601]

[0602] To a solution of 2-amino-4-(2-amino-4-bromo-5-fluoro-phenyl)-4-oxo-butyric acid (1.33 g, 4.36 mmol, 1 eq) and di-tert-butyl dicarbonate (1.14 g, 5.23 mmol, 1.2 eq) in a solvent mixture of dioxane (15 mL) and water (10 mL) was added TEA (1.21 mL, 8.72 mmol, 2 eq) and the mixture was stirred at 25°C for 16 h. Ice water (10 mL) and EtOAc (20 mL) were added and the pH of the solution was adjusted to about 4 with 2N HCl. The organic phase was separated, washed with brine, and purified by Na 2 SO 4 Dry and evaporate in vacuo. The remaining residue is purified by silica gel column chromatography (20% to 40% EtOAc (containing 0.1% AcOH) in PE) to give the title compound as a brown oil (1.2 g, 2.96 mmol, 56% yield). MS (ESI): 351.0 [M-isobutylene + H] + .

[0603] Step e) N-(8-bromo-7-fluoro-2,5-dioxo-3,4-dihydro-1H-1-benzazepine -3-yl)carbamic acid tert-butyl ester

[0604]

[0605] To a solution of 4-(2-amino-4-bromo-5-fluoro-phenyl)-2-(tert-butoxycarbonylamino)-4-oxo-butanoic acid (1.0 g, 2.47 mmol, 1 eq) and DIPEA (1.29 mL, 7.4 mmol, 3 eq) in DCM (20 mL) was added T3P (2.36 g, 3.7 mmol, 1.5 eq) and the reaction mixture was stirred at 20 °C for 16 h. Water (30 mL) was added and the mixture was extracted with EtOAc (10 mL x 2). The organic extract was washed with brine (10 mL x 3) and purified by Na 2 SO 4 Dry and concentrate under vacuum to provide the title compound as a yellow solid (870 mg, 2.25 mmol, 91% yield). MS (ESI): 330.7 [M-isobutylene + H] + .

[0606] Step f) N-[8-bromo-7-fluoro-2,5-dioxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0607]

[0608] At 0°C, N-(8-bromo-7-fluoro-2,5-dioxo-3,4-dihydro-1H-1-benzazepine To a solution of tert-butyl 2-(3-yl)carbamate (900.0 mg, 2.32 mmol, 1 eq) in DMF (30 mL) was added K 2 CO 3 (706.76 mg, 5.11 mmol, 2.2 eq) and 4-(trifluoromethoxy)benzyl bromide (0.37 mL, 2.32 mmol, 1 eq), and the reaction mixture was stirred at 25 °C for 16 h. Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL x 3). The combined extracts were washed with Na 2 SO 4 Dry and concentrate to obtain a liquid, which is purified by silica gel column chromatography (4% to 80% EtOAc in PE) to give the title compound as a yellow oil (1.07 g, 1.91 mmol, 63% yield). MS (ESI): 504.9 [M-isobutylene + H] + .

[0609] Step g) N-[8-bromo-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0610]

[0611] To N-[8-bromo-7-fluoro-2,5-dioxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine at 0°C to 10°C under nitrogen atmosphere DAST (20.0 mL) was added dropwise to tert-butyl]-3-yl]carbamate (2.0 g, 2.85 mmol, 1 eq), and the mixture was stirred at 25 °C for 12 h. MeOH (60 mL) was then added dropwise and the mixture was concentrated. The crude material was dissolved in EtOAc (30 mL), and water (20 mL) was added. The residue was purified by adding NaHCO 3 , the pH of the mixture was adjusted to 8. The phases were separated and the organic phase was washed with brine (100 mL), dried (Na 2 SO 4 ) and concentrated in vacuo. The remaining residue was purified by silica gel column chromatography (MeCN / water (containing formic acid) = 1:5 to 4:1) to obtain the title compound (0.8 g, 1.37 mmol, 48% yield) as a light yellow solid. MS (ESI): 528.9 [M-isobutylene + H] + .

[0612] Step h) 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-Ethyl formate

[0613]

[0614] To N-[8-bromo-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine To a mixture of tert-butyl]-3-yl]carbamate (480.0 mg, 0.820 mmol, 1 eq), 1,3-bis-(diphenylphosphino)propane (67.88 mg, 0.160 mmol, 0.200 eq), and palladium diacetate (18.47 mg, 0.080 mmol, 0.100 eq) in a solvent mixture of ethanol (6 mL) and DMF (12 mL) was added TEA (0.34 mL, 2.47 mmol, 3 eq). The mixture was then degassed with nitrogen three times, and then filled with CO (230.41 mg, 8.23 ​​mmol, 10 eq) three times, and then stirred at 80° C. under CO (45 psi) for 16 h. Water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL x 3). The combined extracts were purified by Na 2 SO 4 Dry, filter and concentrate under vacuum. The remaining residue is purified by silica gel column chromatography (4% to 80% EtOAc in PE) to give the title compound as a yellow oil (437 mg, 0.760 mmol, 87% yield). MS (ESI): 521.0 [M-isobutylene + H] + .

[0615] Step i) 3-(tert-Butyloxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-Formic acid

[0616]

[0617] At 0°C, 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine was added. To a solution of ethyl 8-formate (890.0 mg, 1.54 mmol, 1 eq) in a solvent mixture of THF (8 mL) and water (8 mL) was added LiOH (147.9 mg, 6.18 mmol, 4 eq), and the reaction mixture was stirred at 20° C. for 4 h. The pH of the mixture was then adjusted to 3 to 4 by adding 1N HCl. The mixture was extracted with EtOAc (10 mL x 3), and the extract was purified by Na 2 SO 4 Dry and concentrate under vacuum to give the title compound as a yellow foam (790 mg, 1.44 mmol, 84% yield). MS (ESI): 493.0 [M-isobutylene + H] + .

[0618] Step j) N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0619]

[0620] 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine To a solution of -8-carboxylic acid (430.0 mg, 0.780 mmol, 1 eq) and T3P (748.41 mg, 1.18 mmol, 1.5 eq) in DCM (10 mL) was added DIPEA (0.41 mL, 2.35 mmol, 3 eq) and hydrazine monohydrate (0.16 mL, 3.14 mmol, 4 eq) and the reaction mixture was stirred at 20 ° C for 16 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (5 mL x 3). The combined extracts were washed with brine (5 mL x 3) and purified by Na 2 SO 4 Dry, filter and concentrate under vacuum, and the remaining residue is purified by silica gel column chromatography (4% to 40% EtOAc in PE) to give the title compound as a yellow oil (220 mg, 0.390 mmol, 49% yield). MS (ESI): 507.0 [M-isobutylene + H] + .

[0621] Step k) N-[8-[(2,2-dimethylpropionylamino)carbamoyl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0622]

[0623] At 25°C, N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine was added. To a solution of tert-butyl]-3-yl]carbamate (70.0 mg, 0.120 mmol, 1 eq) in THF (60 mL) was added DIPEA (0.07 mL, 0.370 mmol, 3 eq), HATU (56.79 mg, 0.150 mmol, 1.2 eq) and pivalic acid (13.98 mg, 0.140 mmol, 1.1 eq) and the mixture was stirred at 25 ° C for 4 h. The reaction mixture was concentrated under vacuum to remove THF. EtOAc (20 mL) was then added, and the mixture was washed with water (10 mL) and brine (10 mL x 3), and the mixture was dried over anhydrous Na 2 SO 4 Dry and concentrate under vacuum to obtain the crude product. The crude product was purified by preparative TLC (PE / EA=1:2) to obtain the title compound as a yellow oil (45 mg, 0.070 mmol, 39% yield). MS (ESI): 591.0 [M-isobutylene + H] + .

[0624] Step 1) N-[8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0625]

[0626] At 25°C, N-[8-[(2,2-dimethylpropionylamino)carbamoyl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine was added. To a solution of tert-butyl]-3-yl]carbamate (30.0 mg, 0.050 mmol, 1 eq) in toluene (40 mL) was added Burgess reagent (44.23 mg, 0.190 mmol, 4 eq) and the reaction mixture was heated to 100 °C for 16 h. Water (10 mL) was then added and the mixture was extracted with EtOAc (10 mL x 3). The combined extracts were washed with brine (10 mL x 3), purified by Na 2 SO 4Dry and concentrate in vacuo to give the title compound as a yellow oil (30 mg, 0.050 mmol, 84% yield). MS (ESI): 573.0 [M-isobutylene + H] + .

[0627] Step m) 3-amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0628]

[0629] N-[8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl]-3-yl]carbamate (30.0 mg, 0.05 mmol, 1.0 eq) in HCl / EtOAc (4 M, 2.0 mL, 8.0 mmol, 167.62 eq) was stirred at 20 °C for 2 h. The mixture was concentrated in vacuo and the remaining residue was purified by preparative HPLC to afford the title compound as a yellow oil (12.4 mg, 0.020 mmol, 47% yield). MS (ESI): 529.5 [M+H] + .

[0630] Example 2

[0631] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[0632] and

[0633] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[0634]

[0635] Step a) N-[8-[[(2-cyano-2-methyl-propionyl)amino]carbamoyl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0636]

[0637] To a solution of 2-cyano-2,2-dimethylacetic acid (0.05 mL, 0.51 mmol, 1.7 eq) in THF (1 mL) was added DIPEA (0.13 mL, 0.91 mmol, 3.0 eq) and T3P (345.46 mg, 0.45 mmol, 1.5 eq) and the mixture was stirred at 15° C. for 15 min. Then N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine was added at 15° C. -3-yl]carbamic acid tert-butyl ester (Example 1, step j) (170.0 mg, 0.3 mmol, 1.0 eq) was added and the reaction mixture was stirred at 20° C. for 16 h. The reaction mixture was concentrated under vacuum to remove THF, then it was diluted with EtOAc (20 mL) and washed with H 2 O (10 mL), brine (10 mL x 3) and washed with anhydrous Na 2 SO 4 Dry. The organic layer was concentrated under vacuum to obtain a yellow oil containing the title compound (310.0 mg), which was used in the next reaction step without further purification. MS (ESI): 602.1 [M-isobutylene + H] + .

[0638] Step b) N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0639]

[0640] Similarly to Example 1, step 1, N-[8-[[(2-cyano-2-methyl-propionyl)amino]carbamoyl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate (310.0 mg, 0.47 mmol) was used to prepare the title compound and obtained as a yellow oil (120.0 mg, 0.19 mmol, 36% yield). MS (ESI): 584.1 [M-isobutylene + H] + .

[0641] Step c) 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile and 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[0642]

[0643] N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl]carbamate (60.0 mg, 0.09 mmol, 1.0 eq) in HCl / EtOAc (4 M, 4.0 mL, 16.0 mmol, 170.55 eq) was stirred at 20° C. for 0.5 h. The mixture was concentrated under vacuum and the remaining residue was purified by preparative HPLC (neutral) to obtain pure 2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine This was subjected to chiral SFC to afford 2-methyl-2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile [isomer B] (8.1 mg, 0.02 mmol, 16% yield) (MS (ESI): 540.1 [M+H] + , retention time 1.40 min (see conditions below)) and white powdery 2-methyl-2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile [isomer A] (8.5 mg, 0.02 mmol, 17% yield). MS (ESI): 540.1 [M+H] + ; Retention time 1.05 minutes (column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: MeOH (0.05% DEA) in CO 2 , 5% to 40%; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar).

[0644] Example 3

[0645] (3S)-3-Amino-5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0646] and

[0647] (3R)-3-Amino-5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0648]

[0649] Step a) N-[5,5,7-trifluoro-8-[(morpholine-4-carbonylamino)carbamoyl]-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0650]

[0651] At 25°C, N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine was added. To a solution of tert-butyl]carbamate (Example 1, step j) (100.0 mg, 0.18 mmol, 1.0 eq) in DCM (1 mL) was added pyridine (0.5 mL, 6.18 mmol, 34.77 eq) and morpholine-4-carbonyl chloride (0.06 mL, 0.51 mmol, 2.89 eq), and the mixture was stirred at 30 ° C for 16 h. The mixture was diluted with EtOAc (10 mL), washed with 1N HCl (3 x 8 mL), and then concentrated under vacuum to obtain the title compound (130.0 mg, 0.19 mmol, 94% yield) as a yellow oil, which was used in the next reaction step without further purification. MS (ESI): 620.1 [M-isobutylene + H] + .

[0652] Step b) N-[5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0653]

[0654] Similarly to Example 1, step 1, N-[5,5,7-trifluoro-8-[(morpholine-4-carbonylamino)carbamoyl]-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine was used. -3-yl]carbamic acid tert-butyl ester (280.0 mg, 0.41 mmol) was used to prepare the title compound and obtained as a yellow oil (120.0 mg, 0.18 mmol, 44% yield). MS (ESI): 658.1 [M+H] + Step c) (3S)-3-amino-5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0655]

[0656] N-[5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl 3-amino-5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine (120.0 mg, 0.18 mmol, 1.0 eq) in HCl / EtOAc (4 M, 6.0 mL, 24.0 mmol, 131.51 eq) was stirred at 20° C. for 1 h. The mixture was concentrated under vacuum and the remaining residue was purified by preparative HPLC (neutral) to obtain pure 3-amino-5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine This was subjected to chiral SFC to afford (3-amino-5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto [Isomer B] (16.7 mg, 0.03 mmol, 16% yield) (MS (ESI): 558.1 [M+H] + , retention time 1.53 min (see conditions below)) and white powder (3-amino-5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto [Isomer A] (19.5 mg, 0.03 mmol, 19% yield). MS (ESI): 540.1 [M+H] + ; Retention time 1.86 minutes (column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: MeOH (0.05% DEA) in CO 2 , 5% to 40%; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar).

[0657] Example 4

[0658] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0659] and

[0660] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0661]

[0662] Step a) (3S)-3-(tert-Butyloxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-carboxylic acid and (3R)-3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-Formic acid

[0663]

[0664] To N-[8-bromo-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine To a mixture of tert-butyl 1-3-yl]carbamate (Example 1, Step 1) (490.0 mg, 0.84 mmol, 1.0 eq), 1,3-bis-(diphenylphosphino)propane (69.29 mg, 0.17 mmol, 0.2 eq), palladium diacetate (18.86 mg, 0.08 mmol, 0.1 eq) in a mixture of DMF (10 mL) and water (2 mL) was added TEA (0.35 mL, 2.52 mmol, 3.0 eq), and the mixture was then degassed with nitrogen three times, then filled with CO three times, and then the mixture was stirred at 80° C. under CO (45 psi) for 16 h. The mixture was diluted with 1N HCl (10 mL) and extracted with EtOAc (3× 15 mL). The organic extract was purified by Na 2 SO 4 The reaction mixture was dried and concentrated under vacuum, and the remaining residue was purified by preparative HPLC (HCl) to obtain pure 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine Chiral SFC was performed to obtain (3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine as a yellow powder. -8-carboxylic acid [isomer B] (67.1 mg, 0.12 mmol, 15% yield) (MS (ESI): 492.9 [M-isobutylene + H] + , retention time 1.47 minutes (see the following conditions)) and white powder (3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-Carboxylic acid [isomer A] (63.7 mg, 0.12 mmol, 14% yield). MS (ESI): 492.9 [M-isobutylene + H] + , retention time 1.19 minutes (column: Chiralpak IG-350×4.6mm ID, 3μm; mobile phase: phase A is CO 2 , and phase B was IPA (0.05% DEA); gradient elution: IPA (0.05% DEA), at CO 2 , 5% to 40%; flow rate: 3 mL / min; detector: DAD; column temperature: 35°C; back pressure: 100 bar).

[0665] Step b) N-[(3S)-5,5,7-trifluoro-2-oxo-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-5,5,7-trifluoro-2-oxo-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0666]

[0667] (3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-keto-1-[4-(trifluoromethoxy)benzyl]-3,4-dihydro-1-benzazepine A mixture of -8-carboxylic acid [isomer A] (63 mg, 0.114 mmol, 1 eq), 2,3,3,3-tetrafluoro-2-methoxy-propionyl hydrazide (intermediate 1) (29.03 mg, 0.148 mmol, 1.3 eq) and DIPEA (29.45 mg, 39.01 uL, 0.228 mmol, 2 eq) in THF (0.940 mL) was stirred at room temperature. HATU (64.99 mg, 0.171 mmol, 1.5 eq) was added and stirring was continued for 40 minutes. The solution was concentrated to give a light yellow foam, which was dissolved in THF (0.940 mL), and Burgess reagent (135.78 mg, 0.570 mmol, 5 eq) was added once, and the mixture was stirred for 1 hour. The mixture was diluted with EtOAc and water and extracted with EtOAc. The combined organic phases were purified by Na 2 SO 4 The mixture was dried, filtered and concentrated, and the remaining residue was purified by silica gel column chromatography (0% to 30% EtOAc in heptane) to give N-[5,5,7-trifluoro-2-oxo-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine as a colorless solid. -3-yl] tert-butyl carbamate [isomer A] (54 mg, 68%). MS (ESI): 647.3 [M-isobutylene + H] + N-[5,5,7-trifluoro-2-oxo-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester [isomer B] is similarly prepared from (3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-carboxylic acid [isomer B] was obtained. MS (ESI): 647.1 [M-isobutylene + H] + .

[0668] Step c) (3S)-3-amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0669]

[0670] N-[5,5,7-trifluoro-2-keto-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[4-(trifluoromethoxy)benzyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester [isomer A] (50 mg, 0.071 mmol, 1 eq) and HCl (2 M in Et 2 DCM) (53.38uL, 0.107mmol, 1.5eq) was stirred in 1,1,1,3,3,3-hexafluoro-2-propanol (3.56mL) at room temperature for 2h. The reaction mixture was concentrated in vacuo. The solid was suspended in DCM and concentrated again. The process was repeated three times to give the title compound (45mg, 97%) as an off-white solid hydrochloride salt after drying in high vacuum. MS (ESI): 603.2[M+H] + 3-Amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one [isomer B] was similarly prepared from 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-Carboxylic acid [isomer B] was obtained as an off-white solid. MS (ESI): 603.2 [M+H] + .

[0671] Example 5

[0672] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0673] and

[0674] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0675]

[0676] Step a) N-[8-bromo-7-fluoro-2,5-dioxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0677]

[0678] Similar to Example 1, step f, N-(8-bromo-7-fluoro-2,5-dioxo-3,4-dihydro-1H-1-benzazepine The title compound was prepared from tert-butyl 1-(3-yl)carbamate (1000.0 mg, 2.58 mmol) and 1-(chloromethyl)-4-phenoxy-benzene (700.0 mg, 3.2 mmol, 1.24 eq) and obtained as a light yellow oil containing the title compound (1.6 g). .MS (ESI): 513.0 [M-isobutylene + H] + .

[0679] Step b) N-[8-bromo-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0680]

[0681] At 0°C to 10°C under a nitrogen atmosphere, add N-[8-bromo-7-fluoro-2,5-dioxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (100.0 mg, 0.18 mmol, 1.0 eq) was added DAST (5.0 mL) dropwise, and the mixture was stirred at 25 ° C for 12 h. The reaction was quenched by adding water (20 mL) and extracted with EtOAc (2×20 mL). The combined extracts were washed with Na 2 SO 4 Dry and concentrate. The remaining residue was purified by preparative TLC (PE / EtOAc=5:1) to obtain the title compound (50.0 mg, 0.08 mmol, 54% yield) as a light yellow solid. MS (ESI): 593.1 [M+H]+ .

[0682] Step c) 3-(tert-Butyloxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -8-Formic acid

[0683]

[0684] At 25°C, N-[8-bromo-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine To a mixture of tert-butyl]-3-yl]carbamate (250.0 mg, 0.42 mmol, 1.0 eq), DPPP (35.0 mg, 0.08 mmol, 0.2 eq) and TEA (130.0 mg, 1.28 mmol, 3.04 eq) in a mixture of DMF (10 mL) and water (2 mL) was added Pd(OAc) 2 (10.0 mg, 0.04 mmol, 0.11 eq). The mixture was degassed with nitrogen three times, filled with CO three times, and then stirred at 80° C. under CO (45 psi) for 12 h. The mixture was poured into water (50 mL), and the pH was adjusted to 6 by adding HCl (0.5 M). The mixture was extracted with EtOAc (100 mL), and the organic phase was washed with brine (100 mL), dried (Na 2 O) and 4% paraformaldehyde. 2 SO 4 ) and concentrated under vacuum to give the title compound (160.0 mg, 0.29 mmol, 55% yield) as a light yellow solid, which was used in the next reaction step without further purification. MS (ESI): 557.1 [M+H] + .

[0685] Step d) N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0686]

[0687] Similar to Example 1, step j, 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine was prepared. -8-carboxylic acid (150.0 mg, 0.27 mmol, 1.0 eq) was used to prepare the title compound and obtained as a light yellow solid (120 mg, 0.180 mmol, 69% yield). MS (ESI): 515.2 [M-isobutylene + H] + .

[0688] Step e) N-[5,5,7-trifluoro-8-[[(2-methyl-2-methylsulfonyl-propionyl)amino]carbamoyl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0689]

[0690] Similar to Example 1, step k, N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate (110.0 mg, 0.19 mmol, 1.0 eq) was used to prepare the title compound and obtained as a light yellow solid (120.0 mg, 0.17 mmol, 80% yield), which was used in the next reaction step without further purification. MS (ESI): 719.3 [M+H] + .

[0691] Step f) N-[(3S)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine N-[(3R)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0692]

[0693] Burgess reagent (220.0 mg, 0.92 mmol, 6.03 eq) and N-[5,5,7-trifluoro-8-[[(2-methyl-2-methylsulfonyl-propionyl)amino]carbamoyl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine were added. A solution of tert-butyl]-3-yl]carbamate (110.0 mg, 0.15 mmol, 1.0 eq) in toluene (10 mL) was stirred at 110° C. for 16 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (40 mL). The organic phase was washed with brine (40 mL), dried (Na 2 O) and purified by centrifugation. 2 SO 4 ) and concentrated under vacuum. The remaining residue was purified by preparative TLC (PE / EtOAc=2:1) ​​to give pure N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl]carbamic acid tert-butyl ester (80.0 mg, 0.11 mmol, 72% yield) (MS (ESI): 701.4 [M+H] + ). This material was subjected to chiral SFC to afford N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine as a light yellow solid. -3-yl]carbamic acid tert-butyl ester [isomer B] (29.0 mg, 0.04 mmol, 34% yield) (MS (ESI): 701.4 [M+H] + , retention time 1.33 minutes (see conditions below)) and N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl]carbamic acid tert-butyl ester [isomer A] (28.0 mg, 0.04 mmol, 34% yield). MS (ESI): 701.4 [M+H] + ; Retention time 1.03 minutes (column: Chiralpak AS-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: MeOH (0.05% DEA) in CO 2 , 5% to 40%; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar).

[0694] Step g) (3S)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0695]

[0696] N-[,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl-3-yl]carbamate [isomer A] (25.0 mg, 0.04 mmol, 1.0 eq) in HCl / EtOAc (4 M, 5.0 mL, 20.0 mmol, 560.58 eq) was stirred at 20° C. for 0.5 h. The reaction mixture was concentrated and the remaining solid was dissolved in H 2 O to obtain 3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine as a white solid in the form of the hydrochloride salt after lyophilization. -2-Keto [Isomer A] (20.7 mg, 0.03 mmol, 91% yield). MS (ESI): 601.4 [M+H] + Chiral SFC: retention time 2.0 min. N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine was obtained similarly. -3-yl] tert-butyl carbamate [isomer B]. MS (ESI): 601.4 [M+H] + Chiral SFC: retention time 2.32 minutes (column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: MeOH (0.05% DEA) in CO 2, 5% to 40%; flow rate: 3 mL / min; detector: DAD; column temperature: 35°C; back pressure: 100 bar).

[0697] Example 6

[0698] (3S)-3-Amino-5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0699] and

[0700] (3R)-3-Amino-5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0701]

[0702] Step a) 1-(2-amino-4-bromo-phenyl)-2-chloro-ethanone

[0703]

[0704] At 0-5 °C under nitrogen atmosphere, add BCl 3 To a solution of (1M in DCM, 63.95 mL, 63.95 mmol, 1.1 eq) in toluene (100 mL) was added 3-bromoaniline (6.33 mL, 58.13 mmol, 1.0 eq) dropwise. Then AlCl 3 (9.3g, 69.76mmol, 1.2eq) and chloroacetonitrile (4.78mL, 75.57mmol, 1.3eq), and the mixture was stirred at 0-5°C for 0.5h, and then at 70°C for 12h. The reaction mixture was quenched by slowly adding 100mL HCl (1M) at 50°C, and then stirred at 50°C for 0.5h. The mixture was poured into water (100mL) and extracted with EtOAc (2x 200mL). The combined extracts were washed with brine (100mL), purified by Na 2 SO 4 Dry, filter and concentrate in vacuo. The remaining residue is first purified by silica gel column chromatography (PE / EtOAc=1:0 to 10:1), and then purified by preparative HPLC (XB-CN 10 μm, hexane / EtOH) to give the title compound (4.73 g) as a yellow solid. MS (ESI): 250.0 [M+H] +.

[0705] Step b) 2-Acetylamino-2-[2-(2-amino-4-bromo-phenyl)-2-oxo-ethyl]malonic acid diethyl ester

[0706]

[0707] The title compound was prepared from 1-(2-amino-4-bromo-phenyl)-2-chloro-ethanone (9.28 g) in analogy to Example 1, step b, and obtained as a green oil (8.7 g). MS (ESI): 431.0 [M+H] + Step c) 2-amino-4-(2-amino-4-bromo-phenyl)-4-oxo-butyric acid

[0708]

[0709] A solution of diethyl 2-acetylamino-2-[2-(2-amino-4-bromo-phenyl)-2-oxo-ethyl]malonate (5.5 g, 12.81 mmol, 1.0 eq) in HCl (12 M, 60.0 mL, 720.0 mmol, 56.19 eq) was stirred at 100 ° C for 12 h. The reaction mixture was concentrated under vacuum to give the title compound as a green oil in the form of the hydrochloride salt (3.7 g), which was used in the next reaction step without further purification. MS (ESI): 289.0 [M+H] + .

[0710] Step d) 4-(2-amino-4-bromo-phenyl)-2-(tert-butoxycarbonylamino)-4-oxo-butyric acid

[0711]

[0712] The title compound was prepared from 2-amino-4-(2-amino-4-bromo-phenyl)-4-oxo-butyric acid (2.0 g, 6.97 mmol, 1.0 eq) in analogy to Example 1, step d, and obtained as a pale yellow oil (2.51 g, 6.48 mmol, 93% yield). MS (ESI): 333.1 [M-isobutylene + H] + Step e) N-(8-bromo-2,5-dioxo-3,4-dihydro-1H-1-benzazepine -3-yl)carbamic acid tert-butyl ester

[0713]

[0714] The title compound was prepared from 4-(2-amino-4-bromo-phenyl)-2-(tert-butoxycarbonylamino)-4-oxo-butanoic acid (2.6 g, 6.71 mmol, 1.0 eq) in analogy to Example 1, step e, and obtained as a pale yellow solid (800.0 mg, 2.17 mmol, 29% yield). MS (ESI): 271.0 [M-isobutylene-CO 2 +H] + .

[0715] Step f) N-[8-bromo-2,5-dioxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0716]

[0717] Similar to step f of Example 1, N-(8-bromo-2,5-dioxo-3,4-dihydro-1H-1-benzazepine The title compound was prepared from tert-butyl 1-(3-yl)carbamate (650 mg, 1.76 mmol, 1.0 eq) and 1-(chloromethyl)-4-phenoxy-benzene (385 mg, 1.76 mmol, 1.0 eq) and obtained as a light yellow solid (350.0 mg, 0.635 mmol, 36% yield). MS (ESI): 497.0 [M-isobutylene + H] + .

[0718] Step g) N-[8-bromo-5,5-difluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0719]

[0720] Similar to Example 1, step g, N-[8-bromo-2,5-dioxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate (350.0 mg, 0.63 mmol, 1.0 eq) was added to prepare the title compound. A light yellow oil (400 mg) containing the title compound was obtained and used in the next reaction step without further purification. MS (ESI): 475.0 [M-isobutylene-CO 2 +H] + .

[0721] Step h) 3-(tert-butoxycarbonylamino)-5,5-difluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -8-Formic acid

[0722]

[0723] At 25°C, N-[8-bromo-5,5-difluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine To a solution of tert-butyl 1,2-dihydro-3-yl]carbamate (200.0 mg, 0.35 mmol, 1.0 eq) and DIPEA (90.16 mg, 0.70 mmol, 2.0 eq) in a mixture of THF (8 mL) and water (2 mL) was added Pd(dppp)Cl 2 (61.71 mg, 0.105 mmol, 0.3 eq). The mixture was degassed with nitrogen three times, then filled with CO three times, and then the mixture was stirred at 80 ° C under carbon monoxide (50 psi) for 12 h. The reaction mixture was filtered and the filtrate was poured into water (20 mL). The pH was carefully adjusted to 3-4 by adding 0.5N HCl and the mixture was extracted with EtOAc (3x 30 mL). The combined extracts were washed with brine (10 mL), washed with Na 2 SO 4 Dry, filter and concentrate under vacuum. The remaining brown oil (200 mg) containing the title compound was used in the next reaction step without further purification. MS (ESI): 483.2 [M-isobutylene + H] + .

[0724] Step i) N-[5,5-difluoro-8-(hydrazinecarbonyl)-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0725]

[0726] Similar to Example 1, step j, 3-(tert-butoxycarbonylamino)-5,5-difluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine was prepared. -8-carboxylic acid (270.0 mg, 0.5 mmol, 1.0 eq) was used to prepare the title compound. A light yellow solid (260.0 mg) was obtained, which was used in the next reaction step without further purification. MS (ESI): 497.2 [M-isobutylene + H] + .

[0727] Step j) N-[5,5-difluoro-8-[[(2-methyl-2-methylsulfonyl-propionyl)amino]carbamoyl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0728]

[0729] Similar to Example 1, step k, N-[5,5-difluoro-8-(hydrazinecarbonyl)-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate (260.0 mg, 0.47 mmol, 1.0 eq) and 2-methyl-2-methylsulfonyl-propionic acid (93.84 mg, 0.56 mmol, 1.2 eq) were used to prepare the title compound. A yellow oil (270 mg) containing the title compound was obtained and used in the next reaction step without further purification. MS (ESI): 701.2 [M+H] + .

[0730] Step k) N-[5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0731]

[0732] Similarly to Example 1, step 1, N-[5,5-difluoro-8-[[(2-methyl-2-methylsulfonyl-propionyl)amino]carbamoyl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine was used. -3-yl] tert-butyl carbamate (260.0 mg, 0.37 mmol, 1.0 eq) was used to prepare the title compound and obtained as a light yellow solid (170.0 mg, 0.25 mmol, 67% yield). MS (ESI): 627.3 [M-isobutylene + H] + .

[0733] Step 1) N-[(3S)-5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester and N-[(3R)-5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0734]

[0735] N-[5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (100 mg) was subjected to preparative SFC (Daicel Chiralpak AS (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2 O in MeOH) to obtain N-[5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine as a light yellow oil -3-yl] tert-butyl carbamate [isomer B] (45 mg, 0.07 mmol) (MS (ESI): 627.2 [M-isobutylene + H] + , retention time 1.35 minutes (see conditions below), and N-[5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine was obtained as a light yellow oil -3-yl] tert-butyl carbamate [isomer A] (45 mg, 0.07 mmol). MS (ESI): 627.2 [M-isobutylene + H] + , retention time 1.09 minutes (column: Chiralpak AS-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: MeOH (0.05% DEA) in CO 2 , 5% to 40%; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar).

[0736] Step m) (3S)-3-amino-5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0737]

[0738] N-[5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl-3-yl]carbamate [isomer A] (40.0 mg, 0.06 mmol, 1.0 eq) in HCl / EtOAc (4 M, 4.0 mL, 20.0 mmol, 560.58 eq) was stirred at 20° C. for 0.5 h. The reaction mixture was concentrated and the remaining solid was dissolved in H 2 O and lyophilized. The solid obtained was purified by preparative HPLC (HCl as an additive in the eluent) to obtain, after lyophilization, 3-amino-5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine as a white solid in the form of the hydrochloride salt. -2-Keto [Isomer A] (8.9 mg, 0.01 mmol, 26% yield). MS (ESI): 583.3 [M+H] + Chiral SFC: retention time 2.09 min. 3-amino-5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine was obtained similarly. -2-Keto [isomer B]. MS (ESI): 583.2 [M+H] + Chiral SFC: retention time 2.43 minutes (column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: MeOH (0.05% DEA) in CO 2, 5% to 40%; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar).

[0739] Example 7

[0740] (3S)-3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto

[0741] and

[0742] (3R)-3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto

[0743]

[0744] Step a) N-[8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0745]

[0746] The title compound was prepared in analogy to Example 1, steps a to l (using 1-(bromomethyl)-4-(cyclopentyloxy)benzene [CAS 1094272-95-3] instead of 4-(trifluoromethoxy)benzyl bromide in step f) and obtained as a white solid. MS (ESI): 629.2 [M+H] + .

[0747] Step b) N-[(3S)-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine N-[(3R)-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0748]

[0749] N-[8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -3-yl] carbamate (35 mg) was subjected to preparative SFC (Daicel Chiralpak IC (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2 O in MeOH) to obtain N-[8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine as a white solid -3-yl]carbamic acid tert-butyl ester [isomer B] (12 mg) (MS (ESI): 629.4 [M+H] + , retention time 1.19 minutes (see conditions below) and N-[8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine as a white solid -3-yl] tert-butyl carbamate [isomer A] compound (14 mg). MS (ESI): 629.4 [M+H] + ; Retention time 0.84 min (column: Chiralpak IC-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: MeOH (0.05% DEA) in CO 2 , 5% to 40%; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar).

[0750] Step c) (3S)-3-amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto

[0751]

[0752] N-[8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine A solution of tert-butyl]carbamate [isomer A] (13.0 mg, 0.02 mmol, 1.0 eq) in HCl / EtOH (4 M, 5.0 mL) was stirred at 20° C. for 0.5 h. All volatiles were removed and the remaining solid was dissolved in water to obtain 3-amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine as a light yellow solid in the form of the hydrochloride salt after lyophilization. -2-Keto [Isomer A] (11.2 mg, 0.02 mmol, 94% yield). MS (ESI): 529.3 [M+H] + ; Retention time 1.43 minutes. Similarly, 3-amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine was obtained -2-Keto[isomer B]. MS(ESI):529.3[M+H] + ; Retention time 1.85 minutes (column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and B phase was MeOH (0.05% DEA); gradient elution: 5% to 40% B in A; flow rate: 3 mL / min; detector: DAD; column temperature: 35° C.; back pressure: 100 bar).

[0753] Example 8

[0754] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0755] and

[0756] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0757]

[0758] Step a) N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0759]

[0760] The title compound was prepared similarly to Example 1 steps a to l (using 2-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)pyridine [CAS1056641-21-4] in step f; hydrochloride instead of 4-(trifluoromethoxy)benzyl bromide and 2-methyl-2-methylsulfonyl-propionic acid instead of pivalic acid in step k) and obtained as a white solid. MS (ESI): 754.4 [M+H] + .

[0761] Step b) N-[(3S)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0762]

[0763] N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (95 mg) was subjected to preparative SFC (Daicel Chiralpak IC (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2O in IPA) to obtain N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid -3-yl]carbamic acid tert-butyl ester [isomer B] (28 mg) (MS (ESI): 754.3 [M+H] + , retention time 2.43 minutes (see conditions below) and N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid -3-yl] tert-butyl carbamate [isomer A] (30 mg). MS (ESI): 754.3 [M+H] + ; Retention time 1.88 minutes (column: Chiralpak IC-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was IPA (0.05% DEA); gradient elution: IPA (0.05% DEA), at CO 2 , 5% to 40%; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar).

[0764] Step c) (3S)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0765]

[0766] N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl]carbamate [isomer A] (25.0 mg, 0.03 mmol, 1.0 eq) in HCl / EtOH (4 M, 6.25 mL) was stirred at 20° C. for 0.3 h. All volatiles were removed and the remaining solid was dissolved in water to obtain 3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid in the form of the dihydrochloride salt after lyophilization. -2-Keto [Isomer A] (18.7 mg, 0.03 mmol, 75% yield). MS (ESI): 654.2 [M+H] + ; Retention time 1.82 minutes. Similarly, 3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine was obtained -2-Keto[isomer B]. MS(ESI):654.2[M+H] + ; Retention time 2.10 minutes (column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and B phase was MeOH (0.05% DEA); gradient elution: 5% to 40% B in A; flow rate: 3 mL / min; detector: PDA; column temperature: 35° C.; back pressure: 100 bar).

[0767] Example 9

[0768] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[0769] and

[0770] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[0771]

[0772] Step a) N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0773]

[0774] The title compound was prepared similarly to Example 1 steps a to l (using 1-(chloromethyl)-4-(4-methoxyphenyl)benzene [CAS 93258-73-2] instead of 4-(trifluoromethoxy)benzyl bromide in step f and 2-cyano-2-methyl-propionic acid instead of pivalic acid in step k) and obtained as an off-white solid. MS (ESI): 606.2 [M-isobutylene + H] + .

[0775] Step b) N-[(3S)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine N-[(3R)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0776]

[0777] N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (80 mg) was subjected to preparative SFC (Daicel Chiralpak AD (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2 O in IPA) to obtain N-[8-[5-(1-cyano-1-methyl-ethyl)]-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-[benzazepine] as a yellow solid. -3-yl] tert-butyl carbamate [isomer B] (38 mg) (MS (ESI): 606.2 [M-isobutylene + H] + , retention time 2.22 minutes (see conditions below) and N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine as a yellow solid -3-yl] tert-butyl carbamate [isomer A] (38 mg). MS (ESI): 606.2 [M-isobutylene + H] + , retention time 1.87 minutes (column: Chiralpak IG-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0778] Step c) 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile and 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[0779]

[0780] At 20°C, add N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate [isomer A] (36.0 mg, 0.05 mmol, 1.0 eq) was added to a solution of EtOAc (1 mL) with HCl / EtOAc (4 M, 8.0 mL, 32.0 mmol, 588.15 eq), and the mixture was stirred at 20 ° C for 1 h. The reaction mixture was concentrated in vacuo and water was added to the remaining residue. After freeze drying, an off-white solid 2-methyl-2-[5-[3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine was obtained. -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile [isomer A] (29.2 mg, 0.05 mmol, 84% yield). MS (ESI): 562.1 [M+H] + ; Retention time 0.62 minutes. Similarly, 2-methyl-2-[5-[3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine was obtained -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile [isomer B]. MS (ESI): 562.1 [M+H] + ; Retention time 1.22 minutes (column: Chiralpak AD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was MeOH / MeCN (0.05% DEA); gradient elution: 30% MeOH / MeCN (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0781] Example 10

[0782] (3S)-3-Amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1-benzazepine -2-Keto

[0783] and

[0784] (3R)-3-Amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1-benzazepine -2-Keto

[0785]

[0786] Step a) N-[5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0787]

[0788] The title compound was prepared similarly to Example 1, steps a to l (using 1-(chloromethyl)-4-(4-methoxyphenyl)benzene instead of 4-(trifluoromethoxy)benzyl bromide in step f and 2-methyl-2-methylsulfonyl-propionic acid instead of pivalic acid in step k) and obtained as a white solid. MS (ESI): 659.2 [M-isobutylene + H] + .

[0789] Step b) N-[(3S)-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-3,4-dihydro-1-benzazepine -3-yl] carbamic acid tert-butyl ester and N-[(3R)-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0790]

[0791] N-[5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (60 mg) was subjected to preparative SFC (Daicel Chiralpak IG (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2O in MeCN / EtOH) to afford N-[5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-3,4-dihydro-1-benzazepine as a yellow solid -3-yl] tert-butyl carbamate [isomer B] (22 mg) (MS (ESI): 659.1 [M-isobutylene + H] + , retention time 2.11 minutes (see conditions below) and N-[(5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-3,4-dihydro-1-benzazepine as a yellow solid -3-yl] tert-butyl carbamate [isomer A] (22 mg). MS (ESI): 659.1 [M-isobutylene + H] + , retention time 0.95 min (column: Chiralpak IG-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0792] Step c) (3S)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1-benzazepine -2-Keto

[0793]

[0794] At 20°C, add N-[5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate [isomer A] (20.0 mg, 0.03 mmol, 1.0 eq) was added dropwise in a solution of EtOAc (1 mL) with HCl / EtOAc (4 M, 8.0 mL, 32.0 mmol, 1143.6 eq), and the mixture was stirred at 20 ° C for 1 h. The reaction mixture was concentrated in a vacuum and water was added to the remaining residue. After freeze drying, an off-white solid 3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazole-2-yl]-3,4-dihydro-1-benzazepine was obtained. -2-Keto [Isomer A] (14.6 mg, 0.02 mmol, 77% yield). MS (ESI): 615.1 [M+H] + ; Retention time 0.97 minutes. Similarly, 3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1-benzazepine was obtained -2-Keto[isomer B]. MS(ESI):615.1[M+H] + ; Retention time 1.45 minutes (column: Chiralpak AD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was MeOH / MeCN (0.05% DEA); gradient elution: 30% MeOH / MeCN (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0795] Example 11

[0796] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[0797] and

[0798] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[0799]

[0800] Step a) N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0801]

[0802] The title compound was prepared similarly to Example 1 steps a to l (using 1-(chloromethyl)-4-phenoxy-benzene instead of 4-(trifluoromethoxy)benzyl bromide in step f and 2-cyano-2-methyl-propionic acid instead of pivalic acid in step k) and obtained as a pale yellow solid. MS (ESI): 592.3 [M-isobutylene + H] + .

[0803] Step b) N-[(3S)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine N-[(3R)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0804]

[0805] N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (140 mg) was subjected to preparative SFC (Daicel Chiralpak IC (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2 O in MeOH) to obtain N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl] tert-butyl carbamate [isomer B] (70 mg) (MS (ESI): 592.3 [M-isobutylene + H] + , retention time 2.39 minutes (see conditions below) and N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl] tert-butyl carbamate [isomer A] (60 mg). MS (ESI): 592.3 [M-isobutylene + H] + , retention time 1.75 minutes (column: Chiralpak IC-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0806] Step c) 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile and 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[0807]

[0808] N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl]carbamate [isomer A] (60.0 mg, 0.09 mmol, 1.0 eq) in HCl / EtOAc (4 M, 0.12 mL, 0.46 mmol, 5.0 eq) was stirred at 20 ° C. for 0.5 h, and then all volatiles were removed. The remaining solid was dissolved in water, and 2-methyl-2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine was obtained as a white solid in the form of the hydrochloride salt by lyophilization. -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile [isomer A] (33.6 mg, 0.06 mmol, 60% yield). MS (ESI): 548.3 [M+H] + ; Retention time 1.66 minutes. Similarly, 2-methyl-2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine was obtained -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile [isomer B]. MS (ESI): 548.3 [M+H] + ; Retention time 2.02 minutes (column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: DAD; column temperature: 35°C; back pressure: 100 bar).

[0809] Example 12

[0810] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile and

[0811] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[0812]

[0813] Step a) N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0814]

[0815] The title compound was prepared similarly to Example 1 steps a to l (using 2-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)pyridine in step f; hydrochloride instead of 4-(trifluoromethoxy)benzyl bromide and 2-cyano-2-methyl-propionic acid instead of pivalic acid in step k) and obtained as a pale yellow solid. MS (ESI): 701.3 [M+H] + .

[0816] Step b) N-[(3S)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0817]

[0818] N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (95 mg) was subjected to preparative SFC (Daicel Chiralpak IC (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2 O in EtOH) to obtain N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid -3-yl]carbamic acid tert-butyl ester [isomer B] (33 mg) (MS (ESI): 701.2 [M+H] + , retention time 2.01 minutes (see conditions below) and N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid -3-yl] tert-butyl carbamate [isomer A] (33 mg). MS (ESI): 701.1 [M+H] + ; Retention time 1.44 minutes (column: Chiralpak IC-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0819] Step c) 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile and 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[0820]

[0821] N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl]carbamate [isomer A] (30.0 mg, 0.04 mmol, 1.0 eq) in HCl / EtOAc (4 M, 4.0 mL, 16.0 mmol, 373.67 eq) was stirred at 20° C. for 0.5 h, and then all volatiles were removed. The remaining solid was dissolved in water, and 2-methyl-2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine was obtained as a light yellow solid in the form of the dihydrochloride salt by lyophilization. -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile [isomer A] (28.0 mg, 0.04 mmol, 93% yield). MS (ESI): 601.3 [M+H] +; Retention time 1.51 minutes. Similarly, 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine was obtained -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile [isomer B]. MS (ESI): 601.2 [M+H] + ; Retention time 1.84 minutes (column: Chiralcel OD-3 50×4.6mm ID, 3μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: DAD; column temperature: 35°C; back pressure: 100 bar).

[0822] Example 13

[0823] (3S)-3-Amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0824] and

[0825] (3R)-3-Amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0826]

[0827] Step a) N-[(3S)-5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester and N-[(3R)-5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0828]

[0829] At 20°C, 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine was added. To a mixture of -8-carboxylic acid [isomer A] (Example 4, step a) (280.0 mg, 0.51 mmol, 1.0 eq) and DMF (0.1 mL) in DCM (10 mL) was added oxalyl chloride (77.76 mg, 0.61 mmol, 1.2 eq), and the mixture was stirred for 0.5 h. Monohydrochloride hydrazine (127.0 mg, 1.53 mmol, 3.0 eq) and DIPEA (0.27 mL, 1.53 mmol, 3.0 eq) were then added at 20° C., and the mixture was stirred for 0.5 h at 20° C., and then poured into water. The mixture was extracted with DCM (3 x 20 mL), and the combined extracts were washed with brine (50 mL), washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. Crude N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine is obtained as a yellow solid. -3-yl] tert-butyl carbamate [isomer A] (218.0 mg, 0.39 mmol, 76% yield) and used in the next step without further purification. MS (ESI): 507.1 [M-isobutylene + H] + N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester [isomer B] is similarly prepared from 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-carboxylic acid [isomer B] (Example 4, step a) was obtained. MS (ESI): 507.2 [M-isobutylene + H] + .

[0830] Step b) N-[(3S)-8-[[(1-ethyl-5,5-difluoro-piperidine-3-carbonyl)amino]carbamoyl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-8-[[(1-ethyl-5,5-difluoro-piperidine-3-carbonyl)amino]carbamoyl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0831]

[0832] To a mixture of 1-ethyl-5,5-difluoro-piperidine-3-carboxylic acid (Intermediate 2) (159.72 mg, 0.83 mmol, 1.5 eq) and T3P (50% in EtOAc, 526.1 mg, 0.83 mmol, 1.5 eq) in DCM (5 mL) was added DIPEA (0.29 mL, 1.65 mmol, 3.0 eq) at 25° C. and the mixture was stirred for 0.5 h. Then N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine was added at 25° C. -3-yl] tert-butyl carbamate [isomer A] (310.0 mg, 0.55 mmol, 1.0 eq) and the mixture was stirred at 25 ° C for 0.5 h, and then poured into water. The mixture was extracted with DCM (3× 15 mL), and the combined extracts were washed with brine (40 mL), washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give N-[8-[[(1-ethyl-5,5-difluoro-piperidine-3-carbonyl)amino]carbamoyl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine as a yellow solid -3-yl]carbamate [isomer A] (155.0 mg, 0.21 mmol, 38% yield), which was used in the next step without further purification. MS (ESI): 738.2 [M+H] + N-[8-[[(1-ethyl-5,5-difluoropiperidine-3-carbonyl)amino]carbamoyl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl] carbamate [isomer B] is similarly prepared from N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester [isomer B] was obtained.

[0833] Step c) N-[(3S)-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0834]

[0835] N-[8-[[(1-ethyl-5,5-difluoro-piperidine-3-carbonyl)amino]carbamoyl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine A mixture of tert-butyl-3-yl]carbamate [isomer A] (390.0 mg, 0.34 mmol, 1.0 eq) and Burgess reagent (245.69 mg, 1.03 mmol, 3.0 eq) in toluene (15 mL) was stirred at 100° C. for 12 h, and then poured into water (50 mL). The mixture was extracted with EtOAc (3× 40 mL), and the combined extracts were washed with brine (100 mL), washed with anhydrous Na 2 SO 4 The residue was dried, filtered and concentrated in vacuo. The remaining residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150x25mm, 10 μm, conditions: water (containing formic acid) / ACN) to give N-[8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid. -3-yl]carbamic acid tert-butyl ester [isomer A] (59.0 mg, 0.08 mmol, 23% yield). MS (ESI): 720.2 [M+H] + N-[8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester [isomer B] is similarly prepared from N-[8-[[(1-ethyl-5,5-difluoro-piperidine-3-carbonyl)amino]carbamoyl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate [isomer B] was obtained. MS (ESI): 720.2 [M+H] + Step d) (3S)-3-amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0836]

[0837] At 25°C, add N-[8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine To a solution of tert-butyl]carbamate [isomer A] (55.0 mg, 0.08 mmol, 1.0 eq) in EtOAc (1 mL) was added HCl / EtOAc (4 M, 5.87 mL, 23.47 mmol, 307.04 eq), and the mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo and the remaining residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25 mm, 5 μm, conditions: water (containing NH 4 HCO 3 ) / ACN) to obtain 3-amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine as an off-white solid -2-Keto [Isomer A] (12.6 mg, 0.02 mmol, 26% yield). MS (ESI): 620.2 [M+H] +; Retention time 1.25 minutes. 3-Amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one [isomer B] was similarly prepared from N-[8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate [isomer B] was obtained. MS (ESI): 620.2 [M+H] + , retention time 1.74 and 1.94 min (column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0838] Example 14

[0839] (3S)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0840] and

[0841] (3R)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0842]

[0843] Step a) N-[5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0844]

[0845] Similarly to Example 15 steps d and e, N-[1-[(4-cyanophenyl)methyl]-5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-3,4-dihydro-1-benzazepine was used. -3-yl]carbamic acid tert-butyl ester (Example 15, step c) was used to prepare the title compound and obtained as a light yellow solid. MS (ESI): 694.1 [M+H] + .

[0846] Step b) N-[(3S)-5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0847]

[0848] N-[5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (60 mg) was subjected to preparative SFC (Daicel Chiralpak AD (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2 O in iPrOH) to afford N-[5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl]carbamic acid tert-butyl ester [isomer B] (25 mg) (MS (ESI): 694.1 [M+H] +, retention time 1.76 minutes (see conditions below) and N-[5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl] tert-butyl carbamate [isomer A] (23 mg). MS (ESI): 694.1 [M+H] + ; Retention time 1.27 minutes (column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0849] Step c) (3S)-3-amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0850]

[0851] N-[5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl]carbamate [isomer A] (23.0 mg, 0.03 mmol, 1.0 eq) in HCl / EtOAc (4 M, 5.0 mL, 20.0 mmol, 603.13 eq) was stirred at 20° C. for 0.5 h. All volatiles were removed in vacuo, and the remaining residue was dissolved in water to afford 3-amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid in the form of the hydrochloride salt by lyophilization. -2-Keto [Isomer A] (13.5 mg, 0.02 mmol, 64% yield). MS (ESI): 594.2 [M+H] + ; Retention time 1.59 minutes. 3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one [isomer B] is similarly prepared from N-[5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate [isomer B] was obtained. MS (ESI): 594.2 [M+H] + ; Retention time 2.28 (column: Chiralcel OD-3 50×4.6mm ID, 3μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0852] Example 15

[0853] (3S)-3-Amino-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0854] and

[0855] (3R)-3-Amino-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0856]

[0857] Step a) N-[1-[(4-cyanophenyl)methyl]-5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0858]

[0859] The title compound was prepared in analogy to Example 1, steps a to j (using 4-(bromomethyl)benzonitrile instead of 4-(trifluoromethoxy)benzyl bromide in step f) and obtained as a pale yellow solid. MS (ESI): 448.1 [M-isobutylene + H] + .

[0860] Step b) N-[1-[(4-cyanophenyl)methyl]-5,5,7-trifluoro-2-oxo-8-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0861]

[0862] N-[1-[(4-cyanophenyl)methyl]-5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-3,4-dihydro-1-benzazepine A mixture of tert-butyl]carbamate (1.5 g, 2.98 mmol, 1.0 eq), TEA (0.93 mL, 6.67 mmol, 2.24 eq) and CDI (0.72 g, 4.47 mmol, 1.5 eq) in THF (20 mL) was stirred at 20 ° C for 3 h, and then the reaction mixture was poured into water (50 mL). The mixture was extracted with EtOAc (100 mL), and the organic phase was washed with brine (50 mL), dried (Na 2 O) and 4% paraformaldehyde (50% ethanol). 2 SO 4 ) and concentrated under vacuum to give the title compound as a light yellow solid (1.5 g, 2.83 mmol, 87% yield), which was used in the next step without further purification. MS (ESI): 474.2 [M-isobutylene + H] + .

[0863] Step c) N-[1-[(4-cyanophenyl)methyl]-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester and N-[1-[(4-cyanophenyl)methyl]-5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0864]

[0865] At 25°C, add N-[1-[(4-cyanophenyl)methyl]-5,5,7-trifluoro-2-oxo-8-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3,4-dihydro-1-benzazepine To a mixture of tert-butyl]-3-yl]carbamate (450.0 mg, 0.85 mmol, 1.0 eq), 4,4-difluoropiperidine hydrochloride (202.5 mg, 1.28 mmol, 1.51 eq) and DIPEA (0.45 mL, 2.55 mmol, 3.0 eq) in dry 1,4-dioxane (10 mL) was added PyBroP (475.47 mg, 1.02 mmol, 1.2 eq) and the mixture was stirred at 20° C. under a nitrogen atmosphere for 3 h. The mixture was poured into water (100 mL). The aqueous phase was extracted with EtOAc (200 mL), and the organic extract was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The remaining residue was purified by silica gel column chromatography (PE / EtOAc 10:1 to 1:1) to afford N-[1-[(4-cyanophenyl)methyl]-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl]carbamic acid tert-butyl ester (400.0 mg, 0.63 mmol, 74% yield) (MS (ESI): 633.4 [M+H] +) and a second part, which was further purified by preparative HPLC (column: Phenomenex lunaC18 150x25mm, 10μm; conditions: water (containing formic acid) / ACN 1:1 to 1:4) to obtain N-[1-[(4-cyanophenyl)methyl]-5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-3,4-dihydro-1-benzazepine as a white solid -3-yl]carbamic acid tert-butyl ester (45.0 mg, 0.08 mmol, 9% yield). MS (ESI): 583.5 [M+H] + .

[0866] Step d) N-[8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0867]

[0868] N-[1-[(4-cyanophenyl)methyl]-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine A mixture of tert-butyl]carbamate (35.0 mg, 0.06 mmol, 1.0 eq), sodium acetate (13.62 mg, 0.17 mmol, 3.0 eq) and hydroxylamine hydrochloride (5.77 mg, 0.08 mmol, 1.5 eq) in ethanol (5 mL) was stirred at 50 ° C for 12 h, and then poured into water (20 mL). The mixture was extracted with EtOAc (50 mL), and the organic extract was washed with brine (30 mL), dried (Na 2 O) and 4% paraffin. 2 SO 4 ) and concentrated in vacuo to afford N-[8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine as a white solid -3-yl]carbamic acid tert-butyl ester (33.0 mg, 0.05 mmol, 71% yield), which was used in the next step without further purification. MS (ESI): 666.2 [M+H] + .

[0869] Step e) N-[8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0870]

[0871] N-[8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine A solution of tert-butyl 1-(3-yl)-1-carbamate (190.0 mg, 0.29 mmol, 1.0 eq) and trifluoroacetic anhydride (0.06 mL, 0.46 mmol, 1.6 eq) in THF (10 mL) was stirred at 20 °C for 2 h. The solution was poured into water (20 mL) and heated to room temperature by adding NaHCO 3 The pH of the solution was adjusted to 7 to 8. The mixture was then extracted with EtOAc (40 mL), and the organic extract was washed with brine (30 mL), dried (Na 2 O) and lysine (40 mL). 2 SO 4 ) and concentrated in vacuo. The remaining residue was purified by preparative HPLC (column: Phenomenex luna C18 150x25mm, 10μm; conditions: water (containing formic acid) / ACN 1:1 to 1:4) to obtain N-[8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid. -3-yl]carbamic acid tert-butyl ester (120.0 mg, 0.16 mmol, 55% yield). MS (ESI): 744.4 [M+H] + .

[0872] Step f) N-[(3S)-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0873]

[0874] N-[8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (120 mg) was subjected to preparative SFC (Daicel Chiralcel OD (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2 O in EtOH) to obtain N-[8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid -3-yl]carbamic acid tert-butyl ester [isomer B] (45 mg) (MS (ESI): 744.4 [M+H] + , retention time 1.52 minutes (see conditions below) and N-[8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid -3-yl] tert-butyl carbamate [isomer A] (50 mg). MS (ESI): 744.4 [M+H] + ; Retention time 1.10 min (column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0875] Step g) (3S)-3-amino-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0876]

[0877] N-[8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate [isomer A] (40.0mg, 0.05mmol, 1.0eq) in HCl (4M, 10.0mL, 40.0mmol, 743.6eq) in EtOAc was stirred at 20 ° C for 0.5h. All volatiles were then removed in vacuo and the remaining residue was dissolved in water. After freeze-drying, a white solid 3-amino-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazole-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine was obtained as a hydrochloride salt. -2-Keto [Isomer A] (28.4 mg, 0.04 mmol, 77% yield). MS (ESI): 644.1 [M+H] + ; Retention time 1.47 minutes. 3-Amino-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one [isomer B] is similarly prepared from N-[8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate [isomer B] was obtained. MS (ESI): 644.1 [M+H] + ; Retention time 2.23 minutes (column: Chiralcel OD-350×4.6mm ID, 3μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0878] Example 16

[0879] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0880] and

[0881] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0882]

[0883] Step a) N-[1-[(4-cyanophenyl)methyl]-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0884]

[0885] The title compound was prepared similarly to Example 1 steps a to l (using 4-(bromomethyl)benzonitrile instead of 4-(trifluoromethoxy)benzyl bromide in step f and 2-methyl-2-methylsulfonyl-propionic acid instead of pivalic acid in step k) and obtained as a light yellow solid. MS (ESI): 634.4 [M+H] + .

[0886] Step b) N-[5,5,7-trifluoro-1-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0887]

[0888] N-[1-[(4-cyanophenyl)methyl]-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-3,4-dihydro-1-benzazepine A mixture of tert-butyl]carbamate (190.0 mg, 0.3 mmol, 1.0 eq), potassium acetate (0.06 mL, 0.9 mmol, 3.0 eq) and hydroxylamine hydrochloride (27.0 mg, 0.39 mmol, 1.3 eq) in EtOH (10 mL) was stirred at 50 ° C for 12 h, and then the reaction mixture was poured into water (50 mL). The mixture was extracted with EtOAc (100 mL), the organic extract was washed with brine (50 mL), dried (Na 2 O) and 4% paraformaldehyde (50% ethanol). 2 SO 4 ) and concentrated in vacuo. The remaining residue was purified by preparative TLC (PE / EtOAc=1:2) to give the title compound (150.0 mg, 0.22 mmol, 74% yield) as a light yellow solid. MS (ESI): 667.4 [M+H] + .

[0889] Step c) N-[(3S)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0890]

[0891] N-[5,5,7-trifluoro-1-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-3,4-dihydro-1-benzazepine A solution of tert-butyl-3-yl]carbamate (140.0 mg, 0.21 mmol, 1.0 eq) and trifluoroacetic anhydride (0.04 mL, 0.31 mmol, 1.5 eq) in THF (10 mL) was stirred at 20 °C for 3 h. The reaction mixture was poured into water (30 mL) and heated to 40 °C by adding NaHCO 3 The pH of the mixture was adjusted to 7 to 8. The mixture was extracted with EtOAc (50 mL), and the organic extract was washed with brine (30 mL), dried (Na 2 O) and saturated with 1% ethanol. 2 SO 4 ) and concentrated in vacuo, and the remaining residue was purified by preparative TLC (PE / EtOAc=3:1) to afford N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate. It was subjected to preparative SFC (Daicel Chiralpak AD (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2 O in iPrOH) to obtain N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid -3-yl]carbamic acid tert-butyl ester [isomer B] (30 mg) (MS (ESI): 745.4 [M+H] + , retention time 1.64 minutes (see conditions below) and N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid -3-yl] tert-butyl carbamate [isomer A] (40 mg). MS (ESI): 745.4 [M+H] +; Retention time 1.24 minutes (column: Chiralpak IC-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0892] Step d) (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0893]

[0894] N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl]carbamate [isomer A] (35.0 mg, 0.05 mmol, 1.0 eq) in HCl / EtOAc (4 M, 10.0 mL, 40.0 mmol, 851.04 eq) was stirred at 20° C. for 0.5 h. All volatiles were removed in vacuo, and the remaining residue was dissolved in water to afford 3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid in the form of the hydrochloride salt by lyophilization. -2-Keto [Isomer A] (24.9 mg, 0.04 mmol, 81% yield). MS (ESI): 645.1 [M+H] +; Retention time 1.86 minutes. 3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one [isomer B] was similarly prepared from N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate [isomer B] was obtained. MS (ESI): 645.1 [M+H] + ; Retention time 2.38 minutes (column: Chiralpak IG-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0895] Example 17

[0896] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0897] and

[0898] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0899]

[0900] Step a) N-[5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0901]

[0902] The title compound was prepared in analogy to Example 15 steps a to e (using 4-oxa-7-azaspiro[2.5]octane hydrochloride instead of 4,4-difluoropiperidine hydrochloride in step c) and obtained as a pale yellow solid. MS (ESI): 625.2 [M+H] + .

[0903] Step b) N-[(3S)-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0904]

[0905] N-[5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (70 mg) was subjected to preparative SFC (Daicel Chiralpak AD (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2O in iPrOH) to afford N-[5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a light yellow solid. -3-yl]carbamic acid tert-butyl ester [isomer B] (31 mg) (MS (ESI): 736.3 [M+H] + , retention time 1.46 minutes (see conditions below) and N-[5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl] tert-butyl carbamate [isomer A] (30 mg). MS (ESI): 736.3 [M+H] + ; Retention time 1.09 minutes (column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0906] Step c) (3S)-3-amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0907]

[0908] N-[5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate [isomer A] (30.0 mg, 0.04 mmol, 1.0 eq) in HCl / EtOAc (4M, 5.0 mL, 20.0 mmol, 490.42 eq) was stirred at 20 ° C for 0.5 h. All volatiles were removed in vacuo and the remaining residue was dissolved in water. 3-amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octane-7-yl)-1,3,4-oxadiazole-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine was obtained as a light yellow solid in the form of hydrochloride by freeze drying. -2-Keto [Isomer A] (21.4 mg, 0.03 mmol, 82% yield). MS (ESI): 636.3 [M+H] + ; Retention time 1.53 minutes. 3-Amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one [isomer B] was similarly prepared from N-[5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate [isomer B] was obtained. MS (ESI): 636.3 [M+H] + ; Retention time 2.30 minutes (column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0909] Example 18

[0910] (3S)-3-Amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto

[0911] and

[0912] (3R)-3-Amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto

[0913]

[0914] Step a) N-[8-bromo-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0915]

[0916] The title compound was prepared in analogy to Example 1, steps a to g (using 1-(bromomethyl)-4-chloro-benzene instead of 4-(trifluoromethoxy)benzyl bromide in step f) and obtained as a yellow solid. MS (ESI): 478.9 [M-isobutylene + H] + .

[0917] Step b) N-[8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0918]

[0919] Nitrogen was bubbled through N-[8-bromo-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate (100.0 mg, 0.19 mmol, 1.0 eq), 3-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [CAS1627723-04-9] (53.82 mg, 0.21 mmol, 1.1 eq), K 2 CO 3 (77.68 mg, 0.56 mmol, 3.0 eq) and Pd(dppf)Cl 2-DCM (15.3 mg, 0.02 mmol, 0.1 eq) in a mixture of 1,4-dioxane (5 mL) and water (0.7 mL) for 2 minutes. The reaction mixture was then heated to 80 ° C and stirred for 3 h. All volatiles were removed in vacuo and the remaining residue was purified by preparative TLC (PE / EtOAc=5:1) to give the title compound (95.0 mg, 0.16 mmol, 72% yield) as a yellow oil. MS (ESI): 588.2 [M+H] + .

[0920] Step c) N-[(3S)-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester and N-[(3R)-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0921]

[0922] N-[8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine 4-dihydro-1-benzazepine (50 mg) was subjected to preparative SFC (Daicel Chiralpak AD (250 mm x 30 mm, 10 μm), 0.1% DEA in MeOH) to afford N-[8-(5-tert-butyl-3-pyridinyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine as a yellow oil. -3-yl]carbamic acid tert-butyl ester [isomer B] (45 mg) (MS (ESI): 588.2 [M+H] + , retention time 1.45 min (see conditions below) and yellow oily N-[8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate [isomer A] compound (45 mg). MS (ESI): 588.2 [M+H] + ; Retention time 0.89 minutes (column: Chiralpak AD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2, and phase B was MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0923] Step d) (3S)-3-amino-8-(5-tert-butyl-3-pyridinyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto

[0924]

[0925] At 25°C, add N-[8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate [isomer A] (40.0 mg, 0.07 mmol, 1.0 eq) was added to a solution of EtOAc (1 mL) with HCl / EtOAc (4 M, 8.0 mL, 32.0 mmol, 470.45 eq), and the mixture was stirred at 25 ° C for 1 h. The reaction mixture was concentrated in vacuo and the remaining residue was dissolved in water. 3-amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine was obtained as a yellow solid in the form of dihydrochloride by freeze drying. -2-Keto [Isomer A] (25.8 mg, 0.05 mmol, 65% yield). MS (ESI): 488.2 [M+H] + ; Retention time 2.13 minutes. 3-Amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-one [isomer B] was similarly prepared from N-[8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -3-yl] tert-butyl carbamate [isomer B] was obtained. MS (ESI): 488.2 [M+H] + ; Retention time 1.67 minutes (column: Chiralpak AD-350×4.6mm ID, 3μm; mobile phase: phase A is CO2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: DAD; column temperature: 35°C; back pressure: 100 bar).

[0926] Example 19

[0927] 2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0928] and

[0929] 2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0930]

[0931] Step a) N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0932]

[0933] The title compound was prepared similarly to Example 1 steps a to l (using 2-[4-(chloromethyl)phenyl]-3-fluoro-5-(trifluoromethyl)pyridine (Intermediate 3) instead of 4-(trifluoromethoxy)benzyl bromide in step f and 2-cyano-2-methyl-propionic acid instead of pivalic acid in step k) and obtained as a white solid. MS (ESI): 719.4 [M+H] + .

[0934] Step b) N-[(3S)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine N-[(3R)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0935]

[0936] N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (95 mg) was subjected to preparative SFC (Daicel Chiralcel OD-H (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2 O in MeOH) to obtain N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine as a white solid -3-yl] tert-butyl carbamate [isomer A] (40 mg) (MS (ESI): 719.4 [M+H] + , retention time 1.01 min (see conditions below) and N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine as a white solid -3-yl] tert-butyl carbamate [isomer B] (41 mg). MS (ESI): 719.6 [M+H] + ; Retention time 1.17 minutes (column: Chiralcel OD 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0937] Step c) 2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile and 2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[0938]

[0939] N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine A solution of tert-butyl-3-yl]carbamate [isomer A] (40.0 mg, 0.06 mmol, 1.0 eq) in a mixture of DCM / TFA (3:1, 4.0 mL) was stirred at 25 °C for 1 h. The mixture was then diluted with DCM (3 mL) and quenched by the addition of saturated NaHCO 3 The solution was adjusted to pH 8. The resulting mixture was extracted with DCM (10 mL x 3), and the combined organic layers were dried (Na 2 SO 4 ) and concentrated. The residue was dissolved in EtOAc (30 mL) and HCl / EtOAc (4 M, 0.14 mL) was added. The mixture was concentrated to obtain 2-[5-[3-amino-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine as a white solid in the form of hydrochloride. -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile [isomer A] (33.0 mg, 0.04 mmol, 83% yield). MS (ESI): 619.3 [M+H] + , retention time 1.34 minutes (see conditions below). 2-[5-[3-amino-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine was obtained similarly. -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile [isomer B]. MS (ESI): 619.1 [M+H] + ; Retention time 1.70 minutes (column: Chiralcel OD-3 50×4.6mm ID, 3μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: DAD; column temperature: 35°C; back pressure: 100 bar).

[0940] Example 20

[0941] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[0942] and

[0943] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[0944]

[0945] Step a) N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0946]

[0947] The title compound was prepared similarly to Example 1 steps a to l (using 2-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)tetrazolyl (Intermediate 4) instead of 4-(trifluoromethoxy)benzyl bromide in step f and 2-cyano-2-methyl-propionic acid instead of pivalic acid in step k) and obtained as a pale yellow solid. MS (ESI): 636.1 [M-isobutylene + H] + .

[0948] Step b) N-[(3S)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0949]

[0950] N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (340 mg) was subjected to preparative SFC (Daicel Chiralpak AD (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2 O in EtOH) to afford N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl] tert-butyl carbamate [isomer A] (105 mg) (MS (ESI): 636.1 [M-isobutylene + H] + , retention time 0.86 minutes (see conditions below) and N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl] tert-butyl carbamate [isomer B] (110 mg). MS (ESI): 636.1 [M-isobutylene + H] + , retention time 1.13 minutes (column: Chiralpak AD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2, and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0951] Step c) 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile and 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[0952]

[0953] N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl-3-yl]carbamate [isomer A] (103.0 mg, 0.15 mmol, 1.0 eq) in a mixture of DCM / TFA (3:1, 4.0 mL) was stirred at 20 °C for 0.5 h. The mixture was then stirred by carefully adding saturated NaHCO 3 The pH of the reaction mixture was adjusted to 8 with DCM (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried (Na 2 SO 4 ) and purified by centrifugation. 2 SO 4 ) and concentrated. The remaining residue is dissolved in EtOAc (20mL), and HCl / EtOAc (4M, 0.2mL) is added. The mixture is concentrated, and water (20mL) is added to the remaining solid. The light yellow solid 2-methyl-2-[5-[(3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine in the form of hydrochloride is obtained by freeze drying. -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile [isomer A] (90 mg, 0.14 mmol, 92%). MS (ESI): 592.2 [M+H] +, retention time 1.40 minutes (see conditions below). 2-Methyl-2-[5-[(3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine was obtained similarly. -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile [isomer B]. MS (ESI): 592.3 [M+H] + ; Retention time 1.83 minutes (column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0954] Example 21

[0955] (3S)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0956] and

[0957] (3R)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0958]

[0959] Step a) N-[(3S)-5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0960]

[0961] p-N-[5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (Example 22, step c) (30 mg) was subjected to preparative SFC (Daicel Chiralpak OD (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2 O in EtOH) to obtain N-[5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid -3-yl]carbamic acid tert-butyl ester [isomer A] (10 mg) (MS (ESI): 693.2 [M+H] + , retention time 1.61 minutes (see conditions below) and N-[5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid -3-yl] tert-butyl carbamate [isomer B] (10 mg). MS (ESI): 693.2 [M+H] + ; Retention time 2.07 minutes (column: Chiralpak OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0962] Step b) (3S)-3-amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0963]

[0964] N-[5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl]carbamate [isomer A] (10.0 mg, 0.01 mmol, 1.0 eq) in HCl / EtOAc (4 M, 2.1 mL, 8.42 mmol, 582.9 eq) was stirred at 20° C. for 0.5 h. The mixture was concentrated and the remaining residue was dissolved in MeCN / water to afford 3-amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid in the form of the hydrochloride salt by lyophilization. -2-Keto [Isomer A] (2.0 mg, 20% yield). MS (ESI): 593.2 [M+H] + , retention time 0.57 min (see conditions below). 3-amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine was obtained similarly. -2-Keto[isomer B]. MS(ESI):593.1[M+H] + ; Retention time 1.69 minutes (column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B is EtOH (0.05% DEA); elution: 50% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0965] Example 22

[0966] (3S)-3-Amino-8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0967] and

[0968] (3R)-3-Amino-8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0969]

[0970] Step a) N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0971]

[0972] The title compound was prepared in analogy to Example 1, steps a to j (using 1-[4-(bromomethyl)phenyl]-3-(trifluoromethyl)-1,2,4-triazole (Intermediate 5) instead of 4-(trifluoromethoxy)benzyl bromide in step f) and obtained as a yellow solid. MS (ESI): 636.2 [M+Na] + .

[0973] Step b) N-[5,5,7-trifluoro-2-oxo-8-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0974]

[0975] At 25°C, N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine was added. To a solution of tert-butyl]-3-yl]carbamate (300.0 mg, 0.49 mmol, 1.0 eq) in THF (5 mL) was added CDI (158.58 mg, 0.98 mmol, 2.0 eq) and the mixture was stirred at 25 °C for 12 h. Water (20 mL) was then added and the mixture was extracted with EtOAc (10 mL x 3). The combined extracts were washed with brine (20 mL), dried (Na 2 O) and purified by centrifugation. 2 SO 4 ) and concentrated to give a residue, which was purified by silica gel column chromatography (PE / EtOAc=10:0 to 1:2) to give the title compound as a yellow solid (210.0 mg, 0.33 mmol, 67% yield). MS (ESI): 640.3 [M+H] + .

[0976] Step c) N-[8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine N-[5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0977]

[0978] N-[5,5,7-trifluoro-2-oxo-8-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl]-3-ylcarbamate (200.0 mg, 0.31 mmol, 1.0 eq), PyBroP (153.08 mg, 0.33 mmol, 1.05 eq), DIPEA (0.16 mL, 0.94 mmol, 3.0 eq) and 3,3-difluoropyrrolidine hydrochloride (67.35 mg, 0.47 mmol, 1.5 eq) in 1,4-dioxane (1 mL) was stirred at 20 °C for 3 h. The reaction mixture was poured into water (20 mL), the layers were separated, and the organic phase was extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried (Na 2 O) and purified by centrifugation. 2 SO 4) and concentrated. The remaining residue was purified by preparative TLC (PE / EtOAc=1:2) to give N-[8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a yellow solid -3-yl]carbamic acid tert-butyl ester (140.0 mg, 0.19 mmol, 61% yield) (MS (ESI): 729.3 [M+H] + ) and yellow solid N-[5,5,7-trifluoro-2-oxo-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (30.0 mg, 0.04 mmol, 14% yield). MS (ESI): 693.2 [M+H] + .

[0979] Step d) N-[(3S)-8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0980]

[0981] N-[8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (130 mg) was subjected to preparative SFC (Daicel Chiralpak OX (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2O in EtOH) to afford N-[8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl]carbamic acid tert-butyl ester [isomer A] (55 mg, 41% yield) (MS (ESI): 729.2 [M+H] + , retention time 1.54 minutes (see conditions below) and N-[8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl]carbamic acid tert-butyl ester [isomer B] (56 mg, 43% yield). MS (ESI): 729.2 [M+H] + ; Retention time 2.13 minutes (column: Chiralpak OX-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0982] Step e) (3S)-3-amino-8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0983]

[0984] N-[8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl]carbamate [isomer A] (50.0 mg, 0.07 mmol, 1.0 eq) in HCl / EtOAc (4 M, 10 mL, 40.0 mmol, 582.9 eq) was stirred at 20° C. for 0.5 h. The mixture was concentrated and the remaining residue was dissolved in MeCN / water to afford 3-amino-8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid in the form of the hydrochloride salt by lyophilization. -2-Keto [Isomer A] (40.1 mg, 0.06 mmol, 84% yield). MS (ESI): 629.1 [M+H] + , retention time 0.94 minutes (see conditions below). 3-amino-8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine was obtained similarly. -2-Keto[isomer B]. MS(ESI):629.1[M+H] + ; Retention time 1.91 minutes (column: Chiralpak IG-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B is EtOH (0.05% DEA); elution: 60% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0985] Example 23

[0986] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0987] and

[0988] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0989]

[0990] Step a) N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0991]

[0992] The title compound was prepared similarly to Example 1 steps a to l (using 1-[4-(bromomethyl)phenyl]-3-(trifluoromethyl)-1,2,4-triazole (Intermediate 5) instead of 4-(trifluoromethoxy)benzyl bromide in step f and 2-methyl-2-methylsulfonyl-propionic acid instead of pivalic acid in step k) and obtained as a light yellow solid. MS (ESI): 614.1 [M+H] + .

[0993] Step b) N-[(3S)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[0994]

[0995] p-N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (340 mg) was subjected to preparative SFC (Daicel Chiralpak AD (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2 O in EtOH) to afford N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl] tert-butyl carbamate [isomer A] (30 mg) (MS (ESI): 688.1 [M-isobutylene + H] + , retention time 1.20 minutes (see conditions below) and N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl] tert-butyl carbamate [isomer B] (40 mg). MS (ESI): 688.3 [M-isobutylene + H] + , retention time 2.08 minutes (column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0996] Step c) (3S)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[0997]

[0998] N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester [isomer A] (30.0 mg, 0.04 mmol, 1.0 eq) in HCl / EtOAc (4M, 7.5 mL, 30.0 mmol, 743.7 eq) was stirred at 20° C. for 0.5 h. The mixture was concentrated to afford 3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a yellow solid in the form of hydrochloride. -2-Keto [Isomer A] (24.8 mg, 0.04 mmol, 87% yield). MS (ESI): 644.1 [M+H] + , retention time 1.99 minutes (see conditions below). 3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine was obtained similarly. -2-Keto[isomer B]. MS(ESI):644.1[M+H] + ; Retention time 2.44 minutes (column: Chiralpak AD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0999] Example 24

[1000] 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile and

[1001] 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[1002]

[1003] Step a) N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[1004]

[1005] The title compound was prepared similarly to Example 1 steps a to l (using 2-[4-(chloromethyl)phenyl]-5-(trifluoromethoxy)pyridine hydrochloride [CAS#2338841-95-3] instead of 4-(trifluoromethoxy)benzyl bromide in step f and using 2-cyano-2-methyl-propionic acid instead of pivalic acid in step k) and obtained as a light yellow solid. MS (ESI): 717.5 [M+H] + .

[1006] Step b) N-[(3S)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[1007]

[1008] N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (260 mg) was subjected to preparative SFC (Daicel Chiralpak IC (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2 O in iPrOH) to obtain N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid -3-yl] tert-butyl carbamate [isomer A] (97 mg) (MS (ESI): 717.3 [M+H] + , retention time 1.74 minutes (see conditions below) and N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid -3-yl] tert-butyl carbamate [isomer B] (98 mg). MS (ESI): 717.4 [M+H] + ; Retention time 2.35 minutes (column: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: phase A is CO 2 , and phase B was iPrOH (0.05% DEA); gradient elution: 5% to 40% iPrOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[1009] Step c) 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile and 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile

[1010]

[1011] N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl-3-yl]carbamate [isomer A] (95.0 mg, 0.13 mmol, 1.0 eq) in a mixture of DCM / TFA (3:1, 4.0 mL) was stirred at 20° C. for 1 h. DCM (20 mL) was then added and the mixture was stirred by carefully adding saturated NaHCO 3 The pH of the reaction mixture was adjusted to 8 with the solution. The resulting mixture was extracted with DCM (10 mL x 3), and the combined organic layers were washed with brine (10 mL), dried (Na 2 SO 4 ), and concentrated. The remaining residue is dissolved in EtOAc (30mL), and HCl / EtOAc (4M, 0.1mL) is added. The mixture is concentrated, and water (20mL) is added to the remaining solid. The white solid 2-methyl-2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine in the form of hydrochloride is obtained by freeze drying. -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile [isomer A] (67 mg, 0.1 mmol, 76%). MS (ESI): 617.4 [M+H] + , retention time 1.20 minutes (see conditions below). 2-Methyl-2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine was obtained similarly. -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile [isomer B]. MS (ESI): 617.5 [M+H] +; Retention time 1.82 minutes (column: (SS) Whelk-O1 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[1012] Example 26

[1013] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[1014] and

[1015] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[1016]

[1017] Step a) N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[1018]

[1019] The title compound was prepared similarly to Example 1 steps a to l (using 2-[4-(chloromethyl)phenyl]-5-(trifluoromethoxy)pyridine hydrochloride [CAS#2338841-95-3] instead of 4-(trifluoromethoxy)benzyl bromide in step f and using 2-methyl-2-methylsulfonyl-propionic acid instead of pivalic acid in step k) and obtained as a light yellow solid. MS (ESI): 770.3 [M+H] + .

[1020] Step b) N-[(3S)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[1021]

[1022] p-N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (250 mg) was subjected to preparative SFC (Daicel Chiralpak IC (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2 O in iPrOH) to obtain N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid -3-yl]carbamic acid tert-butyl ester [isomer A] (97 mg) (MS (ESI): 770.3 [M+H] + , retention time 2.01 minutes (see conditions below) and N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid -3-yl] tert-butyl carbamate [isomer B] (92 mg). MS (ESI): 770.5 [M+H] + ; Retention time 2.57 minutes (column: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: phase A is CO 2, and phase B was iPrOH (0.05% DEA); gradient elution: 5% to 40% iPrOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[1023] Step c) (3S)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[1024]

[1025] N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl]carbamate [isomer A] (95.0 mg, 0.12 mmol, 1.0 eq) in HCl / EtOAc (4 M, 10 mL, 40.0 mmol, 324.1 eq) was stirred at 20° C. for 1 h. The mixture was concentrated and the remaining solid was dissolved in water (20 mL) to obtain 3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid in the form of the hydrochloride salt by lyophilization. -2-Keto [Isomer A] (74.1 mg, 0.1 mmol, 83% yield). MS (ESI): 670.4 [M+H] + , retention time 1.96 minutes (see conditions below). 3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine was obtained similarly. -2-Keto[isomer B]. MS(ESI):670.4[M+H] + ; Retention time 2.13 minutes (column: Chiralpak AD-350×4.6mm ID, 3μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[1026] Example 27

[1027] 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[1028] and

[1029] 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[1030]

[1031] Step a) N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[1032]

[1033] The title compound was prepared similarly to Example 1 steps a to l (using 2-[4-(chloromethyl)phenyl]-4-(trifluoromethyl)pyridine hydrochloride (Intermediate 6) instead of 4-(trifluoromethoxy)benzyl bromide in step f and using 2-cyano-2-methyl-propionic acid instead of pivalic acid in step k) and obtained as a light yellow solid. MS (ESI): 701.5 [M+H] + .

[1034] Step b) N-[(3S)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[1035]

[1036] N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester (270 mg) was subjected to preparative SFC (Daicel Chiralcel OD (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2 O in iPrOH) to afford N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl]carbamic acid tert-butyl ester [isomer A] (56 mg) (MS (ESI): 701.5 [M+H] + , retention time 1.08 minutes (see conditions below) and N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl] tert-butyl carbamate [isomer B] (73 mg). MS (ESI): 701.4 [M+H] + ; Retention time 1.29 minutes (column: Chiralcel OD 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2, and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[1037] Step c) 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile and 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[1038]

[1039] N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl-3-yl]carbamate [isomer A] (55.2 mg, 0.08 mmol, 1.0 eq) in a mixture of DCM / TFA (3:1, 4.0 mL) was stirred at 20 °C for 0.5 h. The mixture was then carefully added with saturated NaHCO 3 The pH of the reaction mixture was adjusted to 8 with the solution. The resulting mixture was extracted with DCM (10 mL x 3), and the combined organic layers were washed with brine (10 mL), dried (Na 2 SO 4 ), and concentrated. The remaining residue is dissolved in EtOAc (20mL), and HCl / EtOAc (4M, 0.2mL) is added. The mixture is concentrated, and water (20mL) is added to the remaining solid. The light yellow solid 2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine in the form of hydrochloride is obtained by freeze drying. -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile [isomer A] (49.6 mg, 0.08 mmol, 97%). MS (ESI): 601.4 [M+H] +, retention time 1.28 minutes (see conditions below). 2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine was obtained similarly. -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile [isomer B]. MS (ESI): 601.2 [M+H] + ; Retention time 1.86 minutes (column: (SS) Whelk-O1 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[1040] Example 28

[1041] 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[1042] and

[1043] 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[1044]

[1045] Step a) N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[1046]

[1047] The title compound was prepared similarly to Example 1 steps a to l (using 5-(chloromethyl)-2-[4-(trifluoromethyl)phenyl]pyridine [CAS#851507-54-5] instead of 4-(trifluoromethoxy)benzyl bromide in step f and 2-cyano-2-methyl-propionic acid instead of pivalic acid in step k) and obtained as a light yellow solid. MS (ESI): 701.4 [M+H] + .

[1048] Step b) N-[(3S)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[1049]

[1050] N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine -3-yl] carbamic acid tert-butyl ester was subjected to preparative SFC (Daicel Chiralcel OD (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2 O in EtOH) to afford N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl]carbamic acid tert-butyl ester [isomer A] (42 mg) (MS (ESI): 701.5 [M+H] + , retention time 1.31 minutes (see conditions below) and N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine as a light yellow solid -3-yl] tert-butyl carbamate [isomer B] (68 mg). MS (ESI): 701.5 [M+H] + ; Retention time 1.59 minutes (column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[1051] Step c) 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile and 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile

[1052]

[1053] N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl-3-yl]carbamate [isomer A] (41.2 mg, 0.06 mmol, 1.0 eq) in a mixture of DCM / TFA (3:1, 4.0 mL) was stirred at 20 °C for 0.5 h. The mixture was then carefully added with saturated NaHCO 3 The pH of the reaction mixture was adjusted to 8 with the solution. The resulting mixture was extracted with DCM (10 mL x 3), and the combined organic layers were washed with brine (10 mL), dried (Na 2 SO 4), and concentrated. The remaining residue is dissolved in EtOAc (20mL), and HCl / EtOAc (4M, 0.2mL) is added. The mixture is concentrated, and water (20mL) is added to the remaining solid. The light yellow solid 2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-3,4-dihydro-1-benzazepine in the form of hydrochloride is obtained by freeze drying. -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile [isomer A] (36.4 mg, 0.06 mmol, 96%). MS (ESI): 601.2 [M+H] + , retention time 1.75 minutes (see conditions below). 2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-3,4-dihydro-1-benzazepine was obtained similarly. -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile [isomer B]. MS (ESI): 601.3 [M+H] + ; Retention time 2.22 minutes (column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[1054] Example 29

[1055] (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[1056] and

[1057] (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[1058]

[1059] Step a) N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[1060]

[1061] The title compound was prepared similarly to Example 1 steps a to l (using 1-[4-(chloromethyl)phenyl]-4-(trifluoromethyl)pyrazole [CAS#1486714-19-5] instead of 4-(trifluoromethoxy)benzyl bromide in step f and 2-methyl-2-methylsulfonyl-propionic acid instead of pivalic acid in step k) and obtained as a yellow oil. MS (ESI): 687.0 [M-isobutylene + H] + .

[1062] Step b) N-[(3S)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine N-[(3R)-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl]carbamic acid tert-butyl ester

[1063]

[1064] p-N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -3-yl] carbamic acid tert-butyl ester was subjected to preparative SFC (Daicel Chiralpak AD (250 mm x 30 mm, 10 μm), 0.1% NH 3 -H 2O in EtOH) to obtain N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a yellow solid -3-yl]carbamic acid tert-butyl ester [isomer A] (70 mg) (MS (ESI): 743.4 [M+H] + , retention time 1.18 minutes (see conditions below) and N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a yellow solid -3-yl] tert-butyl carbamate [isomer B] (70 mg). MS (ESI): 743.4 [M+H] + ; Retention time 1.87 minutes (column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO 2 flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[1065] Step c) (3S)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-one and (3R)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto

[1066]

[1067] N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine A solution of tert-butyl]carbamate [isomer A] (65.0 mg, 0.09 mmol, 1.0 eq) in HCl / EtOAc (4 M, 3.45 mL, 13.8 mmol, 157.6 eq) was stirred at 25° C. for 1 h. The mixture was concentrated and the remaining residue was purified by preparative HPLC (column: Phenomenex Luna C18 75×30 mm, 3 m; water (with HCl) / MeCN) to afford 3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine as a white solid in the form of the hydrochloride salt. -2-Keto [Isomer A] (22.3 mg, 0.03 mmol, 36% yield). MS (ESI): 643.2 [M+H] + , retention time 1.72 minutes (see conditions below). 3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine was obtained similarly. -2-Keto[isomer B]. MS(ESI):643.2[M+H] + ; Retention time 2.04 minutes (column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A is CO 2 , and phase B was EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO...

Claims

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

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5-membered heteroaryl group, 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 an oxadiazole, which is optionally substituted with 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 1 is 1,3,4-oxadiazole, which is 10 replace.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 2 For fluorine.

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

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 10 Selected from methyl-methylsulfonyl-ethyl, pyrrolidine, 4-oxa-7-azaspiro[2.5]octan-7-yl, methyl-propionitrile, 1,2,2,2-tetrafluoro-methoxy-ethyl, tert-butyl, 1-ethyl-5,5-difluoro-3-piperidinyl, 4,4-difluoro-1-piperidinyl and azabicyclo[3.1.1]heptane-3-carboxylate.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 11 Selected from 5-(trifluoromethyl)-2-pyridinyl, phenoxy, trifluoromethoxy, methoxy-pyridinyl, cyclopentyloxy, 4-methoxyphenyl, (trifluoromethyl)-1,2,4-oxadiazol-3-yl, 5-(trifluoromethoxy)-2-pyridinyl, 4-(trifluoromethyl)pyrazol-1-yl, chloro, 5-(difluoromethoxy)-2-pyridinyl, 4-[4-(trifluoromethoxy)pyrazol-1-yl, 4-[5-(trifluoromethyl)tetrazol-2-yl.

9. The compound according to claim 1, wherein: R 1 is a 5-membered heteroaryl group, wherein R 1 Optionally, one or more R 10 replace; R 2 is a halogen; R 4 is phenyl or pyridyl; R 10 Selected from: i)C 1-6 -alkyl, which is optionally substituted with one or more halogen, C 1-6 -alkoxy, -S(O)2(C 1-6 -alkyl), cyano substituted; ii) a 3- to 10-membered heterocyclic group, which is optionally substituted with one or more halogens, C 1-10 -alkyl, -C(O)O-(R 10q ), C 3-10 -cycloalkyl substituted, wherein C 1-10 -alkyl is optionally substituted with one or more C 1-6 - alkoxy substitution; iii) heteroaryl, which is optionally substituted with one or more C 1-10 - alkyl substitution; R 11 Selected from: i) halogen; ii) a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more halogens, halo- 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 - alkoxy substitution; iii) phenyl, optionally substituted with one or more C 1-6 -alkoxy, halo-C 1-6 - alkyl substitution; iv)-O(R 11a ); R 11a Selected from C 1-6 -alkyl, C 3-6 -cycloalkyl, phenyl and halo-C 1-6 -alkyl.

10. The compound according to claim 1, wherein: R 1 is 1,3,4-oxadiazole, which is 10 replace; R 2 For fluorine; R 4 is phenyl; R 10 is selected from methyl-methylsulfonyl-ethyl, pyrrolidine, 4-oxa-7-azaspiro[2.5]octan-7-yl, methyl-propionitrile, 1,2,2,2-tetrafluoro-methoxy-ethyl, tert-butyl, 1-ethyl-5,5-difluoro-3-piperidinyl, 4,4-difluoro-1-piperidinyl and azabicyclo[3.1.1]heptane-3-carboxylate; R 11 Selected from 5-(trifluoromethyl)-2-pyridinyl, phenoxy, trifluoromethoxy, methoxy-pyridinyl, cyclopentyloxy, 4-methoxyphenyl, (trifluoromethyl)-1,2,4-oxadiazol-3-yl, 5-(trifluoromethoxy)-2-pyridinyl, 4-(trifluoromethyl)pyrazol-1-yl, chloro, 5-(difluoromethoxy)-2-pyridinyl, 4-[4-(trifluoromethoxy)pyrazol-1-yl and 4-[5-(trifluoromethyl)tetrazol-2-yl.

11. A compound according to any one of claims 1 to 10, selected from: 3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; (3S)-3-Amino-5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5-difluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; (3S)-3-Amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1-benzazepine -2-Keto; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; (3S)-3-Amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; (3S)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-8-[5-(3,3-difluoropyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; (3S)-3-Amino-8-[5-[5,5-difluoro-1-(2-methoxyethyl)-3-piperidinyl]-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-8-[5-[5,5-difluoro-1-(2-methoxyethyl)-3-piperidinyl]-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; 1-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl heptane-3-carboxylate; 1-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl heptane-3-carboxylate; 1-[5-[(3S)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl heptane-3-carboxylate; 1-[5-[(3R)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl heptane-3-carboxylate; 2-[5-[(3S)-3-amino-1-[[4-[5-(1,1-difluoroethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; 2-[5-[(3R)-3-amino-1-[[4-[5-(1,1-difluoroethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-(5-methoxy-2-pyridyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-(5-methoxy-2-pyridyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; (3S)-3-Amino-5,5,7-trifluoro-1-[[4-(5-methoxy-2-pyridyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-1-[[4-(5-methoxy-2-pyridyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1-benzazepine -2-Keto; 2-Methyl-2-[5-[(3S)-3-amino-1-[[4-[5-(difluoromethyl)-2-pyridinyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-1-[[4-[5-(difluoromethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3S)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridinyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridinyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 1-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl heptane-3-carboxylate; 1-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl heptane-3-carboxylate; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[2-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[2-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[3-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[3-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[1-(trifluoromethyl)pyrazol-4-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; and 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[1-(trifluoromethyl)pyrazol-4-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; or a pharmaceutically acceptable salt thereof.

12. A compound according to any one of claims 1 to 11, selected from: 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxy-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentyloxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; (3S)-3-Amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-8-[5-(4,4-difluoro-1-piperidinyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3S)-3-Amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-1,3,4-oxadiazol-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)tetrazol-2-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridinyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; (3S)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; (3R)-3-Amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -2-Keto; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; 1-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl heptane-3-carboxylate; 1-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl heptane-3-carboxylate; 1-[5-[(3S)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl heptane-3-carboxylate; 1-[5-[(3R)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[ 3.1.1] Methyl heptane-3-carboxylate; 2-[5-[(3S)-3-amino-1-[[4-[5-(1,1-difluoroethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; 2-[5-[(3R)-3-amino-1-[[4-[5-(1,1-difluoroethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propionitrile; 2-Methyl-2-[5-[(3S)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridinyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; and 2-Methyl-2-[5-[(3R)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridinyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine -8-yl]-1,3,4-oxadiazol-2-yl]propionitrile; or a pharmaceutically acceptable salt thereof.

13. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, the method comprising reacting a compound of formula (XVIII), Where R 1 , R 2 and R 4 As defined in any one of claims 1 to 11 and PG is an amino protecting group, reacted with a suitable deprotecting agent to form the compound of formula (I).

14. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, which is prepared according to the method according to claim 13.

15. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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

18. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in treating, preventing and / or delaying the progression of cancer.

19. The compound for use according to claim 18, wherein the cancer is associated with aberrant diacylglycerol kinase signaling, wherein the diacylglycerol kinase is selected from DGKα and / or DGKζ.

20. The compound for use according to claim 18 or 19, wherein the cancer is selected from the group consisting of: B-cell acute lymphoid leukemia, T-cell acute lymphoid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative disorders, MALT lymphoma, mantle cell Lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, preleukemia, sarcoma, carcinoma, melanoma, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell carcinoma, melanoma, gastric cancer, brain cancer, lung cancer (e.g., NSCLC), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.

21. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for treating, preventing and / or delaying the progression of cancer.

22. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating, preventing and / or delaying the progression of cancer.

23. 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 12 or a pharmaceutically acceptable salt thereof. 24 . Use of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for inhibiting the activity of at least one diacylglycerol kinase selected from DGKα and DGKζ.

25. 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 12 or a pharmaceutically acceptable salt thereof.

26. The invention as herein described.

Images