Bicyclic Tetrahydroazepine Derivatives

Abstract

The present invention relates to a compound represented by general formula (I) TIFF2025526726000299.tif43170 (in the formula, R 1 , R 2 and R 4 is as defined herein), compositions comprising the compounds, methods of making the compounds, and methods of using the compounds.

Description

[Technical Field]

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

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

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

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

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

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

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

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

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

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

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

[0012] Summary of the Invention A first object of the present invention is to provide a compound of formula (I): TIFF2025526726000002.tif38170 or a pharmaceutically acceptable salt thereof, wherein: R 1 is a 5- or 6-membered heteroaryl, and R 1 but one or more R which may be the same or different 10 is a 5- or 6-membered heteroaryl optionally substituted with R 2 is selected from hydrogen and halogen; R 4 is selected from phenyl and pyridinyl, and R4 is one or more R which may be the same or different 11 may be substituted with R 10 teeth, i) one or more of halogen, amino, C 1~6 -alkoxy, -S(O)2(C 1~6 -alkyl), optionally substituted with cyano, C 1~6 - alkyl; ii) optionally substituted with one or more halogen, cyano, or amino; 3~10 -cycloalkyl; iii) one or more halogens, C 1~10 -Alkyl, Amino, Halo-C 1~6 -Alkyl, hydroxy, cyano, -C(O)O-(R 10q ), C 3~10 -3-10 membered heterocyclyl optionally substituted by cycloalkyl, 1~10 - alkyl is one or more hydroxy, C 1~6 -3-10 membered heterocyclyl optionally substituted by alkoxy; iv)-N(R 10e R 10f ); v) one or more C 1~10 -Alkyl, optionally substituted with halogen, heteroaryl is selected from R 10e and R 10f are each independently i) hydrogen, ii) C, optionally substituted with one or more cyano, halogen, or hydroxy groups; 1~6 - alkyl; iii) one or more halogens, C 1~10 - optionally substituted with alkyl, C 3~10 -cycloalkyl is selected from R 10q is C 1~5 -alkyl, C 1~5 -C, wherein the alkyl is optionally substituted with one or more hydroxy groups. 1~5 -alkyl, R 11 teeth, i) halogens; ii) one or more C 1~6 -Alkyl, C 5~6 -aryl, C 3~10 -cycloalkyl, halo-C 1~6 -Alkyl, C 3~10 -C optionally substituted with heterocyclyl 1~6 -alkoxy, wherein the 3- to 10-membered heterocyclyl is C 1~6 - optionally substituted with alkyl, C 1~6 -alkoxy; iii) 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 -5-6 membered heteroaryl optionally substituted with alkoxy; iv) one or more C 1~6 -Alkoxy, Halo-C 1~6 -phenyl optionally substituted with alkyl; v)-O(R 11a ) is selected from R 11a is C 1~6 -Alkyl, C 3~6 -cycloalkyl, phenyl and halo-C 1~6 -alkyl, or a pharmaceutically acceptable salt thereof.

[0013] A second object of the present invention is a process for the preparation of compounds of formula (I) or pharmaceutically acceptable salts thereof as described herein, comprising the steps of: TIFF2025526726000003.tif38170 (in the formula, R 1 , R 2 , and R 4 is as defined herein and PG is an amino protecting group) with a suitable deprotecting agent to form said compound of formula (I).

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

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

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below.

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

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

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

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

[0021] "Alkyl" refers to an alkyl group having a specified number of carbon atoms (i.e., C1 to 10 refers to a saturated, straight-chain (i.e., unbranched) or branched monovalent hydrocarbon chain, or combinations thereof. Particular alkyl groups are those having 1 to 20 carbon atoms ("C1 to C10"). 20 alkyl"), those having 1 to 12 carbon atoms ("C1 12 alkyl), those having 1 to 10 carbon atoms ("C1 10 alkyl"), those having 1 to 8 carbon atoms ("C1-8 alkyl"), those having 1 to 6 carbon atoms ("C1-6 alkyl"), those having 2 to 6 carbon atoms ("C2-6 alkyl"), or those having 1 to 4 carbon atoms ("C 1~4 Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl; homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

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

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

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

[0025] "Aromatic" is used in the literature, especially in the IUPAC Compendium of Chemical Terminology, 2 nd This refers to the conventional concept of aromaticity as defined in A.D. McNaught & A. Wilkinson (Eds.), Blackwell Scientific Publications, Oxford (1997).

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

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

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

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

[0030] "Cycloalkyl" refers to monocyclic, bicyclic (including bridged bicyclic and cycloalkyl spiro moieties), or tricyclic rings and saturated or partially unsaturated carbocyclic moieties having 3 to 10 carbon atoms, i.e., (C3-C 10(C-C)cycloalkyl. The cycloalkyl moiety may be substituted with one or more substituents. In certain embodiments, the cycloalkyl contains 3 to 8 carbon atoms (i.e., (C-C)cycloalkyl). In other certain embodiments, the cycloalkyl contains 3 to 6 carbon atoms (i.e., (C-C)cycloalkyl). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and their partially unsaturated (cycloalkenyl) derivatives (e.g., cyclopentenyl, cyclohexenyl, and cycloheptenyl), bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptanyl, bicyclo[3.1.1]heptenyl, and bicyclo[1.1.1]pentane. The cycloalkyl moiety can be attached in a "spirocycloalkyl" or "cycloalkylspiro" fashion, such as "spirocyclopropyl." TIFF2025526726000004.tif26170

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

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

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

[0034] "Heteroaryl" refers to an aromatic heterocyclic monocyclic, bicyclic, or tricyclic ring system of 5 to 14 ring atoms, preferably 5 to 10 ring atoms, and more preferably 5 to 6 ring atoms, containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. In some embodiments, the monocyclic heteroaryl ring can be 5 to 6-membered. Bicyclic heteroaryl ring systems include fused bicycles having two fused 5-membered heteroaryl rings (designated 5-5), fused bicycles having a 5-membered aryl ring and a fused 6-membered heteroaryl ring (designated 5-6 and 6-5), and bicycles having two fused 6-membered aryl rings (designated 6-6). Heteroaryl groups may be optionally substituted as defined herein. Examples of heteroaryl include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, benzothiophenyl, indolyl, aza-indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzimidazolyl, benzoxazolyl, benzimidazolyl, benzoxazolyl, benzo ...

[0033] Examples of heteroaryl include benzoisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl and furopyrazinyl. Most preferably, "5-membered heteroaryl" refers to the following groups:

[0035] TIFF2025526726000005.tif37170

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0052] The following abbreviations are used herein:

[0053] BOP = benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, Brine = saturated aqueous NaCl solution, CAS = Chemical Abstracts Registry Number, 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, DIPEA = N,N-diisopropyl propylethylamine, EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, ESI = electrospray ionization, EtOAc = ethyl acetate, EtOH = ethanol, h = hour(s), HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, HBTU = O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluorophosphate, HFIP = Hexafluoroisopropanol, HOBt = hydroxybenzotriazole, HPLC = high performance liquid chromatography, IPA = isopropyl alcohol, m-CPBA = meta-chloroperoxybenzoic acid, MeCN = acetonitrile, MeI = methyloid, MeOH = methanol, min = minute(s), MS = mass spectrum, NBS = N-bromosuccinimide, PDA = photodiode array detection, PE = petroleum ether, PyBroP = bromo-tris-pyrrolidino-phosphonium hexafluorophosphate phosphate, RT = room temperature, TBAF = tetrabutylammonium fluoride, TBAOH = tetrabutylammonium hydroxide, TBDMS = tert-butyldimethylsilyl, TEA = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TMSOTF = trifluoromethanesulfonic acid trimethylsilyl ester, TLC = thin layer chromatography, T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide.

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

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

[0056] Certain compounds may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate individual tautomers usually produce mixtures whose chemical and physical properties match the mixture of compounds. The position of the equilibrium depends on the chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. Common protic tautomers include: TIFF2025526726000006.tif15170 tautomers. The latter two are particularly common in heteroaryl and heterocyclic rings, and the present invention encompasses all tautomeric forms of the compounds.

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

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

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

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

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

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

[0063] Compounds of the Invention In one embodiment, the compound of formula (I) described herein: TIFF2025526726000007.tif42170 or a pharmaceutically acceptable salt thereof, wherein: R 1 is a 5- or 6-membered heteroaryl, and R 1 but one or more R which may be the same or different 10 is a 5- or 6-membered heteroaryl optionally substituted with R 2 is selected from hydrogen and halogen; R 4 is selected from phenyl and pyridinyl, and R 4 is one or more R which may be the same or different 11 may be substituted with R 10teeth, i) one or more of halogen, amino, C 1~6 -alkoxy, -S(O)2(C 1~6 -alkyl), optionally substituted with cyano, C 1~6 - alkyl; ii) optionally substituted with one or more halogen, cyano, or amino; 3~10 -cycloalkyl; iii) one or more halogens, C 1~10 -Alkyl, Amino, Halo-C 1~6 -Alkyl, hydroxy, cyano, -C(O)O-(R 10q ), C 3~10 -3-10 membered heterocyclyl optionally substituted by cycloalkyl, 1~10 - alkyl is one or more hydroxy, C 1~6 -3-10 membered heterocyclyl optionally substituted by alkoxy; iv)-N(R 10e R 10f ); v) one or more C 1~10 -Alkyl, optionally substituted with halogen, heteroaryl is selected from R 10e and R 10f are each independently i) hydrogen, ii) C, optionally substituted with one or more cyano, halogen, or hydroxy groups; 1~6 - alkyl; iii) one or more halogens, C 1~10 - optionally substituted with alkyl, C 3~10 -cycloalkyl is selected from R 10q is C 1~5 -alkyl, C 1~5 -C, wherein the alkyl is optionally substituted with one or more hydroxy groups. 1~5 -alkyl, R 11 teeth, i) halogens; ii) one or more C 1~6 -Alkyl, C5~6 -aryl, C 3~10 -cycloalkyl, halo-C 1~6 -Alkyl, C 3~10 -C optionally substituted with heterocyclyl 1~6 -alkoxy, wherein the 3- to 10-membered heterocyclyl is C 1~6 - optionally substituted with alkyl, C 1~6 -alkoxy; iii) 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 -5-6 membered heteroaryl optionally substituted with alkoxy; iv) one or more C 1~6 -Alkoxy, Halo-C 1~6 -phenyl optionally substituted with alkyl; v)-O(R 11a ) is selected from R 11a is C 1~6 -Alkyl, C 3~6 -cycloalkyl, phenyl and halo-C 1~6 -alkyl, or a pharmaceutically acceptable salt thereof.

[0064] In another embodiment, R 1 is a 5-membered heteroaryl, and R 1 one or more R which may be the same or different 10 or a pharmaceutically acceptable salt thereof.

[0065] In a preferred embodiment, R 1 is oxadiazole, and one or more R 10 or a pharmaceutically acceptable salt thereof.

[0066] In a more preferred embodiment, R 1 is one R 10 or a pharmaceutically acceptable salt thereof.

[0067] In an even more preferred embodiment, R 1 is one R 10 or a pharmaceutically acceptable salt thereof.

[0068] In another embodiment, R 2 Provided is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein is fluorine.

[0069] In another embodiment, R 4 Provided is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein is phenyl.

[0070] In another embodiment, R 10 is selected from methyl-methylsulfonyl-ethyl, pyrrolidine, 4-oxa-7-azaspiro[2.5]octan-7-yl, methyl-propanenitrile, 1,2,2,2-tetrafluoro-methoxy-ethyl, tertbutyl, 1-ethyl-5,5-difluoro-3-piperidyl, 4,4-difluoro-1-piperidyl, and azabicyclo[3.1.1]heptane-3-carboxylate, or a pharmaceutically acceptable salt thereof.

[0071] In another embodiment, R 10 is selected from methyl-methylsulfonyl-ethyl, pyrrolidine, oxa-azaspiro[2.5]octanyl, methyl-propanenitrile, tetrafluoromethoxy-ethyl, or a pharmaceutically acceptable salt thereof.

[0072] In another embodiment, R 11is selected from 5-(trifluoromethyl)-2-pyridyl, phenoxy, trifluoromethoxy, methoxy-pyridyl, cyclopentoxy, 4-methoxyphenyl, (trifluoromethyl)-1,2,4-oxadiazol-3-yl, 5-(trifluoromethoxy)-2-pyridyl, 4-(trifluoromethyl)pyrazol-1-yl, chloro, 5-(difluoromethoxy)-2-pyridyl, 4-[4-(trifluoromethoxy)pyrazol-1-yl, 4-[5-(trifluoromethyl)tetrazol-2-yl].

[0073] In another embodiment, R 11 is selected from (trifluoromethyl)-pyridyl, phenoxy, trifluoromethoxy, (trifluoromethyl)-oxadiazolyl, methoxy-pyridyl, or a pharmaceutically acceptable salt thereof.

[0074] In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a 5-membered heteroaryl, and R 1 but one or more R which may be the same or different 10 is a 5-membered heteroaryl optionally substituted with R 2 is a halogen; R 4 is phenyl or pyridinyl, R 10 but, iv) one or more halogens, C 1~6 -alkoxy, -S(O)2(C 1~6 -alkyl), optionally substituted with cyano, C 1~6 - alkyl; v) one or more halogens, C 1~10 -alkyl, -C(O)O-(R 10q ), C 3~10 -3-10 membered heterocyclyl optionally substituted by cycloalkyl,1~10 -Alkyl is one or more C 1~6 -3-10 membered heterocyclyl optionally substituted by alkoxy; vi) one or more C 1~10 -heteroaryl optionally substituted with alkyl is selected from R 11 teeth, i) halogens; ii) one or more halogens, halo-C 1~6 -Alkyl, C 1~6 -Alkoxy, Halo-C 1~6 -5-6 membered heteroaryl optionally substituted with alkoxy; iii) one or more C 1~6 -Alkoxy, Halo-C 1~6 -phenyl optionally substituted with alkyl; iv)-O(R 11a ) is selected from R 11a is C 1~6 -Alkyl, C 3~6 -cycloalkyl, phenyl and halo-C 1~6 -alkyl, or a pharmaceutically acceptable salt thereof.

[0075] In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a 5-membered heteroaryl, and R 1 but one or more R which may be the same or different 10 is a 5-membered heteroaryl optionally substituted with R 2 is a halogen; R 4 is phenyl, R 10 but, i) one or more of halogen, amino, C 1~6 -alkoxy, -S(O)2(C 1~6 -alkyl), optionally substituted with cyano, C 1~6- alkyl; ii) optionally substituted with one or more halogen, cyano, or amino; 3~10 -cycloalkyl; iii) one or more halogens, -C(O)O-(R 10q 3- to 10-membered heterocyclyl optionally substituted with is selected from R 11 but, i) halogens; ii) one or more halogens, halo-C 1~6 -Alkyl, C 1~6 -5-6 membered heteroaryl optionally substituted with alkoxy; iii) one or more C 1~6 -Alkoxy, Halo-C 1~6 -phenyl optionally substituted with alkyl; iv)-O(R 11a ) is selected from R 11a is C 1~6 -Alkyl, C 3~6 -cycloalkyl, phenyl and halo-C 1~6 -alkyl, or a pharmaceutically acceptable salt thereof.

[0076] In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is one R 10 is a 1,3,4-oxadiazole substituted with R 2 is fluorine, R 4 is phenyl, R 10is selected from methyl-methylsulfonyl-ethyl, pyrrolidine, 4-oxa-7-azaspiro[2.5]octan-7-yl, methyl-propanenitrile, 1,2,2,2-tetrafluoro-methoxy-ethyl, tertbutyl, 1-ethyl-5,5-difluoro-3-piperidyl, 4,4-difluoro-1-piperidyl and azabicyclo[3.1.1]heptane-3-carboxylate; R 11 is selected from 5-(trifluoromethyl)-2-pyridyl, phenoxy, trifluoromethoxy, methoxy-pyridyl, cyclopentoxy, 4-methoxyphenyl, (trifluoromethyl)-1,2,4-oxadiazol-3-yl, 5-(trifluoromethoxy)-2-pyridyl, 4-(trifluoromethyl)pyrazol-1-yl, chloro, 5-(difluoromethoxy)-2-pyridyl, 4-[4-(trifluoromethoxy)pyrazol-1-yl and 4-[5-(trifluoromethyl)tetrazol-2-yl].

[0077] 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, and R 1 but one or more R which may be the same or different 10 is a 5-membered heteroaryl optionally substituted with R 2 is fluorine, R 4 is phenyl, R 10 is selected from difluoro-(methoxyethyl)piperidyl, azabicyclo[3.1.1]heptane-carboxylate, amino-trifluoro-methyl-ethyl, methyl-methylsulfonyl-ethyl, pyrrolidine, oxa-azaspiro[2.5]octanyl, methyl-propanenitrile, tert-butyl, tetrafluoro-methoxy-ethyl, morpholino; R 11is selected from methoxyphenyl, (trifluoromethyl)-pyridyl, cyclopentoxy, phenoxy, trifluoromethoxy, (trifluoromethyl)-oxadiazolyl, chloro, methoxy-pyridyl, or a pharmaceutically acceptable salt thereof.

[0078] In another embodiment, there is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is one R 10 is a 1,3,4-oxadiazole substituted with R 2 is fluorine, R 4 is phenyl, R 10 is selected from methyl-methylsulfonyl-ethyl, pyrrolidine, oxa-azaspiro[2.5]octanyl, methyl-propanenitrile, tetrafluoro-methoxy-ethyl, R 11 is selected from (trifluoromethyl)-pyridyl, phenoxy, trifluoromethoxy, (trifluoromethyl)oxadiazolyl, methoxy-pyridyl, or a pharmaceutically acceptable salt thereof.

[0079] In another embodiment, the compound is 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-benzazepin-2-one; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; (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-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (3S)-3-amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one; (3R)-3-amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one; (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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; (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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; (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-benzazepin-2-one; (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-benzazepin-2-one; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; (3S)-3-amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; (3R)-3-amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (3S)-3-amino-8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-2-one; (3R)-3-amino-8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (3S)-3-amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one; (3R)-3-amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; (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-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; (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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; (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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; (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-benzazepin-2-one; (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-benzazepin-2-one; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; (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-benzazepin-2-one; (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-benzazepin-2-one; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; (3S)-3-amino-8-[5-[5,5-difluoro-1-(2-methoxyethyl)-3-piperidyl]-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; (3R)-3-amino-8-[5-[5,5-difluoro-1-(2-methoxyethyl)-3-piperidyl]-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; Methyl 1-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate; Methyl 1-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate; Methyl 1-[5-[(3S)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate; Methyl 1-[5-[(3R)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; (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-benzazepin-2-one; (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-benzazepin-2-one; 2-methyl-2-[5-[(3S)-3-amino-1-[[4-[5-(difluoromethyl)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; Methyl 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate; Methyl 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; Provided is a compound of formula (I) as described herein, selected from:

[0080] In a preferred embodiment, the compound is 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; (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-benzazepin-2-one; (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-benzazepin-2-one; (3S)-3-amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one; (3R)-3-amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one; (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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; (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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; (3S)-3-amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; (3R)-3-amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (3S)-3-amino-8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-2-one; (3R)-3-amino-8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; (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-benzazepin-2-one; (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-benzazepin-2-one; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; Methyl 1-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate; Methyl 1-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate; Methyl 1-[5-[(3S)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate; Methyl 1-[5-[(3R)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; and 2-Methyl-2-[5-[(3R)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile Provided is a compound of formula (I) as described herein, selected from:

[0081] In a more preferred embodiment, the compound is 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; (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-benzazepin-2-one; (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-benzazepin-2-one; (3S)-3-amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one; (3R)-3-amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one; (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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; (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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; (3S)-3-amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; (3R)-3-amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one; (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-benzazepin-2-one; (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-benzazepin-2-one; (3S)-3-amino-8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-2-one; (3R)-3-amino-8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-2-one; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; (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-benzazepin-2-one; (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-benzazepin-2-one; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; Methyl 1-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate; Methyl 1-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate; Methyl 1-[5-[(3S)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate; Methyl 1-[5-[(3R)-3-amino-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-3-azabicyclo[3.1.1]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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile; and 2-Methyl-2-[5-[(3R)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile Provided is a compound of formula (I) as described herein, selected from:

[0082] Manufacturing method Methods for preparing the compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, are also an object of the present invention.

[0083] The present invention provides a process for the preparation of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, comprising the steps of: TIFF2025526726000008.tif39170 (in the formula, R 1 , R 2 , and R 4 is as defined herein and PG is an amino protecting group) with a suitable deprotecting agent to form said compound of formula (I).

[0084] The preparation of the compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following method descriptions have the meanings given herein unless indicated to the contrary.

[0085] If one of the starting materials, intermediates, or compounds of formula (I) contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, suitable protecting groups (such as those described in "Protective Groups in Organic Chemistry," by T.W. Greene and P.G.M. Hutts, 5th Edition, 2014, John Wiley & Sons, NY) can be introduced prior to a critical step by applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0086] When the starting material or intermediate contains a stereocenter, the compound of formula (I) can be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as chiral HPLC, chiral SFC, or chiral crystallization. Racemates can be separated into their antipodes via diastereomeric salts, for example, by crystallization with an optically pure acid, or by separating the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. Starting materials and intermediates containing a stereocenter can also be separated to obtain diastereomerically / enantiomerically enriched starting materials and intermediates. The use of such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of the compound of formula (I) generally results in the respective diastereomerically / enantiomerically enriched compounds of formula (I).

[0087] Those skilled in the art will recognize that in the synthesis of compounds of formula (I), unless otherwise desired, an "orthogonal protecting group strategy" can be applied to cleave some protecting groups one at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has been described in the literature (e.g., Barany and R.B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0088] Those skilled in the art will recognize that the reaction sequence may vary depending on the reactivity and nature of the intermediates.

[0089] More specifically, compounds of formula (I) can be prepared by the methods described below, the methods described in the Examples, or similar methods. Suitable reaction conditions for the individual reaction steps are known to those skilled in the art. For literature-described reaction conditions affecting the described reactions, see, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock, John Wiley & Sons, New York, NY, 1999. The reactions could be easily carried out with or without a solvent. There are no particular restrictions on the nature of the solvent used, so long as it does not adversely affect the reaction or the reagents involved and is capable of dissolving the reagents to at least some extent. The described reactions can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. The described reactions are conveniently carried out at a temperature range from -78°C to reflux. The reaction time required for the reaction can also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain the intermediates and compounds described. The reaction order is not limited to the order shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities.

[0090] If the starting materials or intermediates are not commercially available or their synthesis is not described in the literature, they can be prepared analogously to existing procedures for similar analogs or as outlined in the experimental section.

[0091] Processes for preparing the compounds of formula (I) described herein are also an object of the present invention.

[0092] The preparation of the compounds of formula (I) of the present invention can be carried out according to sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The substituents and indices used in the following process descriptions have the meanings previously indicated herein, unless otherwise indicated.

[0093] More specifically, the compound of formula (I) can be prepared by the methods shown below, the methods shown in the examples, or similar methods. Suitable reaction conditions for each reaction step are known to those skilled in the art. The reaction order is not limited to the order shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods similar to the methods shown below, the methods described in the references or examples cited herein, or methods known in the art.

[0094] The present compounds of formula (I) and their pharmaceutically acceptable salts may be prepared by the method described below (Scheme 1). TIFF2025526726000009.tif244170

[0095] A suitable starting material for the preparation of compounds of formula (I) is the aniline derivative of formula (II). Compounds of formula (II) can be converted to compounds of formula (III) by reaction with chloroacetonitrile in the presence of AlCl3 and BCl3 at elevated temperature in a solvent such as toluene. Derivative (III) can be converted to aminomalonate derivative (IV) (where R nis alkyl) to give compounds of formula (V). Reaction of compounds of formula (V) with aqueous HCl at elevated temperature gives amino acid derivatives of formula (VI), which can then be N-protected by reaction with di-t-butyl dicarbonate in a solvent mixture such as dioxane and water in the presence of a base such as TEA to give compounds of formula (VII). Derivatives (VII) can be cyclized to compounds of formula (VIII) using T3P in the presence of a base such as DIPEA or TEA in a solvent such as DCM or THF. Introduction of a benzyl substituent to give compounds of formula (X) can be achieved by reaction of a halide or sulfonate of formula (IX) (X) in the presence of a base such as K2CO3 in a solvent such as DMF. 1 The reaction can be achieved by reaction with an alkyl group (wherein O is Cl, Br, I, or OSO2R). Optionally, potassium iodide can be added. Reaction of the compound of formula (X) with DAST provides a derivative of formula (XI), which can be converted to a compound of formula (XII) by a carbonylation reaction using a catalyst such as Pd(OAc)2 / dppp or Pd(dppp)Cl2 in a solvent mixture of DMF and alcohol in the presence of a base such as TEA or DIPEA at elevated temperature. Reaction of the compound of formula (XII) with an alkali hydroxide such as LiOH in an aqueous solvent mixture such as THF and water provides a compound of formula (XIII). Alternatively, the acid derivative (XIII) can be obtained from the compound of formula (XI) by a carbonylation reaction using a catalyst such as Pd(OAc)2 / dppp or Pd(dppp)Cl2 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 compounds of formula (XIII) to compounds of formula (XIV) can be achieved by the reaction of hydrazine after activation of derivative (XIII) with a reagent such as T3P in the presence of DIPEA or oxalyl chloride in the presence of DIPEA and a catalytic amount of DMF in a solvent such as DCM. Activation of compounds of formula (XIV) with a reagent such as HATU or T3P in the presence of a base such as DIPEA and subsequent acid derivative R 10Alternatively, compounds of formula (XV) can be prepared from compounds of formula (XIII) by the reaction of the hydrazide derivative R with COH in the presence of a base such as DIPEA in a solvent such as THF. 10 Compounds of formula (I) (wherein R 1 Compounds of formula (XVI) (wherein X is 1,3,4-oxadiazolyl) can be obtained from compounds of formula (XVI) by reaction with HCl in EtOAc, TFA in DCM or HFIP.

[0096] R 1 Compounds of formula (I) where is a six-membered heteroaryl group can be prepared as shown in Scheme 2. TIFF2025526726000010.tif54170

[0097] Reaction of compounds of formula (XI) with boronic acid (R is H) or boronate ester derivatives (XVII) in the presence of a palladium catalyst such as Pd(dppf)Cl-DCM and a base such as KCO in an aqueous solvent mixture such as dioxane and water provides compounds of formula (XVIII). Compounds of formula (XVIII) can be prepared by conversion of R to R as described for the conversion of compounds of formula (XVI) to compounds of formula (I) in Scheme 1. 1 is a 6-membered heteroaryl group.

[0098] Pharmaceutical Compositions and Administration Another object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0099] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicines in the form of pharmaceutical preparations.The pharmaceutical preparations can be administered to the body orally (for example, in the form of tablets, coated tablets, sugar-coated tablets, hard and soft gelatin capsules, solutions, emulsions, or suspensions), nasally (for example, in the form of nasal drops), or rectally (for example, in the form of suppositories).However, administration can also be carried out parenterally, such as intramuscularly or intravenously (for example, in the form of injections).Administration can also be carried out topically, for example, transdermally, or in the form of eye drops or ear drops.

[0100] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic carriers for the manufacture of pharmaceutical preparations such as tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injectable solutions or topical preparations, etc. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such carriers for tablets, coated tablets, sugar-coated tablets and hard gelatin capsules, for example.

[0101] Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. However, depending on the nature of the active substance, no carrier is usually required for soft gelatin capsules.

[0102] Suitable carriers for the production of solutions and syrups are, for example, water, alcohols, polyols, saccharose, glucose, invert sugar, vegetable oil and the like.

[0103] Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0104] Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

[0105] Suitable carriers for topical ophthalmic formulations are, for example, cyclodextrin, mannitol, or many other carriers and additives known in the art.

[0106] Furthermore, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical formulations of the present invention may further contain other therapeutically valuable substances.

[0107] Pharmaceuticals comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient are also an object of the present invention, as are processes for their preparation, which comprise bringing one or more compounds of formula (I) and / or a pharmaceutically acceptable salt thereof, and, if desired, one or more other therapeutically valuable substances, together with one or more pharmaceutically acceptable excipients, into a galenical dosage form.

[0108] The dosage can vary within a wide range and, of course, must be adjusted to the individual requirements in each specific case. Generally, for oral administration, a daily dosage of about 0.1 mg to 20 mg / kg body weight, preferably 0.5 mg to 4 mg / kg body weight (e.g., about 300 mg / person), preferably divided into 1 to 3 individual doses, each of which may consist of the same amount, would be appropriate. For topical administration, the formulation may contain 0.001% to 15% by weight of the drug, and the required dose, which may be between 0.1 and 25 mg, may be administered as a single dose per day, a single dose per week, multiple doses (2 to 4 times per day), or multiple doses per week. However, it is clear that, where indicated, the upper or lower limits set forth herein may be exceeded.

[0109] The pharmaceutical composition of the present invention can be prepared as follows. TIFF2025526726000011.tif85170Manufacturing Instructions: 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50°C. 3. Pass the granules through suitable grinding equipment. 4. Add ingredient 5, mix for 3 minutes and compress in a suitable press. TIFF2025526726000012.tif80170Manufacturing Instructions: 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into suitable capsules. TIFF2025526726000013.tif54170Manufacturing Instructions: A portion of a compound of formula (I) is dissolved in a mixture of polyethylene glycol 400 and water for injection. The pH is adjusted to 5.0 with acetic acid. The remaining amount of water is added to adjust the volume to 1.0 ml. The solution is filtered, filled into vials using an appropriate overage, and sterilized.

[0110] Indications The compounds of formula (I) can be used in an effective amount to treat subjects, particularly humans, suffering from cancer.

[0111] 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.

[0112] 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 the progression of cancer.

[0113] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment, prevention and / or delay of progression of cancer.

[0114] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment, prevention and / or delay of progression of cancer.

[0115] In a further aspect, the present invention provides a method for the treatment, prevention and / or delay of progression of cancer, comprising administering a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0116] As used herein, the terms "treatment" or "treating" and grammatical variations thereof refer to therapeutic therapy. With respect to a particular condition, treating means: (1) ameliorating the condition or one or more biological manifestations of the condition; (2) (a) interfering with one or more points in the biological cascade that leads to or causes the condition, or (b) one or more biological manifestations of the condition; (3) alleviating one or more symptoms, effects, or side effects associated with the condition or its treatment; or (4) slowing the progression of the condition or one or more biological manifestations of the condition. Prophylactic therapy using the methods and / or compositions of the present invention is also contemplated. Those skilled in the art will understand that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition or its biological manifestations, or to delay the onset of such a condition or its biological manifestations. Prophylactic therapy is appropriate when a subject is considered to be at high risk for developing cancer, for example, when the subject has a strong family history of cancer or when the subject has been exposed to a carcinogen.

[0117] As immunotherapeutics that act on immune cells rather than directly on cancer cells, the present disclosure may also be envisioned for use as an anti-cancer vaccine, including approaches in which immune cells are cultured and engineered ex vivo and the molecules disclosed herein are used as a means of costimulating the ex vivo engineered cells.

[0118] In one embodiment, the cancer is a blood cancer, such as lymphoma, leukemia, or myeloma. Blood cancers contemplated herein include, but are not limited to, one or more leukemias, such as B-cell acute lymphoblastic leukemia ("BALL"), T-cell acute lymphoblastic leukemia ("TALL"), acute lymphoblastic leukemia (ALL); one or more chronic leukemias, including but not limited to, chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL); B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia. These include, but are not limited to, small cell or large cell follicular lymphoma, malignant lymphoproliferative conditions, mucosa-associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, and "preleukemia," which are a diverse collection of hematological conditions united by the ineffective production (or dysplasia) of myeloid blood cells.

[0119] In further embodiments, the cancer is a non-hematological cancer, such as a sarcoma, carcinoma, or melanoma. Non-hematological cancers contemplated herein include, but are not limited to, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell carcinoma, melanoma, gastric cancer, brain cancer, lung cancer (e.g., non-small cell lung cancer - NSCLC), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.

[0120] Co-administration of Compounds of Formula (I) and Other Agents The compound of formula (I) or its salt, or the compound disclosed herein or its pharmaceutically acceptable salt, may be used alone or in combination with other drugs for treatment. For example, the second drug in a combined pharmaceutical formulation or administration regimen may have complementary activity to the compound of formula (I), so that they do not adversely affect each other. The compounds may be administered together in a single pharmaceutical composition or separately. In one embodiment, the compound or its pharmaceutically acceptable salt may be co-administered with a cytotoxic agent to treat proliferative diseases and cancer.

[0121] The term "co-administering" refers to simultaneous administration or separate, sequential administration in any manner of a compound of formula (I) or a salt thereof, or a compound disclosed herein or a pharmaceutically acceptable salt thereof, and additional active pharmaceutical ingredient(s), including cytotoxic agents and radiation therapy. If not administered simultaneously, the compounds are administered in close temporal proximity to each other. Furthermore, it does not matter whether the compounds are administered in the same dosage form; for example, one compound may be administered topically and the other compound may be administered orally.

[0122] Typically, any drug with anti-cancer activity can be co-administered.Examples of such drugs can be found in Cancer Principles and Practice of Oncology by V.T.Devita and S.Heilman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers.Those skilled in the art will be able to identify which combination of drugs is useful based on the specific characteristics of the drug and the disease involved.

[0123] In one aspect, the present invention provides a pharmaceutical composition as described herein, further comprising an additional therapeutic agent.

[0124] In one embodiment, the additional therapeutic agent is a chemotherapeutic agent.

[0125] In one embodiment, the additional therapeutic agent is a cytotoxic agent.

[0126] In one embodiment, the additional therapeutic agent is a cancer immunotherapeutic agent.

[0127] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents the function of cells and / or causes cell death or destruction. Cytotoxic agents include radioisotopes (At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 , and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof, such as nucleases; and toxins (including fragments and / or variants thereof), such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin.

[0128] Exemplary cytotoxic agents may be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, LDH-A inhibitors, fatty acid biosynthesis inhibitors, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism.

[0129] "Chemotherapeutic agents" include chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer / Sugen), letrozole (FEMARA®, Novartis), and rivaroxaban. is), imatinib mesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), lonafamib (SCH66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide, alkylsulfonates such as busulfan, improsulfan, and piposulfan, aziridines such as benzodopa, carboquone, mesuredopa, and uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramine ethylenimines and methylameramines, including methylameramine, acetogenins (especially bullatacin and bullatacinone), camptothecins (including topotecan and irinotecan), bryostatin, kallistatin, CC-1065 (including its azozelesin, carzelesin, and bizelesin synthetic analogs), cryptophycins (especially cryptophycin 1 and cryptophycin 8), corticosteroids (including prednisone and prednisolone),cyproterone acetate, finasteride, and dutasteride (5a-reductase inhibitors), vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat, dolastatins, aldesleukin, talc, duocarmycin (synthetic analogs KW-2189 and CBI-TM I), eleutherobin, pancratistatin, sarcodictyin, spongistatin, nitrogen mustards such as chlorambucil, chromafazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicine, fenesterine, prednimustine, trofosfamide, uracil mustard, nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine, antibiotics such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin γ1I and calicheamicin chol (Angew Chem. Inti. Ed. Engl. 1994) 33:183-186); dynemicins, e.g., dynemicin A, bisphosphonates, e.g., clodronate, esperamicin, and neocarzinostatin chromophores and related enediyne antibiotic chromophores), aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxo rubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rhodolubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, antimetabolites such as methotrexate and 5-fluorouracil (5-FU), folic acid analogues such as denopterin, methotrexate,Pteropterin, trimetrexate, purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone, antiadrenal agents such as aminoglutethimide, mitotane, trilostane, folic acid replacement solutions such as furoic acid, aceglatone, aldophosphamide glycosides , aminolevulinic acid, eniluracil, amsacrine, bestravcil, bisantrene, edatrexate, defofamine, demecolcine, diaziquone, elfomitin, elliptinium acetate, epothilone, etoglucide, gallium nitrate, hydroxyurea, lentinan, lonidynin, maytansinoids such as maytansine and ansamitocins, mitoguazone, mitoxantrone, mopidamol, nitraelin, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllic acid, 2-ethylhydrazide, procarbazine, PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.), razoxane, rhizoxin, schizofuran, spirogermanium, tenuazonic acid, triaziquone, 2,2',2"-trichlorotriethylamine, trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidine), urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside ("Ara-C"), cyclophosphamide, thiotepa, taxoids such as TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE® (docetaxel; Sanofi-Aventis), chlorambucil, GEMZAR® (gemcitabine),6-thioguanine, mercaptopurine, methotrexate, platinum analogs such as cisplatin and carboplatin, vinblastine, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, NAVELBINE® (vinorelbine), novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine (XELODA®), ibandronate, CPT-II, the topoisomerase inhibitor RFS2000, difluoromethylomithine (DMFO), retinoids such as retinoic acid, and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0130] Chemotherapeutic agents also include: (i) antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen (including NOLVADEX®, tamoxifen citrate), raloxifene, droxifene, iodoxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) adrenal gland estrogen inhibitors; aromatase inhibitors, which inhibit the enzyme aromatase, which regulates strogen production, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megstrol acetate), AROMASIN® (exemestane; Pfizer), formestany, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) flutamide, nilutamide, bicalutamide, Antiandrogens such as leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all-trans retionic acid, fenretinide, and troxacitabine (1,3-dioxolane nucleoside cytosine analogue); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, especially agents that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, e.g., PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®), HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, e.g., ALLOVECTIN®, LEUVECTIN®, VAXID®; PROLEUKIN®, rIL-2; topoisomerase I inhibitors such as LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0131] Chemotherapeutic agents also include antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idee), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody-drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, celizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, nat ... tuzumab, nimotuzumab, norobizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pexelizumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, reslizumab, reslivizumab, rovelizumab, lupizumab, sibrotuzumab, siplizumab, sontuzumab, tacatatuzumab tetraxetan, tadoxizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoreukin, tuxituuzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and interleukin-12 and anti-interleukin-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), an all-human sequence, full-length IgGi lambda antibody engineered to recognize the p40 protein.

[0132] Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or otherwise directly interact with EGFR and inhibit or reduce the signaling activity of EGFR, alternatively referred to as "EGFR antagonists." Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include MAb579 (ATCC CRL HB8506), MAb455 (ATCC CRL HB8507), MAb225 (ATCC CRL8508), MAb528 (ATCC CRL8509) (see U.S. Pat. No. 4,943,533, Mendelsohn et al.), and variants thereof, such as chimerized 225 (C225 or cetuximab, ERBUTIX®) and reconstituted human 225 (H225) (see WO 96 / 40210, Imclone Systems, Inc.). Inc.), IMC-11F8, a fully human EGFR-targeting antibody (Imclone), antibodies that bind to type II mutant EGFR (U.S. Pat. No. 5,212,290), humanized and chimeric antibodies that bind to EGFR as described in U.S. Pat. No. 5,891,996, and human antibodies that bind to EGFR, such as ABX-EGF or panitumumab (WO 98 / 50433, Abgenix / Amgen), EMD55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)), EMD7200 (matuzumab), a humanized EGFR antibody against EGFR that competes for EGFR binding of both EGF and TGF-alpha (EMD / Merck), the human EGFR antibody, HuMax-EGFR (GenMab), the fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, and E7.6.3, and described in U.S. Pat. No. 6,235,883, MDX-447 (Medarex Inc), and mAb806 or humanized mAb806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)).Anti-EGFR antibodies can be conjugated to cytotoxic agents to produce immunoconjugates (see, for example, European Patent Application Publication No. 659,439, Merck Patent GmbH). EGFR antagonists include those described in U.S. Patent Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, and small molecules such as compounds described in PCT Publications WO 98 / 14451, WO 98 / 50038, WO 99 / 09016, and WO 99 / 24037.Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA®, Genentech / OSI Pharmaceuticals), PD183805 (CI1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.), ZD1839, gefitinib (IRESSA®) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca), ZM105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca), BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim), Ingelheim), PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide), EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7 -ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butynamide) (Wyeth), AG1478 (Pfizer); AG1571 (SU5271, Pfizer), and dual EGFR / HER2 tyrosine kinase inhibitors, such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

[0133] Chemotherapeutic agents include "tyrosine kinase inhibitors," such as the EGFR-targeted drugs described in the previous paragraph; small molecule HER2 tyrosine kinase inhibitors, such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors, such as EKB-569 (available from Wyeth), which preferentially binds to EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016, available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors, such as canertinib (CI-1033, Pharmacia); Raf-1 inhibitors, such as ISIS, which inhibits Raf-1 signaling. non-HER-targeted TK inhibitors, such as imatinib mesylate (GLEEVEC®, available from GlaxoSmithKline); multi-targeted tyrosine kinase inhibitors, such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors, such as vatalanib (PTK787 / ZK222584, available from Novartis / Schering AG); the MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, such as PD153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP60261, and CGP62706; pyrazolopyrimidine, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide); tyrphostins containing a nitrothiophene moiety; PD-0183805 (Warner-Lamber); antisense molecules (e.g., those that bind to HER-encoding nucleic acids); quinoxalines (U.S. Patent No. 5,804,396); tryphostins (U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca);PTK-787 (Novartis / Schering AG); pan-HER inhibitors, such as CI-1033 (Pfizer); Affinitac (ISIS3521, Isis / Lilly); imatinib mesylate (GLEEVEC®); PKI166 (Novartis); GW2016 (GlaxoSmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); INC-ICl I (Imclone), rapamycin (sirolimus, RAPAMUNE®); or the following patent publications: U.S. Pat. No. 5,804,396, WO 1999 / 09016 (American Cyanamid), WO 1998 / 43960 (American Cyanamid), 1997 / 38983 (Warner Lambert), 1999 / 06378 (Warner Lambert), 1999 / 06396 (Warner Lambert), 1996 / 30347 (Pfizer, Inc.), 1996 / 33978 (Zeneca), 1996 / 3397 (Zeneca), and 1996 / 33980 (Zeneca).

[0134] Chemotherapeutic agents include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG (raw), bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, erlotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, and interferon alfa- 2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.

[0135] Chemotherapeutic agents include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, and hydrocortisone-17- butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasone-17-propionate, fluocortolone caproate, fluocortolone pivalate, and fluprednidene acetate; phenylalanine-glutamine-glycine (PEG) and its D-form (feG) (IMULAN) Immunoselective anti-inflammatory peptides (ImSAIDs) such as BioTherapeutics, LLC; antirheumatic drugs such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, and sulfasalazine; etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), cetolithumab pegol (Cimzia), and golimumab (Symptoms); tumor necrosis factor alpha (TNFα) blockers such as lebrikizumab (Kineret); interleukin 1 (IL-1) blockers such as anakinra (Kineret); T-cell costimulation blockers such as abatacept (Orencia); interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) blockers such as rontalizumab; beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as anti-M1 prime; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa1 / β2 blockers such as anti-lymphotoxin alpha (LTa); radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212、P 32 、Pb 212, and radioactive isotopes of Lu); various investigational drugs such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, and farnesyltransferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavins, flavanols, procyanidins, betulinic acid and its derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); Tarapachone; lapachol; colchicine; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin; podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); clodronate (e.g., BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate, bisphosphonates such as thiazolinone (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines such as the THERATOPE® vaccine; perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteosome inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); orafenib, ABT510; oblimersen sodium (GENASENSE®) pixantrone; farnesyltransferase inhibitors such as lonafarnib (SCH6636, SARASAR™); and pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of CHOP, which is an abbreviation for the combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, which is an abbreviation for the treatment regimen with oxaliplatin (ELOXATIN™) in combination with 5-FU and leucovorin.

[0136] In another embodiment, the compound of formula (I) can be co-formulated with a cancer immunotherapeutic agent. Cancer immunotherapeutic agents include, for example, small molecule drugs, antibodies, or other biological or small molecules. Examples of biological cancer immunotherapeutic agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human. In another aspect, the antibody is a bispecific antibody.

[0137] In one aspect, the cancer immunotherapeutic agent is either (i) an agonist of a stimulatory (including costimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on T cells, both of which result in amplification of antigen-specific T cell responses (often referred to as immune checkpoint modulators).

[0138] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or coinhibitory receptors are CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTfiR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNPβ, TNFR2, TNFα, LT R, lymphotoxin α It is a TNF family molecule that binds to cognate TNF receptor family members, including 1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0139] In one aspect, a T cell response may be stimulated by a combination of a compound of Formula (I) and (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin-9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) one or more of B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0140] Other drugs that can be combined with the compound of formula (I) for the treatment of cancer include the antagonist of inhibitory receptors on NK cells or the agonist of activating receptors on NK cells.For example, the compound of formula (I) can be combined with the antagonist of KIR, such as lirilumab.

[0141] Still other agents for combination therapy include agents that inhibit or deplete macrophages or monocytes, including CSF-1R antagonists such as CSF-1R antagonist antibodies, including, but not limited to, RG7155 or FPA-008.

[0142] In another embodiment, the compounds of formula (I) can be used in conjunction with one or more agents that include agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome different immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor binding (e.g., PD-L1 / PD-1 interactions), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell anergy or exhaustion), and innate immune activation and / or inflammation at the tumor site.

[0143] In some embodiments, the cancer immunotherapeutic agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. In another aspect, the cancer immunotherapeutic agent is a PD-1 antagonist, such as an antagonist PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO 2012 / 145493). Cancer immunotherapeutic agents may also include pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned. Another approach to targeting the PD-1 receptor is a recombinant protein called AMP-224, which consists of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0144] In another embodiment, the cancer immunotherapeutic agent is a PD-L1 antagonist, such as an antagonist PD-L1 antibody. Suitable PD-L1 antibodies include, for example, TECENTRIQ (atezolizumab) (RG7446; WO 2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO 2007 / 005874), and MSB0010718C (WO 2013 / 79174).

[0145] In another embodiment, the cancer immunotherapeutic agent is a LAG-3 antagonist, for example, an antagonist LAG-3 antibody.Suitable LAG3 antibodies include, for example, BMS-986016 (WO2010 / 19570, WO2014 / 08218), or IMP-731 or IMP-321 (WO2008 / 132601, WO2009 / 44273).

[0146] In another embodiment, the cancer immunotherapeutic agent is a CD137 (4-1BB) agonist, such as an agonist CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO 2012 / 32433).

[0147] In another embodiment, the cancer immunotherapeutic agent is a GITR agonist, for example, an agonistic GITR antibody.Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO2006 / 105021, WO2009 / 009116) and MK-4166 (WO2011 / 028683).

[0148] In another embodiment, the cancer immunotherapeutic agent is IDO antagonist.Suitable IDO antagonist includes, for example, INCB-024360 (WO2006 / 122150, WO2007 / 75598, WO2008 / 36653, WO2008 / 36642), indoximod or NLG-919 (WO2009 / 73620, WO2009 / 1156652, WO2011 / 56652, WO2012 / 142237).

[0149] In another embodiment, the cancer immunotherapeutic agent is an OX40 agonist, for example, an agonist OX40 antibody.Suitable OX40 antibody includes, for example, MEDI-6383 or MEDI-6469.In another embodiment, the cancer immunotherapeutic agent is an OX40L antagonist, for example, an antagonist OX40 antibody.Suitable OX40L antagonist includes, for example, RG-7888 (WO06 / 029879).

[0150] In another aspect, the cancer immunotherapeutic agent is a CD40 agonist, e.g., an agonist CD40 antibody. In yet another embodiment, the cancer immunotherapeutic agent is a CD40 antagonist, such as an antagonist CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0151] In another embodiment, the cancer immunotherapeutic agent is a CD27 agonist, such as an agonist CD27 antibody. Suitable CD27 antibodies include, for example, valilumab.

[0152] In another embodiment, the cancer immunotherapeutic agent is MGA271 (directed against B7H3) (WO 2011 / 109400). [Example]

[0153] The present invention will be more fully understood by reference to the following examples, which, however, should not be construed as limiting the scope of the claims to the examples.

[0154] 1) Preparation Examples 1.1) Intermediates Intermediate 1 2-Ethoxy-2,3,3,3-tetrafluoropropanehydrazide TIFF2025526726000014.tif23170 To a solution of 2-ethoxy-2,3,3,3-tetrafluoropropanoic acid [CAS 10186-67-1] (200 mg, 0.92 mmol, 1 equiv.) in EtOH (1.5 ml), hydrazine monohydrate (54.25 mg, 1.1 mmol, 1.2 equiv.) was added and the mixture was heated to 80° C. for 8 h. The resulting colorless solution was concentrated under reduced pressure and dried under high vacuum to give the title compound (119 mg, 60%) as a white solid. MS (ESI): 205.1 [M+H] + .

[0155] Intermediate 2 1-Ethyl-5,5-difluoro-piperidine-3-carboxylic acid Step a) Methyl 1-ethyl-5,5-difluoro-piperidine-3-carboxylate To a solution of methyl 5,5-difluoropiperidine-3-carboxylate; hydrochloride [CAS 1359656-87-3] (370.0 mg, 1.72 mmol, 1.0 equiv.) and TEA (0.24 mL, 1.72 mmol, 1.0 equiv.) in MeOH (5 mL), acetaldehyde (0.14 mL, 2.57 mmol, 1.5 equiv.) was added at 25° C., and the mixture was stirred for 1 h. Sodium cyanoborohydride (323.48 mg, 5.15 mmol, 3.0 equiv.) 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, CDCl3)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=11.2 Hz,1H),1.97-1.80(m,1H),1.11(t,J=7.2 Hz,3H).

[0156] Step b) 1-Ethyl-5,5-difluoro-piperidine-3-carboxylic acid To a solution of methyl 1-ethyl-5,5-difluoro-piperidine-3-carboxylate (340.0 mg, 1.64 mmol, 1.0 equiv.) in THF (10 mL) was added dropwise a solution of LiOH monohydrate (131.26 mg, 3.28 mmol, 2.0 equiv.) in water (2 mL), and the reaction mixture was stirred at 20° C. for 2 hours. The mixture was poured into water (10 mL), and the pH was adjusted to 5 by the addition of HCl (1 M). The mixture was then lyophilized to give a white solid (300 mg) containing the title compound. 1H NMR(400 MHz,D2O)δ=4.04-3.58(m,2H),3.57-2.96(m,5H),2.87-2.08(m,2H),1.35(t,J=7.2 Hz,3H).

[0157] Intermediate 3 2-[4-(chloromethyl)phenyl]-3-fluoro-5-(trifluoromethyl)pyridine TIFF2025526726000017.tif16170Step a) [4-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]phenyl]methanol To a mixture of 4-(hydroxymethyl)phenylboronic acid [CAS#59016-93-2] (1000.0 mg, 6.58 mmol, 1.0 equiv.), Pd(dppf)Cl2 (70.03 mg, 0.66 mmol, 0.1 equiv.), and potassium carbonate (2728.47 mg, 19.74 mmol, 3.0 equiv.) in a solvent mixture of water (3 mL) and 1,4-dioxane (24 mL), 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine [CAS#89402-29-9] (1926.66 mg, 7.9 mmol, 1.2 equiv.) was added under a nitrogen atmosphere at 25 °C. 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 × 3). The combined extracts were washed with brine (200 mL × 2), dried (Na2SO4), and concentrated. The remaining residue was purified by silica gel column chromatography (PE / EtOAc = 1:0 to 3:1) to afford the title compound (1650.0 mg, 6.08 mmol, 92% yield) as a yellow solid. MS (ESI): 272.1 [M+H] + .

[0158] Step b) 2-[4-(chloromethyl)phenyl]-3-fluoro-5-(trifluoromethyl)pyridine To a solution of [4-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]phenyl]methanol (1600.0 mg, 5.9 mmol, 1.0 equiv) in DCM (10 mL) was added thionyl chloride (1.39 mL, 19.11 mmol, 3.0 equiv) at 25 °C, 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 × 3). The combined extracts were washed with brine (100 mL × 2), dried (Na SO ), and concentrated to give the title compound (1600.0 mg) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.96(s,1H),8.43(d,J=10.5 Hz,1H),8.00-7.96(m,2H),7.63(d,J=8.3 Hz,2H),4.85(s,2H).

[0159] Intermediate 4 2-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)tetrazole A solution of 2-(p-tolyl)-5-(trifluoromethyl)tetrazole [CAS#1817810-19-7] (300.0 mg, 1.31 mmol, 1.0 equiv.), N-bromosuccinimide (304.22 mg, 1.71 mmol, 1.3 equiv.), and AIBN (107.95 mg, 0.66 mmol, 0.5 equiv.) in chlorobenzene (10 mL) was stirred at 100 °C for 12 h. The mixture was concentrated, and the remaining residue was purified by column chromatography on silica gel (PE / EtOAc = 1:0 to 50:1) to afford the title compound (200.0 mg, 0.65 mmol, 50% yield) as a yellow oil. 1 H NMR(400 MHz, CDCl3)δ=8.17(d,J=8.8 Hz,2H),7.64(d,J=8.8 Hz,2H),4.56(s,2H).

[0160] Intermediate 5 1-[4-(bromomethyl)phenyl]-3-(trifluoromethyl)-1,2,4 triazole The title compound was prepared from 1-(p-tolyl)-3-(trifluoromethyl)-1,2,4-triazole [CAS No. 2850321-26-3] in analogy to Intermediate 4 and obtained as a white solid. MS (ESI): 308.0 [M+H] + .

[0161] Intermediate 6 2-[4-(chloromethyl)phenyl]-4-(trifluoromethyl)pyridine; hydrochloride TIFF2025526726000022.tif20170 The title compound was prepared from [4-[4-(trifluoromethyl)-2-pyridyl]phenyl]methanol [CAS#1185444-74-9] in a similar manner to Intermediate 3, step b, and obtained as a white solid. MS(ESI): 272.0 [M+H] + .

[0162] Intermediate 7 2-[4-(chloromethyl)phenyl]-5-(1,1-difluoroethyl)pyridine TIFF2025526726000023.tif11170Step a) [4-[5-(1,1-difluoroethyl)-2-pyridyl]phenyl]methanol The title compound was prepared from 2-bromo-5-(1,1-difluoroethyl)pyridine [CAS#1211521-60-6] and 4-(hydroxymethyl)phenylboronic acid [CAS#59016-93-2] in analogy to step a of Intermediate 3, and obtained as a pale yellow solid. MS(ESI): 250.3 [M+H] + .

[0163] Step b) 2-[4-(chloromethyl)phenyl]-5-(1,1-difluoroethyl)pyridine TIFF2025526726000025.tif11170 The title compound was prepared from [4-[5-(1,1-difluoromethyl)-2-pyridyl]phenyl]methanol in analogy to Intermediate 3, step b, as a pale yellow solid. MS (ESI): 268.1 [M+H]+ .

[0164] Intermediate 8 2-[4-(chloromethyl)phenyl]-5-(difluoromethyl)pyridine TIFF2025526726000026.tif11170Step a) [4-[5-(difluoromethyl)-2-pyridyl]phenyl]methanol The title compound was prepared from 2-bromo-5-(difluoromethyl)pyridine [CAS#1221272-81-6] and 4-(hydroxymethyl)phenylboronic acid [CAS#59016-93-2] in analogy to step a of Intermediate 3, and obtained as a white solid. MS(ESI): 236.1 [M+H] + .

[0165] Step b) 2-[4-(chloromethyl)phenyl]-5-(difluoromethyl)pyridine TIFF2025526726000028.tif11170 The title compound was prepared from [4-[5-(difluoromethyl)-2-pyridyl]phenyl]methanol in analogy to Intermediate 3, step b, and obtained as a pale yellow solid. MS (ESI): 254.1 [M+H] + .

[0166] Intermediate 9 2-[4-(chloromethyl)phenyl]-5-(difluoromethoxy)pyridine TIFF2025526726000029.tif16170Step a) [4-[5-(difluoromethoxy)-2-pyridyl]phenyl]methanol TIFF2025526726000030.tif16170 The title compound was prepared from 2-bromo-5-(difluoromethoxy)pyridine [CAS# 845827-14-7] and 4-(hydroxymethyl)phenylboronic acid [CAS# 59016-93-2] in analogy to step a of Intermediate 3, and obtained as a white solid. MS (ESI): 252.1 [M+H] + .

[0167] Step b) 2-[4-(chloromethyl)phenyl]-5-(difluoromethoxy)pyridine TIFF2025526726000031.tif16170 The title compound was prepared from [4-[5-(difluoromethoxy)-2-pyridyl]phenyl]methanol in analogy to Intermediate 3, step b, and obtained as a pale yellow solid. MS (ESI): 270.0 [M+H] + .

[0168] Intermediate 10 1-[4-(bromomethyl)phenyl]-4-(trifluoromethoxy)pyrazole TIFF2025526726000032.tif12170Step a) O-[1-(p-tolyl)pyrazol-4-yl]methylsulfanylmethanethioate To a solution of 1-(p-tolyl)pyrazol-4-ol (2300.0 mg, 13.2 mmol, 1.0 equiv) [CAS#77458-34-5] and methyl 3-methylimidazol-3-ium-1-carbodithioate (3431.78 mg, 19.8 mmol, 1.5 equiv) in MeCN (40 mL), TEA (3.68 mL, 26.41 mmol, 2.0 equiv) was added at 25 °C, 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 × 3). The combined organic extracts were washed with brine (100 mL), dried (Na SO ), 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, CDCl3)δ=8.04(s,1H),7.69(s,1H),7.57(d,J=8.4 Hz,2H),7.29(s,2H),2.71(s,3H),2.42(s,3H).

[0169] Step b) 3,5-Dibromo-1-(p-tolyl)-4-(trifluoromethoxy)pyrazole and 5-bromo-1-(p-tolyl)-4-(trifluoromethoxy)pyrazole A solution of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (8652.12 mg, 30.26 mmol, 4.0 equiv) and HF-pyridine (1165.27 mg, 7.57 mmol, 1.0 equiv) in DCM (15 mL) was stirred at −70° C. for 0.5 h. Then, O-[1-(p-tolyl)pyrazol-4-yl]methylsulfanyl methanethioate (2.0 g, 7.57 mmol, 1.0 equiv) in DCM (15 mL) was 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 a saturated aqueous solution of NaHCO (80 mL), and the resulting mixture was extracted with EtOAc (3 × 60 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The remaining residue was purified by silica gel column chromatography (PE / EtOAc = 1:0 to 10:1) to give a mixture of 3,5-dibromo-1-(p-tolyl)-4-(trifluoromethoxy)pyrazole (1550.0 mg, 3.88 mmol, 51% yield) and 5-bromo-1-(p-tolyl)-4-(trifluoromethoxy)pyrazole (600.0 mg, 1.87 mmol, 25% yield) as a yellow solid. MS (ESI): 400.9 [M+H] + and 323.0[M+H] + .

[0170] Step c) 1-(p-tolyl)-4-(trifluoromethoxy)pyrazole A solution of 3,5-dibromo-1-(p-tolyl)-4-(trifluoromethoxy)pyrazole (1550.0 mg, 3.88 mmol, 1.0 equiv.) and 5-bromo-1-(p-tolyl)-4-(trifluoromethoxy)pyrazole (600.0 mg, 1.87 mmol, 0.48 equiv.) in MeOH (5 mL) was added to a suspension of Pd / C (500.0 mg, 18.69 mmol, 4.82 equiv.) in MeOH (5 mL) under a nitrogen atmosphere. The reaction mixture was degassed and charged with hydrogen three times, and then the mixture was stirred under a hydrogen atmosphere at 25° C. for 1 h. The mixture was filtered through celite 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] + .

[0171] Step d) 1-[4-(bromomethyl)phenyl]-4-(trifluoromethoxy)pyrazole TIFF2025526726000036.tif12170 The title compound was prepared from 1-(p-tolyl)-4-(trifluoromethoxy)pyrazole in analogy to Intermediate 4 and obtained as a yellow solid. MS (ESI): 323.0 [M+H] + .

[0172] Intermediate 11 1-[4-(chloromethyl)-3-fluoro-phenyl]-4-(trifluoromethyl)pyrazole TIFF2025526726000037.tif16170Step a) Methyl 2-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]benzoate To a solution of methyl 4-bromo-2-fluorobenzoate [CAS# 179232-29-2] (5.14 g, 22.05 mmol, 1.0 equiv.), 4-(trifluoromethyl)-1H-pyrazole [CAS# 52222-73-8] (3.0 g, 22.05 mmol, 1.0 equiv.), and trans-N,N-dimethylcyclohexane-1,2-diamine (6.27 g, 44.09 mmol, 2.0 equiv.) in DMSO (50 mL), CuI (4.2 g, 22.05 mmol, 1.0 equiv.) was added 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 (NaSO), and concentrated. The remaining residue was purified by column chromatography on silica gel (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] + .

[0173] Step b) [2-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methanol To a solution of methyl 2-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]benzoate (3400.0 mg, 11.8 mmol, 1.0 equiv.) in THF (40 mL) was added diisobutylaluminum hydride (50.0 mL, 50.0 mmol, 4.24 equiv.) at 0° C. The mixture was then warmed to 25° C. and stirred for 12 hours. 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 (Na2SO4), and concentrated to give the title compound (2500.0 mg, 9.61 mmol, 79% yield) as a white solid, which was used in the next step without further purification. MS (ESI): 261.1 [M+H] + .

[0174] Step c) 1-[4-(chloromethyl)-3-fluoro-phenyl]-4-(trifluoromethyl)pyrazole TIFF2025526726000040.tif16170 The title compound was prepared from [2-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methanol in analogy to step b of intermediate 3 and obtained as a brown oil. 1 H NMR(400 MHz, CDCl3)δ=8.00(s,1H),7.72(s,1H),7.38-7.27(m,3H),4.47(s,2H).

[0175] Intermediate 12 3-(Chloromethyl)-2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]pyridine TIFF2025526726000041.tif16170Step a) Methyl 2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]pyridine-3-carboxylate A mixture of 4-(trifluoromethyl)-1H-pyrazole (3.0 g, 22.05 mmol, 1.0 equiv), potassium carbonate (9140.61 mg, 66.14 mmol, 3.0 equiv), and methyl 2,6-difluoropyridine-3-carboxylate (4579.89 mg, 26.46 mmol, 1.2 equiv) 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 SO ), and concentrated. The remaining residue was purified by silica gel column chromatography (PE / EtOAc = 20:1 to 5:1) to give a pale 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 (2.1 g, 7.26 mmol, 32% yield) as a pale yellow solid. MS (ESI): 290.0 [M+H] + .

[0176] Step b) [2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]methanol TIFF2025526726000043.tif16170 The title compound was prepared from methyl 2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]pyridine-3-carboxylate in analogy to step b of Intermediate 11, and obtained as a pale yellow solid. MS (ESI): 262.1 [M+H] + .

[0177] Step c) 3-(chloromethyl)-2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]pyridine TIFF2025526726000044.tif16170 The title compound was prepared from [2-fluoro-6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]methanol in analogy to Intermediate 3, step b, and obtained as a pale yellow solid. MS (ESI): 280.1 [M+H] + .

[0178] Intermediate 13 5-(chloromethyl)-2-[4-(trifluoromethyl)pyrazol-1-yl]pyridine TIFF2025526726000045.tif16170Step a) Methyl 6-[4-(trifluoromethyl)pyrazol-1-yl]pyridine-3-carboxylate To a mixture of 4-(trifluoromethyl)-1H-pyrazole (2.0 g, 14.7 mmol, 1.0 equiv.) and potassium carbonate (6.1 g, 44.1 mmol, 3.0 equiv.) in DMF (48 mL) was added a solution of methyl 6-chloronicotinate (2.27 g, 13.2 mmol, 0.9 equiv.) in DMF (24 mL) dropwise at 25 °C, and the mixture was then 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 SO ), 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] + .

[0179] Step b) 6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]methanol TIFF2025526726000047.tif16170 The title compound was prepared from methyl-6-[4-(trifluoromethyl)pyrazol-1-yl]pyridine-3-carboxylate in analogy to step b of Intermediate 11 and obtained as a yellow solid. MS (ESI): 244.3 [M+H] + .

[0180] Step c) 5-(chloromethyl)-2-[4-(trifluoromethyl)pyrazol-1-yl]pyridine TIFF2025526726000048.tif16170 The title compound was prepared from 6-[4-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]methanol in analogy to intermediate 3, step b, and obtained as a yellow oil. MS (ESI): 262.2 [M+H] + .

[0181] Intermediate 14 1-[4-(chloromethyl)-2-fluoro-phenyl]-4-(trifluoromethyl)pyrazole TIFF2025526726000049.tif16170Step a) Methyl 3-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]benzoate A mixture of 4-(trifluoromethyl)-1H-pyrazole (200.0 mg, 1.47 mmol, 1.0 equiv.), potassium carbonate (609.37 mg, 4.41 mmol, 3.0 equiv.), and methyl 3,4-difluorobenzoate (379.48 mg, 2.2 mmol, 1.5 equiv.) 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 (NaSO), and concentrated. The remaining residue was purified by column chromatography on silica gel (PE / EtOAc = 1:0 to 5:1) to afford the title compound (400.0 mg, 1.39 mmol, 80% yield) as a pale yellow solid. MS(ESI):289.0[M+H] + .

[0182] Step b) [3-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methanol TIFF2025526726000051.tif16170 The title compound was prepared from methyl 3-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]benzoate in analogy to step b of Intermediate 11 and obtained as a white solid. MS (ESI): 261.0 [M+H] + .

[0183] Step c) 1-[4-(chloromethyl)-2-fluoro-phenyl]-4-(trifluoromethyl)pyrazole TIFF2025526726000052.tif16170 The title compound was prepared from [3-fluoro-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]methanol in analogy to step b of Intermediate 3, and obtained as a pale yellow solid. MS (ESI): 279.0 [M+H] + .

[0184] Intermediate 15 4-[4-(chloromethyl)phenyl]-1-(trifluoromethyl)pyrazole TIFF2025526726000053.tif17170Step a) [4-[1-(trifluoromethyl)pyrazol-4-yl]phenyl]methanol TIFF2025526726000054.tif17170 Potassium carbonate (2571.19 mg, 18.6 mmol, 2.5 equiv.), 4-bromobenzyl alcohol [CAS#873-75-6] (1391.8 mg, 7.44 mmol, 1.0 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane) in a mixture of water (1 mL) and 1,4-dioxane (8 mL). A mixture of (saborolan-2-yl)-1-(trifluoromethyl)pyrazole [CAS#1046831-98-4] (1950.0 mg, 7.44 mmol, 1.0 equiv.) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (607.24 mg, 0.74 mmol, 0.1 equiv.) was stirred at 90°C under a nitrogen atmosphere for 3 hours. The reaction mixture was concentrated in vacuo, and the remaining residue was purified by silica gel column chromatography to give the title compound (1620.0 mg, 6.69 mmol, 90% yield) as a yellow oil. MS(ESI): 243.1 [M+H] + .

[0185] Step b) 4-[4-(chloromethyl)phenyl]-1-(trifluoromethyl)pyrazole To a solution of [4-[1-(trifluoromethyl)pyrazol-4-yl]phenyl]methanol (1600.0 mg, 6.61 mmol, 1.0 equiv.) in DCM (10 mL) was added thionyl chloride (1.4 mL, 19.82 mmol, 3.0 equiv.) slowly at 20° C., and the solution was stirred at 20° C. for 1 h. The reaction mixture was concentrated in vacuo to afford 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] + .

[0186] Intermediate 16 5,5-Difluoro-1-(2-methoxyethyl)piperidine-3-carboxylic acid TIFF2025526726000056.tif31170 Step a) Methyl 5,5-difluoro-1-(2-methoxyethyl)piperidine-3-carboxylate To a mixture of methyl 5,5-difluoropiperidine-3-carboxylate hydrochloride (1100.0 mg, 5.1 mmol, 1.0 equiv.), 2-bromoethyl methyl ether (1.44 mL, 15.3 mmol, 3.0 equiv.), and potassium carbonate (2115.1 mg, 15.3 mmol, 3.0 equiv.) in MeCN (20 mL), potassium iodide (0.14 mL, 2.55 mmol, 0.5 equiv.) was added 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 in vacuo (Na2SO4), and concentrated. 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 H NMR(400 MHz, CDCl3)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).

[0187] Step b) 5,5-Difluoro-1-(2-methoxyethyl)piperidine-3-carboxylic acid To a solution of methyl 5,5-difluoro-1-(2-methoxyethyl)piperidine-3-carboxylate (500.0 mg, 2.11 mmol, 1.0 equiv.) in THF (10 mL) was added dropwise a solution of LiOH—HO (168.61 mg, 4.22 mmol, 2.0 equiv.) in water (2 mL), 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 the addition of HCl (1 M). The mixture was lyophilized to afford the title compound (450.0 mg) as a white solid (containing LiCl). 1 H NMR(400MHz,DMSO-d6)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).

[0188] 1.2) Synthesis of Examples Example 1 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-benzazepin-2-one TIFF2025526726000059.tif38170 Step a) 1-(2-amino-4-bromo-5-fluoro-phenyl)-2-chloro-ethanone Chloroacetonitrile (4.6 mL, 72.63 mmol, 1.38 equiv.) was added dropwise to a mixture of AlCl (8.84 g, 66.31 mmol, 1.26 equiv.) and BCl (1 M in DCM, 61.05 mL, 61.05 mmol, 1.16 equiv.) in toluene (200 mL), and the mixture was stirred at 0 °C for 0.5 h under a nitrogen atmosphere. 3-Bromo-4-fluoroaniline (6.33 mL, 52.63 mmol, 1 equiv.) was added, and the reaction mixture was stirred at 20 °C for 0.5 h and then heated to 70 °C for 16 h. HCl (100 mL) was then added over 30 min at 50 °C. The mixture was cooled to room temperature and extracted with DCM (2 × 30 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed under reduced pressure to give a residue which was purified by preparative HPLC to give the title compound as a brown solid (3.3 g, 12.38 mmol, 23% yield). 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)

[0189] Step b) Diethyl 2-acetamido-2-[2-(2-amino-4-bromo-5-fluoro-phenyl)-2-oxo-ethyl]propanedioate Sodium ethyl acetate (21 wt% in ethanol, 1.09 mL, 13.9 mmol, 1.61 equiv.) was added to a solution of diethyl 2-acetamidopropanedioate (1.87 g, 8.63 mmol, 1 equiv.) 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 equiv.) and 1-(2-amino-4-bromo-5-fluorophenyl)-2-chloroethanone (2.3 g, 8.63 mmol, 1 equiv.) in THF (10 mL) was added, and the resulting mixture was stirred at 50 °C for 16 h.

[0190] The reaction mixture was added to ice / water (15 mL), and the resulting mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the 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] + .

[0191] Step c) 2-amino-4-(2-amino-4-bromo-5-fluoro-phenyl)-4-oxo-butanoic acid A solution of diethyl 2-acetamido-2-[2-(2-amino-4-bromo-5-fluoro-phenyl)-2-oxo-ethyl]propanedioate (1.95 g, 4.36 mmol, 1 equiv.) in hydrochloric acid (0.218 M, 20.0 mL, 4.36 mmol, 1 equiv.) was stirred at 110 °C for 16 h. The mixture was concentrated in vacuo to give 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 directly in the next reaction step.

[0192] Step d) 4-(2-amino-4-bromo-5-fluoro-phenyl)-2-(tert-butoxycarbonylamino)-4-oxo-butanoic acid To a solution of 2-amino-4-(2-amino-4-bromo-5-fluoro-phenyl)-4-oxobutanoic acid (1.33 g, 4.36 mmol, 1 equiv.) and di-t-butyl dicarbonate (1.14 g, 5.23 mmol, 1.2 equiv.) in a dioxane (15 mL) and water (10 mL) solvent mixture, TEA (1.21 mL, 8.72 mmol, 2 equiv.) was added 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 approximately 4 with 2 N HCl. The organic phase was separated, washed with brine, dried over Na SO , and evaporated in vacuo. The remaining residue was purified by column chromatography on silica gel (20% to 40% EtOAc in PE (containing 0.1% AcOH)) to give the title compound (1.2 g, 2.96 mmol, 56% yield) as a brown oil. MS (ESI): 351.0 [M-isobutene + H] + .

[0193] Step e) tert-butyl N-(8-bromo-7-fluoro-2,5-dioxo-3,4-dihydro-1H-1-benzazepin-3-yl)carbamate 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 equiv.) and DIPEA (1.29 mL, 7.4 mmol, 3 equiv.) in DCM (20 mL), T3P (2.36 g, 3.7 mmol, 1.5 equiv.) was added, 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 × 2). The organic extract was washed with brine (10 mL × 3), dried over Na2SO4, and concentrated in vacuo to give the title compound (870 mg, 2.25 mmol, 91% yield) as a yellow solid. MS(ESI):330.7[M-isobutene+H] + .

[0194] Step f) tert-butyl N-[8-bromo-7-fluoro-2,5-dioxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate To a solution of tert-butyl N-(8-bromo-7-fluoro-2,5-dioxo-3,4-dihydro-1H-1-benzazepin-3-yl)carbamate (900.0 mg, 2.32 mmol, 1 equiv.) in DMF (30 mL) was added KCO (706.76 mg, 5.11 mmol, 2.2 equiv.) and 4-(trifluoromethoxy)benzyl bromide (0.37 mL, 2.32 mmol, 1 equiv.) at 0° C., 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 × 3). The combined extracts were dried over NaSO and concentrated to give a liquid, which was purified by silica gel column chromatography (4% to 80% EtOAc in PE) to give the title compound (1.07 g, 1.91 mmol, 63% yield) as a yellow oil. MS (ESI): 504.9 [M-isobutene + H] + .

[0195] Step g) tert-butyl N-[8-bromo-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate To tert-butyl N-[8-bromo-7-fluoro-2,5-dioxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (2.0 g, 2.85 mmol, 1 equiv.) was added DAST (20.0 mL) dropwise at 0-10 °C under a nitrogen atmosphere, 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 pH of the mixture was adjusted to 8 by the addition of NaHCO3. The phases were separated, and the organic phase was washed with brine (100 mL), dried (Na2SO4), 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 give the title compound (0.8 g, 1.37 mmol, 48% yield) as a pale yellow solid. MS (ESI): 528.9 [M-isobutene + H] + .

[0196] Step h) Ethyl 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-8-carboxylate To a mixture of tert-butyl N-[8-bromo-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (480.0 mg, 0.820 mmol, 1 equiv.), 1,3-bis-(diphenylphosphino)propane (67.88 mg, 0.160 mmol, 0.200 equiv.) and palladium diacetate (18.47 mg, 0.080 mmol, 0.100 equiv.) in a solvent mixture of ethanol (6 mL) and DMF (12 mL), TEA (0.34 mL, 2.47 mmol, 3 equiv.) was added. The mixture was then degassed three times with nitrogen, then charged three times with CO (230.41 mg, 8.23 mmol, 10 equiv.), and stirred under CO (45 psi) at 80° C. for 16 h. Water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL×3). The combined extracts were dried over NaSO, filtered, and concentrated in vacuo. The remaining residue was purified by column chromatography on silica gel (4% to 80% EtOAc in PE) to give the title compound (437 mg, 0.760 mmol, 87% yield) as a yellow oil. MS (ESI): 521.0 [M-isobutene + H] + .

[0197] Step i) 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-8-carboxylic acid To a solution of ethyl 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-8-carboxylate (890.0 mg, 1.54 mmol, 1 equiv.) in a solvent mixture of THF (8 mL) and water (8 mL), LiOH (147.9 mg, 6.18 mmol, 4 equiv.) was added at 0° C., and the reaction mixture was then stirred at 20° C. for 4 h. The pH of the mixture was then adjusted to 3-4 by the addition of 1 N HCl. The mixture was extracted with EtOAc (10 mL x 3), and the extract was dried over NaSO and concentrated in vacuo to give the title compound (790 mg, 1.44 mmol, 84% yield) as a yellow foam. MS (ESI): 493.0 [M-isobutene + H] + .

[0198] Step j) tert-Butyl N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate To a solution of 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-8-carboxylic acid (430.0 mg, 0.780 mmol, 1 equiv.) and T3P (748.41 mg, 1.18 mmol, 1.5 equiv.) in DCM (10 mL), DIPEA (0.41 mL, 2.35 mmol, 3 equiv.) and hydrazine monohydrate (0.16 mL, 3.14 mmol, 4 equiv.) were added, 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 × 3). The combined extracts were washed with brine (5 mL x 3), dried over NaSO, filtered, and concentrated in vacuo, and the remaining residue was purified by silica gel column chromatography (4% to 40% EtOAc in PE) to afford the title compound (220 mg, 0.390 mmol, 49% yield) as a yellow oil. MS (ESI): 507.0 [M-isobutene + H] + .

[0199] Step k) tert-Butyl N-[8-[(2,2-dimethylpropanoylamino)carbamoyl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate To a solution of tert-butyl N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (70.0 mg, 0.120 mmol, 1 equiv.) in THF (60 mL) was added DIPEA (0.07 mL, 0.370 mmol, 3 equiv.), HATU (56.79 mg, 0.150 mmol, 1.2 equiv.), and pivalic acid (13.98 mg, 0.140 mmol, 1.1 equiv.) at 25 °C, and the mixture was stirred at 25 °C for 4 h. The reaction mixture was concentrated in vacuo to remove THF. Then, EtOAc (20 mL) was added, and the mixture was washed with water (10 mL) and brine (10 mL × 3), dried over anhydrous NaSO, and concentrated in vacuo to give the crude product. The crude product was purified by preparative TLC (PE / EA = 1:2) to give the title compound (45 mg, 0.070 mmol, 39% yield) as a yellow oil. MS (ESI): 591.0 [M-isobutene + H] + .

[0200] Step l) tert-butyl 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-benzazepin-3-yl]carbamate To a solution of tert-butyl N-[8-[(2,2-dimethylpropanoylamino)carbamoyl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (30.0 mg, 0.050 mmol, 1 equiv.) in toluene (40 mL) was added Burgess reagent (44.23 mg, 0.190 mmol, 4 equiv.) at 25 °C, 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 × 3). The combined extracts were washed with brine (10 mL x 3), dried over NaSO, and concentrated in vacuo to give the title compound (30 mg, 0.050 mmol, 84% yield) as a yellow oil. MS (ESI): 573.0 [M-isobutene + H] + .

[0201] 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-benzazepin-2-one A solution of tert-butyl 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-benzazepin-3-yl]carbamate (30.0 mg, 0.05 mmol, 1.0 equiv.) in TIFF2025526726000072.tif38170HCl / EtOAc (4 M, 2.0 mL, 8.0 mmol, 167.62 equiv.) 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 (12.4 mg, 0.020 mmol, 47% yield) as a yellow oil. MS (ESI): 529.5 [M+H] + .

[0202] Example 2 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile and 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile TIFF2025526726000073.tif38170 Step a) tert-Butyl N-[8-[[(2-cyano-2-methyl-propanoyl)amino]carbamoyl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000074.tif41170To a solution of 2-cyano-2,2-dimethylacetic acid (0.05 mL, 0.51 mmol, 1.7 equiv) in THF (1 mL), DIPEA (0.13 mL, 0.91 mmol, 3.0 equiv) and T3P (345.46 mg, 0.45 mmol, 1.5 equiv) were added and the mixture was stirred at 15°C for 15 min. Then, tert-butyl N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (Example 1, Step j) (170.0 mg, 0.3 mmol, 1.0 equivalent) was added at 15° C., and the reaction mixture was stirred at 20° C. for 16 hours. The reaction mixture was concentrated in vacuo to remove THF, which was then diluted with EtOAc (20 mL), washed with HO (10 mL), brine (10 mL×3), and dried over anhydrous NaSO. The organic layer was concentrated in vacuo to give a yellow oil (310.0 mg) containing the title compound, which was used in the next reaction step without further purification. MS (ESI): 602.1 [M-isobutene + H] + .

[0203] Step b) tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000075.tif41170 The title compound was prepared from N-[8-[[(2-cyano-2-methyl-propanoyl)amino]carbamoyl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (310.0 mg, 0.47 mmol) in analogy to Step 1 of Example 1, and obtained as a yellow oil (120.0 mg, 0.19 mmol, 36% yield). MS (ESI): 584.1 [M-isobutene + H] + .

[0204] Step c) 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile and 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile A solution of tert-butyl 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-benzazepin-3-yl]carbamate (60.0 mg, 0.09 mmol, 1.0 equiv) in TIFF2025526726000076.tif38170HCl / EtOAc (4 M, 4.0 mL, 16.0 mmol, 170.55 equiv) 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 give pure 2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile. This was subjected to chiral SFC to give 2-methyl-2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile [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 2-methyl-2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile [Isomer A] (8.5 mg, 0.02 mmol, 17% yield) was obtained as a white powder. MS(ESI): 540.1 [M+H] + , retention time 1.05 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0205] Example 3 (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-benzazepin-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-benzazepin-2-one TIFF2025526726000077.tif38170 Step a) tert-Butyl N-[5,5,7-trifluoro-8-[(morpholine-4-carbonylamino)carbamoyl]-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate To a solution of tert-butyl N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (Example 1, step j) (100.0 mg, 0.18 mmol, 1.0 equiv) in DCM (1 mL) was added pyridine (0.5 mL, 6.18 mmol, 34.77 equiv) and morpholine-4-carbonyl chloride (0.06 mL, 0.51 mmol, 2.89 equiv) at 25° C., and the mixture was stirred at 30° C. for 16 h. The mixture was diluted with EtOAc (10 mL), washed with 1N HCl (3×8 mL), and then concentrated in vacuo to give 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-isobutene + H] + .

[0206] Step b) tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000079.tif41170 The title compound was prepared from tert-butyl N-[5,5,7-trifluoro-8-[(morpholine-4-carbonylamino)carbamoyl]-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (280.0 mg, 0.41 mmol) in a similar manner to Step 1 of Example 1, and obtained as a yellow oil (120.0 mg, 0.18 mmol, 44% yield). MS (ESI): 658.1 [M+H] + .

[0207] 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-benzazepin-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-benzazepin-2-one A solution of tert-butyl 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-benzazepin-3-yl]carbamate (120.0 mg, 0.18 mmol, 1.0 equiv) in TIFF2025526726000080.tif38170HCl / EtOAc (4 M, 6.0 mL, 24.0 mmol, 131.51 equiv) was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo, and the remaining residue was purified by preparative HPLC (neutral) to give 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-benzazepin-2-one. This was subjected to chiral SFC to give (3-amino-5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one [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 (3-amino-5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazol-2-yl)-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one [Isomer A] (19.5 mg, 0.03 mmol, 19% yield) was obtained as a white powder. MS (ESI): 540.1 [M+H] + , retention time 1.86 min (column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0208] Example 4 (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-benzazepin-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-benzazepin-2-one TIFF2025526726000081.tif38170 Step a) (3S)-3-(tert-butoxycarbonylamino)-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-carboxylic acid TIFF2025526726000082.tif41170 tert-Butyl N-[8-bromo-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (Example 1, Step 1) (490.0 mg, 0.84 mmol, 1.0 equiv) in a mixture of DMF (10 mL) and water (2 mL). To a mixture of 1,3-bis-(diphenylphosphino)propane (69.29 mg, 0.17 mmol, 0.2 equiv.), palladium diacetate (18.86 mg, 0.08 mmol, 0.1 equiv.) was added TEA (0.35 mL, 2.52 mmol, 3.0 equiv.), and the mixture was then degassed three times with nitrogen and then filled with CO three times, and the mixture was stirred under CO (45 psi) at 80° C. for 16 h. The mixture was diluted with 1 N HCl (10 mL) and extracted with EtOAc (3×15 mL). The organic extract was dried over NaSO and concentrated under vacuum, and the remaining residue was purified by preparative HPLC (HCl) to give pure 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-8-carboxylic acid. This was subjected to chiral SFC to give 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-8-carboxylic acid [isomer B] (67.1 mg, 0.12 mmol, 15% yield) as a yellow powder (MS(ESI): 492.9 [M-isobutene + H]). + , retention time 1.47 min (see conditions below)) to give 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) as a white powder. MS (ESI): 492.9 [M - isobutene + H] +, retention time 1.19 min (column: Chiralpak IG-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for IPA (0.05% DEA); gradient elution: 5% to 40% IPA (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: DAD; column temperature: 35 °C; back pressure: 100 bar).

[0209] Step b) tert-butyl 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-benzazepin-3-yl]carbamate and tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000083.tif41170 (3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-keto-1-[4-(trifluoromethoxy)benzyl]-3,4-dihydro-1-benzazepine-8-carboxylic acid [Isomer A] (63 mg, 0.114 mmol, 1 equiv.), 2,3,3,3-tetrafluoro-2- A mixture of methoxy-propionohydrazide (Intermediate 1) (29.03 mg, 0.148 mmol, 1.3 equiv) and DIPEA (29.45 mg, 39.01 uL, 0.228 mmol, 2 equiv) was stirred at room temperature. HATU (64.99 mg, 0.171 mmol, 1.5 equiv) was added and stirring was continued for 40 minutes. The solution was concentrated to give a pale yellow foam, which was dissolved in THF (0.940 mL). To the residue, Burgess's reagent (135.78 mg, 0.570 mmol, 5 equiv.) was added in one portion, and the mixture was stirred for 1 h. The mixture was diluted with EtOAc and water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The remaining residue was purified by silica gel column chromatography (0% to 30% EtOAc in heptane) to give tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (54 mg, 68%) as a colorless solid. MS (ESI): 647.3 [M - isobutene + H] +tert-Butyl 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-benzazepin-3-yl]carbamate [Isomer B] was obtained similarly 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]. MS (ESI): 647.1 [M-isobutene + H] + .

[0210] 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-benzazepin-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-benzazepin-2-one 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-benzazepin-3-yl]carbamic acid tert-butyl ester [Isomer A] (50 mg, 0.071 mmol, 1 equiv.) was stirred with HCl (2 M in EtO) (53.38 μL, 0.107 mmol, 1.5 equiv.) in 1,1,1,3,3,3-hexafluoro-2-propanol (3.56 mL) at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The solid was suspended in DCM and concentrated again. This process was repeated three times to give the title compound as the hydrochloride salt (45 mg, 97%) as an off-white solid after drying under 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-benzazepin-2-one [Isomer B] was similarly obtained 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] as an off-white solid. MS (ESI): 603.2 [M+H] + .

[0211] Example 5 (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-benzazepin-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-benzazepin-2-one TIFF2025526726000085.tif37170 Step a) tert-Butyl N-[8-bromo-7-fluoro-2,5-dioxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000086.tif41170 The title compound was prepared from tert-butyl N-(8-bromo-7-fluoro-2,5-dioxo-3,4-dihydro-1H-1-benzazepin-3-yl)carbamate (1000.0 mg, 2.58 mmol) and 1-(chloromethyl)-4-phenoxy-benzene (700.0 mg, 3.2 mmol, 1.24 equiv.) in analogy to Example 1, step f, to give the title compound as a pale yellow oil (1.6 g). MS (ESI): 513.0 [M-isobutene + H] + .

[0212] Step b) tert-butyl N-[8-bromo-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate To tert-butyl N-[8-bromo-7-fluoro-2,5-dioxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (100.0 mg, 0.18 mmol, 1.0 equiv.) was added DAST (5.0 mL) dropwise at 0–10 °C under a nitrogen atmosphere, and the mixture was stirred at 25 °C for 12 h. The reaction was quenched by the addition of water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined extracts were dried over NaSO and concentrated. The remaining residue was purified by preparative TLC (PE / EtOAc = 5:1) to afford the title compound (50.0 mg, 0.08 mmol, 54% yield) as a pale yellow solid. MS(ESI):593.1[M+H] + .

[0213] Step c) 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine-8-carboxylic acid To a mixture of tert-butyl N-[8-bromo-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (250.0 mg, 0.42 mmol, 1.0 equiv.), DPPP (35.0 mg, 0.08 mmol, 0.2 equiv.), and TEA (130.0 mg, 1.28 mmol, 3.04 equiv.) in a mixture of DMF (10 mL) and water (2 mL) was added Pd(OAc)2 (10.0 mg, 0.04 mmol, 0.11 equiv.) at 25 °C. The mixture was degassed three times with nitrogen and filled with CO three times, then stirred under CO (45 psi) at 80° C. 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 (NaSO), and concentrated in vacuo to give the title compound (160.0 mg, 0.29 mmol, 55% yield) as a pale yellow solid, which was used in the next reaction step without further purification. MS (ESI): 557.1 [M+H] + .

[0214] Step d) tert-butyl N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000089.tif41170 The title compound was prepared from 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine-8-carboxylic acid (150.0 mg, 0.27 mmol, 1.0 equiv.) in analogy to Example 1, step j, and obtained as a pale yellow solid (120 mg, 0.180 mmol, 69% yield). MS (ESI): 515.2 [M-isobutene + H] + .

[0215] Step e) tert-butyl N-[5,5,7-trifluoro-8-[[(2-methyl-2-methylsulfonyl-propanoyl)amino]carbamoyl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000090.tif41170 The title compound was prepared from tert-butyl N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (110.0 mg, 0.19 mmol, 1.0 equiv.) in analogy to Step k of Example 1, and obtained as a pale 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] + .

[0216] Step f) tert-butyl 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-benzazepin-3-yl]carbamate and tert-butyl 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-benzazepin-3-yl]carbamate A solution of Burgess reagent (220.0 mg, 0.92 mmol, 6.03 equiv.) and tert-butyl N-[5,5,7-trifluoro-8-[[(2-methyl-2-methylsulfonyl-propanoyl)amino]carbamoyl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (110.0 mg, 0.15 mmol, 1.0 equiv.) 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 SO ), and concentrated in vacuo. The remaining residue was purified by preparative TLC (PE / EtOAc=2:1) to give pure tert-butyl 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-benzazepin-3-yl]carbamate (80.0 mg, 0.11 mmol, 72% yield) as a pale yellow solid (MS(ESI): 701.4 [M+H]). + This material was subjected to chiral SFC to give tert-butyl 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-benzazepin-3-yl]carbamate [Isomer B] (29.0 mg, 0.04 mmol, 34% yield) as a pale yellow solid (MS(ESI): 701.4 [M+H] + , retention time 1.33 minutes (see conditions below)), and a pale yellow solid, tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (28.0 mg, 0.04 mmol, 34% yield), was obtained. MS (ESI): 701.4 [M+H] +, retention time 1.03 min (column: Chiralpak AS-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0217] 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-benzazepin-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-benzazepin-2-one A solution of tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (25.0 mg, 0.04 mmol, 1.0 equiv) in TIFF2025526726000092.tif37170HCl / EtOAc (4 M, 5.0 mL, 20.0 mmol, 560.58 equiv) was stirred at 20° C. for 0.5 h. The reaction mixture was concentrated, and the remaining solid was dissolved in HO to give, after lyophilization, 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-benzazepin-2-one [Isomer A] (20.7 mg, 0.03 mmol, 91% yield) as a white solid. MS(ESI): 601.4 [M+H] +Chiral SFC: Retention time 2.0 min. tert-Butyl 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-benzazepin-3-yl]carbamate [Isomer B] was obtained similarly. MS (ESI): 601.4 [M+H] + Chiral SFC: retention time 2.32 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: DAD; column temperature: 35 °C; back pressure: 100 bar).

[0218] Example 6 (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-benzazepin-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-benzazepin-2-one TIFF2025526726000093.tif39170 Step a) 1-(2-amino-4-bromo-phenyl)-2-chloro-ethanone To a solution of BCl3 (1 M in DCM, 63.95 mL, 63.95 mmol, 1.1 equiv.) in toluene (100 mL), 3-bromoaniline (6.33 mL, 58.13 mmol, 1.0 equiv.) was added dropwise at 0-5 °C under a nitrogen atmosphere. AlCl3 (9.3 g, 69.76 mmol, 1.2 equiv.) and chloroacetonitrile (4.78 mL, 75.57 mmol, 1.3 equiv.) were then added, and the mixture was stirred at 0-5 °C for 0.5 h and then at 70 °C for 12 h. The reaction mixture was quenched by the slow addition of 100 mL of HCl (1 M) at 50 °C and then stirred at 50 °C for 0.5 h. The mixture was poured into water (100 mL) and extracted with EtOAc (2 x 200 mL). The combined extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The remaining residue was purified first by column chromatography on silica gel (PE / EtOAc = 1:0 to 10:1) and then 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] + .

[0219] Step b) Diethyl 2-acetamido-2-[2-(2-amino-4-bromo-phenyl)-2-oxo-ethyl]propanedioate TIFF2025526726000095.tif26170 The title compound was prepared from 1-(2-amino-4-bromo-phenyl)-2-chloro-ethanone (9.28 g) in analogy to step b of Example 1 and obtained as a green oil (8.7 g). MS (ESI): 431.0 [M+H] + .

[0220] Step c) 2-amino-4-(2-amino-4-bromo-phenyl)-4-oxo-butanoic acid A solution of diethyl 2-acetamido-2-[2-(2-amino-4-bromo-phenyl)-2-oxo-ethyl]propanedioate (5.5 g, 12.81 mmol, 1.0 equiv) in HCl (12 M, 60.0 mL, 720.0 mmol, 56.19 equiv) was stirred at 100° C. for 12 h. The reaction mixture was concentrated in vacuo to give the title compound as the hydrochloride salt (3.7 g) as a green oil, which was used in the next reaction step without further purification. MS (ESI): 289.0 [M+H] + .

[0221] Step d) 4-(2-amino-4-bromo-phenyl)-2-(tert-butoxycarbonylamino)-4-oxo-butanoic acid TIFF2025526726000097.tif26170 The title compound was prepared from 2-amino-4-(2-amino-4-bromo-phenyl)-4-oxo-butanoic acid (2.0 g, 6.97 mmol, 1.0 equiv.) in analogy to step d of Example 1, and obtained as a pale yellow oil (2.51 g, 6.48 mmol, 93% yield). MS (ESI): 333.1 [M-isobutene + H] + .

[0222] Step e) tert-butyl N-(8-bromo-2,5-dioxo-3,4-dihydro-1H-1-benzazepin-3-yl)carbamate TIFF2025526726000098.tif22170 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 equiv.) as in Example 1, step e, and obtained as a pale yellow solid (800.0 mg, 2.17 mmol, 29% yield). MS (ESI): 271.0 [M-isobutene-CO2 + H] + .

[0223] Step f) tert-butyl N-[8-bromo-2,5-dioxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000099.tif41170 The title compound was prepared from tert-butyl N-(8-bromo-2,5-dioxo-3,4-dihydro-1H-1-benzazepin-3-yl)carbamate (650 mg, 1.76 mmol, 1.0 equiv.) and 1-(chloromethyl)-4-phenoxy-benzene (385 mg, 1.76 mmol, 1.0 equiv.) in analogy to Example 1, step f, and obtained as a pale yellow solid (350.0 mg, 0.635 mmol, 36% yield). MS (ESI): 497.0 [M-isobutene + H] + .

[0224] Step g) tert-butyl N-[8-bromo-5,5-difluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000100.tif41170 The title compound was prepared from tert-butyl N-[8-bromo-2,5-dioxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (350.0 mg, 0.63 mmol, 1.0 equiv.) in a similar manner to Step g of Example 1. A pale yellow oil (400 mg) containing the title compound was obtained, which was used in the next reaction step without further purification. MS (ESI): 475.0 [M-isobutene-CO2 + H] + .

[0225] Step h) 3-(tert-butoxycarbonylamino)-5,5-difluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine-8-carboxylic acid To a solution of tert-butyl N-[8-bromo-5,5-difluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (200.0 mg, 0.35 mmol, 1.0 equiv.) and DIPEA (90.16 mg, 0.70 mmol, 2.0 equiv.) in a mixture of THF (8 mL) and water (2 mL) was added Pd(dppp)Cl (61.71 mg, 0.105 mmol, 0.3 equiv.) at 25° C. The mixture was degassed with nitrogen three times and then filled with CO three times, and then the mixture was stirred under carbon monoxide (50 psi) at 80° C. 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 0.5 N HCl, and the mixture was extracted with EtOAc (3 x 30 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. 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-isobutene + H] + .

[0226] Step i) tert-butyl N-[5,5-difluoro-8-(hydrazinecarbonyl)-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate The title compound (TIFF2025526726000102.tif41170) was prepared from 3-(tert-butoxycarbonylamino)-5,5-difluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine-8-carboxylic acid (270.0 mg, 0.5 mmol, 1.0 equiv.) in analogy to Step j of Example 1. A pale yellow solid (260.0 mg) was obtained, which was used in the next reaction step without further purification. MS (ESI): 497.2 [M-isobutene + H] + .

[0227] Step j) tert-butyl N-[5,5-difluoro-8-[[(2-methyl-2-methylsulfonyl-propanoyl)amino]carbamoyl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000103.tif41170 The title compound was prepared from N-[5,5-difluoro-8-(hydrazinecarbonyl)-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (260.0 mg, 0.47 mmol, 1.0 equiv.) and 2-methyl-2-methylsulfonyl-propanoic acid (93.84 mg, 0.56 mmol, 1.2 equiv.) in the same manner as in Step k of Example 1. A yellow oil (270 mg) containing the title compound was obtained, which was used in the next reaction step without further purification. MS (ESI): 701.2 [M+H] + .

[0228] Step k) tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000104.tif41170 The title compound was prepared from N-[5,5-difluoro-8-[[(2-methyl-2-methylsulfonyl-propanoyl)amino]carbamoyl]-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (260.0 mg, 0.37 mmol, 1.0 equiv.) in a similar manner to Step 1 of Example 1, and obtained as a pale yellow solid (170.0 mg, 0.25 mmol, 67% yield). MS (ESI): 627.3 [M-isobutene + H] + .

[0229] Step l) tert-butyl 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-benzazepin-3-yl]carbamate and tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000105.tif41170 tert-Butyl 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-benzazepin-3-yl]carbamate (100 mg) was separated using SFC (Daicel Chiralpak Upon subjecting to AS (250 mm × 30 mm, 10 μm, 0.1% NH3-H2O in MeOH), tert-butyl 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-benzazepin-3-yl]carbamate [Isomer B] (45 mg, 0.07 mmol) (MS(ESI): 627.2 [M + H]). + , retention time 1.35 min (see conditions below) was obtained as a pale yellow oil, and tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (45 mg, 0.07 mmol) was obtained as a pale yellow oil. MS (ESI): 627.2 [M-isobutene + H] +, retention time 1.09 min (column: Chiralpak AS-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0230] 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-benzazepin-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-benzazepin-2-one A solution of tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (40.0 mg, 0.06 mmol, 1.0 equiv) in HCl / EtOAc (4 M, 4.0 mL, 20.0 mmol, 560.58 equiv) was stirred for 0.5 h at 20° C. The reaction mixture was concentrated, and the remaining solid was dissolved in HO and lyophilized. The resulting solid was purified by preparative HPLC (HCl as an additive in the eluent) and, after lyophilization as the hydrochloride salt, 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-benzazepin-2-one [Isomer A] (8.9 mg, 0.01 mmol, 26% yield) was obtained as a white solid. 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-benzazepin-2-one [Isomer B] was obtained similarly. MS (ESI): 583.2 [M+H] + Chiral SFC: retention time 2.43 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0231] Example 7 (3S)-3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one and (3R)-3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one TIFF2025526726000107.tif37170 Step a) tert-Butyl N-[8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate The title compound was prepared as in Example 1, steps a-l, using 1-(bromomethyl)-4-(cyclopentoxy)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] + .

[0232] Step b) tert-butyl N-[(3S)-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl N-[(3R)-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000109.tif41170N-[8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate (35 mg) was separated by SFC (Daicel Chiralpak IC (250 mm × 30 mm, 10 μm), 0.1% NH3-H2O in MeOH, gave tert-butyl N-[8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer B] (12 mg) (MS(ESI): 629.4 [M+H] + , retention time 1.19 minutes (see conditions below) was obtained as a white solid, and tert-butyl N-[8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] compound (14 mg) was obtained as a white solid. 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 for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0233] Step c) (3S)-3-amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one and (3R)-3-amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one A solution of tert-butyl N-[8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (13.0 mg, 0.02 mmol, 1.0 equiv) 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 give, after lyophilization, 3-amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one [Isomer A] (11.2 mg, 0.02 mmol, 94% yield) as the hydrochloride salt as a pale yellow solid. MS(ESI): 529.3 [M+H] +, retention time 1.43 min. 3-Amino-8-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one [Isomer B] was obtained in the same manner. MS (ESI): 529.3 [M+H] + , retention time 1.85 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for 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).

[0234] Example 8 (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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one TIFF2025526726000111.tif52170 Step a) tert-Butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate The title compound (TIFF2025526726000112.tif53170) was prepared similarly to steps a-l of Example 1 (using 2-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)pyridine [CAS1056641-21-4]; hydrochloride salt instead of 4-(trifluoromethoxy)benzyl bromide in step f, and 2-methyl-2-methylsulfonyl-propanoic acid instead of pivalic acid in step k) as a white solid. MS (ESI): 754.4 [M+H] + .

[0235] Step b) tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000113.tif53170 tert-Butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (95 mg) was separated using preparative SFC (Daicel Chiralpak IC (250 mm × 30 mm, 10 μm), 0.1% NH3-H2O in IPA) yielded tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer B] (28 mg) (MS(ESI): 754.3 [M+H] + , retention time 2.43 minutes (see conditions below) was obtained as a white solid, and tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (30 mg) was obtained as a white solid. MS (ESI): 754.3 [M+H] + , retention time 1.88 min (column: Chiralpak IC-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for IPA (0.05% DEA); gradient elution: 5% to 40% IPA (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0236] 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one A solution of tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (25.0 mg, 0.03 mmol, 1.0 equiv) 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 give, after lyophilization, 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-benzazepin-2-one [Isomer A] (18.7 mg, 0.03 mmol, 75% yield) as a white solid dihydrochloride salt. MS(ESI): 654.2 [M+H] + , retention time 1.82 min. 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-benzazepin-2-one [Isomer B] was obtained in the same manner. MS (ESI): 654.2 [M+H] +, retention time 2.10 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for 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).

[0237] Example 9 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile and 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile TIFF2025526726000115.tif47170 Step a) tert-Butyl 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-benzazepin-3-yl]carbamate The title compound was prepared analogously to Example 1, steps a-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-propanoic acid instead of pivalic acid in step k, as an off-white solid. MS (ESI): 606.2 [M-isobutene + H] + .

[0238] Step b) tert-butyl 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-benzazepin-3-yl]carbamate and tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000117.tif48170 tert-Butyl 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-benzazepin-3-yl]carbamate (80 mg) was separated using a preparative SFC (Daicel Chiralpak Upon subjecting to AD (250 mm × 30 mm, 10 μm, 0.1% NH3-H2O in IPA), tert-butyl 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-benzazepin-3-yl]carbamate [Isomer B] (38 mg) (MS(ESI): 606.2 [M + H]). + , retention time 2.22 min (see conditions below) was obtained as a yellow solid, tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (38 mg) was obtained as a yellow solid. MS (ESI): 606.2 [M-isobutene + H] +, retention time 1.87 min (column: Chiralpak IG-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0239] 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile and 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile To a solution of tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (36.0 mg, 0.05 mmol, 1.0 equiv) in EtOAc (1 mL) was added HCl / EtOAc (4 M, 8.0 mL, 32.0 mmol, 588.15 equiv) at 20° C., 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 lyophilization, 2-methyl-2-[5-[3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile [Isomer A] (29.2 mg, 0.05 mmol, 84% yield) was obtained as an off-white solid. MS(ESI): 562.1 [M+H] +, retention time 0.62 min. 2-Methyl-2-[5-[3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile [Isomer B] was obtained in the same manner. MS (ESI): 562.1 [M+H] + , retention time 1.22 min (column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH / MeCN (0.05% DEA); gradient elution: 30% MeOH / MeCN (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0240] Example 10 (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-benzazepin-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-benzazepin-2-one TIFF2025526726000119.tif47170 Step a) tert-Butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000120.tif48170 The title compound was prepared similarly to Example 1, steps a-l (substituting 1-(chloromethyl)-4-(4-methoxyphenyl)benzene for 4-(trifluoromethoxy)benzyl bromide in step f and 2-methyl-2-methylsulfonyl-propanoic acid for pivalic acid in step k) and obtained as a white solid. MS (ESI): 659.2 [M-isobutene + H] + .

[0241] Step b) tert-butyl 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-benzazepin-3-yl]carbamate and tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000121.tif49170

[0242] tert-Butyl 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-benzazepin-3-yl]carbamate (60 mg) was separated using preparative SFC (Daicel Chiralpak Upon subjecting to IG (250 mm × 30 mm, 10 μm), 0.1% NH3-H2O in MeCN / EtOH, tert-butyl 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-benzazepin-3-yl]carbamate [Isomer B] (22 mg) (MS(ESI): 659.1 [M-isobutene + H]) + , retention time 2.11 min (see conditions below) was obtained as a yellow solid, giving tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (22 mg) as a yellow solid. MS (ESI): 659.1 [M-isobutene + H] + , retention time 0.95 min (column: Chiralpak IG-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0243] 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-benzazepin-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-benzazepin-2-one To a solution of tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (20.0 mg, 0.03 mmol, 1.0 equiv) in EtOAc (1 mL) at 20° C., HCl / EtOAc (4 M, 8.0 mL, 32.0 mmol, 1143.6 equiv) was added dropwise, 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. 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-benzazepin-2-one [Isomer A] (14.6 mg, 0.02 mmol, 77% yield) was obtained as an off-white solid after lyophilization. MS(ESI): 615.1 [M+H] + , retention time 0.97 min. 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-benzazepin-2-one [Isomer B] was obtained in the same manner. MS (ESI): 615.1 [M+H] +, retention time 1.45 min (column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH / MeCN (0.05% DEA); gradient elution: 30% MeOH / MeCN (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0244] Example 11 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile and 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile TIFF2025526726000123.tif37170

[0245] Step a) tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000124.tif38170 The title compound was prepared analogously to Example 1, steps a-l (substituting 1-(chloromethyl)-4-phenoxy-benzene for 4-(trifluoromethoxy)benzyl bromide in step f and 2-cyano-2-methyl-propanoic acid for pivalic acid in step k) and obtained as a pale yellow solid. MS (ESI): 592.3 [M-isobutene + H] + .

[0246] Step b) tert-butyl 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-benzazepin-3-yl]carbamate and tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000125.tif37170 tert-Butyl 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-benzazepin-3-yl]carbamate (140 mg) was separated using SFC (Daicel Chiralpak IC (250 mm × 30 mm, 10 μm), 0.1% NH3-H2O in MeOH) yielded tert-butyl 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-benzazepin-3-yl]carbamate [Isomer B] (70 mg) (MS(ESI): 592.3 [M + H]). + , retention time 2.39 min (see conditions below) was obtained as a pale yellow solid, and tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (60 mg) was obtained as a pale yellow solid. MS (ESI): 592.3 [M-isobutene + H] +, retention time 1.75 min (column: Chiralpak IC-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0247] Step c) 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile and 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile A solution of tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (60.0 mg, 0.09 mmol, 1.0 equiv) in TIFF2025526726000126.tif37170HCl / EtOAc (4 M, 0.12 mL, 0.46 mmol, 5.0 equiv) was stirred at 20° C. for 0.5 h, and then all volatiles were removed. The remaining solid was dissolved in water and lyophilized as the hydrochloride salt to give 2-methyl-2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile [Isomer A] (33.6 mg, 0.06 mmol, 60% yield) as a white solid. MS(ESI): 548.3 [M+H] +, retention time 1.66 min. 2-Methyl-2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile [Isomer B] was obtained in the same manner. MS (ESI): 548.3 [M+H] + , retention time 2.02 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: DAD; column temperature: 35 °C; back pressure: 100 bar).

[0248] Example 12 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile and 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile TIFF2025526726000127.tif49170 Step a) tert-Butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate The title compound (TIFF2025526726000128.tif51170) was prepared in a similar manner to Example 1, steps a-l (using 2-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)pyridine; hydrochloride salt instead of 4-(trifluoromethoxy)benzyl bromide in step f, and 2-cyano-2-methyl-propanoic acid instead of pivalic acid in step k) as a pale yellow solid. MS (ESI): 701.3 [M+H] + .

[0249] Step b) tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000129.tif51170 tert-Butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (95 mg) was separated using a Daicel Chiralpak SFC. IC (250 mm × 30 mm, 10 μm), 0.1% NH3-H2O in EtOH, gave tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer B] (33 mg) (MS(ESI): 701.2 [M+H] +, retention time 2.01 min (see conditions below) was obtained as a white solid, and tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (33 mg) was obtained as a white solid. MS (ESI): 701.1 [M+H] + , retention time 1.44 min (column: Chiralpak IC-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0250] Step c) 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile and 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile A solution of tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (30.0 mg, 0.04 mmol, 1.0 equiv) in HCl / EtOAc (4 M, 4.0 mL, 16.0 mmol, 373.67 equiv) was stirred at 20° C. for 0.5 h, and then all volatiles were removed. The remaining solid was dissolved in water and lyophilized to give 2-methyl-2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile [Isomer A] (28.0 mg, 0.04 mmol, 93% yield) as a pale yellow solid dihydrochloride salt. MS(ESI): 601.3 [M+H] + , retention time 1.51 min. 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile [Isomer B] was also obtained in the same manner. MS (ESI): 601.2 [M+H] + , retention time 1.84 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: DAD; column temperature: 35 °C; back pressure: 100 bar).

[0251] Example 13 (3S)-3-Amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one and (3R)-3-Amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one TIFF2025526726000131.tif37170 Step a) tert-butyl N-[(3S)-5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl N-[(3R)-5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000132.tif38170To a mixture of 3-(tert-butoxycarbonylamino)-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-8-carboxylic acid [Isomer A] (Example 4, Step a) (280.0 mg, 0.51 mmol, 1.0 equiv) and DMF (0.1 mL) in DCM (10 mL) was added oxalyl chloride (77.76 mg, 0.61 mmol, 1.2 equiv) at 20°C and the mixture was stirred for 0.5 h. Hydrazine monohydrochloride (127.0 mg, 1.53 mmol, 3.0 equiv.) and DIPEA (0.27 mL, 1.53 mmol, 3.0 equiv.) were then added at 20 °C, and the mixture was stirred at 20 °C for 0.5 h and then poured into water. The mixture was extracted with DCM (3 × 20 mL), and the combined extracts were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. Crude tert-butyl N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (218.0 mg, 0.39 mmol, 76% yield) was obtained as a yellow solid, which was used in the next step without further purification. MS(ESI):507.1[M-isobutene+H] + tert-Butyl N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer B] was obtained similarly 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). MS (ESI): 507.2 [M-isobutene + H] + .

[0252] Step b) tert-butyl 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-benzazepin-3-yl]carbamate and tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000133.tif47170To a mixture of 1-ethyl-5,5-difluoro-piperidine-3-carboxylic acid (Intermediate 2) (159.72 mg, 0.83 mmol, 1.5 equiv) and T3P (50% in EtOAc, 526.1 mg, 0.83 mmol, 1.5 equiv) in DCM (5 mL), DIPEA (0.29 mL, 1.65 mmol, 3.0 equiv) was added at 25° C. and the mixture was stirred for 0.5 h. Then, tert-butyl N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (310.0 mg, 0.55 mmol, 1.0 equiv) was added at 25° C., and the mixture was stirred at 25° C. for 0.5 h and then poured into water. The mixture was extracted with DCM (3 x 15 mL), and the combined extracts were washed with brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated 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-benzazepin-3-yl]carbamate [Isomer A] (155.0 mg, 0.21 mmol, 38% yield) as a yellow solid, which was used in the next step without further purification. MS (ESI): 738.2 [M+H] +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-benzazepin-3-yl]carbamate [Isomer B] was obtained similarly from tert-butyl N-[5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer B].

[0253] Step c) tert-butyl N-[(3S)-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl N-[(3R)-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000134.tif38170 A mixture of tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (390.0 mg, 0.34 mmol, 1.0 equiv) and Burgess reagent (245.69 mg, 1.03 mmol, 3.0 equiv) in toluene (15 mL) was stirred at 100° C. for 12 hours 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), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The remaining residue was purified by preparative HPLC (Phenomenex Synergi C18 150 × 25 mm, 10 μm column, water (with formic acid) / ACN) to give tert-butyl N-[8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (59.0 mg, 0.08 mmol, 23% yield) as a white solid. MS (ESI): 720.2 [M+H] + tert-Butyl N-[8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer B] was obtained similarly from tert-butyl 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-benzazepin-3-yl]carbamate [Isomer B]. MS (ESI): 720.2 [M+H] + .

[0254] Step d) (3S)-3-amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one and (3R)-3-amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one To a solution of tert-butyl N-[8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (55.0 mg, 0.08 mmol, 1.0 equiv) in EtOAc (1 mL) was added HCl / EtOAc (4 M, 5.87 mL, 23.47 mmol, 307.04 equiv) at 25° C., 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 (Phenomenex Synergi C18 150x25 mm, 5 μm column, conditions: water (with NH4HCO3) / ACN) to give 3-amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one [Isomer A] (12.6 mg, 0.02 mmol, 26% yield) as an off-white solid. MS(ESI): 620.2 [M+H] +, retention time 1.25 min. 3-Amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one [Isomer B] was obtained similarly from tert-butyl N-[8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer B]. MS (ESI): 620.2 [M+H] + , retention times 1.74 and 1.94 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0255] Example 14 (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-benzazepin-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-benzazepin-2-one TIFF2025526726000136.tif44170 Step a) tert-Butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000137.tif46170 The title compound was prepared from 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-benzazepin-3-yl]carbamate (Example 15, Step c) in analogy with Steps d and e of Example 15, and obtained as a pale yellow solid. MS (ESI): 694.1 [M+H] + .

[0256] Step b) tert-butyl 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-benzazepin-3-yl]carbamate and tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000138.tif46170 tert-Butyl 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-benzazepin-3-yl]carbamate (60 mg) was separated using a preparative SFC (Daicel Chiralpak Upon subjecting to AD (250 mm × 30 mm, 10 μm), 0.1% NH3-H2O in iPrOH, tert-butyl 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-benzazepin-3-yl]carbamate [Isomer B] (25 mg) (MS(ESI): 694.1 [M+H] + , retention time 1.76 minutes (see conditions below) was obtained as a pale yellow solid, and tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (23 mg) was obtained as a pale yellow solid. MS (ESI): 694.1 [M+H] + , retention time 1.27 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0257] 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-benzazepin-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-benzazepin-2-one A solution of tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (23.0 mg, 0.03 mmol, 1.0 equiv) in TIFF2025526726000139.tif44170HCl / EtOAc (4 M, 5.0 mL, 20.0 mmol, 603.13 equiv) was stirred at 20° C. for 0.5 h. All volatiles were removed in vacuo, and the remaining residue was dissolved in water and lyophilized as the hydrochloride salt to give 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-benzazepin-2-one [Isomer A] (13.5 mg, 0.02 mmol, 64% yield) as a white solid. MS(ESI): 594.2 [M+H] +, retention time 1.59 min. 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-benzazepin-2-one [Isomer B] was obtained similarly from tert-butyl 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-benzazepin-3-yl]carbamate [Isomer B]. MS (ESI): 594.2 [M+H] + , retention time 2.28 (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0258] Example 15 (3S)-3-Amino-8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-2-one and (3R)-3-Amino-8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-2-one TIFF2025526726000140.tif44170

[0259] Step a) tert-butyl N-[1-[(4-cyanophenyl)methyl]-5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate The title compound was prepared analogously to steps aj of Example 1 (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-isobutene + H] + .

[0260] Step b) tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000142.tif41170 A mixture of tert-butyl N-[1-[(4-cyanophenyl)methyl]-5,5,7-trifluoro-8-(hydrazinecarbonyl)-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate (1.5 g, 2.98 mmol, 1.0 equiv), TEA (0.93 mL, 6.67 mmol, 2.24 equiv) and CDI (0.72 g, 4.47 mmol, 1.5 equiv) in THF (20 mL) was stirred at 20°C for 3 hours, 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 (NaSO) and concentrated in vacuo to give the title compound (1.5 g, 2.83 mmol, 87% yield) as a pale yellow solid, which was used in the next step without further purification. MS (ESI): 474.2 [M-isobutene + H] + .

[0261] Step c) tert-butyl N-[1-[(4-cyanophenyl)methyl]-8-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000143.tif42170 tert-Butyl 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-benzazepin-3-yl]carbamate (450 mL) in dry 1,4-dioxane (10 mL). To a mixture of 4,4-difluoropiperidine hydrochloride (202.5 mg, 1.28 mmol, 1.51 equiv.), 4,4-difluoropiperidine hydrochloride (202.5 mg, 1.28 mmol, 1.51 equiv.), and DIPEA (0.45 mL, 2.55 mmol, 3.0 equiv.), PyBroP (475.47 mg, 1.02 mmol, 1.2 equiv.) was added at 25 °C, 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 give tert-butyl N-[1-[(4-cyanophenyl)methyl]-8-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate (400.0 mg, 0.63 mmol, 74% yield) as a pale yellow solid (MS(ESI): 633.4 [M+H] +The second fraction was further purified by preparative HPLC (Phenomenex Luna C18 150 × 25 mm, 10 μm column; conditions: water (containing formic acid) / ACN 1:1 to 1:4) to give tert-butyl 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-benzazepin-3-yl]carbamate (45.0 mg, 0.08 mmol, 9% yield) as a white solid. MS(ESI): 583.5 [M+H] + .

[0262] Step d) tert-butyl N-[8-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000144.tif42170 A mixture of tert-butyl N-[1-[(4-cyanophenyl)methyl]-8-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate (35.0 mg, 0.06 mmol, 1.0 equiv), sodium acetate (13.62 mg, 0.17 mmol, 3.0 equiv) and hydroxylamine hydrochloride (5.77 mg, 0.08 mmol, 1.5 equiv) in ethanol (5 mL) was stirred at 50° C. for 12 hours 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 (NaSO), and concentrated in vacuo to give tert-butyl N-[8-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate (33.0 mg, 0.05 mmol, 71% yield) as a white solid, which was used in the next step without further purification. MS (ESI): 666.2 [M+H] + .

[0263] Step e) tert-butyl N-[8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-3-yl]carbamate A solution of tert-butyl N-[8-[5-(4,4-difluoro-1-piperidyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-1-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate (190.0 mg, 0.29 mmol, 1.0 equiv.) and trifluoroacetic anhydride (0.06 mL, 0.46 mmol, 1.6 equiv.) in THF (10 mL) was stirred for 2 h at 20 °C. The solution was poured into water (20 mL), and the pH of the solution was adjusted to 7-8 by the addition of NaHCO. The mixture was then extracted with EtOAc (40 mL), and the organic extract was washed with brine (30 mL), dried (NaSO), and concentrated in vacuo. The remaining residue was purified by preparative HPLC (Phenomenex Luna C18 150 × 25 mm, 10 μm column; conditions: water (with formic acid) / ACN 1:1 to 1:4) to afford tert-butyl N-[8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-3-yl]carbamate (120.0 mg, 0.16 mmol, 55% yield) as a white solid. MS(ESI):744.4[M+H] + .

[0264] Step f) tert-butyl N-[(3S)-8-[5-(4,4-difluoro-1-piperidyl)-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-bbenzazepin-3-yl]carbamate and tert-butyl N-[(3R)-8-[5-(4,4-difluoro-1-piperidyl)-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-bbenzazepin-3-yl]carbamate TIFF2025526726000146.tif46170 tert-Butyl N-[8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-3-yl]carbamate (120 mg) was separated using preparative SFC (Daicel Chiralcel OD (250 mm × 30 mm, 10 μm), 0.1% NH3-H2O in EtOH) gave tert-butyl N-[8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-3-yl]carbamate [Isomer B] (45 mg) (MS(ESI): 744.4 [M+H] +, retention time 1.52 minutes (see conditions below) was obtained as a white solid, and tert-butyl N-[8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-3-yl]carbamate [Isomer A] (50 mg) was obtained as a white solid. 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 for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0265] Step g) (3S)-3-amino-8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-2-one and (3R)-3-amino-8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-2-one A solution of tert-butyl N-[8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-3-yl]carbamate [Isomer A] (40.0 mg, 0.05 mmol, 1.0 equiv) in HCl in EtOAc (4 M, 10.0 mL, 40.0 mmol, 743.6 equiv) was stirred for 0.5 h at 20 °C. All volatiles were then removed in vacuo, and the remaining residue was dissolved in water. 3-Amino-8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-2-one [Isomer A] was obtained as the hydrochloride salt after lyophilization as a white solid (28.4 mg, 0.04 mmol, 77% yield). MS(ESI): 644.1 [M+H] + 3-Amino-8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-2-one [isomer B] was obtained similarly from tert-butyl N-[8-[5-(4,4-difluoro-1-piperidyl)-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-benzazepin-3-yl]carbamate [isomer B]. MS(ESI):644.1[M+H] +, retention time 2.23 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0266] Example 16 (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-benzazepin-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-benzazepin-2-one TIFF2025526726000148.tif44170 Step a) tert-Butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000149.tif41170 The title compound was prepared similarly to Example 1, steps a-l (substituting 4-(bromomethyl)benzonitrile for 4-(trifluoromethoxy)benzyl bromide in step f and 2-methyl-2-methylsulfonyl-propanoic acid for pivalic acid in step k) and obtained as a pale yellow solid. MS (ESI): 634.4 [M+H] + .

[0267] Step b) tert-butyl 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-benzazepin-3-yl]carbamate A mixture of tert-butyl 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-benzazepin-3-yl]carbamate (190.0 mg, 0.3 mmol, 1.0 equiv), potassium acetate (0.06 mL, 0.9 mmol, 3.0 equiv) and hydroxylamine hydrochloride (27.0 mg, 0.39 mmol, 1.3 equiv) in EtOH (10 mL) was stirred at 50° C. for 12 hours, and then the reaction mixture was poured into water (50 mL). The mixture was extracted with EtOAc (100 mL), and the organic extract was washed with brine (50 mL), dried (NaSO), 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 pale yellow solid. MS (ESI): 667.4 [M+H] + .

[0268] Step c) tert-butyl 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-benzazepin-3-yl]carbamate and tert-butyl 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-benzazepin-3-yl]carbamate A solution of tert-butyl 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-benzazepin-3-yl]carbamate (140.0 mg, 0.21 mmol, 1.0 equiv) and trifluoroacetic anhydride (0.04 mL, 0.31 mmol, 1.5 equiv) in THF (10 mL) was stirred for 3 h at 20 °C. The reaction mixture was poured into water (30 mL), and the pH of the mixture was adjusted to 7-8 by the addition of NaHCO. The mixture was extracted with EtOAc (50 mL), and the organic extract was washed with brine (30 mL), dried (NaSO), concentrated in vacuo, and the remaining residue was purified by preparative TLC (PE / EtOAc=3:1) to give tert-butyl 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-benzazepin-3-yl]carbamate. This was subjected to preparative SFC (Daicel Chiralpak AD (250 mm × 30 mm, 10 μm), 0.1% NH3-H2O in iPrOH) to obtain tert-butyl 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-benzazepin-3-yl]carbamate [Isomer B] (30 mg) (MS(ESI): 745.4 [M+H] +, retention time 1.64 minutes (see conditions below) was obtained as a white solid, and tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (40 mg) was obtained as a white solid. MS (ESI): 745.4 [M+H] + , retention time 1.24 min (column: Chiralpak IC-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0269] 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-benzazepin-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-benzazepin-2-one A solution of tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (35.0 mg, 0.05 mmol, 1.0 equiv) in TIFF2025526726000152.tif44170HCl / EtOAc (4 M, 10.0 mL, 40.0 mmol, 851.04 equiv) was stirred at 20° C. for 0.5 h. All volatiles were removed in vacuo, and the remaining residue was dissolved in water and lyophilized as the hydrochloride salt to give 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-benzazepin-2-one [Isomer A] (24.9 mg, 0.04 mmol, 81% yield) as a white solid. MS(ESI): 645.1 [M+H] + 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-benzazepin-2-one [isomer B] was obtained similarly from tert-butyl 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-benzazepin-3-yl]carbamate [isomer B]. MS(ESI):645.1[M+H] +, retention time 2.38 min (column: Chiralpak IG-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0270] Example 17 (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-benzazepin-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-benzazepin-2-one TIFF2025526726000153.tif44170 Step a) tert-Butyl 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-benzazepin-3-yl]carbamate The title compound was prepared in a similar manner to steps a to e of Example 15 (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] + .

[0271] Step b) tert-butyl 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-benzazepin-3-yl]carbamate and tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000155.tif46170 tert-Butyl 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-benzazepin-3-yl]carbamate (70 mg) was separated using a preparative SFC (Daicel Chiralpak Upon subjecting to AD (250 mm × 30 mm, 10 μm), 0.1% NH3-H2O in iPrOH, tert-butyl 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-benzazepin-3-yl]carbamate [isomer B] (31 mg) (MS(ESI): 736.3 [M+H] +, retention time 1.46 minutes (see conditions below) was obtained as a pale yellow solid, and tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (30 mg) was obtained as a pale yellow solid. MS (ESI): 736.3 [M+H] + , retention time 1.09 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0272] 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-benzazepin-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-benzazepin-2-one A solution of tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (30.0 mg, 0.04 mmol, 1.0 equiv) in TIFF2025526726000156.tif44170HCl / EtOAc (4 M, 5.0 mL, 20.0 mmol, 490.42 equiv) was stirred at 20° C. for 0.5 h. All volatiles were removed in vacuo, and the remaining residue was dissolved in water. Lyophilization afforded 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-benzazepin-2-one [Isomer A] (21.4 mg, 0.03 mmol, 82% yield) as a pale yellow solid, hydrochloride salt. MS(ESI): 636.3 [M+H] + 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-benzazepin-2-one [Isomer B] was purified by tert-butyl 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-benzazepin-3-yl]carbamate [isomer B] was obtained in the same manner. MS (ESI): 636.3 [M+H] +, retention time 2.30 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0273] Example 18 (3S)-3-Amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one and (3R)-3-Amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one TIFF2025526726000157.tif36170 Step a) tert-Butyl N-[8-bromo-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate The title compound was prepared as in Example 1, steps a-g, using 1-(bromomethyl)-4-chlorobenzene instead of 4-(trifluoromethoxy)benzyl bromide in step f, as a yellow solid. MS (ESI): 478.9 [M-isobutene + H] + .

[0274] Step b) tert-butyl N-[8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000159.tif37170 Nitrogen was removed by tert-butyl N-[8-bromo-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate (100.0 mg, 0.19 mmol, 1.0 equiv.), 3-tert-butyl N-[8-bromo-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate (100.0 mg, 0.19 mmol, 1.0 equiv.), in a mixture of 1,4-dioxane (5 mL) and water (0.7 mL). A mixture of t-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [CAS 1627723-04-9] (53.82 mg, 0.21 mmol, 1.1 equiv.), K2CO3 (77.68 mg, 0.56 mmol, 3.0 equiv.), and Pd(dppf)Cl2-DCM (15.3 mg, 0.02 mmol, 0.1 equiv.) was bubbled through for 2 minutes. The reaction mixture was then heated to 80 °C and stirred for 3 hours. 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] + .

[0275] Step c) tert-butyl N-[(3S)-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl N-[(3R)-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000160.tif37170 tert-Butyl N-[8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate (95 mg) was separated using a preparative SFC (Daicel Chiralpak Upon subjecting to ion exchange chromatography (250 mm × 30 mm, 10 μm), 0.1% DEA in MeOH, tert-butyl N-[8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer B] (45 mg) (MS(ESI): 588.2 [M+H] + , retention time 1.45 min (see conditions below) was obtained as a yellow oil, and tert-butyl N-[8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (45 mg) was obtained as a yellow oil. MS (ESI): 588.2 [M+H] + , retention time 0.89 min (column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0276] Step d) (3S)-3-amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one and (3R)-3-amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one To a solution of tert-butyl N-[8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (40.0 mg, 0.07 mmol, 1.0 equiv) in EtOAc (1 mL) was added HCl / EtOAc (4 M, 8.0 mL, 32.0 mmol, 470.45 equiv) at 25° C., and the mixture was stirred for 1 h at 25° C. 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-benzazepin-2-one [Isomer A] (25.8 mg, 0.05 mmol, 65% yield) was obtained as the dihydrochloride salt as a yellow solid by lyophilization. MS(ESI): 488.2 [M+H] + , retention time 2.13 min. 3-Amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepin-2-one [Isomer B] was obtained similarly from tert-butyl N-[8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer B]. MS (ESI): 488.2 [M+H] + , retention time 1.67 min (column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: DAD; column temperature: 35 °C; back pressure: 100 bar).

[0277] Example 19 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile TIFF2025526726000162.tif49170 Step a) tert-Butyl 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-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate The title compound (TIFF2025526726000163.tif51170) was prepared in a similar manner to steps a-l of Example 1, 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-propanoic acid instead of pivalic acid in step k, and obtained as a white solid. MS (ESI): 719.4 [M+H] + .

[0278] Step b) tert-butyl 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-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl 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-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000164.tif51170 tert-Butyl 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-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate (95 mg) was separated using preparative SFC (Daicel Chiralcel Upon subjecting to OD-H (250 mm × 30 mm, 10 μm, 0.1% NH3-H2O in MeOH), tert-butyl tert-butyl 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-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (40 mg) (MS(ESI): 719.4 [M+H] +, retention time 1.01 min, see conditions below) was obtained as a white solid, and tert-butyl 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-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer B] (41 mg) was obtained as a white solid. MS(ESI): 719.6 [M+H] + , retention time 1.17 min (Column: Chiralcel OD 50 × 4.6 mm ID, 3 μm; Mobile phase: Phase A for CO2, Phase B for MeOH (0.05% DEA); Gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35 °C; Back pressure: 100 bar).

[0279] 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile A solution of tert-butyl 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-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (40.0 mg, 0.06 mmol, 1.0 equiv) 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 the pH was adjusted to 8 by adding saturated NaHCO solution. The resulting mixture was extracted with DCM (10 mL x 3), and the combined organic layers were dried (NaSO) 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 give 2-[5-[3-amino-5,5,7-trifluoro-1-[[4-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-2-oxo-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile [Isomer A] (33.0 mg, 0.04 mmol, 83% yield) as the hydrochloride salt as a white solid. MS(ESI): 619.3 [M+H] + , retention time 1.34 min (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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile [isomer B] was obtained in the same manner. MS (ESI): 619.1 [M+H] + , retention time 1.70 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: DAD; column temperature: 35 °C; back pressure: 100 bar).

[0280] Example 20 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile TIFF2025526726000166.tif44170 Step a) tert-Butyl 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-benzazepin-3-yl]carbamate The title compound (TIFF2025526726000167.tif46170) was prepared similarly to steps a-l of Example 1 (using 2-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)tetrazole (Intermediate 4) instead of 4-(trifluoromethoxy)benzyl bromide in step f, and 2-cyano-2-methyl-propanoic acid instead of pivalic acid in step k) as a pale yellow solid. MS (ESI): 636.1 [M-isobutene + H] + .

[0281] Step b) tert-butyl 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-benzazepin-3-yl]carbamate and tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000168.tif46170 tert-Butyl 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-benzazepin-3-yl]carbamate (340 mg) was separated using a preparative SFC (Daicel Chiralpak Upon subjecting to AD (250 mm × 30 mm, 10 μm, 0.1% NH3-H2O in EtOH), tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (105 mg) (MS(ESI): 636.1 [M+H]) was obtained. + , retention time 0.86 min (see conditions below) was obtained as a pale yellow solid, and tert-butyl 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-benzazepin-3-yl]carbamate [Isomer B] (110 mg) was obtained as a pale yellow solid. MS(ESI): 636.1 [M-isobutene + H]+ , retention time 1.13 min (column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0282] 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile A solution of tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (103.0 mg, 0.15 mmol, 1.0 equiv) in a mixture of DCM / TFA (3:1, 4.0 mL) was stirred at 20 °C for 0.5 h. The pH of the reaction mixture was adjusted to 8 by careful addition of saturated NaHCO solution, and the resulting mixture was extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (5 mL), dried (NaSO), and concentrated. The remaining residue was dissolved in EtOAc (20 mL) and HCl / EtOAc (4 M, 0.2 mL) was added. The mixture was concentrated, and water (20 mL) was added to the remaining solid. Lyophilization afforded 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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile [Isomer A] (90 mg, 0.14 mmol, 92%) as the hydrochloride salt as a yellow solid. MS (ESI): 592.2 [M+H] + , retention time 1.40 min (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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile [Isomer B] was obtained similarly. MS (ESI): 592.3 [M+H] + , retention time 1.83 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0283] Example 21 (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-benzazepin-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-benzazepin-2-one TIFF2025526726000170.tif44170 Step a) tert-butyl 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-benz[a]a tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000171.tif47170 tert-Butyl 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-benzazepin-3-yl]carbamate (Example 22, step c) (30 mg) was separated and purified by SFC (Daicel Chiralpak OD (250 mm × 30 mm, 10 μm), 0.1% NH3-H2O in EtOH) gave tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (10 mg) (MS(ESI): 693.2 [M+H] + , retention time 1.61 minutes (see conditions below) was obtained as a white solid, and tert-butyl 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-benzazepin-3-yl]carbamate [Isomer B] (10 mg) was obtained as a white solid. MS (ESI): 693.2 [M+H] + , retention time 2.07 min (column: Chiralpak OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0284] 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-benzazepin-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-benzazepin-2-one A solution of tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (10.0 mg, 0.01 mmol, 1.0 equiv) in TIFF2025526726000172.tif44170HCl / EtOAc (4 M, 2.1 mL, 8.42 mmol, 582.9 equiv) was stirred at 20° C. for 0.5 h. The mixture was concentrated, and the remaining residue was dissolved in MeCN / water and lyophilized to give 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-benzazepin-2-one [Isomer A] (2.0 mg, 20% yield) as the hydrochloride salt as a white solid. 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-benzazepin-2-one [Isomer B] was obtained in the same manner. MS (ESI): 593.1 [M+H] +, retention time 1.69 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); elution: 50% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0285] Example 22 (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-benzazepin-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-benzazepin-2-one TIFF2025526726000173.tif44170 Step a) tert-Butyl 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-benzazepin-3-yl]carbamate The title compound was prepared in a similar manner to steps aj of Example 1 (except that in step f, 1-[4-(bromomethyl)phenyl]-3-(trifluoromethyl)-1,2,4-triazole (Intermediate 5) was used instead of 4-(trifluoromethoxy)benzyl bromide) and obtained as a yellow solid. MS (ESI): 636.2 [M+Na] + .

[0286] Step b) tert-butyl 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-benzazepin-3-yl]carbamate To a solution of tert-butyl 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-benzazepin-3-yl]carbamate (300.0 mg, 0.49 mmol, 1.0 equiv.) in THF (5 mL) was added CDI (158.58 mg, 0.98 mmol, 2.0 equiv.) at 25° C., 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 × 3). The combined extracts were washed with brine (20 mL), dried (NaSO), 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 (210.0 mg, 0.33 mmol, 67% yield) as a yellow solid. MS (ESI): 640.3 [M+H] + .

[0287] Step c) tert-butyl 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-benzazepin-3-yl]carbamate and tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000176.tif461701,4-tert-Butyl 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- in dioxane (1 mL) A solution of 1-benzazepin-3-yl]carbamate (200.0 mg, 0.31 mmol, 1.0 equiv), PyBroP (153.08 mg, 0.33 mmol, 1.05 equiv), DIPEA (0.16 mL, 0.94 mmol, 3.0 equiv), and 3,3-difluoropyrrolidine hydrochloride (67.35 mg, 0.47 mmol, 1.5 equiv) was stirred at 20 °C for 3 h. The reaction mixture was poured into water (20 mL), the layers were separated, and the aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine (20 mL), dried (Na SO ), and concentrated. The remaining residue was purified by preparative TLC (PE / EtOAc=1:2) to give tert-butyl 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-benzazepin-3-yl]carbamate (140.0 mg, 0.19 mmol, 61% yield) as a yellow solid (MS(ESI): 729.3 [M+H]). + ), tert-butyl 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-benzazepin-3-yl]carbamate (30.0 mg, 0.04 mmol, 14% yield) was obtained as a yellow solid. MS(ESI): 693.2 [M+H] + .

[0288] Step d) tert-butyl 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-benzazepin-3-yl]carbamate and tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000177.tif46170 tert-Butyl 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-benzazepin-3-yl]carbamate (130 mg) was separated using a preparative SFC (Daicel Chiralpak OX (250 mm × 30 mm, 10 μm), 0.1% NH3-H2O in EtOH to give tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (55 mg, 41% yield) as a pale yellow solid (MS(ESI): 729.2 [M+H]). +tert-Butyl 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-benzazepin-3-yl]carbamate [Isomer B] (56 mg, 43% yield) was obtained as a pale yellow solid with a retention time of 1.54 minutes (see conditions below). MS(ESI): 729.2 [M+H] + , retention time 2.13 min (column: Chiralpak OX-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0289] 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-benzazepin-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-benzazepin-2-one A solution of tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (50.0 mg, 0.07 mmol, 1.0 equiv) in HCl / EtOAc (4 M, 10 mL, 40.0 mmol, 582.9 equiv) was stirred at 20° C. for 0.5 h. The mixture was concentrated, and the remaining residue was dissolved in MeCN / water and lyophilized to give 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-benzazepin-2-one [Isomer A] (40.1 mg, 0.06 mmol, 84% yield) as the hydrochloride salt as a white solid. MS(ESI): 629.1 [M+H] + , retention time 0.94 min (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-benzazepin-2-one [Isomer B] was obtained in the same manner. MS (ESI): 629.1 [M+H] + , retention time 1.91 min (column: Chiralpak IG-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); elution: 60% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0290] Example 23 (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-benzazepin-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-benzazepin-2-one TIFF2025526726000179.tif44170 Step a) tert-Butyl 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-benzazepin-3-yl]carbamate The title compound was prepared in a similar manner to steps a-l of Example 1 (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-propanoic acid instead of pivalic acid in step k) and obtained as a pale yellow solid. MS (ESI): 614.1 [M+H] + .

[0291] Step b) tert-butyl 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-benzazepin-3-yl]carbamate and tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000181.tif47170 tert-Butyl 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-benzazepin-3-yl]carbamate (340 mg) was separated using preparative SFC (Daicel Chiralpak Upon subjecting to AD (250 mm × 30 mm, 10 μm, 0.1% NH3-H2O in EtOH), tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (30 mg) (MS(ESI): 688.1 [M + H]) was obtained. +, retention time 1.20 min (see conditions below) was obtained as a pale yellow solid, and tert-butyl 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-benzazepin-3-yl]carbamate [Isomer B] (40 mg) was obtained as a pale yellow solid. MS (ESI): 688.3 [M-isobutene + H] + , retention time 2.08 min (column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0292] 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-benzazepin-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-benzazepin-2-one A solution of tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (30.0 mg, 0.04 mmol, 1.0 equiv) in TIFF2025526726000182.tif44170HCl / EtOAc (4 M, 7.5 mL, 30.0 mmol, 743.7 equiv) was stirred at 20° C. for 0.5 h. The mixture was concentrated to give 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-benzazepin-2-one [Isomer A] (24.8 mg, 0.04 mmol, 87% yield) as the hydrochloride salt as a yellow solid. MS(ESI): 644.1 [M+H] + Retention time 1.99 min (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-benzazepin-2-one [Isomer B] was obtained similarly. MS (ESI): 644.1 [M+H] + , retention time 2.44 min (column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0293] Example 24 2-Methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile and 2-Methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile TIFF2025526726000183.tif47170 Step a) tert-Butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate The title compound (TIFF2025526726000184.tif48170) was prepared in a similar manner to steps a-l of Example 1 (using 2-[4-(chloromethyl)phenyl]-5-(trifluoromethoxy)pyridine, hydrochloride salt [CAS#2338841-95-3] instead of 4-(trifluoromethoxy)benzyl bromide in step f and 2-cyano-2-methyl-propanoic acid instead of pivalic acid in step k) and obtained as a pale yellow solid. MS (ESI): 717.5 [M+H] + .

[0294] Step b) tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000185.tif48170 tert-Butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (260 mg) was separated using a preparative SFC (Daicel Chiralpak IC (250 mm × 30 mm, 10 μm), 0.1% NH3-H2O in iPrOH, gave tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (97 mg) (MS(ESI): 717.3 [M+H] + , retention time 1.74 minutes (see conditions below) was obtained as a white solid, and tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer B] (98 mg) was obtained as a white solid. MS (ESI): 717.4 [M+H] +, retention time 2.35 min (column: Chiralpak IC-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for iPrOH (0.05% DEA); gradient elution: 5% to 40% iPrOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0295] Step c) 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile and 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile A solution of tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (95.0 mg, 0.13 mmol, 1.0 equiv) in a mixture of DCM / TFA (3:1, 4.0 mL) was stirred for 1 h at 20 °C. DCM (20 mL) was then added, and the pH of the reaction mixture was adjusted to 8 by careful addition of saturated NaHCO solution. The resulting mixture was extracted with DCM (10 mL x 3), and the combined organic layers were washed with brine (10 mL), dried (NaSO), and concentrated. The remaining residue was dissolved in EtOAc (30 mL), and HCl / EtOAc (4 M, 0.1 mL) was added. The mixture was concentrated, and water (20 mL) was added to the remaining solid. Lyophilization afforded 2-methyl-2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile [Isomer A] (67 mg, 0.1 mmol, 76%) as the hydrochloride salt as a white solid. MS (ESI): 617.4 [M+H] + , retention time 1.20 min (see conditions below). 2-Methyl-2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]propanenitrile [Isomer B] was obtained in the same manner. MS (ESI): 617.5 [M+H] + , retention time 1.82 min (Column: (SS) Whelk-O1 50 × 4.6 mm ID, 3 μm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA); Gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35 °C; Back pressure: 100 bar).

[0296] Example 26 (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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one TIFF2025526726000187.tif47170 Step a) tert-Butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate The title compound (TIFF2025526726000188.tif48170) was prepared in a similar manner to steps a-l of Example 1 (using 2-[4-(chloromethyl)phenyl]-5-(trifluoromethoxy)pyridine, hydrochloride salt [CAS#2338841-95-3] instead of 4-(trifluoromethoxy)benzyl bromide in step f and 2-methyl-2-methylsulfonyl-propanoic acid instead of pivalic acid in step k) and obtained as a pale yellow solid. MS (ESI): 770.3 [M+H] + .

[0297] Step b) tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000189.tif48170 tert-Butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (250 mg) was separated using SFC (Daicel Chiralpak IC (250 mm × 30 mm, 10 μm), 0.1% NH3-H2O in iPrOH, gave tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (97 mg) (MS(ESI): 770.3 [M+H] + , retention time 2.01 minutes (see conditions below) was obtained as a white solid, and tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer B] (92 mg) was obtained as a white solid. MS (ESI): 770.5 [M+H]+ , retention time 2.57 min (column: Chiralpak IC-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for iPrOH (0.05% DEA); gradient elution: 5% to 40% iPrOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0298] 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one A solution of tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (95.0 mg, 0.12 mmol, 1.0 equiv) in HCl / EtOAc (4 M, 10 mL, 40.0 mmol, 324.1 equiv) was stirred at 20 °C for 1 h. The mixture was concentrated, and the remaining residue was dissolved in water (20 mL) and lyophilized to give 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-benzazepin-2-one [Isomer A] (74.1 mg, 0.1 mmol, 83% yield) as the hydrochloride salt as a white solid. MS(ESI): 670.4 [M+H] +Retention time 1.96 min (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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one [Isomer B] was obtained similarly. MS (ESI): 670.4 [M+H] + , retention time 2.13 min (column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0299] Example 27 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile and 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile TIFF2025526726000191.tif52170 Step a) tert-Butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate The title compound, TIFF2025526726000192.tif53170, was prepared similarly to Example 1, steps a-l (using 2-[4-(chloromethyl)phenyl]-4-(trifluoromethyl)pyridine; hydrochloride salt (Intermediate 6) instead of 4-(trifluoromethoxy)benzyl bromide in step f, and 2-cyano-2-methyl-propanoic acid instead of pivalic acid in step k) and obtained as a pale yellow solid. MS (ESI): 701.5 [M+H] + .

[0300] Step b) tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000193.tif53170 tert-Butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (270 mg) was separated using preparative SFC (Daicel Chiralcel OD (250 mm × 30 mm, 10 μm), 0.1% NH3-H2O in iPrOH gave tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (56 mg) (MS(ESI): 701.5 [M+H] +, retention time 1.08 min (see conditions below) was obtained as a pale yellow solid, and tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer B] (73 mg) was obtained as a pale yellow solid. MS(ESI): 701.4 [M+H] + , retention time 1.29 min (Column: Chiralcel OD 50 × 4.6 mm ID, 3 μm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA); Gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35 °C; Back pressure: 100 bar).

[0301] Step c) 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile and 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile A solution of tert-butyl 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-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (55.2 mg, 0.08 mmol, 1.0 equiv) in a mixture of DCM / TFA (3:1, 4.0 mL) was stirred for 0.5 h at 20 °C. The pH of the reaction mixture was adjusted to 8 by careful addition of saturated NaHCO solution. The resulting mixture was extracted with DCM (10 mL x 3), and the combined organic layers were washed with brine (10 mL), dried (NaSO), and concentrated. The remaining residue was dissolved in EtOAc (20 mL), and HCl / EtOAc (4 M, 0.2 mL) was added. The mixture was concentrated, and water (20 mL) was added to the remaining solid. 2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile [Isomer A] was obtained by lyophilization as the hydrochloride salt (49.6 mg, 0.08 mmol, 97%) as a pale yellow solid. MS (ESI): 601.4 [M+H] + , retention time 1.28 min (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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile [Isomer B] was obtained in the same manner. MS (ESI): 601.2 [M+H] + , retention time 1.86 min (Column: (SS) Whelk-O1 50 × 4.6 mm ID, 3 μm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA); Gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35 °C; Back pressure: 100 bar).

[0302] Example 28 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile and 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile TIFF2025526726000195.tif49170 Step a) tert-Butyl 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-pyridyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate The title compound (TIFF2025526726000196.tif51170) was prepared in a similar manner to Example 1, steps a-l (substituting 5-(chloromethyl)-2-[4-(trifluoromethyl)phenyl]pyridine [CAS#851507-54-5] for 4-(trifluoromethoxy)benzyl bromide in step f, and 2-cyano-2-methyl-propanoic acid for pivalic acid in step k), and obtained as a pale yellow solid. MS (ESI): 701.4 [M+H] + .

[0303] Step b) tert-butyl 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-pyridyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl 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-pyridyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000197.tif51170 tert-Butyl 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-pyridyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate was separated by preparative SFC (Daicel Chiralcel OD (250 mm × 30 mm, 10 μm), 0.1% NH3-H2O in EtOH) gave tert-butyl 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-pyridyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (42 mg) (MS(ESI): 701.5 [M+H] + , retention time 1.31 min (see conditions below) was obtained as a pale yellow solid, and tert-butyl 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-pyridyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer B] (68 mg) was obtained as a pale yellow solid. MS (ESI): 701.5 [M+H] +, retention time 1.59 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0304] Step c) 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile and 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile A solution of tert-butyl 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-pyridyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (41.2 mg, 0.06 mmol, 1.0 equiv) in a mixture of DCM / TFA (3:1, 4.0 mL) was stirred for 0.5 h at 20 °C. The pH of the reaction mixture was adjusted to 8 by careful addition of saturated NaHCO solution. The resulting mixture was extracted with DCM (10 mL x 3), and the combined organic layers were washed with brine (10 mL), dried (NaSO), and concentrated. The remaining residue was dissolved in EtOAc (20 mL), and HCl / EtOAc (4 M, 0.2 mL) was added. The mixture was concentrated, and water (20 mL) was added to the remaining solid. Lyophilization afforded 2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile [Isomer A] as the hydrochloride salt (36.4 mg, 0.06 mmol, 96%) as a pale yellow solid. MS (ESI): 601.2 [M+H] + , retention time 1.75 min (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-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile [isomer B] was obtained in the same manner. MS (ESI): 601.3 [M+H] + , retention time 2.22 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0305] Example 29 (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-benzazepin-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-benzazepin-2-one TIFF2025526726000199.tif44170 Step a) tert-Butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000200.tif47170 The title compound was prepared similarly to steps a-l of Example 1 (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-propanoic acid instead of pivalic acid in step k) and obtained as a yellow oil. MS (ESI): 687.0 [M-isobutene + H] + .

[0306] Step b) tert-butyl 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-benzazepin-3-yl]carbamate and tert-butyl 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-benzazepin-3-yl]carbamate TIFF2025526726000201.tif47170 tert-Butyl 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-benzazepin-3-yl]carbamate was separated by preparative SFC (Daicel Chiralpak Upon subjecting to AD (250 mm × 30 mm, 10 μm), 0.1% NH3-H2O in EtOH, tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (70 mg) (MS(ESI): 743.4 [M+H] + , retention time 1.18 minutes (see conditions below) was obtained as a yellow solid, and tert-butyl 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-benzazepin-3-yl]carbamate [Isomer B] (70 mg) was obtained as a yellow solid. MS (ESI): 743.4 [M+H]+ , retention time 1.87 min (column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0307] 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-benzazepin-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-benzazepin-2-one A solution of tert-butyl 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-benzazepin-3-yl]carbamate [Isomer A] (65.0 mg, 0.09 mmol, 1.0 equiv) in TIFF2025526726000202.tif44170HCl / EtOAc (4 M, 3.45 mL, 13.8 mmol, 157.6 equiv) 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 75x30 mm, 3 μm; water (containing HCl) / MeCN) to give 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-benzazepin-2-one [Isomer A] (22.3 mg, 0.03 mmol, 36% yield) as the hydrochloride salt as a white solid. MS(ESI): 643.2 [M+H] + , retention time 1.72 min (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-benzazepin-2-one [Isomer B] was obtained in the same manner. MS (ESI): 643.2 [M+H] + , retention time 2.04 min (column: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0308] Example 30 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile and 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile TIFF2025526726000203.tif44170 Step a) tert-Butyl N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000204.tif46170 The title compound was prepared similarly to steps a-l of Example 1 (using 1-[4-(bromomethyl)phenyl]-3-(trifluoromethyl)pyrazole [CAS# 1284983-51-2] instead of 4-(trifluoromethoxy)benzyl bromide in step f and 2-cyano-2-methyl-propanoic acid instead of pivalic acid in step k) and obtained as a yellow oil. MS (ESI): 634.1 [M-isobutene + H] + .

[0309] Step b) tert-butyl N-[(3S)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl N-[(3R)-8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000205.tif47170 tert-Butyl N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (25 mg) was separated using preparative SFC (Daicel Chiralcel OX-3 (50 × 4.6 mm, 3 μm), 0.05% DEA in EtOH) gave tert-butyl N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (11 mg) (MS(ESI): 634.1 [M-isobutene + H]). + , retention time 1.12 min (see conditions below) was obtained as an off-white solid, and tert-butyl N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer B] (10 mg) was obtained as an off-white solid. MS(ESI): 634.1 [M-isobutene + H] +, retention time 1.50 min (column: Chiralcel OX-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0310] Step c) 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile and 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile A solution of tert-butyl N-[8-[5-(1-cyano-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (11 mg, 0.02 mmol, 1.0 equiv) in a mixture of DCM / TFA (3:1, 4.0 mL) was stirred for 1 h at 25 °C. DCM (3 mL) was added, and the pH of the mixture was adjusted to 8 by careful addition of saturated NaHCO solution. The resulting mixture was extracted with DCM (5 mL x 3), and the combined organic layers were washed with brine (10 mL), dried (NaSO), and concentrated to give 2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile [Isomer A] as a yellow solid (5.3 mg, 0.01 mmol, 54%). MS (ESI): 590.2 [M+H] + , retention time 1.55 min (see conditions below). 2-[5-[3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepin-8-yl]-1,3,4-oxadiazol-2-yl]-2-methyl-propanenitrile [Isomer B] was obtained in the same manner. MS (ESI): 590.1 [M+H] + , retention time 2.27 min (column: Chiralcel OX-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar).

[0311] Example 32 (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-benzazepin-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)phenyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-2-one TIFF2025526726000207.tif49170 Step a) tert-Butyl N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate The title compound (TIFF2025526726000208.tif52170) was prepared similarly to steps a-l of Example 1 (using 1-(chloromethyl)-4-[4-(trifluoromethyl)phenyl]benzene [CAS# 454464-38-1] instead of 4-(trifluoromethoxy)benzyl bromide in step f and 2-methyl-2-methylsulfonyl-propanoic acid instead of pivalic acid in step k) as a pale yellow solid. MS (ESI): 697.2 [M-isobutene + H] + .

[0312] Step b) tert-butyl 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)phenyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate and tert-butyl 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)phenyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate TIFF2025526726000209.tif52170 tert-Butyl N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate (190 mg) was separated using SFC (Daicel Chiralpak Upon subjecting to AD (250 × 30 mm, 10 μm, 0.1% NH3-H2O in EtOH), tert-butyl N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer A] (60 mg) (MS(ESI): 697.3 [M + H]) was obtained. + , retention time 1.16 min (see conditions below) was obtained as a white solid, and tert-butyl N-[5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonyl-ethyl)-1,3,4-oxadiazol-2-yl]-2-oxo-1-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-3,4-dihydro-1-benzazepin-3-yl]carbamate [Isomer B] (65 mg) was obtained as a white solid. MS (ESI): 697.3 [M-isobutene + H] +, retention time 1.81 min (column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A for CO2, phase B for EtOH (0.05% DEA); gradient elution: 5% to 40% EtOH (0.05%...

Claims

1. Equation (I) A compound or a pharmaceutically acceptable salt thereof, wherein, R １ is a 5- or 6-membered heteroaryl, R １ However, one or more R may be the same or different. １０ A 5- or 6-membered heteroaryl, which may be substituted with R ２ It is selected from hydrogen and halogens. R ４ R is selected from phenyl and pyridinyl. ４ R may be one or more R which are the same or different １１ It may also be replaced with R １０ teeth, i) C-alkyl optionally substituted with one or more halogen, amino, C １～６ -alkoxy, -S(O) ２ (C １～６ -alkyl), cyano; １～６ -alkyl; ii) C which may be substituted with one or more halogens, cyano, or amino ３～１０ - Cycloalkyl; iii) One or more halogens, C １～１０ -Alkyl, amino, halo-C １～６ -Alkyl, hydroxy, cyano, -C(O)O-(R １０ｑ ), C ３～１０ - A 3- to 10-membered heterocycline which may be substituted with a cycloalkyl group, C １～１０ - Alkyl group contains one or more hydroxy, C １～６ - 3- to 10-membered heterocyclines, which may be substituted with alkoxy groups; iv-N(R １０ｅ R １０ｆ ); v) One or more C １～１０ - Heteroaryls, which may be substituted with alkyl or halogens. Selected from, R １０ｅ and R １０ｆ Each of them operates independently. i) Hydrogen, ii) C which may be substituted with one or more cyano, halogen, or hydroxyl groups. １～６ - Alkyl; iii) One or more halogens, C １～１０ - May be substituted with alkyl, C ３～１０ - Cycloalkyl Selected from, R １０ｑ C １～５ - Alkyl, C １～５ - The alkyl group may be substituted with one or more hydroxyls. １～５ -It is alkyl, R １１ teeth, i) Halogen; ii) One or more C １～６ - Alkyl, C ５～６ - Aryl, C ３～１０ -Cycloalkyl, Halo-C １～６ - Alkyl, C ３～１０ - C may be substituted with a heterocyclyl. １～６ - An alkoxy, wherein a 3- to 10-membered heterocyclyl is C １～６ - May be substituted with alkyl, C １～６ - Alkoxy; iii) 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 - Five- to six-membered heteroaryls, which may be substituted with alkoxy; iv) One or more C １～６ - Alkoxy, Halo-C １～６ - Phenyl that may be substituted with alkyl groups; v)-O(R １１ａ ) Selected from, R １１ａ C １～６ - Alkyl, C ３～６ -Cycloalkyl, phenyl and halo-C １～６ - A compound selected from alkyl groups or a pharmaceutically acceptable salt thereof.

2. R １ However, it is a 5-membered heteroaryl, R １ However, one or more R may be the same or different. １０ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with.

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

4. R １ However, one R １０ The compound according to claim 1, which is a 1,3,4-oxadiazole substituted with , or a pharmaceutically acceptable salt thereof.

5. R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is fluorine.

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

7. R １０ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from methyl-methylsulfonyl-ethyl, pyrrolidine, 4-oxa-7-azaspiro[2.5]octan-7-yl, methyl-propanenitrile, 1,2,2,2-tetrafluoro-methoxyethyl, tert-butyl, 1-ethyl-5,5-difluoro-3-piperidyl, 4,4-difluoro-1-piperidyl, and azabicyclo[3.1.1]heptan-3-carboxylate.

8. R １１ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from 5-(trifluoromethyl)-2-pyridyl, phenoxy, trifluoromethoxy, methoxypyridyl, cyclopentoxy, 4-methoxyphenyl, (trifluoromethyl)-1,2,4-oxadiazole-3-yl, 5-(trifluoromethoxy)-2-pyridyl, 4-(trifluoromethyl)pyrazole-1-yl, chloro, 5-(difluoromethoxy)-2-pyridyl, 4-(trifluoromethoxy)pyrazole-1-yl, and 5-(trifluoromethyl)tetrazole-2-yl.

9. R １ However, it is a 5-membered heteroaryl, R １ However, one or more R may be the same or different. １０ A five-membered heteroaryl which may be substituted with, R ２ However, it is a halogen, R ４ However, it is phenyl or pyridinyl, R １０ but, i) One or more halogens, C １～６ -alkoxy, -S(O) ２ (C １～６ -alkyl), may be substituted with cyano, C １～６ - Alkyl; ii) One or more halogens, C １～１０ -alkyl, -C(O)O-(R １０ｑ ), C ３～１０ - A 3- to 10-membered heterocycline which may be substituted with a cycloalkyl group, C １～１０ - Alkyl group contains one or more C １～６ - 3- to 10-membered heterocyclines, which may be substituted with alkoxy groups; iii) One or more C １～１０ - Heteroaryl, which may be substituted with alkyl. Selected from, R １１ but, i) Halogen; ii) One or more halogens, halo-C １～６ - Alkyl, C １～６ - Alkoxy, Halo-C １～６ - Five- to six-membered heteroaryls, which may be substituted with alkoxy; iii) One or more C １～６ - Alkoxy, Halo-C １～６ - Phenyl that may be substituted with alkyl groups; iv-O(R １１ａ ) Selected from, R １１ａ is C １～６ -alkyl, C ３～６ -cycloalkyl, phenyl and halo-C １～６ -alkyl selected, the compound according to claim 1.

10. R １ However, one R １０ It is a 1,3,4-oxadiazole substituted with, R ２ However, it is fluorine, R ４ However, it is phenyl, R １０ However, selected from methyl-methylsulfonyl-ethyl, pyrrolidine, 4-oxa-7-azaspiro[2.5]octan-7-yl, methyl-propanenitrile, 1,2,2,2-tetrafluoro-methoxyethyl, tert-butyl, 1-ethyl-5,5-difluoro-3-piperidyl, 4,4-difluoro-1-piperidyl and azabicyclo[3.1.1]heptan-3-carboxylate, R １１ The compound according to claim 1, selected from 5-(trifluoromethyl)-2-pyridyl, phenoxy, trifluoromethoxy, methoxypyridyl, cyclopentoxy, 4-methoxyphenyl, (trifluoromethyl)-1,2,4-oxadiazole-3-yl, 5-(trifluoromethoxy)-2-pyridyl, 4-(trifluoromethyl)pyrazole-1-yl, chloro, 5-(difluoromethoxy)-2-pyridyl, 4-(trifluoromethoxy)pyrazole-1-yl, and 5-(trifluoromethyl)tetrazole-2-yl.

11. 3-amino-8-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; 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-oxadiazole-2-yl]propanenitrile; 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-oxadiazole-2-yl]propanenitrile; (3S)-3-amino-5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazole-2-yl)-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-8-(5-morpholino-1,3,4-oxadiazole-2-yl)-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3S)-3-amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxyethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxyethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3S)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine-2-one; (3S)-3-amino-5,5-difluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5-difluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1-benzazepine-2-one; (3S)-3-amino-8-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-8-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine-2-one; (3S)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; 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-oxadiazole-2-yl]propanenitrile; 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-oxadiazole-2-yl]propanenitrile; (3S)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-1-[[4-(4-methoxyphenyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-3,4-dihydro-1-benzazepine-2-one; 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-oxadiazole-2-yl]propanenitrile; 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-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[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-oxadiazole-2-yl]propanenitrile; 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-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; (3S)-3-amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazole-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazole-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3S)-3-amino-5,5,7-trifluoro-8-(5-pyrrolidine-1-yl-1,3,4-oxadiazole-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-8-(5-pyrrolidine-1-yl-1,3,4-oxadiazole-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3S)-3-amino-8-[5-(4,4-difluoro-1-piperidyl)-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-2-one; (3R)-3-amino-8-[5-(4,4-difluoro-1-piperidyl)-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-2-one; (3S)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3S)-3-amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-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-2-one; (3R)-3-amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-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-2-one; (3S)-3-amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-8-(5-tert-butyl-3-pyridyl)-1-[(4-chlorophenyl)methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine-2-one; 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-oxadiazole-2-yl]-2-methyl-propanenitrile; 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-oxadiazole-2-yl]-2-methyl-propanenitrile; 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-oxadiazole-2-yl]propanenitrile; 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-oxadiazole-2-yl]propanenitrile; (3S)-3-amino-5,5,7-trifluoro-8-(5-pyrrolidine-1-yl-1,3,4-oxadiazole-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazole-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-8-(5-pyrrolidine-1-yl-1,3,4-oxadiazole-2-yl)-1-[[4-[3-(trifluoromethyl)-1,2,4-triazole-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3S)-3-amino-8-[5-(3,3-difluoropyrrolidine-1-yl)-1,3,4-oxadiazole-2-yl]-5,5,7-trifluoro-1-[[4-[3-(trifluoromethyl)-1,2,4-triazole-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-8-[5-(3,3-difluoropyrrolidine-1-yl)-1,3,4-oxadiazole-2-yl]-5,5,7-trifluoro-1-[[4-[3-(trifluoromethyl)-1,2,4-triazole-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3S)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[3-(trifluoromethyl)-1,2,4-triazole-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[3-(trifluoromethyl)-1,2,4-triazole-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; (3S)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridyl]phenyl]methyl]3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]-2-methyl-propanenitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)-2-pyridyl]phenyl]methyl]3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]-2-methyl-propanenitrile; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]-2-methyl-propanenitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)phenyl]-3-pyridyl]methyl]-3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]-2-methyl-propanenitrile; (3S)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazole-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazole-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazole-1-yl]phenyl]methyl]3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]-2-methyl-propanenitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[3-(trifluoromethyl)pyrazole-1-yl]phenyl]methyl]3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]-2-methyl-propanenitrile; (3S)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazole-1-yl]phenyl]methyl]3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]-2-methyl-propanenitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazole-1-yl]phenyl]methyl]3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]-2-methyl-propanenitrile; (3S)-3-amino-8-[5-[5,5-difluoro-1-(2-methoxyethyl)-3-piperidyl]-1,3,4-oxadiazole-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-8-[5-[5,5-difluoro-1-(2-methoxyethyl)-3-piperidyl]-1,3,4-oxadiazole-2-yl]-5,5,7-trifluoro-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; Methyl 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-oxadiazole-2-yl]-3-azabicyclo[3.1.1]heptan-3-carboxylate; Methyl 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-oxadiazole-2-yl]-3-azabicyclo[3.1.1]heptan-3-carboxylate; Methyl 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-oxadiazole-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate; Methyl 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-oxadiazole-2-yl]-3-azabicyclo[3.1.1]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-oxadiazole-2-yl]-2-methyl-propanenitrile; 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-oxadiazole-2-yl]-2-methyl-propanenitrile; 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-oxadiazole-2-yl]propanenitrile; 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-oxadiazole-2-yl]propanenitrile; (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-oxadiazole-2-yl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-1-[[4-(5-methoxy-2-pyridyl)phenyl]methyl]-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-3,4-dihydro-1-benzazepine-2-one; 2-methyl-2-[5-[(3S)-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-oxadiazole-2-yl]propanenitrile; 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-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridyl]phenyl]methyl]5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; Methyl 1-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate; Methyl 1-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethoxy)pyrazole-1-yl]phenyl]methyl]3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethoxy)pyrazole-1-yl]phenyl]methyl]3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[2-fluoro-4-[4-(trifluoromethyl)pyrazole-1-yl]phenyl]methyl]2-oxo-3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[2-fluoro-4-[4-(trifluoromethyl)pyrazole-1-yl]phenyl]methyl]2-oxo-3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[2-fluoro-6-[4-(trifluoromethyl)pyrazole-1-yl]-3-pyridyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[2-fluoro-6-[4-(trifluoromethyl)pyrazole-1-yl]-3-pyridyl]methyl]-2-oxo-3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)pyrazole-1-yl]-3-pyridyl]methyl]-3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[6-[4-(trifluoromethyl)pyrazole-1-yl]-3-pyridyl]methyl]-3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-1-[[3-fluoro-4-[4-(trifluoromethyl)pyrazole-1-yl]phenyl]methyl]2-oxo-3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-1-[[3-fluoro-4-[4-(trifluoromethyl)pyrazole-1-yl]phenyl]methyl]2-oxo-3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[1-(trifluoromethyl)pyrazole-4-yl]phenyl]methyl]3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; and 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[1-(trifluoromethyl)pyrazole-4-yl]phenyl]methyl]3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

12. 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-oxadiazole-2-yl]propanenitrile; 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-oxadiazole-2-yl]propanenitrile; (3S)-3-amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxyethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-8-[5-(1,2,2,2-tetrafluoro-1-methoxyethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3S)-3-amino-8-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-8-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-1-[[4-(cyclopentoxy)phenyl]methyl]-5,5,7-trifluoro-3,4-dihydro-1-benzazepine-2-one; (3S)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[5-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; 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-oxadiazole-2-yl]propanenitrile; 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-oxadiazole-2-yl]propanenitrile; 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-oxadiazole-2-yl]propanenitrile; 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-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[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-oxadiazole-2-yl]propanenitrile; 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-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; (3S)-3-amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazole-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-8-[5-(1-ethyl-5,5-difluoro-3-piperidyl)-1,3,4-oxadiazole-2-yl]-5,5,7-trifluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3S)-3-amino-5,5,7-trifluoro-8-(5-pyrrolidine-1-yl-1,3,4-oxadiazole-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-8-(5-pyrrolidine-1-yl-1,3,4-oxadiazole-2-yl)-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3S)-3-amino-8-[5-(4,4-difluoro-1-piperidyl)-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-2-one; (3R)-3-amino-8-[5-(4,4-difluoro-1-piperidyl)-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-2-one; (3S)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3S)-3-amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-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-2-one; (3R)-3-amino-5,5,7-trifluoro-8-[5-(4-oxa-7-azaspiro[2.5]octan-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-2-one; 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-oxadiazole-2-yl]propanenitrile; 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-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; 2-methyl-2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[5-(trifluoromethoxy)-2-pyridyl]phenyl]methyl]3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; (3S)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazole-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; (3R)-3-amino-5,5,7-trifluoro-8-[5-(1-methyl-1-methylsulfonylethyl)-1,3,4-oxadiazole-2-yl]-1-[[4-[4-(trifluoromethyl)pyrazole-1-yl]phenyl]methyl]-3,4-dihydro-1-benzazepine-2-one; 2-[5-[(3S)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazole-1-yl]phenyl]methyl]3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]-2-methyl-propanenitrile; 2-[5-[(3R)-3-amino-5,5,7-trifluoro-2-oxo-1-[[4-[4-(trifluoromethyl)pyrazole-1-yl]phenyl]methyl]3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]-2-methyl-propanenitrile; Methyl 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-oxadiazole-2-yl]-3-azabicyclo[3.1.1]heptan-3-carboxylate; Methyl 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-oxadiazole-2-yl]-3-azabicyclo[3.1.1]heptan-3-carboxylate; Methyl 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-oxadiazole-2-yl]-3-azabicyclo[3.1.1]heptane-3-carboxylate; Methyl 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-oxadiazole-2-yl]-3-azabicyclo[3.1.1]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-oxadiazole-2-yl]-2-methyl-propanenitrile; 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-oxadiazole-2-yl]-2-methyl-propanenitrile; 2-methyl-2-[5-[(3S)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile; and 2-methyl-2-[5-[(3R)-3-amino-1-[[4-[5-(difluoromethoxy)-2-pyridyl]phenyl]methyl]-5,5,7-trifluoro-2-oxo-3,4-dihydro-1-benzazepine-8-yl]-1,3,4-oxadiazole-2-yl]propanenitrile A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

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, wherein the compound of formula (XVIII) (wherein R １ , R ２ and R ４ are as defined in any one of claims 1 to 10, and PG is an amino protecting group), reacting the compound with a suitable deprotecting agent to form the compound of formula (I).

14. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, as produced according to the method of 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 a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

17. The pharmaceutical composition according to 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 the treatment, prevention and / or delay of the progression of cancer.

19. The compound for use according to claim 18 or a pharmaceutically acceptable salt thereof, wherein the cancer is associated with abnormal diacylglycerol kinase signaling, and the diacylglycerol kinase is selected from DGKα and / or DGKζ.

20. The aforementioned cancers include B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative conditions, A compound for use according to claim 18, selected from the group consisting of MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell tumor, Waldenström macroglobulinemia, preleukemia, sarcoma, carcinoma, melanoma, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, squamous cell carcinoma (e.g., NSCLC), melanoma, gastric cancer, brain cancer, lung cancer (e.g., NSCLC), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.

21. Use of any one of the compounds or pharmaceutically acceptable salts thereof according to claims 1 to 12 for the treatment, prevention and / or delay of the progression of cancer.

22. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 for the preparation of a pharmaceutical for the treatment, prevention and / or delay of the progression of cancer.

23. A method for treating, preventing and / or delaying the progression of cancer, comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of claims 1 to 12.

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

25. A method for inhibiting the activity of at least one diacylglycerol kinase selected from DGKα and DGKζ, comprising administering a therapeutically effective amount of at least one compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof to a subject in need.

26. The invention is as described above.

Images