Substituted 3,6-dihydro-2H-1,3,4-oxadiazin-2-ones for the treatment of sarcomas

Abstract

The present invention provides a method for treating sarcoma by administering to a patient in need of treatment a compound represented by general formula (I The present invention provides a method for treating sarcoma comprising administering a compound of formula (I) of formula (I) to a patient having a sarcoma, the method comprising administering to the patient a compound of formula (I) of formula (I) or (II) of formula (II ... 1 , R 2 , R 3 , and R 4 is as defined herein.

Description

[Technical field]

[0001] The present invention provides the use of compounds, in particular compounds of general formula (I) as described and defined herein, for the treatment of sarcomas, and also provides the use of pharmaceutical compositions of said compounds, either as sole agents or in combination with other active ingredients, for the treatment of sarcomas. [Background technology]

[0002] Cancer causes more than 550,000 deaths in the United States and more than 8 million deaths worldwide each year. New agents, including small molecules, molecules that affect tissue-specific growth requirements, and immunomodulators, have been shown to benefit small populations of patients whose cancers have unique genomic mutations or other characteristics. Unfortunately, many cancer patients remain without effective treatment options. Sarcomas are a group of cancers in which chemotherapy has been shown to be effective in some cases and to result in increased survival. However, chemotherapy has not improved the prognosis of patients with aggressive or metastatic sarcomas, and there is a great medical need for improved targeted therapies.

[0003] One approach to identifying new anticancer drugs is phenotypic screening to discover novel small molecules that exhibit strong selectivity among cancer cell lines, followed by predictive chemogenomics to identify cellular features associated with drug response. In the 1990s, Weinstein and colleagues demonstrated that the cytotoxicity profile of a compound can be used to identify cellular characteristics, e.g., gene expression profiles and DNA copy number, that correlate with drug sensitivity. In recent years, automated high-throughput chemosensitivity testing of large panels of cell lines, combined with comprehensive genomic and phenotypic characterization of cell lines, has greatly increased the ability to identify features of cancer cell lines that mediate response to small molecules. Phenotypic observations of small molecule sensitivity can be correlated with expression patterns or somatic alterations, as in the case of trastuzumab-sensitive HER2-amplified breast cancer or erlotinib-sensitive EGFR-mutated lung cancer.

[0004] Phenotypic screening has identified some compounds known in the literature to be PDE3 inhibitors that are useful for treating certain cancers. Co-expression of PDE3A and / or PDE3B with Schlafen 12 (SLFN12) polynucleotides or polypeptides is typically required for cells to become sensitized. PDE3A / B inhibitors that cause drug sensitivity, and even weak PDE3A / PDE3B inhibitors in some cases, have been found to stabilize the formation of complexes between PDE3A or PDE3B and SLFN12. PDE3A / PDE3B inhibitors that do not cause cell sensitivity typically do not stabilize the PDE3A- or PDE3B-SLFN12 complex.

[0005] Sarcomas are cancerous tumors of connective tissues, such as blood vessels, bone, cartilage, deep skin tissue, fat, fibrous tissue, lymphatic vessels, muscle, and nerves. Sarcomas are difficult to diagnose, and unlike the typical tumors that begin growing in epithelial cells, sarcomas begin in the mesenchymal cells that build soft tissues and bone. Sarcomas occur in adults and children. In children, sarcomas account for approximately 15% of all cancer diagnoses. Thus, there appears to be an urgent need to find new treatments. Summary of the Invention [Means for solving the problem]

[0006] It has now been found that compounds of formula (I), and in particular (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, are useful in the treatment of sarcomas.

[0007] According to a first aspect, the present invention relates to a compound of general formula (I) for use in the treatment of sarcomas [ka] or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof, During the ceremony, R 1 is selected from a hydrogen atom, a halogen atom, a cyano group, a C1-C3-alkyl group, a C1-C3-haloalkyl group, and a C1-C3-haloalkoxy group, R 2 is selected from a hydrogen atom and a halogen atom; R 3 teeth, C1-C6-alkyl groups optionally substituted by 1 or 2 substituents, each of which is independently selected from hydroxy groups, C1-C4-alkoxy groups, and 3- to 7-membered heterocycloalkyl groups; C2-C6-alkenyl groups, optionally substituted by C1-C4-alkoxy groups, C3-C9-cycloalkyl groups optionally substituted by hydroxy groups, C5-C9-cycloalkenyl groups optionally substituted by hydroxy groups; -O-, -S-, -S(O)-, S(O)2, and -NR 9 -, wherein - is a 3- to 9-membered heterocycloalkyl group containing 1, 2, or 3 heteroatoms independently selected from -O-, -NR 9 -, -CH2-, -CH2-CH2-, -O-CH2-, -CH2-O-, -NR 9 -CH2-, and -CH2-NR 9 -, optionally further comprising a bridging group selected from A 3- to 9-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents, each of which is Halogen atoms, oxo (=O) group, Cyano group, Hydroxy groups, C1-C3-alkyl groups optionally further substituted by hydroxy groups; C1-C3-haloalkyl group, C1-C3 alkoxy group, C1-C3-haloalkoxy group, C(O)NR 5 R 6 base, and N.R. 5 R 6(independently selected from the group consisting of Partially unsaturated, 5-9 membered heterocycloalkyl groups, optionally substituted with 1, 2 or 3 substituents, each of which may be an oxo group (=O), a C1-C3-alkyl group, -C(O)R 5 R 6 groups, and halogen atoms); Aryl groups optionally substituted with 1, 2, 3 or 4 substituents, each of which is selected from the group consisting of halogen atoms, hydroxy groups, cyano groups, C1-C3-alkyl groups, C1-C3-haloalkyl groups, C1-C3-alkoxy groups, C1-C3-haloalkoxy groups, and NR 5 R 6 (independently selected from the group consisting of Monocyclic or bicyclic heteroaryl groups optionally substituted with 1, 2 or 3 substituents, each of which is selected from the group consisting of halogen atoms, C1-C3-alkyl groups, cyano groups, C1-C3-haloalkyl groups, C1-C3-hydroxyalkyl groups, C1-C3-alkoxy groups, hydroxy groups and NR 5 R 6 groups, with the proviso that said monocyclic heteroaryl group is not 4-pyridyl; and N.R. 7 R 8 base is selected from R 4 is selected from a hydrogen atom and a C1-C3-alkyl group, R 5 / R 6 are independently selected from a hydrogen atom, a C1-C6-alkyl group, a -C1-C5-alkylene-O-C1-C5-alkyl group, a -C1-C5-alkylene-S-C1-C5-alkyl group, a C3-C6-cycloalkyl group, and a C3-C5-heterocycloalkyl group; R 7 / R 8 is a hydrogen atom (where R 7 =R 8 = Hydrogen excluded), C1-C6 alkyl group which is optionally substituted with 1, 2, 3, or 4 substituents, said substituents being Halogen atoms, Cyano group, Hydroxy groups, C(O)NR 5 R 6 basis, NR 5 R 6 basis, C1-C3 alkoxy group, C3-C7-cycloalkyl groups optionally substituted by one or two substituents, said substituents being independently selected from C1-C3-alkyl groups, oxo (=O) groups, hydroxy groups and C1-C3-hydroxyalkyl groups, 3-7 membered heterocycloalkyl groups, themselves optionally substituted by C1-C3-alkyl or oxo (=O) groups; heteroaryl groups, which themselves are optionally substituted with C1-C3-alkyl groups, -C1-C5-alkylene-O-C1-C5-alkyl group, -C1-C5-alkylene-S-C1-C5-alkyl group, -C1~C5-Alkylene-NR 5 -C1 to C5 alkyl group, C3-C6-cycloalkyl groups optionally substituted by hydroxy groups, and a 3-6 membered heterocycloalkyl group optionally substituted with one or two substituents, said substituents being independently selected from C1-C3-alkyl groups and hydroxy groups; are independently selected from R 9 is a hydrogen atom or a C1-C3 alkyl group or a bond. The compounds of general formula (I) may be used, for example, as described herein, for the treatment, prevention, or control of sarcoma in a subject in need thereof.

[0008] definition Unless otherwise defined, all scientific and technical terms used herein have the meanings commonly understood by those skilled in the art to which the present invention belongs. The following references provide those skilled in the art with general definitions for many of the terms used in the present invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd Edition 1994); The Cambridge Dictionary of Science and Technology (Walker, ed., 1988); The Glossary of Genetics, 5th Edition, R. Rieger et al. (ed.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the following meanings ascribed to them unless otherwise specified.

[0009] The structure depicted includes all allowed rotations about the bonds.

[0010] The term "substituted" means that one or more hydrogen atoms on the specified atom or group are replaced with one selected from the indicated group, provided that the normal valence of the specified atom in the context of the conditions present is not exceeded. Combinations of substituents and / or variables are permitted.

[0011] The term "optionally substituted" means that the number of substituents can be equal to or different from 0. Unless otherwise indicated, an optionally substituted group can be substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. In general, the number of optional substituents, if present, can be 1, 2, 3, particularly 1 or 2.

[0012] As used herein, the term "one or more" in the definition of substituents, for example, in the compounds of general formula (I) of the present invention, means "1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more particularly 1, 2 or 3, and even more particularly 1 or 2".

[0013] As used herein, an oxo substituent represents an oxygen atom that is attached to a carbon or sulfur atom via a double bond.

[0014] The term "ring substituent" means a substituent attached to an aromatic or non-aromatic ring that replaces an available hydrogen atom on the ring.

[0015] When a composite substituent consists of more than one moiety, such as (C1-C4-alkyl)-O-(C1-C4-alkyl)-, the first or last hyphen of such composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule. When a composite substituent is substituted, said substituent may be attached at any suitable carbon atom of the composite substituent.

[0016] When a ring that contains carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen, or sulfur atoms, is substituted, for example with a substituent, said substituent may be attached at any suitable position on said ring and is attached to a suitable carbon atom and / or a suitable heteroatom.

[0017] The term "comprising" as used herein includes "consisting of."

[0018] In the text, when any item is referred to as "mentioned in this specification", it means that the item may be mentioned anywhere in the text. The terms referred to in this text have the following meanings:

[0019] The term "halogen atom" means a fluorine, chlorine, bromine or iodine atom, in particular a fluorine, chlorine or bromine atom.

[0020] The term "C1-C6-alkyl" means a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl, or 1,3-dimethylbutyl group, or an isomer thereof. In particular, said groups have 1, 2, 3 or 4 carbon atoms ("C1-C4-alkyl"), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl groups, and more in particular have 1, 2 or 3 carbon atoms ("C1-C3-alkyl"), such as methyl, ethyl, n-propyl or isopropyl groups.

[0021] The term "alkylene" is derived from the term "alkyl" as a divalent moiety designated by adding "ene" to the term "alkyl", e.g., "methyl" becomes "methylene", meaning a "-CH-" moiety with open bonds of branched moieties located at each end of the longest chain.

[0022] The term "C1-C6-haloalkyl" means a linear or branched saturated monovalent hydrocarbon radical, in which the term "C1-C6-alkyl" is as defined above, and in which one or more hydrogen atoms are replaced, identically or differently, by halogen atoms. In particular, said halogen atoms are fluorine atoms. Said C1-C6-haloalkyl radicals are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl, more particularly trifluoromethyl or difluoromethyl.

[0023] The term "C1-C6-alkoxy" means a linear or branched saturated monovalent radical of the formula (C1-C6-alkyl)-O-, where the term "C1-C6-alkyl" is as defined above and means, for example, a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, or n-hexyloxy radical, or an isomer thereof.

[0024] The term "C1-C6-haloalkoxy" means a linear or branched saturated monovalent C1-C6-alkoxy group as defined above, in which one or more hydrogen atoms are replaced by identical or different halogen atoms. In particular, said halogen atoms are fluorine atoms. Said C1-C6-haloalkoxy groups are, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.

[0025] The term "C2-C6-alkenyl" means a linear or branched monovalent hydrocarbon radical containing one or two double bonds and having 2, 3, 4, 5, or 6 carbon atoms, in particular 2 or 4 carbon atoms ("C2-C4-alkenyl"), it being understood that if said alkenyl group contains more than one double bond, said double bonds may be isolated from one another or may be conjugated to one another. The alkenyl groups include, for example, ethenyl (or "vinyl"), prop-2-en-1-yl (or "allyl"), prop-1-en-1-yl, but-3-enyl, but-2-enyl, but-1-enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1-enyl, hex-5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-1-enyl, prop-1-en-2-yl (also or "isopropenyl"), 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, 1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, 2-methylbut-2-enyl, 1-methylbut-2-enyl, 3-methylbut-1-enyl, 2-methylbut-1-enyl, 1-methylbut-1-enyl, 1,1-Dimethylprop-2-enyl, 1-Ethylprop-1-enyl, 1-Propylvinyl, 1-Isopropylvinyl, 4-Methylpent-4-enyl, 3-Methylpent-4-enyl, 2-Methylpent-4-enyl, 1-Methylpent-4-enyl, 4-Methylpent-3-enyl, 3-Methylpent-3-enyl, 2-Methylpent-3-enyl, 1-Methylpent-3-enyl, 4-Methylpent-2-enyl, 3-Methylpent-2-enyl, 2-Methylpent-2-enyl, 1-Methylpent-2-enyl, 4-Methylpent-1-enyl, 3-Methylpent-1-enyl, 2-Methylpent-1-enyl, 1-Methylpent-1-enyl, 3-Ethylbut-3-enyl, 2-Ethylbut-3-enyl 1-ethylbut-3-enyl, 3-ethylbut-2-enyl, 2-ethylbut-2-enyl, 1-ethylbut-2-enyl, 3-ethylbut-1-enyl, 2-ethylbut-1-enyl, 1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, 2-propylprop-1-enyl, 1-propylprop-1-enyl, 2-isopropylprop-1-enyl, 1-isopropylprop-1-enyl, 3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl, buta-1,3-dienyl, penta-1,4-dienyl, or hexa-1,5-dienyl. In particular, the group is a vinyl or allyl, propenyl, isopropenyl, butenyl or isobutenyl group.

[0026] The term "C2-C6-alkynyl" denotes a linear or branched monovalent hydrocarbon radical containing one triple bond and containing 2, 3, 4, 5, or 6 carbon atoms, in particular 2 or 3 carbon atoms ("C2-C3-alkynyl"). The C2-C6 alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl (or "propargyl"), but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 1-ethylprop-2-ynyl, 1-ethylpent-4-ynyl, 1-methylpent-4-ynyl, 1-methylbut-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 1-methylpent-4 ... alkynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl radicals. In particular, said alkynyl radicals are ethynyl, prop-1-ynyl or prop-2-ynyl.

[0027] The term "C3-C9-cycloalkyl" denotes a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 3, 4, 5, 6, 7 or 8 carbon atoms. Said C3-C8-cycloalkyl group is, for example, a monocyclic hydrocarbon ring, such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, which also includes fused, bridged and spirocycloalkyl ring systems, such as bicyclic hydrocarbon rings, such as bicyclo[4.2.0]octyl, bicyclo[2.2.1]heptyl or octahydropentalenyl, and spirocycloalkyl systems as defined below.

[0028] The term "spirocycloalkyl" refers to a saturated monovalent bicyclic hydrocarbon group in which two rings share one common ring carbon atom, said bicyclic hydrocarbon group containing 5, 6, 7, 8, or 9 carbon atoms, and said spirocycloalkyl group can be attached to the remainder of the molecule through any one of the carbon atoms except the spiro carbon atom. The spirocycloalkyl group can be, for example, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl, or spiro[5.5]undecyl.

[0029] The term "C5-C6-cycloalkenyl" refers to the resulting cyclopentenyl, cyclohexenyl, cyclopentadienyl, and cyclohexadienyl groups.

[0030] The term "C4-C9-cycloalkenyl" denotes a monovalent monocyclic or bicyclic hydrocarbon ring containing 4, 5, 6, 7, 8 or 9 carbon atoms and one double bond. In particular, the ring contains 4, 5 or 6 carbon atoms ("C4-C6-cycloalkenyl"). The C4-C8-cycloalkenyl group is, for example, a monocyclic hydrocarbon ring, such as a cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl group, or a bridged ring system, as well as a bicyclic hydrocarbon ring, such as a bicyclo[2.2.1]hept-2-enyl, or a bicyclo[2.2.2]oct-2-enyl, a bicyclo[3.1.0]hex-2-enyl.

[0031] The terms "3-9 membered heterocycloalkyl" and "3-6 membered heterocycloalkyl" refer to saturated heterocycles having a total of 3, 4, 5, 6, 7, 8, or 9 ring atoms, respectively 3, 4, 5, or 6 ring atoms, containing one or two identical or different ring heteroatoms selected from the series N, O, and S, said heterocycloalkyl group being attached to the remainder of the molecule via any one of the carbon atoms or heteroatoms. These also include bicyclic ring systems that are either fused, bridged, or spiro systems as defined below. This also includes NR 7 R 8 In particular, the compounds of formula (I) may have a group, where the N atom is 7 and R 8 belongs to a ring formed by bonding with R 7 and R 8 form a non-aromatic ring containing the N atom to which they are attached. As used herein, the term "heterocycloalkane" refers to a compound consisting of a heterocycloalkyl group, as defined herein, and a hydrogen atom to which said heterocycloalkyl group is attached at one of its valencies.

[0032] The heterocycloalkyl group can be, but is not limited to, a three- or four-membered ring, such as azacyclopropyl, oxacyclopropyl, azetidinyl, oxetanyl, or thietanyl; a five-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, or 1,3-thiazolidinyl; a six-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl, or 1,2-oxazinanyl, or a fused system, such as azabicyclo[3.1.0]hexan-3-yl.

[0033] In particular, "4- to 6-membered heterocycloalkyl" refers to a 4- to 6-membered heterocycloalkyl as defined above, containing one ring nitrogen atom or oxygen atom or sulfur atom, and if it contains a nitrogen atom, it may optionally contain one further ring heteroatom from the series N, O, S. More particularly, "5- or 6-membered heterocycloalkyl" refers to a monocyclic saturated heterocycle having a total of 5 or 6 ring atoms, containing one ring nitrogen atom and optionally containing one further ring heteroatom from the series N, O. Said heterocycloalkyl group is bonded to the rest of the molecule through any carbon atom or, if applicable, through any nitrogen atom. Both of these may include the bicyclic ring systems described above. "5- or 6-membered heterocycloalkyl" groups may in particular be substituted with one or two fluorine atoms or methyl groups.

[0034] The term "partially unsaturated 3-9 membered heterocycloalkyl" refers to a monocyclic unsaturated non-aromatic heterocycle having a total of 5, 6, 7, 8, or 9 ring atoms, including one or two double bonds and one or two identical or different ring heteroatoms from the series N, O, S. The partially unsaturated heterocycloalkyl group can be bonded to the remainder of the molecule through any one of the carbon atoms or, if present, the nitrogen atom. As used herein, the term "partially unsaturated heterocycloalkane" refers to a compound consisting of a partially unsaturated heterocycloalkyl group, as defined herein, and a hydrogen atom to which the partially unsaturated heterocycloalkyl group is bonded at one of its valencies.

[0035] The partially unsaturated heterocycloalkyl groups are, for example, 4H-pyranyl, 2H-pyranyl, 3,6-dihydro-2H-pyran-4-yl, 5,6-dihydro-2H-pyran-3-yl, tetrahydropyridinyl, such as 1,2,3,6-tetrahydropyridin-4-yl, dihydropyridinyl, such as 1,6-dihydropyridinyl, 6-oxo-1,6-dihydropyridin-3-yl, 2,5-dihydro-1H-pyrrolyl, [1,3]dioxolyl, 4H-[1,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl.

[0036] The term "fused heterocycloalkyl" means a bicyclic saturated heterocycle having a total of 6, 7, 8, or 9 ring atoms, or a total of 5, 6, or 7 ring atoms, respectively, where two rings share two adjacent ring atoms, and "fused heterocycloalkyl" contains one or two identical or different ring heteroatoms from the series N, O, S. Said fused heterocycloalkyl group can be attached to the remainder of the molecule through any one of the carbon atoms or, if present, the nitrogen atom.

[0037] The fused heterocycloalkyl group can be, for example, 3-azabicyclo[3.1.0]hexan-3-yl, 3-azabicyclo[3.2.0]heptan-3-yl, azabicyclo[3.3.0]octyl, azabicyclo[4.3.0]nonyl, diazabicyclo[4.3.0]nonyl, oxazabicyclo[4.3.0]nonyl, or thiazabicyclo[4.3.0]nonyl.

[0038] The term "bridged heterocycloalkyl" means a bicyclic saturated heterocycle having a total of 7, 8, or 9 ring atoms, or a total of 7 ring atoms, respectively, where the two rings share two common ring atoms that are not adjacent, and a "bridged heterocycloalkyl" contains one or two identical or different ring heteroatoms from the series N, O, S. The bridged heterocycloalkyl group can be attached to the remainder of the molecule through any one of the carbon atoms or, if present, the nitrogen atom. The bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, diazabicyclo[ 3.2.1]octyl, oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, diazabicyclo[3.3.1]nonyl, oxazabicyclo[3.3.1]nonyl, thiazabicyclo[3.3.1]nonyl, azabicyclo[4.2.1]nonyl, diazabicyclo[4.2.1]nonyl, oxazabicyclo[4.2.1]nonyl, thiazabicyclo[4.2.1]nonyl.

[0039] The term "heterospirocycloalkyl" means a bicyclic saturated heterocycle having a total of 6, 7, 8, or 9 ring atoms, where the two rings share one common ring carbon atom, and "heterospirocycloalkyl" contains one or two identical or different ring heteroatoms from the series N, O, S. The heterospirocycloalkyl group can be bonded to the rest of the molecule through any one of the carbon atoms, except the spiro carbon atom, or the nitrogen atom, if present. The heterospirocycloalkyl group can be, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxaazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, 2λ 6 -thia-6-azaspiro[3.3]heptane-2,2-dione, oxaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, or further homologous scaffolds such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-, spiro[2.6]-, spiro[3.5]-, spiro[3.6]-, spiro[4.5]-, and spiro[4.6]-.

[0040] The term "aryl" refers to an aromatic monocyclic, bicyclic (two fused rings), tricyclic (three fused rings), or polycyclic (two or more fused rings) hydrocarbon ring system having 6 to 20 (e.g., 6 to 10 ring carbon atoms). Non-limiting examples of aryl groups include phenyl, or naphthyl (e.g., 1-naphthyl, 2-naphthyl, etc.). In particular, an aryl group is a phenyl group optionally substituted with one or two substituents independently selected from fluorine, difluoromethyl, and trifluoromethyl.

[0041] The term "heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic ring having 5, 6, 8, 9, or 10 ring atoms ("5-10 membered heteroaryl" groups), particularly 5, 6, 9, or 10 ring atoms, containing at least one ring heteroatom and optionally containing 1, 2, or 3 additional ring heteroatoms from the series N, O, and / or S, and bonded to the remainder of the molecule via a ring carbon atom or heteroatom. As used herein, the term "heteroarene" refers to a compound consisting of a heteroaryl group, as defined herein, and a hydrogen atom to which said heteroaryl group is bonded at one of its valencies.

[0042] The heteroaryl group can be a 5-membered heteroaryl group, such as thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, or tetrazolyl; a 6-membered heteroaryl group, such as pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl; a tricyclic heteroaryl group, such as carbazolyl, acridinyl, or phenazinyl; a 9-membered heteroaryl group, such as benzofuranyl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl, or purinyl; or a 10-membered heteroaryl group, such as quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, or pteridinyl.

[0043] In general, unless otherwise stated, a heteroaryl or heteroarylene group includes all its possible isomeric forms, such as tautomers and positional isomers, with respect to the point of attachment to the remainder of the molecule. Thus, for some illustrative non-limiting examples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl, or the term thienyl includes thien-2-yl and thien-3-yl.

[0044] In particular, the heteroaryl groups are 2H-pyrrol-1-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, optionally substituted with one or two methyl groups; 1,2-thiazol-4-yl, 1,3-thiazol-5-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-5-yl, each of which is optionally substituted with one or two substituents, each of which is independently selected from halogen atoms, methyl groups, trifluoromethyl groups, methoxy groups, and NH groups; 1H-indol-6-yl, 1H-indazol-6-yl, and 1H-benzimidazol-6-yl, each of which is optionally substituted with one or two substituents, each of which is independently selected from halogen atoms, methyl groups, trifluoromethyl groups, methoxy groups, and NH groups.

[0045] In particular, the heteroaryl group is a 2H-pyrrol-1-yl group, optionally substituted with one or two substituents, each substituent being independently selected from a hydrogen atom, a cyano group, and a methyl group; a 1H-pyrazol-4-yl group optionally substituted by one or two methyl groups; a 1H-pyrazol-5-yl group optionally substituted by one or two methyl groups; a 1,2-thiazol-4-yl group optionally substituted by one or two methyl groups; a 1,3-thiazol-5-yl group optionally substituted by one or two methyl groups; pyridin-3-yl and pyridin-5-yl groups, each of which is optionally substituted with one or two substituents, each of which is independently selected from halogen atoms, methyl groups, trifluoromethyl groups, methoxy groups, and NH groups; 1H-indol-6-yl, 1H-indazol-6-yl, and 1H-benzimidazol-6-yl groups It is.

[0046] More particularly, the heteroaryl group is a pyridinyl group optionally substituted with an amino group, or a pyrazolyl group optionally substituted with a difluoromethyl or trifluoromethyl group.

[0047] Even more particularly, the heteroaryl group is 1H-pyrazol-4-yl or 1H-pyrazol-1-yl groups, optionally substituted by difluoromethyl or trifluoromethyl groups It is.

[0048] The term "C1-C6" as used herein, for example in the context of the definitions of "C1-C6-alkyl", "C1-C6-haloalkyl", "C1-C6-alkoxy" or "C1-C6-haloalkoxy", refers to an alkyl group having a finite number of carbon atoms, from 1 to 6, i.e., 1, 2, 3, 4, 5 or 6 carbon atoms.

[0049] Furthermore, as used herein, the term "C3-C8" as used herein, for example, in the context of the definition of "C3-C8-cycloalkyl", refers to a cycloalkyl group having a finite number of carbon atoms, from 3 to 8, i.e., 3, 4, 5, 6, 7, or 8 carbon atoms.

[0050] Ring heteroatoms can be substituted to the extent permitted by valence (and aromaticity, if appropriate), to include, for example, -S(O)-, -S(O)2-, and -N(R)- as heteroatoms in the ring system (where, for example, R can be a hydrogen atom or a C1-C3-alkyl group).

[0051] When a range of numerical values ​​is given, the range includes each value and subrange within the range.

[0052] for example, "C1~C6" means C1, C2, C3, C4, C5, C6, C1~C6, C1~C5, C1~C4, C1~C3, C1~C2, C2~C6 , C2~C5, C2~C4, C2~C3, C3~C6, C3~C5, C3~C4, C4~C6, C4~C5, and C5~C6, "C2 to C6" includes C2, C3, C4, C5, C6, C2 to C6, C2 to C5, C2 to C4, C2 to C3, C3 to C6, C3 to C5, C3 to C4, C4 to C6, C4 to C5, and C5 to C6, "C3~C 10 ” is C3, C4, C5, C6, C7, C8, C9, C 10 , C3~C 10 , C3~C9, C3~C8, C3~C7, C3~C6, C3~C5, C3~C4, C4~C 10 , C4~C9, C4~C8, C4~C7, C4~C6, C4~C5, C5~C 10 , C5~C9, C5~C8, C5~C7, C5~C6, C6~C 10 , C6~C9, C6~C8, C6~C7, C7~C 10 , C7~C9, C7~C8, C8~C 10 , C8-C9, and C9-C 10 Inclusive of "C3-C8" includes C3, C4, C5, C6, C7, C8, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C8, C4-C7, C4-C6, C4-C5, C5-C8, C5-C7, C5-C6, C6-C8, C6-C7, and C7-C8; "C3 to C6" includes C3, C4, C5, C6, C3 to C6, C3 to C5, C3 to C4, C4 to C6, C4 to C5, and C5 to C6, "C4-C8" includes C4, C5, C6, C7, C8, C4-C8, C4-C7, C4-C6, C4-C5, C5-C8, C5-C7, C5-C6, C6-C8, C6-C7, and C7-C8; "C4-C7" includes C4, C5, C6, C7, C4-C7, C4-C6, C4-C5, C5-C7, C5-C6, and C6-C7; "C4-C6" includes C4, C5, C6, C4-C6, C4-C5, and C5-C6, "C5~C 10 ” is C5, C6, C7, C8, C9, C 10 , C5~C 10 , C5~C9, C5~C8, C5~C7, C5~C6, C6~C 10 , C6~C9, C6~C8, C6~C7, C7~C 10 , C7~C9, C7~C8, C8~C 10 , C8-C9, and C9-C 10 Inclusive of "C6~C 10 " is C6, C7, C8, C9, C 10 , C6~C 10 , C6~C9, C6~C8, C6~C7, C7~C 10 , C7~C9, C7~C8, C8~C 10 , C8-C9, and C9-C 10 Includes:

[0053] Unless otherwise specified or obvious from the context, the term "about" as used herein is understood to be within the normal tolerance range in the art, for example, within 2 standard deviations of the mean. About can be understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the specified value. Unless otherwise clear from the context, all numerical values ​​given herein are modified by the term about.

[0054] By "agent" is meant any small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide, or fragments thereof.

[0055] By "ameliorate" is meant to reduce, inhibit, attenuate, reduce, halt, or stabilize the onset or progression of a disease.

[0056] By "analog" is meant a molecule that is not identical but has similar functional or structural characteristics. For example, a polypeptide analog retains the biological activity of the corresponding native polypeptide while having certain biochemical modifications that enhance the function of the analog compared to the native polypeptide. Such biochemical modifications could increase the analog's protease resistance, membrane permeability, or half-life, for example, without altering ligand binding. Analogs can include unnatural amino acids.

[0057] In this disclosure, "comprises," "comprising," "containing," "having," and the like can have the meaning ascribed to them in U.S. patent law and can mean "includes," "including," and the like. "Consisting essentially of" or "consists essentially" likewise have the meaning ascribed to them in U.S. patent law, and the term is open-ended, permitting the presence of more than what is recited, so long as the basic or novel characteristics of what is recited are not altered by the presence of more than what is recited, but excluding prior art embodiments.

[0058] "Controlling" a disease such as a sarcoma can refer to any reduction in the rate of progression of the disease.

[0059] "Detecting" refers to identifying the presence, absence, or amount of the analyte being detected. In certain embodiments, the analyte is a PDE3A or SLFN12 polypeptide.

[0060] "Disease" refers to any condition or disease that impairs or interferes with the normal function of a cell, tissue, or organ. Examples of diseases include sarcomas (e.g., malignant fibrous histiocytoma, lymphosarcoma, osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma, and synovial sarcoma).

[0061] "Effective amount" refers to the amount of compound described herein that inhibits the growth or proliferation of sarcoma compared to the growth or proliferation of sarcoma in untreated patients.The effective amount of one or more active compounds used to carry out the present invention for the therapeutic treatment of disease varies depending on the mode of administration, the age, weight, and general health of the subject.The attending physician or veterinarian will ultimately determine the appropriate amount and administration regimen.Such amount is called "effective" amount.

[0062] As used herein, the term "leaving group" refers to an atom or group of atoms that is displaced in a chemical reaction as a stable species with the bonding electrons. In particular, such leaving groups are selected from the group including halide, particularly fluoride, chloride, bromide, or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy, and [(4-methoxyphenyl)sulfonyl]oxy.

[0063] As used herein, unless otherwise stated or obvious from context, the term "or" is understood to be inclusive. As used herein, unless otherwise stated or obvious from context, the terms "a," "an," and "the" are understood to be singular or plural.

[0064] When the plural of terms such as compounds, salts, polymorphs, hydrates, solvates, etc. are used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate, etc.

[0065] By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0066] The term "prodrugs" or "prodrug" refers to compounds that may themselves be biologically active or inactive, but are converted (e.g., metabolically or hydrolytically) into the compound of formula (I) during their residence time in the body. Derivatives of compound 6 and its salts (biological precursors or prodrugs) that are converted into compound 6 or its salts in a biological system are covered by the present invention. The biological system may be, for example, a mammalian organism, particularly a human subject. The biological precursors are, for example, converted into the compound of formula (I) or its salts by metabolic processes.

[0067] The term "one or more pharma- ceutically acceptable salts" of the compounds of formula (I) includes those derived from pharma- ceutically acceptable inorganic and organic acids and bases. See, for example, S. M. Berge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

[0068] As used herein, the term "pharmaceutically acceptable salts" refers to salts formed by the addition of a pharmaceutically acceptable acid or base to a compound disclosed herein.

[0069] As used herein, the phrase "pharmaceutical acceptable" refers to a substance that is acceptable for use in medicinal applications from a toxicological standpoint and does not adversely interact with active ingredients.

[0070] As used herein, "sarcoma" or "sarcomas" includes, but is not limited to, sarcomas of soft tissue and bone, more particularly osteosarcoma, malignant fibrous histiocytoma, soft tissue sarcoma, synovial sarcoma, lymphosarcoma, and rhabdomyosarcoma. In some embodiments, a sarcoma is not a soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, or rhabdomyosarcoma, and in some embodiments, a sarcoma does not include rhabdomyosarcoma or lymphosarcoma.

[0071] "Subject" refers to a mammal, including but not limited to a human or non-human mammal, such as a cow, horse, dog, sheep, rodent, or cat. A subject in need of treatment is typically a subject for whom it is desirable to treat a disease, disorder, or condition (e.g., sarcoma) described herein. For example, a subject in need of treatment may be a human or animal that is seeking or in need of treatment, may be requesting treatment, may be undergoing treatment, may be undergoing treatment in the future, or is being cared for by a professional trained in a particular disease, disorder, or condition.

[0072] As used herein, unless otherwise specified or obvious from the context, when a range is given, the upper and lower limits are always included.Ranges given herein are understood to be shorthand for all values ​​within the range.For example, a range of 1-50 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0073] "Reference" refers to a standard or control condition, which may be healthy cells or the average expression in a representative panel of tumor cells or tumor cell lines. For example, the growth or proliferation of a sarcoma treated with a compound described herein is compared to the growth or proliferation of a reference untreated sarcoma.

[0074] The recitation of a list of chemical groups when defining a variable herein includes a definition of that variable as any single group or combination of the listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0075] Preferred isomers are those which result in the more desirable biological activity. These separated, pure or partially purified isomers or racemic mixtures of the compounds used in the present invention are also included within the scope of the present invention. Purification and separation of such materials can be accomplished by standard techniques known in the art.

[0076] Thus, as one embodiment of the present invention for the use of compounds of formula (I) for the treatment of sarcoma, R 4 , especially R 4 =C1-C3-alkyl, more particularly R 4 The configuration of the alkyl group with respect to =methyl is as shown in formula (Ia) [ka] It has the S configuration shown in FIG.

[0077] Optical isomers can be obtained by conventional resolution of racemic mixtures, for example, by forming diastereoisomeric salts with optically active acids or bases, or by forming covalent diastereomers. Examples of suitable acids include tartaric acid, diacetyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into individual diastereomers based on their physical and / or chemical differences by methods known in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are then liberated from the separated diastereomeric salts. Another method for separating optical isomers involves the use of chiral chromatography (e.g., HPLC columns using chiral phases) with or without conventional derivatization optimally selected to maximize the separation of the enantiomers. Suitable HPLC columns using chiral phases are commercially available, for example, those manufactured by Daicel, among others, such as Chiracel OD and Chiracel OJ, all of which are routinely selectable. Enzymatic separations, with or without derivatization, are also useful. The optically active compounds of this invention can also be obtained by chiral syntheses utilizing optically active starting materials.

[0078] To distinguish different types of isomers from each other, reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

[0079] Additionally, compounds for use in the present invention may exist as tautomers. For example, any compound of the present invention that includes an imidazopyridine moiety as a heteroaryl group may exist as, for example, a 1H tautomer or a 3H tautomer, or any amount of the two tautomers, i.e. [ka] It may exist as a mixture of

[0080] For the use of compounds of formula (I), all possible tautomers may be used, either as single tautomers or as any mixture of said tautomers, in any ratio.

[0081] Useful forms of the compounds employed in the present invention for the treatment of sarcoma can be, for example, metabolites, hydrates, solvates, prodrugs, salts, particularly pharma- ceutically acceptable salts, and / or coprecipitates.

[0082] These compounds can also exist as hydrates or solvates, and the compounds of the present invention contain polar solvents, particularly water, methanol, or ethanol, for example, as structural elements of the crystal lattice of the compounds. The amount of polar solvent, particularly water, can be in stoichiometric or non-stoichiometric ratios. In the case of stoichiometric solvates, such as hydrates, hemi-, (semi), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates are possible, respectively. The present invention includes all these hydrates or solvates.

[0083] Furthermore, the compounds used in the present invention include all possible crystalline forms or polymorphs of the compounds of formula (I), either as a single polymorph or as a mixture of two or more polymorphs in any ratio. [Brief description of the drawings]

[0084] [Figure 1] Figure 1 shows the in vivo antitumor effect of (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one ("the compound") in a xenograft model derived from a sarcoma patient. Tumor growth of the xenograft model SA3831 derived from a sarcoma patient subcutaneously in immunodeficient mice treated with the compound or vehicle. The compound showed a significant antitumor effect with a T(treatment) / C(vehicle control) ratio of 0.01. The T / C ratio was based on the final tumor size, and statistical evaluation was performed by unpaired t-test (ns=P>0.05, *=P≦0.05, **=P≦0.01, ***=P≦0.001). [Diagram 2]Figure 1 shows the in vivo antitumor effect of (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one in a xenograft model derived from a sarcoma patient. Tumor growth of the xenograft model SA4058 derived from a sarcoma patient subcutaneously in immunodeficient mice treated with the compound or vehicle. The compound showed a significant antitumor effect with a T(treatment) / C(vehicle control) ratio of 0.12. The T / C ratio was based on the final tumor size, and statistical evaluation was performed by unpaired t-test (ns=P>0.05, *=P≦0.05, **=P≦0.01, ***=P≦0.001). [Diagram 3] Figure 1 shows the in vivo antitumor effect of (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one in a xenograft model derived from a sarcoma patient. Tumor growth of the xenograft model SA16044 derived from a sarcoma patient subcutaneously in immunodeficient mice treated with the compound or vehicle. The compound showed a significant antitumor effect with a T(treatment) / C(vehicle control) ratio of 0.35. The T / C ratio was based on the final tumor size, and statistical evaluation was performed by unpaired t-test (ns=P>0.05, *=P≦0.05, **=P≦0.01, ***=P≦0.001). [Figure 4]1 shows the in vivo antitumor effect of (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one in a xenograft model derived from a sarcoma patient. Tumor growth of the xenograft model SA10199 derived from a sarcoma patient subcutaneously in immunodeficient mice treated with (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one or vehicle. (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one showed significant antitumor effect with a T(treated) / C(vehicle control) ratio of 0.31. T / C ratios were based on final tumor size and statistical evaluation was performed by unpaired t-test (ns=P>0.05, *=P≦0.05, **=P≦0.01, ***=P≦0.001). [Diagram 5] Figure 1 shows the in vivo antitumor effect of (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one in a xenograft model derived from a patient with sarcoma. Tumor growth of the xenograft model SA10245 derived from a patient with sarcoma subcutaneously in immunodeficient mice treated with (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one or vehicle. (6S)-5-[4'-Fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one showed non-significant signs of antitumor efficacy with a T(treated) / C(vehicle control) ratio of 0.73. T / C ratios were based on final tumor size and statistical evaluation was performed by unpaired t-test (ns=P>0.05, *=P≦0.05, **=P≦0.01, ***=P≦0.001). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0085] According to a first aspect, the present invention comprises a method of treating sarcoma, comprising administering to a patient in need of treatment thereof a compound of general formula (I) [ka] or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof, or the above compound for use in the treatment of sarcoma, During the ceremony, R 1 is selected from a hydrogen atom, a halogen atom, a cyano group, a C1-C3-alkyl group, a C1-C3-haloalkyl group, and a C1-C3-haloalkoxy group, R 2 is selected from a hydrogen atom and a halogen atom; R 3 teeth, C1-C6-alkyl groups optionally substituted by 1 or 2 substituents, each of which is independently selected from hydroxy groups, C1-C4-alkoxy groups, and 3- to 7-membered heterocycloalkyl groups; C2-C6-alkenyl groups optionally substituted by C1-C4-alkoxy groups, C3-C9-cycloalkyl groups optionally substituted by hydroxy groups, C5-C9-cycloalkenyl groups optionally substituted by hydroxy groups; -O-, -S-, -S(O)-, S(O)2, and -NR 9 -, wherein - is a 3- to 9-membered heterocycloalkyl group containing 1, 2, or 3 heteroatoms independently selected from -O-, -NR 9 -, -CH2-, -CH2-CH2-, -O-CH2-, -CH2-O-, -NR 9 -CH2-, and -CH2-NR 9 -, optionally further comprising a bridging group selected from A 3- to 9-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents, each of which is Halogen atoms, oxo (=O) group, Cyano group, Hydroxy groups, C1-C3-alkyl groups optionally further substituted by hydroxy groups; C1-C3-haloalkyl group, C1-C3 alkoxy group, C1-C3-haloalkoxy group, C(O)NR 5 R 6 base, and N.R. 5 R 6 (independently selected from the group consisting of Partially unsaturated, 5-9 membered heterocycloalkyl groups, optionally substituted with 1, 2 or 3 substituents, each of which may be an oxo group (=O), a C1-C3-alkyl group, -C(O)R 5 R 6 groups, and halogen atoms); Aryl groups optionally substituted with 1, 2, 3 or 4 substituents, each of which is selected from the group consisting of halogen atoms, hydroxy groups, cyano groups, C1-C3-alkyl groups, C1-C3-haloalkyl groups, C1-C3-alkoxy groups, C1-C3-haloalkoxy groups, and NR 5 R 6 (independently selected from the group consisting of Monocyclic or bicyclic heteroaryl groups optionally substituted with 1, 2 or 3 substituents, each of which is selected from the group consisting of halogen atoms, C1-C3-alkyl groups, cyano groups, C1-C3-haloalkyl groups, C1-C3-hydroxyalkyl groups, C1-C3-alkoxy groups, hydroxy groups and NR 5 R 6 groups, with the proviso that said monocyclic heteroaryl group is not 4-pyridyl; and N.R. 7 R 8 base is selected from R 4 is selected from a hydrogen atom and a C1-C3-alkyl group, R 5 / R 6are independently selected from a hydrogen atom, a C1-C6-alkyl group, a -C1-C5-alkylene-O-C1-C5-alkyl group, a -C1-C5-alkylene-S-C1-C5-alkyl group, a C3-C6-cycloalkyl group, and a C3-C5-heterocycloalkyl group; R 7 / R 8 is a hydrogen atom (where R 7 =R 8 = Hydrogen excluded), C1-C6 alkyl group which is optionally substituted with 1, 2, 3, or 4 substituents, said substituents being Halogen atoms, Cyano group, Hydroxy groups, C(O)NR 5 R 6 base, NR 5 R 6 base, C1-C3 alkoxy group, C3-C7-cycloalkyl groups optionally substituted by one or two substituents, said substituents being independently selected from C1-C3-alkyl groups, oxo (=O) groups, hydroxy groups and C1-C3-hydroxyalkyl groups, 3-7 membered heterocycloalkyl groups, themselves optionally substituted by C1-C3-alkyl or oxo (=O) groups; heteroaryl groups, which themselves are optionally substituted with C1-C3-alkyl groups, -C1-C5-alkylene-O-C1-C5-alkyl group, -C1-C5-alkylene-S-C1-C5-alkyl group, -C1~C5-Alkylene-NR 5 -C1 to C5 alkyl group, C3-C6-cycloalkyl groups optionally substituted by hydroxy groups, and a 3-6 membered heterocycloalkyl group optionally substituted with one or two substituents, said substituents being independently selected from C1-C3-alkyl groups and hydroxy groups; are independently selected from R 9 is a hydrogen atom or a C1-C3 alkyl group or a bond.

[0086] According to a second embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is selected from a hydrogen atom, a halogen atom, a cyano group, a C1-C3-alkyl group, a C1-C3-haloalkyl group, and a C1-C3-haloalkoxy group, R 2 is selected from a hydrogen atom and a halogen atom; R 3 teeth, C1-C6-alkyl groups optionally substituted with substituents selected from hydroxy groups, C1-C4-alkoxy groups and 3- to 7-membered heterocycloalkyl groups, C2-C6-alkenyl groups, optionally substituted by C1-C4-alkoxy groups, C3-C7-cycloalkyl groups optionally substituted by hydroxy groups; C5-C7-cycloalkenyl groups optionally substituted by hydroxy groups; -O-, S(O)2, and -NR 9 -, wherein the 3- to 7-membered heterocycloalkyl group contains 1 or 2 heteroatoms independently selected from A 3- to 7-membered heterocycloalkyl group optionally substituted with 1 or 2 substituents, each of which is Halogen atoms, Cyano group, Hydroxy groups, C1-C3-alkyl groups optionally further substituted by hydroxy groups; C1-C3 alkoxy group, C(O)NR 5 R 6 Groups, and NR 5 R 6 (independently selected from the group consisting of -O-, -S-, and -NR 9 - a 5-7 membered heterocycloalkyl group containing a heteroatom selected from -, which is partially unsaturated and optionally substituted with substituents selected from C1-C3-alkyl groups and halogen atoms; Aryl groups optionally substituted with 1, 2 or 3 substituents, each of which is selected from the group consisting of halogen atoms, hydroxy groups, cyano groups, C1-C3-alkyl groups, C1-C3-haloalkyl groups, C1-C3-alkoxy groups and NR 5 R 6 (independently selected from the group consisting of Monocyclic or bicyclic heteroaryl groups, optionally substituted by substituents, such as halogen atoms, C1-C3-alkyl groups, cyano groups, C1-C3-haloalkyl groups, C1-C3-alkoxy groups, and NR 5 R 6 with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group; and N.R. 7 R 8 basis is selected from R 4 is selected from a hydrogen atom and a C1-C3-alkyl group, R 5 / R 6 are independently selected from a hydrogen atom and a C1-C6-alkyl group; R 7 / R 8 is a hydrogen atom (where R 7 =R 8 = Hydrogen excluded), C1-C6-alkyl groups, which are optionally substituted with 1, 2, 3 or 4 substituents, said substituents being Halogen atoms, Cyano group, Hydroxy groups, C(O)NR 5 R 6 base, NR5 R 6 base, C1-C3 alkoxy group, C3-C7-cycloalkyl groups optionally further substituted by one or two substituents, said substituents being independently selected from C1-C3-alkyl groups, oxo (=O) groups, hydroxy groups and C1-C3-hydroxyalkyl groups; -O- and -NR 9 -, a 3- to 7-membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from, optionally further substituted with a C1-C3-alkyl group; heteroaryl groups optionally further substituted with C1-C3-alkyl groups, C3-C7-cycloalkyl groups, optionally substituted by hydroxy groups or C1-C3-alkyl groups, and a 3-6 membered heterocycloalkyl group optionally substituted with one or two substituents, said substituents being independently selected from C1-C3-alkyl groups and hydroxy groups; are independently selected from R 9 is a hydrogen atom or a C1-C3 alkyl group or a bond.

[0087] According to a third embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is selected from a hydrogen atom, a halogen atom, a C1-C3-alkyl group, a C1-C3-haloalkyl group, and a C1-C3-haloalkoxy group, R 2 is selected from a hydrogen atom and a halogen atom; R 3 teeth, C1-C6-alkyl groups optionally substituted with substituents selected from hydroxy groups, C1-C4-alkoxy groups and 3- to 7-membered heterocycloalkyl groups, C2-C6-alkenyl groups, optionally substituted by C1-C4-alkoxy groups, C3-C7-cycloalkyl groups optionally substituted by hydroxy groups; C5-C7-cycloalkenyl group, -O- and -NR 9 -, wherein the 3- to 7-membered heterocycloalkyl group contains 1 or 2 heteroatoms independently selected from A 3- to 7-membered heterocycloalkyl group, optionally further substituted with one or two substituents, each of which is Halogen atoms, Cyano group, Hydroxy groups, C1-C3-alkyl groups optionally further substituted by hydroxy groups; C1-C3 alkoxy groups, and C(O)NR 5 R 6 (independently selected from the group consisting of -O- and -NR 9 - a 5-7 membered heterocycloalkyl group containing a heteroatom selected from -, which is partially unsaturated and optionally substituted with substituents selected from C1-C3-alkyl groups and halogen atoms; Aryl groups optionally substituted with 1, 2 or 3 substituents, each of which is selected from the group consisting of halogen atoms, hydroxy groups, cyano groups, C1-C3-alkyl groups, C1-C3-haloalkyl groups and NR 5 R 6 (independently selected from the group consisting of Monocyclic or bicyclic heteroaryl groups, optionally substituted by substituents, such as halogen atoms, C1-C3-alkyl groups, C1-C3-haloalkyl groups, C1-C3-alkoxy groups, and NR 5 R 6 with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group; and N.R.7 R 8 basis is selected from R 4 is selected from a hydrogen atom and a C1-C3-alkyl group, R 5 / R 6 are independently selected from a hydrogen atom and a C1-C6-alkyl group; R 7 / R 8 is a hydrogen atom (where R 7 =R 8 = Hydrogen excluded), C1-C6-alkyl groups, which are optionally substituted with 1, 2, 3 or 4 substituents, said substituents being Halogen atoms, Cyano group, Hydroxy groups, NR 5 R 6 base, C1-C3 alkoxy group, C3-C7-cycloalkyl groups optionally further substituted by one or two substituents, said substituents being independently selected from C1-C3-alkyl groups, oxo (=O) groups, hydroxy groups and C1-C3-hydroxyalkyl groups; -O- and -NR 9 -, a 3- to 7-membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from, optionally further substituted with a C1-C3-alkyl group; heteroaryl groups optionally further substituted with C1-C3-alkyl groups, C3-C7-cycloalkyl groups, optionally substituted by hydroxy groups or C1-C3-alkyl groups, and a 3-6 membered heterocycloalkyl group optionally substituted with one or two substituents, said substituents being independently selected from C1-C3-alkyl groups and hydroxy groups; are independently selected from R 9 is a hydrogen atom or a C1-C3 alkyl group or a bond.

[0088] According to a fourth embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is selected from a hydrogen atom, a halogen atom, a C1-C3-alkyl group, a C1-C3-haloalkyl group, and a C1-C3-haloalkoxy group, R 2 is selected from a hydrogen atom and a halogen atom; R 3 teeth, C1-C6-alkyl groups optionally substituted with substituents selected from hydroxy groups, C1-C4-alkoxy groups and 3- to 7-membered heterocycloalkyl groups, C2-C6-alkenyl groups optionally substituted by C1-C4-alkoxy groups, C4-C6-cycloalkyl groups optionally substituted by hydroxy groups, C5-C7-cycloalkenyl group, -O- and -NR 9 -, wherein - is a 3- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from A 3- to 6-membered heterocycloalkyl group, optionally further substituted with one or two substituents, each of which is Halogen atoms, Cyano group, Hydroxy groups, C1-C3-alkyl groups optionally further substituted with hydroxy groups; -O- and -NR 9 -, a 5-6 membered heterocycloalkyl group containing a heteroatom selected from -, which is partially unsaturated and optionally substituted with substituents selected from C1-C3-alkyl groups and halogen atoms, An aryl group optionally substituted by one or two substituents, each of which is selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a C1-C3-alkyl group, a C1-C3-haloalkyl group, and a NR 5 R 6 (independently selected from the group consisting of Monocyclic or bicyclic heteroaryl groups, optionally substituted by substituents, such as halogen atoms, C1-C3-alkyl groups, C1-C3-haloalkyl groups, C1-C3-alkoxy groups, and NR 5 R 6 with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group; and N.R. 7 R 8 basis is selected from R 4 is selected from a hydrogen atom and a C1-C3-alkyl group, R 5 / R 6 are independently selected from a hydrogen atom and a C1-C6-alkyl group; R 7 / R 8 is a hydrogen atom (where R 7 =R 8 = Hydrogen excluded), C1-C6-alkyl groups, which are optionally substituted with 1, 2, 3 or 4 substituents, said substituents being Halogen atoms, Hydroxy groups, C1-C3 alkoxy group, C3-C6-cycloalkyl groups optionally further substituted by one or two substituents, said substituents being independently selected from C1-C3-alkyl groups and C1-C3-hydroxyalkyl groups, -O- and -NR 9 -, a 4-6 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from, optionally further substituted with a C1-C3-alkyl group; heteroaryl groups optionally further substituted with C1-C3-alkyl groups, C3-C6-cycloalkyl groups optionally substituted by hydroxy groups or C1-C3-alkyl groups, a 3-6 membered heterocycloalkyl group optionally substituted with one or two substituents, said substituents being independently selected from C1-C3-alkyl groups and hydroxy groups; are independently selected from R 9 is a hydrogen atom or a C1-C3 alkyl group or a bond.

[0089] According to a fifth embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is selected from a hydrogen atom, a halogen atom, a C1-C3-alkyl group, and a C1-C3-haloalkyl group, R 2 is selected from a hydrogen atom and a halogen atom; R 3 teeth, C1-C6-alkyl groups optionally substituted with 1 or 2 substituents, each of which is independently selected from a hydroxy group, a C1-C4-alkoxy group, and a 3- to 7-membered heterocycloalkyl group. C2-C6-alkenyl groups, optionally substituted by C1-C3-alkoxy groups, C3-C7-cycloalkyl groups optionally substituted by hydroxy groups; C5-C6-cycloalkenyl groups optionally substituted by hydroxy groups, -O- and -NR 9 -, wherein - is a 3- to 6-membered heterocycloalkyl group containing 1, 2, or 3 heteroatoms independently selected from A 3- to 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents, each of which is Halogen atoms, oxo (=O) group, Cyano group, Hydroxy groups, C1-C3-alkyl groups optionally further substituted with hydroxy groups; partially unsaturated, optionally substituted with one or two substituents, 5-7 membered heterocycloalkyl groups, each substituent being independently selected from C1-C3-alkyl groups and halogen atoms; Aryl groups optionally substituted with 1, 2, 3 or 4 substituents, each of which is selected from the group consisting of halogen atoms, hydroxy groups, cyano groups, C1-C3-alkyl groups, C1-C3-haloalkyl groups, C1-C3-alkoxy groups, C1-C3-haloalkoxy groups, and NR 5 R 6 (independently selected from the group consisting of Monocyclic or bicyclic heteroaryl groups, optionally substituted by one or two substituents, each of which is selected from the group consisting of halogen atoms, C1-C3-alkyl groups, cyano groups, C1-C3-haloalkyl groups, C1-C3-alkoxy groups, hydroxy groups and NR 5 R 6 groups, with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group; and N.R. 7 R 8 basis is selected from R 4 is selected from a hydrogen atom and a C1-C3-alkyl group, R 5 / R 6 are independently selected from a hydrogen atom and a C1-C6-alkyl group; R 7 / R 8 is a hydrogen atom (where R 7 =R 8 = Hydrogen excluded), C1-C6-alkyl groups, which are optionally substituted with 1, 2, 3 or 4 substituents, said substituents being Halogen atoms, Cyano group, Hydroxy groups, C1-C3 alkoxy group, C3-C7-cycloalkyl groups optionally substituted by one or two substituents, said substituents being independently selected from C1-C3-alkyl groups, hydroxy groups and C1-C3-hydroxyalkyl groups, 3- to 7-membered heterocycloalkyl groups, which themselves are optionally substituted by C1-C3-alkyl groups; and heteroaryl groups optionally further substituted with C1-C3-alkyl groups, C3-C6-cycloalkyl groups optionally substituted by hydroxy groups, and a 3-6 membered heterocycloalkyl group optionally substituted with one or two substituents, said substituents being independently selected from C1-C3-alkyl groups and hydroxy groups; are independently selected from R 9 is a hydrogen atom or a C1-C3 alkyl group or a bond.

[0090] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is selected from a hydrogen atom, a halogen atom, a C1-C3-alkyl group, and a C1-C3-haloalkyl group, R 2 is selected from a hydrogen atom and a halogen atom; R 3 teeth, -O- and -NR 9 -, wherein - is a 3- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from A 3- to 6-membered heterocycloalkyl group, optionally further substituted with one or two substituents, each of which is Halogen atoms, Hydroxy groups, and C1-C3-alkyl groups optionally further substituted with hydroxy groups), an aryl group optionally substituted with one or two substituents, each substituent being independently selected from a halogen atom, a hydroxy group, and a C1-C3-haloalkyl group; Monocyclic or bicyclic heteroaryl groups, optionally substituted by substituents, such as halogen atoms, C1-C3-alkyl groups, C1-C3-haloalkyl groups, and NR 5 R 6 with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group; and N.R. 7 R 8 base is selected from R 4 is selected from a hydrogen atom and a C1-C3-alkyl group, R 5 / R 6 are independently selected from a hydrogen atom and a C1-C3-alkyl group; R 7 / R 8 is a hydrogen atom (where R 7 =R 8 = Hydrogen excluded), C1-C6-alkyl groups, which are optionally substituted with 1, 2, 3 or 4 substituents, said substituents being Halogen atoms, Hydroxy groups, C1-C3 alkoxy group, C3-C5-cycloalkyl groups optionally further substituted by one or two substituents, said substituents being independently selected from C1-C3-alkyl groups and C1-C3-hydroxyalkyl groups, -O- and -NR 9 -, a 5-6 membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from -, optionally further substituted with a C1-C3-alkyl group, heteroaryl groups optionally further substituted with C1-C3-alkyl groups, C3-C6-cycloalkyl groups optionally substituted by hydroxy groups or C1-C3-alkyl groups, a 4-5 membered heterocycloalkyl group optionally substituted with one or two substituents, said substituents being independently selected from C1-C3-alkyl groups and hydroxy groups; are independently selected from R 9 is a hydrogen atom or a C1-C3 alkyl group or a bond.

[0091] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment thereof a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof, During the ceremony, R 1 is selected from CF3 and a fluorine atom, R 2 is a hydrogen atom, R 3 teeth, Aryl groups optionally substituted with substituents selected from halogen atoms and C1-C3-haloalkyl groups, C1-C3-Haloalkyl groups and NR 5 R 6 a monocyclic heteroaryl group substituted with a substituent selected from the group and N.R. 7 R 8 basis is selected from R 4 is selected from a hydrogen atom and a methyl group; R 5 / R 6 are independently selected from a hydrogen atom and a methyl group; R 7 / R 8 teeth, Hydrogen atom (where R 7 =R 8 = Hydrogen excluded), C1-C3-alkyl groups, which are optionally substituted with 1, 2 or 4 substituents, said substituents being Halogen atoms, hydroxyl groups, and methoxy groups are independently selected from are independently selected from

[0092] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment thereof a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof, During the ceremony, R 1 is selected from CF3 and a fluorine atom, R 2 is a hydrogen atom, R 3 teeth, Aryl groups optionally substituted with substituents selected from halogen atoms and C1-C3-haloalkyl groups, C1-C3-Haloalkyl groups and NR 5 R 6 a monocyclic heteroaryl group substituted with a substituent selected from the group and N.R. 7 R 8 basis is selected from R 4 is a hydrogen atom, R 5 / R 6 are independently selected from a hydrogen atom and a methyl group; R 7 / R 8 teeth, Hydrogen atom (where R 7 =R 8 = Hydrogen excluded), C1-C3-alkyl groups, which are optionally substituted with 1, 2 or 4 substituents, said substituents being Halogen atoms, hydroxyl groups, and methoxy groups are independently selected from are independently selected from

[0093] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment thereof a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof, During the ceremony, R 1 is selected from CF3 and a fluorine atom, R 2 is a hydrogen atom, R 3 teeth, An aryl group optionally substituted with a substituent selected from halogen atoms and C1-C3-haloalkyl groups. is selected from R 4 is selected from a hydrogen atom.

[0094] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment thereof a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof, During the ceremony, R 1 is selected from CF3 and a fluorine atom, R 2 is a hydrogen atom, R 3 teeth, C1-C3-Haloalkyl groups and NR 5 R 6 a monocyclic heteroaryl group substituted with a substituent selected from the group and N.R. 7 R 8 base is selected from R 4 is selected from a hydrogen atom, R 5 / R 6 are independently selected from a hydrogen atom and a methyl group; R7 / R 8 teeth, Hydrogen atom (where R 7 =R 8 = Hydrogen excluded), C1-C3-alkyl groups, which are optionally substituted with 1, 2 or 4 substituents, said substituents being Halogen atoms, hydroxyl groups, and methoxy groups are independently selected from are independently selected from

[0095] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment thereof a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof, During the ceremony, R 1 is selected from CF3 and a fluorine atom, R 2 is a hydrogen atom, R 3 teeth, Aryl groups optionally substituted with substituents selected from halogen atoms and C1-C3-haloalkyl groups, C1-C3-Haloalkyl groups and NR 5 R 6 a monocyclic heteroaryl group substituted with a substituent selected from the group and N.R. 7 R 8 basis is selected from R 4 is a methyl group, R 5 / R 6 are independently selected from a hydrogen atom and a methyl group; R 7 / R 8 teeth, Hydrogen atom (where R 7 =R 8 = Hydrogen excluded), C1-C3-alkyl groups, which are optionally substituted with 1, 2 or 4 substituents, said substituents being Halogen atoms, hydroxyl groups, and methoxy groups are independently selected from are independently selected from

[0096] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment thereof a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof, During the ceremony, R 1 is selected from CF3 and a fluorine atom, R 2 is a hydrogen atom, R 3 teeth, An aryl group optionally substituted with a substituent selected from halogen atoms and C1-C3-haloalkyl groups. is selected from R 4 is a methyl group.

[0097] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment thereof a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof, During the ceremony, R 1 is selected from CF3 and a fluorine atom, R 2 is a hydrogen atom, R 3 teeth, C1-C3-Haloalkyl groups and NR 5 R 6 a monocyclic heteroaryl group substituted with a substituent selected from the group and N.R. 7 R 8 basis is selected from R 4 is a methyl group, R 5 / R 6 are independently selected from a hydrogen atom and a methyl group; R 7 / R 8 teeth, Hydrogen atom (where R 7 =R 8 = Hydrogen excluded), C1-C3-alkyl groups, which are optionally substituted with 1, 2 or 4 substituents, said substituents being Halogen atoms, hydroxyl groups, and methoxy groups (independently selected from are independently selected from

[0098] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is selected from C1-C3-alkyl groups (e.g., CH3 groups), C1-C3-haloalkyl groups (e.g., CF3 groups), and halogens (e.g., fluorine atoms), R 2 is a hydrogen atom, R 3 teeth, C1-C6-alkyl groups optionally substituted by C1-C4-alkoxy groups (for example methoxy groups); -O- and -NR 9 -6-membered heterocycloalkyl groups containing 1 or 2 heteroatoms independently selected from A 6-membered heterocycloalkyl group, optionally further substituted with one or two substituents, each of which is independently selected from halogen atoms and C1-C3-alkyl groups, a phenyl group substituted by one or two substituents selected from a halogen atom or a C1-C3-haloalkyl group; A monocyclic 5-membered heteroaryl group substituted with a substituent selected from C1-C3-haloalkyl groups. is selected from R 4 is selected from a hydrogen atom and a C1-C3-alkyl group (e.g., a methyl group), R 9 is a bond or a C1-C3-alkyl group (eg, methyl).

[0099] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is selected from C1-C3-alkyl groups (e.g., CH3 groups), C1-C3-haloalkyl groups (e.g., CF3 groups), and halogens (e.g., fluorine atoms), R 2 is a hydrogen atom, R 3 teeth, C1-C6-alkyl groups optionally substituted by C1-C4-alkoxy groups (for example methoxy groups); -O- and -NR 9 -6-membered heterocycloalkyl groups containing 1 or 2 heteroatoms independently selected from A 6-membered heterocycloalkyl group, optionally further substituted with one or two substituents, each of which is independently selected from halogen atoms and C1-C3-alkyl groups, a phenyl group substituted by one or two substituents selected from a halogen atom or a C1-C3-haloalkyl group; A monocyclic 5-membered heteroaryl group substituted with a substituent selected from C1-C3-haloalkyl groups. is selected from R 4 is a hydrogen atom, R 9 is a bond or a C1-C3-alkyl group (eg, methyl).

[0100] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is selected from C1-C3-alkyl groups (e.g., CH3 groups), C1-C3-haloalkyl groups (e.g., CF3 groups), and halogens (e.g., fluorine atoms), R 2 is a hydrogen atom, R 3 teeth, C1-C6-alkyl groups optionally substituted by C1-C4-alkoxy groups (for example methoxy groups); -O- and -NR 9 -6-membered heterocycloalkyl groups containing 1 or 2 heteroatoms independently selected from A 6-membered heterocycloalkyl group, optionally further substituted with one or two substituents, each of which is independently selected from halogen atoms and C1-C3-alkyl groups, a phenyl group substituted by one or two substituents selected from a halogen atom or a C1-C3-haloalkyl group; A monocyclic 5-membered heteroaryl group substituted with a substituent selected from C1-C3-haloalkyl groups. is selected from R 4 is a C1-C3 alkyl group (e.g., a methyl group), R 9 is a bond or a C1-C3-alkyl group (eg, methyl).

[0101] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is selected from C1-C3-alkyl groups (e.g., CH3 groups), C1-C3-haloalkyl groups (e.g., CF3 groups), and halogens (e.g., fluorine atoms), R 2 is a hydrogen atom, R 3 teeth, Halogen atoms, C1-C6-alkyl groups optionally substituted by C1-C4-alkoxy groups (for example methoxy groups); -O- and -NR 9 -6-membered heterocycloalkyl groups containing 1 or 2 heteroatoms independently selected from A 6-membered heterocycloalkyl group, optionally further substituted with one or two substituents, each of which is independently selected from halogen atoms and C1-C3-alkyl groups, a phenyl group substituted by one or two substituents selected from a halogen atom or a C1-C3-haloalkyl group; A monocyclic 5-membered heteroaryl group substituted with a substituent selected from C1-C3-haloalkyl groups. is selected from R 4 is selected from a hydrogen atom and a C1-C3-alkyl group (e.g., a methyl group), R 9 is a C1-C3 alkyl group (eg, methyl).

[0102] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is selected from a CH3 group, a CF3 group, and a fluorine atom; R 2 is a hydrogen atom, R 3 teeth, fluorine atom, -(CH2)2C(CH3)3 group, -(CH2)3-OCH3 group, -N-methyl-piperidine-group, morpholino group, 4,4-difluoropiperidin-1-yl group, a phenyl group substituted by one or two substituents independently selected from a fluorine atom and a difluoromethyl group; Pyrazole group substituted with difluoromethyl or trifluoromethyl group is selected from R 4 is selected from a hydrogen atom and a methyl group.

[0103] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is selected from a CH3 group, a CF3 group, and a fluorine atom; R 2 is a hydrogen atom, R 3 teeth, -CH3 group, -(CH2)2C(CH3)3 group, -(CH2)3-OCH3 group, -N-methyl-piperazine- group, morpholino group, 4,4-difluoropiperidin-1-yl group, a phenyl group substituted by one or two substituents independently selected from a fluorine atom and a difluoromethyl group; Pyrazole group substituted with difluoromethyl or trifluoromethyl group is selected from R 4 is selected from a hydrogen atom and a methyl group.

[0104] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is a C1-C3 haloalkyl group, R 2 is a hydrogen atom, R 3 teeth, -NR 9 - a 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a monocyclic 5-membered heteroaryl group substituted with a substituent selected from a C1-C3-haloalkyl group, and Phenyl group substituted with halogen atoms is selected from R 4 is a methyl group, R 9 is a bond or a C1-C3 alkyl group.

[0105] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is a CF group, R 2 is a hydrogen atom, R 3 teeth, -N-methyl-piperazine- group, trifluoromethylpyrazole group, and fluorine-substituted phenyl group is selected from R 4 is a methyl group.

[0106] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is a CF group, R 2 is a hydrogen atom, R 3 teeth, -N-methyl-piperidine-group or phenyl group substituted with a fluorine atom is selected from R 4 is a methyl group.

[0107] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is selected from a CH3 group, a CF3 group, and a fluorine atom; R 2 is a hydrogen atom, R 3 teeth, fluorine atom, -(CH2)2C(CH3)3 group, -(CH2)3-OCH3 group, morpholino group, 4,4-difluoropiperidin-1-yl group, a phenyl group substituted by one or two substituents independently selected from a fluorine atom and a difluoromethyl group; Pyrazole group substituted with difluoromethyl or trifluoromethyl group is selected from R 4 is a hydrogen atom.

[0108] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is selected from a CH3 group, a CF3 group, and a fluorine atom; R 2 is a hydrogen atom, R 3 teeth, -CH3 group, -(CH2)2C(CH3)3 group, -(CH2)3-OCH3 group, morpholino group, 4,4-difluoropiperidin-1-yl group, a phenyl group substituted by one or two substituents independently selected from a fluorine atom and a difluoromethyl group; Pyrazole group substituted with difluoromethyl or trifluoromethyl group is selected from R 4 is a hydrogen atom or a -CH3 group.

[0109] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as defined above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound as defined above for use in the treatment of a sarcoma, During the ceremony, R 1 is selected from a CH3 group, a CF3 group, and a fluorine atom; R 2 is a hydrogen atom, R 3 teeth, CH3 group, -(CH2)2C(CH3)3 group, -(CH2)3-OCH3 group, morpholino group, 4,4-difluoropiperidin-1-yl group, a phenyl group substituted by one or two substituents independently selected from a fluorine atom and a difluoromethyl group; Difluoromethyl-substituted pyrazole group is selected from R 4 is a hydrogen atom.

[0110] According to a further embodiment of the first aspect, the present invention comprises a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, selected from the following group, or a compound as above for use in the treatment of a sarcoma: 5-[4-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(4-fluoro-4-methylpiperidin-1-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(4-fluoropiperidin-1-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(4'-fluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(3',4'-difluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(4'-fluoro-2,2'-dimethylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3,6-dihydro-2H-pyran-4-yl)-3-methylphenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-methyl-4-(1H-pyrazol-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-methyl-4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-methyl-4-(pyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-methyl-4-(pyrimidin-5-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(3'-fluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-6-methyl-5-(3,4,5-trifluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-[3,5-difluoro-4-(morpholin-4-yl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-{3,5-difluoro-4-[(2S)-2-methylmorpholin-4-yl]phenyl}-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-(4-bromophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (rac)-6-methyl-5-[4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3,5-difluoro-4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 2-(morpholin-4-yl)-5-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)benzonitrile, 3-chloro-2-(morpholin-4-yl)-5-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)benzonitrile, 5-{4-[2,6-dimethylmorpholin-4-yl]-3-fluorophenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-(3-fluoro-4-morpholinophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-(3,5-difluoro-4-morpholinophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3,3-difluoropyrrolidin-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-methyl-4-(2-methylpyrimidin-5-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-methyl-4-(1-methyl-1H-pyrazol-5-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,4'-difluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-chloro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(pyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-amino-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3'-hydroxy-4'-methyl-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{3-(trifluoromethyl)-4-[6-(trifluoromethyl)pyridin-3-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-fluoro-3'-hydroxy-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[5'-amino-2',4'-difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-amino-3'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(6-aminopyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3'-amino-4'-chloro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3'-amino-4'-methyl-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3'-amino-2'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-amino-2'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-methyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3-methyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1H-indazol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(5-fluoro-6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1,2-thiazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 1-methyl-5-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]-1H-pyrrole-2-carbonitrile, 5-[2,4'-bis(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1,3-dimethyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(2-methoxy-6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(2-methyl-1,3-thiazol-5-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-(methylamino)-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3'-amino-4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3',4',5'-trifluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[2',5'-difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3'-amino-4'-fluoro-2-(trifluoromethoxy)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3',4'-difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1H-indol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(2-methylprop-1-en-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[2',3'-difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(morpholin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(butylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-methyl-1H-pyrazol-4-yl)-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(propylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(6-methylpyridin-3-yl)-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-chloro-2-(trifluoromethoxy)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(azetidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-methyl-1H-benzimidazol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(pentylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-methyl-1H-indazol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-fluoro-2-(trifluoromethoxy)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(6-fluoropyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(3-methylpyridin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(2-methylpyridin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(4'-amino-2-fluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluoro-2'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2'-chloro-2,4'-difluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(cyclopent-1-en-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2'-ethyl-2-fluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,4'-difluoro-3'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluoro-3'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluoro-4'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(2-aminopyridin-4-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(3'-amino-2-fluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-(difluoromethyl)-2-fluorobiphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(pyridin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(2-methylpyrimidin-5-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(2-methoxypyridin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(2-methylpyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(6-methylpyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,2',4',5'-tetrafluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,2',3',4'-tetrafluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,2',5'-trifluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 2'-fluoro-4'-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)biphenyl-4-carbonitrile, 5-(2'-amino-2-fluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(3'-amino-2-fluoro-4'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluoro-3'-hydroxybiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluoro-4'-hydroxybiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluoro-2'-hydroxybiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,3',4'-trifluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(pyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,2',3'-trifluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,3',5'-trifluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,2',4'-trifluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluoro-2',4'-dimethylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,3'-difluoro-4'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,2'-difluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,2',6'-trifluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluoro-2'-methoxybiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,3'-difluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(4-methylpyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-(3-fluoro-4-morpholinophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[4-(morpholin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-(-[(3-chloro-4-(morpholin-4-yl)-5-(trifluoromethyl)phenyl)-)]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-(-[(4-chloro-3-(trifluoromethyl)phenyl)-)]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-(-[(4-fluoro-3-(trifluoromethyl)phenyl)-)]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-chloro-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(4-chloro-3-methylphenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-6-methyl-5-(4-morpholino-3-(trifluoromethyl)phenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3,5-dimethyl-1,2-oxazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-ethyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[cyclopentyl(methyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[butyl(methyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(cyclopentylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(cyclopentylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-methyl-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[3-methoxyprop-1-en-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-[4'-hydroxy-2-(trifluoromethyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(5,6-dihydro-2H-pyran-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[3,3-dimethylbut-1-en-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{3-(trifluoromethyl)-4-[5-(trifluoromethyl)thiophen-3-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(prop-1-en-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-benzothiophen-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(2,5-dihydrofuran-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(cyclopent-1-en-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-ethyl-1H-imidazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 3-methyl-5-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]thiophene-2-carbonitrile, 5-{4-[1-(propan-2-yl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-[4-(bicyclo[2.2.1]hept-2-en-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[2'-fluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{3-(trifluoromethyl)-4-[5-(trifluoromethyl)thiophen-2-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(5-methylpyridin-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(5-fluoropyridin-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(5-chloropyridin-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(pyridin-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[2'-(difluoromethyl)-2-fluoro[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,4'-difluoro-2'-methyl[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 2'-fluoro-2-methyl-4'-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)[1,1'-biphenyl]-4-carbonitrile, 5-[4-(2-methylprop-1-en-1-yl)-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4-(2-aminopyridin-4-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[4-(pyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[4-(6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[2'-fluoro-4'-methyl-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[2',4',5'-trifluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[2',3',4'-trifluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[2',5'-difluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 4'-[(6S)-6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl]-2'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonitrile, (6S)-5-[4-(1H-indol-5-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4'-hydroxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[3'-hydroxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[3'-amino-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[2',4'-difluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[3'-fluoro-4'-methyl-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[2'-fluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[2'-methoxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[3'-fluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[4-(4-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[4-(3-methylpyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[4-(2-methylpyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4-(1H-indol-6-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4-(6-methoxypyridin-3-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4'-methoxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[4'-methyl-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)-phenyl}-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)-phenyl}-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-fluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-fluoro-5-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{3-(difluoromethyl)-4-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-{4-[(morpholin-4-yl)methyl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(morpholin-4-yl)methyl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[2-(difluoromethyl)-4'-fluoro[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-chloro-2-(difluoromethyl)[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-(difluoromethyl)-4-(6-methylpyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(cyclopent-1-en-1-yl)-3-(difluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3-hydroxy-3-methylazetidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-[4-{[3,3,3-trifluoro-2-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(oxan-4-yl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(cis / trans)-3-hydroxycyclobutyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(rac)-2,4-dimethylazetidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(cis or trans)-2,4-dimethylazetidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[3,3,3-trifluoro-2(S)-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-hydroxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(trans)-4-hydroxycyclohexyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(cyclopropylmethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(3-methyloxetan-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, -{4-[(3-methoxypropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-({[(rac)-oxolan-2-yl]methyl}amino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[2(R)-2-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(3R)-3-hydroxybutyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(2S)-2-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(1-hydroxycyclobutyl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(3-methylbutyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-methoxyethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[ethyl(methyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(tert-butylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-({[(2R)-oxolan-2-yl]methyl}amino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(pyrazin-2-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(4-hydroxypiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(2S)-1-hydroxybutan-2-yl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3-hydroxypiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (racemic mixture), (rac)-1-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]piperidine-3-carboxamide, 5-{4-[(3-hydroxy-2,2-dimethylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(1R,2R,4R)-bicyclo[2.2.1]heptan-2-yl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(3S)-3-hydroxypyrrolidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-{4-[(2-hydroxy-3-methoxypropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(1-methyl-1H-pyrazol-5-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(1H-pyrazol-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[2-(1H-pyrazol-1-yl)ethyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 1-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]piperidine-4-carbonitrile, (rac)-5-{4-[(1-cyclopropylethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-{4-[(2-ethoxypropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (rac)-5-{4-[(2-methoxypropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one 5-[4-(3-ethoxyazetidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(pyrimidin-2-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(oxolan-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (racemic mixture), 5-[4-{[(2S)-4-hydroxybutan-2-yl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-[4-{[(6-oxopiperidin-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-[4-{[(2,2-dimethylcyclopropyl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-({[1-(hydroxymethyl)cyclobutyl]methyl}amino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2S)-2-(hydroxymethyl)azetidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 3-methyl-1-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]azetidine-3-carbonitrile, 5-[4-(3-azabicyclo[3.1.0]hexan-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(4-ethyl-4-hydroxypiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 4-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)anilino]butanenitrile, 6-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]-2λ 6 -thia-6-azaspiro[3.3]heptane-2,2-dione, N 2 -[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]glycinamide, 5-{4-[(3R)-3-hydroxypyrrolidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-methoxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one 5-[4-({[(2S)-oxolan-2-yl]methyl}amino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-ethoxyethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(1S,2R)-2-hydroxycyclopentyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(oxetan-3-yl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{3-(difluoromethyl)-4-[1-(propan-2-yl)-1H-pyrazol-4-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(morpholin-4-yl)-5-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-{3-(trifluoromethyl)-4-[4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3-methoxypropyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(2-methylpropyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3,3-dimethylbutyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(propan-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-{4-[oxan-3-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (trans)-5-{4-[4-hydroxycyclohexyl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (trans isomer), (cis)-5-{4-[4-hydroxycyclohexyl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-aminoethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one hydrochloride salt, 5-{4-[1-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-(trifluoromethyl)-phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one-hydrochloric acid salt, 5-[4-(methylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(2-hydroxypropan-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4-(3,3-difluoroazetidin-1-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, and (6S)-5-[4-(3-hydroxy-3-methylazetidin-1-yl)-3-(trifluoromethyl)-phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0111] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, selected from the following group, or any one of these compounds used in the treatment of a sarcoma: 5-[4-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one 5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(4'-fluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(3',4'-difluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one 5-[4'-(difluoromethyl)-2-fluoro[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-methyl-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3-methoxypropyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3,3-dimethylbutyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, and (6S)-6-Methyl-5-[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0112] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) as above, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, selected from the following group, or any one of these compounds used in the treatment of a sarcoma: 5-[4-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one 5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-Fluoro-4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one 5-(4'-fluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(3',4'-difluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one 5-[4'-(difluoromethyl)-2-fluoro[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one 5-[4-Methyl-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (6S)-6-Methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one 5-[4-(3-Methoxypropyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one 5-[4-(3,3-dimethylbutyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0113] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) selected from the following group, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or any one of these compounds used in the treatment of a sarcoma: 5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(4'-fluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-chloro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)-phenyl}-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[3,3,3-trifluoro-2(S)-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-hydroxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-methoxyethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4-(2-aminopyridin-4-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, and (6S)-6-Methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0114] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) selected from the following group, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or any one of these compounds used in the treatment of a sarcoma: 5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(4'-fluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-chloro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, and (6S)-5-[4'-Fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0115] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) selected from the following group, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or any one of these compounds used in the treatment of a sarcoma: (6S)-5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)-phenyl}-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[3,3,3-trifluoro-2(S)-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-hydroxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-methoxyethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4-(2-aminopyridin-4-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, and (6S)-6-Methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0116] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) selected from the following group, or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof, or any one of these compounds used in the treatment of a sarcoma: 5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(4'-fluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-chloro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)-phenyl}-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[3,3,3-trifluoro-2(S)-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-hydroxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, and 5-{4-[(2-methoxyethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0117] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) selected from the following group, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or any one of these compounds used in the treatment of a sarcoma: (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4-(2-aminopyridin-4-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, and (6S)-6-Methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0118] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) selected from the following group, or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or any one of these compounds used in the treatment of a sarcoma: (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-Methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0119] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) selected from the following group, or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof, or any one of these compounds used in the treatment of a sarcoma: (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, Methyl-5-[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0120] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment of a sarcoma a compound of general formula (I) selected from the following group, or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof, or any one of these compounds used in the treatment of a sarcoma: (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, Methyl-5-[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0121] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment for a sarcoma a compound of general formula (I) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound used in the treatment of a sarcoma, which is: 5-[4-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0122] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment for a sarcoma a compound of general formula (I) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound used in the treatment of a sarcoma, which is: 5-[4'-Fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0123] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment for a sarcoma a compound of general formula (I) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound used in the treatment of a sarcoma, which is: 5-[3-Fluoro-4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0124] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment for a sarcoma a compound of general formula (I) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound used in the treatment of a sarcoma, which is: 5-(4'-Fluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0125] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment for a sarcoma a compound of general formula (I) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound used in the treatment of a sarcoma, which is: 5-(3',4'-Difluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0126] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment for a sarcoma a compound of general formula (I) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound used in the treatment of a sarcoma, which is: 5-[4'-(difluoromethyl)-2-fluoro[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0127] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment for a sarcoma a compound of general formula (I) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound used in the treatment of a sarcoma, which is: (6S)-5-[4'-Fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0128] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment for a sarcoma a compound of general formula (I) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound used in the treatment of a sarcoma, which is: 5-[4-Methyl-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0129] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment for a sarcoma a compound of general formula (I) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound used in the treatment of a sarcoma, which is: 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0130] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment for a sarcoma a compound of general formula (I) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound used in the treatment of a sarcoma, which is: (6S)-6-Methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0131] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment for a sarcoma a compound of general formula (I) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound used in the treatment of a sarcoma, which is: 5-[4-(3-methoxypropyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0132] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment for a sarcoma a compound of general formula (I) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound used in the treatment of a sarcoma, which is: 5-[4-(3,3-dimethylbutyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0133] According to a further embodiment of the first aspect, the present invention provides a method of treating a sarcoma, comprising administering to a patient in need of treatment for a sarcoma a compound of general formula (I) or a stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, or a compound used in the treatment of a sarcoma, which is: (6S)-6-Methyl-5-[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one.

[0134] In another embodiment, the present invention provides a compound of Formula (I), or any subgroup disclosed herein, for the manufacture of a medicament for the treatment of a sarcoma.

[0135] In certain further embodiments of the first aspect, the invention includes combinations of two or more of the above embodiments under the heading "Further embodiments of the first aspect of the invention" for use in the treatment of sarcoma.

[0136] Compounds of general formula (I) for use in the treatment of sarcomas can be prepared according to the disclosures in WO 2019 / 025562, which is incorporated herein by reference in its entirety, particularly with respect to the syntheses described for Examples 1-330 therein.

[0137] The compounds of the present invention can be used to treat sarcoma, which method includes administering to a mammal, such as a human, in need of treatment for sarcoma an amount of a compound of formula (I) or a pharma- ceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate, or ester thereof effective to treat sarcoma.

[0138] The present invention also provides a method of treating a sarcoma, comprising the step of administering an effective amount of a compound of formula (I) to a patient in need of such treatment.

[0139] The present invention further includes a method of treating sarcoma comprising the steps of: (a) analyzing a patient tumor sample for the production of PDE3A or PDE3B and SLFN12; (b) if expression of PDE3A or PDE3B and SLFN12 is found, treating said patient with a compound of formula (I) disclosed herein.

[0140] Analytical methods can be performed as described in the art, for example, J. Biol. Chem. (2020) 295(11), 3431-3446.

[0141] Sarcoma-type cancers have been characterized in humans, but also exist in other mammals and can be treated by administering pharmaceutical compositions of the compounds of formula (I). Sarcomas originate from bone-forming mesenchymal cells and arise in various sites in the body, beginning in bone, bone marrow or cartilage or connective tissues, such as blood vessels, cartilage, deep skin, fat, fibrous tissue, joints, ligaments, lymphatic vessels, muscles, nerves, and tendons. For sarcoma-type cancers, there can be more than 70 subtypes of sarcomas, such as angiosarcoma, chondrosarcoma, dermatofibrosarcoma protuberans, desmoplastic small round cell tumor, epithelioid sarcoma, Ewing's sarcoma, fibrous histiocytoma, gastrointestinal stromal tumor, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, malignant peripheral nerve sheath tumor, myxofibrosarcoma, osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma, solitary fibrous tumor, synovial sarcoma, and undifferentiated pleomorphic sarcoma, malignant fibrous histiocytoma, lymphosarcoma, osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma, and synovial sarcoma.

[0142] As used herein, the term "treating" or "treatment" is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, ameliorating, ameliorating, and, most successfully, eliminating a sarcoma entirely. When referring to treatment or prophylaxis, treatment is preferred.

[0143] According to a further aspect, the present invention provides a compound of general formula (I) as defined above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular its pharma- ceutically acceptable salts, or mixtures thereof, for use in the treatment or prophylaxis of sarcomas, in particular in the treatment of sarcomas, more particularly in the treatment of osteosarcoma, synovial sarcoma, soft tissue sarcoma, sarcoma (represented by the cell line SA10199, which represents a recurrent malignant solitary fibrous tumor, see the Examples section), malignant fibrous histiocytoma sarcomas.

[0144] According to a further aspect, the present invention provides a compound of general formula (I) as above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular pharmaceutically acceptable salts thereof, or mixtures thereof, for use in the treatment of sarcomas including osteosarcoma, synovial sarcoma, soft tissue sarcoma, sarcoma (represented by the cell line SA10199 representing a recurrent malignant solitary fibrous tumor, see the Examples section), or fibrous histiocytoma.

[0145] According to a further aspect, the present invention comprises the use of a compound of general formula (I) as defined above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular its pharmaceutically acceptable salts, or mixtures thereof, for the treatment or prevention of sarcomas, in particular in the treatment of sarcomas, more particularly in the treatment of osteosarcoma, synovial sarcoma, soft tissue sarcoma, sarcoma (represented by the cell line SA10199, representing a recurrent malignant solitary fibrous tumor, see the Examples section), malignant fibrous histiocytoma.

[0146] According to a further aspect, the present invention comprises the use of a compound of general formula (I) as defined above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular its pharmaceutically acceptable salts, or mixtures thereof, in a method for treating or preventing sarcomas, in particular in the treatment of osteosarcoma, synovial sarcoma, soft tissue sarcoma, sarcoma (represented by the cell line SA10199, representing a recurrent malignant solitary fibrous tumor, see the Examples section), malignant fibrous histiocytoma.

[0147] According to a further aspect, the present invention comprises the use of a compound of general formula (I) as defined above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular its pharmaceutically acceptable salts, or mixtures thereof, for the preparation of a pharmaceutical composition, preferably a medicament, for the prevention or treatment of sarcomas, in particular osteosarcoma, synovial sarcoma, soft tissue sarcoma, sarcoma (represented by the cell line SA10199, representing a recurrent malignant solitary fibrous tumor, see the Examples section), malignant fibrous histiocytoma.

[0148] According to a further aspect, the present invention comprises a method for treating or preventing sarcomas, in particular for treating sarcomas, more in particular for treating osteosarcoma, synovial sarcoma, soft tissue sarcoma, sarcoma (represented by cell line SA10199, representing recurrent malignant solitary fibrous tumor, see the Examples section), malignant fibrous histiocytoma, using an effective amount of a compound of general formula (I) as above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular its pharmaceutically acceptable salts, or mixtures thereof.

[0149] According to a further aspect, the present invention comprises a pharmaceutical composition, in particular a medicament, comprising a compound of the above general formula (I), or a stereoisomer, tautomer, hydrate, solvate, salt thereof, in particular a pharmaceutical acceptable salt, or a mixture thereof, and one or more excipients, in particular one or more pharmaceutical acceptable excipients, for use in the treatment of sarcomas, in particular for the treatment of sarcomas, more particularly for the treatment of osteosarcoma, synovial sarcoma, soft tissue sarcoma, sarcoma (represented by cell line SA10199, which represents recurrent malignant solitary fibrous tumor, see the Examples section), malignant fibrous histiocytoma. Conventional procedures for preparing such pharmaceutical compositions in suitable dosage forms can be utilized.

[0150] The present invention further comprises pharmaceutical compositions, in particular medicinal products, which comprise at least one compound of formula (I), customarily together with one or more pharma- ceutical suitable excipients, for the treatment of sarcomas, in particular for use in the treatment of sarcomas, more particularly in the treatment of osteosarcoma, synovial sarcoma, soft tissue sarcoma, sarcoma (represented by cell line SA10199, representing recurrent malignant solitary fibrous tumor, see the Examples section), malignant fibrous histiocytoma.

[0151] According to a further aspect, the present invention comprises the use of a compound of general formula (I) as defined above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular its pharmaceutically acceptable salts, or mixtures thereof, in a method for treating or preventing sarcomas, in particular in the treatment of sarcomas, more particularly in the treatment of soft tissue sarcomas, osteosarcoma, malignant fibrous histiocytoma, sarcomas represented by SA10199, or synovial sarcoma.

[0152] According to a further aspect, the present invention comprises the use of a compound of general formula (I) as defined above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular its pharma- ceutically acceptable salts, or mixtures thereof, in a method for treating or preventing sarcomas, in particular in the treatment of sarcomas, more particularly in the treatment of soft tissue sarcomas, osteosarcomas, sarcomas represented by SA10199, or synovial sarcomas.

[0153] According to a further aspect, the present invention comprises the use of a compound of general formula (I) as defined above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular its pharma- ceutically acceptable salts, or mixtures thereof, in a method for treating or preventing sarcomas, in particular in the treatment of sarcomas, more particularly in the treatment of soft tissue sarcomas, malignant fibrous histiocytoma, sarcomas represented by SA10199, or synovial sarcoma.

[0154] According to a further aspect, the present invention comprises the use of a compound of general formula (I) as defined above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular its pharma- ceutically acceptable salts, or mixtures thereof, in a method for treating or preventing sarcoma, in particular in the treatment of sarcoma, more in particular in the treatment of osteosarcoma.

[0155] Further, one embodiment of the first aspect of the present invention is a method of treating osteosarcoma, synovial sarcoma, soft tissue sarcoma, sarcoma (represented by model S10199), or fibrous histiocytoma comprising administering (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one to a patient in need of treatment for the sarcoma.

[0156] The compounds used to treat sarcomas can have systemic and / or local activity. To this end, they can be administered in an appropriate manner, for example, orally, parenterally, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, auricular, or as an implant or stent.

[0157] For these administration routes, the compounds of formula (I) may be administered in suitable dosage forms.

[0158] For oral administration, the compound of formula (I) can be formulated into dosage forms known in the art that deliver the compound of the invention quickly and / or in a modified manner, such as tablets (uncoated or coated, for example with a delayed dissolving or insoluble enteric or controlled release coating), orally disintegrating tablets, films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols, or solutions. The compound of formula (I) can be incorporated into said dosage forms in crystalline and / or amorphous and / or dissolved form.

[0159] Parenteral administration can be accomplished by avoiding the absorption step (e.g., intravenously, intraarterially, intracardially, intrathecally, or intralumbarly) or by including absorption (e.g., intramuscularly, subcutaneously, intradermally, transdermally, or intraperitoneally). Suitable dosage forms for parenteral administration are, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates, or sterile powders.

[0160] Examples suitable for other routes of administration include pharmaceutical forms for inhalation (particularly powder inhalers, nebulizers), nose drops, nasal solutions, nasal sprays; tablets / films / wafers / capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, eye inserts, ear drops, ear sprays, ear powders, ear rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (e.g. patches), milks, pastes, foams, powders, implants or stents.

[0161] The compounds of formula (I) can be incorporated into the above-mentioned dosage forms. This can be done in a manner known per se by mixing with pharma- ceutical suitable excipients. Pharmaceutically suitable excipients include, inter alia: Fillers and carriers (e.g. cellulose, microcrystalline cellulose (e.g. Avicel®), lactose, mannitol, starch, calcium phosphate (e.g. Di-Cafos®), Ointment bases (e.g. petrolatum, paraffin, triglycerides, wax, wool wax, wool wax alcohol, lanolin, hydrophilic ointments, polyethylene glycols), Suppository bases (e.g. polyethylene glycol, cocoa butter, hard fats), Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium chain triglyceride fatty oils, liquid polyethylene glycols, paraffin), surfactants, emulsifiers, dispersants or wetting agents (e.g. sodium dodecyl sulfate), lecithins, phospholipids, fatty alcohols (e.g. Lanette®), sorbitan fatty acid esters (e.g. Span®), polyoxyethylene sorbitan fatty acid esters (e.g. Tween®), polyoxyethylene fatty acid glycerides (e.g. Cremophor®), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (e.g. Pluronic®), Buffers, acids, and bases (e.g., phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), Isotonic agents (e.g., glucose, sodium chloride), Adsorbents (e.g. highly dispersible silica), thickening, gel-forming, thickening and / or binding agents (e.g., polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch, carbomer, polyacrylic acid (e.g., Carbopol®); alginates, gelatin); Disintegrants (e.g., modified starch, sodium carboxymethylcellulose, sodium starch glycolate (e.g., Explotab®), cross-linked polyvinylpyrrolidone, croscarmellose sodium (e.g., AcDiSol®), Flow regulators, lubricants, glidants and release agents (e.g. magnesium stearate, stearic acid, talc, highly disperse silica (e.g. Aerosil®), coating materials (e.g. sugars, shellac) and film formers for rapidly or modified dissolving films or diffusion membranes (e.g. polyvinylpyrrolidones (e.g. Kollidon®), polyvinyl alcohols, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates (e.g. Eudragit®)), capsule materials (e.g., gelatin, hydroxypropyl methylcellulose), synthetic polymers (e.g. polylactic acid, polyglycolic acid, polyacrylates, polymethacrylates (e.g. Eudragit®), polyvinylpyrrolidones (e.g. Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols, and copolymers and block copolymers thereof); Plasticizers (e.g. polyethylene glycol, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate), Penetration enhancers, stabilizers (e.g. antioxidants (e.g. ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate)); Preservatives (e.g., parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), Colorants (e.g. inorganic pigments (e.g. iron oxide, titanium dioxide)), Flavoring, sweetening, flavoring and / or odor masking agents.

[0162] The present invention further relates to the use of a pharmaceutical composition comprising at least one compound according to the invention, customarily together with one or more pharma- ceutically suitable excipients, for the treatment of sarcomas.

[0163] According to another aspect, the present invention comprises a pharmaceutical combination, in particular a medicinal product, comprising at least one compound of general formula (I) and at least one or more further active ingredients, in particular for the treatment and / or prevention of sarcomas.

[0164] In particular, the present invention provides one or more first active ingredients, in particular compounds of general formula (I) as defined above, one or more further active ingredients (e.g. anticancer drugs); The present invention includes a pharmaceutical combination for the treatment of sarcoma, comprising

[0165] As further active ingredients for the combination, for example bevacizumab, paliperidone, or trabectedin as further sarcoma agents may be used.

[0166] Alternatively, it may be combined with other anticancer drugs such as: 131I-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronate, alitretinoin, alpharazine, altretamine, amifostine, aminoglutethimide, hexylaminolevulinic acid, amrubicin, amsacrine, anastrozole, ancestim, anetholedithiolthione, anetumab ravtansine, angiotensin II, Antithrombin III, apalutamide, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, avelumab, axicabtagene ciloreucel, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, bosutinib, buserelin, brentuximab vedotin, brigatinib, busulfan, cabazitaxel, cabozantinib, calcitonin , calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine, carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, cermoleukin, cemiplimab, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronate, clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine Jin, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, durvalumab, eculizumab, edrecolomab, elliptinium acetate,Elotuzumab, Eltrombopag, Enasidenib, Endostatin, Enocitabine, Enzalutamide, Epirubicin, Epitiostanol, Epoetin alfa, Epoetin beta, Epoetin zeta, Eptaplatin, Eribulin, Erlotinib, Esomeprazole, Estradiol, Estramustine, Ethinyl estradiol, Etoposide, Everolimus, Exemestane, Fadrozole, Fentanyl, Filgrastim, Fluoxetine Xymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoterate meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glucarpidase, glutoxime, GM-CSF, goserelin, granisetron, granulocyte colony -stimulatory factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seed, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, inotuzumab ozogamicin, interferon alpha, interferon beta, interferon gamma, io Vitridol, Iobenguane (123I), Iomeprol, Ipilimumab, Irinotecan, Itraconazole, Ixabepilone, Ixazomib, Lanreotide, Lansoprazole, Lapatinib, IASOcholine, Lenalidomide, Lenvatinib, Lenograstim, Lentinan, Letrozole, Leuprorelin, Levamisole, Levonorgestrel, Levothyroxine Sodium, Lisuride, Lobaplatin, Lomustine, Lonidamine, Lutetium Lu 177 Dotatate, Masoprocol, Medroxyprogesterone, Megestrol, Melarsoprol, Melphalan, Mepitiostane, Mercaptopurine, Mesna, Methadone, Methotrexate, Methoxsalen, Methylaminolevulinate, Methylprednisolone, Methyltestosterone, Metyrosine, Midostaurin, Mifamurtide, Miltefosine, Miriplatin, Mitobronitrile, Mitoguazone, Mitolactol, Mitomycin,Mitotane, Mitoxantrone, Mogamulizumab, Molgramostim, Mopidamol, Morphine hydrochloride, Morphine sulfate, MVASI, Nabilone, Nabiximols, Nafarelin, Naloxone + Pentazocine, Naltrexone, Nartograstim, Necitumumab, Nedaplatin, Nelarabine, Neratinib, Neridronic acid, Netupitant + Palonosetron, Nivolumab, Pentetreotide, Nilotinib, Nilutamide, Nimorazole, Nimotuzumab, Nimustine, Nintedanib, Niraparib, Nitracrine, Nivolumab, Obinutuzumab, Octreotide, Off Atumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, olilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicin, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronate, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pegaspargase Ambrolizumab, pegfilgrastim, peg interferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, perflubutan, perfosfamide, pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusum, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone Zon, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium 223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, ribociclib, risedronate, etidronate rhenium-186, rituximab, rolapitant, romidepsin, romiplostim, romurtide, rucaparib, samarium (153Sm) lexidronam, sargramostim, sarilumab, satumomab, secretin,Siltuximab, sipuleucel-T, sizofiran, sobuzoxane, glycididazole sodium, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentane, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alpha, thioguanine, tisagenlecroy Cell, tislelizumab, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trophosphamide, thrombopoietin, tryptophan, ubenimex, baratinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium 90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.,

[0167] The term "combination" in the present invention is used as known to the person skilled in the art, and said combination can be a fixed combination, a non-fixed combination or a kit-of-parts.

[0168] "Fixed combination" is used as known to those skilled in the art, and is defined as, for example, a combination in which a first active ingredient, for example, one or more compounds of the present invention's general formula (I), and a further active ingredient are present together in one unit dosage or single entity.One example of "fixed combination" is a pharmaceutical composition in which the first active ingredient and the further active ingredient are present in admixture for simultaneous administration, such as in a pharmaceutical preparation.Another example of "fixed combination" is a pharmaceutical combination in which the first active ingredient and the further active ingredient are present in one unit without admixture.

[0169] Non-fixed combination or "kit of parts" is used as known to those skilled in the art and is defined as the combination of the first active ingredient and the further active ingredient present in two or more units.An example of non-fixed combination or kit of parts is the combination of the first active ingredient and the further active ingredient present separately.The components of non-fixed combination or kit of parts can be administered separately, sequentially, simultaneously, simultaneously or staggered.

[0170] The compounds of formula (I) can be administered as the sole pharmaceutical agent or in combination with one or more other active pharmaceutical ingredients, provided that the combination does not result in unacceptable side effects for the treatment of sarcoma. For example, the compounds of formula (I) can be combined with known anti-sarcoma agents or other anti-cancer agents.

[0171] Anti-sarcoma agents may be selected from, for example, bevacizumab, paliperidone, trabectedin, vincristine, actinomycin D, doxorubicin, and cyclophosphamide, although this should not be considered an exclusive list.

[0172] Effective dosages of the compounds of the present invention can be easily determined for treating each desired indication based on standard laboratory techniques known to evaluate compounds useful for treating sarcomas by standard toxicity tests and standard pharmacological assays to determine the treatment of previously identified conditions in mammals, and by comparing the results of these with those of known active ingredients or pharmaceuticals used to treat these conditions. The amount of active ingredient administered in the treatment of one of these conditions can vary widely depending on such considerations as the specific compound and dosage unit used, the mode of administration, the duration of treatment, the age and sex of the patient being treated, and the nature and extent of the condition being treated.

[0173] The total amount of active ingredient administered is generally in the range of about 0.001 mg / kg to about 500 mg / kg body weight per day, particularly about 0.001 mg / kg to about 200 mg / kg body weight per day, and more particularly about 0.01 mg / kg to about 50 mg / kg body weight per day. Clinically useful dosing schedules range from 1 to 3 doses per day to once every 4 weeks. Additionally, "drug holidays" during which the patient is not administered the drug for a period of time may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dose may contain about 0.5 mg to about 1500 mg of active ingredient and may be administered more than once a day, or less than once a day. The average daily dosage by administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injections, as well as by use of infusion techniques, will preferably be 0.01 to 200 mg / kg total body weight. The average daily rectal dosage regimen will preferably be 0.01-200 mg / kg total body weight. The average daily vaginal dosage regimen will preferably be 0.01-200 mg / kg total body weight. The average daily topical dosage regimen will preferably be 0.1-200 mg administered 1-4 times per day. The transdermal concentration will preferably be that required to maintain a daily dose of 0.01-200 mg / kg. The average daily inhalation dosage regimen will preferably be 0.01-100 mg / kg total body weight. For oral administration, the dosage schedule will be once or twice or three times per day, with the dosage ranges mentioned above for general administration possible.

[0174] Naturally, the specific initial and subsequent dosing regimens for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound used, the age and general condition of the patient, the duration of administration, the route of administration, the excretion rate of the drug, drug combinations, etc. The desired treatment mode and frequency of administration of the compound of general formula (I), or a pharma- ceutically acceptable salt or ester or composition thereof, can be ascertained by one skilled in the art using conventional treatment trials. EXAMPLES

[0175] The abbreviations used have their customary meanings to those skilled in the art.

[0176] Compounds of general formula (I) for use in the treatment of sarcomas can be prepared according to the disclosure of WO 2019 / 025562. The example numbers referred to in the Examples section of this specification refer to the example numbers in this publication.

[0177] Various aspects of the invention described in this application are illustrated by the following examples, which are not intended to be limiting of the invention in any way.

[0178] The example testing experiments described herein serve to illustrate the invention, but the invention is not limited to the examples given.

[0179] Example Section - General Part All reagents for which synthesis or other methods of preparation are not described in the experimental section are either commercially available, known, or can be formed from known components by known methods by one of ordinary skill in the art.

[0180] EXAMPLES SECTION - BIOLOGICAL ASSAYS In the selected biological assays, the Examples were tested one or more times. When tested more than once, the data are reported as either the mean or median, where: The average value, also called the arithmetic mean value, is calculated by dividing the total number of tests performed. · The median is the middle number in a group of values ​​when sorted in ascending or descending order. If the number of values ​​in a data set is odd, the median is the middle value. If the number of values ​​in a data set is even, the median is the arithmetic mean of the two middle values.

[0181] The Examples were synthesized one or more times. When synthesized more than once, the biological assay data represent the mean or median values ​​calculated utilizing data sets derived from testing of one or more synthesis batches.

[0182] The in vitro activity of the compounds may be demonstrated in the following assays.

[0183] Assay 1 In human sarcoma cell line G-292 clone A141B1 In vitro Cell proliferation assay The antiproliferative activity of the compounds of general formula (I) was investigated in vitro in the human sarcoma cell line G-292 clone A141B1 (from ATCC). For this purpose, an appropriate number of cells (1000) were seeded in a 384-well plate containing the appropriate growth medium McCoy's 5a Medium Modified, FCS 10% final (Biochrom; number S 0415) and incubated overnight at 37°C. To determine the cell viability at the start of treatment, after 24 hours, the cells on one plate (0-hour plate) were treated with 30 μl / cavity of CTG solution (Promega Cell Titer Glo (catalog numbers G755B and G756B)), incubated for 10 minutes at room temperature and the luminescence was measured by VICTOR V (Perkin Elmer). The cells on the test plate were treated with a set of compounds of general formula (I) as shown below and incubated at 37°C for 72 hours. Compounds were added to cells using a HP D300 digital dispenser in ten 2.5-fold dilution series, typically starting with a maximum final drug concentration of 100 nM. As a control, cells were treated with vehicle (DMSO at a final concentration of 0.3%). To determine cell viability at the end of treatment, after 72 hours, cells were treated with 30 μl / cavity of CTG solution (Promega Cell Titer Glo (catalog numbers G755B and G756B)), incubated for 10 minutes at room temperature, and luminescence was measured by VICTOR V (Perkin Elmer). Values ​​from the 0-hour plate (=maximum inhibition) and the DMSO control (=minimal inhibition) were used to determine the effect (%) on cell growth, and the resulting IC50, for each test substance. IC50 values ​​were calculated using a four-parameter fit.

[0184] In summary, all the examples shown in Table 1 exhibited anti-proliferative activity in the human sarcoma cell line G-292 clone A141B1 with IC50s ranging from 604 to 13 nM.

[0185] [Table 1A] [Table 1B]

[0186] Assay 2 In vivo xenograft model The antitumor activity of (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one was investigated in mouse xenograft models of human cancer. For this purpose, tumor pieces were implanted subcutaneously in mice. The average tumor size was 20-40 mm. 2 At , animals were randomly divided into treatment and control groups (at least n = 10 animals / group) and treatment was initiated with vehicle only or the respective compound (formulation: 90% PEG400 / 10% ethanol; application route: by mouth ("po"), orally). The oral application volume was 10 ml / kg. For twice daily treatments, the time interval between the two daily applications was 6-7 h. Tumor size and body weight were measured at least once a week. Tumor area was detected by electronic calipers [length (mm) x width (mm)]. The experiment was terminated when the study reached the predefined ethical end point according to German and European animal welfare regulations. The in vivo antitumor efficacy is shown in Table 2 as the T / C ratio (treated / control; mean tumor weight of the treatment group / mean tumor weight of the control group) at the end of the study. Compounds with a T / C of less than 0.5 are defined as active (i.e., effective). Statistical analysis was evaluated using SigmaStat software. One-way analysis of variance was performed to compare differences from controls by pairwise comparison procedures (Dunn's method).

[0187] (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one was effective in reducing tumor volume in the sarcoma models used and specified in Table 2.

[0188] [Table 2]

[0189] Patient-derived xenograft models created by direct implantation of fresh human tumors are believed to more closely resemble the heterogeneity of real human tumors compared to xenograft models created from cell lines that have been cultured in vitro for decades. The antitumor activity of (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one was evaluated in patient-derived xenograft models of sarcoma, a tumor type with many subtypes and high medical need due to the lack of approved targeted therapies. The tumor model was from CrownBio.

[0190] Patient-derived xenograft sarcoma models responded to treatment with (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one with reduced tumor growth compared to the vehicle control group. Model SA3831 was the most sensitive model, showing strong tumor growth inhibition reflected by a T / C ratio of 0.01 at the end of treatment (Figure 1). Model SA4058 was the second most sensitive model, showing strong tumor growth inhibition reflected by a T / C ratio of 0.12 at the end of treatment (Figure 2). Models SA16044 and SA10199 also responded to treatment with (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, showing moderate tumor growth inhibition as reflected by T / C ratios of 0.33 and 0.34, respectively, at the end of treatment (Figures 3 and 4). Model SA10245 was the least sensitive model, with a T / C ratio of only 0.73 (Figure 5).

[0191] In summary, (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one had significant antitumor activity in patient-derived xenograft models of several sarcomas.

[0192] Thus, one embodiment of the first aspect of the present invention is a method of treating a sarcoma, more particularly an osteosarcoma, a synovial sarcoma, a soft tissue sarcoma, a sarcoma represented by cell line SA10199, or a fibrous histiocytoma, comprising the step of administering (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one to a patient in need of treatment for such a sarcoma.

Claims

1. A compound of general formula (I) for use in a method for inhibiting the growth or proliferation of a sarcoma 【Chemistry 1】 or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof, wherein the method comprises administering to a subject having a sarcoma: During the ceremony, R 1 is a hydrogen atom, a halogen atom, a cyano group, C 1 ~C 3 -Alkyl group, C 1 ~C 3 -Haloalkyl groups, and C 1 ~C 3 -haloalkoxy groups, R 2 is selected from a hydrogen atom and a halogen atom; R 3 teeth, C optionally substituted with 1 or 2 substituents 1 ~C 6 -Alkyl group (each substituent is a hydroxyl group, C 1 ~C 4 -alkoxy groups, and 3- to 7-membered heterocycloalkyl groups; In some cases C 1 ~C 4 - C substituted with an alkoxy group 2 ~C 6 - an alkenyl group, C optionally substituted with a hydroxy group 3 ~C 9 - a cycloalkyl group, C optionally substituted with a hydroxy group 5 ~C 9 -cycloalkenyl group, -O-, -S-, -S(O)-, S(O) 2 , and -NR 9 - a 3- to 9-membered heterocycloalkyl group containing 1, 2, or 3 heteroatoms independently selected from -O-, -NR 9 -, -CH 2 -, -CH 2 -CH 2 -, -O-CH 2 -, -CH 2 -O-, -NR 9 -CH 2 - and -CH 2 -NR 9 -, optionally further comprising a bridging group selected from A 3- to 9-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents, each of which is Halogen atoms, oxo (=O) group, Cyano group, Hydroxy groups, C optionally further substituted with hydroxy groups 1 ~C 3 -alkyl group, C 1 ~C 3 - a haloalkyl group, C 1 ~C 3 -alkoxy group, C 1 ~C 3 - a haloalkoxy group, C(O)NR 5 R 6 base, and N.R. 5 R 6 (independently selected from the group consisting of Partially unsaturated, 5- to 9-membered heterocycloalkyl groups, optionally substituted with 1, 2, or 3 substituents, each of which may be an oxo group (=O), C 1 ~C 3 -Alkyl group, -C(O)R 5 R 6 groups, and halogen atoms); An aryl group optionally substituted with 1, 2, 3, or 4 substituents, each of which may be a halogen atom, a hydroxyl group, a cyano group, a C 1 ~C 3 -Alkyl group, C 1 ~C 3 -Haloalkyl group, C 1 ~C 3 -alkoxy group, C 1 ~C 3 -haloalkoxy group, and NR 5 R 6 (independently selected from the group consisting of Monocyclic or bicyclic heteroaryl groups optionally substituted with 1, 2 or 3 substituents, each of which may be a halogen atom, 1 ~C 3 -Alkyl group, cyano group, C 1 ~C 3 -Haloalkyl group, C 1 ~C 3 -Hydroxyalkyl group, C 1 ~C 3 -Alkoxy groups, hydroxy groups, and NR 5 R 6 groups, with the proviso that said monocyclic heteroaryl group is not 4-pyridyl; and N.R. 7 R 8 basis is selected from R 4 is a hydrogen atom and C 1 ~C 3 - alkyl groups, R 5 / R 6 is a hydrogen atom, C 1 ~C 6 -Alkyl group, -C 1 ~C 5 -Alkylene-O-C 1 ~C 5 -Alkyl group, -C 1 ~C 5 -Alkylene-S-C 1 ~C 5 -Alkyl group, C 3 ~C 6 -Cycloalkyl groups, and C 3 ~C 5 -heterocycloalkyl groups, R 7 / R 8 is a hydrogen atom (where R 7 = R 8 (Hydrogen excluded) C 1 ~C 6 -Alkyl group which is optionally substituted with 1, 2, 3, or 4 substituents, said substituents being Halogen atoms, Cyano group, Hydroxy groups, C(O)NR 5 R 6 base, NR 5 R 6 base, C 1 ~C 3 -alkoxy group, C optionally substituted with 1 or 2 substituents 3 ~C 7 - a cycloalkyl group (wherein the substituent is C 1 ~C 3 -Alkyl groups, oxo (=O) groups, hydroxy groups, and C 1 ~C 3 -hydroxyalkyl groups, Itself may be C 1 ~C 3 - a 3- to 7-membered heterocycloalkyl group substituted with an alkyl or oxo (=O) group; Itself may be C 1 ~C 3 -alkyl-substituted heteroaryl groups, -C 1 ~C 5 -Alkylene-O-C 1 ~C 5 -alkyl group, -C 1 ~C 5 -Alkylene-S-C 1 ~C 5 -alkyl group, -C 1 ~C 5 -Alkylene-NR 5 -C 1 ~C 5 -alkyl group, C optionally substituted with a hydroxy group 3 ~C 6 -cycloalkyl groups, and 3-6 membered heterocycloalkyl groups optionally substituted with 1 or 2 substituents, said substituents being C 1 ~C 3 - independently selected from alkyl groups and hydroxy groups are independently selected from R 9 is a hydrogen atom or C 1 ~C 3 - an alkyl group or a bond, A composition comprising the step of administering a compound of general formula (I) or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof.

2. R 1 is a hydrogen atom, a halogen atom, a cyano group, C 1 ~C 3 -Alkyl group, C 1 ~C 3 -Haloalkyl groups, and C 1 ~C 3 -haloalkoxy groups, R 2 is selected from a hydrogen atom and a halogen atom; R 3 but, Hydroxy group, C 1 ~C 4 - C optionally substituted with a substituent selected from an alkoxy group and a 3- to 7-membered heterocycloalkyl group 1 ~C 6 -alkyl group, In some cases C 1 ~C 4 - C substituted with an alkoxy group 2 ~C 6 - an alkenyl group, C optionally substituted with a hydroxy group 3 ~C 7 - a cycloalkyl group, C optionally substituted with a hydroxy group 5 ~C 7 -cycloalkenyl group, -O-, S(O) 2 , and -NR 9 - a 3- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from A 3- to 7-membered heterocycloalkyl group, optionally substituted with 1 or 2 substituents, each of which is Halogen atoms, Cyano group, Hydroxy groups, C optionally further substituted with hydroxy groups 1 ~C 3 -alkyl group, C 1 ~C 3 -alkoxy group, C(O)NR 5 R 6 Groups, and NR 5 R 6 (independently selected from the group consisting of -O-, -S-, and -NR 9 - is a 5- to 7-membered heterocycloalkyl group that is partially unsaturated and contains a heteroatom selected from C 1 ~C 3 - a 5- to 7-membered heterocycloalkyl group, optionally substituted with substituents selected from alkyl groups and halogen atoms; An aryl group optionally substituted with 1, 2, or 3 substituents, each of which may be a halogen atom, a hydroxyl group, a cyano group, a C 1 ~C 3 -Alkyl group, C 1 ~C 3 -Haloalkyl group, C 1 ~C 3 -alkoxy group, and NR 5 R 6 (independently selected from the group consisting of Monocyclic or bicyclic heteroaryl groups optionally substituted with substituents, the substituents being halogen atoms, C 1 ~C 3 -Alkyl group, cyano group, C 1 ~C 3 -Haloalkyl group, C 1 ~C 3 -alkoxy group, and NR 5 R 6 with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group; and N.R. 7 R 8 basis is selected from R 4 is hydrogen atom and C 1 ~C 3 - alkyl groups, R 5 / R 6 is hydrogen atom and C 1 ~C 6 - independently selected from alkyl groups, R 7 / R 8 but, Hydrogen atom (where R 7 = R 8 (Hydrogen excluded) C 1 ~C 6 an alkyl group, which is optionally substituted with 1, 2, 3 or 4 substituents, said substituents being Halogen atoms, Cyano group, Hydroxy groups, C(O)NR 5 R 6 base, NR 5 R 6 base, C 1 ~C 3 -alkoxy group, C optionally further substituted with 1 or 2 substituents 3 ~C 7 - a cycloalkyl group (wherein the substituent is C 1 ~C 3 -Alkyl groups, oxo (=O) groups, hydroxy groups, and C 1 ~C 3 -hydroxyalkyl groups, -O- and -NR 9 - a 3- to 7-membered heterocycloalkyl group containing 1, 2, or 3 heteroatoms independently selected from, optionally C 1 ~C 3 - a 3- to 7-membered heterocycloalkyl group, which is further substituted with an alkyl group; In some cases C 1 ~C 3 -heteroaryl groups further substituted with alkyl groups; Optionally, a hydroxy group or C 1 ~C 3 -C substituted with alkyl group 3 ~C 7 -cycloalkyl groups, and 3-6 membered heterocycloalkyl groups optionally substituted with 1 or 2 substituents, said substituents being C 1 ~C 3 - independently selected from alkyl groups and hydroxy groups are independently selected from R 9 is a hydrogen atom or C 1 ~C 3 - an alkyl group or a bond, 2. The composition of claim 1.

3. R 1 is hydrogen atom, halogen atom, C 1 ~C 3 -Alkyl group, C 1 ~C 3 -Haloalkyl groups, and C 1 ~C 3 -haloalkoxy groups, R 2 is selected from a hydrogen atom and a halogen atom; R 3 but, Hydroxy group, C 1 ~C 4 - C optionally substituted with a substituent selected from an alkoxy group and a 3- to 7-membered heterocycloalkyl group 1 ~C 6 -alkyl group, In some cases C 1 ~C 4 - C substituted with an alkoxy group 2 ~C 6 - an alkenyl group, C optionally substituted with a hydroxy group 3 ~C 7 - a cycloalkyl group, C 5 ~C 7 -cycloalkenyl group, -O- and -NR 9 - a 3- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from A 3- to 7-membered heterocycloalkyl group, optionally further substituted with one or two substituents, each of which is Halogen atoms, Cyano group, Hydroxy groups, C optionally further substituted with hydroxy groups 1 ~C 3 -alkyl group, C 1 ~C 3 -alkoxy groups, and C(O)NR 5 R 6 (independently selected from the group consisting of -O- and -NR 9 - is a 5- to 7-membered heterocycloalkyl group that is partially unsaturated and contains a heteroatom selected from C 1 ~C 3 - a 5- to 7-membered heterocycloalkyl group, optionally substituted with substituents selected from alkyl groups and halogen atoms; An aryl group optionally substituted with 1, 2, or 3 substituents, each of which may be a halogen atom, a hydroxyl group, a cyano group, a C 1 ~C 3 -Alkyl group, C 1 ~C 3 -Haloalkyl groups, and NR 5 R 6 (independently selected from the group consisting of Monocyclic or bicyclic heteroaryl groups optionally substituted with substituents, the substituents being halogen atoms, C 1 ~C 3 -Alkyl group, C 1 ~C 3 -Haloalkyl group, C 1 ~C 3 -alkoxy group, and NR 5 R 6 with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group; and N.R. 7 R 8 basis is selected from R 4 is hydrogen atom and C 1 ~C 3 - alkyl groups, R 5 / R 6 is hydrogen atom and C 1 ~C 6 - independently selected from alkyl groups, R 7 / R 8 but, Hydrogen atom (where R 7 = R 8 (Hydrogen excluded) C 1 ~C 6 an alkyl group, which is optionally substituted with 1, 2, 3 or 4 substituents, said substituents being Halogen atoms, Cyano group, Hydroxy groups, NR 5 R 6 base, C 1 ~C 3 -alkoxy group, C optionally further substituted with 1 or 2 substituents 3 ~C 7 - a cycloalkyl group (wherein the substituent is C 1 ~C 3 -Alkyl groups, oxo (=O) groups, hydroxy groups, and C 1 ~C 3 -hydroxyalkyl groups, -O- and -NR 9 - a 3- to 7-membered heterocycloalkyl group containing 1, 2, or 3 heteroatoms independently selected from, optionally C 1 ~C 3 - a 3- to 7-membered heterocycloalkyl group, which is further substituted with an alkyl group; In some cases C 1 ~C 3 -heteroaryl groups further substituted with alkyl groups; Optionally, a hydroxy group or C 1 ~C 3 -C substituted with alkyl group 3 ~C 7 -cycloalkyl groups, and 3-6 membered heterocycloalkyl groups optionally substituted with 1 or 2 substituents, said substituents being C 1 ~C 3 - independently selected from alkyl groups and hydroxy groups are independently selected from R 9 is a hydrogen atom or C 1 ~C 3 - an alkyl group or a bond, 2. The composition of claim 1.

4. R 1 is hydrogen atom, halogen atom, C 1 ~C 3 -Alkyl group, C 1 ~C 3 -Haloalkyl groups, and C 1 ~C 3 -haloalkoxy groups, R 2 is selected from a hydrogen atom and a halogen atom; R 3 but, Hydroxy group, C 1 ~C 4 - C optionally substituted with a substituent selected from an alkoxy group and a 3- to 7-membered heterocycloalkyl group 1 ~C 6 -alkyl group, In some cases C 1 ~C 4 - C substituted with an alkoxy group 2 ~C 6 - an alkenyl group, C optionally substituted with a hydroxy group 4 ~C 6 - a cycloalkyl group, C 5 ~C 7 -cycloalkenyl group, -O- and -NR 9 - a 3- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from A 3- to 6-membered heterocycloalkyl group, optionally further substituted with one or two substituents, each of which is Halogen atoms, Cyano group, Hydroxy groups, C optionally further substituted with hydroxy groups 1 ~C 3 -alkyl groups), -O- and -NR 9 - is a 5- to 6-membered heterocycloalkyl group that is partially unsaturated and contains a heteroatom selected from C 1 ~C 3 - a 5- to 6-membered heterocycloalkyl group, optionally substituted with substituents selected from alkyl groups and halogen atoms; An aryl group optionally substituted with one or two substituents, each of which may be a halogen atom, a hydroxyl group, a cyano group, a C 1 ~C 3 -Alkyl group, C 1 ~C 3 -Haloalkyl groups, and NR 5 R 6 (independently selected from the group consisting of Monocyclic or bicyclic heteroaryl groups optionally substituted with substituents, the substituents being halogen atoms, C 1 ~C 3 -Alkyl group, C 1 ~C 3 -Haloalkyl group, C 1 ~C 3 -alkoxy group, and NR 5 R 6 with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group; and N.R. 7 R 8 basis is selected from R 4 is hydrogen atom and C 1 ~C 3 - alkyl groups, R 5 / R 6 is hydrogen atom and C 1 ~C 6 - independently selected from alkyl groups, R 7 / R 8 but, Hydrogen atom (where R 7 = R 8 (Hydrogen excluded) C 1 ~C 6 an alkyl group, which is optionally substituted with 1, 2, 3 or 4 substituents, said substituents being Halogen atoms, Hydroxy groups, C 1 ~C 3 -alkoxy group, C optionally further substituted with 1 or 2 substituents 3 ~C 6 - a cycloalkyl group (wherein the substituent is C 1 ~C 3 -Alkyl groups and C 1 ~C 3 -hydroxyalkyl groups, -O- and -NR 9 - a 4- to 6-membered heterocycloalkyl group containing 1, 2, or 3 heteroatoms independently selected from, optionally C 1 ~C 3 - a 4- to 6-membered heterocycloalkyl group further substituted with an alkyl group; In some cases C 1 ~C 3 -heteroaryl groups further substituted with alkyl groups; Optionally, a hydroxy group or C 1 ~C 3 -C substituted with alkyl group 3 ~C 6 - a cycloalkyl group, 3-6 membered heterocycloalkyl groups optionally substituted with 1 or 2 substituents, said substituents being C 1 ~C 3 - independently selected from alkyl groups and hydroxy groups are independently selected from R 9 is a hydrogen atom or C 1 ~C 3 - an alkyl group or a bond, 2. The composition of claim 1.

5. R 1 is hydrogen atom, halogen atom, C 1 ~C 3 -Alkyl groups, and C 1 ~C 3 - haloalkyl groups, R 2 is selected from a hydrogen atom and a halogen atom; R 3 but, C optionally substituted with 1 or 2 substituents 1 ~C 6 -Alkyl group (each substituent is a hydroxyl group, C 1 ~C 4 -alkoxy groups, and 3- to 7-membered heterocycloalkyl groups; In some cases C 1 ~C 3 - C substituted with an alkoxy group 2 ~C 6 - an alkenyl group, C optionally substituted with a hydroxy group 3 ~C 7 - a cycloalkyl group, C optionally substituted with a hydroxy group 5 ~C 6 -cycloalkenyl group, -O- and -NR 9 - a 3- to 6-membered heterocycloalkyl group containing 1, 2, or 3 heteroatoms independently selected from A 3- to 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents, each of which is Halogen atoms, oxo (=O) group, Cyano group, Hydroxy groups, C optionally further substituted with hydroxy groups 1 ~C 3 -alkyl groups), Partially unsaturated, optionally substituted with 1 or 2 substituents, 5- to 7-membered heterocycloalkyl groups, each of which is selected from the group consisting of C 1 ~C 3 - independently selected from alkyl groups and halogen atoms; An aryl group optionally substituted with 1, 2, 3, or 4 substituents, each of which may be a halogen atom, a hydroxyl group, a cyano group, a C 1 ~C 3 -Alkyl group, C 1 ~C 3 -Haloalkyl group, C 1 ~C 3 -alkoxy group, C 1 ~C 3 -haloalkoxy group, and NR 5 R 6 (independently selected from the group consisting of Monocyclic or bicyclic heteroaryl groups optionally substituted with one or two substituents, each of which may be a halogen atom, 1 ~C 3 -Alkyl group, cyano group, C 1 ~C 3 -Haloalkyl group, C 1 ~C 3 -Alkoxy groups, hydroxy groups, and NR 5 R 6 groups, with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group; and N.R. 7 R 8 basis is selected from R 4 is hydrogen atom and C 1 ~C 3 - alkyl groups, R 5 / R 6 is hydrogen atom and C 1 ~C 6 - independently selected from alkyl groups, R 7 / R 8 but, Hydrogen atom (where R 7 = R 8 (Hydrogen excluded) C 1 ~C 6 -Alkyl group which is optionally substituted with 1, 2, 3, or 4 substituents, said substituents being Halogen atoms, Cyano group, Hydroxy groups, C 1 ~C 3 -alkoxy group, C optionally substituted with 1 or 2 substituents 3 ~C 7 - a cycloalkyl group (wherein the substituent is C 1 ~C 3 -Alkyl groups, hydroxyl groups, and C 1 ~C 3 -hydroxyalkyl groups, Itself may be C 1 ~C 3 - a 3- to 7-membered heterocycloalkyl group substituted with an alkyl group; and possibly C 1 ~C 3 -heteroaryl groups further substituted with alkyl groups; C optionally substituted with a hydroxy group 3 ~C 6 -cycloalkyl groups, and 3-6 membered heterocycloalkyl groups optionally substituted with 1 or 2 substituents, said substituents being C 1 ~C 3 - independently selected from alkyl groups and hydroxy groups are independently selected from R 9 is a hydrogen atom or C 1 ~C 3 - an alkyl group or a bond, 2. The composition of claim 1.

6. R 1 is hydrogen atom, halogen atom, C 1 ~C 3 -Alkyl groups, and C 1 ~C 3 - haloalkyl groups, R 2 is selected from a hydrogen atom and a halogen atom; R 3 but, -O- and -NR 9 - a 3- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from A 3- to 6-membered heterocycloalkyl group, optionally further substituted with one or two substituents, each of which is Halogen atoms, Hydroxy groups, and C optionally further substituted with a hydroxy group 1 ~C 3 -alkyl groups), An aryl group optionally substituted with one or two substituents, each of which is selected from the group consisting of a halogen atom, a hydroxyl group, and a C 1 ~C 3 -haloalkyl groups, Monocyclic or bicyclic heteroaryl groups optionally substituted with substituents, the substituents being halogen atoms, C 1 ~C 3 -Alkyl group, C 1 ~C 3 -Haloalkyl groups, and NR 5 R 6 with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group; and N.R. 7 R 8 basis is selected from R 4 is hydrogen atom and C 1 ~C 3 - alkyl groups, R 5 / R 6 is hydrogen atom and C 1 ~C 3 - independently selected from alkyl groups, R 7 / R 8 but, Hydrogen atom (where R 7 = R 8 (Hydrogen excluded) C 1 ~C 6 an alkyl group, which is optionally substituted with 1, 2, 3 or 4 substituents, said substituents being Halogen atoms, Hydroxy groups, C 1 ~C 3 -alkoxy group, C optionally further substituted with 1 or 2 substituents 3 ~C 5 - a cycloalkyl group (wherein the substituent is C 1 ~C 3 -Alkyl groups and C 1 ~C 3 -hydroxyalkyl groups, -O- and -NR 9 -, a 5- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from, optionally 1 ~C 3 - a 5- to 6-membered heterocycloalkyl group, which is further substituted with an alkyl group; In some cases C 1 ~C 3 -heteroaryl groups further substituted with alkyl groups; Optionally, a hydroxy group or C 1 ~C 3 -C substituted with alkyl group 3 ~C 6 - a cycloalkyl group, 4-5 membered heterocycloalkyl groups optionally substituted with 1 or 2 substituents, said substituents being C 1 ~C 3 - independently selected from alkyl groups and hydroxy groups are independently selected from R 9 is a hydrogen atom or C 1 ~C 3 - an alkyl group or a bond, 2. The composition of claim 1.

7. R 1 But, C 1 ~C 3 -Alkyl groups (e.g., CH 3 group), C 1 ~C 3 -Haloalkyl groups (e.g., CF 3 group), and halogen (e.g., fluorine atom); R 2 is a hydrogen atom, R 3 but, In some cases C 1 ~C 4 - C substituted with an alkoxy group (e.g., a methoxy group) 1 ~C 6 -alkyl group, -O- and -NR 9 - a 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from A 6-membered heterocycloalkyl group, optionally further substituted with one or two substituents, each of which is Halogen atoms and C 1 ~C 3 -alkyl groups), Halogen atom or C 1 ~C 3 - a phenyl group substituted by one or two substituents selected from haloalkyl groups, C 1 ~C 3 - a monocyclic 5-membered heteroaryl group substituted with a substituent selected from haloalkyl groups is selected from R 4 is hydrogen atom and C 1 ~C 3 - an alkyl group (for example a methyl group), R 9 But bond or C 1 ~C 3 - an alkyl group (e.g. methyl), 2. The composition of claim 1.

8. R 1 But CF 3 and a fluorine atom; R 2 is a hydrogen atom, R 3 but, Halogen atoms and C 1 ~C 3 an aryl group optionally substituted with a substituent selected from haloalkyl groups, C 1 ~C 3 -Haloalkyl groups and NR 5 R 6 a monocyclic heteroaryl group substituted with a substituent selected from the group and N.R. 7 R 8 basis is selected from R 4 is selected from a hydrogen atom and a methyl group; R 5 / R 6 are independently selected from a hydrogen atom and a methyl group; R 7 / R 8 but, Hydrogen atom (where R 7 = R 8 (Hydrogen excluded) C 1 ~C 3 an alkyl group, which is optionally substituted with 1, 2 or 4 substituents, said substituents being independently selected from a halogen atom, a hydroxyl group, and a methoxy group. are independently selected from 2. The composition of claim 1.

9. R 1 But, CH 3 Base, CF 3 group, and a fluorine atom; R 2 is a hydrogen atom, R 3 but, Halogen atoms, C optionally substituted with a methoxy group 1 ~C 6 -alkyl group, -O- and -NR 9 - a 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from A 6-membered heterocycloalkyl group, optionally further substituted with one or two substituents, each of which is Halogen atoms and C 1 ~C 3 -alkyl groups), Halogen atom or C 1 ~C 3 - a phenyl group substituted by one or two substituents selected from haloalkyl groups, C 1 ~C 3 - a monocyclic 5-membered heteroaryl group substituted with a substituent selected from haloalkyl groups is selected from R 4 is selected from a hydrogen atom and a methyl group; R 9 But, C 1 ~C 3 is an alkyl group, 2. The composition of claim 1.

10. The compound of general formula (I) 5-[4-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(4-fluoro-4-methylpiperidin-1-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(4-fluoropiperidin-1-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(4'-fluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(3',4'-difluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(4'-fluoro-2,2'-dimethylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3,6-dihydro-2H-pyran-4-yl)-3-methylphenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-methyl-4-(1H-pyrazol-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-methyl-4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-methyl-4-(pyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-methyl-4-(pyrimidin-5-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(3'-fluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-6-methyl-5-(3,4,5-trifluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-[3,5-difluoro-4-(morpholin-4-yl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-{3,5-difluoro-4-[(2S)-2-methylmorpholin-4-yl]phenyl}-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-(4-bromophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (rac)-6-methyl-5-[4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3,5-difluoro-4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 2-(morpholin-4-yl)-5-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)benzonitrile, 3-chloro-2-(morpholin-4-yl)-5-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)benzonitrile, 5-{4-[2,6-dimethylmorpholin-4-yl]-3-fluorophenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-(3-fluoro-4-morpholinophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-(3,5-difluoro-4-morpholinophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3,3-difluoropyrrolidin-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-methyl-4-(2-methylpyrimidin-5-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-methyl-4-(1-methyl-1H-pyrazol-5-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,4'-difluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-chloro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(pyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-amino-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3'-hydroxy-4'-methyl-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{3-(trifluoromethyl)-4-[6-(trifluoromethyl)pyridin-3-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-fluoro-3'-hydroxy-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[5'-amino-2',4'-difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-amino-3'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(6-aminopyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3'-amino-4'-chloro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3'-amino-4'-methyl-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3'-amino-2'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-amino-2'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-methyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3-methyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1H-indazol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(5-fluoro-6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1,2-thiazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 1-methyl-5-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]-1H-pyrrole-2-carbonitrile, 5-[2,4'-bis(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1,3-dimethyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(2-methoxy-6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(2-methyl-1,3-thiazol-5-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-(methylamino)-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3'-amino-4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3',4',5'-trifluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[2',5'-difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3'-amino-4'-fluoro-2-(trifluoromethoxy)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3',4'-difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1H-indol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(2-methylprop-1-en-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[2',3'-difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(morpholin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(butylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-methyl-1H-pyrazol-4-yl)-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(propylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(6-methylpyridin-3-yl)-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-chloro-2-(trifluoromethoxy)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(azetidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-methyl-1H-benzimidazol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(pentylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-methyl-1H-indazol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-fluoro-2-(trifluoromethoxy)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(6-fluoropyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(3-methylpyridin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(2-methylpyridin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(4'-amino-2-fluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluoro-2'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2'-chloro-2,4'-difluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(cyclopent-1-en-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2'-ethyl-2-fluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,4'-difluoro-3'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluoro-3'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluoro-4'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(2-aminopyridin-4-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(3'-amino-2-fluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-(difluoromethyl)-2-fluorobiphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(pyridin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(2-methylpyrimidin-5-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(2-methoxypyridin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(2-methylpyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(6-methylpyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,2',4',5'-tetrafluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,2',3',4'-tetrafluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,2',5'-trifluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 2'-fluoro-4'-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)biphenyl-4-carbonitrile, 5-(2'-amino-2-fluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(3'-amino-2-fluoro-4'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluoro-3'-hydroxybiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluoro-4'-hydroxybiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluoro-2'-hydroxybiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,3',4'-trifluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(pyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,2',3'-trifluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,3',5'-trifluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,2',4'-trifluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluoro-2',4'-dimethylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,3'-difluoro-4'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,2'-difluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,2',6'-trifluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2-fluoro-2'-methoxybiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,3'-difluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(4-methylpyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-(3-fluoro-4-morpholinophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[4-(morpholin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-(-[(3-chloro-4-(morpholin-4-yl)-5-(trifluoromethyl)phenyl)-)]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-(-[(4-chloro-3-(trifluoromethyl)phenyl)-)]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-(-[(4-fluoro-3-(trifluoromethyl)phenyl)-)]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-chloro-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(4-chloro-3-methylphenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-6-methyl-5-(4-morpholino-3-(trifluoromethyl)phenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3,5-dimethyl-1,2-oxazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-ethyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[cyclopentyl(methyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[butyl(methyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(cyclopentylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(cyclopentylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-methyl-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[3-methoxyprop-1-en-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-[4'-hydroxy-2-(trifluoromethyl)-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(5,6-dihydro-2H-pyran-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[3,3-dimethylbut-1-en-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{3-(trifluoromethyl)-4-[5-(trifluoromethyl)thiophen-3-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(prop-1-en-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-benzothiophen-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(2,5-dihydrofuran-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(cyclopent-1-en-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-ethyl-1H-imidazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 3-methyl-5-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]thiophene-2-carbonitrile, 5-{4-[1-(propan-2-yl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-[4-(bicyclo[2.2.1]hept-2-en-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[2'-fluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{3-(trifluoromethyl)-4-[5-(trifluoromethyl)thiophen-2-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(5-methylpyridin-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(5-fluoropyridin-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(5-chloropyridin-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(pyridin-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[2'-(difluoromethyl)-2-fluoro[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,4'-difluoro-2'-methyl[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 2'-fluoro-2-methyl-4'-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)[1,1'-biphenyl]-4-carbonitrile, 5-[4-(2-methylprop-1-en-1-yl)-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4-(2-aminopyridin-4-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[4-(pyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[4-(6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[2'-fluoro-4'-methyl-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[2',4',5'-trifluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[2',3',4'-trifluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[2',5'-difluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 4'-[(6S)-6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl]-2'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonitrile, (6S)-5-[4-(1H-indol-5-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4'-hydroxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[3'-hydroxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[3'-amino-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[2',4'-difluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[3'-fluoro-4'-methyl-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[2'-fluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[2'-methoxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[3'-fluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[4-(4-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[4-(3-methylpyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[4-(2-methylpyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4-(1H-indol-6-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4-(6-methoxypyridin-3-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4'-methoxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[4'-methyl-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)-phenyl}-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)-phenyl}-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-fluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-fluoro-5-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{3-(difluoromethyl)-4-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-{4-[(morpholin-4-yl)methyl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(morpholin-4-yl)methyl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[2-(difluoromethyl)-4'-fluoro[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-chloro-2-(difluoromethyl)[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-(difluoromethyl)-4-(6-methylpyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(cyclopent-1-en-1-yl)-3-(difluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3-hydroxy-3-methylazetidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-[4-{[3,3,3-trifluoro-2-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(oxan-4-yl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(cis / trans)-3-hydroxycyclobutyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(rac)-2,4-dimethylazetidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(cis or trans)-2,4-dimethylazetidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[3,3,3-trifluoro-2(S)-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-hydroxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(trans)-4-hydroxycyclohexyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(cyclopropylmethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(3-methyloxetan-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, -{4-[(3-methoxypropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-({[(rac)-oxolan-2-yl]methyl}amino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[2(R)-2-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(3R)-3-hydroxybutyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(2S)-2-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(1-hydroxycyclobutyl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(3-methylbutyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-methoxyethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[ethyl(methyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(tert-butylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-({[(2R)-oxolan-2-yl]methyl}amino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(pyrazin-2-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(4-hydroxypiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(2S)-1-hydroxybutan-2-yl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3-hydroxypiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (racemic mixture), (rac)-1-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]piperidine-3-carboxamide, 5-{4-[(3-hydroxy-2,2-dimethylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(1R,2R,4R)-bicyclo[2.2.1]heptan-2-yl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(3S)-3-hydroxypyrrolidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-{4-[(2-hydroxy-3-methoxypropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(1-methyl-1H-pyrazol-5-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(1H-pyrazol-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[2-(1H-pyrazol-1-yl)ethyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 1-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]piperidine-4-carbonitrile, (rac)-5-{4-[(1-cyclopropylethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-{4-[(2-ethoxypropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (rac)-5-{4-[(2-methoxypropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one 5-[4-(3-ethoxyazetidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(pyrimidin-2-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(oxolan-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (racemic mixture), 5-[4-{[(2S)-4-hydroxybutan-2-yl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-[4-{[(6-oxopiperidin-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-[4-{[(2,2-dimethylcyclopropyl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-({[1-(hydroxymethyl)cyclobutyl]methyl}amino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2S)-2-(hydroxymethyl)azetidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 3-methyl-1-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]azetidine-3-carbonitrile, 5-[4-(3-azabicyclo[3.1.0]hexan-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(4-ethyl-4-hydroxypiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 4-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)anilino]butanenitrile, 6-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]-2λ 6 -thia-6-azaspiro[3.3]heptane-2,2-dione, N 2 -[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]glycinamide, 5-{4-[(3R)-3-hydroxypyrrolidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-methoxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one 5-[4-({[(2S)-oxolan-2-yl]methyl}amino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-ethoxyethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(1S,2R)-2-hydroxycyclopentyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(oxetan-3-yl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{3-(difluoromethyl)-4-[1-(propan-2-yl)-1H-pyrazol-4-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(morpholin-4-yl)-5-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-{3-(trifluoromethyl)-4-[4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3-methoxypropyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(2-methylpropyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3,3-dimethylbutyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(propan-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (rac)-5-{4-[oxan-3-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (trans)-5-{4-[4-hydroxycyclohexyl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (trans isomer), (cis)-5-{4-[4-hydroxycyclohexyl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[(2-aminoethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one hydrochloride salt, 5-{4-[1-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-(trifluoromethyl)-phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one hydrochloride, 5-[4-(methylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(2-hydroxypropan-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4-(3,3-difluoroazetidin-1-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, and (6S)-5-[4-(3-hydroxy-3-methylazetidin-1-yl)-3-(trifluoromethyl)-phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof.

11. The compound is 5-[4-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[3-fluoro-4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(4'-fluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(3',4'-difluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4'-(difluoromethyl)-2-fluoro[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-methyl-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (6S)-6-methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3-methoxypropyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(3,3-dimethylbutyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, and (6S)-6-methyl-5-[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof.

12. The compound is (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof.

13. The compound is (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, or a stereoisomer, tautomer, hydrate, solvate, or salt thereof, or a mixture thereof.

14. A composition according to any one of claims 1 to 12, further comprising one or more pharma- ceutically acceptable excipients.

15. - one or more first active ingredients of general formula (I) as defined in any one of claims 1 to 12, one or more further active ingredients; 13. The composition of any one of claims 1 to 12, comprising:

16. 16. A composition for use in a method for controlling sarcoma in a subject, comprising an effective amount of at least one compound defined in any one of claims 1 to 12, or a composition defined in claim 14 or 15.

17. 16. The composition of any one of claims 1 to 15, wherein the sarcoma is a soft tissue or bone sarcoma.

18. 16. The composition of any one of claims 1 to 15, wherein the sarcoma is selected from malignant fibrous histiocytoma, osteosarcoma, sarcoma, soft tissue sarcoma, and synovial sarcoma.

19. 1. A composition comprising (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one for use in a method of inhibiting the growth or proliferation of a sarcoma, the method comprising the step of administering an effective amount of (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one to a subject having a sarcoma selected from the group consisting of osteosarcoma, synovial sarcoma, soft tissue sarcoma, sarcomas represented by recurrent malignant solitary fibrous tumors, and fibrous histiocytoma.

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