EA041614B1 - DIHYDROXADIAZINONES - Google Patents

Description

The invention provides dihydrooxadiazinon compounds of general formula (I) as described and defined in the present invention, methods for the preparation of said compounds, pharmaceutical compositions and the use of said compounds for the treatment and prevention of diseases, in particular hyperproliferative diseases.

State of the art

More than 550,000 people in the United States and more than 8 million people worldwide die each year from cancer. New agents, including small molecules, molecules that affect tissue-specific growth conditions, and immunomodulatory agents, have been shown to benefit a group of patients whose cancer has unique genomic mutations or other characteristics. Unfortunately, many cancer patients are still without effective therapeutic agents.

One approach to identifying new anticancer agents is phenotypic screening to detect novel small molecules showing strong selectivity between cancer cell lines, followed by predictive chemogenomics to identify cellular features associated with drug response. In the 1990s, Weinstein and colleagues demonstrated that the cytotoxic profile of a compound can be used to identify cellular characteristics such as gene expression patterns and DNA copy number that correlate with drug sensitivity. The ability to identify features of cancer cell lines that mediate their response to small molecules has greatly increased in recent years due to automated high-throughput chemical sensitivity testing of large panels of cell lines in combination with comprehensive genomic and phenotypic characterization of cell lines. Phenotypic observations of small molecule sensitivity may be related to expression patterns or somatic changes, as in trastuzumab-responsive HER2-positive breast cancer or erlotinib-responsive EGFR-mutated lung cancer.

Phenotypic screening has revealed that some of the compounds known in the literature are PDE3 inhibitors, which can be used to treat certain types of cancer. Co-expression of PDE3A and/or PDE3B and Schlafen 12 (SLFN12) polynucleotides or polypeptides is usually required for cell sensitivity. PDE3A/B inhibitors that cause drug sensitivity have been found to stabilize complex formation between PDE3A or PDE3B and SLFN12. PDE3A/B inhibitors that do not sensitize cells usually do not stabilize the PDE3A- or PDE3B-SLFN12 complex.

Several PDE-3 inhibitors, such as milrinone, cilostazol, and levosimendan, have been approved for the clinical treatment of cardiovascular disease or thrombocythemia (anagrelide), but not for cancer indication. The latest review of PDE inhibitors (Nature Reviews Drug Discovery 13, 290-314 (2014)) barely mentions cancer. Several PDE3 inhibitors are known from WO 2014/164704, WO2017/027854 and WO2017/134231.

In particular, adverse cardiac effects of PDE-3 inhibitors (Movsesian & Kukreja, SH Francis et al. (Eds.), Phosphodiesterases as Dargets, Handbook of Experimental Pharmacology 204, 2011; p 237ff) may limit their therapeutic use. when PDE3 inhibitory agents are used on a short and/or long term basis, such as in cancer patients, and a suitable therapeutic window is needed.

Some dihydrooxydiazinones are known, however, dihydrooxadiazinones compounds of general formula (I) according to the present invention are not described in the prior art as described and defined herein.

The essence of the invention

The present inventors have found, and this forms at least in part the first basis of the present invention, that the compounds of the present invention have surprising and advantageous properties.

In particular, it has surprisingly been found that the compounds of the present invention inhibit the proliferation of tumor cells with IC ₅₀ values <100 nM, for example in HeLa cells. In addition, the compounds require higher concentrations to inhibit PDE3A and/or PDE3B, where IC ₅₀ values for enzymatic inhibition of PDE3A and/or PDE3B can be >2.5 times higher than IC ₅₀ values for tumor cell proliferation. Without wishing to be bound by any theory, this difference in inhibitory properties may be due to induction of the PDE3ASLFN12 complex and/or improved in vitro or in vivo pharmacokinetic parameters and/or improved physicochemical properties and/or improved safety pharmacological properties. Because of these preferred properties, the compounds described herein can therefore be used in the treatment or prevention of hyperproliferative diseases such as cancers.

The present invention provides compounds of formula (I) which modulate the formation of a PDE3A- and/or PDE3B-SLFN12 complex, methods for their preparation, a pharmaceutical composition and its use, and methods for the treatment or prevention of diseases, in particular hyperproliferative diseases, more specifically cancer. diseases. These and other features of the present invention are set forth herein.

In accordance with the first object, the present invention provides compounds of formula (I)

formula (I) wherein R ¹ is selected from a hydrogen atom, a halogen atom, a cyano group, a C ₁ -C ₃ alkyl group, a C 1 -C ₃ haloalkyl group, a C ₁ -C ₃ haloalkoxy group;

R ² is selected from a hydrogen atom and a halogen atom;

R ³ is selected from

a C1- _C6 alkyl group which is optionally substituted with one or two substituents, and each substituent is independently selected from hydroxy, _C1 - _C4 alkoxy, and a 3-7 membered heterocycloalkyl group,

C ₂ -C ₆ -alkenyl group, which is optionally substituted with C ₁ -C ₄ -alkoxy group,

C ₃ -C 9 -cycloalkyl group, which is optionally substituted by hydroxy group,

a C5-C9 cycloalkenyl group which is optionally substituted with a hydroxy group,

3-9 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O-, -S-, -S(O)-, S(O) ₂ and -NR ⁹ -, and the specified heterocycloalkyl group optionally additionally contains a bridging group selected from -O-, -NR ⁹ -, -CH2-, -CH2-CH2-, -O-CH2-, -CH2-O-, -NR9-CH2- and -CH2-NR ⁹ -;

and said heterocycloalkyl group is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom;

oxo (=O) groups;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

C ₁ -C ₃ haloalkyl group;

C _g C ₃ alkoxy groups;

C ₁ -C ₃ haloalkoxy groups;

C(O)NR5R ⁶ groups, and

NR5R ⁶ groups,

5-9 membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from oxo group (=O), C1-C ₃ -alkyl group, -C(O)R5R ⁶ group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C ₁ C ₃ alkyl group, a C 1 -C ₃ haloalkyl group, C 1 -C ₃ -alkoxy group, C _g C ₃ -haloalkoxy group and NR ⁵ R ⁶ group, mono - or bicyclic heteroaryl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, C 1 -C ₃ - an alkyl group, a cyano group, a C1- _C3 haloalkyl group, a C1- _C3 alkoxy group, a hydroxy group, and an ^NR5R6 group, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R group ⁸ ;

R ⁴ is selected from a hydrogen atom and a C1- _C3 alkyl group;

R5/ ^R6 is independently selected from a hydrogen atom, a C1- _C6 alkyl group, -C1 _{- C5} alkylene- _OC1 - _C5 alkyl group, _{-C1- C5} alkylene-S- _C1 -C ₅ -alkyl group, C ₃ -C ₆ -cycloalkyl group and C ₃ -C ₅ heterocycloalkyl group;

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C1- _C6 alkyl group which is optionally substituted with one, two, three or four substituents, and said substituent is independently selected from halogen atom, cyano group, hydroxy group, C(O)NR5R ⁶ group, NR5R ⁶ group,

C1-C ₃ -alkoxy groups,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted with one or two substituents, and these substituents are independently selected from C 1 -C ₃ -alkyl group, oxo (=O) group, hydroxy - 2 041614 group and C ₁ -C ₃ - a hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a CrQ alkyl group or an oxo (=O) group, a heteroaryl group which itself is optionally substituted with a C ₁ -C ₃ 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 ₁ -C ₅ -alkylene-NR ⁵ -C ₁ -C ₅ -alkyl group,

C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C ₁ -C ₃ alkyl group and a hydroxy group,

R ⁹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

The compounds are suitable for the treatment of a patient suffering from cancer who is responsive to treatment with a phosphodiesterase 3A/B (PDE3A/B) modulator by detecting co-expression of mRNA, polynucleotides or polypeptides of PDE3A and/or PDE3B and Schlafen 12 (SLFN12) and/or SLFN12L and /or the absence of a decrease in the expression of CREB3L1 mRNA, polynucleotides or polypeptides in cancer cells obtained from such patients.

Definitions

Unless otherwise indicated, all technical and scientific terms used in the present invention have the meaning generally understood by a person skilled in the art to which the present invention pertains. The following references provide the person skilled in the art with a general definition of many of the terms used in the present invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings assigned to them below, unless otherwise indicated.

The presented structures include all possible rotations around bonds.

The term "substituted" means that one or more hydrogen atoms on the designated atom or group are replaced by a substituent selected from the specified group, provided that the normal valence of the designated atom under existing conditions is not exceeded. Combinations of substituents and/or variables are allowed.

The term optionally substituted means that the number of substituents may be equal to or other than zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as may be attached by replacing a hydrogen atom with a non-hydrogen atom at any available carbon or nitrogen atom. Typically, the number of optional substituents, if present, may be 1, 2, 3, in particular 1 or 2.

As used in the description of the present invention, the term one or more, for example, in the definition of substituents of compounds of general formula (I) according to the present invention, means 1, 2, 3, 4 or 5, especially 1, 2, 3 or 4, more specifically 1 , 2 or 3, even more specifically 1 or 2.

As used herein, an oxo substituent is an oxygen atom that is bonded to a carbon atom or a sulfur atom via a double bond.

The term ring substituent means a substituent attached to an aromatic or non-aromatic ring that replaces an available atom of an atom in the ring.

If a complex substituent consists of more than one part, for example, (C ₁ -C ₄ -alkyl)-O-(C ₁ -C ₄ alkyl)-, a hyphen at the beginning or end of such a complex substituent indicates the point of attachment of the specified complex substituent to the rest of the molecule. If a compound substituent is substituted, said substituent may be bonded to any suitable carbon atom of the compound substituent.

If a ring containing carbon atoms and optionally one or more heteroatoms such as a nitrogen atom, an oxygen atom or a sulfur atom, for example, is substituted with a substituent, optionally said substituent may be bonded at any suitable position of said ring, to a suitable carbon atom and/or suitable heteroatom.

The term containing when used in the description of the present invention includes consisting of.

If in the description of the present invention any feature is accompanied as indicated in the description of the present invention, this means that it can be mentioned anywhere in the description of the present invention.

The terms used in the description of the present invention have the following meanings.

The term halogen atom means a fluorine, chlorine, bromine or iodine atom, in particular a fluorine, chlorine or bromine atom.

The term C ₁ -C ₆ -alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, for example, 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, 3methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3dimethylbutyl groups, or an isomer thereof . In particular, said group has 1, 2, 3 or 4 carbon atoms (C 1 -C ₄ -alkyl), for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl group, more specifically 1, 2 or 3 carbon atoms (C1-G3 alkyl), for example a methyl, ethyl, n-propyl or isopropyl group.

The term alkylene is derived from the term alkyl, being a bivalent moiety, named by adding ene to the term alkyl, e.g., methyl becomes methylene, meaning a -CH ₂ moiety, whereby the open bonds of the branched components are located at the respective ends of the longest chain.

The term C ₁ -C ₆ -haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group, in which the term C ₁ -C ₆ -alkyl has the meaning as defined above, and in which one or more hydrogen atoms are substituted, independently or differently, a halogen atom. In particular, said halogen atom is a fluorine atom. Said C ₁ -C ₆ haloalkyl group is, 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 specifically trifluoromethyl or trifluoromethyl.

The term C ₁ -C ₆ -alkoxy means a linear or branched, saturated, monovalent group of the formula (C 1 -C ₆ -alkyl)-O-, in which the term C ₁ -C ₆ -alkyl has the meaning as defined above, for example, methoxy , ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof.

The term C ₁ -C ₆ -haloalkoxy means a linear or branched, saturated, monovalent C ₁ -C ₆ -alkoxy group, as defined above, in which one or more hydrogen atoms are replaced, independently or differently, by a halogen atom. In particular, said halogen atom is a fluorine atom. Said C ₁ -C ₆ haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.

The term C ₂ -C ₆ -alkenyl means a linear or branched, monovalent hydrocarbon group which contains one or two double bonds and which has 2, 3, 4, 5 or 6 carbon atoms, in particular 2 or 4 carbon atoms (C ₂ -C ₄ -alkenyl), it is clear that in the case in which the specified alkenyl group contains more than one double bond, then it is possible that each double bond is separated from one another or conjugated with each other. Said alkenyl group is, for example, ethynyl (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 (or isopropenyl), 2-methylprop-2-enyl, 1-methylprop2-enyl, 2-methylprop-1-enyl, 1-methylprop-1- enyl, 3-methylbut-3-enyl, 2-methylbut-3enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, 2-methylbut-2-enyl, 1-methylbut-2enyl, 3-methylbut- 1-enyl, 2-methylbut-1-enyl, 1-methylbut-1-enyl, 1,1-dimethylprop2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4enyl, 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-2enyl, 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-3enyl, 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, 1isopropylprop-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 group. In particular, said group is a vinyl or allyl, propenyl, isopropenyl, butenyl, or isobutenyl group.

The term C ₂ -C ₆ alkynyl means a linear or branched, monovalent hydrocarbon group which contains one triple bond and which contains 2, 3, 4, 5 or 6 carbon atoms, in particular 2 or 3 carbon atoms (C ₂ -C ₃ -alkynyl). Said C ₂ -C ₆ 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-5ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2

- 4 041614 inyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl , 1-methylpent-3-ynyl, 4-methylpent2-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-isopropylprop2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut -2-ynyl or 3,3-dimethylbut-1-ynyl group. In particular, said alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

The term C ₃ -C ₉ cycloalkyl means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms. Said C ₃ -C ₈ -cycloalkyl group is, for example, a monocyclic hydrocarbon ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, it also includes conjugated, bridged and spiro-cycloalkyl ring systems, such as for example , bicyclic hydrocarbon ring, for example, bicyclo[4.2.0]octal, bicyclo[2.2.1]heptyl or octahydropentalenyl, as well as spirocycloalkyl systems, as defined below.

The term spirocycloalkyl means a saturated, monovalent bicyclic hydrocarbon group in which the two rings share one common ring carbon atom and where said bicyclic hydrocarbon group contains 5, 6, 7, 8 or 9 carbon atoms, optionally said spirocycloalkyl group is attached to the remainder of the molecule via any one of the carbon atoms, with the exception of the spiro carbon atom. Said spirocycloalkyl group is, 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.

The term C ₅ -C ₆ -cycloalkenyl means the resulting cyclopentenyl group, cyclohexenyl group, cyclopentadienyl group, cyclohexadienyl group.

The term C ₄ -C ₉ -cycloalkenyl means a monovalent, mono - or bicyclic hydrocarbon ring, which contains 4, 5, 6, 7, 8 or 9 carbon atoms and one double bond. In particular, said ring contains 4, 5 or 6 carbon atoms (C ₄ -C ₆ -cycloalkenyl). Said C ₄ -C ₈ 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 bicyclo[2.2.1]hept2 -enyl or bicyclo[2.2.2]oct2-enyl, bicyclo[3.1.0]hex-2-enyl.

The terms 3-9 membered heterocycloalkyl and 3-6 membered heterocycloalkyl mean a saturated heterocycle with 3, 4, 5, 6, 7, 8 or 9 ring atoms in total, respectively 3, 4, 5 or 6 ring atoms in total, which contains one or two identical or different heteroatoms in the ring, selected from the series N, O and S, and these heterocycloalkyl groups are attached to the rest of the molecule through any of the carbon atoms or heteroatoms. It also includes bicyclic ring systems that are either fused, bridged, or spiro systems, as defined below. It also includes compounds of formula (I) having a potential group NR7R ⁸ where the N-atom belongs to the ring formed by the compound R ⁷ and R ⁸ forming a non-aromatic ring, including the N-atom to which they are associated. The term heterocycloalkane as used herein refers to a compound consisting of a heterocycloalkyl group as defined herein and a hydrogen atom to which said heterocycloalkyl group is bonded by its one valence.

Said heterocycloalkyl group may, without limitation, be a 3- or 4-membered ring such as azacyclopropyl, oxacyclopropyl, azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3thiazolidinyl, for example; or a 6-membered ring such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazinanyl, or a conjugated system such as azabicyclo[3.1. 0]hexan-3-yl, for example.

In particular, 4-6 membered heterocycloalkyl means 4-6 membered heterocycloalkyl as defined above, containing one ring nitrogen atom or an oxygen atom or a sulfur atom, and if it contains a nitrogen atom, it may additionally contain another ring heteroatom from the series : N, O, S. More specifically, 5- or 6-membered heterocycloalkyl means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing one nitrogen atom in the ring and, optionally, one more heteroatom in the ring from the series: N, O. Said heterocycloalkyl group is attached to the rest of the molecule through any carbon atom or, where applicable, through any nitrogen atom. They can both include bicyclic ring systems as discussed above.

The term partially unsaturated 3-9 membered heterocycloalkyl means a monocyclic unsaturated non-aromatic heterocycle with 5, 6, 7, 8 or 9 ring atoms, which contains one or two double bonds and one or two identical or different ring heteroatoms from the series: N, O, S;

- 5 041614 it is possible that these partially unsaturated heterocycloalkyl groups are attached to the rest of the molecule through any carbon atom or, if present, a nitrogen atom. The term partially unsaturated heterocycloalkane as used herein refers to a compound consisting of a partially unsaturated heterocycloalkyl group as defined herein and a hydrogen atom to which said partially unsaturated heterocycloalkyl group is bonded by its one valence.

Said partially unsaturated heterocycloalkyl group is, for example, 4H-pyranyl, 2H-pyranyl, 3,6-dihydro-2H-pyran-4-yl, 5,6-dihydro-2H-pyran-3-yl, tetrahydropyridinyl, for example, 1,2,3,6-tetrahydropyridin-4-yl, dihydropyridinyl, e.g. ,3]dioxolyl, 4H-[1,3,4]thiadiazinyl, 2,5dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5dihydrooxazolyl, or 4H-[1,4]thiazinyl .

The term conjugated heterocycloalkyl means a bicyclic saturated heterocycle with 6, 7, 8 or 9 ring atoms in total or respectively 5, 6 or 7 ring atoms in total, in which the two rings share two adjacent ring atoms, where the fused heterocycloalkyl contains one or two of the same or different ring heteroatoms from the series: N, O, S; said fused heterocycloalkyl group may be attached to the rest of the molecule through any of the carbon atom or, if present, the nitrogen atom.

Said fused heterocycloalkyl group is, for example, 3azabicyclo[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.

The term "bridged heterocycloalkyl" means a bicyclic saturated heterocycle with 7, 8 or 9 ring atoms in total, or respectively 7 ring atoms in total, in which the two rings share two common ring atoms that are not adjacent, where the bridged heterocycloalkyl contains one or two identical or different a heteroatom in the ring from the series: N, O, S; said bridged heterocycloalkyl group may be attached to the rest of the molecule through any of the carbon atoms or, if present, a nitrogen atom. Said 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.

The term heterospirocycloalkyl means a bicyclic saturated heterocycle with 6, 7, 8 or 9 ring atoms in total, in which two rings share one common ring carbon atom, wherein the heterospirocycloalkyl contains one or two identical or different ring heteroatoms from the series: N, O, S; said heterospirocycloalkyl group may be attached to the rest of the molecule through any carbon atom other than the spiro carbon atom or, if present, a nitrogen atom. Said heterospirocycloalkyl group is, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxaazaspiro[ ^3.3 ]heptyl, thiaazaspiro[3.3]heptyl, [3.3]heptyl, oxaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, diazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, or one of the other homologous backbones 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]-.

The term aryl refers to a monocyclic, bicyclic (2 conjugated rings), tricyclic (3 conjugated rings), or pyrocyclic (two or more conjugated 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 (eg, 1-naphthyl, 2-naphthyl, etc.).

The term heteroaryl means a monovalent, monocyclic or bicyclic aromatic ring having 5, 6, 8, 9 or 10 ring atoms (5-10 membered heteroaryl group), in particular 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three additional ring heteroatoms from the series: N, O and/or S, and which is connected via a ring carbon atom or heteroatom to the rest of the molecule. The term heteroarene as used herein refers to a compound consisting of a heteroaryl group as defined herein and a hydrogen atom to which said heteroaryl group is bonded by its one valency.

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

In general, and unless otherwise indicated, heteroaryl or heteroarylene groups include all their possible isomeric forms, for example: tautomers and positional isomers relative to the point of connection with the rest 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.

In particular, the heteroaryl group is a 2H-pyrrol-1-yl group, 1H-pyrrazol4-yl group, 1H-pyrrazol-5-yl group which is optionally substituted with one or two methyl groups, 1,2-thiazol-4-yl group , 1,3-thiazol-5-yl group, pyridin-3-yl, pyridin-4-yl and pyridin-5-yl group, each group optionally substituted with one or two substituents and each substituent independently selected from a halogen atom, methyl group, trifluoromethyl group, methoxy group and NH ₂ group, 1H-indol-6-yl group, 1H-indazol-6yl group, and 1H-benzimidazol-6-yl group, each group optionally substituted with one or two substituents, and each the substituent is independently selected from a halogen atom, a methyl group, a trifluoromethyl group, a methoxy group, and an NH ₂ group.

In particular, a heteroaryl group is:

a 2H-pyrrol-1-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a hydrogen atom, a cyano group, and a methyl group,

1H-pyrrazol-4-yl group which is optionally substituted with one or two methyl groups,

1H-pyrrazol-5-yl group which is optionally substituted with one or two methyl groups,

a 1,2-thiazol-4-yl group which is optionally substituted with one or two methyl groups,

1,3-thiazol-5-yl group which is optionally substituted with one or two methyl groups, pyridin-3-yl and pyridin-5-yl group, each group is optionally substituted with one or two substituents and each substituent is independently selected from atom halogen, methyl group, trifluoromethyl group, methoxy group and NH ₂ group,

1H-indol-6-yl group, 1H-indazol-6-yl group, and 1H-benzimidazol-6-yl group.

More specifically, the heteroaryl group is a pyridinyl group which is optionally substituted with an amino group, or a pyrazolyl group which is optionally substituted with a difluoromethyl group or a trifluoromethyl group.

Even more specifically, a heteroaryl group is

a 4-pyridinyl group which is substituted with an amino group, or

1H-pyrazol-4-yl yl 1H-pyrazol-1-yl group which is optionally substituted with a difluoromethyl group or a trifluoromethyl group.

The term C ₁ -C ₆ as used in this text, for example, in the context of the definition of C ₁ -C ₆ alkyl, C 1 -C ₆ -haloalkyl, C ₁ -C ₆ -alkoxy or C ₁ -C ₆ -haloalkoxy means 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.

In addition, as used herein, the term C ₃ -C ₈ as used in this text, for example, in the context of the definition of C ₃ -C ₈ -cycloalkyl, means a cycloalkyl group having a finite number of carbon atoms from 3 to 8, t .e. 3, 4, 5, 6, 7 or 8 carbon atoms.

When a range of values is specified, the specified range provides each value and subrange within the specified range.

For example

Ci-Sat covers Ci, C ₂ , Cs, C ₄ , C5, Ce, Ci-Sat, C1-C5, Ci-C ₄ , C1-C3, Ci-C ₂ , C ₂ -Sat,

C ₂ -Cs, C ₂ -C ₄ , C ₂ -Cs, Cs-Cb, C3-C5, Cs-C ₄ , C ₄ -Cb, C ₄ -Cs, and Cs-Ce;

C ₂ -C ₆ covers C ₂ , C ₃ , C ₄ , C ₅ , C _{6 , C 2 -C 6 , C 2} -C ₅ , C ₂ -C ₄ , C ₂ -C ₃ , C ₃ -C ₆ , C ₃ -C ₅ ,

CsC ₄ , C ₄ -C ₆ , C ₄ -Cs, and C ₅ -C ₆ ;

- 7 041614

Cz-Su covers Cs, C ₄ , C5, Sat, C ₇ , C ₈ , C9, Xu, C3-C10, C3-C9, Cs-C ₈ , C3-C7,

Cs-Sb, C3-C5, C3-C4, C ₄ -Cu, C4-C9, C ₄ -C ₈ , C4-C7, C4-C6, C4-C5, C5-C10, C5-C9, Cs-Cs ,

C ₅ -C ₇ , C ₅ -C ₆ , C ₆ -Su, C ₆ -C ₉ , C ₆ -C ₈ , C ₆ -C ₇ , C ₇ -C ₁₀ , C ₇ -C ₉ , C ₇ - C ₈ , C ₈ -C ₁₀ , C ₈ -C ₉ and

C ₉ - Xu;

C ₃ -C ₈ covers C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C 3 -C 8 , C ₃ -C ₇ , C ₃ -C ₆ , C _{3 -C 5 ,} C ₃ -С ₄ , С ₄ -С ₈ ,

C ₄ -C ₇ , C ₄ -C ₆ , C ₄ -C ₅ , C ₅ -C ₈ , C 5 -C ₇ , C _{5 -C 6} , Sat-C ₈ , C ₆ -C ₇ and C ₇ - From ₈ ;

Sz-Sb covers C3, C ₄ , C5, Sb, Sz-Sb, C3-C5, Sz-C ₄ , C ₄ -Sb, C ₄ -Cj, and Cj-Sb;

C ₄ -C ₈ covers C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₄ -C 8 , C 4 -C ₇ , C ₄ -C ₆ , C _{4 -C 5} , C _{5 -C 8} , C ₅ -C ₇ ,

C ₃ -Sb, C ₆ -C ₈ , C ₆ -C ₇ and C ₇ -C ₈ ;

C ₄ -C ₇ covers C ₄ , C ₅ , C ₆ , C ₇ , C 4 -C 7 , C ₄ -C ₆ , C ₄ -C ₅ , C ₅ -C ₇ , C _{5 -C 6} and _{C 6} -C ₇ ;

C ₄ -C ₆ covers C ₄ , C ₅ , C ₆ , C ₄ -C ₆ , C ₄ -C ₅ and C ₅ -C ₆ ;

C ₅ -Su covers C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₅ -C ₁₀ , C 5 -C ₉ , C ₅ -C ₈ , C _{5 -C 7} , C ₅ - C ₆ , C ₆ Xu, Sb-S ₉ , Sb-S 8, Sb-S ₇ , C ₇ -Su, C ₇ -C ₉ , C ₇ -Cs, Cs _- Su, C ₈ -C ₉ and C ₉ -Su;

Sb-Su covers C ₆ , C ₇ , C ₈ , C ₉ , C, C _{6 -C, C 6} -C ₉ , C _{6 -C 8} , C ₆ -C ₇ , C ₇ -C, C ₇ -C ₉ ,

C ₇ -C ₈ , C ₈ -C ₁₀ , C ₈ -C ₉ and C ₉ -Su

Unless otherwise specifically indicated or obvious from the context, as used herein, the term about is understood to be within the range of normal tolerances in the art, such as within 2 standard deviations of the mean. About can be understood as within 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.05 or 0.01% of the declared value. Unless otherwise clear from the context, all numerical values given here are modified by the term about.

The term agent refers to any small chemical compound, antibody, nucleic acid molecule or polypeptide, or fragments thereof.

By the term alleviate is meant the reduction, suppression, attenuation, reduction, cessation or stabilization of the development or progression of a disease.

By the term analogue is meant a molecule that is not identical, but has similar functional or structural features. For example, a polypeptide analog retains the biological activity of the corresponding naturally occurring polypeptide while having certain biochemical modifications that enhance the function of the analog relative to the naturally occurring polypeptide. Such biochemical modifications can increase the protease stability of the analog, the membrane permeability of the analog, or the half-life of the analog without altering, for example, ligand binding. The analog may include a non-natural amino acid.

In the present disclosure, the term contains, containing, including and having, and the like. may have the meaning assigned under US patent law and may mean includes, including, etc.; essentially consisting of or essentially consisting of similarly have the meaning ascribed under US patent law, and this term is open-ended and allows the presence of more than what is specified, provided that the essential or new characteristics of what is specified is not changed if more than that is indicated, but excludes prior art embodiments.

The term detection refers to the identification of the presence, absence, or amount of what is to be detected. In specific embodiments, the analyte is a PDE3A or SLFN12 polypeptide.

The term disease refers to any condition or disease that disrupts or interferes with the normal function of a cell, tissue, or organ. Examples of diseases include hyperproliferative disorder, types of cancer such as, for example, adenocarcinoma, breast cancer, cervical cancer, liver cancer, lung cancer, and melanoma.

By effective amount is meant the amount of a compound described herein required to relieve the symptoms of a disease compared to an untreated patient. The effective amount of active compound(s) used in the practice of the present invention for the therapeutic treatment of a disease varies with the route of administration, age, body weight and general health of the subject. Ultimately, the treating physician or veterinarian will determine the appropriate amount and dosage regimen. This amount is called the effective amount. In other embodiments, the PDE3A modulator is a compound of formula (I).

As used herein, the term leaving group means an atom or group of atoms that are replaced in a chemical reaction as stable species that carry away bonding electrons with them. In particular, such a leaving group is selected from the group consisting of: halide, in particular 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.

By modulator is meant any agent that binds to a polypeptide and alters the biological function or activity of the polypeptide. A modulator includes, without limitation, agents that reduce or eliminate the biological function or activity of a polypeptide (eg, an inhibitor). For example, a modulator may inhibit the catalytic activity of a polypeptide. A modulator includes, without limitation, agents that increase or decrease the binding of a polypeptide to another agent. For example, a modulator may facilitate the binding of a polypeptide to another polypeptide.

Unless otherwise specifically indicated or evident from the context, as used herein, the term or is understood to be inclusive. Unless otherwise specifically indicated or evident from the context, the singular form as used herein is understood to include the singular or plural.

When the plural form of a compound, salt, polymorph, hydrate, solvate, and the like is used in the description of the present invention, it also means a single compound, salt, polymorph, isomer, hydrate, solvate, or the like.

By a stable compound or structure is meant a compound that is sufficiently stable to be isolated in useful purity from a reaction mixture and converted into an effective therapeutic agent.

The term prodrugs or prodrug refers to compounds that may or may not be biologically active or inactive in themselves, but are converted (eg, metabolically or hydrolytically) to the compounds of the present invention during their residence time in the body. Derivatives of Compound 6 and its salts that are converted to Compound 6 or its salts in a biological system (bioprecursors or prodrugs) are encompassed by the present invention. Said biological system may be, for example, a mammalian organism, in particular a human. The bioprecursor, for example, is converted to a compound of formula (I) or a salt thereof by metabolic processes.

The term pharmaceutically acceptable salt(s) of compounds of formula (I) includes derivatives of pharmaceutically acceptable inorganic and organic acids and bases. For example, see S. M. Berge, et al. Pharmaceutical Salts, J. Pharm. sci. 1977, 66, 1-19.

As used herein, the term pharmaceutically acceptable salt refers to a salt formed by adding a pharmaceutically acceptable acid or base to a compound disclosed herein.

As used herein, the phrase pharmaceutically acceptable refers to a substance that is toxicologically acceptable for pharmaceutical use and does not interact adversely with the active ingredient.

Unless specifically stated or obvious from the context, as used herein, when a range is specified, the inclusion of an upper and lower limit is always implied. The ranges presented herein are understood to be intended for all values in the range. For example, the range from 1 to 50 is considered 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.

By control is meant a standard or control condition.

Reference to a list of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of the listed groups. The indication of an embodiment for a variable or object herein includes that embodiment as any single embodiment or in combination with any other embodiments or parts thereof.

- 9 041614

Detailed description

As a first aspect, the present invention provides compounds of formula (I)

Formula (I) wherein R ¹ is selected from a hydrogen atom, a halogen atom, a cyano group, a C1-C ₃ alkyl group, a C1C ₃ haloalkyl group, a C ₁ -C ₃ haloalkoxy group;

R ² is selected from a hydrogen atom and a halogen atom;

R ³ is selected from

a C1- _C6 alkyl group which is optionally substituted with one or two substituents, and each substituent is independently selected from hydroxy, _C1 - _C4 alkoxy, and a 3-7 membered heterocycloalkyl group,

C ₂ -C ₆ -alkenyl group, which is optionally substituted by C1-C ₄ -alkoxy group,

C ₃ -C ₉ -cycloalkyl group, which is optionally substituted by hydroxy group,

C ₅ -C ₉ -cycloalkenyl group, which is optionally substituted by hydroxy group,

3-9 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O-, -S-, -S(O)-, S(O) ₂ and -NR ⁹ -, and the specified heterocycloalkyl group optionally additionally contains a bridging group selected from -O-, -NR ⁹ -, -CH ₂ -, -CH2-CH2-, -O-CH2-, -CH2-O-, -NR ⁹ -CH2- and -CH2- NR ⁹ -;

and said heterocycloalkyl group is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom;

oxo (=O) groups;

cyano groups;

hydroxy groups;

a C1- _C3 alkyl group which is optionally further substituted with hydroxy;

C1- _C3 haloalkyl group;

C1-C3 alkoxy groups;

C1- _C3 haloalkoxy groups;

C(O)NR ⁵ R ⁶ groups and

NR5R ⁶ groups,

5-9 membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from oxo (=0), C1- _C3 alkyl, -C(O) ^R5 R ⁶ group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C ₁ C ₃ alkyl group, a C 1 -C ₃ haloalkyl group , C1- _C3 alkoxy groups, C1- _C3 haloalkoxy groups and NR ⁵ R ⁶ groups, a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, C1-C ₃ alkyl group, cyano group, C1-C ₃ haloalkyl group, C1-C ₃ alkoxy group, hydroxy group and NR5R ⁶ group, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R group ⁸ ;

R ⁴ is selected from a hydrogen atom and a C1- _C3 alkyl group;

R5/ ^R6 is independently selected from a hydrogen atom, a C1- _C6 alkyl group, -C1 _{- C5} alkylene- _OC1 - _C5 alkyl group, _{-C1- C5} alkylene-S- _C1 -C ₅ -alkyl group, C ₃ -C ₆ -cycloalkyl group, and C ₃ -C ₅ heterocycloalkyl group;

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

a C1- _C6 alkyl group which is optionally substituted with one, two, three or four substituents, and said substituent is independently selected from halogen atom, cyano group, hydroxy group, C(O)NR ⁵ R ⁶ group, NR5R ⁶ group,

C1-C ₃ -alkoxy groups,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted with one or two substituents, and these substituents are independently selected from C1-C ₃ -alkyl group, oxo (=0) group, hydroxy group and C1-C ₃ -hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a C1- _C3 alkyl group or an oxo (=0) group,

- 10 041614 a heteroaryl group which itself is optionally substituted with a _{C 1} -C ₃ alkyl group;

-С ₁ -С ₅ -alkylene-О-С । -C ₅ -alkyl group,

-C ₁ -C ₅ -alkylene-SC 1 -C ₅ -alkyl group,

-C ₁ -C ₅ -alkylene-NR ⁵ -C ₁ -C ₅ -alkyl group,

C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C ₁ -C ₃ alkyl group and a hydroxy group,

R ⁹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

The invention is further based, at least in part, on the discovery that the compounds of formula (I) are modulators of the PDE3A- or PDE3B-SLFN12 complex.

Accordingly, in a further embodiment, the present invention further provides methods for selecting a subject suffering from cancer that responds to a PDE3A or PDE3B-SLFN12 complex modulator, especially a compound of formula (I), wherein the method of selection comprises detecting co-expression of PDE3A and/or PDE3B polypeptides or polynucleotides. and Schlafen 12 (SLFN12) in a cancer cell obtained from such subjects.

According to a further embodiment, the present invention provides methods for determining that expression of a CREB3L1 or SLFN12 polynucleotide or polypeptide is reduced or undetectable in a cancer cell that has become resistant to a PDE3A- and/or PDE3B-SLFN12 complex modulator, preventing ineffective treatment with a compound of formula (I ).

Accordingly, the present invention provides methods comprising the steps of identifying subjects with cancer that may respond to treatment with a PDE3A- and/or PDE3B-SLF12 complex modulator, especially treatment with a compound of formula (I), based on the expression level of PDE3A and/or PDE3B and SLFN12 in in a biological sample of a subject containing cancer cells, administering an effective amount of a compound of formula (I).

In specific embodiments, the present invention provides methods comprising the steps of identifying subjects that have a cancer that is resistant to treatment with a modulator of the PDE3A-and/or PDE3B-SLF12 complex, especially treatment with a compound of formula (I), based on loss or reduction in PDE3A expression level. and/or PDE3B and SLFN12 relative to the control, and then exclude them from the intended course of treatment with the compound of formula (I).

Forms and salts of compounds

The compounds of formula (I) may exist in free form, for example as a free base or as a free acid, or as a zwitterion, or may exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt that is routinely used in the pharmaceutical industry, or that is used, for example, to isolate or purify the compounds of the present invention.

For example, a salt can be formed between an anion and a positively charged substituent (eg, amino) in a compound described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate and acetate. Similarly, a salt can also form between a cation and a negatively charged substituent (eg, a carboxylate) in a compound described herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion and ammonium cation such as tetramethylammonium ion. Examples of prodrugs include C ₁ _ ₆ alkyl esters of carboxylic acid groups which, when administered to a subject, are capable of producing active compounds.

A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid addition salt of a compound of the present invention bearing a nitrogen atom in the chain or ring, for example, which is sufficiently basic, such as an acid addition salt with an inorganic acid or a mineral acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric or nitric acid, for example, or with an organic acid such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamon, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, 3-fenapropionic, pivalic, 2-hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic, dodecylsulfonic, ethanesulfonic, benzo lsulfonic, para-toluenesulfonic, methanesulfonic, 2-naphthalenesulfonic, naphthalenedisulfonic, camphorsulfonic, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, almond, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic or thiocyanic acid, for example.

Additional examples of suitable acid salts include acetate, adipinate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glucolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids such as oxalic acid, although not pharmaceutically acceptable per se, may be used in the preparation of salts useful as intermediates in the preparation of the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

Furthermore, another suitable pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic is an alkali metal salt such as a sodium or potassium salt, an alkaline earth metal salt such as calcium, magnesium or strontium, or an aluminum or zinc salt, or an ammonium salt, derivative from ammonia or from an organic primary, secondary or tertiary amine having from 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine , dibenzylamine, N-methylmorpholine, arginine, lysine, 1,2-ethylenediamine, N-methylpiperidine, N-methylglucamine, N,N-dimethyl-glucamine, N-ethyl-glucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol , 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt with a quaternary ammonium ion having from 1 to 20 carbon atoms kind, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium.

In some embodiments, salts derived from suitable bases include alkali metal (eg sodium), alkaline earth metal (eg magnesium), ammonium and N-(alkyl) ₄ ⁺ salts. The present invention also contemplates the quaternization of any of the basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products can be obtained by such quaternization. Salt forms of the compounds of any of the formulas herein may be salts of amino acids and carboxyl groups (eg, salts of L-arginine, -lysine, -histidine).

A list of suitable salts is found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; Journal of Pharmaceutical Science, 66, 2 (1977); and Pharmaceutical Salts: Properties, Selection, and Use A Handbook; Wermuth, C. G. and Stahl, P. H. (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN 3-906390-26-8], each of which is incorporated herein in its entirety by reference.

Those skilled in the art will also appreciate that acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid using any of a number of known methods. Alternatively, the alkali and alkaline earth metal salts of the acidic compounds of the present invention are prepared by reacting the compounds of the present invention with an appropriate base by a variety of known methods.

The present invention includes all possible salts of the compounds of the present invention as individual salts, or as any mixture of said salts, in any ratio.

The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the usual manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to the parent form of the compound for purposes of the present invention.

In the description of the present invention, in particular in the Experimental part, for the synthesis of intermediates and examples according to the present invention, when the compound is mentioned in the form of a salt with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the corresponding preparation method and/ or cleaning, in most cases is unknown.

Unless otherwise indicated, suffixes in chemical names or structural formulas referring to salts, such as hydrochloride, trifluoroacetate, sodium salt, or x HCl, x CF3COOH, x Na ⁺ , for example, mean the salt form, where the stoichiometry of the salt form is not specified.

This applies similarly to cases where intermediates or exemplary compounds or salts thereof have been obtained by the described preparation and/or purification processes, in the form of solvates, such as hydrates, with (if determined) an unknown stoichiometric composition.

In addition to salt forms, the present invention provides compounds that are in prodrug form. Prodrugs of the compounds described herein are those compounds that undergo chemical changes under physiological conditions to give the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical means under ex vivo conditions. For example, prodrugs can be slowly converted to compounds of the present invention when placed in a transdermal patch with a suitable enzyme or chemical. Prodrugs are often useful because they are easier to administer than the parent drug in some situations. They may, for example, be more orally bioavailable than the parent drug. The prodrug may also have improved solubility in pharmacological compositions compared to the parent drug. A large number of prodrug derivatives are known in the art, such as those based on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (prodrug) but is then metabolically hydrolyzed to a carboxylic acid, the active substance. Additional examples include peptidyl derivatives of the compounds of the present invention.

The compounds of the present invention may exist as a hydrate or as a solvate, where the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol, for example, as a structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, for example, hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates, respectively, are possible. The present invention includes all such solvates or hydrates.

The present invention also includes various hydrate and solvate forms of the compounds.

The compounds of the present invention may also contain non-naturally occurring proportions of atomic isotopes at one or more of the atoms constituting such compounds. For example, compounds can be radioactively labeled with radioactive isotopes such as, for example, tritium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). All isotopic variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention. In particular, deuterium-containing compounds of formula (I).

Formula (1a)

Formula (Ia) shows the positions D ¹ , D ² , D ³ and D ⁴ in which any of the hydrogen atoms can be replaced by a deuterium atom. In addition, in residues R1-R ⁴ , if these residues contain a heteroatom-H or carbon-H bond available for a chemical reaction, such an exchange may be possible. Hydrogen atoms can be replaced by deuterium atoms using methods known to those skilled in the art to form a heteroatom-D or carbon-D bond. Any of R ¹ , R ² , or R ⁴ itself can be deuterium instead of hydrogen.

Thus, one aspect of the invention are those compounds in which, independently, any of R ¹ , R ² , or R ⁴ is deuterium and/or any of the hydrogen atoms as shown in formula (I) is replaced by a deuterium atom, and/or any of R ¹ , R ² , R ³ , or R ⁴ carries a deuterium atom in a chemically accessible position, or any combination of positions simultaneously deuterated.

The term isotopic variant of a compound or reagent is defined as a compound that exhibits a non-naturally occurring proportion of one or more of the isotopes that make up that compound. The term isotopic variant of a compound of general formula (I) is defined as a compound of general formula (I) exhibiting a non-naturally occurring proportion of one or more isotopes that constitute such a compound. The expression non-naturally occurring proportion means the proportion of such an isotope, which is higher than its content in nature. Natural abundances of isotopes applicable in this context are described in Isotopic Compositions of the Elements 1997, Pure Appl. Chem., 70(1), 217-235, 1998. Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br , ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I, and ¹³¹ I, respectively.

With respect to the treatment and/or prevention of the disorders indicated in the present invention, the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium (deuterium-containing compounds of general formula (I)). Isotopic variants of compounds of general formula (I) in which one or more radioactive isotopes, such as ³ H or ¹⁴ C, are included are useful for

- 13 041614 example, in studies of the distribution of the drug and/or substrate in tissues. These isotopes are particularly preferred because of their ease of incorporation and detection. Positron active isotopes such as ¹⁸ F or ^P C may be included in the compound of general formula (I). These isotopic variants of the compound of general formula (I) are useful for in vivo imaging applications. Deuterium-containing and ¹³ C-containing compounds of general formula (I) can be used in mass spectrometry analyzes in the context of preclinical or clinical studies.

Isotopic variants of the compounds of general formula (I) can usually be obtained by methods known to the person skilled in the art, such as those described in the schemes and/or examples in the description of the present invention, by replacing the reagent with an isotopic variant of the specified reagent, preferably a deuterium-containing reagent. Depending on the desired deuteration sites, in some cases the deuterium from D2O can be incorporated either directly into compounds or into reagents that are useful in the synthesis of such compounds. Deuterium in the form of a gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and acetyl bonds is a fast way to incorporate deuterium. Metal-based catalysts (ie, Pd, Pt, and Rh) in the presence of gas deuterium can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons. Various deuterated reagents and synthetic building blocks are commercially available from companies such as, for example, C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.

The term deuterium-containing compound of general formula (I) is defined as a compound of general formula (I), in which one or more hydrogen atoms are replaced by one or more deuterium atoms, and in which the content of deuterium in such a deuterated position of the compound of general formula (I) is higher, than the content of deuterium in nature, which is about 0.015%. In particular, in the deuterium-containing compound of general formula (I), the deuterium content in each deuterated position of the compound of general formula (I) is more than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably more than 90%, 95%, 96% or 97%, even more preferably more than 98% or 99% at the indicated position(s). It is understood that the deuterium content of each deuterium position is independent of the deuterium content of the other deuterium position(s).

The selective incorporation of one or more deuterium atoms into a compound of general formula (I) may change the physicochemical properties (such as, for example, acidity [C. L. Perrin, et al., J. Am. Chem. Soc, 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc, 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271]), and /or the metabolic profile of the molecule and may lead to changes in the ratio of the parent compound and metabolites or the amounts of metabolites formed. Such changes may result in certain therapeutic benefits and may therefore be preferred in some applications. Decreased metabolic rates and metabolic shutdown, in which the ratio of metabolites changes, have been described (A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes upon exposure to the parent drug and metabolites may have important implications for the pharmacodynamics, tolerability and efficacy of the deuterium-containing compound of general formula (I). In some cases, deuterium substitution reduces or eliminates the formation of an undesirable or toxic metabolite and enhances the formation of the desired metabolite (e.g., Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al. , Toxicol Appl Pharmacol 2000, 169, 102). In other cases, the main effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased. Potential clinical benefits would include the ability to maintain similar systemic exposure with reduced peak levels and increased trough levels. This may lead to reduced side effects and improved efficacy, depending on the particular pharmacokinetic/pharmacodynamic relationship of the particular compound. ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208) and Odanacatib (K. Kassahun et al., WO2012/112363) are examples of this deuterium effect. Other cases have also been reported in which reduced metabolic rates lead to increased drug exposure without altering the systemic clearance rate (eg, Rofecoxib: F. Schneider et al., Arzneim. Forsch./Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs exhibiting this effect may have reduced dosage requirements (eg, fewer doses or lower dose to achieve the desired effect) and/or may result in lower metabolic loads.

The compound of general formula (I) may have many potential sites of influence on metabolism. To optimize the above effects in terms of physicochemical properties and metabolic profile, deuterium-containing compounds of general formula (I) having a specific pattern of one or more deuterium-hydrogen exchange(s) can be selected. In particular, the deuterium atom(s) of the deuterium-containing compound(s) of general formula (I) are/are attached to a carbon atom and/or are/are located at those positions of the compound

- 14 041614 of the general formula (I), which are the sites of action.

In some aspects, the compounds of formula (I) may be isomers. Isomers are different compounds that have the same molecular formula. Stereoisomers are isomers that differ only in how the atoms are arranged in space. As used herein, the term isomer includes any geometric isomers and stereoisomers. For example, isomers include geometric cis and trans double bond isomers, also referred to as E and Z isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (l)isomers, their racemic mixture; and other mixtures thereof falling within the scope of this invention.

Symbol ²²²²² denotes a bond, which may be single or double, as described herein. Provided herein are various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or the arrangement of substituents around a carbocyclic ring. Substituents around the carbon-carbon double bond are designated as being in the Z or E configuration, where the terms Z and E are used in accordance with IUPAC standards. Unless otherwise indicated, structures showing double bonds encompass both the E and Z isomers.

Substituents around a carbon-carbon double bond may alternatively be referred to as cis or trans, where cis represents substituents on the same side of the double bond and trans represents substituents on opposite sides of the double bond. The arrangement of substituents around the carbocyclic ring can also be referred to as cis or trans. The term cis represents substituents on the same side of the ring plane, and the term trans represents substituents on opposite sides of the ring plane. Mixtures of compounds in which substituents are located both on the same and on opposite sides of the ring plane are designated as cis/trans.

The compounds of the present invention optionally contain one or more asymmetric centers, depending on the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms (R) or (S) are present in the configuration, which can lead to racemic mixtures in the case of a single asymmetric center, and diastereomeric mixtures in the case of multiple asymmetric centers. The term (±) is used to denote a racemic mixture when appropriate. In some cases, it is possible that asymmetry is also present due to limited rotation about a given bond, for example, a central bond adjacent to two substituted aromatic rings of these compounds. When a compound is an enantiomer, the stereochemistry of each chiral carbon may be indicated as either (R) or (S). Isolated compounds whose absolute configuration is unknown may be designated (+) or (-) depending on the direction (right or left hand) in which they rotate plane polarized light at sodium D-line wavelength. Some of the compounds described herein contain one or more asymmetric centers and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry at each asymmetric atom as (R)- or (S)-. It is intended that the chemical compounds of the present invention, pharmaceutical compositions and methods include all such possible isomers, including racemic mixtures, optically substantially pure forms, and mixtures of intermediates.

Preferred compounds are compounds that provide more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers, or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. Purification and separation of such materials can be performed by standard methods known in the art, including chiral high performance liquid chromatography (HPLC), formation and crystallization of chiral salts, or obtained through asymmetric syntheses.

Optical isomers can be obtained by separating racemic mixtures according to conventional methods, for example by forming diastereomeric salts using an optically active acid or base, or by forming covalent diastereomers. Examples of suitable acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers based on their physical and/or chemical differences by methods known in the art, for example by chromatography or fractional crystallization. Optically active bases or acids are then released from the separated diastereomeric salts. Various methods for separating optical isomers include the use of chiral chromatography (eg, HPLC columns using a chiral phase), with or without conventional derivatization, optionally chosen to maximize separation of enantiomers. Stable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, eg Chiracel OD and Chiracel OJ, for example, among many others, all of which are routinely available for selection. Enzymatic separations, with or without derivatization, also apply. Optically active compounds according to the present invention can likewise be prepared via chiral syntheses using optically active starting materials.

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

The present invention includes all possible stereoisomers of the compounds of the present invention, as single stereoisomers, or as any mixture of said stereoisomers, eg (R)- or (S)-isomers in any ratio. Preferred is the stereoisomer which shows the desired effect. For compounds of formula (I) where R ⁴ = methyl, it has been found that compounds having said methyl group in the S-configuration actually have a significantly better pharmacological effect.

Thus, as one aspect of the present invention for the configuration of the alkyl group in R ⁴ the invention preferably includes those compounds in which R ⁴ = C ₁ -C ₃ -alkyl, more specifically R ⁴ = methyl with S-configuration, as indicated in the formula (Ia)

Formula (1a)

Isolation of one stereoisomer, eg one enantiomer or one diastereomer, of a compound of the present invention is achieved by any suitable prior art method such as chromatography, especially chiral chromatography, for example.

In addition, the compounds of the present invention may exist as tautomers. For example, any compound of the present invention which contains an imidazopyridine moiety as a heteroaryl group, for example, may exist as a 1H-tautomer or 3H-tautomer, or even a mixture of any number of two tautomers, namely

1H tautomer 3H tautomer

The present invention includes all possible tautomers of the compounds of the present invention as single tautomers or as any mixture of said tautomers in any ratio.

In addition, the compounds of the present invention can potentially exist as N-oxides, which are defined by the fact that at least one nitrogen of the compounds of the present invention is oxidized. The present invention includes all such chemically possible N-oxides.

In addition, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as a single polymorph or as a mixture of more than one polymorph in any ratio.

In addition, the present invention also includes prodrugs of the compounds of the present invention. The term prodrugs, as used herein, refers to compounds that may themselves be biologically active or inactive, but are converted (eg, metabolically or hydrolytically) to the compounds of the present invention during their residence time in the body.

Thus, the present invention includes prodrugs of the compounds of formula (I).

In yet another embodiment, the present invention includes stereoisomers, tautomes, N-oxides, hydrates, solvates or salts or mixtures thereof of compounds of formula (I).

In another embodiment, the present invention includes stereoisomers, tautomes, hydrates, solvates or salts or a mixture thereof of compounds of formula (I).

In another embodiment, the present invention includes stereoisomers, tautomes, solvates or salts or a mixture thereof of compounds of formula (I).

In yet another embodiment, the present invention includes stereoisomers, tautomers, solvates or salts or a mixture thereof of compounds of formula (I).

In yet another embodiment, the present invention includes stereoisomers, tautomers or salts or a mixture thereof of the compounds of formula (I).

Other aspects and embodiments

According to an embodiment of the first aspect of the present invention, the present invention provides compounds of formula (I) wherein R ¹ is selected from a hydrogen atom, a halogen atom, a cyano group, a C ₁ -C ₃ -alkyl group, a C ₁ -C ₃ haloalkyl group, and a C ₁ - C ₃ haloalkoxy groups;

- 16 041614

R ² is selected from a hydrogen atom and a halogen atom;

R ³ is selected from

C ₁ -C ₆ -alkyl group, which is optionally substituted by a substituent, which is selected from hydroxy group, G-04-alkoxy group and 3-7-membered heterocycloalkyl group,

C ₂ -C ₆ -alkenyl group, which is optionally substituted with C ₁ -C ₄ -alkoxy group, C ₃ -C ₇ -cycloalkyl group, which is optionally substituted with hydroxy group, C ₅ -C ₇ -cycloalkenyl group, which is optionally substituted with hydroxy group, 3- A 7-membered heterocycloalkyl group containing one or two heteroatoms that are independently selected from -O-, S(O) ₂ and -NR ⁹ - and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom ;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

0 ₁ -0 ₃ -alkoxy groups;

C(O)NR ⁵ R ⁶ groups and

NR5R ⁶ groups;

A 5-7 membered heterocycloalkyl group containing a heteroatom selected from -O-, -S- and NR ⁹ - which is partially unsaturated and optionally substituted with a substituent selected from a C ₁ -C ₃ -alkyl group, -C( O)R ⁵ R ⁶ group and a halogen atom, an aryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, hydroxy group, cyano group, C ₁ -C ₃ -alkyl group, C ₁ -C ₃ haloalkyl group, C ₁ -C ₃ alkoxy group and NR5R ⁶ group, mono- or bicyclic heteroaryl group which is optionally substituted with a substituent selected from a halogen atom, C ₁ -C ₃ -alkyl group, cyano group, C ₁ -C _{a 3} haloalkyl group, a C ₁ -C ₃ alkoxy group and an NR5R ⁶ group, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R group ⁸ ;

R ⁴ is selected from a hydrogen atom and a C ₁ -C ₃ alkyl group;

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group;

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, C(O)NR ⁵ R ⁶ group, NR ⁵ R ⁶ group,

0 ₁ -0 ₃ -alkoxy groups,

C ₃ -C ₇ -cycloalkyl group, which is optionally further substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group, oxo (=O) group, hydroxy group and C ₁ -C ₃ -hydroxyalkyl group ;

a 3-7 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C ₁ -C ₃ alkyl group, a heteroaryl group which is optionally further substituted with C ₁ -C ₃ -alkyl group,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted by hydroxy group or 0 ₁ -0 ₃ alkyl group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C ₁ -C ₃ alkyl group and a hydroxy group,

R ⁹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to an embodiment of the first aspect of the present invention, the present invention provides compounds of formula (I) wherein R ¹ is selected from a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, and a C ₁ -C ₃ -haloalkoxy groups;

R ² is selected from a hydrogen atom and a halogen atom;

R ³ is selected from

C ₁ -C ₆ -alkyl group, which is optionally substituted by a substituent, which is selected from hydroxy group, C ₁ -C ₄ -alkoxy group and 3-7-membered heterocycloalkyl group,

C ₂ -C ₆ -alkenyl group, which is optionally substituted with C ₁ -C ₄ -alkoxy group, C ₃ -C ₇ -cycloalkyl group, which is optionally substituted with hydroxy group, C ₅ -C ₇ -cycloalkenyl group,

- 17 041614

a 3-7 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

cyano groups;

hydroxy groups;

a Ci-C3-alkyl group which is optionally further substituted with a hydroxy group;

C ₁ -C ₃ alkoxy groups; And

C(O)NR ⁵ R ⁶ groups,

a 5-7 membered heterocycloalkyl group containing a heteroatom selected from -O- and NR ⁹ - which is partially unsaturated and optionally substituted with a substituent selected from a C ₁ -C ₃ -alkyl group and a halogen atom, an aryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group and an NR5R ⁶ group, a mono- or bicyclic heteroaryl group which is optionally substituted with a substituent selected from a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a 0 ₁ -C ₃ alkoxy group, and an NR ⁵ R ⁶ group;

and NR ⁷ R ⁸ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

R ⁴ is selected from a hydrogen atom and a C1-C3 alkyl group; R5/ ^R6 is independently selected from a hydrogen atom and a C1- _C6 alkyl group;

R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, NR ⁵ R ⁶ group,

C ₁ -C ₃ -alkoxy group,

C ₃ -C ₇ -cycloalkyl group, which is optionally further substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group, oxo (=O) group, hydroxy group and C ₁ -C ₃ -hydroxyalkyl group ;

a 3-7 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C ₁ -C ₃ alkyl group, a heteroaryl group which is optionally further substituted with C ₁ -C ₃ -alkyl group,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted by hydroxy group or 01-03 alkyl group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C ₁ -C ₃ alkyl group and a hydroxy group,

R ⁹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to an embodiment of the first aspect of the present invention, the present invention provides compounds of formula (I) wherein R ¹ is selected from a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ -haloalkoxy groups;

R ² is selected from a hydrogen atom and a halogen atom;

R ³ is selected from

C ₁ -C ₆ -alkyl group, which is optionally substituted by a substituent, which is selected from hydroxy group, C ₁ -C ₄ -alkoxy group and 3-7-membered heterocycloalkyl group,

C ₂ -C ₆ -alkenyl group, which is optionally substituted with C ₁ -C ₄ -alkoxy group,

C ₄ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group,

C ₅ -C ₇ -cycloalkenyl group,

a 3-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

cyano groups;

hydroxy groups

C ₁ -C ₃ -alkyl group, which is optionally further substituted by hydroxy;

- 18 041614

a 5-6 membered heterocycloalkyl group containing a heteroatom which is selected from -O- and NR ⁹ - which is partially unsaturated and optionally substituted by a substituent which is selected from a C1- _C3 -alkyl group and a halogen atom, an aryl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C ₁ -C ₃ alkyl group, a Cl-C ₃ haloalkyl group and an NR5R ⁶ group, a mono- or bicyclic heteroaryl group which is optionally substituted a substituent selected from a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C 1 -C ₃ alkoxy group, and an NR5R ⁶ group;

and NR7R ⁸ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

R ⁴ is selected from a hydrogen atom and a C ₁ -C ₃ alkyl group;

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group;

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group, € ₁ - € ₃ -alkoxy group,

C ₃ -C ₆ -cycloalkyl group, which is optionally additionally substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group and C1-C ₃ hydroxyalkyl group;

a 4-6 membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C ₁ -C ₃ -alkyl group, a heteroaryl group which is optionally further substituted with C ₁ -C ₃ -alkyl group;

C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group or C ₁ -C ₃ alkyl group,

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C1- _C3 alkyl group and a hydroxy group, and

R ⁹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to an embodiment of the first aspect of the present invention, the present invention provides compounds of formula (I)

Formula (I) wherein 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 is selected from a halogen atom,

C ₂ -C ₆ -alkenyl group,

C ₃ -C ₆ -cycloalkyl group,

C ₅ -C ₆ -cycloalkenyl group,

C ₃ -C ₇ -heterocycloalkyl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom and a C1 -C ₃ -alkyl group, hydroxy group, NR5R ⁶ group, C1 -C ₃ -haloalkyl group and C1-C ₃ -haloalkoxy groups,

C ₅ -C ₇ -heterocycloalkyl group, which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from oxo group (=O), C1-C ₃ -alkyl group and halogen atom, aryl group, which is optionally substituted with one, two, _{three or four substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C1C3 alkyl group, a C1-C3 haloalkyl} group, a C1- _C3 alkoxy group, a C1- _C3 -haloalkoxy group and NR5R ⁶ group, mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from halogen atom, C1- _C3 alkyl group, cyano group, C1- _C3 haloalkyl group , C1-C ₃ -alkoxy groups, hydroxy groups and NR5R ⁶ groups;

- 19 041614 and NR7R ⁸ groups,

R ⁴ is selected from a hydrogen atom and a C 1 -C ₃ -alkyl group,

R5/R ⁶ is independently selected from hydrogen atom, C1-C ₆ alkyl group, -C ₁ -C ₅ alkylene-OC ₁ -C ₅ alkyl group, -C ₁ -C ₅ alkylene-SC ₁ -C ₅ -alkyl group, C ₃ -C ₆ -cycloalkyl group, and C ₃ -C ₅ heterocycloalkyl group,

R ⁷ /R ⁸ is independently selected from a hydrogen atom, and a C1-C6 alkyl group, -C1-C5 alkylene-O-C1-C5 alkyl group, -C1-C5 alkylene-S-C1-C5 alkyl group, - C1-C5-alkylene-NR ⁵ -C1-C ₅ -alkyl group, C ₃ -C ₆ -cycloalkyl group, C ₃ -C ₅ -heterocycloalkyl group, or R ⁷ and R ⁸ together form 3-, 4-, 5 -, 6- or 7-membered ring, optionally containing one or two additional heteroatoms selected from the group consisting of -O-, -S- and -NR ⁹ -, and which is optionally substituted one, two or three times with a substituent selected from a halogen atom, a C ₁ -C ₃ alkyl group, a hydroxy group, a cyano group, an oxo group (=O), and an NR5R ⁶ group, and if R ⁷ and R ⁸ together form a 5-, 6-, or 7-membered ring, said ring may optionally contain a bridging group selected from -O-, -NR ⁹ -, -CH2-, -CH2-CH2-, -O-CH2-, -NR ⁹ -CH ₂ -;

R ⁹ is a hydrogen atom or a C ₁ -C ₃ alkyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to an embodiment of the first aspect of the present invention, the present invention provides compounds of formula (I) wherein R ¹ is selected from a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ -haloalkoxy groups;

R ² is selected from a hydrogen atom and a halogen atom,

R ³ is selected from a halogen atom,

C2-C4-alkenyl group,

C5-C6-cycloalkenyl group,

a C3-C6 heterocycloalkyl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom and a C ₁ -C ₃ alkyl group;

a C ₅ -C ₆ heterocycloalkyl group which is partially unsaturated and optionally substituted with one or two substituents, and each substituent is independently selected from an oxo group (=O), a C ₁ -C ₃ alkyl group and a halogen atom;

an aryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, and an NR ⁵ R ⁶ group;

a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a C1-C3 alkyl group, a cyano group, a C1- _C3 haloalkyl group, a C1- _C3 alkoxy group, and NR5R ⁶ groups;

and NR ⁷ R ⁸ groups;

R ⁴ is selected from a hydrogen atom and a C1- _C3 alkyl group;

R5/R ⁶ is independently selected from hydrogen atom, C1-C ₆ alkyl group, -C ₁ -C ₃ alkylene-OC ₁ -C ₃ alkyl group, -C ₁ -C ₃ alkylene-SC ₁ -C ₃ -alkyl group, and C ₃ -C ₅ -heterocycloalkyl group,

R7/ ^R8 is independently selected from a hydrogen atom, and a C1-C6 alkyl group, -C1-C3 alkylene-O-C1-C3 alkyl group, -C1-C3 alkylene-S-C1-C3 alkyl group, -C1 -C3-alkylene-NR ⁵ -C1-C ₃ -alkyl group, C ₃ -C ₆ -cycloalkyl group, C ₃ -C ₅ -heterocycloalkyl group, or R ⁷ and R ⁸ together form 3-, 4-, 5- , 6- or 7-membered ring, optionally containing one or two additional heteroatoms selected from the group consisting of -O-, -S- and -NR ⁹ -, and which is optionally substituted one, two or three times with a substituent selected from a halogen atom, a C1- _C3 alkyl group, a hydroxy group, a cyano group, an oxo group (=O), and an NR5R ⁶ group,

R ⁹ is a hydrogen atom or a C1- _C3 alkyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to a second embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R1 is selected from 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 is selected from a halogen atom,

C ₂ -C ₄ -galkenyl group,

C ₅ -C ₆ -cycloalkylenyl group,

C ₃ -C ₆ -heterocycloalkyl group, which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom and C1-C ₃ -alkyl group;

C ₅ -C ₆ -heterocycloalkyl group, which is partially unsaturated and optionally substituted by oxo group (=O);

a phenyl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a C1- _C3 alkyl group, a _C1C3 haloalkyl group, and an ^NR5R6 group;

- 20 041614 mono - or bicyclic heteroaryl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, C ₁ -C ₃ -alkyl group, cyano group, C ₁ -C ₃ -haloalkyl group, C ₁ -C ₃ alkoxy groups and NR5R ⁶ groups;

and NR7R group ⁸ ;

R ⁴ is selected from a hydrogen atom and a methyl group;

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₃ alkyl group; And

R 7 /R ⁸ is independently selected from a hydrogen atom, a C ₃ -C ₅ cycloalkyl group and a C ₁ -C ₆ alkyl group;

or R ⁷ and R ⁸ together form a 4-, 5- or 6-membered ring, optionally containing one additional oxygen atom, and which is optionally substituted once or twice with a substituent selected from a halogen atom and a C ₁ -C ₃ alkyl group;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to a third embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from CF ₃ , -CH ₃ , -OCF ₃ and a fluorine atom,

R ² is selected from a hydrogen atom,

R ³ is selected from a halogen atom,

C ₂ -C ₄ -alkenyl group,

C ₅ -C ₆ -cycloalkylenyl group,

a C3-C6 heterocycloalkyl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom and a C ₁ -C ₃ alkyl group;

C ₅ -C ₆ -heterocycloalkyl group, which is partially unsaturated and optionally substituted by oxo group (=O);

a phenyl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a C ₁ -C ₃ alkyl group, a C ₁ C ₃ haloalkyl group, and an NR ⁵ R ⁶ group;

a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ -alkoxy groups and NR5R ⁶ groups;

and NR ⁷ R ⁸ groups;

R ⁴ is selected from a hydrogen atom and a C ₁ -C ₃ alkyl group;

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₃ alkyl group; And

R7/R ⁸ is independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group;

or R ⁷ and R ⁸ together form a 4-, 5- or 6-membered ring, optionally containing one additional oxygen atom, and which is optionally substituted once or twice with a substituent selected from a halogen atom and a C ₁ -C ₃ -alkyl group;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to a fourth embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from CF ₃ , -CH ₃ , -OCF ₃ and a fluorine atom,

R ² is selected from a hydrogen atom,

R ³ is selected from a halogen atom, a prop-1-en-1-yl group which is optionally substituted with a methyl group, a piperidin-1-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a fluorine atom and a methyl group , a morpholin-4-yl group which is optionally substituted with one or two methyl groups, a pyrrolidin-1-yl group which is optionally substituted with one or two halogen atoms, a 1,2,3,6-tetrahydropyridin-4-yl group which is optionally substituted with a methyl group, an azitidin-1 -yl group,

3,6-dihydro-1 H-pyran-4-yl group,

a 6-oxo-1,6-dihydropyridin-3-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a hydrogen atom and a methyl group, a cyclopent-1-en-1-yl group, a phenyl group which optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a methyl group, an ethyl group, a CF ₃ , a CF ₂ H group, a methoxy group, a CF ₃ O group, an NH2 group, and an NHCH3 group,

a 2H-pyrrol-1-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a hydrogen atom, a cyano group, and a methyl group,

1H-pyrrazol-4-yl group which is optionally substituted with one or two substituents, and

- 21 041614 each substituent is independently selected from a methyl group, an ethyl group or a CF3 group, a 1H-pyrrazol-5-yl group which is optionally substituted with a methyl group, 1,2-oxazol-4-yl which is optionally substituted with one or two methyl groups , 1,2-thiazol-4-yl group which is optionally substituted with methyl group, 1,3-thiazol-5-yl group which is optionally substituted with methyl group, pyridin-3-yl, pyridin-4-yl and pyridin-5 -yl group, each group optionally substituted with one or two substituents, and each substituent independently selected from a halogen atom, a methyl group, a CF ₃ group, a methoxy group and an NH ₂ group, a pyrimidin-5-yl group which is optionally substituted with a methyl group, 1H -indol-6-yl group,

1H-indazol-6-yl group which is optionally substituted with methyl group, 1H-benzimidazol-6-yl group which is optionally substituted with methyl group, NH(C ₂ H ₅ ) group, NH(C ₃ H7) group, NH(C ₄ H ₉ ) groups, NCH ₃ (C ₄ H ₉ ) groups, NH(C ₅ H _n ) groups, NH(cyclopentyl) groups, NCH ₃ (cyclopentyl) groups;

R ⁴ is selected from a hydrogen atom and a C ₁ -C ₃ alkyl group;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group, and a C ₁ -C ₃ haloalkyl group;

R ² is selected from a hydrogen atom and a halogen atom;

R ³ is selected from

C ₁ -C ₆ -alkyl group, which is optionally substituted with one or two substituents, and each substituent is independently selected from hydroxy group, C ₁ -C ₄ -alkoxy group and 3-7 membered heterocycloalkyl group,

C ₂ -C ₆ -alkenyl group, which is optionally substituted by C ₁ -C ₃ -alkoxy group, C ₃ -C ₇ -cycloalkyl group, which is optionally substituted by hydroxy group, C ₅ -C ₆ -cycloalkenyl group, which is optionally substituted by hydroxy group, 3- a 6-membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom;

oxo (=O) groups;

cyano groups;

hydroxy groups;

C ₁ -C ₃ -alkyl group, which is optionally substituted by hydroxy;

a 5-7 membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one or two substituents, and each substituent is independently selected from a C ₁ -C ₃ alkyl group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C ₁ C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, a C ₁ -C ₃ haloalkoxy group, and NR5R ⁶ group, a mono- or bicyclic heteroaryl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ -alkoxy groups, hydroxy groups and NR5R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R group ⁸ ;

R ⁴ is selected from a hydrogen atom and a C ₁ -C ₃ alkyl group;

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group;

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group and hydroxy group,

C ₁ -C ₃ -alkoxy groups,

a C3-C7 cycloalkyl group which is optionally substituted with one or two substituents, and said substituents are independently selected from C ₁ -C ₃ alkyl group, hydroxy group and C ₁ -C ₃ hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a C ₁ -C ₃ - 22 041614 alkyl group, a heteroaryl group which is optionally further substituted with a C ₁ -C ₃ alkyl group;

C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C ₁ -C ₃ alkyl group and a hydroxy group,

R ⁹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group, and a C ₁ -C ₃ haloalkyl group;

R ² is selected from a hydrogen atom and a halogen atom;

R ³ is selected from

a 3-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

hydroxy groups,

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

an aryl group that is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a hydroxy group and a C ₁ -C ₃ haloalkyl group, a mono- or bicyclic heteroaryl group that is optionally substituted with a substituent that is selected from a halogen atom, C ₁ -C ₃ -alkyl group, C ₁ -C ₃ -haloalkyl group and NR5R ⁶ group, provided that the specified monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R group ⁸ ;

R ⁴ is selected from a hydrogen atom and a C ₁ -C ₃ alkyl group;

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₃ alkyl group;

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one or two, three or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group, € ₁ - € ₃ -alkoxy group,

C ₃ -C ₅ -cycloalkyl group, which is optionally further substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group and Ο ₁ -Ο ₃ hydroxyalkyl group;

a 5-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C ₁ -C ₃ -alkyl group, a heteroaryl group which is optionally further substituted with C ₁ - With ₃ -alkyl group;

C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group or € ₁ - € ₃ alkyl group,

a 4-5 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C ₁ -C ₃ alkyl group and a hydroxy group, and

R ⁹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I):

R ¹ is selected from CF ₃ and a fluorine atom;

R ² represents a hydrogen atom;

R ³ is selected from an aryl group which is optionally substituted with a substituent which is selected from a halogen atom and a C ₁ -C ₃ haloalkyl group, a monocyclic heteroaryl group substituted with a substituent which is selected from an Ο ₁ -Ο ₃ haloalkyl group and an NR ⁵ R ⁶ group ;

and NR ⁷ R ⁸ groups;

R ⁴ is selected from a hydrogen atom and a methyl group;

R ⁵ /R ⁶ represents a hydrogen atom or a methyl group;

- 23 041614

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₃ -alkyl group, which is optionally substituted with one, two or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group and methoxy group, or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or their mixture.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from a hydrogen atom, a fluorine atom, a cyano group, a methyl group, an OCF3 group, a CHF2 group, and a CF3 group,

R2 is selected from a hydrogen atom or a fluorine atom;

R ³ is selected from

a C ₁ -C ₆ alkyl group which is optionally substituted with a substituent, said substituent being selected from a 2-hydroxy group, a methoxy group and a morpholino group;

C ₂ -C ₆ -alkenyl group, which is optionally substituted by methoxy;

a cyclohexyl group which is optionally substituted with a hydroxy group;

C ₅ -C ₇ -cycloalkenyl group;

3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituents being independently selected from fluorine atom, -C(O)NH ₂ group, hydroxy group, methyl group, ethyl group, hydroxymethyl group, cyano group, and amino group ;

a partially unsaturated 5-6 membered heterocycloalkyl group which is optionally substituted with a methyl group;

a phenyl group which is optionally substituted with one, two or three substituents, said substituents being independently selected from methyl group, ethyl group, fluorine atom, chlorine atom, amino group, hydroxy group, methoxy group, cyano group, difluoromethyl group, trifluoromethyl group and methylamino group;

a 5-membered heteroaryl group which is optionally substituted with one or two substituents, said substituents being independently selected from a methyl group, an ethyl group, a trifluoromethyl group, a difluoromethyl group, and a cyano group,

a 6-membered heteroaryl group which is optionally substituted with one or two substituents, said substituents being independently selected from a methyl group, a fluorine atom, a chlorine atom, a trifluoromethyl group, an amino group and a methoxy group, a bicyclic heteroaryl group which is optionally substituted with a methyl group;

NR ⁷ R ⁸ groups, where R ⁷ R ⁸ are independently selected from a hydrogen atom,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one or two substituents, and these substituents are independently selected from amino group, methoxy group, ethoxy group, cyano group, hydroxy group, trifluoromethyl group, cyclopropyl group, 2,2dimethylcyclopropyl group, 1-hydroxycyclobutyl group , 3-hydroxycyclobutyl group, methyloxetanyl group, oxolanyl group, oxanyl group, methyloxanyl group, tetrahydrofuranyl group, oxopyrrolidinyl group, oxopiperidinyl group, methyl-III-imidazolyl group, 1H-pyrazolyl group, 1H-imidazolyl group, 1-methyl1H-pyrazolyl group , pyrazinyl group, pyridinyl group, pyrimidinyl group,

C ₅ -C ₇ -cycloalkyl group, which is optionally substituted by hydroxy group, 4-6-membered heterocycloalkyl group, which is optionally substituted by methyl group,

R ⁴ represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from a hydrogen atom, a fluorine atom, a cyano group, a CH ₃ group, an OCF ₃ group, a CHF 2 group, and a CF ₃ group,

R ² is selected from a hydrogen atom (many examples) or a fluorine atom;

R ³ is selected from a methyl group, a propan-2-yl group, a 2-methylpropyl group, a 2-hydroxypropan-2yl group, a 3,3-dimethylbutyl group, a 3-methoxypropyl group,

-CH2-(morpholin-4-yl) group, prop-1-en-2-yl group, 2-methylprop-1-en-1-yl group, 3,3-dimethylbut-1-en-1-yl group , 3-methoxyprop-1-en-1-yl group,

4-hydroxycyclohexyl group, cyclopent-1-en-1-yl group, cyclohex-1-en-1-yl group, bicyclo[2.2.1]hept-2-en-2yl group,

- 24 041614 oxan-3-yl group, 3,3-difluoroazetidin-1-yl group, zetidin-3-carboxamide, 2hydroxyazetidin-1-yl group, 3-hydroxy-3-methylazetidin-1-yl group, 2(hydroxymethyl )azetidin-1-yl group, 3-cyano-3-methylazetidin-1-yl group, 2,4dimethylazetidin-1-yl group, -2lambda ⁶ -thia-6-azaspiro[3.3]heptan-2,2-dione group , 3-hydroxypyrrolidin-1-yl group, 3,3-difluoropyrrolidin-1-yl group, 3azabicyclo[3.1.0]hexan-3-yl group, 1-amino-3-azabicyclo[3.1.0]hexan-3-yl group , 4fluoropiperidin-1-yl group, 4,4-fluoropiperidin-1-yl group, 4-cyano-piperidin-1-yl group, 4-fluoro-4-methylpiperidin-1-yl group, 4-ethyl-4-hydroxypiperidine -1-yl group, 4hydroxypiperidin-1-yl group, 3-hydroxypiperidin-1-yl group, 3aminocarbonylpiperidin-1-yl group, morpholin-4-yl group, 2-methylmorpholin-4-yl group, 2,6-dimethylmorpholine -4-yl group, 4-methylpiperazin-1-yl group,

2,5-dihydrofuran-3-yl group, 5,6-dihydro-2H-pyran-3-yl group, 3,6-dihydro-2Hpyran-4-yl group, 1,2,3,6-tetrahydropyridin-4 -yl group, 1-methyl-1,2,3,6tetrahydropyridin-4-yl group, 6-oxo-1,6-dihydropyridin-3-yl group, phenyl group, 2-methylphenyl group, 2-ethylphenyl group, 2 -fluorophenyl group, 2-aminophenyl group, 2-hydroxyphenyl group, 2-methoxyphenyl group, 2,4dimethylphenyl group, 2-fluoro-4-methylphenyl group, 2-fluoro-4-aminophenyl group, 4cyano-2-methylphenyl group, 2 -chloro-4-fluorophenyl group, 2,3-difluorophenyl group, 2fluoro-3-aminophenyl group, 2,5-difluorophenyl group, 2,6-difluorophenyl group, 4-fluoro-6methylphenyl group, (2-difluoromethyl)phenyl group , 2-cyanophenyl group, 2,4difluorophenyl group, 3-methylphenyl group, 3-aminophenyl group, 3-fluorophenyl group, 3-hydroxyphenyl group, 3,4-difluorophenyl group, 3-amino-4-methylphenyl group, 3-amino -4-chlorophenyl group, 3-a mino-4-fluorophenyl group, 3-fluoro-4-methylphenyl group, 4-amino-3-fluorophenyl group, 4-fluoro-3-methylphenyl group, 4-fluoro-3hydroxyphenyl group, 3-hydroxy-4-methylphenyl group, 4-methylphenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-(difluoromethyl)phenyl group, 4(trifluoromethyl)phenyl group, 4-cyanophenyl group, 4-aminophenyl group, 4(methylamino)phenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 3,5-difluorophenyl group, 2,4,5-trifluorophenyl group, 2,3,4-trifluorophenyl group, 3,4,5-trifluorophenyl group, 3-amino-4,6-difluorophenyl group,

1H-pyrazol-4-yl group, 1-methyl-1H-pyrazol-4-yl group, 1-ethyl-3-(trifluoromethyl)-1Hpyrazol-1-yl group, 1H-pyrazol-4-yl group, 1- (propan-2-yl)-1H-pyrazol-4-yl group, 1-(difluoromethyl)-1H-pyrazol-4-yl group, 1-methyl-1H-pyrazol-5-yl group, 3-methyl-1Hpyrazole -4-yl group, 1,3-dimethyl-1H-pyrazol-4-yl group, 3,5-dimethyl-1H-pyrazol-4-yl group, 1-methyl-3-(trifluoromethyl)-1H-pyrazol- 4-yl group, 3-(trifluoromethyl)-1H-pyrazol-4yl group, 1-methyl-5-cyano-1H-pyrrol-2-yl group, 1-ethyl-1H-imidazol-4-yl group, 4( trifluoromethyl)-1H-imidazol-1-yl group, 3,5-dimethyl-1,2-oxazol-4-yl group, 1,2-thiazol-4yl group, 2-methyl-1,3-thiazol-5- yl group, 5-(trifluoromethyl)thiophen-2-yl group, 5-cyano-4-methyl-thiophen-2-yl group, 5-(trifluoromethyl)thiophen-3-yl group, pyridin-2-yl group, 5-methyl -pyridin-2-yl group, 5-chloro-pyridin-2-yl group, 5-fluoro-pyridin-2-yl group, pyridin-3-yl group, 4-methylpyridin-3-yl group ppy, 2methylpyridin-3-yl group, 6-fluoropyridin-3-yl group, 6-methylpyridin-3-yl group, 6(trifluoromethyl)pyridin-3-yl group, 6-aminopyridin-3-yl group, 6-methoxypyridine -3yl group, 5-fluoro-6-methylpyridin-3-yl group, 2-methoxy-6-methylpyridin-3-yl group, pyridin-4-yl group, 2-methylpyridin-4-yl group, 2-methoxypyridin- 4-yl group, 2-aminopyridin-4-yl group, 3-methylpyridin-4-yl group, pyrimidin-5-yl group, 2-methylpyrimidin-5-yl group,

1-benzothiophen-2-yl group, imidazo[1,2-a]pyridin-6-yl group, 1-methyl-1Hbenzimidazol-6-yl group, 1-methyl-1H-indazol-6-yl group, 1H- indazol-6-yl group, 1H-indol-6-yl group, 1H-indol-5-yl group, methylamino group, ethylamino group, (propan-2-yl)amino group, propylamino group, butylamino group, tert-butylamino group, pentylamino group, ethyl(methyl)amino group, (butyl)methylamino group, aminocarbonylmethyl group, (2-aminoethyl)amino group, (2methylpropyl)amino group, (3-methylbutyl)amino group, (2-methoxyethyl)amino group , (2ethoxyethyl)amino groups, (3-methoxypropyl)amino groups, (3-cyanopropyl)amino groups, (2hydroxypropyl)amino groups, (2-hydroxy-2-methylpropyl)amino groups, (2-methoxypropyl)amino groups, ( 2-ethoxypropyl)amino groups, (3,3,3-trifluoro-2-hydroxypropyl)amino groups, (2-methoxy-2methylpropyl)amino groups, (2-methoxybutyl)amino groups, (3-hydroxybutyl)amino groups, ( 1hydroxybutan-2-yl)amino groups, (4-hydroxybutan-2-yl)amino groups , (1-hydroxypentan-2-yl)amino groups, (3-hydroxy-3-methylbutyl)amino groups, (2-hydroxy-3-methoxypropyl)amino groups, (cyclopropylmethyl)amino groups, (1-cyclopropylethyl)amino groups , ((1-hydroxycyclobutyl)methyl)amino groups, (1-hydroxy-4-methylpentan-2-yl)amino groups, (1,3-dihydroxybutan-2-yl)amino groups, (2,2-25 041614 dimethylcyclopropyl )methyl]amino group, (dicyclopropylmethyl)amino group, (3hydroxycyclobutyl)amino group, [1-(hydroxymethyl)cyclobutyl]methyl group, cyclopentylamino group, (2-hydroxycyclopentyl)amino group, (cyclopentyl)(methyl)amino group, ( 4hydroxycyclohexyl)amino groups, bicyclo[2.2.1]heptan-2-yl]amino groups, [(3-methyloxetan-3yl)methyl]amino groups, (oxetan-3-yl)amino groups, (oxolan-3-yl) methyl)amino groups, (tetrahydrofuran-2-ylmethyl)amino groups, (oxan-4-yl)amino groups, ((oxan-4-yl)methyl)amino groups, ((4methyloxan-4-yl)methyl)amino groups , (3-methyloxetan-3-yl)methyl]amino groups, [(5-oxopyrrolidin2-yl)methyl]amino groups, [(6-oxopiperidin- 3-yl)methyl]amino groups, [(1-methyl-III-imidazol-2yl)methyl]amino groups, [2-(III-pyrazol-1-yl)ethyl]amino groups, [2-(1H-imidazole -5-yl)ethyl]amino groups, (3-(1H-imidazol-1-yl)propyl)amino groups, [(1-methyl-1H-pyrazol-5-yl)methyl]amino groups, [(1 H -pyrazol-3 -yl)methyl]amino groups, [(1 -methyl-1 H-pyrazol-3 -yl)methyl]amino groups, [(1 -methyl-1Hpyrazol-4-yl)methyl]amino groups, [( pyrazin-2-yl)methyl]amino groups, [(pyridin-3-yl)methyl]amino groups, [(pyrimidin-5-yl)methyl]amino groups, [(pyrimidin-2-yl)methyl]amino groups,

R ⁴ represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from CF3 and a fluorine atom,

R ² is selected from a hydrogen atom,

R ³ is selected from a halogen atom, a prop-1-en-1-yl group which is optionally substituted with a methyl group, a piperidin-1-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a fluorine atom and a methyl group , a morpholin-4-yl group which is optionally substituted with one or two methyl groups, a pyrrolidin-1-yl group which is optionally substituted with one or two halogen atoms, a 1,2,3,6-tetrahydropyridin-4-yl group which is optionally substituted by a methyl group, an azitidin-1-yl group,

3,6-dihydro-1 H-pyran-4-yl group,

a 6-oxo-1,6-dihydropyridin-3-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a hydrogen atom and a methyl group, a cyclopent-1-en-1-yl group, a phenyl group which optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a methyl group, an ethyl group, a CF ₃ , a CF2H group, a methoxy group, a CF3O group, an NH2 group, and an NHCH3 group,

a 2H-pyrrol-1-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a hydrogen atom, a cyano group, and a methyl group,

1H-pyrrazol-4-yl group, which is optionally substituted with one or two substituents, and each substituent is independently selected from a methyl group, an ethyl group, or a CF ₃ group,

1H-pyrrazol-5-yl group which is optionally substituted with a methyl group, 1,2-oxazol-4-yl which is optionally substituted with one or two methyl groups, 1,2-thiazol-4-yl group which is optionally substituted with a methyl group , 1,3-thiazol-5-yl group, which is optionally substituted with a methyl group, pyridin-3-yl, pyridin-4-yl and pyridin 5-yl groups, each group is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a methyl group, a CF3 group, a methoxy group and an NH2 group, a pyrimidin-5-yl group which is optionally substituted with a methyl group, a 1H-indol-6-yl group, a 1H-indazol-6-yl group which is optionally substituted methyl group, 1H-benzimidazol-6-yl group which is optionally substituted with methyl group, NH(C ₂ H ₅ ) group, NH(C ₃ H7) group, NH(C ₄ H ₉ ) group, NCH ₃ (C ₄ H ₉ ) groups, NH(C ₅ H11) groups, NH(cyclopentyl) groups, NCH ₃ (cyclopentyl) groups;

R ⁴ is selected from a hydrogen atom and a methyl group; or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is selected from the group

- 26 041614

5-[4-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-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-oxadiaz in-2one,

5-[3-fluoro-4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

-[3-fluoro-4-(4-fluoro-4-methylpiperidin-1-yl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

5-[3-fluoro-4-(4-fluoro-piperidin-1-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiaz in-2one,

-(4'-fluoro-2-methylbiphenyl-4-yl)-3, 6-d ihydro-2H-1,3,4-oxad iazin-2-one,

5-(3',4'-difluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

- 27 041614

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-1,3,4oxadiazin-2-one,

5-[3-methyl-4-(1H-pyrazol-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

-[3-methyl-4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-[3 -methyl-4-(pyride in-3 -yl)phenyl] -3,6-d ihydro-2H-1,3,4-oxadiazin-2-one,

-[3-methyl-4-(pyrimidin-5-yl)phenyl]-3,6-d ihydro-2H-1,3,4-oxad iazin-2-one,

-(3'-fluoro-2-methylbiphenyl-4-yl)-3,6-d ihydro-2H-1,3,4-oxad iazin-2-one, (gas)-6-methyl-5-(3 ,4,5-trifluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (gas)-5 - [3,5-difluoro-4-(morpholin-4-yl) phenyl] -6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one, (gas)-5 - {3,5-difluoro-4-[(2 8)-2-methylmorpholine- 4-yl]phenyl} -6-methyl-3,6-dihydro2H-1,3,4-oxad andaz in-2-one, (gas)-5-(4-bromophenyl)-6-methyl-3,6 -dihydro-2H-1,3,4-oxadiazin-2-one, (gas)-6-methyl-5-[4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1, 3,4-oxad iaz in-2one,

5-(3,5-difluoro-4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

- 28 041614

2-(morpholin-4-yl)-5-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5yl)benzonitrile,

3-chloro-2-(morpholin-4-yl)-5-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5yl)benzonitrile,

5-{4-[2,6-dimethylmorpholin-4-yl]-3-fluorophenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one, (68)-5-(3-fluoro -4-morpholinophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2one, (6 S)-5-(3,5-d iftor-4-morpholinophenyl)-6- methyl-3,6-d and hydro-2H-1,3,4oxadiazin-2-one,

-[4-(3,3-difluoro-pyrrolidin-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-(2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

-[3-methyl-4-(2-methylpyrimidin-5-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxad iazin2-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-oxadiaz in-2one,

- 29 041614

5-[4-(6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-[4-(pyridin-3 -yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxad iazin-2 she,

5-[4'-amino-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

5-[3'-hydroxy-4'-methyl-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

- {3 - (trifluoromethyl) -4- [6- (trifluoromethyl) pyride in-3 -yl] phenyl} -3,6-d ihydro-2H1,3,4-oxadiazin-2-one,

5-[4'-fluoro-3'-hydroxy-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[5'-amino-2',4'-difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-[4'-amino-3'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

5-[4-(6-aminopyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[3'-amino-4'-chloro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-[3'-amino-4'-methyl-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

- 30 041614

-[3'-amino-2'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

5-[4'-amino-2'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-[4-(1-methyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

-[4-(3-methyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

5-(4-(1 H-indazol-6-yl)-3 -(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

- (4- (5 -fluoro-6-methylpyridin-3 -yl) -3 - (trifluoromethyl) phenyl] -3,6-d and hydro-2H1,3,4-oxadiazin-2-one,

5-(4-(1,2-thiazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one,

-methyl-5-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxad iazin-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-d ihydro-2H1,3,4-oxadiazin-2-one,

-[4-(2-methoxy-6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H1,3,4-oxadiazin-2-one,

- 31 041614

5-[4-(2-methyl-1,3-thiazol-5-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[4'-(methylamino)-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-[3'-amino-4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

-[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-1,3,4oxadiazin-2-one,

5-[2',5'-difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one,

5-[3'-amino-4'-fluoro-2-(trifluoromethoxy)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[3',4'-difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one,

5-[4-(1H-indol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one,

-[4-(2-methylprop-1-en-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[2',3'-difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one,

- 32 041614

- [4-(morpholin-4-yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one,

- [4-(butylamino)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

- [4-(ethylamino)-3 -(trifluoromethyl)phenyl] -3,6-dihydro-2H-1,3,4-oxad iazin-2one,

- [4-(1-methyl-1 H-pyrazol-4-yl)-3 -(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

- [4- (propylamino) -3 - (trifluoromethyl) phenyl] -3, 6-d ihydro-2H-1,3,4-oxadiazin-2one,

- [4-(6-methylpyridin-3 -yl)-3 -(trifluoromethoxy)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

5-[4'-chloro-2-(trifluoromethoxy)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

- [4- (azetidin-1 -yl) -3 - (trifluoromethyl) phenyl] -3,6-d ihydro-2H-1,3,4-oxadiazin-2one,

- [4-(1-methyl-1 H-benzimidazol-6-yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H1,3,4-oxadiazin-2-one,

- [4-(pentylamino)-3 -(trifluoromethyl)phenyl] -3,6-d ihydro-2H-1,3,4-oxad iazin-2one,

5-[4-(1-methyl-1H-indazol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

- 33 041614

5-[4'-fluoro-2-(trifluoromethoxy)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

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-2one,

5-[3-fluoro-4-(2-methylpyridin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

-(4'-amino-2-fluorobiphenyl-4-yl)-3,6-d ihydro-2H-1,3,4-oxad iazin-2-one,

-(2-fluoro-2'-methylbiphenyl-4-yl)-3,6-d and hydro-2H-1,3,4-oxad iazin-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-2one,

5-(2,4'-difluoro-3'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

-(2-fluoro-3'-methylbiphenyl-4-yl)-3,6-d and hydro-2H-1,3,4-oxad iazin-2-one,

-(2-fluoro-4'-methylbiphenyl-4-yl)-3,6-d and hydro-2H-1,3,4-oxad iazin-2-one,

5-(2-fluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

- 34 041614

5-[4-(2-Aminopyridin-4-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiaz in-2one,

-(3'-amino-2-fluorobiphenyl-4-yl)-3, 6-d ihydro-2H-1,3,4-oxad iazin-2-one,

5-[4'-(difluoromethyl)-2-fluorobiphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiaz in-2-one,

-[3-fluoro-4-(pyridin-4-yl)phenyl]-3,6-d ihydro-2H-1,3,4-oxadiazin-2-one,

5-[3-fluoro-4-(2-methylpyrimidin-5-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

5-[3-fluoro-4-(2-methoxypyridin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

-[3-fluoro-4-(2-methylpyridin-3-yl)phenyl]-3,6-d ihydro-2H-1,3,4-oxadiazin-2one,

-[3-fluoro-4-(6-methylpyridin-3-yl)phenyl]-3,6-d ihydro-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-4carbonitrile,

5-(2'-amino-2-fluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

- 35 041614

5-(3'-amino-2-fluoro-4'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2 she,

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-(pyride in-3-yl)phenyl]-3,6-d ihydro-2H-1,3,4-oxad iazin-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,

- 36 041614

5-[3-fluoro-4-(4-methylpyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one, (rac)-5 -(3-Fluoro- 4-morpholinophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxad iazin-2one, (6 8)-6-methyl-5 - [4-(morphol in-4-yl) -3 -(trifluoromethyl)phenyl] -3,6-dihydro-2H1,3,4-oxadiazin-2-one, (65)-5-(-[(3-chloro-4-(morpholin-4-yl )-5-(trifluoromethyl)phenyl)-)]-6-methyl-3,6dihydro-2H-1,3,4-oxad iazin-2-one, (65)-5 -(-[(4-chloro- 3 -(trifluoromethyl)phenyl)-)]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one, (6 S)-5 -(- [(4-fluoro-3 - (trifluoromethyl)phenyl)-)]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-[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, (gas)-6-methyl-5-(4-morpholino-3-( trifluoromethyl)phenyl)-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

- { 4- [ 1 -methyl-3 - (trifluoromethyl) -1 H-pyrazol-4-yl] -3 - (trifluoro methyl) phenyl} -3,6dihydro-2H-1,3,4-oxad iazin-2 -she,

-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H1,3,4-oxadiazin-2-one,

- 37 041614

-(4-(3,5-dimethyl-1,2-oxazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H1,3,4-oxadiazin-2-one,

- { 3 - (trifluoromethyl) -4- [3 - (trifluoromethyl) -1 H-pyrazol-4-yl] phenyl } -3,6-d ihydro2H-1,3,4-oxad iazin-2-one,

5-[4-(1-ethyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

- { 4- (cyclopentyl (methyl) amino] -3 - (trifluoro methyl) 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]-3,6dihydro-2H-1,3,4-oxad iazin-2 -she,

- { 4- (butyl (methyl) amino] -3 - (trifluoro methyl) phenyl } -3, 6-d ihydro-2H-1,3,4 oxadiazin-2-one, (68) -5-[4'- fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[4-(cyclopentylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[4-(cyclopentylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one and

5-[3'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiaz in-2one, or their stereoisomer, tautomer, N-oxide, hydrate , solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is selected from the group

- 38 041614

5-[4-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazine

2-she,

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-oxadiaz in-2one,

5-[3-fluoro-4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

-[3-fluoro-4-(4-fluoro-4-methylpiperidin-1-yl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

5-[3-fluoro-4-(4-fluoro-piperidin-1-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiaz in-2one,

-(4'-fluoro-2-methylbiphenyl-4-yl)-3,6-d ihydro-2H-1,3,4-oxad iazin-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-1,3,4oxadiazin-2-one,

5-[3-methyl-4-(1H-pyrazol-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

- 39 041614

-[3-methyl-4-(6-oxo-1,6-dihydropyridin-3 -yl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-[3 -methyl-4-(pyride in-3 -yl)phenyl] -3,6-d ihydro-2H-1,3,4-oxadiazin-2-one,

-[3-methyl-4-(pyrimidin-5-yl)phenyl]-3,6-d ihydro-2H-1,3,4-oxad iazin-2-one,

-(3'-fluoro-2-methylbiphenyl-4-yl)-3,6-d ihydro-2H-1,3,4-oxad iazin-2-one, (gas)-6-methyl-5-(3 ,4,5-trifluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, (gas)-5 - [3,5-difluoro-4-(morpholin-4-yl) phenyl] -6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one, (gas)-5 - {3,5-difluoro-4-[(2 8)-2-methylmorpholine- 4-yl] phenyl } -6-methyl-3,6-dihydro2H-1,3,4-oxad iazin-2-one, (gas)-6-methyl-5 - [4-(morpholin-4-yl) phenyl]-3,6-dihydro-2H-1,3,4-oxade of iazin-2one,

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-5yl)benzonitrile,

3-chloro-2-(morpholin-4-yl)-5-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5yl)benzonitrile,

5-{4-[2,6-dimethylmorpholin-4-yl]-3-fluorophenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

- 40 041614 (68)-5-(3-fluoro-4-morpholinophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2one, (68)-5-(3, 5-difluoro-4-morpholinophenyl)-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-[4-(3,3-difluoro-pyrrolidin-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-(2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

-[3-methyl-4-(2-methylpyrimidin-5-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxad iazin2-one,

5-[3-methyl-4-(1-methyl-1H-pyrazol-5-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-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-oxadiaz in-2one,

5-[4-(6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-[4-(pyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxad iazin-2one,

5-[4'-amino-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

- 41 041614

5-[3'-hydroxy-4'-methyl-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

- { 3 - (trifluoromethyl) -4- [6- (trifluoromethyl) pyride in-3 -yl] phenyl } -3,6-d ihydro-2H1,3,4-oxadiazin-2-one,

5-[4'-fluoro-3'-hydroxy-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[5'-amino-2',4'-difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-[4'-amino-3'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

5-[4-(6-aminopyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-[3'-amino-4'-chloro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

5-[3'-amino-4'-methyl-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-[3'-amino-2'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

5-[4'-amino-2'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-[4-(1-methyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

- 42 041614

5-(4-(3-methyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

5-(4-(1 H-indazol-6-yl)-3 -(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

-(4-(5-fluoro-6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H1,3,4-oxadiazin-2-one,

5-(4-(1,2-thiazol-4-yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one,

-methyl-5-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxad iazin-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-d ihydro-2H1,3,4-oxadiazin-2-one,

-[4-(2-methoxy-6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H1,3,4-oxadiazin-2-one,

5-[4-(2-methyl-1,3-thiazol-5-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[4'-(methylamino)-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-[3'-amino-4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

- 43 041614

-[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-1,3,4oxadiazin-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-1,3,4oxadiazin-2-one,

5-[3',4'-difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin 2-one,

-[4-( 1 H-indol-6-yl)-3 -(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4-oxadiazin2-one,

-[4-(2-methylprop-1-en-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-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-oxadiazin2-one,

-[4-(butylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxad iazin-2one,

- 44 041614

5-[4-(1-methyl-1H-pyrazol-4-yl)-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[4-(propylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

-[4-(6-methylpyridin-3-yl)-3-(trifluoromethoxy)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

5-[4'-chloro-2-(trifluoromethoxy)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

5-[4-(azetidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

-[4-(1-methyl-1 H-benzimidazol-6-yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H1,3,4-oxadiazin-2-one,

-[4-(pentylamino)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxad iazin-2one,

5-[4-(1-methyl-1H-indazol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiaz in-2-one,

5-[4'-fluoro-2-(trifluoromethoxy)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

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-2one,

- 45 041614

5-[3-fluoro-4-(2-methylpyridin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

-(4'-amino-2-fluorobiphenyl-4-yl)-3, 6-d ihydro-2H-1,3,4-oxad iazin-2-one,

-(2-fluoro-2'-methylbiphenyl-4-yl)-3, 6-d ihydro-2H-1,3,4-oxad iazin-2-one,

5-(2'-chloro-2,4'-difluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

-[4-(cyclopent-1-en-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxad iazin-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-2one,

5-(2,4'-difluoro-3'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

-(2-fluoro-3'-methylbiphenyl-4-yl)-3,6-d and hydro-2H-1,3,4-oxad iazin-2-one,

-(2-fluoro-4'-methylbiphenyl-4-yl)-3,6-d and hydro-2H-1,3,4-oxad iazin-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-oxadiaz in-2one,

-(3'-amino-2-fluorobiphenyl-4-yl)-3,6-d ihydro-2H-1,3,4-oxad iazin-2-one,

-[4'-(difluoromethyl)-2-fluorobiphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

- 46 041614

-[3-fluoro-4-(pyridin-4-yl)phenyl]-3,6-d ihydro-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-2one,

5-[3-fluoro-4-(2-methylpyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

5-[3-fluoro-4-(6-methylpyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

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-4carbonitrile,

-(2'-amino-2-fluorobiphenyl-4-yl)-3, 6-d ihydro-2H-1,3,4-oxad iazin-2-one,

5-(3'-amino-2-fluoro-4'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

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,

- 47 041614

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,

-[3-fluoro-4-(pyridin-3-yl)phenyl]-3,6-d ihydro-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-2one, (gas)-5 -(3-fluoro- 4-morpholinophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxad iazin-2 one,

- 48 041614 (6 8) -6-methyl-5 - [4- (morphol in-4-yl) -3 - (trifluoro methyl) phenyl] -3,6-dihydro-2H1,3,4-oxadiazin-2 -one, (65)-5-(-[(3-chloro-4-(morpholin-4-yl)-5-(trifluoromethyl)phenyl)-)]-6-methyl-3,6dihydro-2H-1, 3,4-oxad iazin-2-one, (65)-5-(-[(4-chloro-3-(trifluoromethyl)phenyl)-)]-6-methyl-3,6-dihydro-2H-1, 3,4oxadiazin-2-one, (6S)-5 -(- [(4-fluoro-3 -(trifluoromethyl)phenyl)-)] -6-methyl-3,6-dihydro-2H-1,3, 4oxadiazin-2-one,

-[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, (gas)-6-methyl-5-(4-morpholino-3-( trifluoromethyl)phenyl)-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

- { 4- [ 1 -methyl-3 - (trifluoromethyl) -1 H-pyrazol-4-yl] -3 - (trifluoro methyl) phenyl } -3,6dihydro-2H-1,3,4-oxad iazin-2 -she,

5-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H1,3,4-oxadiazin-2-one,

5-(4-(3,5-dimethyl-1,2-oxazol-4-yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H1,3,4-oxadiazin-2-one,

- { 3 - (trifluoromethyl) -4- [3 - (trifluoromethyl) -1 H-pyrazol-4-yl] phenyl } -3,6-d ihydro2H-1,3,4-oxad iazin-2-one,

-49041614

- [4-(1-ethyl-1 H-pyrazol-4-yl)-3 -(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

- { 4- [cyclopentyl (methyl) amino] -3 - (trifluoro methyl) phenyl } -3,6-dihydro-2H-1,3,4 oxadiazin-2-one,

-[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3 -(trifluoromethyl)phenyl]-3,6dihydro-2H-1,3,4-oxad iazin-2- she,

- { 4- [butyl (methyl) amino] -3 - (trifluoro methyl) phenyl } -3,6-d ihydro-2H-1,3,4 oxadiazin-2-one, (68) -5-[4'- fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[4-(cyclopentylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[4-(cyclopentylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one, and

5-[3'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one, or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is selected from the group

- 50 041614

5-[4-methyl-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

- { 4- [3-methoxyprop-1 -en-1 -yl] -3 - (trifluoromethyl) phenyl } -3,6-dihydro-2H-1,3,4 oxadiazin-2-one, (gas) -5- [4'-hydroxy-2-(trifluoromethyl)-2',3',4',5'-tetrahydro[1,H-biphenyl]-4-yl]3,6-dihydro-2H-1,3,4 -oxad iazin-2-one,

-[4-(5,6-d ihydro-2H-pyran-3 -yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[4-(imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

- {4-[3,3-dimethylbut-1-en-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

- { 3 - (trifluoromethyl) -4- [5 - (trifluoromethyl) thiophen-3 -yl] phenyl } -3,6-d ihydro-2H1,3,4-oxadiazin-2-one,

- { 4- [ 1 - (difluoromethyl) -1 H-pyrazol-4-yl] -3 - (trifluoromethyl) phenyl } -3,6-dihydro2H-1,3,4-oxad iazin-2-one,

-[4-(prop-1-en-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one,

-[4-(1-benzothiophen-2-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4-51 041614 oxadiazin-2-one,

5-(4-(2,5-dihydrofuran-3-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

-[4-(cyclopent-1-en-1-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

5-(4-(1-ethyl-1H-imide azol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

-methyl-5-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxad iazin-5 -yl)-2(trifluoromethyl)phenyl]thiophene-2-carbonitrile,

- { 4- [ 1 - (propan-2-yl) -1 H-pyrazol-4-yl] -3 - (trifluoromethyl) phenyl } -3,6-d ihydro2H-1,3,4-oxad iazin- 2-one, (gas)-5 - [4-(bicyclo[2.2.1] hept-2-en-2-yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro2H-1,3, 4-oxad iazin-2-one,

5-[2'-fluoro-2-(trifluoromethyl)[1,G-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

- { 3 - (trifluoromethyl) -4- [5 - (trifluoromethyl) thiophen-2-yl] phenyl } -3,6-d ihydro-2H1,3,4-oxadiazin-2-one,

5-[4-(5-methylpyridin-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-52 041614 oxadiazin-2-one,

5-[4-(5-fluoropyridin-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[4-(5-chloropyridin-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-[4-(pyridin-2-yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxad iazin-2one,

5-[2'-(difluoromethyl)-2-fluoro[1,G-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one,

5-(2,4'-difluoro-2'-methyl [1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

2'-fluoro-2-methyl-4'-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)[1,G-biphenyl]4-carbonitrile,

5-[4-(2-methylprop-1-en-1-yl)-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one, (6 S) -5-[4-(2-Aminopyridin-4-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro2H-1,3,4-oxad iazin-2-one, (6 8) -6-methyl-5 - [4- (pyridin-4-yl) -3 - (trifluoro methyl) phenyl] -3,6-d and hydro-2H-1,3,4- 53 041614 oxadiazin-2- she, (68)-6-methyl-5-[4-(6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro2H-1,3,4-oxad iazin-2- she, (6 S)-5 - [2'-fluoro-4'-methyl-2-(trifluoromethyl) [1,1 '-biphenyl] -4-yl] -6-methyl-3,6dihydro-2H-1 ,3,4-oxad iazin-2-one, (68)-6-methyl-5-[2',4',5'-trifluoro-2-(trifluoromethyl)[1,G-biphenyl]-4-yl ]-3,6dihydro-2Н-1,3,4-oxad iazin-2-one, (68)-6-methyl-5-[2',3',4'-trifluoro-2-(trifluoromethyl)[1 ,H-biphenyl]-4-yl]-3,6dihydro-2H-1,3,4-oxad andaz in-2-one, (68)-5-[2',5'-difluoro-2-(trifluoromethyl )[1,G-biphenyl]-4-yl]-6-methyl-3,6-dihydro2H-1,3,4-oxad iazin-2-one,

4'-[(68)-6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl]-2'(trifluoromethyl)[1,1'-biphenyl] -2-carbonitrile, (6 S) -5 - [4- ( 1 H-indol-5 -yl) -3 - (trifluoromethyl) phenyl] -6-methyl-3, 6-d ihydro-2H-1,3 ,4oxadiazin-2-one, (6S)-5-[4'-hydroxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-d ihydro2H- 1,3,4-oxad iazin-2-one, (6 S)-5 - [3'-hydroxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3 ,6-d ihydro- 54 041614

2H-1,3,4-oxad iazin-2-one, (6 S)-5-[3'-amino-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl -3,6-d ihydro-2H1,3,4-oxadiazin-2-one, (68)-5-[2',4'-difluoro-2-(trifluoromethyl)[1,G-biphenyl]-4- yl]-6-methyl-3,6-dihydro2H-1,3,4-oxad iazin-2-one, (6 S)-5 - [3'-fluoro-4'-methyl-2-(trifluoromethyl) [ 1,1'-biphenyl]-4-yl]-6-methyl-3,6dihydro-2H-1,3,4-oxad iazin-2-one, (6S)-5-[2'-fluoro-2 -(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H1,3,4-oxadiazin-2-one, (6S)-5-[2' -methoxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-d ihydro-2H1,3,4-oxadiazin-2-one, (6 S)- 5 - [3'-fluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H1,3,4-oxadiazin-2-one, ( 68)-6-methyl-5-[4-(4-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro2H-1,3,4-oxad iazin-2-one, ( 6 8)-6-methyl-5-[4-(3-methylpyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro2H-1,3,4-oxad iazin-2-one, (6 8)-6-methyl-5-[4-(2-methylpyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro- 55 041614

2H-1,3,4-oxad iazin-2-one, (6 S)-5 - [4-( 1 H-indol-6-yl)-3 - (trifluoromethyl) phenyl] -6-methyl-3, 6-d ihydro-2H-1,3,4oxadiazin-2-one, (6 S)-5- [2'-ethyl-2-(trifluoromethyl) [1,1'-biphenyl]-4-yl] - 6-methyl-3,6-d ihydro-2H1,3,4-oxadiazin-2-one, (6S)-5-[4-(6-methoxypyridin-3-yl)-3-(trifluoromethyl)phenyl ]-6-methyl-3,6-d ihydro2H-1,3,4-oxad iazin-2-one, (68)-5-[4'-methoxy-2-(trifluoromethyl)[1, r-biphenyl] -4-yl]-6-methyl-3,6-dihydro-2H1,3,4-oxadiazin-2-one, (6 8)-6-methyl-5 - [4'-methyl-2-(trifluoromethyl ) [1,1 '-biphenyl] -4-yl] -3,6-dihydro-2H1,3,4-oxadiazin-2-one, (6S)-5-{4-[l -(difluoromethyl)- 1 H-pyrazol-4-yl] -3 -(trifluoromethyl)-phenyl} -6-methyl3,6-dihydro-2H-1,3,4-oxad iazin-2-one,

- { 4- [ 1 - (difluoromethyl) -1 H-pyrazol-4-yl] -3 - (trifluoromethyl) -phenyl } -6-methyl-3,6dihydro-2H-1,3,4-oxad iazin-2 -she,

5-[4'-fluoro-2-(trifluoromethyl)[1,G-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

- { 4- [ 1 - (difluoromethyl) -1 H-pyrazol-4-yl] -3 - fluoro-5 - (trifluoro methyl) phenyl } -3,6- 56 041614 dihydro-2H-1,3,4- oxad iazin-2-one,

- { 3 - (difluoromethyl) -4-[ 1 - (d ifluoromethyl) -1 H-pyrazol-4-yl] phenyl } -3,6-dihydro2H-1,3,4-oxad iazin-2-one, (6 8)-6-methyl-5 - {4-[(morpholin-4-yl)methyl] -3 -(trifluoromethyl)phenyl} -3,6-dihydro2H-1,3,4-oxad iazin-2- she,

- { 4- [(morpholin-4-yl) methyl] -3 - (trifluoromethyl) phenyl } -3,6-dihydro-2H-1,3,4 oxadiazin-2-one,

5-[2-(difluoromethyl)-4'-fluoro[1,G-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one,

5-[4'-chloro-2-(difluoromethyl)[1,G-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one,

-[3 - (d iftor methyl) -4- (6-methylpyridin-3 -yl) phenyl] -3,6-d ihydro-2H-1,3,4 oxadiazin-2-one,

-[4-(cyclopent-1-en-1-yl)-3-(d iftoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[3-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one,

-[4-(3-hydroxy-3-methylazetidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro- 57 041614

2H-1,3,4-oxad iazin-2-one, (gas)-5 - [4- {[3,3,3-trifluoro-2-hydroxypropyl] amino } -3 - (trifluoro methyl) phenyl] 3 ,6-dihydro-2H-1,3,4-oxade of iazin-2-one,

- {4-[(oxan-4-yl)amino]-3-(trifluoromethyl)phenyl}-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

-[4-{[(cis/trans)-3-hydroxycyclobutyl]amino}-3-(trifluoromethyl)phenyl]-3,6dihydro-2H-1,3,4-oxad iazin-2-one,

- { 4- [(gas) -2,4-Dimethylazetidin-1 -yl] -3 - (trifluoromethyl) phenyl } -3,6-dihydro-2H1,3,4-oxadiazin-2-one,

5-{4-[(cis or trans)-2,4-Dimethylazetidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6dihydro-2H-1,3,4-oxad paz in-2-one ,

-[4-{[3,3,3-trifluoro-2(8)-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6dihydro-2H-1,3,4-oxade iazine-2- she,

- { 4- [(2-hydroxy-2-methylpropyl) amino] -3 - (trifluoromethyl) phenyl } -3,6-dihydro2H-1,3,4-oxad iazin-2-one,

-[4- {[(trans)-4-hydroxycyclohexyl] amino} -3 -(trifluoromethyl)phenyl] -3,6dihydro-2H-1,3,4-oxad iazin-2-one,

- {4-[(cyclopropylmethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-58 041614 oxadiazin-2-one,

-[4-{[(3-methyloxetan-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro2H-1,3,4-oxad iazin-2-one,

- { 4- [(3 - methox and propyl) amino] -3 - (trifluoromethyl) phenyl } -3,6-dihydro-2H-1,3,4 oxadiazin-2-one,

-[4-({ [(gas)-oxolan-2-yl] methyl } amino)-3 -(trifluoromethyl)phenyl]-3,6-dihydro2H-1,3,4-oxad iazin-2-one,

-[4-{[2(K)-2-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H1,3,4-oxadiazin-2-one,

-[4-{[(3R)-3-hydroxybutyl]amino}-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H1,3,4-oxadiazin-2-one,

-[4- {[(2 8)-2-hydroxypropyl] amino } -3 - (trifluoromethyl) phenyl] -3,6-d ihydro-2H1,3,4-oxadiazin-2-one,

-[4-{[(1-hydroxycyclobutyl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6dihydro-2H-1,3,4-oxad iazin-2-one,

- { 4- [(3 -methylbutyl) amino] -3 - (trifluoromethyl) phenyl } -3,6-dihydro-2H-1,3,4 oxadiazin-2-one,

- { 4- [(2-methylpropyl) amino] -3 - (trifluoro methyl) phenyl } -3,6-d ihydro-2H-1,3,4- 59 041614 oxadiazin-2-one,

- { 4- [(2-methox and ethyl) amino] -3 - (trifluoro methyl) phenyl } -3,6-d ihydro-2H-1,3,4 oxadiazin-2-one,

- {4-[ethyl(methyl)amino]-3-(trifluoromethyl)phenyl}-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

5-[4-(tert-butylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[4-({[(2K)-oxolan-2-yl]methyl}amino)-3-(trifluoromethyl)phenyl]-3,6-dihydro2H-1,3,4-oxad iazin-2-one,

-[4-{[(pyrazin-2-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H1,3,4-oxadiazin-2-one,

-[4-(4-hydroxypiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4 oxadiazin-2-one,

5-[4-{[(28)-1-hydroxybutan-2-yl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro2H-1,3,4-oxad iazin-2-one,

-[4-(3-hydroxypiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4 oxadiazin-2-one (racemic mixture), (gas )-1 - [4-(2-oxo-3,6-d ihydro-2H-1,3,4-oxadiazin-5 -yl)-2-60 041614 (trifluoromethyl)phenyl]piperidine-3-carboxamide,

- {4-[(3-hydroxy-2,2-dimethylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6dihydro-2H-1,3,4-oxad iazin-2-one,

-[4-(4,4-d ifluoropiper idin-1 -yl)-3 -(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

-[4-{[(1 K,2K,4R)-bicyclo[2.2.1]heptan-2-yl]amino}-3-(trifluoromethyl)phenyl] 3,6-dihydro-2H-1,3,4 -oxad iazin-2-one,

- { 4- [(3 S)-3 -hydroxypyrrolidin-1 -yl] -3 - (trifluoromethyl) phenyl } -3,6-d ihydro2H-1,3,4-oxad iazin-2-one, ( gas)-5 - { 4- [(2-hydroxy-3-methoxypropyl) amino] -3 - (trifluoromethyl) phenyl } -3,6 dihydro-2H-1,3,4-oxad iazin-2-one,

-[4- {[(1 -methyl-1 H-pyrazol-5 -yl)methyl] amino } -3 -(trifluoromethyl)phenyl] -3,6dihydro-2H-1,3,4-oxad iazin-2- she,

-[4-{[(1H-pyrazol-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H1,3,4-oxadiazin-2-one,

-[4-{[2-(1H-pyrazol-1-yl)ethyl]amino}-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H1,3,4-oxadiazine-2- she,

1-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2- 61 041614 (trifluoromethyl)phenyl]piperidine-4-carbonitrile, (rac)- 5 - { 4- [(1 -cyclopropylethyl) amino] -3 - (trifluoromethyl) phenyl } -3,6-d ihydro-2H1,3,4-oxadiazin-2-one, (gas) -5 - { 4 - [(2-ethoxypropyl) amino] -3 - (trifluoromethyl) phenyl } -3,6-d ihydro-2H1,3,4-oxadiazin-2-one (gas) -5 - { 4- [(2-methoxypropyl )amino] -3 -(trifluoromethyl)phenyl } -3,6-dihydro-2H1,3,4-oxadiazin-2-one

-[4-(3-ethoxyazetidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one,

-[4-{[(pyrimidin-2-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H1,3,4-oxadiazin-2-one,

-[4-{[(oxolan-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H1,3,4-oxadiazin-2-one (racemic mixture),

5-[4-{[(28)-4-hydroxybutan-2-yl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro2Н-1,3,4-oxad iazin-2-one, ( gas)-5 - [4- {[(6-oxopiper id in-3 -yl)methyl] amino} -3 - (trifluoromethyl) phenyl] -3,6dihydro-2H-1,3,4-oxad iazine- 2-one, (gas)-5 - [4- {[(2,2-dimethylcyclopropyl) methyl] amino} -3 - (trifluoromethyl) phenyl] - 62 041614

3,6-dihydro-2H-1,3,4-oxade of iazin-2-one,

5-[4-({[1-(hydroxymethyl)cyclobutyl]methyl}amino)-3-(trifluoromethyl)phenyl]-3,6dihydro-2H-1,3,4-oxad iazin-2-one,

- { 4- [(2 8) -2- (hydroxymethyl) azetide in-1 -yl] -3 - (trifluoromethyl) phenyl } -3,6 dihydro-2H-1,3,4-oxad iazin-2-one,

-methyl-1 - [4-(2-oxo-3,6-dihydro-2H-1,3,4-oxad iazin-5 -yl)-2(trifluoromethyl)phenyl]azetidine-3-carbonitrile,

-[4-(3-azabicyclo[3.1.0]hexan-3-yl)-3-(trifluoromethyl)phenyl]-3,6-d ihydro-2H1,3,4-oxadiazin-2-one,

5-[4-(4-ethyl-4-hydroxypiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro2H-1,3,4-oxad iazin-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] 2 lambda ^6- thia-6-azaspiro[ 3.3] heptane-2,2-dione,

X ² -[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2(trifluoromethyl)phenyl]glycinamide,

- { 4- [(3R)-3 -hydroxypyrrolidin-1 -yl] -3 - (trifluoromethyl) phenyl } -3,6-dihydro- 63 041614

2H-1,3,4-oxad iazin-2-one,

- {4-[(2-methoxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-d ihydro2H-1,3,4-oxad iazin-2-one,

5-[4-({[(28)-oxolan-2-yl]methyl}amino)-3-(trifluoromethyl)phenyl]-3,6-dihydro2H-1,3,4-oxad iazin-2-one,

- { 4- [(2-ethoxyethyl) amino] -3 - (trifluoromethyl) phenyl } -3,6-d ihydro-2H-1,3,4 oxadiazin-2-one,

-[4-{[(18,2K)-2-hydroxycyclopentyl]amino}-3-(trifluoromethyl)phenyl]-3,6dihydro-2H-1,3,4-oxad iazin-2-one,

- { 4- [(oxetan-3 -yl) amino] -3 - (trifluoromethyl) phenyl } -3,6-d ihydro-2H-1,3,4 oxadiazin-2-one,

- { 3 - (difluoromethyl) -4- [ 1 - (propan-2-yl) -1 H-pyrazol-4-yl] phenyl } -3,6-d ihydro-2H1,3,4-oxadiazin-2 -she,

-[3 -fluoro-4-(morpholin-4-yl)-5 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one, (68)-6- methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}3,6-dihydro-2H-1,3,4-iazin-2-one oxad , (68)-6-methyl-5-{3-(trifluoromethyl)-4-[4-(trifluoromethyl)-1H-imidazol-1-64 041614 yl]phenyl}-3,6-dihydro-2H-1, 3,4-oxadiazin-2-one,

5-[4-(3-methoxypropyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[4-(2-methylpropyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one,

5-[4-(3,3-dimethylbutyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

5-[4-(propan-2-yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one, (gas)-5 - { 4- [oxane -3 -yl] -3 -(trifluoromethyl)phenyl } -3,6-d ihydro-2H-1,3,4oxadiazin-2-one, (trans)-5 - {4- [4-hydroxycyclohexyl] -3 -(trifluoromethyl)phenyl } -3,6-dihydro-2H1,3,4-oxadiazin-2-one (trans isomer), (ci s)-5 - { 4-[4-hydroxycyclohexyl] -3 -(trifluoromethyl )phenyl } -3,6-d ihydro-2H1,3,4-oxadiazin-2-one,

- { 4- [(2-aminoethyl) amino] -3 - (trifluoromethyl) phenyl } -3,6-dihydro-2H-1,3,4 oxadiazin-2-one - salt of hydrochloric acid,

- {4-[1-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-(trifluoromethyl)-phenyl}-3,6-65 041614 dihydro-2H-1,3,4-oxadiazine -2-one is a salt of hydrochloric acid,

5-[4-(methylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one, (68)-6-methyl-5-[4-(4 -methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro2H-1,3,4-oxadiazin-2-one,

5-[4-(2-hydroxypropan-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one, (6 S)-5-[4 -(3,3-difluoroazetidin-1-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6dihydro-2H-1,3,4-oxad iazin-2-one and (68)-5- [4-(3-hydroxy-3-methylazetidin-1-yl)-3-(trifluoromethyl)-phenyl]-6-methyl3,6-dihydro-2H-1,3,4-oxad iazin-2-one or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I): wherein the compound is selected from the group

-[4-(4,4-difluoropiperidin-1 -yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one,

- [4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

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,

- [4'-chloro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

5-[4-(1,2-thiazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one

- [4-(2-methyl-1,3-thiazol-5-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

- [4-(propylamino)-3 -(trifluoromethyl)phenyl] -3,6-dihydro-2H-1,3,4-oxad iazin-2one

- [4'-fluoro-2-(trifluoromethoxy)biphenyl-4-yl]-3,6-d ihydro-2H-1,3,4-oxadiazin-2one

- 66 041614 (6 S) - 5 - [4'-fluoro-2- (trifluoromethyl) biphenyl-4-yl] -6-methyl-3, 6-d ihydro-2H-1,3,4 oxadiazin-2-one ,

5-[4-(cyclopentylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

- { 4-[ 1 - (d ifluoromethyl) -1 H-pyrazol-4-yl] -3 - (trifluoromethyl) phenyl } -3,6-d ihydro2H-1,3,4-oxadiazin-2-one,

- [4-(2,5-dihydrofuran-3 -yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

- [4-(5-chloropyridin-2-yl)-3 -(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one (6 S)-5 -[4 -(2-aminopyride in-4-yl)-3 -(trifluoromethyl)phenyl]-6-methyl-3,6-d ihydro2H-1,3,4-oxadiazin-2-one and (6S)-5- {4-[l -(difluoromethyl)-1 H-pyrazol-4-yl] -3 -(trifluoromethyl)-phenyl} -6-methyl3,6-dihydro-2H-1,3,4-oxadiazin-2- she,

- {4-[(morphol in-4-yl)methyl] -3 -(trifluoromethyl)phenyl} -3,6-d ihydro-2H-1,3,4oxadiazin-2-one (cis/trans)-5 -[4-{[3-hydroxycyclobutyl]amino}-3-(trifluoromethyl)phenyl]-3,6dihydro-2H-1,3,4-oxadiaz in-2-one

- [4-{[3,3,3-trifluoro-2(8)-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6dihydro-2H-1,3,4-oxadiaz in-2-one ,

- {4-[(2-hydroxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-d ihydro2H-1,3,4-oxadiazin-2-one,

5-{4-[(2-methoxyethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

- 67 041614

- [4- {[(pyrazin-2-yl)methyl] amino } -3 - (trifluoromethyl) phenyl] -3,6-d ihydro-2H1,3,4-oxad iazin-2-one (6 8) - 6-methyl-5 - { 3 - (trifluoromethyl) -4- [3 - (trifluoromethyl) -1 H-pyrazol-1 -yl] phenyl } 3,6-dihydro-2H-1,3,4-oxadiazin- 2-she,

- [4-(2-methylpropyl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one and (68)-5-[4-(3-hydroxy -3-methylazetidin-1-yl)-3-(trifluoromethyl)phenyl]-6-methyl3,6-dihydro-2H-1,3,4-oxadiazin-2-one or their stereoisomer, tautomer, N-oxide, hydrate , solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is selected from the group

5-[4-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one

5-(3',4'-difluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- [4-(1,2-thiazol-4-yl)-3 -(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4-oxad iazin2-one

- [4-(2-methyl-1,3-thiazol-5-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

- 68 041614

- [4-(propylamino)-3 -(trifluoromethyl)phenyl] -3,6-dihydro-2H-1,3,4-oxad iazin-2one

- [4'-fluoro-2-(trifluoromethoxy)biphenyl-4-yl]-3,6-d ihydro-2H-1,3,4-oxadiazin-2one

- [4-(cyclopentylamino)-3 -(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one

- [4-(2,5-dihydrofuran-3 -yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

- [4-(5-chloropyridin-2-yl)-3 -(trifluoromethyl)phenyl]-3,6-d ihydro-2H-1,3,4oxadiazin-2-one

5-{4-[(morpholin-4-yl)methyl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one (cis/trans)-5 -[ 4-{[3-hydroxycyclobutyl]amino}-3-(trifluoromethyl)phenyl]-3,6dihydro-2H-1,3,4-oxadiaz in-2-one

- [4- {[(pyrazin-2-yl)methyl] amino} -3 - (trifluoromethyl) phenyl] -3,6-d ihydro-2H1,3,4-oxad iazin-2-one

- [4-(2-methylpropyl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one (68)-5-[4-(3-hydroxy- 3-methylazetidin-1-yl)-3-(trifluoromethyl)phenyl]-6-methyl3,6-dihydro-2H-1,3,4-oxadiazin-2-one or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is selected from the group

- 69 041614

- [4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one,

5-(4'-fluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

- [4'-chloro-2-(trifluoromethyl)biphenyl-4-yl] -3,6-dihydro-2H-1,3,4-oxadiazin-2one, (6 S)-5 - {4- [ 1 - (difluoromethyl)-1 H-pyrazol-4-yl]-3-(trifluoromethyl)-phenyl}-6-methyl3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

- [4-{[3,3,3-trifluoro-2(8)-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6dihydro-2H-1,3,4-oxadiaz in-2-one ,

- {4-[(2-hydroxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-d ihydro2H-1,3,4-oxadiazin-2-one,

5-{4-[(2-methoxyethyl)amino]-3-(trifluoromethyl)phenyl }-3,6-dihydro-2H-1,3,4oxadiazin-2-one, (68)-5-[4'- fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

- {4-[ 1 - (difluoromethyl) -1 H-pyrazol-4-yl] -3 - (trifluoro methyl) phenyl} -3,6-d ihydro2H-1,3,4-oxadiazin-2-one, ( 68)-5-[4-(2-aminopyridin-4-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro2H-1,3,4-oxadiazin-2-one and (6 8)-6-methyl-5 - { 3 - (trifluoromethyl) -4- [3 - (trifluoro methyl) -1 H-pyrazol-1 -yl] phenyl } 3,6-dihydro-2H-1,3,4 -oxadiazin-2-one, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is selected from the group

5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one,

-(4'-fluoro-2-methylbiphenyl-4-yl)-3,6-d ihydro-2H-1,3,4-oxad iazin-2-one,

5-[4'-chloro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one and (6S)-5-[4'-fluoro -2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-d ihydro2H-1,3,4-oxad iazin-2-one,

- 70 041614 or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is selected from the group (6S)-5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3 -(trifluoromethyl)-phenyl}-6-methyl3,6-dihydro-2H-1,3,4-oxadiazin-2-one,

5-[4-{[3,3,3-trifluoro-2(8)-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6d ihydro-2H-1,3,4-oxadiazin-2 -she,

- {4-[(2-hydroxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-d ihydro2H-1,3,4-oxadiazin-2-one,

- { 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-dihydro2H-1,3,4-oxadiazin-2-one, (68) -5-[4-(2-aminopyridin-4-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro2H-1,3,4-oxadiazin-2-one and (68)- 6-methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}3,6-dihydro-2H-1,3,4-oxadiazin-2- she, or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is selected from the group

5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiaz in-2one,

-(4'-fluoro-2-methylbiphenyl-4-yl)-3,6-d ihydro-2H-1,3,4-oxad iazin-2-one,

5-[4'-chloro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiaz in-2one, (6S)-5-{4-[l -(difluoromethyl)-1 H-pyrazol-4-yl] -3 -(trifluoromethyl)-phenyl} -6-methyl3,6-dihydro-2H-1,3,4-oxad iazin-2-one,

- 71 041614

-[4-{[3,3,3-trifluoro-2(8)-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6dihydro-2H-1,3,4-oxade iazine-2- she,

- { 4- [(2-hydroxy-2-methylpropyl) amino] -3 - (trifluoromethyl) phenyl } -3,6-dihydro2H-1,3,4-oxadiazin-2-one and

- { 4- [(2-methox and ethyl) amino] -3 - (trifluoro methyl) phenyl } -3,6-d ihydro-2H-1,3,4 oxadiazin-2-one, or their stereoisomer, tautomer, N- oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is selected from the group (68)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl- 3,6-dihydro-2H-1,3,4oxadiazin-2-one,

- {4- [ 1 - (difluoromethyl) -1 H-pyrazol-4-yl] -3 - (trifluoromethyl) phenyl } -3,6-dihydro2H-1,3,4-oxadiazin-2-one, (6 S )-5-[4-(2-Aminopyridin-4-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro2H-1,3,4-oxadiazin-2-one and (68 )-6-methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}3,6-dihydro-2H-1,3,4-oxad iazine -2-one, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is (6S)-5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl- 3,6-dihydro-2H-1,3,4oxadiazin-2-one, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is

- { 4- [ 1 - (difluoromethyl) -1 H-pyrazol-4-yl] -3 - (trifluoromethyl) phenyl } -3,6-dihydro2H-1,3,4-oxad iazin-2-one, or its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is (68)-5-[4-(2-aminopyridin-4-yl)-3-(trifluoromethyl)phenyl]-6- methyl-3,6-dihydro2H-1,3,4-oxadiazin-2-one and or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is (68)-6-methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazole -1-yl]phenyl}3,6-dihydro-2H-1,3,4-oxadiazin-2-one, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

- 72 041614

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is

5-[4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiaz in-2-one, or its stereoisomer, tautomer, N-oxide , hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is

5-(4'-fluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, or its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is

- [4'-chloro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, or its stereoisomer, tautomer, N-oxide, hydrate , solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is (6S)-5-{4-[ 1 -(difluoromethyl)-1 H-pyrazol-4-yl]-3- (trifluoromethyl)-phenyl}-6-methyl3,6-dihydro-2H-1,3,4-oxadiazin-2-one, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is

- [4-{[3,3,3-trifluoro-2(8)-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6dihydro-2H-1,3,4-oxadiazin-2-one , or its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is

- {4-[(2-hydroxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-d ihydro2H-1,3,4-oxadiazin-2-one and or its stereoisomer, tautomer , N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein the compound is

- {4-[(2-methoxyethyl)amino] -3 -(trifluoromethyl)phenyl} -3,6-dihydro-2H-1,3,4oxadiazin-2-one, or its stereoisomer, tautomer, N-oxide, hydrate , solvate or salt, or a mixture thereof.

In accordance with another embodiment of the first object, the present invention provides compounds, specific examples of which are presented in the experimental part, or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from hydrogen, halogen, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ - C ₃ haloalkoxy groups;

R ² is selected from a hydrogen atom and a halogen atom;

R ³ is selected from

C ₁ -C ₆ -alkyl group, which is optionally substituted with one or two substituents, and each substituent is independently selected from hydroxy group, C ₁ -C ₄ -alkoxy group and 3-7 membered heterocycloalkyl group,

C ₂ -C ₆ -alkenyl group, which is optionally substituted with C ₁ -C ₄ -alkoxy group,

C ₃ -C 9 -cycloalkyl group, which is optionally substituted by hydroxy group,

C ₅ -C ₉ -cycloalkenyl group, which is optionally substituted by hydroxy group,

a 3-9 membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O-, -S-, -S(O)-, S(O) ₂ and -NR ⁹ -,

- 73 041614 and said heterocycloalkyl group optionally further comprises a bridging group selected from -O-, -NR ⁹ -, -CH ₂ -, -CH2-CH2-, -O-CH2-, -CH2-O-, -NR ⁹ -CH2- and -CH2-NR ⁹ -;

and said heterocycloalkyl group is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom;

oxo (=O) groups;

cyano groups;

hydroxy groups;

a C1- _C3 alkyl group which is optionally substituted with hydroxy;

C1- _C3 haloalkyl group;

Ci-C3-alkoxy groups;

C ₁ -C3-haloalkoxy groups;

C(O)NR ⁵ R ⁶ groups and

NR5R ⁶ groups,

5-9 membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from oxo group (=O), C ₁ -C ₃ -alkyl group, -C(O)R ⁵ R ⁶ group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C1C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group , C ₁ -C ₃ -alkoxy groups, C ₁ -C ₃ -haloalkoxy groups and NR ⁵ R ⁶ group, mono - or bicyclic heteroaryl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, C ₁ - _C3 alkyl group, cyano group, C1- _C3 haloalkyl group, C1- _C3 alkoxy group, hydroxy group and ^NR5R6 group, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R group ⁸ ;

R ⁴ represents a hydrogen atom;

R5/ ^R6 is independently selected from a hydrogen atom, a C1- _C6 alkyl group, -C1 _{- C5} alkylene- _OC1 - _C5 alkyl group, _{-C1- C5} alkylene-S- _C1 -C ₅ -alkyl group, C ₃ -C ₆ -cycloalkyl group, and C ₃ -C ₅ heterocycloalkyl group;

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

a C1- _C6 alkyl group which is optionally substituted with one, two, three or four substituents, and said substituent is independently selected from halogen atom, cyano group, hydroxy group, C(O)NR ⁵ R ⁶ group, NR5R ⁶ group,

C1-C ₃ -alkoxy groups,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted with one or two substituents, and these substituents are independently selected from C1-C ₃ -alkyl group, oxo (=O) group, hydroxy group and C1-C ₃ -hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a C1- _C3 alkyl group or an oxo (=O) group, a heteroaryl group which itself is optionally substituted with a C1- _C3 alkyl group;

- C1-C ₅ -alkylene-O-C 1 -C ₅ -alkyl group,

- C1-C ₅ -alkylene-S-C 1 -C ₅ -alkyl group,

- C1-C ₅ -alkylene-NR ⁵ -C1-C5 -alkyl group,

C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C1- _C3 alkyl group and a hydroxy group,

R ⁹ is a hydrogen atom or a C1- _C3 alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein 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 groups;

R ² is selected from a hydrogen atom and a halogen atom,

R ³ is selected from a halogen atom,

C2-C6-alkenyl group,

C3-C6-cycloalkyl group,

C ₅ -C ₆ -cycloalkenyl group,

C ₃ -C ₇ -heterocycloalkyl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom and a C ₁ -C ₃ -alkyl group, hydroxy group, NR5R ⁶ group, C ₁ -C ₃ -haloalkyl group and C ₁ -C ₃ -haloalkoxy group,

a C ₅ -C 7 heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from an oxo group (=O), a C ₁ -C ₃ alkyl group and a halogen atom, an aryl group, which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C _i C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, C ₁ -C ₃ -haloalkoxy group and NR5R ⁶ group, mono - or bicyclic heteroaryl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, C ₁ -C ₃ -alkyl group, cyano group, C ₁ -C ₃ haloalkyl group, C ₁ -C ₃ alkoxy group, hydroxy group and NR5R ⁶ group, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R ⁸ groups,

R ⁴ is a hydrogen atom,

R5/R ⁶ is independently selected from 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 group, and C ₃ -C ₅ heterocycloalkyl group,

R7/ ^R8 is independently selected from a hydrogen atom, and a C1-C6 alkyl group, -C1-C5 alkylene-O-C1-C5 alkyl group, -C1-C5 alkylene-S-C1-C5 alkyl group, -C1 -C5-alkylene-NR ⁵ -C1-C ₅ -alkyl group, C ₃ -C ₆ -cycloalkyl group, C ₃ -C ₅ -heterocycloalkyl group, or R7 and R ⁸ together form 3-, 4-, 5-, A 6- or 7-membered ring optionally containing one or two additional heteroatoms selected from the group consisting of -O-, -S- and -NR ⁹ - and which is optionally substituted one, two or three times with a substituent selected from an atom halogen, C ₁ -C ₃ alkyl group, hydroxy group, cyano group, oxo group (=O), and NR5R ⁶ group, and if R ⁷ and R ⁸ together form a 5-, 6-, or 7-membered ring, said ring may optionally contain a bridging group selected from -O-, -NR ⁹ -, -CH2-, -CH2-CH2-, -O-CH2-, -NR ⁹ -CH ₂ -;

R ⁹ represents a hydrogen atom or a C ₁ -C ₃ -alkyl group, or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from hydrogen, halogen, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ - C ₃ haloalkoxy groups;

R ² is selected from a hydrogen atom and a halogen atom;

R ³ is selected from

a C ₁ -C ₆ alkyl group which is optionally substituted with a substituent selected from a hydroxy group, a C ₁ -C ₄ alkoxy group and a 3-7 membered heterocycloalkyl group,

C ₂ -C ₆ -alkenyl group, which is optionally substituted with C ₁ -C ₄ -alkoxy group,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted by hydroxy group,

C ₅ -C ₇ -cycloalkenyl group, which is optionally substituted by hydroxy group,

a 3-7 membered heterocycloalkyl group containing one or two heteroatoms which are independently selected from -O-, S(O)2 and -NR ⁹ - and said heterocycloalkyl group is optionally substituted with one or two substituents and each substituent is independently selected from a halogen atom;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

C ₁ -C ₃ alkoxy groups;

C(O)NR ⁵ R ⁶ groups and

NR ⁵ R ⁶ groups;

a 5-7 membered heterocycloalkyl group containing a heteroatom selected from -O-, -S- and NR ⁹ -, which is partially unsaturated and optionally substituted with a substituent selected from a C ₁ -C ₃ -alkyl group and a halogen atom, an aryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ - an alkoxy group and an NR5R ⁶ group, a mono- or bicyclic heteroaryl group which is optionally substituted with a substituent selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ - alkoxy groups and

NR ⁵ R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R group ⁸ ;

R ⁴ represents a hydrogen atom;

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group;

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

Cl-C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, C(O)NR ⁵ R ⁶ group, NR5R ⁶ group,

C ₁ -C ₃ -alkoxy groups,

C ₃ -C ₇ -cycloalkyl group, which is optionally additionally substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group, oxo (=O) group, hydroxy group and C ₁ -C3-hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C ₁ -C ₃ alkyl group, a heteroaryl group which is optionally further substituted with C ₁ -C ₃ -alkyl group,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted by hydroxy group or C ₁ -C ₃ alkyl group,

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C ₁ -C ₃ alkyl group and a hydroxy group,

R ⁹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from hydrogen, halogen, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ - C ₃ haloalkoxy groups;

R ² is selected from a hydrogen atom and a halogen atom;

R ³ is selected from

C ₁ -C ₆ -alkyl group, which is optionally substituted by a substituent, which is selected from hydroxy group, C ₁ -C ₄ -alkoxy group and 3-7-membered heterocycloalkyl group,

C ₂ -C ₆ -alkenyl group, which is optionally substituted with C ₁ -C ₄ -alkoxy group, C3-C7 -cycloalkyl group, which is optionally substituted with hydroxy group, C ₅ -C ₇ -cycloalkenyl group, which is optionally substituted with hydroxy group, 3-7- a membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O-, S(O) ₂ and -NR ⁹ -, and said heterocycloalkyl group is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

cyano groups;

hydroxy groups;

C ₁ -C ₃ -alkyl group, which is optionally further substituted by hydroxy;

C ₁ -C ₃ alkoxy groups;

C(O)NR ⁵ R ⁶ groups;

and NR5R ⁶ groups;

a 5-7 membered heterocycloalkyl group containing a heteroatom selected from -O-, -S- and NR ⁹ -, which is partially unsaturated and optionally substituted with a substituent selected from a C ₁ -C ₃ -alkyl group and a halogen atom, an aryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ - an alkoxy group and an NR5R ⁶ group, a mono- or bicyclic heteroaryl group which is optionally substituted with a substituent selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ - alkoxy groups and NR5R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R group ⁸ ;

R ⁴ represents a C ₁ -C ₃ -alkyl group;

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group;

R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four per

- 76 041614 substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, C(O)NR ⁵ R ⁶ group, NR5R ⁶ group,

C ₁ -C ₃ -alkoxy groups,

C ₃ -C 7 -cycloalkyl group, which is optionally additionally substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group, oxo (=O) group, hydroxy group and C ₁ -C ₃ -hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C ₁ -C ₃ alkyl group, a heteroaryl group which is optionally further substituted with C1 -C3-alkyl group,

a C3-C7 cycloalkyl group which is optionally substituted with a hydroxy group or a C1-C3 alkyl group,

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C1-C3 alkyl group and a hydroxy group,

R ⁹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ -haloalkoxy groups;

R ² is selected from a hydrogen atom, and a halogen atom,

R ³ is selected from a halogen atom C ₂ -C ₄ -alkenyl group,

C ₅ -C ₆ -cycloalkenyl group,

C ₃ -C ₆ -heterocycloalkyl group, which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom and C ₁ -C ₃ -alkyl group;

a C ₅ -C ₆ heterocycloalkyl group which is partially unsaturated and optionally substituted with one or two substituents, and each substituent is independently selected from an oxo group (=O), a C ₁ -C ₃ alkyl group and a halogen atom;

an aryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, and an NR5R ⁶ group;

a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ -alkoxy groups and NR5R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R group ⁸ ;

R ⁴ is a hydrogen atom,

R5/R ⁶ is independently selected from hydrogen atom, C ₁ -C ₆ alkyl group, -C ₁ -C ₃ alkylene-O-C ₁ -C ₃ alkyl group, -C ₁ -C ₃ alkylene-S-C ₁ -C ₃ -alkyl group, and C ₃ -C ₅ -heterocycloalkyl group,

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 = hydrogen is excluded, and a C ₁ -C ₆ alkyl group, -C ₁ -C ₃ -alkylene-O-C ₁ -C ₃ - alkyl group, -C ₁ -C ₃ -alkylene-S-C ₁ -C ₃ alkyl group, -C ₁ -C ₃ -alkylene-NR ⁵ -C ₁ -C ₃ -alkyl group, C ₃ -C ₆ -cycloalkyl group, a C3-C5 heterocycloalkyl group, or R ⁷ and R ⁸ together form a 3-, 4-, 5-, 6- or 7-membered ring, optionally containing one or two additional heteroatoms selected from the group consisting of -O-, -S- and -NR ⁹ -, and which is optionally substituted one, two or three times with a substituent selected from a halogen atom, a C ₁ -C ₃ -alkyl group, hydroxy group, cyano group, oxo group (=O), and NR5R ⁶ groups,

R ⁹ is a hydrogen atom or a C ₁ -C ₃ alkyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from CF ₃ , -CH ₃ , -OCF ₃ and a fluorine atom,

R ² is selected from a hydrogen atom,

R ³ is selected from a halogen atom,

C2-C4-alkenyl group,

C5-C6-cycloalkylenyl group,

C ₃ -C ₆ -heterocycloalkyl group, which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom and C ₁ -C ₃ -alkyl group;

- 77 041614

C ₅ -C ₆ -heterocycloalkyl group, which is partially unsaturated and optionally substituted by oxo group (=O);

a phenyl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a C ₁ -C ₃ alkyl group, a C ₁ C ₃ haloalkyl group, and an NR5R ⁶ group;

a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ -alkoxy groups and NR5R ⁶ groups;

and NR7R group ⁸ ;

R ⁴ is a hydrogen atom,

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₃ alkyl group; And

R7/R ⁸ is independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group;

or R ⁷ and R ⁸ together form a 4-, 5- or 6-membered ring, optionally containing one additional oxygen atom, and which is optionally substituted once or twice with a substituent selected from a halogen atom and a C ₁ -C ₃ -alkyl group;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from CF ₃ , -CH ₃ , -OCF ₃ and a fluorine atom,

R ² is selected from a hydrogen atom,

R ³ is selected from a halogen atom, a prop-1-en-1-yl group which is optionally substituted with a methyl group, a piperidin-1-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a fluorine atom and a methyl group , a morpholin-4-yl group which is optionally substituted with one or two methyl groups, a pyrrolidin-1-yl group which is optionally substituted with one or two halogen atoms, a 1,2,3,6-tetrahydropyridin-4-yl group which is optionally substituted with a methyl group, an azitidin-1 -yl group,

3,6-dihydro-1 H-pyran-4-yl group,

a 6-oxo-1,6-dihydropyridin-3-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a hydrogen atom and a methyl group, a cyclopent-1-en-1-yl group, a phenyl group which optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a methyl group, an ethyl group, a CF ₃ , a CF ₂ H group, a methoxy group, a CF ₃ O group, an NH2 group, and an NHCH3 group,

a 2H-pyrrol-1-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a hydrogen atom, a cyano group, and a methyl group,

1H-pyrrazol-4-yl group, which is optionally substituted with one or two substituents, and each substituent is independently selected from a methyl group, an ethyl group, or a CF ₃ group,

1H-pyrrazol-5-yl group which is optionally substituted with a methyl group, 1,2-oxazol-4-yl which is optionally substituted with one or two methyl groups, 1,2-thiazol-4-yl group which is optionally substituted with a methyl group , 1,3-thiazol-5-yl group, which is optionally substituted with a methyl group, pyridin-3-yl, pyridin-4-yl and pyridin 5-yl groups, each group is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a methyl group, a CF ₃ group, a methoxy group and an NH ₂ group, a pyrimidin-5-yl group which is optionally substituted with a methyl group,

1H-indol-6-yl group,

1H-indazol-6-yl group which is optionally substituted with methyl group, N-benzimidazol-6-yl group which is optionally substituted with methyl group, NH(C ₂ H ₅ ) group, NH(C ₃ H ₇ ) group, NH( C ₄ H ₉ ) groups, NCH ₃ (C ₄ H ₉ ) groups, NH(C ₅ H ₁₁ ) groups, NH(cyclopentyl) groups, NCH ₃ (cyclopentyl) groups;

R ⁴ represents a hydrogen atom, or a stereoisomer, tautomer, N-oxide, hydrate, MES or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from CF3, -CH3, -OCF3 and a fluorine atom,

R ² is selected from a hydrogen atom,

R ³ is selected from

- 78 041614 a prop-1-en-1-yl group which is optionally substituted with a methyl group, a piperidin-1-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a fluorine atom and a methyl group, morpholine-4 -yl group which is optionally substituted with one or two methyl groups, pyrrolidin-1-yl group which is optionally substituted with one or two halogen atoms, 1,2,3,6-tetrahydropyridin-4-yl group which is optionally substituted with methyl group, azitidin-1-yl group,

3,6-dihydro-1 H-pyran-4-yl group,

a 6-oxo-1,6-dihydropyridin-3-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a hydrogen atom and a methyl group, a cyclopent-1-en-1-yl group, a phenyl group which optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a methyl group, an ethyl group, a CF ₃ , a CF ₂ H group, a methoxy group, a CF3O group, an NH2 group, and an NHCH3 group,

a 2H-pyrrol-1-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a hydrogen atom, a cyano group, and a methyl group,

a 1H-pyrrazol-4-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a methyl group, an ethyl group, or a CF3 group,

1H-pyrrazol-5-yl group which is optionally substituted with a methyl group, 1,2-oxazol-4-yl which is optionally substituted with one or two methyl groups, 1,2-thiazol-4-yl group which is optionally substituted with a methyl group , 1,3-thiazol-5-yl group, which is optionally substituted with a methyl group, pyridin-3-yl, pyridin-4-yl and pyridin 5-yl groups, each group is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a methyl group, a CF3 group, a methoxy group and an NH2 group, a pyrimidin-5-yl group which is optionally substituted with a methyl group,

1H-indol-6-yl group,

1H-indazol-6-yl group, which is optionally substituted with a methyl group,

1H-benzimidazol-6-yl group, which is optionally substituted with a methyl group,

NH(C ₂ H ₅ ) groups, NH(C ₃ H7) groups, NH(C ₄ H ₉ ) groups, NCH ₃ (C ₄ H ₉ ) groups, NH(C ₅ H11) groups, NH(cyclopentyl) groups, NCH ₃ (cyclopentyl) groups;

R ⁴ represents a hydrogen atom, or a stereoisomer, tautomer, N-oxide, hydrate, MES or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, C ₁ -C ₃ -haloalkoxy groups;

R ² is selected from a hydrogen atom and a halogen atom;

R ³ is selected from

a C ₁ -C ₆ alkyl group which is optionally substituted with a substituent selected from hydroxy, C 1 -C ₄ alkoxy and a 3-7 membered heterocycloalkyl group,

C ₂ -C ₆ -alkenyl group, which is optionally substituted by C1-C ₄ -alkoxy group, C3-C7-cycloalkyl group, which is optionally substituted by hydroxy group, C ₅ -C ₇ -cycloalkenyl group, 3-7-membered heterocycloalkyl group containing one or two heteroatoms that are independently selected from —O— and —NR ⁹ —, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

C ₁ -C ₃ -alkoxy groups; And

C(O)NR5R ⁶ groups,

a 5-7 membered heterocycloalkyl group containing a heteroatom selected from -O- and NR ⁹ - which is partially unsaturated and optionally substituted with a substituent selected from a C ₁ -C ₃ -alkyl group and a halogen atom, an aryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group and an NR5R ⁶ group, a mono- or bicyclic heteroaryl group , which is optionally substituted by a substituent,

- 79 041614 which is selected from a halogen atom, a C1- _C3 alkyl group, a C1- _C3 haloalkyl group, a C1- _C3 alkoxy group and an ^NR5R6 group, provided that said monocyclic heteroaryl group is not pyridine-4- silt group;

and NR7R group ⁸ ;

R ⁴ represents a hydrogen atom;

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group;

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, NR5R ⁶ group,

C1-C ₃ -alkoxy groups,

a C3-C7 cycloalkyl group which is optionally further substituted with one or two substituents, and said substituents are independently selected from a C1- _C3 alkyl group, an oxo (=O) group, a hydroxy group, and a C1- _C3 hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C1- _C3 alkyl group, a heteroaryl group which is optionally further substituted with C1- With a ₃ -alkyl group,

a C ₃ -C ₇ cycloalkyl group which is optionally further substituted with a hydroxy group or a C 1 -C ₃ alkyl group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C1- _C3 alkyl group and a hydroxy group,

R ⁹ is a hydrogen atom or a C1- _C3 alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to still another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from a hydrogen atom, a halogen atom, a C1- _C3 alkyl group, a C1- _C3 haloalkyl group, a C1- _C3 -haloalkoxy groups;

R ² is selected from a hydrogen atom and a halogen atom;

R ³ is selected from

a C1- _C6 alkyl group which is optionally substituted with a substituent selected from a hydroxy group, a C1- _C4 alkoxy group and a 3-7 membered heterocycloalkyl group,

C ₂ -C ₆ -alkenyl group, which is optionally substituted by C1-C ₄ -alkoxy group,

a C3-C7 cycloalkyl group which is optionally substituted with a hydroxy group,

C ₅ -C ₇ -cycloalkenyl group,

a 3-7 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

cyano groups;

hydroxy groups;

a C1- _C3 alkyl group which is optionally further substituted with hydroxy;

C1- _C3 alkoxy groups;

and C(O)NR ⁵ R ⁶ groups,

a 5-7 membered heterocycloalkyl group containing a heteroatom selected from -O- and NR ⁹ - which is partially unsaturated and optionally substituted with a substituent selected from a C1- _C3 alkyl group and a halogen atom, an aryl group which is optionally substituted with one, two, or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C1- _C3 alkyl group, a C1- _C3 haloalkyl group, and an ^NR5R6 group, a mono- or bicyclic heteroaryl group, which is optionally substituted by a substituent selected from a halogen atom, a C1- _C3 alkyl group, a C1- _C3 haloalkyl group, a C1- _C3 alkoxy group, and an NR ⁵ R ⁶ group, provided that said monocyclic heteroaryl group is not a pyridine- 4-yl group;

and NR ⁷ R ⁸ groups;

R ⁴ is a C1- _C3 alkyl group;

R5/R ⁶ is independently selected from a hydrogen atom and a C1- _C6 alkyl group;

R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded,

- 80 041614

a C1- _C6 alkyl group which is optionally substituted with one, two, three or four substituents, and said substituent is independently selected from halogen atom, cyano group, hydroxy group, NR5R ⁶ group,

C1-C3-alkoxy groups,

C ₃ -C 7 -cycloalkyl group, which is optionally additionally substituted with one or two substituents, and these substituents are independently selected from C 1 -C ₃ -alkyl group, oxo (=O) group, hydroxy group and C 1 -C ₃ -hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C1- _C3 alkyl group, a heteroaryl group which is optionally further substituted with C1- With a ₃ -alkyl group,

a C ₃ -C ₇ cycloalkyl group which is optionally further substituted with a hydroxy group or a C 1 -C ₃ alkyl group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C1- _C3 alkyl group and a hydroxy group,

R ⁹ is a hydrogen atom or a C1- _C3 alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R1 is selected from 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 is selected from a halogen atom,

C ₂ -C ₄ -alkenyl group,

C ₅ -C ₆ -cycloalkylenyl group,

C ₃ -C ₆ -heterocycloalkyl group, which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom and C1-C ₃ -alkyl group;

C ₅ -C ₆ -heterocycloalkyl group, which is partially unsaturated and optionally substituted by oxo group (=O);

a phenyl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a C1- _C3 alkyl group, a _C1C3 haloalkyl group, and an ^NR5R6 group;

a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a C1- _C3 alkyl group, a cyano group, a C1- _C3 haloalkyl group, a C1- _C3 alkoxy group and NR5R ⁶ groups;

and NR7R group ⁸ ;

R ⁴ is a hydrogen atom,

R5/R ⁶ is independently selected from a hydrogen atom and a C1- _C3 alkyl group; And

R 7 /R ⁸ is independently selected from a hydrogen atom, a C ₃ -C ₆ cycloalkyl group, and a C 1 -C ₆ alkyl group;

or R ⁷ and R ⁸ together form a 4-, 5-, or 6-membered ring, optionally containing one additional oxygen atom, and which is optionally substituted once or twice with a substituent selected from a halogen atom and a C1- _C3 alkyl group;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R1 is selected from a hydrogen atom, a halogen atom, a C1- _C3 alkyl group, a C1- _C3 haloalkyl group, a C1- _C3 - haloalkoxy groups;

R ² is selected from a hydrogen atom and a halogen atom;

R ³ is selected from

a C1- _C6 alkyl group which is optionally substituted with a substituent selected from a hydroxy group, a C1- _C4 alkoxy group and a 3-7 membered heterocycloalkyl group,

C ₂ -C ₆ -alkenyl group, which is optionally substituted by C1-C ₄ -alkoxy group,

C ₄ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group,

C ₅ -C ₇ -cycloalkenyl group,

a 3-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

cyano groups;

- 81 041614 hydroxy groups;

a C1- _C3 alkyl group which is optionally further substituted with hydroxy;

a 5-6 membered heterocycloalkyl group containing a heteroatom which is selected from -O- and NR ⁹ - which is partially unsaturated and optionally substituted by a substituent which is selected from a C1- _C3 -alkyl group and a halogen atom, an aryl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, and an NR5R ⁶ group, a mono- or bicyclic heteroaryl group, which is optionally substituted with a substituent selected from a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C 1 -C ₃ alkoxy group, and an NR5R ⁶ group, provided that said monocyclic heteroaryl group is not a pyridine- 4-yl group;

and NR7R group ⁸ ;

R ⁴ represents a hydrogen atom;

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group;

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group,

C ₁ -C ₃ -alkoxy group,

C ₃ -C ₆ -cycloalkyl group, which is optionally additionally substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group and C1-C ₃ hydroxyalkyl group;

a 4-6 membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C1- _C3 alkyl group, a heteroaryl group which is optionally further substituted with C1- With ₃ -alkyl group;

C ₃ -C ₆ -cycloalkyl group, which is optionally additionally substituted by hydroxy group or C1-C ₃ -alkyl group,

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C1- _C3 alkyl group and a hydroxy group, and

R ⁹ is a hydrogen atom or a C1- _C3 alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to still another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from a hydrogen atom, a halogen atom, a C1- _C3 alkyl group, a C1- _C3 haloalkyl group, a C1- _C3 -haloalkoxy groups;

R ² is selected from a hydrogen atom and a halogen atom;

R ³ is selected from

a C1- _C6 alkyl group which is optionally substituted with a substituent selected from a hydroxy group, a C1- _C4 alkoxy group and a 3-7 membered heterocycloalkyl group,

C ₂ -C ₆ -alkenyl group, which is optionally substituted by C1-C ₄ -alkoxy group,

C ₄ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group,

C ₅ -C ₇ -cycloalkenyl group,

a 3-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

cyano groups;

hydroxy groups;

a C1- _C3 alkyl group which is optionally further substituted with hydroxy;

a 5-6 membered heterocycloalkyl group containing a heteroatom which is selected from -O- and NR ⁹ - which is partially unsaturated and optionally substituted by a substituent which is selected from a C1- _C3 -alkyl group and a halogen atom, an aryl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C1- _C3 alkyl group, a C1- _C3 haloalkyl group and an ^NR5R6 group, a mono- or bicyclic heteroaryl group, which is optionally substituted with a substituent which is selected from a halogen atom, a C1- _C3 alkyl group, a C1- _C3 haloalkyl group, a C1- _C3 alkoxy group, and an ^NR5R6 group, provided that said monocyclic heteroaryl group is not pyridine-4 -yl group;

and NR7R group ⁸ ;

R ⁴ is a C ₁ -C ₃ alkyl group;

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group;

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

Cl-C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group,

Ci-C ₃ -alkoxy groups,

C ₃ -C ₆ -cycloalkyl group, which is optionally additionally substituted with one or two substituents, and these substituents are independently selected from C1-C ₃ -alkyl group and Ci-C ₃ hydroxyalkyl group;

a 4-6 membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C1- _C3 alkyl group, a heteroaryl group which is optionally further substituted with C1- With ₃ -alkyl group;

C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group or C 1 -C ₃ alkyl group,

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C1- _C3 alkyl group and a hydroxy group, and

R ⁹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from CF ₃ and a fluorine atom,

R ² is selected from a hydrogen atom,

R ³ is selected from a halogen atom, a prop-1-en-1-yl group which is optionally substituted with a methyl group, a piperidin-1-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a fluorine atom and a methyl group , a morpholin-4-yl group which is optionally substituted with one or two methyl groups, a pyrrolidin-1-yl group which is optionally substituted with one or two halogen atoms, a 1,2,3,6-tetrahydropyridin-4-yl group which is optionally substituted with a methyl group, an azitidin-1 -yl group,

3,6-dihydro-1 H-pyran-4-yl group,

a 6-oxo-1,6-dihydropyridin-3-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a hydrogen atom and a methyl group, a cyclopent-1-en-1-yl group, a phenyl group which optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a methyl group, an ethyl group, a CF ₃ , a CF ₂ H group, a methoxy group, a CF ₃ O group, an NH2 group, and an NHCH3 group,

a 2H-pyrrol-1-yl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a hydrogen atom, a cyano group, and a methyl group,

1H-pyrrazol-4-yl group, which is optionally substituted with one or two substituents, and each substituent is independently selected from a methyl group, an ethyl group, or a CF ₃ group,

1H-pyrrazol-5-yl group which is optionally substituted with a methyl group, 1,2-oxazol-4-yl which is optionally substituted with one or two methyl groups, 1,2-thiazol-4-yl group which is optionally substituted with a methyl group , 1,3-thiazol-5-yl group, which is optionally substituted with a methyl group, pyridin-3-yl, pyridin-4-yl and pyridin 5-yl groups, each group is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a methyl group, a CF ₃ group, a methoxy group and an NH2 group, a pyrimidin-5-yl group which is optionally substituted with a methyl group,

1H-indol-6-yl group,

1H-indazol-6-yl group which is optionally substituted with methyl group, 1H-benzimidazol-6-yl group which is optionally substituted with methyl group, NH(C ₂ H ₅ ) group, NH(C ₃ H ₇ ) group, NH( C ₄ H ₉ ) groups, NCH ₃ (C ₄ H ₉ ) groups, NH(C ₅ H _u ) groups,

- 83 041614

NH(cyclopentyl) groups, NCH ₃ (cyclopentyl) groups;

R ⁴ represents a hydrogen atom, or a stereoisomer, tautomer, N-oxide, hydrate, MES or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group, and a C ₁ -C ₃ haloalkyl group;

R ² is selected from a hydrogen atom and a halogen atom;

R ³ is selected from

C ₁ -C ₆ -alkyl group, which is optionally substituted with one or two substituents, and each substituent is independently selected from hydroxy group, C ₁ -C ₄ -alkoxy group and 3-7 membered heterocycloalkyl group,

C ₂ -Cb-alkenyl group, which is optionally substituted by C ₁ -C ₃ -alkoxy group,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted by hydroxy group,

C ₅ -C ₆ -cycloalkenyl group, which is optionally substituted by hydroxy group,

3-6 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O- and -NR ⁹ - and said heterocycloalkyl group is optionally substituted with one, two or three substituents and each substituent is independently selected from a halogen atom ;

oxo (=O) groups;

cyano groups;

hydroxy groups;

C ₁ -C ₃ -alkyl group, which is optionally substituted by hydroxy;

5-7 membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one or two substituents, and each substituent is independently selected from Ο ₁ -Ο ₃ alkyl group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C ₁ C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, a C ₁ -C ₃ haloalkoxy group, and NR ⁵ R ⁶ group, mono - or bicyclic heteroaryl group, which is optionally substituted with one or two substituents, and each substituent is independently selected from halogen atom, C ₁ -C ₃ -alkyl group, cyano group, C ₁ -C ₃ -haloalkyl group, C ₁ -C ₃ alkoxy, hydroxy and NR5R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R group ⁸ ;

R ⁴ represents a hydrogen atom;

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group;

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group and hydroxy group,

C1-C ₃ -alkoxy groups,

a C3-C7 cycloalkyl group which is optionally substituted with one or two substituents, and said substituents are independently selected from a C1- _C3 alkyl group, a hydroxy group and a C1- _C3 hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a C1-C3 alkyl group; a heteroaryl group which is optionally further substituted with a C1- _C3 alkyl group;

C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C1- _C3 alkyl group and a hydroxy group,

R ⁹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein 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;

- 84 041614

R ³ is selected from

a C1- _C6 alkyl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a hydroxy group, a C1- _C4 alkoxy group, and a 3-7 membered heterocycloalkyl group,

a C2- _C6 alkenyl group which is optionally substituted with a _C1 - _C3 alkoxy group,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted by hydroxy group,

C ₅ -C ₆ -cycloalkenyl group, which is optionally substituted by hydroxy group,

3-6 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O- and -NR ⁹ - and said heterocycloalkyl group is optionally substituted with one, two or three substituents and each substituent is independently selected from a halogen atom ;

oxo (=O) groups;

cyano groups;

hydroxy groups;

C ₁ -C ₃ -alkyl group, which is optionally substituted by hydroxy;

5-7 membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one or two substituents, and each substituent is independently selected from a C1- _C3 alkyl group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents , and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C1C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, a C ₁ -C ₃ haloalkoxy group, and an NR ⁵ R ⁶ group , a mono- or bicyclic heteroaryl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ -alkoxy groups, hydroxy groups and NR5R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R group ⁸ ;

R ⁴ is a C ₁ -C ₃ alkyl group;

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group;

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group and hydroxy group,

Ci-C ₃ -alkoxy groups,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted with one or two substituents, and these substituents are independently selected from C1-C ₃ -alkyl group, hydroxy group and C1-C ₃ hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a C1- _C3 alkyl group; a heteroaryl group which is optionally further substituted with a C1- _C3 alkyl group;

a C3-C6 cycloalkyl group which is optionally substituted with a hydroxy group and a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C1- _C3 alkyl group and a hydroxy group,

R ⁹ is a hydrogen atom or a C1- _C3 alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein 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 is selected from

a 3-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

hydroxy groups;

C ₁ -C ₃ -alkyl group, which is optionally further substituted by hydroxy;

- 85 041614 an aryl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a hydroxy group and a C ₁ -C ₃ haloalkyl group, a mono- or bicyclic heteroaryl group which is optionally substituted with a substituent which is selected from an atom a halogen, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group and an NR5R ⁶ group, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R group ⁸ ;

R ⁴ represents a hydrogen atom;

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₃ alkyl group;

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one or two, three or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group,

C ₁ -C ₃ -alkoxy groups,

C ₃ -C ₅ -cycloalkyl group, which is optionally further substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group and C ₁ -C ₃ hydroxyalkyl group;

a 5-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C ₁ -C ₃ -alkyl group, a heteroaryl group which is optionally further substituted with C ₁ - With ₃ -alkyl group;

C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group or Q-C3 alkyl group,

a 4-5 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C ₁ -C ₃ alkyl group and a hydroxy group, and

R ⁹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group, and a C ₁ -C ₃ haloalkyl group;

R ² is selected from a hydrogen atom and a halogen atom;

R ³ is selected from

a 3-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

hydroxy groups;

C ₁ -C ₃ -alkyl group, which is optionally further substituted by hydroxy;

an aryl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a hydroxy group and a C ₁ -C ₃ haloalkyl group, a mono- or bicyclic heteroaryl group which is optionally substituted with a substituent which is selected from a halogen atom, C ₁ -C ₃ alkyl group, C ₁ -C ₃ haloalkyl group and NR5R ⁶ group, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR ⁷ R ⁸ groups;

R ⁴ represents a C ₁ -C ₃ -alkyl group;

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₃ alkyl group;

R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one or two, three or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group,

C ₁ -C ₃ -alkoxy groups,

C ₃ -C ₅ -cycloalkyl group, which is optionally further substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group and C ₁ -C ₃ hydroxyalkyl group;

a 5-6 membered heterocycloalkyl group containing one or two heteroatoms that are independently selected from -O- and -NR ⁹ -, which is optionally further substituted with a C ₁ -C ₃ -alkyl group, a heteroaryl group, which is optionally additionally substituted with a C ₁ -C ₃ alkyl group;

C ₃ -C ₆ -cycloalkyl group, which is optionally additionally substituted by hydroxy group or C ₁ -C ₃ -alkyl group,

a 4-5 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C ₁ -C ₃ alkyl group and a hydroxy group, and

R ⁹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group or bond;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from CF ₃ and a fluorine atom;

R ² represents a hydrogen atom;

R ³ is selected from an aryl group which is optionally substituted with a substituent selected from a halogen atom and a C ₁ -C ₃ haloalkyl group, a monocyclic heteroaryl group substituted with a substituent selected from an Ο ₁ -Ο ₃ haloalkyl group and an NR5R ⁶ group;

and NR7R group ⁸ ;

R ⁴ represents a hydrogen atom;

R5/R ⁶ represents a hydrogen atom or a methyl group;

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₃ -alkyl group, which is optionally substituted with one, two or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group and methoxy group, or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or their mixture.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from CF ₃ and a fluorine atom;

R ² represents a hydrogen atom;

R ³ is selected from an aryl group which is optionally substituted with a substituent selected from a halogen atom and a C ₁ -C ₃ haloalkyl group, a monocyclic heteroaryl group substituted with a substituent selected from an Ο ₁ -Ο ₃ haloalkyl group and an NR5R ⁶ group;

and NR ⁷ R ⁸ groups;

R ⁴ is a C ₁ -C ₃ alkyl group;

R5/R ⁶ represents a hydrogen atom or a methyl group;

R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded,

C ₁ -C ₃ -alkyl group, which is optionally substituted with one, two or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group and methoxy group, or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or their mixture.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from CF3 and a fluorine atom;

R ² represents a hydrogen atom;

R ³ is selected from an aryl group which is optionally substituted with a substituent selected from a halogen atom and a C ₁ -C ₃ haloalkyl group, a monocyclic heteroaryl group substituted with a substituent selected from an Ο ₁ -Ο ₃ haloalkyl group and an NR5R ⁶ group;

and NR ⁷ R ⁸ groups;

R ⁴ is a methyl group;

R5/R ⁶ represents a hydrogen atom or a methyl group;

R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded,

C ₁ -C ₃ -alkyl group, which is optionally substituted with one, two or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group and methoxy group,

- 87 041614 or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is selected from CF ₃ and a fluorine atom;

R ² represents a hydrogen atom;

R ³ is selected from an aryl group which is optionally substituted with a substituent selected from a halogen atom and a C ₁ -C ₃ haloalkyl group, a monocyclic heteroaryl group substituted with a substituent selected from a Ci-C ₃ haloalkyl group and an NR5R ⁶ group;

and NR7R group ⁸ ;

R ⁴ is a methyl group having the S-configuration;

R5/R ⁶ represents a hydrogen atom or a methyl group;

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₃ -alkyl group, which is optionally substituted with one, two or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group and methoxy group, or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or their mixture.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF ₃ group, a fluorine atom, an OCF ₃ group, or a CH ₃ group,

R ² is a hydrogen atom,

R ³ is selected from

a C1-C4 alkyl group, a phenyl group which is optionally substituted with one or two substituents, said substituents being selected from a halogen atom,

a 4-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituents being selected from a halogen atom, a methyl group or a hydroxy group,

a 5-membered heterocycloalkyl group that is partially unsaturated, a heteroaryl group that is optionally substituted with a C ₁ -C ₃ haloalkyl group, an NH ₂ group, a methyl group, a chlorine atom, a C ₁ -C ₃ haloalkyl group, and

NR ⁷ R ⁸ groups,

R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded,

a C ₄ -C ₅ cycloalkyl group or a C 1 -C ₄ alkyl group which is optionally substituted one or two times with substituents, and said substituents are independently selected from a halogen atom, a hydroxy group, a heterocycloalkyl group, or a heteroaryl group, and

R ⁴ represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF3 group, a fluorine atom, an OCF3 group, or a CH3 group,

R ² is a hydrogen atom,

R ³ is selected from

a C1-C4 alkyl group, a phenyl group which is optionally substituted with one or two substituents, said substituents being selected from a fluorine atom or a chlorine atom,

a 4-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituents being selected from a fluorine atom, a methyl group or a hydroxy group,

a 5-membered heterocycloalkyl group which is partially unsaturated, a heteroaryl group which is optionally substituted with an NH ₂ group, a methyl group, a chlorine atom, a trifluoromethyl group, and a difluoromethyl group,

NR ⁷ R ⁸ groups,

R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded,

a C ₄ -C ₅ cycloalkyl group or a C 1 -C ₄ alkyl group which is optionally substituted one or two times with substituents, and said substituents are independently selected from a fluorine atom, a hydroxy group, a heterocycloalkyl group, or a heteroaryl group, and

R ⁴ represents a hydrogen atom or a methyl group,

- 88 041614 or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF ₃ group or CH ₃ group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is optionally substituted with a halogen atom, a heteroaryl group which is optionally substituted by a C ₁ -C ₃ haloalkyl group, or an NR7R ⁸ group,

R7/ ^R8 are independently selected from hydrogen, provided that ^R7 = ^R8 = hydrogen is excluded, or a C ₁ -C ₄ alkyl group which is optionally substituted one or two times with substituents, and said substituents are independently selected from halogen , hydroxy or C ₁ -C ₃ alkoxy groups, and

R ⁴ represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF ₃ group or CH ₃ group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is optionally substituted with a fluorine atom or a chlorine atom, a pyridyl group or a pyrazolyl group which is optionally substituted with a CHF2 group or a CF3 group or an NR ⁷ R ⁸ group,

R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded, or a C ₂ -C ₄ halkyl group which is optionally substituted one or two times with substituents, and said substituents are independently selected from an atom fluorine, hydroxy group or methoxy group, and

R ⁴ represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF ₃ group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is optionally substituted with a halogen atom or a heteroaryl group which is optionally substituted by a C ₁ -C ₃ haloalkyl group, and

R ⁴ represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, Noxide, hydrate, MES or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF ₃ group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is optionally substituted with a halogen atom or a heteroaryl group which is optionally substituted with a CHF ₂ group or a CF ₃ group, and

R ⁴ represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF3 group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is optionally substituted with a halogen atom or a heteroaryl group which is optionally substituted with a C ₁ -C ₃ haloalkyl group, and

R ⁴ represents a hydrogen atom, or a stereoisomer, tautomer, N-oxide, hydrate, MES or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF3 group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is optionally substituted with a halogen atom or a heteroaryl group which is optionally substituted by a C ₁ -C ₃ haloalkyl group, and

R ⁴ is a methyl group or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I),

- 89 041614 where R ¹ represents a CF ₃ group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is optionally substituted with a halogen atom or a 5-membered heteroaryl group which is optionally substituted by a C ₁ -C ₃ haloalkyl group, and

R ⁴ represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF ₃ group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is optionally substituted with a halogen atom or a 6-membered heteroaryl group which is optionally substituted by a C ₁ -C ₃ haloalkyl group, and

R ⁴ represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF ₃ group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is substituted by a fluorine atom or a chlorine atom, a pyrazolyl group which is substituted by a CHF2 group or a CF ₃ group, and a pyridine group which is substituted by an NH2 group or an NHCH3 group.

R ⁴ represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF ₃ group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is substituted by a fluorine atom, a pyrazolyl group which is substituted by a CHF2 group or a CF ₃ group, and a pyridine group which is substituted by an NH2 group or an NHCH3 group.

R ⁴ represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF3 group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is substituted by a fluorine atom or a chlorine atom, a pyrazolyl group which is substituted by a CHF2 group or a CF ₃ group, and a pyridine group which is substituted by an NH ₂ group or an NHCH3 group.

R ⁴ represents a hydrogen atom, or a stereoisomer, tautomer, N-oxide, hydrate, MES or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF3 group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is substituted by a fluorine atom;

a pyrazolyl group which is substituted by a CHF2 group or a _CF3 group, and a pyridine group which is substituted by an _NH2 group or an _NHCH3 group;

R ⁴ represents a hydrogen atom;

or their stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF3 group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is substituted by a fluorine atom or a chlorine atom, a pyrazolyl group which is substituted by a CHF2 group or a CF ₃ group, and a pyridine group which is substituted by an NH ₂ group or an NHCH ₃ group.

- 90 041614

R ⁴ is a methyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF ₃ group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is substituted by a fluorine atom, a pyrazolyl group which is substituted by a CHF2 group or a CF ₃ group, and a pyridine group which is substituted by an NH ₂ group or an NHCH3 group.

R ⁴ is a methyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF ₃ group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is substituted by a fluorine atom, or a 1H-pyrazol-4-yl group or a 1H-pyrazol-1-yl group which is substituted by a CHF2 group or a CF ₃ group, and

R ⁴ represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF3 group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is substituted by a fluorine atom, or a 1H-pyrazol-4-yl group or a 1H-pyrazol-1-yl group which is substituted by a CHF ₂ group or a CF ₃ group, and

R ⁴ represents a hydrogen atom, or a stereoisomer, tautomer, N-oxide, hydrate, MES or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF ₃ group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is substituted by a fluorine atom, or a 1H-pyrazol-4-yl group or a 1H-pyrazol-1-yl group which is substituted by a CHF2 group or a CF3 group, and

R ⁴ is a methyl group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF ₃ group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is substituted by a fluorine atom, or a 1H-pyrazol-4-yl group which is substituted by a CHF2 group, or a 1H-pyrazol-1-yl group which is substituted by a CF ₃ group, and

R ⁴ represents a hydrogen atom or a methyl group, or a stereoisomer, tautomer, N-oxide, hydrate, MES or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF3 group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is substituted by a fluorine atom, or a 1H-pyrazol-4-yl group which is substituted by a CHF ₂ group, or a 1H-pyrazol-1-yl group which is substituted by a CF ₃ group, and

R ⁴ represents a hydrogen atom, or a stereoisomer, tautomer, N-oxide, hydrate, MES or salt, or a mixture thereof.

According to yet another embodiment of the first aspect, the present invention provides compounds of formula (I) wherein R ¹ is a CF3 group,

R ² is a hydrogen atom,

R ³ is selected from a phenyl group which is substituted by a fluorine atom, or a 1H-pyrazol-4-yl group which is substituted by a CHF2 group, or a 1H-pyrazol-1-yl group which is substituted by a CF ₃ group, and

R ⁴ is a methyl group or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

- 91 041614

Other embodiments of the present invention

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ¹ represents a hydrogen atom, a halogen atom, a cyano group, a C ₁ -C ₃ -alkyl group, a C1C ₃ -haloalkyl group or a C ₁ -C ₃ -haloalkoxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts , as well as their mixtures.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ¹ represents a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group or a C ₁ -C ₃ haloalkoxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts , as well as their mixtures.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ¹ represents a hydrogen atom, a fluorine atom, a methyl group, a trifluoromethyl group or a trifluoromethoxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ¹ represents a hydrogen atom, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ¹ represents a halogen atom, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ¹ represents a C ₁ -C ₃ -haloalkyl group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ¹ represents a CHF2 group or a CF ₃ group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ¹ represents a fluorine atom or a trifluoromethyl group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ¹ represents a fluorine atom, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ¹ is a trifluoromethyl group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In other embodiments of the first entity, or any embodiment derived therefrom, if R ¹ and R 2 are each independently a halogen atom (e.g., F and/or Cl) and R ⁴ is methyl, then R ³ is not morpholinyl .

In other embodiments of the first entity, or any embodiment derived therefrom, if R ¹ and R ² are each independently a halogen atom (eg, F and/or Cl) or a C ₁ -C ₃ haloalkyl group, and R ⁴ is is methyl, then R ³ is not morpholinyl.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ² represents a hydrogen atom or a halogen atom, and their stereoisomers, tautomers, Noxides, hydrates, solvates and salts, as well as mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ¹ is a fluorine atom or a trifluoromethyl group, and R ² is a hydrogen atom or a methyl group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ¹ is a trifluoromethyl group and R ² is a hydrogen atom, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ¹ is a fluorine atom and R ² is a hydrogen atom, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ² represents a hydrogen atom, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from

a Q-C6 alkyl group which is optionally substituted with one or two substituents, and each substituent is independently selected from hydroxy, C ₁ -C ₄ alkoxy, and a 3-7 membered heterocycloalkyl group,

C ₂ -Cb-alkenyl group, which is optionally substituted with C ₁ -C ₄ -alkoxy group,

C ₃ -C ₉ -cycloalkyl group, which is optionally substituted by hydroxy group,

C ₅ -C ₉ -cycloalkenyl group, which is optionally substituted by hydroxy group,

3-9 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O-, -S-, -S(O)-, S(O) ₂ and -NR ⁹ -, and the specified heterocycloalkyl group optionally additionally contains a bridging group selected from -O-, -NR ⁹ -, -CH2-, -CH2-CH2-, -O-CH2-, -CH2-O-, -NR ⁹ -CH2- and -CH2-NR ⁹ -;

and said heterocycloalkyl group is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom;

oxo (=O) groups;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

C ₁ -C ₃ -haloalkyl group;

C ₁ -C ₃ alkoxy groups;

C ₁ -C ₃ haloalkoxy groups;

C(O)NR ⁵ R ⁶ groups and

NR5R ⁶ groups

5-9 membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from oxo group (=O), C ₁ -C ₃ -alkyl group, -C(O)R ⁵ R ⁶ group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C1C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group , C ₁ -C ₃ -alkoxy groups, C ₁ -C ₃ -haloalkoxy groups and NR ⁵ R ⁶ group, mono - or bicyclic heteroaryl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, C ₁ -C ₃ -alkyl group, cyano group, C ₁ -C ₃ -haloalkyl group, C ₁ -C ₃ -alkoxy group, hydroxy group and NR5R ⁶ group, provided that the specified monocyclic heteroaryl group is not a pi- 93 041614 ridin- 4-iln th group; And

NR7R ⁸ groups; and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from

C ₁ -C ₆ -alkyl group, which is optionally substituted with one or two substituents, and each substituent is independently selected from hydroxy group, C ₁ -C ₄ -alkoxy group and 3-7-membered heterocycloalkyl group,

C2-C6-alkenyl group, which is optionally substituted with C ₁ -C ₄ alkoxy group,

C ₃ -C ₉ -cycloalkyl group, which is optionally substituted by hydroxy group,

C ₅ -C ₉ -cycloalkenyl group, which is optionally substituted by hydroxy group,

3-9 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O-, -S-, -S(O)-, S(O) ₂ and -NR ⁹ -, and the specified heterocycloalkyl group optionally additionally contains a bridging group selected from -O-, -NR ⁹ -, -CH2-, -CH2-CH2-, -O-CH2-, -CH2-O-, -NR ⁹ -CH ₂ - and -CH2- NR ⁹ -;

and said heterocycloalkyl group is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom;

oxo (=O) groups;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

C ₁ -C ₃ -haloalkyl group;

C ₁ -C ₃ alkoxy groups;

C ₁ -C ₃ haloalkoxy groups;

C(O)NR ⁵ R ⁶ groups and

NR5R ⁶ groups

5-9 membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from oxo group (=O), C ₁ -C ₃ -alkyl group, -C(O)R ⁵ R ⁶ group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, hydroxy group, cyano group, C1C ₃ -alkyl group, C ₁ -C ₃ -haloalkyl group , C ₁ -C ₃ -alkoxy groups, C ₁ -C ₃ -haloalkoxy groups and NR ⁵ R ⁶ group, mono - or bicyclic heteroaryl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, C ₁ -C ₃ alkyl group, cyano group, C ₁ -C ₃ haloalkyl group, C ₁ -C ₃ alkoxy group, hydroxy group and NR5R ⁶ group, provided that said monocyclic heteroaryl group is not a pyridinyl group; And

NR7R ⁸ groups; and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from

C ₁ -C ₆ -alkyl group, which is optionally substituted with one or two substituents, and each substituent is independently selected from hydroxy group, C ₁ -C ₄ -alkoxy group and 3-7 membered heterocycloalkyl group,

C ₂ -C ₆ -alkenyl group, which is optionally substituted with C ₁ -C ₄ -alkoxy group,

C ₃ -C ₉ -cycloalkyl group, which is optionally substituted by hydroxy group,

C ₅ -C ₉ -cycloalkenyl group, which is optionally substituted by hydroxy group,

a 3-9 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O-, -S-, -S(O)-, S(O)2 and -NR ⁹ - and said heterocycloalkyl group optionally additionally contains a bridging group selected from -O-, -NR ⁹ -, -CH2-, -CH2-CH2-, -O-CH2-, -CH2-O-, -NR ⁹ -CH2- and -CH2-NR ⁹ -;

and said heterocycloalkyl group is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom;

oxo (=O) groups;

cyano groups;

- 94 041614 hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

C1-C3 haloalkyl group;

€ ₁ - € ₃ -alkoxy groups;

C ₁ -C ₃ haloalkoxy groups;

C(O)NR ⁵ R ⁶ groups, and

NR5R ⁶ groups,

a 5-9 membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from an oxo group (=O),

C ₁ -C ₃ -alkyl group, -C(O)R ⁵ R ⁶ group and halogen atom, aryl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from halogen atom, hydroxy group, cyano group , C1C 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 group, mono- or bicyclic heteroaryl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, a hydroxy group, and an NR5R ⁶ group, provided that said monocyclic heteroaryl group is not a pyridin-2-yl group, a pyridin-3-yl group, and a pyridin-4-yl group; And

NR7R ⁸ groups; and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

if any R ³ is a heterocycloalkyl moiety, said moiety is optionally substituted with one, two or three substituents and each substituent is independently selected from a fluorine atom;

oxo (=O) groups;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

C ₁ -C ₃ haloalkyl group;

€ ₁ - € ₃ -alkoxy groups;

C ₁ -C ₃ haloalkoxy groups;

C(O)NR ⁵ R ⁶ groups, and

NR5R ⁶ groups, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

if any R ³ is a heterocycloalkyl moiety, said moiety is optionally substituted with one or two substituents and each substituent is independently selected from a fluorine atom;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

€ ₁ - € ₃ -alkoxy groups;

C(O)NR ⁵ R ⁶ groups, and

NR ⁵ R ⁶ groups;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

if any R ³ is a heterocycloalkyl moiety, said moiety is optionally substituted with one or two substituents and each substituent is independently selected from a fluorine atom;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

C ₁ -C ₃ alkoxy groups; And

- 95 041614

C(O)NR ⁵ R ⁶ groups, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

if any R ³ is a heterocycloalkyl moiety, said moiety is optionally substituted with one or two substituents and each substituent is independently selected from a fluorine atom;

cyano groups;

hydroxy groups

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

if any R ³ is a heterocycloalkyl moiety, said moiety is optionally substituted with one, two or three substituents and each substituent is independently selected from a fluorine atom;

oxo (=O) groups;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

if any R ³ is a heterocycloalkyl moiety, said moiety is optionally substituted with one or two substituents and each substituent is independently selected from a fluorine atom;

hydroxy groups

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from

a C ₁ -C ₆ alkyl group which is optionally substituted with a substituent selected from hydroxy, C 1 -C ₄ alkoxy and a 3-7 membered heterocycloalkyl group,

C2- _C6 alkenyl group which is optionally substituted by C1- _C4 alkoxy group, _C3 - _C7 cycloalkyl group which is optionally substituted by hydroxy group, _C5 - _C7 cycloalkenyl group which is optionally substituted by hydroxy group, 3-7- a membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O-, S(O)2 and -NR ⁹ -, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

€ ₁ - € ₃ -alkoxy groups;

C(O)NR ⁵ R ⁶ groups, and

NR5R ⁶ groups;

A 5-7 membered heterocycloalkyl group containing a heteroatom selected from -O-, -S- and NR ⁹ - which is partially unsaturated and optionally substituted with a substituent selected from a C ₁ -C ₃ -alkyl group, -C( O)R ⁵ R ⁶ group and a halogen atom, an aryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, hydroxy group, cyano group, C ₁ -C ₃ -alkyl group, C ₁ -C ₃ haloalkyl group, C ₁ -C ₃ alkoxy group and NR5R ⁶ group, mono- or bicyclic heteroaryl group which is optionally substituted with a substituent selected from a halogen atom, C ₁ -C ₃ -alkyl group, cyano group, C ₁ -C ₃ haloalkyl group, C ₁ -C ₃ alkoxy group and

- 96 041614

NR5R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group; And

NR7R ⁸ groups; and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from

a C ₁ -C ₆ alkyl group which is optionally substituted with a substituent selected from hydroxy, C 1 -C ₄ alkoxy and a 3-7 membered heterocycloalkyl group,

a C2- _C6 alkenyl group which is optionally substituted with a C1- _C4 alkoxy group,

a C3-C7 cycloalkyl group which is optionally substituted with a hydroxy group,

C ₅ -C ₇ -cycloalkenyl group,

a 3-7 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

C ₁ -C ₃ -alkoxy groups; And

C(O)NR ⁵ R ⁶ groups,

a 5-7 membered heterocycloalkyl group containing a heteroatom selected from -O- and NR ⁹ - which is partially unsaturated and optionally substituted with a substituent selected from a C ₁ -C ₃ -alkyl group and a halogen atom, an aryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group and an NR5R ⁶ group, a mono- or bicyclic heteroaryl group , which is optionally substituted with a substituent which is selected from a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, € ₁ - € ₃ alkoxy group, and an NR ⁵ R ⁶ group, provided that said monocyclic heteroaryl the group is not a pyridin-4-yl group; And

NR7R ⁸ groups; and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from

a C ₁ -C ₆ alkyl group which is optionally substituted with a substituent selected from hydroxy, C 1 -C ₄ alkoxy and a 3-7 membered heterocycloalkyl group,

a C2- _C6 alkenyl group which is optionally substituted with a C1- _C4 alkoxy group,

a C3-C7 cycloalkyl group which is optionally substituted with a hydroxy group,

C5-C7-cycloalkenyl group,

a 3-7 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

C ₁ -C ₃ -alkoxy groups; And

C(O)NR ⁵ R ⁶ groups,

a 5-7 membered heterocycloalkyl group containing a heteroatom selected from -O- and NR ⁹ - which is partially unsaturated and optionally substituted with a substituent selected from a C ₁ -C ₃ -alkyl group and a halogen atom, an aryl group which substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C ₁ -C ₃ -alkyl group, € ₁ - € ₃ haloalkyl group and an NR ⁵ R ⁶ group, a mono- or bicyclic heteroaryl group , which is optionally substituted with a substituent which is selected from a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ -97 041614 alkoxy group, and an NR5R ⁶ group, provided that said monocyclic the heteroaryl group is not a pyridin-4-yl group; And

NR7R ⁸ groups; and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from

a 3-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

cyano groups;

hydroxy groups

Cl-C ₃ -alkyl group, which is optionally further substituted with hydroxy;

a 5-6 membered heterocycloalkyl group containing a heteroatom selected from -O- and NR ⁹ - which is partially unsaturated and optionally substituted with a substituent selected from a C ₁ -C ₃ -alkyl group and a halogen atom, an aryl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a Cl-C ₃ alkyl group, a Cl-C ₃ haloalkyl group and an NR5R ⁶ group, a mono- or bicyclic heteroaryl group which is optionally substituted a substituent which is selected from a halogen atom, a C ₁ -C ₃ -alkyl group, a C ₁ -C ₃ -haloalkyl group, a C 1 -C ₃ alkoxy group and an NR ⁵ R ⁶ group, provided that said monocyclic heteroaryl group is not a pyridine- 4-yl group; And

NR7R ⁸ groups;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from

a 3-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

cyano groups;

hydroxy groups

a C1- _C3 alkyl group which is optionally further substituted with hydroxy;

a 5-6 membered heterocycloalkyl group containing a heteroatom which is selected from -O- and NR ⁹ - which is partially unsaturated and optionally substituted by a substituent which is selected from a C1- _C3 -alkyl group and a halogen atom, an aryl group which is substituted one or two substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C1- _C3 alkyl group, a C1- _C3 haloalkyl group and an ^NR5R6 group, a mono- or ^bicyclic heteroaryl group, which is optionally substituted with a substituent which is selected from a halogen atom, a C1- _C3 alkyl group, a C1- _C3 haloalkyl group, a C1- _C3 alkoxy group and an NR ⁵ R ⁶ group, provided that said monocyclic heteroaryl group is not pyridine-4- silt group;

and NR7R group ⁸ ;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from

a C1-C6 alkyl group which is optionally substituted with one or two substituents, and each substituent is independently selected from hydroxy, C ₁ -C ₄ alkoxy, and a 3-7 membered heterocycloalkyl group,

a C2- _C6 alkenyl group which is optionally substituted with a C1- _C3 alkoxy group,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted by hydroxy group,

C ₅ -C ₆ -cycloalkenyl group, which is optionally substituted by hydroxy group,

- 98 041614

3-6 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O- and -NR ⁹ - and said heterocycloalkyl group is optionally substituted with one, two or three substituents and each substituent is independently selected from a halogen atom ;

oxo (=O) groups;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

a 5-7 membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one or two substituents, and each substituent is independently selected from a C ₁ -C ₃ alkyl group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C1C3 alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, a C ₁ -C ₃ haloalkoxy group, and an NR5R ⁶ group, mono - or a bicyclic heteroaryl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group , hydroxy groups and NR5R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group; And

NR7R ⁸ groups;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from

a C ₁ -C ₆ alkyl group which is optionally substituted with one or two substituents, and each substituent is independently selected from hydroxy, C ₁ -C ₄ alkoxy, and a 3-7 membered heterocycloalkyl group,

a C2- _C6 alkenyl group which is optionally substituted with a _C1 - _C3 alkoxy group,

a C3- _C7 cycloalkyl group which is optionally substituted with a hydroxy group,

C ₅ -C ₆ -cycloalkenyl group, which is optionally substituted by hydroxy group,

3-6 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O- and -NR ⁹ - and said heterocycloalkyl group is optionally substituted with one, two or three substituents and each substituent is independently selected from a halogen atom ;

oxo (=O) groups;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

a 5-7 membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one or two substituents, and each substituent is independently selected from a C ₁ -C ₃ alkyl group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C1C3 alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, a C ₁ -C ₃ haloalkoxy group, and an NR5R ⁶ group, mono - or a bicyclic heteroaryl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group , hydroxy groups and NR5R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group; And

NR7R ⁸ groups;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from

a C ₁ -C ₆ alkyl group which is optionally substituted with one or two substituents, and each substituent is independently selected from hydroxy, C ₁ -C ₄ alkoxy, and a 3-7 membered heterocycloalkyl group,

C2-C6-alkenyl group, which is optionally substituted by C ₁ -C ₃ alkoxy group,

C ₃ -C 7 -cycloalkyl group, which is optionally substituted by hydroxy group,

C ₅ -C ₆ -cycloalkenyl group, which is optionally substituted by hydroxy group,

3-6 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O- and -NR ⁹ - and said heterocycloalkyl group is optionally substituted with one, two or three substituents and each substituent is independently selected from a halogen atom ;

oxo (=O) groups;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

a 5-7 membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one or two substituents, and each substituent is independently selected from a C ₁ -C ₃ alkyl group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C1C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, a C ₁ -C ₃ haloalkoxy group, and NR ⁵ R ⁶ group, a mono- or bicyclic heteroaryl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ -alkoxy groups, hydroxy groups and NR5R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group; And

NR7R ⁸ groups;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from

a 3-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

hydroxy groups

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

an aryl group that is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a hydroxy group and a C ₁ -C ₃ haloalkyl group, a mono- or bicyclic heteroaryl group that is optionally substituted with a substituent that is selected from a halogen atom, C ₁ -C ₃ -alkyl group, C ₁ -C ₃ -haloalkyl group and NR5R ⁶ group, provided that the specified monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R group ⁸ ;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from

a 3-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

hydroxy groups

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

a phenyl group which is optionally substituted with one or two substituents and each substituent is independently selected from a halogen atom, a hydroxy group and a C ₁ -C ₃ haloalkyl group, a mono- or bicyclic heteroaryl group which is optionally substituted with a substituent which is selected from a halogen atom, C ₁ -C ₃ -alkyl group, C ₁ -C ₃ -haloalkyl group and NR5R ⁶ group, provided that the specified monocyclic heteroaryl group is not pyri

- 100 041614 a din-4-yl group;

and NR7R group ⁸ ;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from

a 3-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is independently substituted with one or two substituents, and each substituent is independently selected from a halogen atom;

hydroxy groups

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

a phenyl group which is substituted with one or two substituents and each substituent is independently selected from a halogen atom, a hydroxy group and a C ₁ -C ₃ haloalkyl group, a mono- or bicyclic heteroaryl group which is optionally substituted with a substituent which is selected from a halogen atom, C ₁ -C ₃ -alkyl group, C ₁ -C ₃ -haloalkyl group and NR5R ⁶ group, provided that the specified monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R group ⁸ ;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from an aryl group which is optionally substituted with a substituent selected from a halogen atom and a C ₁ -C ₃ haloalkyl group, a monocyclic heteroaryl group substituted with a substituent selected from a C ₁ -C ₃ haloalkyl group and an NR5R ⁶ group;

and NR7R group ⁸ ;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from a phenyl group which is optionally substituted with a substituent selected from a halogen atom and a C ₁ -C ₃ haloalkyl group, a monocyclic heteroaryl group substituted with a substituent selected from a C ₁ -C ₃ haloalkyl group and an NR5R ⁶ group;

and NR7R group ⁸ ;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein

R ³ is selected from a methyl group, a propan-2-yl group, a 2-methylpropyl group, a 2-hydroxypropan-2yl group, a 3,3-dimethylbutyl group, a 3-methoxypropyl group,

-CH ₂ -(morpholin-4-yl) group, prop-1-en-2-yl group, 2-methylprop-1-en-1-yl group, 3,3-dimethylbut-1-en-1-yl group group, 3-methoxyprop-1-en-1-yl group,

4-hydroxycyclohexyl group, cyclopent-1-en-1-yl group, cyclohex-1-en-1-yl group, bicyclo[2.2.1]hept-2-en-2yl group, oxan-3-yl group, 3, 3-difluoroazetidin-1-yl group, zetidin-3-carboxamide, 2hydroxyazetidin-1-yl group, 3-hydroxy-3-methylazetidin-1-yl group, 2(hydroxymethyl)azetidin-1-yl group, 3-cyano- 3-methylazetidin-1-yl group, 2,4dimethylazetidin-1-yl group, -2lambda ^6- thia-6-azaspiro[3.3]heptan-2,2-dione group, 3hydroxypyrrolidin-1-yl group, 3,3- difluoropyrrolidin-1-yl group, 3azabicyclo[3.1.0]hexan-3-yl group, 1-amino-3-azabicyclo[3.1.0]hexan-3-yl group, 4fluoropiperidin-1-yl group, 4,4- fluoropiperidin-1-yl group, 4-cyano-piperidin-1-yl group, 4-fluoro-4-methylpiperidin-1-yl group, 4-ethyl-4-hydroxypiperidin-1-yl group, 4-101 041614 hydroxypiperidin- 1-yl group, 3-hydroxypiperidin-1-yl group, 3-aminocarbonyl-lupiperidin-1-yl group, morpholin-4-yl group, 2-methylmorphol n-4-yl group, 2,6-dimethylmorpholin-4-yl group, 4-methylpiperazin-1-yl group,

2,5-dihydrofuran-3-yl group, 5,6-dihydro-2H-pyran-3-yl group, 3,6-dihydro-2Hpyran-4-yl group, 1,2,3,6-tetrahydropyridin-4 -yl group, 1-methyl-1,2,3,6tetrahydropyridin-4-yl group, 6-oxo-1,6-dihydropyridin-3-yl group, phenyl group, 2-methylphenyl group, 2-ethylphenyl group, 2 -fluorophenyl group, 2-aminophenyl group, 2-hydroxyphenyl group, 2-methoxyphenyl group, 2,4dimethylphenyl group, 2-fluoro-4-methylphenyl group, 2-fluoro-4-aminophenyl group, 4cyano-2-methylphenyl group, 2 -chloro-4-fluorophenyl group, 2,3-difluorophenyl group, 2fluoro-3-aminophenyl group, 2,5-difluorophenyl group, 2,6-difluorophenyl group, 4-fluoro-6methylphenyl group, (2-difluoromethyl)phenyl group , 2-cyanophenyl group, 2,4difluorophenyl group, 3-methylphenyl group, 3-aminophenyl group, 3-fluorophenyl group, 3-hydroxyphenyl group, 3,4-difluorophenyl group, 3-amino-4-methylphenyl group, 3-amino -4-chlorophenyl group, 3-a mino-4-fluorophenyl group, 3-fluoro-4-methylphenyl group, 4-amino-3-fluorophenyl group, 4-fluoro-3-methylphenyl group, 4-fluoro-3hydroxyphenyl group, 3-hydroxy-4-methylphenyl group, 4-methylphenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-(difluoromethyl)phenyl group, 4(trifluoromethyl)phenyl group, 4-cyanophenyl group, 4-aminophenyl group, 4(methylamino)phenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 3,5-difluorophenyl group, 2,4,5-trifluorophenyl group, 2,3,4-trifluorophenyl group, 3,4,5-trifluorophenyl group, 3-amino-4,6-difluorophenyl group,

1H-pyrazol-4-yl group, 1-methyl-1H-pyrazol-4-yl group, 1-ethyl-3-(trifluoromethyl)-1Hpyrazol-1-yl group, 1H-pyrazol-4-yl group, 1- (propan-2-yl)-1H-pyrazol-4-yl group, 1-(difluoromethyl)-1H-pyrazol-4-yl group, 1-methyl-1H-pyrazol-5-yl group, 3-methyl-1Hpyrazole -4-yl group, 1,3-dimethyl-1H-pyrazol-4-yl group, 3,5-dimethyl-1H-pyrazol-4-yl group, 1-methyl-3-(trifluoromethyl)-1H-pyrazol- 4-yl group, 3-(trifluoromethyl)-1H-pyrazol-4yl group, 1-methyl-5-cyano-1H-pyrrol-2-yl group, 1-ethyl-1H-imidazol-4-yl group, 4( trifluoromethyl)-1H-imidazol-1-yl group, 3,5-dimethyl-1,2-oxazol-4-yl group, 1,2-thiazol-4yl group, 2-methyl-1,3-thiazol-5- yl group, 5-(trifluoromethyl)thiophen-2-yl group, 5-cyano-4-methyl-thiophen-2-yl group, 5-(trifluoromethyl)thiophen-3-yl group, pyridin-2-yl group, 5-methyl -pyridin-2-yl group, 5-chloro-pyridin-2-yl group, 5-fluoro-pyridin-2-yl group, pyridin-3-yl group, 4-methylpyridin-3-yl group group, 2-methylpyridin-3-yl group, 6-fluoropyridin-3-yl group, 6-methylpyridin-3-yl group, 6(trifluoromethyl)pyridin-3-yl group, 6-aminopyridin-3-yl group, 6-methoxypyridine -3yl group, 5-fluoro-6-methylpyridin-3-yl group, 2-methoxy-6-methylpyridin-3-yl group, pyridin-4-yl group, 2-methylpyridin-4-yl group, 2-methoxypyridin- 4-yl group, 2-aminopyridin-4-yl group, 3-methylpyridin-4-yl group, pyrimidin-5-yl group, 2-methylpyrimidin-5-yl group,

1-benzothiophen-2-yl group, imidazo[1,2-a]pyridin-6-yl group, 1-methyl-Hbenzimidazol-6-yl group, 1-methyl-1H-indazol-6-yl group, 1H- indazol-6-yl group, 1H-indol-6-yl group, N-indol-5-yl group, methylamino group, ethylamino group, (propan-2-yl)amino group, propylamino group, butylamino group, tert-butylamino group, pentylamino group, ethyl(methyl)amino group, (butyl)methylamino group, aminocarbonylmethyl group, (2-aminoethyl)amino group, (2methylpropyl)amino group, (3-methylbutyl)amino group, (2-methoxyethyl)amino group , (2ethoxyethyl)amino groups, (3-methoxypropyl)amino groups, (3-cyanopropyl)amino groups, (2hydroxypropyl)amino groups, (2-hydroxy-2-methylpropyl)amino groups, (2-methoxypropyl)amino groups, ( 2-ethoxypropyl)amino groups, (3,3,3-trifluoro-2-hydroxypropyl)amino groups, (2-methoxy-2methylpropyl)amino groups, (2-methoxybutyl)amino groups, (3-hydroxybutyl)amino groups, ( 1hydroxybutan-2-yl)amino groups, (4-hydroxybutan-2-yl)amino groups, (1-hydroxypentan-2-yl)amino groups, (3-hydroxy-3-methylbutyl)amino groups, (2-hydroxy-3-methoxypropyl)amino groups, (cyclopropylmethyl)amino groups, (1-cyclopropylethyl)amino groups, ((1-hydroxycyclobutyl)methyl)amino groups, (1-hydroxy-4-methylpentan-2-yl)amino groups, (1,3-dihydroxybutan-2-yl)amino groups, (2,2dimethylcyclopropyl)methyl]amino groups , (dicyclopropylmethyl)amino groups, (3hydroxycyclobutyl)amino groups, [1-(hydroxymethyl)cyclobutyl]methyl group, cyclopentylamino groups, (2-hydroxycyclopentyl)amino groups, (cyclopentyl)(methyl)amino groups, (4hydroxycyclohexyl)amino groups, bicyclo[2.2.1]heptan-2-yl]amino groups, [(3-methyloxetan-3yl)methyl]amino groups, (oxetan-3-yl)amino groups, (oxolan-3-yl)methyl)amino groups, (tetrahydrofuran-2-ylmethyl)amino groups, (oxan-4-yl)amino groups, ((oxan-4-yl)methyl)amino groups, ((4methyloxan-4-yl)methyl)amino groups, (3-methyloxetane) -3-yl)methyl]amino groups, [(5-oxopyrrolidin2-yl)methyl]amino groups, [(6-oxopiperidin-3-yl)methyl]ami but groups, [(1-methyl-1H-imidazol-2- 102 041614 yl)methyl]amino groups, [2-(1H-pyrazol-1-yl)ethyl]amino groups, [2-(1H-imidazol-5 -yl)ethyl]amino groups, (3-(III-imidazol-1-yl)propyl)amino groups, [(1-methyl-1H-pyrazol-5-yl)methyl]amino groups,

[(1 H-pyrazol-3-yl)methyl]amino groups, [(1-methyl-1H-pyrazol-3-yl)methyl]amino groups, [(1-methyl-1Hpyrazol-4-yl)methyl]amino groups, [(pyrazin-2-yl)methyl]amino groups, [(pyridin-3-yl)methyl]amino groups, [(pyrimidin-5-yl)methyl]amino groups, [(pyrimidin-2-yl)methyl] amino groups, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, in which the aryl group R ³ is a phenyl group which is optionally substituted with one or two fluorine atoms, atoms chlorine or trifluoromethyl groups, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, in which the aryl group R ³ is a phenyl group which is substituted by a fluorine atom, and their stereoisomers, tautomers , N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein R ³ is a phenyl group which is optionally substituted with one, two or three substituents, and each the substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a Ci-C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, and an NR5R ⁶ group;

a mono- or bicyclic heteroaryl group which is optionally substituted with a substituent selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group and an NR5R ⁶ group, with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R ⁸ group; and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, in which R ³ is a monocyclic heteroaryl group which is optionally substituted with a substituent which is selected from a halogen atom, C ₁ -C ₃ alkyl group, cyano group, C ₁ -C ₃ haloalkyl group, Ci-C ₃ alkoxy group and NR5R ⁶ group;

or NR7R ⁸ groups; and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, in which R ³ is a monocyclic heteroaryl group which is optionally substituted with a substituent which is selected from a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group and an NR5R ⁶ group;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein R ³ is a substituted heterocycloalkyl group such as 4,4-difluoropiperidin-1-yl a group, a heterocycloalkyl group which is partially unsaturated, such as a 2,5-dihydrofuran-3-yl group, a substituted phenyl group such as a 4-fluorophenyl group, a 3,4-difluorophenyl group, a 4-chlorophenyl group, a substituted heteroaryl group such as 1,2-thiazol-4-yl group, 2-methyl-1,3-thiazol-5yl group, 1-(difluoromethyl)-1H-pyrazol-4-yl group, 3-(trifluoromethyl)-1H-pyrazol-1 -yl group, 5-chloropyridin-2-yl group, 2-aminopyridin-4-yl group, (morpholin-4-yl)methyl group, 2-hydroxy-2-methylpropyl group, 2-methylpropyl group, pyrazin-2- yl)methyl group, 3-hydroxy-3-methylazetidin-1-yl group, and

NR7R ⁸ group such as 4-(propylamino) group, 4-(cyclopentylamino group; [3hydroxycyclobutyl]amino group, [3,3,3-trifluoro-2-hydroxypropyl]amino group, 2methoxyethyl)amino group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein R ³ is a C ₁ -C ₆ alkyl group which is optionally substituted with one or

- 103 041614 with two substituents, and each substituent is independently selected from a hydroxy group, a C1-C4 alkoxy group and a 3-7 membered heterocycloalkyl group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein R ³ is a C2- _C6 alkenyl group which is optionally substituted with a C1-C4 alkoxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein R ³ is a C3-C9 cycloalkyl group which is optionally substituted with hydroxy, and their stereoisomers , tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof. In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein R ³ is a C5- _C9 cycloalkenyl group, C5:150,201,C7:154 (bridged) which is optionally substituted with a hydroxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof. In another embodiment of the first aspect of the present invention, or in any embodiment derived from it, the present invention provides compounds of formula (I) above, in which R ³ is a 3-9 membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O-, -S-, -S(O)-, S(O) ₂ and -NR ⁹ -, and said heterocycloalkyl group may optionally further contain a bridging group selected from -O-, -NR ^9- , -CH2-, -CH2-CH2-, -O-CH2-, -CH2-O-, -NR9-CH2- and -CH2-NR ⁹ -;

and said heterocycloalkyl group is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom;

oxo(=O) groups;

cyano groups;

hydroxy groups;

C ₁ -C ₃ -alkyl group, which is optionally substituted with one, two or three substituents and, and these substituents are independently selected from hydroxy;

C ₁ -C ₃ haloalkyl group;

C1-Q alkoxy groups;

C ₁ -C ₃ haloalkoxy groups;

C ₁ -C ₃ -hydroxyalkoxy groups;

C(O)NR ⁵ R ⁶ groups and NR5R ⁶ groups;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, in which R ³ is a 5-9 membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O, -S- and -NR ⁹ which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from oxo (=O), C ₁ -C ₃ -alkyl groups, and a halogen atom, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof. In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein R ³ is an aryl group which is optionally substituted with one, three or four substituents, and each the substituent is independently selected from a halogen atom, a hydroxy group, a cyano group,

C ₁ -C ₃ -alkyl group,

C ₁ -C ₃ -haloalkyl group,

C ₁ -C ₃ -alkoxy groups,

C ₁ -C ₃ haloalkoxy groups, and

NR ⁵ R ⁶ groups, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof. In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein R ³ is a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom,

- 104 041614

C ₁ -C ₃ -alkyl group, cyano group,

C ₁ -C ₃ -haloalkyl group,

C ₁ -C ₃ alkoxy groups, hydroxy groups, and NR5R ⁶ groups;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, in which R ³ is a 5-9 membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O, -S- and -NR ⁹ which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from oxo (=O), C ₁ -C ₃ -alkyl groups, and a halogen atom, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof. In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein R ³ is an aryl group which is optionally substituted with one, three or four substituents, and each the substituent is independently selected from a halogen atom, a hydroxy group, a cyano group,

C ₁ -C ₃ -alkyl group,

C ₁ -C ₃ -haloalkyl group,

C1-C3-alkoxy groups,

C ₁ -C ₃ -haloalkoxy groups and

NR ⁵ R ⁶ groups, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof. In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein R ³ is a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom,

C ₁ -C ₃ -alkyl group, cyano group,

C ₁ -C ₃ -haloalkyl group,

C1-C3 alkoxy groups, hydroxy groups, and NR ⁵ R ⁶ groups;

where the heterocycloalkyl group is a 6-membered ring, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, in which R ³ is a 5-9 membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O, -S- and -NR ⁹ which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from an oxo group (=O), a C1-C3 alkyl group, and halogen atoms, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof. In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein R ³ is an aryl group which is optionally substituted with one, three or four substituents, and each the substituent is independently selected from a halogen atom, a hydroxy group, a cyano group,

C ₁ -C ₃ -alkyl group,

C ₁ -C ₃ -haloalkyl group,

C1-C3-alkoxy groups,

C ₁ -C ₃ haloalkoxy groups, and

NR ⁵ R ⁶ groups, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof. In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above wherein R ³

- 105 041614 is a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom,

C1-C ₃ -alkyl group, cyano group,

C ₁ -C ₃ -haloalkyl group,

C1- _C3 alkoxy groups, hydroxy groups, and

NR5R ⁶ groups;

where the heterocycloalkyl group is a 5-membered ring, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein R ³ is an NR7R ⁸ group; and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein R ³ is an NR7R ⁸ group; and R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, C(O)NR ⁵ R ⁶ group, NR5R ⁶ group,

C1-C ₃ -alkoxy groups,

a C3-C7 cycloalkyl group which is optionally substituted with one or two substituents, and said substituents are independently selected from a C1- _C3 alkyl group, an oxo (=O) group, a hydroxy group, and a C1- _C3 hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a C1- _C3 alkyl group or an oxo (=O) group, a heteroaryl group which itself is optionally substituted with a C1- _C3 alkyl group;

- C1-C ₅ -alkylene-O-C 1 -C ₅ -alkyl group,

- C1-C ₅ -alkylene-S-C 1 -C ₅ -alkyl group,

- C1-C ₅ -alkylene-NR ⁵ -C1-C ₅ -alkyl group,

a C3-C6 cycloalkyl group which is optionally substituted with a hydroxy group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C1- _C3 alkyl group and a hydroxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and their mixtures.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein R ³ is an NR ⁷ R ⁸ group; And

R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded,

a C1- _C6 alkyl group which is optionally substituted with one, two, three or four substituents, and said substituent is independently selected from halogen atom, cyano group, hydroxy group, C(O)NR ⁵ R ⁶ group, NR5R ⁶ group,

C1-C ₃ -alkoxy groups,

a C3-C7 cycloalkyl group which is optionally further substituted with one or two substituents, and said substituents are independently selected from a C1- _C3 alkyl group, an oxo (=O) group, a hydroxy group, and a C1- _C3 hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C1- _C3 alkyl group, a heteroaryl group which is optionally further substituted with C1- With a ₃ -alkyl group,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted by hydroxy group or C 1 -C ₃ alkyl group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C1- _C3 alkyl group and a hydroxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and their mixtures.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is a halogen atom,

- 106 041614

C2-C6-alkenyl group,

C ₃ -C _b -cycloalkyl group,

C ₅ -C _b -cycloalkenyl group,

A _{C 3} -C 7 heterocycloalkyl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom and a C ₁ -C ₃ alkyl group, a hydroxy group, an NR5R6 group, a C ₁ -C ₃ haloalkyl group and C ₁ -C ₃ -haloalkoxy groups,

a C ₅ -C 7 -heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from an oxo group (=O), a Cl-C ₃ -alkyl group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from halogen, hydroxy, cyano, C ₁ C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ -haloalkoxy group and NR5R6 group, mono - or bicyclic heteroaryl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, C ₁ -C ₃ -alkyl group, cyano group, C ₁ - C ₃ haloalkyl group, C ₁ -C ₃ alkoxy group, hydroxy group and NR5R6 group;

and NR7R ⁸ groups.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is a C2-C6-alkenyl group,

C3-C6-cycloalkyl group,

C ₅ -C _b -cycloalkenyl group,

a C3-C7 heterocycloalkyl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom and _{a C1} - _C3 alkyl group, a hydroxy group, an NR5R6 group, a _C1 - _C3 haloalkyl group, and C ₁ -C ₃ -haloalkoxy groups,

a C ₅ -C 7 heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from an oxo group (=O), a C ₁ -C ₃ alkyl group and a halogen atom, an aryl group, which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C ₁ C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, C ₁ -C ₃ haloalkoxy and NR5R6 groups, a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from halogen, C ₁ -C ₃ alkyl, cyano, C ₁ -C ₃ haloalkyl group, C ₁ -C ₃ alkoxy group, hydroxy group and NR5R6 group, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and NR7R ⁸ group.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is a halogen atom,

C2-C6-alkenyl group,

C ₅ -C _b -cycloalkyl group, which is optionally partially unsaturated,

a C3-C6 heterocycloalkyl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom and a C ₁ -C ₃ alkyl group,

a C ₅ -C _b heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from an oxo group (=0), a C ₁ -C ₃ alkyl group and a halogen atom, an aryl group , which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, a cyano group, and NR5R6 groups;

and a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a C1-C3 alkyl group, a cyano group, a _C1 - _C3 haloalkyl group, a _C1 - _C3 alkoxy group and NR5R6 groups;

or NR ⁷ R ⁸ groups, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

- 107 041614

R ³ is

C2-C6-alkenyl group,

C ₅ -C ₆ -cycloalkyl group, which is optionally partially unsaturated,

C ₃ -C ₆ -heterocycloalkyl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom and a C ₁ -C ₃ -alkyl group,

C ₅ -C ₆ -heterocycloalkyl group, which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from oxo group (=O), C ₁ -C ₃ -alkyl group and halogen atom, aryl group , which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a C ₁ -C ₃ alkyl group, a Ci-C ₃ haloalkyl group, a C 1 -C ₃ alkoxy group, a cyano group, and an NR5R ⁶ group ;

and a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a C1- _C3 alkyl group, a cyano group, a C1- _C3 haloalkyl group, a _C1 - _C3 — alkoxy groups and NR5R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4yl group;

or NR7R ⁸ group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is a halogen atom,

C2-C ₆ -alkenyl group,

C ₃ -C ₆ -cycloalkyl group

C ₅ -C ₆ -cycloalkenyl group,

C ₃ -C ₇ - heterocycloalkyl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom and C 1 -C ₃ -alkyl group, hydroxy group, NR5R ⁶ group, C 1 -C ₃ -haloalkyl group and C1-C ₃ -haloalkoxy groups,

C ₅ -C ₇ -heterocycloalkyl group, which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from oxo group (=O), C1-C ₃ -alkyl group and halogen atom, phenyl group, which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from halogen, hydroxy, cyano, Cp, C ₃ alkyl, C 1 -C ₃ haloalkyl, C 1 -C ₃ alkoxy, C 1 -C ₃ haloalkoxy groups and NR5R ⁶ groups, a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a C1- _C3 alkyl group, a cyano group, a C1- _C3 haloalkyl groups, C ₁ -C ₃ alkoxy groups, hydroxy groups and NR5R ⁶ groups;

and NR7R ⁸ groups, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is a C2-C ₆ alkenyl group,

C ₃ -C ₆ -cycloalkyl group,

C ₅ -C ₆ -cycloalkenyl group,

A C ₃ -C ₇ heterocycloalkyl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom and a C 1 -C ₃ alkyl group, a hydroxy group, an NR5R ⁶ group, a C 1 -C ₃ haloalkyl group and C1-C ₃ -haloalkoxy groups,

C ₅ -C ₇ -heterocycloalkyl group, which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from oxo group (=O), C1-C ₃ -alkyl group and halogen atom, phenyl group, which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from halogen, hydroxy, cyano, Cp, C ₃ alkyl, C 1 -C ₃ haloalkyl, C 1 -C ₃ alkoxy, C 1 -C ₃ haloalkoxy groups and NR5R ⁶ groups, a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a C1- _C3 alkyl group, a cyano group, a C1- _C3 haloalkyl groups, C ₁ -C ₃ alkoxy groups, hydroxy groups and NR5R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

- 108 041614 and NR7R ⁸ group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In yet another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is a halogen atom,

C2-C ₆ -alkenyl group,

C ₅ -C ₆ -cycloalkenyl group,

C ₃ -C ₆ -heterocycloalkyl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom and a Cl-C ₃ -alkyl group,

a C ₅ -C ₆ heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from an oxo group (=O), a Cl-C ₃ -alkyl group and a halogen atom, a phenyl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a C ₁ -C ₃ alkyl group, a C 1 C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, a cyano group, and an NR5R ⁶ group;

and a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a C1- _C3 alkyl group, a cyano group, a _C1 - _C3 haloalkyl group, a _C1 - _C3 -alkoxy groups and NR5R ⁶ groups;

or NR7R ⁸ group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In yet another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is a C2-C6 alkenyl group,

C ₅ -C ₆ -cycloalkenyl group,

C ₃ -C ₆ -heterocycloalkyl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom and a C ₁ -C ₃ -alkyl group,

a C ₅ -C ₆ heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from an oxo group (=O), a C1-C ₃ alkyl group and a halogen atom, a phenyl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a C1- _C3 alkyl group, a _C1C3 haloalkyl group, a C1- _C3 alkoxy group, a cyano group, and an ^NR5R6 group;

and a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a C1- _C3 alkyl group, a cyano group, a C1- _C3 haloalkyl group, a _C1 - _C3- alkoxy groups and NR5R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4yl group;

or NR7R ⁸ group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In yet another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is a halogen atom,

a C2-C6 alkenyl group, or an NR7R ⁸ group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In yet another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is a C ₂ -C ₆ alkenyl group, or NR7R ⁸ group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In yet another embodiment of the first aspect, the present invention provides compounds of formula (I) above, wherein:

R ³ is a C3-C6 cycloalkyl group

C ₅ -C ₆ -cycloalkenyl group,

A C ₃ -C ₇ heterocycloalkyl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom and a C 1 -C ₃ alkyl group, a hydroxy group, an NR5R ⁶ group, a C 1 -C ₃ haloalkyl group and C1-C ₃ -haloalkoxy groups,

C ₅ -C ₇ -heterocycloalkyl group, which is partially unsaturated and optionally

- 109 041614 substituted with one, two or three substituents, and each substituent is independently selected from an oxo group (=O), a C1-C ₃ -alkyl group and a halogen atom, a phenyl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C1C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, a C ₁ -C ₃ haloalkoxy group, and an NR5R ⁶ group, mono- or a bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ alkyl group, a methylcyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ - alkoxy, methoxy, hydroxy and NR5R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In yet another embodiment of the first aspect, the present invention provides compounds of formula (I) above, wherein:

R ³ represents a C ₅ -C ₆ -cycloalkyl group,

C ₅ -C ₆ -cycloalkenyl group (cyclopentenyl),

C ₃ -C ₆ -heterocycloalkyl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom and a C ₁ -C ₃ -alkyl group,

a C ₅ -C ₆ heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from an oxo group (=O), a C ₁ -C ₃ alkyl group and a halogen atom, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In yet another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is a phenyl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from halogen, hydroxy, cyano, C ₁ C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ -alkoxy groups, C ₁ -C ₃ -haloalkoxy groups and NR5R ⁶ groups, a mono- or bicyclic heteroaryl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, C ₁ -C ₃ an alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, a hydroxy group and an NR5R ⁶ group, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In yet another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ represents a phenyl group which is optionally substituted with a halogen atom, a monocyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ -alkyl group, a cyano group, a C ₁ - C ₃ haloalkyl group, C ₁ -C ₃ alkoxy group, hydroxy group, and

NR7R ⁸ group;

where R ⁷ , R ⁸ are independently selected from a hydrogen atom, a C2-C ₃ -alkyl group, which is optionally substituted with one or two substituents independently selected from a hydroxy group, a trifluoromethyl group or a methoxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In yet another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is a phenyl group which is optionally substituted with a halogen atom, a monocyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, an amino group and a Ci-C ₃ haloalkyl group, and

NR ⁷ R ⁸ group;

where R ⁷ represents a hydrogen atom, and R ⁸ represents a C 1 -C ₆ -alkyl group, which is optionally substituted with one or two substituents independently selected from hydroxy group, trifluoromethyl group or methoxy group, and their stereoisomers, tautomers, N-oxides, hydrates , solvates and salts, and mixtures thereof.

- 110 041614

In yet another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is a phenyl group which is optionally substituted with a halogen atom, a monocyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, an amino group, and a C ₁ -C ₃ haloalkyl group, and

NR7R ⁸ group;

where R ⁷ is a hydrogen atom and R ⁸ is a C2- _C3 alkyl group which is optionally substituted with one or two substituents independently selected from hydroxy, trifluoromethyl or methoxy.

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In yet another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is

NR ⁷ R ⁸ group;

where R ⁷ is a hydrogen atom and R ⁸ is a C ₂ -C ₃ alkyl group which is optionally substituted with one or two substituents independently selected from hydroxy, trifluoromethyl or methoxy.

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In yet another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is a monocyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from an amino group and a C ₁ -C ₃ haloalkyl group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from an aryl group which is optionally substituted with a substituent selected from a halogen atom and a C ₁ -C ₃ haloalkyl group, a monocyclic heteroaryl group substituted with a substituent selected from a C ₁ -C ₃ haloalkyl group and an NR5R ⁶ group;

and NR ⁷ R ⁸ groups;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from a phenyl group which is optionally substituted with a substituent which is selected from a fluorine atom or a chlorine atom and a CHF 2 group and a CF ₃ group,

1H-pyrazol-4-yl group, 1H-pyrazol-1-yl group and pyridin-4-yl group which are optionally substituted with a substituent selected from CHF2 group, CF3 group and NH2 group;

- NH-(CH2)-CH(OH)(CH ₃ ) groups, -NH-(CH2)2-O-CH ₃ groups, -NH-CH2-CH(OH)CF ₃ groups;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ³ is selected from a phenyl group which is optionally substituted with a substituent which is selected from a fluorine atom or a chlorine atom and a CF3 group,

1H-pyrazol-4-yl group, 1H-pyrazol-1-yl group and pyridin-4-yl group which are optionally substituted with a substituent selected from CF3 group and NH2 group;

- NH-(CH2)-CH(OH)(CH3) groups, -NH-(CH2)2-O-CH3 groups, -NH-CH2-CH(OH)CF3 groups;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In yet another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of the formula

- 111 041614 (I), above, in which:

R ⁴ represents a hydrogen atom, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In yet another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ⁴ is a C1- _C3 alkyl group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In yet another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ⁴ represents a methyl group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ⁴ is a C ₁ -C ₃ -alkyl group having the S configuration, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ⁴ is a methyl group having an S configuration and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R5/R ⁶ is independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R5/ ^R6 are independently selected from a hydrogen atom and a methyl group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R 5 /R ⁶ represent a hydrogen atom, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, C(O)NR5R ⁶ group, NR5R ⁶ group,

C1-C ₃ -alkoxy groups,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted with one or two substituents, and these substituents are independently selected from C1-C ₃ -alkyl group, oxo (=O) group, hydroxy group and C1-C ₃ -hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a C1- _C3 alkyl group or an oxo (=O) group, a heteroaryl group which itself is optionally substituted with a C1- _C3 alkyl group;

- C ₁ -C ₅ -alkylene-O-C 1 -C ₅ -alkyl group,

- C1-C ₅ -alkylene-SC 1 -C ₅ -alkyl group,

- C1-C ₅ -alkylene-NR ⁵ -C1-C ₅ -alkyl group,

a C3-C6 cycloalkyl group which is optionally substituted with a hydroxy group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C1- _C3 alkyl group and a hydroxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and their mixtures.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I), above, in

- 112 041614 which:

R ⁷ is a hydrogen atom and R ⁸ is selected from

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, C(O)NR5R ⁶ group, NR5R ⁶ group,

C ₁ -C ₃ -alkoxy groups,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group, oxo (=O) group, hydroxy group and C ₁ -C ₃ -hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a CrQ alkyl group or an oxo (=O) group, a heteroaryl group which itself is optionally substituted with a C ₁ -C ₃ 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 ₁ -C ₅ -alkylene-NR ⁵ -C ₁ -C ₅ -alkyl group,

C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from C ₁ -C ₃ alkyl group and hydroxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and also their mixtures.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, C(O)NR ⁵ R ⁶ group, NR5R ⁶ group,

C ₁ -C ₃ -alkoxy groups,

C ₃ -C ₇ -cycloalkyl group, which is optionally further substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group, oxo (=O) group, hydroxy group and C ₁ -C ₃ -hydroxyalkyl group ;

a 3-7 membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C ₁ -C ₃ -alkyl group, a heteroaryl group which is optionally further substituted with C ₁ -C ₃ -alkyl group,

a C3-C7 cycloalkyl group which is optionally further substituted with a hydroxy group or a C ₁ -C ₃ alkyl group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from C ₁ -C ₃ alkyl group and hydroxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and also their mixtures.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ⁷ is a hydrogen atom and R ⁸ is selected from

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, C(O)NR ⁵ R ⁶ group, NR5R ⁶ group,

C ₁ -C ₃ -alkoxy groups,

C ₃ -C ₇ -cycloalkyl group, which is optionally further substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group, oxo (=O) group, hydroxy group and C ₁ -C ₃ -hydroxyalkyl group ;

a 3-7 membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C ₁ -C ₃ -alkyl group, a heteroaryl group which is optionally further substituted with C ₁ -C ₃ -alkyl group,

a C3-C7 cycloalkyl group which is optionally further substituted with a hydroxy group or a C ₁ -C ₃ alkyl group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from C ₁ -C ₃ alkyl group and hydroxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and also their mixtures.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I), above, in

- 113 041614 which:

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

0 ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, NR5R ⁶ group,

0 ₁ -0 ₃ -alkoxy groups,

C ₃ -C ₇ -cycloalkyl group, which is optionally further substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group, oxo (=0) group, hydroxy group and C ₁ -C ₃ -hydroxyalkyl group ;

a 3-7 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C ₁ -C ₃ alkyl group, a heteroaryl group which is optionally further substituted with C ₁ -C ₃ -alkyl group,

A C ₃ -C ₇ cycloalkyl group which is optionally further substituted with hydroxy or a C ₁ -C ₃ alkyl group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from C ₁ -C ₃ alkyl group and hydroxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and also their mixtures.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ⁷ is a hydrogen atom and R ⁸ is selected from

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, NR5R ⁶ group,

0 ₁ -0 ₃ -alkoxy groups,

C ₃ -C ₇ -cycloalkyl group, which is optionally further substituted with one or two substituents, and these substituents are independently selected from 0 ₁ -C ₃ -alkyl group, oxo (=0) group, hydroxy group and 0 ₁ -C ₃ -hydroxyalkyl group ;

a 3-7 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O- and -NR ⁹ - which is optionally further substituted with a 0 ₁ -C ₃ -alkyl group, a heteroaryl group which is optionally further substituted with 0 ₁ -C ₃ -alkyl group,

a C3-C7 cycloalkyl group which is optionally further substituted with a hydroxy group or a 0 ₁ -C ₃ alkyl group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from C ₁ -C ₃ alkyl group and hydroxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and also their mixtures.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group,

0 ₁ -0 ₃ -alkoxy groups,

C ₃ -C ₆ -cycloalkyl group, which is optionally additionally substituted with one or two substituents, and these substituents are independently selected from 0 ₁ -C ₃ -alkyl group and 0 ₁ -C ₃ hydroxyalkyl group;

a 4-6 membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O- and -NR ⁹ - which is optionally further substituted with a 0 ₁ -C ₃ -alkyl group, a heteroaryl group which is optionally further substituted with 0 ₁ -C ₃ -alkyl group;

a 03-06 cycloalkyl group which is optionally further substituted with a hydroxy group or a 01-03 alkyl group,

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from 0 ₁ -C ₃ alkyl group and hydroxy group,

- 114 041614 and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group,

Q-C-alkoxy groups,

C3-C ₆ -cycloalkyl group, which is optionally additionally substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group and C ₁ -C ₃ hydroxyalkyl group;

a 4-6 membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C ₁ -C ₃ -alkyl group, a heteroaryl group which is optionally further substituted with C ₁ -C ₃ -alkyl group;

C ₃ -C ₆ -cycloalkyl group, which is optionally further substituted by hydroxy group or C ₁ -C ₃ -alkyl group

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from C ₁ -C ₃ alkyl group and hydroxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and also their mixtures.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group and hydroxy group,

C ₁ -C ₃ -alkoxy groups,

a C3-C7 cycloalkyl group which is optionally substituted with one or two substituents, and said substituents are independently selected from C ₁ -C ₃ alkyl group, hydroxy group and C ₁ -C ₃ hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a _{C 1} -C ₃ alkyl group; a heteroaryl group which is optionally further substituted with a _{C 1} -C ₃ alkyl group;

C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from C ₁ -C ₃ alkyl group and hydroxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and also their mixtures.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ⁷ is a hydrogen atom and R ⁸ is selected from

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group and hydroxy group,

C ₁ -C ₃ -alkoxy group,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group, hydroxy group and C ₁ -C ₃ hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a _{C 1} -C ₃ alkyl group; a heteroaryl group which is optionally further substituted with a _{C 1} -C ₃ alkyl group;

a C3-C6 cycloalkyl group which is optionally substituted with a hydroxy group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from C ₁ -C ₃ alkyl group and hydroxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and also their mixtures.

- 115 041614

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one or two, three or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group,

CrC-alkoxy groups,

C ₃ -C ₅ -cycloalkyl group, which is optionally additionally substituted with one or two substituents, and these substituents are independently selected from C ₁ -C3-alkyl group and C ₁ -C ₃ hydroxyalkyl group;

a 5-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C ₁ -C ₃ -alkyl group, a heteroaryl group which is optionally further substituted with C ₁ - With ₃ -alkyl group;

C ₃ -C ₆ -cycloalkyl group, which is optionally additionally substituted by hydroxy group or C ₁ -C ₃ -alkyl group,

a 4-5 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from C ₁ -C ₃ alkyl group and hydroxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and also their mixtures.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ⁷ is a hydrogen atom and R ⁸ is selected from

C ₁ -C ₆ -alkyl group, which is optionally substituted with one or two, three or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group,

C ₁ -C ₃ -alkoxy groups,

C ₃ -C ₅ -cycloalkyl group, which is optionally additionally substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group and C ₁ -C ₃ hydroxyalkyl group;

a 5-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ - which is optionally further substituted with a C ₁ -C ₃ alkyl group, a heteroaryl group which is optionally further substituted with C ₁ - With ₃ -alkyl group;

C ₃ -C ₆ -cycloalkyl group, which is optionally additionally substituted by hydroxy group or C ₁ -C ₃ -alkyl group,

a 4-5 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from C ₁ -C ₃ alkyl group and hydroxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and also their mixtures.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded,

C ₁ -C ₃ -alkyl group, which is optionally substituted with one, two or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group and methoxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as their mixtures.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ⁷ is a hydrogen atom and R ⁸ is selected from

C ₁ -C ₃ -alkyl group, which is optionally substituted with one, two or four substituents, and the specified substituent is independently selected from a halogen atom, hydroxy group and methoxy group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as their mixtures.

In yet another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ⁷ represents a hydrogen atom, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded, and a _C1 - _C6 alkyl group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and also their mixtures.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ⁷ /R ⁸ are independently selected from hydrogen, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded, and a C ₁ -C ₆ alkyl group which is optionally substituted one or two times with a substituent selected from hydroxy, trifluoromethyl, and methoxy groups, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein:

R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded, and a C ₁ -C ₄ alkyl group which is optionally substituted one or two times with a substituent selected from a hydroxy group and a trifluoromethyl group, and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof.

In another embodiment of the first aspect of the present invention, or in any embodiment derived therefrom, the present invention provides compounds of formula (I) above, wherein: R ⁹ is a bond, said bond being a compound from a nitrogen atom with which R ⁹ is linked to the rest of the molecule.

In another aspect, the present invention provides a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or excipients and a compound of formula (I) or stereoisomers, tautomers, N-oxides, hydrates, solvates, salts or mixtures thereof.

In yet another aspect, the present invention provides a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or excipients and a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof.

Control in the context of the present invention means average expression in a representative panel of tumor cells or tumor cell lines.

In various embodiments of any of the entities detailed herein, the cancer responds to a modulator of the PDE3A- and/or PDE3B-SLFN12 complex.

In various embodiments, the subject has been diagnosed with a cancer that responds to a modulator of the PDE3A- and/or PDE3B-SLFN12 complex.

In various embodiments of any subject matter detailed herein, the cancer is brain cancer (especially glioma, more specifically glioblastoma, astrocytoma), breast cancer (especially ductal carcinoma and adenocarcinoma), cervical cancer, AML (especially erythroleukemia), lung cancer (especially NSCLC and SCLC adenocarcinoma), skin cancer (especially melanoma), esophageal cancer (especially squamous cell carcinoma), ovarian cancer (especially teratocarcinoma, adenocarcinoma), pancreatic cancer and prostate cancer.

In various embodiments of any subject matter detailed herein, the cancer is brain cancer, breast cancer, cervical cancer, AML, lung cancer, skin cancer, esophageal cancer, ovarian cancer, pancreatic cancer, and prostate cancer.

In various embodiments, the cancer is melanoma, endometrial, lung, hematopoietic/lymphoid sarcoma, ovarian cancer, cervical cancer, soft tissue sarcoma, leiomyosarcoma, urinary tract, pancreatic, thyroid, kidney, glioblastoma, or breast cancer.

In various embodiments, the cancer is skin cancer, especially melanoma, lung adenocarcinoma, or cervical cancer.

In various embodiments of any of the entities detailed herein, the modulator of the PDE3A- and/or PDE3B-SLFN12 complex is administered orally.

In various embodiments of any of the entities detailed herein, the modulator of the PDE3A- and/or PDE3B-SLFN12 complex is administered by intravenous injection.

The present invention provides methods for treating a subject for cancer identified as responsive to treatment with a PDE3A- and/or PDE3B-SLFN12 modulator of the complex of formula (I) by detecting co-expression of PDE3A and/or PDE3B polynucleotides or polypeptides and

Schlafen 12 (SLFN12) and/or no decrease in polynucleotide or polypeptide expression

CREB3L1 cancer.

The compositions and products defined by the present invention have been isolated or otherwise made in accordance with the examples below. Other features and advantages of the present invention will be apparent from the detailed description and from the claims.

According to a specific other embodiment of the first aspect, the present invention provides combinations of two or more of the above embodiments under the heading other embodiments of the first aspect of the present invention.

The present invention provides any subcombination, in any embodiment or aspect of the present invention, of the compounds of general formula (I) above.

The present invention provides any subcombination, in any embodiment or aspect of the present invention, of the intermediates of general formula (I).

The present invention provides compounds of general formula (I) which are disclosed in the Examples section of this text, below.

Sets

The present invention provides a kit containing a compound of formula (I) and/or a means for determining the sensitivity or resistance of a subject to a modulator of the PDE3A- and/or PDE3BSLFN12 complex, especially to treatment with compounds of formula (I).

The present invention also provides kits which may include a compound of formula (I) in the form of a therapeutic composition containing an effective amount of said compound, eg in unit dosage form.

In some embodiments, the kit comprises a sterile container that includes a therapeutic or diagnostic composition; such containers may be boxes, ampoules, bottles, vials, test tubes, pouches, pouch packs, blister packs, or other suitable container forms known in the art. Such containers may be made of plastic, glass, laminated paper, metal foil, or other materials suitable for storing medicines.

In one embodiment, if desired, the kit further includes instructions for dosing PDE3A and/or PDE3B and SLFN12 and/or instructions for administering a PDE3A- and/or PDE3B-SLFN12 complex modulator to a subject suffering from a cancer, e.g., a cancer of the selected of those responding to treatment with a modulator of the PDE3A- and/or PDE3B-SLFN12 complex.

In specific embodiments, the instructions include at least one of the following: a description of the therapeutic agent; dosing and administration schedule for the treatment or prevention of malignant tumors or their symptoms; precautionary measures; warnings; indications; contraindications; dosage information; adverse reactions; pharmacology in animals; clinical researches; and/or links. Instructions may be printed directly on the container (if available), or as a label applied to the container, or as a separate sheet, brochure, card, or folder supplied in or with the container.

In the practice of the present invention, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology are used, which are within the skill of the art. Such methods are fully described in literature such as Molecular Cloning: A Laboratory Manual, second edition (Sambrook, 1989); Oligonucleotide Synthesis (Gait, 1984); Animal Cell Culture (Freshney, 1987); Methods in Enzymology Handbook of Experimental Immunology (Weir, 1996); Gene Transfer Vectors for Mammalian Cells (Miller and Calos, 1987); Current Protocols in Molecular Biology (Ausubel, 1987); PCR: The Polymerase Chain Reaction, (Mullis, 1994); Current Protocols in Immunology (Coligan, 1991). These techniques are applicable to the production of polynucleotides and polypeptides of the present invention and, as such, may be considered in making and using the present invention. In particular, useful techniques for specific embodiments will be discussed in the following sections.

The following examples are provided to provide those skilled in the art with a complete disclosure and description of how to make and use the assay, screening and treatment methods of the present invention and are not intended to limit the scope of the present invention.

General synthesis of compounds of formula (I)

Compounds according to the present invention of general formula (I) can be obtained according to schemes 1-9. The schemes and procedures described below illustrate routes for the synthesis of the compounds of general formula (I) of the invention and are not intended to be limiting. One skilled in the art will appreciate that the order of transformations shown in Schemes 1-9 can be modified in various ways. Therefore, the order of transformations given as an example in these diagrams is not

- 118 041614 is limiting. In addition, the interconversion of any of the R ¹ , R ² , R ³ , or R ⁴ substituents can be achieved before and/or after the transformation examples given. These modifications may be such as the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, metalation, substitution, or other reactions known to the person skilled in the art. These transformations include those that introduce a functional group that allows further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts in Protective Groups in Organic Synthesis, ^3rd edition, Wiley 1999). Specific examples are described in the following paragraphs.

Seven ways to obtain compounds of General formula (I) are described in schemes 1-9.

Synthesis routes

Route 1: Synthesis of compounds of formula (I) via a transition metal catalyzed reaction such as Suzuki coupling reaction, Negishi coupling reaction, Kumada coupling reaction, Stille coupling reaction, Buchwald-Hartwig coupling reaction, preferably Suzuki coupling reaction, or via nucleophilic aromatic substitution

Part I: Synthesis of intermediates of formula (II).

Scheme 1

Scheme 1: the way to obtain intermediate compounds of formula (II), in which R ¹ , R ² and R ⁴ are as defined above; the meaning of X is as defined in the context of Scheme 2 and paragraphs (i), (j), (k) for compounds of formula (II).

(a) Hydroxy(tosyloxy)iodo)benzene, DMSO, water, room temperature, 18 hours; or iodine, DMSO,

60°C, 18 hours. To obtain the starting material for steps (a) and (h), see, for example, scheme 3.

(b) H ₂ NNHCOOCH ₃ , HCl (aq), MeOH, room temperature, 5 h;

(c) potassium carbonate, acetonitrile, 60°C, 18 h or NaOEt/EtOH, 0°C, 10 min, or NaH, EtOH, 0°C 10 min;

(d) sodium formate, sodium bicarbonate, CH3CN, water, 65°C, 24 h;

(e) potassium acetate, potassium iodide, 18 hours, room temperature;

(f) H ₂ NNHCOOCH ₃ , HCl (aq.), MeOH, room temperature, 5-18 hours;

(g) potassium carbonate, CH3CN, 60°C, 18 h or NaOEt/EtOH, 0°C 10 min, or NaH, EtOH, 0°C 10 min;

(h) acetic acid, bromine, hydrogen bromide, 18 hours, room temperature; for starting material for steps (a) and (h), see e.g. Scheme 3.

Compounds of formula (II) containing chiral centers may optionally be separated by methods known to those skilled in the art, such as, for example, chiral chromatography, to obtain individual enantiomers or diastereomers.

Part II: conversion of intermediates of formula (II) to compounds of general formula (I).

Scheme 2

(j), (k): R ³ = NR ⁷ R ⁸ , optionally substituted N-linked heterocycloalkyl, partially unsaturated heterocycloalkyl or heteroaryl;

(i): R ³ = optionally substituted alkyl, alkenyl, cycloalkenyl, heterocycloalkyl, partially unsaturated heterocycloalkyl, aryl, heteroaryl.

Scheme 2: the way to obtain compounds of General formula (I) through formula (II), in which R ¹ , R ² and R ⁴ have the meaning as defined above, where R ³ in General formula (I) represents an optionally substituted alkyl, alkenyl, cycloalkenyl, heterocycloalkyl, partially unsaturated heterocycloalkyl, aryl or heteroaryl, as defined in more detail below in paragraph (i); or R ³ is NR7R ⁸ , or an optionally substituted N-linked heterocycloalkyl, partially unsaturated heterocycloalkyl, or heteroaryl, as defined in more detail below in paragraph (j) and (k), respectively; and where the terms N-linked heterocycloalkyl, N-linked, partially unsaturated heterocycloalkyl and N-linked heteroaryl refer to 3-9 membered heterocycloalkyl, 3-9 membered partially unsaturated heterocycloalkyl or heteroaryl group as defined for R ³ above, which is bonded with the rest of the molecule through the nitrogen atom which constitutes the ring atom of said heterocycloalkyl, partially unsaturated heterocycloalkyl or heteroaryl group.

(i) Route 1 via Suzuki coupling reaction with organoboron compounds.

Compounds of general formula (I) where R ³ is R ^x as defined below for formulas (IIIa), (IIIb), and (IIIc) can be prepared by reaction of intermediates (II) where X is Cl, Br , I (as reflected in scheme 2), or a group selected from (C ₁ -C ₄ alkylsulfonyl)oxy, (C ₁ -C ₄ -fluoroalkylsulfonyl)oxy and (phenylsulfonyl)oxy, and phenyl present in (phenylsulfonyl)oxy , optionally substituted with one, two, three, four or five substituents each independently selected from halo, nitro, cyano, C1-C4 alkyl, and C1C4 alkoxy;

R ¹ or R ² are as defined above but other than Cl, Br, I, and

R ⁴ is as defined above with boronic acids R ^x B(OH)2 (formula (IIIa)), or boronic acid esters R ^x B(OR ^y )2 (formula (IIIb)), or tetrafluoroborate salts R ^x BF ₄ (formula (IIIc)), in the presence of a base such as, for example, potassium carbonate or potassium acetate, a palladium catalyst, such as, for example, dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(0), palladium acetate (P)/ triscyclohexylphosphine, tris(dibenzylideneacetone)dipalladium, bis(diphenylphosphineferrocenyl)palladium(II) chloride, 1,3-bis(2,6-diisopropylphenyl)imidazole-2ylidene(1,4-naphthoquinone)palladium dimer, allyl(chlorine)(1, 3-dimesityl-1,3-dihydro-2H-imidazol-2ylidene)palladium, palladium (II) acetate/dicyclohexyl(2',4',6'-triisopropyl-biphenyl-2-yl)phosphine, [1,1bis( diphenylphosphino)ferrocene]palladium(II) chloride monodichloromethane adduct, [1,1'Bis(diphenylphosphino)ferrocene]dichloropalladium(II), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) , palladium (II) acetate, (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(P ), or chloro(2dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) as preferred embodiment chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), and optionally further a ligand such as, for example, 2-(dicyclohexylphosphino)2',4',6'-triisopropylbiphenyl, in a solvent such as, for example, dioxane, toluene or water, or a mixture thereof, under a nitrogen atmosphere or an argon atmosphere, at 80- 120°C, for 2 h-7 d;

wherein ^Rx is

a C ₁ -C ₆ alkyl group which is optionally substituted with one or two substituents, and each substituent is independently selected from hydroxy, C ₁ -C ₄ alkoxy, and a 3-7 membered heterocycloalkyl group; preferably a methyl group which is optionally substituted with a 3-7 membered heterocycloalkyl group,

C ₂ -C ₆ -alkenyl group, which is optionally substituted with C ₁ -C ₄ -alkoxy group,

C ₅ -C ₉ -cycloalkenyl group, which is optionally substituted by hydroxy group,

A 3-9 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O-, -S-, -S(O)-, S(O) ₂ and -NR ⁹ - and said heterocycloalkyl group optionally additionally contains a bridging group selected from -O-, -NR ⁹ -, -CH2-, -CH2-CH2-, -O-CH2-, -CH2-O-, -NR ⁹ -CH2- and -CH2-NR ⁹ -;

and said heterocycloalkyl group is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom;

oxo (=O) groups;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

- 120 041614

C ₁ -C ₃ -haloalkyl group;

Ci-C3-alkoxy groups;

C ₁ -C ₃ haloalkoxy groups;

C(O)NR ⁵ R ⁶ groups and

NR5R ⁶ groups,

A 5-9 membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from oxo (=O), C ₁ -C ₃ alkyl, -C(O)R ⁵ R ⁶ group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a CiC ₃ alkyl group, a C ₁ -C ₃ haloalkyl group , C ₁ -C ₃ -alkoxy groups, C ₁ -C ₃ -haloalkoxy groups and NR ⁵ R ⁶ groups, a mono- or bicyclic heteroaryl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, C ₁ - _C3 alkyl group, cyano group, C1- _C3 haloalkyl group, C1- _C3 alkoxy group, hydroxy group and ^NR5R6 group, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group; R ^y is C1-C6 alkyl, or the two R ^y residues together represent a C2-C6 alkylene group, preferably —C(CH ₃ )2 —C(CH ₃ )2— to form a pinacol ester.

As will be apparent to those skilled in the art, compounds of general formula (I) obtained, for example, by a Suzuki coupling reaction, where R ³ has a group containing an olefinic double bond (for example, if R ³ is alkenyl, cycloalkenyl, or partially unsaturated heterocycloalkyl), can be easily converted to compounds in which R ³ has a corresponding saturated group (eg alkyl, cycloalkyl, heterocycloalkyl) by methods known to those skilled in the art, such as, for example, catalytic hydrogenolysis using a suitable catalyst, such as, for example, palladium on carbon.

(j) Route 1 via nucleophilic aromatic substitution introducing R ³ substituents selected from -NR ⁷ R ⁸ , an N-linked heterocycloalkyl group, a partially unsaturated N-linked heterocycloalkyl group, and an N-linked heteroaryl group, the term N-linked being understood, as described in the context of diagram 2.

Compounds of general formula (I), where R ³ is selected from -NR ⁷ R ⁸ , an N-linked 3-9-membered heterocycloalkyl group, an N-linked, partially unsaturated 3-9-membered heterocycloalkyl group, and an N-linked heteroaryl group, and the term N-linked is understood as described in the context of Scheme 2, and where the terms 3-9 membered heterocycloalkyl, partially unsaturated 3-9 membered heterocycloalkyl, and heteroaryl are and are optionally substituted as defined for R ³ , above, can be obtained by reactions of intermediates (II), where R ⁴ is as defined above,

X is F or Cl (as depicted in Scheme 2), and if X is Cl, R ¹ or R ² may not be F; preferably X is F;

R ¹ and R ² have the meaning as defined above, provided that if X is Cl, R ¹ or R ² need not be F, and provided that at least one of R ¹ and R ² exhibits an electron withdrawing effect ; preferably, R ¹ is selected from fluorine, cyano, and -CF3, and R ² is hydrogen or fluorine; more preferably, R ¹ is -CF _3; and R ² is hydrogen;

with the corresponding amine, optionally in the form of a free base or in the form of a salt, such as, for example, a hydrochloride salt selected from HNR7R ⁸ and a cyclic amine having one NH as ring atom, the cyclic amine being selected from a 3-9 membered heterocycloalkane, a partially unsaturated 3-9 membered heterocycloalkane, and a heteroarene containing one NH as ring atom, respectively, optionally in the presence of a base such as, for example, triethylamine, DIPEA, or cesium carbonate, in an inert solvent, such as, for example, CH ₃ CN, DMF or DMSO, at optionally elevated temperatures ranging from room temperature to 160°C, preferably from 60 to 150°C, for 2 h-7 d;

wherein R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, C(O)NR ⁵ R ⁶ group, NR ⁵ R ⁶ group,

C ₁ -C ₃ -alkoxy groups,

a C3-C7 cycloalkyl group which is optionally substituted with one or two substituents, and

- 121 041614 said substituents are independently selected from C ₁ -C ₃ -alkyl group, oxo (=O) group, hydroxy group and C ₁ -C ₃ -hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a C ₁ -C ₃ alkyl group or an oxo (=O) group, a heteroaryl group which itself is optionally substituted with a C ₁ -C ₃ alkyl group;

- C ₁ -C ₅ -alkylene-O-C ₁ -C ₅ -alkyl group,

- C ₁ -C ₅ -alkylene-SC ₁ -C ₅ -alkyl group,

- C ₁ -C ₅ -alkylene-NR ⁵ -C ₁ -C ₅ -alkyl group,

C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group, and

3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from C ₁ -C ₃ alkyl group and hydroxy group, (k) Alternative route via transition metal catalyzed, preferably palladium catalyzed amination, introducing R ³ substituents selected from -NR ⁷ R ⁸ , an N-linked heterocycloalkyl group, a partially unsaturated N-linked heterocycloalkyl group, and an N-linked heteroaryl group, the term N-linked being understood as described in the context of Scheme 2.

Compounds of general formula (I), where R ³ is selected from -NR7R ⁸ , an N-linked 3-9-membered heterocycloalkyl group, an N-linked, partially unsaturated 3-9-membered heterocycloalkyl group, and an N-linked heteroaryl group, the term N- linked is understood as described in the context of Scheme 2, and where the terms 3-9 membered heterocycloalkyl, partially unsaturated 3-9 membered heterocycloalkyl, and heteroaryl are meaningful and optionally substituted as defined for R ³ , above, can be obtained by the reaction intermediate compounds (II), where X represents Cl, Br, I (as reflected in scheme 2), or a group selected from (C ₁ -C ₄ -alkylsulfonyl)oxy, (C ₁ -C ₄ fluoroalkylsulfonyl)oxy and ( phenylsulfonyl)oxy wherein the phenyl present in (phenylsulfonyl)oxy is optionally substituted with one, two, three, four or five substituents each independently selected from halogen, nitro, cyano, C ₁ -C ₄ -alkyl and C ₁ - C ₄ alkoxy;

R ¹ or R ² are as defined above, but other than Cl, Br, I; preferably R ¹ is -CF ₃ and R ² is hydrogen;

R ⁴ is as defined above with the corresponding amine, optionally as a free base or as a salt, such as, for example, a hydrochloride salt selected from HNR7R ⁸ and a cyclic amine having one NH as ring atom, wherein the cyclic amine selected from a 3-9 membered heterocycloalkane, a partially unsaturated 3-9 membered heterocycloalkane and a heteroarene containing one NH as ring atom, respectively, in the presence of a base such as, for example, potassium phosphate or cesium carbonate, a palladium catalyst such as , for example, tris(dibenzylideneacetone)dipalladium(0), a ligand such as, for example, 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl or 2,2'-bis( diphenylphosphino)1,1'-binaphthalene, in an inert solvent such as, for example, dioxane or toluene, at elevated temperatures in the range of 60-160° C., for 2 h-7 d;

wherein R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, C(O)NR ⁵ R ⁶ group, NR5R ⁶ group,

C ₁ -C ₃ -alkoxy groups,

a C3-C7 cycloalkyl group which is optionally substituted with one or two substituents, and said substituents are independently selected from C ₁ -C ₃ alkyl group, oxo (=O) group, hydroxy group and C ₁ -C ₃ hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a C ₁ -C ₃ alkyl group or an oxo (=O) group, a heteroaryl group which itself is optionally substituted with a _{C 1} -C ₃ alkyl group;

- C ₁ -C ₅ -alkylene-O-C ₁ -C ₅ -alkyl group,

- C ₁ -C ₅ -alkylene-SC ₁ -C ₅ -alkyl group,

- C ₁ -C ₅ -alkylene-NR ⁵ -C ₁ -C ₅ -alkyl group,

C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C ₁ -C ₃ alkyl group and a hydroxy group,

The compounds of formula (I) thus obtained containing chiral centers may optionally be separated by chiral chromatography to obtain individual enantiomers or diastereomers.

- 122 041614

Path 2.

Part I: Synthesis of intermediates of formula (III) from compounds of formula (IV).

Scheme 3

Scheme 3: route for preparing intermediates of formula (III) from compounds of formula (IV) wherein R ¹ and R ² are as defined above.

The benzoic acids of formula (IV) are well known to those skilled in the art and are commercially available in a significant structural variety.

Step (a)(IV)-(IV-1).

The compound of formula (IV) and oxalyl chloride, in a solvent such as, for example, DMF/DCM, react in the temperature range from 0°C to room temperature, for 1-20 h, then HN(OCH ₃ )CH ₃ -HCl, Et ₃ N/CH ₂ Cl ₂ is added at room temperature and the mixture then reacts for 1 h - 3 d;

Step (b) (IV-1)-(III).

The compound (IV-1) and R ⁴ CH ₂ MgBr, where R ⁴ has the meaning as defined above, in a solvent such as, for example, THF, react at 0°C to room temperature, for 1-20 h, to obtain an intermediate compound of formula (III);

Part II: conversion of intermediates of formula (III) to compounds of general formula (I).

Scheme 4

Scheme 4: route for preparing compounds of general formula (I) from an intermediate of formula (III) via intermediates of formula (V) wherein R ¹ , R ² , R ³ , and R ⁴ are as defined above.

Intermediates of formula (III) may be converted to intermediates of formula (V) as described in more detail in the following paragraphs (i), (j) and (k):

(i) Route 1 via Suzuki coupling reaction with organoboron compounds

Intermediates of formula (V) where R ³ is R ^x as defined below for formulas (IIIa), (IIIb), and (IIIc) can be prepared by reaction of intermediates (III) where X is Cl, Br , I (as depicted in Scheme 2), or a group selected from (C1-C4 alkylsulfonyl)oxy, (C1-C ₄ -fluoroalkylsulfonyl)oxy and (phenylsulfonyl)oxy, wherein the phenyl present in (phenylsulfonyl)oxy is optionally substituted with one , two, three, four or five substituents each independently selected from halo, nitro, cyano, C1- _C4 alkyl, and _C1C4 alkoxy;

R ¹ or R ² are as defined above but other than Cl, Br, I, and

R ⁴ is as defined above with boronic acids R ^x B(OH)2 (formula (IIIa)), or boronic acid esters R ^x B(OR ^y )2 (formula (IIIb)), or tetrafluoroborate salts R ^x BF ₄ (formula (IIIc)), in the presence of a base such as, for example, potassium carbonate or potassium acetate, a palladium catalyst, such as, for example, dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(0), palladium acetate (P)/ triscyclohexylphosphine, tris(dibenzylideneacetone)dipalladium, bis(diphenylphosphineferrocenyl)palladium(II) chloride, 1,3-bis(2,6-diisopropylphenyl)imidazole-2- 123 041614 ylidene(1,4-naphthoquinone)palladium dimer, allyl(chlorine [ 1,1bis(diphenylphosphino)ferrocene]palladium(11) chloride monodichloromethane adduct, [1,1'Bis(diphenylphosphino)ferrocene]dichloropalladium(11), chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1, 1'-biphenyl)[2-(2'-amino-1,1'-biphenyl) ]palladium(II), palladium(II) acetate and (2dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] palladium(P), as a preferred embodiment chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] palladium(II), and optionally an additional ligand such as, for example, 2-(dicyclohexylphosphino)2',4',6'-triisopropylbiphenyl, in a solvent such as, for example, dioxane, toluene or water, or a mixture thereof, under an atmosphere nitrogen or argon atmosphere, at 80°C-120°C, for 2 h-7 d;

wherein ^Rx is

a C ₁ -C ₆ alkyl group which is optionally substituted with one or two substituents, and each substituent is independently selected from hydroxy, C ₁ -C ₄ alkoxy, and a 3-7 membered heterocycloalkyl group; preferably a methyl group which is optionally substituted with a 3-7 membered heterocycloalkyl group,

C ₂ -C ₆ -alkenyl group, which is optionally substituted by C1-C ₄ -alkoxy group, C ₅ -C ₉ -cycloalkenyl group, which is optionally substituted by hydroxy group, 3-9-membered heterocycloalkyl group containing one, two or three heteroatoms, which independently selected from -O-, -S-, -S(O)-, S(O) ₂ and -NR ⁹ -, and the specified heterocycloalkyl group optionally additionally contains a bridging group selected from -O-, -NR ⁹ -, -CH2-, -CH2-CH2-, -O-CH2-, -CH2-O-, -NR ⁹ -CH2- and -CH ₂ -NR ⁹ -;

and said heterocycloalkyl group is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom;

oxo (=O) groups;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

C ₁ -C ₃ haloalkyl group;

C1- _C3 alkoxy groups;

C ₁ -C ₃ haloalkoxy groups;

C(O)NR ⁵ R ⁶ groups and

NR5R ⁶ groups,

A 5-9 membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from oxo (=O), C ₁ -C ₃ alkyl, -C(O)R ⁵ R ⁶ group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, hydroxy group, cyano group, C1C ₃ alkyl group, C ₁ -C ₃ haloalkyl group , C ₁ -C ₃ -alkoxy groups, C ₁ -C ₃ -haloalkoxy groups and NR5R ⁶ groups, a mono- or bicyclic heteroaryl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, C ₁ - C ₃ alkyl group, cyano group, C 1 -C ₃ haloalkyl group, C 1 -C ₃ alkoxy group, hydroxy group and NR5R ⁶ group, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

R ^y is C1-C6 alkyl, or the two R ^y residues together represent a C2-C6 alkylene group, preferably -C(CH3) ₂ -C(CH ₃ ) ₂ - to form a pinacol ester.

(j) Route 1 via nucleophilic aromatic substitution introducing R ³ substituents selected from -NR7R ⁸ , an N-linked heterocycloalkyl group, a partially unsaturated N-linked heterocycloalkyl group, and an N-linked heteroaryl group, the term N-linked being understood as described in the context of Scheme 2 .

Intermediates of formula (V) wherein R ³ is selected from -NR7R ⁸ , an N-linked 3-9 membered heterocycloalkyl group, an N-linked partially unsaturated 3-9 membered heterocycloalkyl group, and an N-linked heteroaryl group, wherein the term N -linked is understood as described in the context of Scheme 2, and where the terms 3-9 membered heterocycloalkyl, partially unsaturated 3-9 membered heterocycloalkyl, and heteroaryl have the meaning and are optionally substituted as defined for R ³ , above, can be obtained by reaction of intermediates (III) where R ⁴ is as defined above,

- 124 041614

X is F or Cl (as depicted in Scheme 2), and if X is Cl, R ¹ or R ² may not be F; preferably X is F;

R ¹ and R ² have the meaning as defined above, provided that if X is Cl, R ¹ or R ² need not be F, and provided that at least one of R ¹ and R ² exhibits an electron withdrawing effect ; preferably R ¹ is selected from fluorine, cyano and -CF3 and R ² is hydrogen or fluorine; more preferably R ¹ is -CF3; and R ² is hydrogen;

with the corresponding amine, optionally as a free base or as a salt, such as, for example, a hydrochloride salt selected from HNR7R ⁸ and a cyclic amine having one NH as ring atom, the cyclic amine being selected from heterocycloalkane, a partially unsaturated heterocycloalkane, and a heteroarene containing one NH as ring atom, suitably optionally in the presence of a base such as, for example, triethylamine, DIPEA, or cesium carbonate, in an inert solvent, such as, for example, CH ₃ CN, DMF, or DMSO, at optionally elevated temperatures ranging from room temperature to 160°C, preferably from 60 to 150°C, for 2 h-7 d;

wherein R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, C(O)NR5R ⁶ group, NR5R ⁶ group, € ₁ - € ₃ -alkoxy groups,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group, oxo (=O) group, hydroxy group and C ₁ -C ₃ -hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a Ci-C ₃ alkyl group or an oxo (=O) group, a heteroaryl group which itself is optionally substituted with a C ₁ -C ₃ alkyl group;

- C ₁ -C ₅ -alkylene-O-C 1 -C ₅ -alkyl group,

- C ₁ -C ₅ -alkylene-SC 1 -C ₅ -alkyl group,

- C1-C ₅ -alkylene-NR ⁵ -C1-C ₅ -alkyl group,

A _{C 3} -C ₆ cycloalkyl group which is optionally substituted with a hydroxy group; and a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C ₁ -C ₃ alkyl group and a hydroxy group.

(k) An alternative route via a transition metal catalyzed, preferably palladium catalyzed amination, introducing R ³ substituents selected from NR ⁷ R ⁸ , an N-linked heterocycloalkyl group, a partially unsaturated N-linked heterocycloalkyl group and an N-linked heteroaryl group, the term N- bound'' is understood as described in the context of diagram 2.

Intermediates of formula (V) wherein R ³ is selected from -NR7R ⁸ , an N-linked 3-9 membered heterocycloalkyl group, an N-linked, partially unsaturated 3-9 membered heterocycloalkyl group, and an N-linked heteroaryl group, wherein the term N-linked is understood as described in the context of Scheme 2, and where the terms 3-9 membered heterocycloalkyl, partially unsaturated 3-9 membered heterocycloalkyl, and heteroaryl have the meaning and are optionally substituted as defined for R ³ , above, can be obtained by the reaction of intermediates compounds (III), where X represents Cl, Br, I (as reflected in scheme 2), or a group selected from (C1-C ₄ -alkylsulfonyl)oxy, (C1-C4 fluoroalkylsulfonyl)oxy and (phenylsulfonyl)oxy, and phenyl present in (phenylsulfonyl)oxy is optionally substituted with one, two, three, four or five substituents each independently selected from halo, nitro, cyano, C1- _C4 alkyl, and C1- _C4 alkoxy;

R ¹ or R ² are as defined above, but other than Cl, Br, I; preferably R ¹ is -CF ₃ and R ² is hydrogen;

R ⁴ is as defined above with the corresponding amine, optionally as a free base or as a salt, such as, for example, a hydrochloride salt selected from HNR ⁷ R ⁸ and a cyclic amine having one NH as ring atom, wherein the cyclic amine is selected from a 3-9 membered heterocycloalkane, a partially unsaturated 3-9 membered heterocycloalkane and a heteroarene containing one NH as ring atom, respectively, in the presence of a base such as, for example, potassium phosphate or cesium carbonate, a palladium catalyst such such as, for example, tris(dibenzylideneacetone)dipalladium(0), a ligand such as, for example, 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl or 2,2'-bis( diphenylphosphino)-1,1'-125 041614 binaphthalene, in an inert solvent such as, for example, dioxane or toluene, at elevated temperatures in the range of 60-160°C, for 2 h-7 d;

wherein R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, C(O)NR ⁵ R ⁶ group, NR5R ⁶ group, € ₁ -€ ₃ -alkoxy groups,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group, oxo (=O) group, hydroxy group and C ₁ -C ₃ -hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a Ci-C ₃ alkyl group or an oxo (=O) group, a heteroaryl group which itself is optionally substituted with a C ₁ -C ₃ alkyl group;

- C1-C ₅ -alkylene-O-C 1 -C ₅ -alkyl group,

- C1-C ₅ -alkylene-S-C 1 -C ₅ -alkyl group,

- C1-C ₅ -alkylene-NR ⁵ -C ₁ -C ₅ -alkyl group,

C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group, and

A 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C ₁ -C ₃ alkyl group and a hydroxy group.

The subsequent conversion of the obtained compounds of formula (V) into compounds of general formula (I) can, for example, be carried out by means of the following sequence of reactions according to stages (a)-(h).

Stage (a).

A compound of formula (V) and hydroxy(tosyloxy)iodo)benzene in a solvent such as, for example, DMSO, water, are reacted at room temperature for 18 hours; or a compound of formula (V) and iodine, in a solvent such as, for example, DMSO, react at 60°C for 18 hours

Step (b).

The reaction product of step (a), H ₂ NNHCOOCH ₃ , and HCl (aq) are reacted in a solvent such as, for example, MeOH at room temperature for 5 hours;

Stage (s).

The reaction product of step (b) and potassium carbonate are reacted in a solvent such as e.g. acetonitrile at 60°C for 18 hours or the reaction product of step (b) and NaOEt/EtOH are reacted at 0°C for 10 minutes , or the reaction product of step (b) and NaH, react in EtOH, at 0°C for 10 min;

Step (d).

The reaction product of step (h), sodium formate and sodium hydrogen carbonate, are reacted in a solvent such as, for example, CH3CN, water, at 65° C. for 24 hours to obtain the same product as from step (a), which is then can be converted to a compound of formula (1) via steps (b) and (c);

Stage (e).

The reaction product of step (h), potassium acetate and potassium iodide are reacted for 18 hours at room temperature;

Step (f).

The reaction product of step (e), H2NNHCOOCH3 and HCl (aq), are reacted in a solvent such as, for example, MeOH at room temperature for 5-18 hours;

Step (g).

The reaction product of step (f) and potassium carbonate are reacted in a solvent such as, for example, acetonitrile at 60°C for about 18 hours, or the reaction product of step (f) and NaOEt/EtOH are reacted at 0°C for 10 min, or the reaction product of step (f) and NaH, react in a solvent such as, for example, EtOH, at 0° C. for 10 min to obtain a compound of formula (I);

Step (h).

The compound of formula (V), acetic acid and bromine, hydrogen bromide react for 18 hours at room temperature.

The resulting compounds of general formula (I), if they contain chiral centers, can optionally be separated by chiral chromatography to obtain individual enantiomers or diastereomers.

Pathway 3: Stereoselective synthesis of intermediates of formula (IIa) wherein R ⁴ is other than hydrogen

- 126 041614

Scheme 5

Scheme 5: A stereoselective route for preparing intermediates of formula (IIa) comprising consecutive intermediates of formula (II) from intermediates of formula (III) wherein R ¹ , R ² , and R ³ are as defined above, provided that R ⁴ is other than hydrogen.

(c) LiHMDS/THF, 1 h, -78°C, then tBDMSCl (tert-butyldimethylchlorosilane), -78°C to room temperature, 15 h - 2d;

(d) AD-Mix-α, CH ₃ SO ₂ NH ₂ /tBuOH/water, 0° C. to room temperature, 15 h-2 d;

(e) 1. H ₂ NNHCOOCH ₃ , HCl, MeOH; 2. NaOEt/EtOH or NaOMe/MeOH or NaH/EtOH;

Route 4: stereoselective synthesis of compounds of formula (Ia).

Scheme 6

Scheme 6: stereoselective route for the preparation of compounds of formula (Ia) comprising the general formula (I) in succession from intermediates of formula (V) wherein R ¹ , R ² , R ³ and R ⁴ are as defined above, provided that R ⁴ is other than hydrogen.

(b) LiHMDS/THF, 1 h, -78°C, then tBDMSCl (tert-butyldimethylchlorosilane), -78°C to room temperature, 15 h - 2 d;

(c) AD-Mix-α, CH ₃ SO ₂ NH ₂ /tBuOH/water, 0°C to room temperature, 15 h-2 d;

(d) 1. methyl hydrazinocarboxylate, HCl (aq)/MeOH, 60° C., 1 h; 2. NaOEt/EtOH or NaOMe/MeOH, room temperature, 1-2 hours.

Route 5: Synthesis of compounds of formula (Ic).

Scheme 7

Scheme 7: a route for preparing compounds of formula (Ic) from compounds of formula (Ib) wherein R ¹ and R ⁴ are as defined above and R ³ is NR7R ⁸ or a 3-7 membered heterocycloalkyl group. Both formulas (Ib) and (Ic) constitute contracts of general formula (I); compounds of formula (Ib) are readily available according to other synthetic routes discussed in this chapter and in the experimental section below.

(a) N-chloro succinimide (NCS, 1-Chloro-pyrrolidine-2,5-dione), THF, room temperature, 18 hours, or, NaOCl/HOAc, 10-15°C, 1-2 hours.

Route 6: alternative synthesis of intermediates of formula (II).

Scheme 8

Scheme 8: route for preparing intermediates of formula (II) from compounds of formulas (VI) and

- 127 041614 (VII), where R ¹ , R ² and R ⁴ have the meaning as defined above, and M represents a metal-containing group, such as, for example, Li, or MgBr, or MgCl; and X is F, Cl, or Br; and DG is a group displaceable from compounds of formula (VII) with reagents of formula (VI) selected from morpholinyl or N(OCH ₃ )CH ₃ (Weinreb's Amide); and PG is a protecting group suitable for hydroxy groups, for example a tri(C1- _C4 alkyl)silyl group such as, for example, t-butyldimethylsilyl. Compounds of formula (VI) and (VII) are known to those skilled in the art and can be readily prepared from commercially available precursors by known methods.

(a) THF, -20-20°C, 1-24 h, (b) 1. H ₂ NNHCOOCH ₃ , HCl, MeOH; 2. TBAF (tetrabutylammonium fluoride), THF; 3. NaOEt/EtOH or NaOMe/MeOH;

Compounds of formula (II) may be converted to compounds of general formula (I) as described above in the context of Scheme 2.

Route 7: alternative synthesis of compounds of general formula (I).

Scheme 9

formula (VIII) formula (VII) formula (I)

Scheme 9: route for obtaining compounds of general formula (I) from compounds of formulas (VIII) and (VII), where R ¹ , R ² , R ³ , and R ⁴ are as defined above, and M is a metal-containing group, such as, for example, Li or MgBr or MgCl; and DG is a group displaced from compounds of formula (VII) by reagents of formula (VIII) selected from morpholinyl or N(OCH ₃ )CH ₃ (Weinreb's amide); and PG is a protecting group suitable for hydroxy groups, eg tri(C1-C ₄ -alkyl)silyl, such as eg t-butyldimethylsilyl. Compounds of formulas (VIII) and (VII) are known to those skilled in the art and can be readily prepared from commercially available precursors by known methods.

(a) THF, -20-20°C, 1-24 h, (b) 1. H ₂ NNHCOOCH ₃ , HCl, MeOH; 2. TBAF, THF; 3. NaOEt/EtOH or NaOMe/MeOH;

Some additional aspects of the invention are the synthesis routes according to schemes 1-9 above, in accordance with which R ^x and/or R7/R ⁸ respectively are determined similarly to that described above, but are limited according to paragraphs 2-7 of the claims.

The present invention further provides methods for preparing compounds of the present invention of general formula (I), said methods comprising the steps as described in the Experimental section hereinafter.

The present invention further provides a process for preparing a compound of general formula (I) as defined above, said process comprising either the step A of providing for the reaction of an intermediate of general formula (II)

r ₂ (II), where X represents Cl, Br, I, or a group selected from (C ₁ -C ₄ -alkylsulfonyl)oxy, (C ₁ -C ₄ fluoroalkylsulfonyl)oxy and (phenylsulfonyl)oxy, and phenyl, present in (phenylsulfonyl)oxy, optionally substituted with one, two, three, four or five substituents each independently selected from halo, nitro, cyano, C1- _C4 alkyl, and C1- _C4 alkoxy;

R ¹ is selected from a hydrogen atom, a fluorine atom, a cyano group, a C ₁ -C ₃ alkyl group, a C 1 -C ₃ haloalkyl group, a C 1 -C ₃ haloalkoxy group;

R ² is selected from a hydrogen atom, a fluorine atom;

R ⁴ is selected from a hydrogen atom and a C1- _C3 alkyl group;

under transition metal-catalyzed coupling reaction conditions such as Suzuki coupling reaction, Negishi coupling reaction, Kumada coupling reaction, Stille coupling reaction, preferably Suzuki coupling reaction, by allowing said intermediate of formula (II) to be reacted with an organoboron compound selected from boronic acids of formula (IIIa)

- 128 041614 (R ^x )B(OH) ₂ (Sha), a boronic acid ester of the formula (R ^x )B(OR ^y )2 (SHb), and a tetrafluoroborate salt of the formula (R ^x )bf ₄ (Wc), and R ^x is a C ₁ -C ₆ alkyl group which is optionally substituted with one or two substituents, and each substituent is independently selected from hydroxy, CrC ₄ alkoxy, and a 3-7 membered heterocycloalkyl group; preferably a methyl group which is optionally substituted with a 3-7 membered heterocycloalkyl group,

C ₂ -Cb-alkenyl group, which is optionally substituted with C ₁ -C ₄ -alkoxy group,

C ₅ -C ₉ -cycloalkenyl group, which is optionally substituted by hydroxy group,

A 3-9 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O-, -S-, -S(O)-, S(O) ₂ and -NR ⁹ - and said heterocycloalkyl group optionally additionally contains a bridging group selected from -O-, -NR ⁹ -, -CH2-, -CH2-CH2-, -O-CH2-, -CH2-O-, -NR9-CH2- and -CH2-NR ⁹ -;

and said heterocycloalkyl group is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom;

oxo (=O) groups;

cyano groups;

hydroxy groups;

a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy;

C ₁ -C ₃ haloalkyl group;

C ₁ -C ₃ alkoxy groups;

C ₁ -C ₃ haloalkoxy groups;

C(O)NR ⁵ R ⁶ groups and

NR5R ⁶ groups,

A 5-9 membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from oxo (=O), C ₁ -C ₃ alkyl, -C(O)R ⁵ R ⁶ group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, hydroxy group, cyano group, C1C3 alkyl group, C ₁ -C ₃ haloalkyl group, C ₁ -C ₃ -alkoxy groups, C ₁ -C ₃ -haloalkoxy groups and NR ⁵ R ⁶ groups, a mono- or bicyclic heteroaryl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, C ₁ -C ₃ alkyl group, cyano group, C ₁ -C ₃ haloalkyl group, C ₁ -C ₃ alkoxy group, hydroxy group and NR5R ⁶ group, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

R ^y is C1-C6 alkyl, or the two R ^y residues together represent a C2-C ₆ alkylene group, preferably —C(CH ₃ ) ₂ —C(CH3) ₂ — to form a pinacol ester, in the presence of a base , in a preferred embodiment potassium carbonate or potassium acetate, a palladium catalyst selected from dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(0), palladium(P) acetate/triscyclohexylphosphine, tris(dibenzylideneacetone)dipalladium, bis(diphenylphosphineferrocenyl)palladium(II) chloride , 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene(1,4-naphthoquinone)palladium dimer, allyl(chlorine)(1,3-dimesityl-1,3-dihydro-2H-imidazole-2 -ylidene)palladium, palladium (P) acetate/dicyclohexyl(2',4',6'-triisopropyl-biphenyl-2-yl)phosphine, [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride monodichloromethane adduct , [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'amino- 1,1'-biphenyl)]palladium(II), ace palladium(II) tata and (2-dicyclohexylphosphino-2',4',6'triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), or chlorine(2-dicyclohexylphosphino- 129 041614

2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(I), as a preferred embodiment chloro(2-dicyclohexylphosphino -2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino1,1'-biphenyl)]palladium(II), and optionally an additional ligand such as, for example, 2 -(dicyclohexylphosphino)2',4',6'-triisopropylbiphenyl, or said method comprises a step B of providing the reaction of an intermediate compound of general formula (II)

r ₂ (P), where R ⁴ has the meaning as defined above,

X is F or Cl, with the proviso that if X is Cl, R ¹ or R ² may not be F; preferably X is F;

R ¹ is selected from a hydrogen atom, a halogen atom, a cyano group, a C ₁ -C ₃ alkyl group, a C 1 -C 3 haloalkyl group, and a C 1 -C ₃ haloalkoxy group;

preferably R ¹ is selected from a fluorine atom, a cyano group, and a -CF3 group, and with the proviso that if X is Cl, R ¹ may not represent a fluorine atom; more preferably R ¹ is -CF3;

R ² is selected from a hydrogen atom and a halogen atom, with the proviso that if X is Cl, R ² may not be a fluorine atom; more preferably R ² is hydrogen;

with the proviso that at least one of R ¹ and R ² exhibits an electron-withdrawing effect;

R ⁴ is selected from a hydrogen atom and a C1- _C3 alkyl group;

with the corresponding amine, optionally in the form of a free base or in the form of a salt, such as, for example, a hydrochloride salt selected from HNR7R ⁸ and a cyclic amine having one NH as a ring atom, the cyclic amine being selected from a 3-9 membered heterocycloalkane, a partially unsaturated 3-9 membered heterocycloalkane, and a heteroarene containing one NH as ring atom, respectively, wherein R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

a C1- _C6 alkyl group which is optionally substituted with one, two, three or four substituents, and said substituent is independently selected from halogen atom, cyano group, hydroxy group, C(O)NR ⁵ R ⁶ group, NR5R ⁶ group,

C 1-C ₃ -alkoxy groups,

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted with one or two substituents, and these substituents are independently selected from C1-C ₃ -alkyl group, oxo (=O) group, hydroxy group and C1-C ₃ -hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a C1-C3 alkyl group or an oxo (=O) group, a heteroaryl group which itself is optionally substituted with a C1- _C3 alkyl group;

- C ₁ -C ₅ -alkylene-O-C ₁ -C ₅ -alkyl group,

- C ₁ -C ₅ -alkylene-SC ₁ -C ₅ -alkyl group,

- C ₁ -C ₅ -alkylene-NR ⁵ -C ₁ -C ₅ -alkyl group,

C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C1- _C3 alkyl group and a hydroxy group,

3-9 membered heterocycloalkane containing one NH as a ring atom, which is to be understood as a cyclic amine corresponding to a 3-9 membered heterocycloalkyl group as defined for R ³ above, provided that it contains one NH as a ring atom , a partially unsaturated 3-9 membered heterocycloalkane containing one NH as ring atom, which is to be understood as a cyclic amine corresponding to a partially unsaturated 3-9 membered heterocycloalkyl group as defined for R ³ above, provided that it contains one NH as a ring atom, and a heteroarene containing one NH as a ring atom, which is to be understood as a cyclic amine corresponding to the heteroaryl group as defined for R ³ above, provided that it contains one NH as a ring atom, optionally in the presence of base, and optionally in the presence of an inert solvent, and at a temperature from room temperature to 160°C,

- 130 041614 or the specified method includes stage C providing the reaction of an intermediate compound of general formula (II):

r ₂ (II), where X represents Cl, Br, I, or a group selected from (C ₁ -C ₄ -alkylsulfonyl)oxy, (C ₁ -C ₄ fluoroalkylsulfonyl)oxy and (phenylsulfonyl)oxy, and phenyl, present on (phenylsulfonyl)oxy, optionally substituted with one, two, three, four or five substituents each independently selected from halo, nitro, cyano, C _g C ₄ alkyl, and C 1 -C ₄ alkoxy;

R ¹ is selected from a hydrogen atom, a fluorine atom, a cyano group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C 1 -C ₃ haloalkoxy group;

R ² is selected from a hydrogen atom, a fluorine atom;

R ⁴ is selected from a hydrogen atom and C _g C ₃ -alkyl group;

with the corresponding amine, optionally in the form of a free base or in the form of a salt, such as, for example, a hydrochloride salt selected from HNR7R ⁸ and a cyclic amine having one NH as ring atom, the cyclic amine being selected from a 3-9 membered heterocycloalkane, a partially unsaturated 3-9 membered heterocycloalkane, and a heteroarene containing one NH as ring atom, respectively, wherein R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded,

a C1- _C6 alkyl group which is optionally substituted with one, two, three or four substituents, and said substituent is independently selected from halogen atom, cyano group, hydroxy group, C(O)NR ⁵ R ⁶ group, NR5R ⁶ group,

C _g C ₃ -alkoxy groups,

a C3-C7 cycloalkyl group which is optionally substituted with one or two substituents, and said substituents are independently selected from a C1- _C3 alkyl group, an oxo (=O) group, a hydroxy group, and a C1- _C3 hydroxyalkyl group;

a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a C1-C3 alkyl group or an oxo (=O) group, a heteroaryl group which itself is optionally substituted with a C1- _C3 alkyl group;

-C ₁ -C ₅ -alkylene-O-C ₁ -C ₅ -alkyl group,

-C ₁ -C ₅ -alkylene-SC ₁ -C ₅ -alkyl group,

-C ₁ -C ₅ -alkylene-NR ⁵ -C ₁ -C ₅ -alkyl group,

a C3-C6 cycloalkyl group which is optionally substituted with a hydroxy group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C1- _C3 alkyl group and a hydroxy group,

a 3-9 membered heterocycloalkane containing one NH as a ring atom, which is to be understood as a cyclic amine corresponding to a 3-9 membered heterocycloalkyl group as defined for R ³ above, provided that it contains one NH as a ring atom, a partially unsaturated 3-9 membered heterocycloalkane containing one NH as ring atom, which is to be understood as a cyclic amine corresponding to a partially unsaturated 3-9 membered heterocycloalkyl group as defined for R ³ above, provided that it contains one NH as a ring atom, and a heteroarene containing one NH as a ring atom, which is to be understood as a cyclic amine corresponding to a heteroaryl group as defined for R ³ above, provided that it contains one NH as a ring atom, in the presence of a base and a palladium catalyst such as, for example, tris(dibenzylideneacetone)dipalladium(0), a ligand, such as, for example, 2-(di cyclohexylphosphino)2',4',6'-triisopropyl-1,1'-biphenyl or 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene, in an inert solvent, and in the presence of an inert solvent, and at a temperature in the range from 60 to 160°C, to obtain a compound of formula (I), using one of these stages.

Some other aspects of the present invention are methods A, B, or C, as set forth immediately above, starting with the compound of general formula (II) and providing two other alternative routes, with R ^x and/or R7/R ⁸ having the same meanings as described above, but limited according to claims 2-7 or any of the embodiments defined below.

- 131 041614

In some aspects, the present invention provides methods for preparing compounds of general formula (I) as set forth above, said methods including, for compound (II): R ¹ is trifluoromethyl and R ² is hydrogen, for step A:

Suzuki coupling reaction conditions apply and the palladium catalyst is chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'biphenyl) ]palladium(II) and the ligand is 2-(dicyclohexylphosphino)-2',4',6'triisopropylbiphenyl and/or for step B:

the two R ^y residues together are -C(CH ₃ ) ₂ -C(CH ₃ ) ₂ - to form a pinacol ester, the base is potassium carbonate or potassium acetate, and/or for step C:

the palladium catalyst is tris(dibenzylideneacetone)dipalladium(0) and the ligand is 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl or 2,2'bis(diphenylphosphino)-1 ,1'-binaphthalene.

In some aspects, the present invention provides a process as set forth above, wherein for compound (II): R ¹ is trifluoromethyl and R ² is hydrogen, for step A:

Suzuki coupling reaction conditions apply and the palladium catalyst is chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'biphenyl) ]palladium(II) and the ligand is 2-(dicyclohexylphosphino)-2',4',6'triisopropylbiphenyl and/or for step B:

the two R ^y residues together are -C(CH3)2-C(CH3)2- to form a pinacol ester, the base is potassium carbonate or potassium acetate, and/or for step C:

the palladium catalyst is tris(dibenzylideneacetone)dipalladium(0), and the ligand is 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl or 2,2'bis(diphenylphosphino)- 1,1'-binaphthalene.

The present invention specifically provides a process for the preparation of a compound of general formula (I) according to any one of claims 1 to 8, said method comprising the step A of providing for the reaction of an intermediate of general formula (II)

(P) where R ¹ , R ² and R ⁴ are as defined for the compound of general formula (I) above and X=F, Cl, Br, I

a) if X=Cl, Br, I, and with the mandatory proviso that R1/R ² is not Cl, Br, I, under transition metal-catalyzed coupling conditions such as, for example, Suzuki coupling reaction, Negishi coupling reaction , Kumada coupling reaction, Stille coupling reaction, but preferably Suzuki coupling reaction, with boronic acid of formula (R ^x )B(OH) ₂ (Sha) wherein R ^x is

C ₂ -C ₆ -alkenyl group,

a C5- _C6 cycloalkyl group, which is optionally partially unsaturated,

C ₃ -C ₇ -heterocycloalkyl group, which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom and a C ₁ -C ₃ -alkyl group, hydroxy group, NR5R ⁶ group, C ₁ -C ₃ - a haloalkyl group and a C ₁ -C ₃ -haloalkoxy group,

C ₅ -C ₇ -heterocycloalkyl group, which is partially unsaturated and optionally substituted with one, two or three substituents, and each substituent is independently selected from oxo group, C ₁ -C ₃ -alkyl group, -C(O)R ⁵ R ⁶ group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, hydroxy group, cyano group, C1C ₃ -alkyl group, C ₁ -C ₃ -haloalkyl group, C ₁ -C ₃ alkoxy groups, C ₁ -C ₃ haloalkoxy groups and NR5R ⁶ groups;

- 132 041614 and a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a Ci-C ₃ alkyl group, a cyano group, a C1-C ₃ haloalkyl group, a C1-C ₃ -alkoxy groups, hydroxy groups and

NR5R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group;

or a boronic acid ester of the formula (R ^x )B(OR ^y ) ₂ (SHb) where R ^x is as defined for boronic acid above and R ^y is Ci-C ₆ alkyl, or the two R ^y residues together form a complex pinacol ester, or other suitable boronic acid esters used in this reaction by those skilled in the art/potassium carbonate/palladium catalyst from the following list:

dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(0), palladium(P)acetate/triscyclohexylphosphine, tris(dibenzylideneacetone)dipalladium, bis(diphenylphosphineferrocenyl)palladium(II) chloride, 1,3-bis(2,6-diisopropylphenyl)imidazole-2 -ylidene (1,4-naphthoquinone) palladium dimer, allyl (chlorine) (1,3-dimesityl-1,3-dihydro-2H-imidazol-2-ylidene) palladium, palladium (II) acetate / dicyclohexyl (2', 4',6'-triisopropyl-biphenyl-2-yl)phosphine, [1,1-bis(diphenylphosphino)ferrocene]palladium(P) chloride monodichloromethane adduct, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P ), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'biphenyl)]palladium(II), or (2 -dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino1,1'-biphenyl)]palladium(11), as a preferred embodiment chloro(2dicyclohexylphosphino- 2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(11), to give a compound of formula (I), where R ³ is R ^x or

b) if X=F, and with the mandatory proviso that R1/R ² is at least partially electron withdrawing, preferably R ¹ is F, CF3, CN and R ² is F or CF3, even more specifically R ¹ is F or CF ₃ , R ² =H, F with HNR ⁷ R ⁸ , where R ⁷ and R ⁸ are as defined in any of claims 1-7, optionally in the presence of a base, and optionally in the presence of an inert solvent, and optionally heating to the boiling point of the base present or the solvent present, preferably at room temperature to 150° C., to give a compound of formula (I).

A suitable solvent for the methods described above is an inert solvent as known to those skilled in the art, such as, for example, dimethylformamide, or dioxane/water mixtures, or any solvent as disclosed in the Examples.

According to another aspect, the present invention provides intermediates which are useful in the preparation of compounds of general formula (I) above.

In particular, the present invention provides intermediates of general formula (II)

r ₂ (II), where R ¹ , R ² and R ⁴ have the meaning as defined for the compound of general formula (I) above, and X=F, Cl, Br, I, provided that if X=Cl, Br, I, R1/R ² is not Cl, Br, I.

In particular, the present invention provides intermediates of general formula (II) wherein R ¹ is selected from a fluorine atom, a cyano group, an OCF ₃ group, and -CF ₃ , R ² is a hydrogen atom or a fluorine atom, and R ⁴ is a hydrogen atom or a methyl group, preferably a methyl group having the ^-configuration

More specifically, the present invention provides intermediates of general formula (II) wherein R ¹ is selected from a fluorine atom, a cyano group and a trifluoromethyl group, R ² is a hydrogen atom or a fluorine atom, and R ⁴ is a hydrogen atom or a methyl group.

More specifically, the present invention provides intermediates of general formula (II) wherein R ¹ is a fluorine atom or a trifluoromethyl group, R ² is a hydrogen atom or a fluorine atom, and R ⁴ is a hydrogen atom or a methyl group.

Even more specifically, the present invention provides intermediates of general formula (II) wherein R ¹ is a trifluoromethyl group, R ² is a hydrogen atom, and R ⁴ is a hydrogen atom or a methyl group.

In particular, the present invention provides intermediate compounds of general formula (II),

- 133 041614 in particular Intermediate 63, Intermediate 64, Intermediate

76, Intermediate 65, Intermediate 73, Intermediate 66, Intermediate 68, and Intermediate 74 as illustrated in the experimental section.

In addition, the present invention provides intermediates of general formula (II), in particular intermediate 50, intermediate 57, intermediate 63, intermediate 64, intermediate 65, intermediate 66, intermediate 68, intermediate 73, intermediate 74, Intermediate 75 and Intermediate 76 as illustrated in the experimental section.

In addition, the present invention provides intermediates of general formula (II), in particular intermediate 49, intermediate 51, intermediate 57, intermediate 58, intermediate 62, intermediate 63, intermediate 64, intermediate 65, intermediate 66, Intermediate 68, Intermediate 73, Intermediate 74, Intermediate 75, Intermediate 76, and Intermediate 78 as illustrated in the experimental section.

Even more specifically, the present invention provides intermediates of general formula (II), in particular intermediate 50, intermediate 57, intermediate 64, intermediate 66, intermediate 74, intermediate 75.

According to another aspect, the present invention provides intermediates of general formula (II), in particular intermediate 64, intermediate 66, intermediate 74 and intermediate 75.

According to another aspect, the present invention provides intermediates of general formula (II), in particular intermediate 64, intermediate 74 and intermediate 75.

In one aspect, the present invention provides a process for the preparation of compounds of formula (I), said process comprising either the step A of providing an intermediate of formula (IIb) to react:

(IIc), or an intermediate compound of formula (IIc)

(PS) wherein X is selected from Cl, Br and I via a Suzuki coupling reaction with a boronic acid of formula (IIId) (R ^x )B(OH) ₂ (PI), R ^x is selected from a phenyl group which is substituted with one or two substituents independently selected from a fluorine atom and a chlorine atom, a pyrazolyl group which is substituted with one difluoromethyl group or one trifluoromethyl group, and a pyridyl group which is substituted with one NH2 group, or with a boronic acid ester of the formula (R ^X )B(OR ^Y ) ₂ (Ne),

- 134 041614 wherein R ^x is as defined for the boronic acid of formula (Illd) above and R ^y is C ₁ -C ₆ alkyl, or two R ^y residues together form a C 2 -C ₆ alkylene group, preferably -C(CH ₃ ) ₂ -C(CH3) ₂ - to form a pinacol ester in the presence of a base, preferably potassium carbonate, and a palladium catalyst selected from:

dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(0), palladium(P) acetate/triscyclohexylphosphine, tris(dibenzylideneacetone)dipalladium, bis(diphenylphosphineferrocenyl)palladium(11) chloride, 1,3-bis(2,6-diisopropylphenyl)imidazole-2 -ylidene (1,4-naphthoquinone) palladium dimer, allyl (chlorine) (1,3-dimesityl-1,3-dihydro-2H-imidazol-2-ylidene) palladium, palladium acetate (P) / dicyclohexyl (2', 4',6'-triisopropyl-biphenyl-2-yl)phosphine, [1,1-bis(diphenylphosphino)ferrocene]palladium(I) monodichloromethane adduct chloride, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P ), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(I), and ( 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'biphenyl)]palladium(II), as a preferred embodiment chloro( 2-dicyclohexylphosphino-2',4',6'triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(11), optionally in the presence of an additional ligand, preferably 2(dicyclo hexylphosphino)-2',4',6'-triisopropylbiphenyl, in the presence of a solvent, preferably dioxane or water, or a mixture thereof, at a temperature of from 80 to 120°C, to obtain a compound of formula (I), where R ¹ represents trifluoromethyl a group, R ² is a hydrogen atom, R ³ is R ^x as defined above for formula (IIId), and R ⁴ is a hydrogen atom or a methyl group, or the process comprises the step B of causing an intermediate of formula (IIb) to react

(IIc), or the indicated intermediate compound of formula (IIc)

CF ₃ (Ps) where X is a fluorine atom with the amine HNR7R ⁸ where R ⁷ is a hydrogen atom and R ⁸ is a 3,3,3-trifluoro-2-hydroxypropyl group, 2-hydroxy-2-methylpropyl group or a 2-methoxyethyl group, or with 1H-pyrazole which is substituted with a trifluoromethyl group and unsubstituted at N-1, optionally in the presence of a base, preferably cesium carbonate, and optionally in the presence of an inert solvent, preferably DMF, and optionally heating to the reflux temperature of the present base or solvent present, preferably from room temperature to 150°C to obtain a compound of formula (I), where R ¹ represents a trifluoromethyl group, R ² represents a hydrogen atom,

R ³ is an NR ⁷ R ⁸ group, wherein R ⁷ is hydrogen and R ⁸ is 3,3,3-trifluoro-2-hydroxypropyl, 2-hydroxy-2-methylpropyl or 2-methoxyethyl, or R ³ is is a 1H-pyrazol-1-yl group which is substituted with a trifluoromethyl group, and R ⁴ is a hydrogen atom or a methyl group, or the process comprises the step of providing the reaction of an intermediate of formula (IIb):

- 135 041614

or said intermediate of formula (IIc)

where X is a chlorine atom, with an amine which is a cyclic amine, in a preferred embodiment selected from 3-hydroxy-3-methylazetidine, 3,3-difluoroazetidine, 4,4-difluoropiperidine and 3(trifluoromethyl)-1H- pyrazole, as the free base or as the hydrochloride salt, in the presence of a base, in the preferred embodiment, potassium phosphate, a palladium catalyst, preferably tris(dibenzylideneacetone)dipalladium(0), a ligand, in the preferred embodiment, 2-(dicyclohexylphosphino)-2 ',4',6'-triisopropyl-1,1'-biphenyl, and in the presence of an inert solvent, in the preferred embodiment, 1,4-dioxane, at a temperature of from 80 to 120°C, to obtain a compound of formula (I) , where R ¹ is a trifluoromethyl group, R ² is a hydrogen atom,

R ³ is a group selected from 3-hydroxy-3-methylazetidin-1-yl and 3,3difluoroazetidin-1-yl-, and

R ⁴ represents a hydrogen atom or a methyl group.

According to another aspect, the present invention provides a process for the preparation of compounds of formula (I), said process comprising either the step A of providing for the reaction of an intermediate of formula (IIb)

or an intermediate of formula (IIc) wherein X is selected from Cl, Br and I via a Suzuki coupling reaction, with a boronic acid of formula (IIId) (R ^x )B(OH) ₂ (Hid), R ^x is selected from a phenyl group which is substituted with one or two substituents independently selected from a halogen atom, a C ₁ -C ₃ alkyl group and an NR5R ⁶ group, a heteroaryl group which is substituted with a substituent selected from a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl groups and NR5R ⁶ groups, or with a boronic acid ester of the formula

- 136 041614 (R ^x )B(OR ^y ) ₂ x ^(She) ' where R ^x is as defined for boronic acid of formula (IIId) above and R ^y is C1-C6 alkyl, or two residues R ^y together form a C2- _C6 alkylene group, in a preferred embodiment -C(CH ₃ ) ₂ -C(CH3) ₂ - to form a pinacol ester, in the presence of a base, preferably potassium carbonate, and a palladium catalyst, selected from:

dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(0), palladium(P) acetate/triscyclohexylphosphine, tris(dibenzylideneacetone)dipalladium, bis(diphenylphosphineferrocenyl)palladium(II) chloride, 1,3-bis(2,6-diisopropylphenyl)imidazole-2 -ylidene(1,4-naphthoquinone)palladium dimer, allyl(chloro)(1,3-dimesityl-1,3-dihydro-2H-imidazol-2-ylidene)palladium, palladium(II) acetate/dicyclohexyl(2', 4',6'-triisopropyl-biphenyl-2-yl)phosphine, [1,1-bis(diphenylphosphino)ferrocene]palladium(P) monodichloromethane adduct chloride, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P ), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), and (2 -dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'biphenyl)]palladium(II), as a preferred embodiment chloro(2dicyclohexylphosphino -2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), optionally in the presence of an additional ligand such as, for example, 2(dici clohexylphosphino)-2',4',6'-triisopropylbiphenyl, in the presence of a solvent such as, for example, dioxane or water, or mixtures thereof, at a temperature of from 80 to 120°C, to obtain a compound of formula (I), where R ¹ is a trifluoromethyl group, R ² is a hydrogen atom, R ³ is R ^x as defined above for formula (IIId), and R ⁴ is a hydrogen atom or a methyl group, or the process includes the step B of causing the intermediate to react formulas (IIb)

CF ₃ (IIc) or the indicated intermediate of formula (IIc)

where X is a fluorine atom, with the amine HNR7R ⁸ , where R ⁷ is a hydrogen atom and R ⁸ is selected from

C ₁ -C ₆ -alkyl group, which is optionally substituted by a substituent, and the specified substituent is independently selected from a halogen atom, hydroxy group,

O1-C3 -alkoxy groups,

C ₃ -C ₇ -cycloalkyl group, which is optionally further substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group, hydroxy group and C ₁ -C ₃ -hydroxyalkyl group;

A 3-7 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O-, -S- and -NR ⁹ -, which is optionally further substituted with a C ₁ -C ₃ -alkyl group or an oxo (=O) group ;

a heteroaryl group which is optionally further substituted with a C ₁ -C ₃ alkyl group;

C ₃ -C ₇ -cycloalkyl group, which is optionally substituted by hydroxy group or C ₁ -C ₃ alkyl group, and

a 3-6 membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent being independently selected from a C ₁ -C ₃ alkyl group and a hydroxy group,

- 137 041614 and carry an unsubstituted nitrogen atom at N-1, optionally in the presence of a base such as, for example, cesium carbonate, and optionally in the presence of an inert solvent, such as, for example, DMF, and optionally heating to the boiling point of the base present or the solvent present , preferably at a temperature from room temperature to 150°C to obtain a compound of formula (I), where R ¹ represents a trifluoromethyl group, R ² represents a hydrogen atom,

R ³ is an NR7R ⁸ group, where R ⁷ is hydrogen and R ⁸ is as defined above, and

R ⁴ represents a hydrogen atom or a methyl group.

One other aspect of the present invention is a process for the preparation of compounds of formula (I), said process comprising either the step A of providing for the reaction of an intermediate of formula (IIb):

(IIb), or an intermediate compound of formula (IIc) ^Η ψθ^ο ^NH Η] ^N

CF ₃ (lie), where X is selected from Cl, Br and I by means of a Suzuki coupling reaction, with boronic acid of formula (IIId) (R ^x )B(OH) ₂ (PI), wherein R ^x is selected from a phenyl group which is substituted with one or two substituents independently selected from a fluorine atom and a chlorine atom, a pyrazolyl group which is substituted with one difluoromethyl group or one trifluoromethyl group, and a pyridyl group which is substituted with one NH ₂ group, or with a boronic acid ester of the formula (R ^x )B (OR ^y ) ₂ (She) where R ^x is as defined for the boronic acid of formula (IIId) above and R ^y is C1-C6 alkyl, or two R ^y residues together form C2-C ₆ - an alkylene group, in a preferred embodiment, -C(CH ₃ ) ₂ -C(CH ₃ ) ₂ - to form a pinacol ester in the presence of a base, preferably potassium carbonate, and a palladium catalyst selected from:

dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(0), palladium(P) acetate/triscyclohexylphosphine, tris(dibenzylideneacetone)dipalladium, bis(diphenylphosphineferrocenyl)palladium(II) chloride, 1,3-bis(2,6-diisopropylphenyl)imidazole-2 -ylidene (1,4-naphthoquinone) palladium dimer, allyl (chlorine) (1,3-dimesityl-1,3-dihydro-2H-imidazol-2-ylidene) palladium, palladium (II) acetate / dicyclohexyl (2', 4',6'-triisopropyl-biphenyl-2-yl)phosphine, [1,1-bis(diphenylphosphino)ferrocene]palladium(II) monodichloromethane adduct chloride, [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(Н ), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'biphenyl)]palladium(II), and (2 -dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-138 041614 biphenyl)]palladium(11), as a preferred embodiment chloro(2dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), optionally in the presence of an additional ligand, such as n for example, 2(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl, in the presence of a solvent such as, for example, dioxane or water, or mixtures thereof, at a temperature of from 80 to 120°C, to obtain a compound of formula (I ), where R ¹ represents a trifluoromethyl group, R ² represents a hydrogen atom, R ³ represents R ^x as defined above for formula (IIId), and R ⁴ represents a hydrogen atom or a methyl group, or this method includes stage B allowing the reaction of an intermediate of formula (IIb)

CF ₃ (lib), or the indicated intermediate compound of formula (IIc)

(PS) where X is a fluorine atom with the amine HNR7R ⁸ where R ⁷ is a hydrogen atom and R ⁸ is a 3,3,3-trifluoro-2-hydroxypropyl group, a 2-hydroxy-2-methylpropyl group, or 2 -methoxyethyl group, or with 1H-pyrazole which is substituted with a trifluoromethyl group and not substituted at N-1, optionally in the presence of a base such as, for example, cesium carbonate, and optionally in the presence of an inert solvent, such as, for example, DMF, and optionally heating to the boiling point of the base present or the solvent present, preferably at a temperature from room temperature to 150°C, to obtain a compound of formula (I), where R ¹ represents a trifluoromethyl group, R ² represents a hydrogen atom,

R ³ is an NR ⁷ R ⁸ group, wherein R ⁷ is hydrogen and R ⁸ is 3,3,3-trifluoro-2-hydroxypropyl, 2-hydroxy-2-methylpropyl or 2-methoxyethyl, or R ³ is is a 1H-pyrazol-1-yl group which is substituted with a trifluoromethyl group, and

R ⁴ represents a hydrogen atom or a methyl group.

According to another aspect, the present invention provides the use of said intermediate of formulas (II), (IIa) and (IIb) as defined above to obtain a compound of general formula (I) as defined above.

The present invention provides intermediates, which are disclosed in the Examples of the present invention, below.

The present invention embraces any subcombination within any embodiment of the present invention or subject matter of the present invention of intermediates of general formula (I), above.

The compounds of general formula (I) according to the present invention can be converted into any salt, preferably pharmaceutically acceptable salts, as described herein, by any method known to a person skilled in the art. Similarly, any salt of the compound of general formula (I) according to the present invention may be converted to the free compound by any method known to the person skilled in the art.

Application

The compounds of general formula (I) according to the present invention show a valuable pharmacological spectrum of activity which could not be predicted. The compounds of the present invention have surprisingly been found to effectively modulate PDE3A, and therefore the use of said compounds for the treatment or prevention of diseases, more specifically hyperproliferative diseases, even more specifically cancers in humans and animals, is possible. More specifically, the compounds of formula (I) are suitable for the treatment of a patient suffering from cancer who responds to treatment with a phosphodiesterase 3A/B (PDE3A/B)-SLF12 complex modulator by detecting co-expression of PDE3A and/or PDE3B mRNA, polynucleotides or polypeptides and Schlafen 12 (SLFN12) and/or SLFN12L and/or no reduction in expression of CREB3L1 mRNA, polynucleotides or polypeptides in the cancer cells of such patients.

The compounds of the present invention can be used to inhibit, block, decrease, reduce, etc., cell proliferation and/or division and/or the production of apoptosis. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of general formula (I) according to the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, which is effective for treating a disease.

The compounds of formula (I) according to the present invention may additionally show improved physicochemical properties and/or properties of an improved pharmacological safety profile.

Thus, another aspect of the present invention are compounds of formula (I) which show improved physicochemical properties compared to prior art compounds.

Another aspect of the present invention are the compounds of formula (I) which show the properties of an improved pharmacological safety profile.

Other definitions

The term change means a change (increase or decrease) in the levels of expression or activity of a gene or polypeptide, as detected by standard methods known in the art, such as those described herein. As used herein, in one embodiment, the change comprises about 10% change in expression levels, preferably about 25% change, more preferably about 40% change, and most preferably about 50% or more (e.g., 60% or more, 70% or more, 80% or more, 90% or more) change in expression levels. In certain embodiments, the change comprises 10% or less (including 10%) change in expression levels, preferably 25% or less (including 25%) change, more preferably 40% or less (including 40%) change, and most preferably 50% or less (including 50%) or more change in expression levels. In other embodiments, the change comprises a 9-11% (including 9% and 11%) change in expression levels, preferably a 10%-25% (including 10 and 25%) change, more preferably a 25-40% (including 25% and 40% ) change, and most preferably 40-50% (including 40-50%) or more than 50% (including 50%) change in expression levels. In other specific embodiments, the change comprises a 9-11% (including 9 and 11%) change in expression levels, preferably a 22-28% (including 22 and 28%) change, more preferably a 35-45% (including 35 and 45%) change , and most preferably 45-55% (including 45-55%) or more or equal to 55% change in expression levels

The term fragment means a portion of a polypeptide or nucleic acid molecule. This portion preferably contains at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% of the entire length of the reference molecule nucleic acid or polypeptide. In certain embodiments, this portion preferably contains at least 9-11% (including 9 and 11%), 18-22% (including 18 and 22%), 27-33% (including 27 and 33%), 36 -44% (including 36 and 44%), 45-55% (including 45 and 55%), 54-66% (including 54 and 66%), 63-77% (including 63 and 77%), 72-88 % (including 72 and 88%), or 81-99% (including 81 and 99%) of the entire length of the reference nucleic acid molecule or polypeptide. A fragment may contain about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 600, about 700 , about 800, about 900, or about 1000 nucleotides or amino acids. In certain embodiments, the fragment may contain 9-11, about 1822, 27-33, 36-44, 45-55, 54-66, 63-77, 72-88, 81-99, 90-110, 180-220, 270-330, 360-440, 450-550, 540-660, 630-770, 720-880, 810-990, or 900-1100 nucleotides or amino acids and 11.

Hematopoietic hyperproliferative diseases, also known as myeloproliferative diseases, include, for example, polycythemia vera, essential thrombocythemia, thrombocytosis, primary myelofibrosis, and others.

Hyperproliferative diseases include, but are not limited to, for example: psoriasis, keloids and other hyperplasias affecting the skin, benign hyperproliferative diseases, hematopoietic hyperproliferative diseases (including polycythemia vera, essential thrombocythemia, thrombocytosis, primary myelofibrosis), benign prostatic hyperplasia (BPH) , cancer (especially metastatic or malignant tumors, especially solid tumors and hematological tumors).

Benign hyperproliferative diseases include, for example, endometriosis, leukemia, and benign prostatic hyperplasia.

The term "marker" or "biomarker" means a protein or polynucleotide having a change in expression level or activity (eg, protein or mRNA level) that is associated with a disease or disorder. In specific embodiments, the marker of the present invention is a PDE3A/PBE3B or SLFN12 or CREB3L1 polypeptide or polynucleotide.

By modulator is meant any agent that binds to a polypeptide and alters the biological function or activity of the polypeptide. A modulator includes, without limitation, agents that reduce or eliminate the biological function or activity of a polypeptide (eg, an inhibitor). For example, a modulator may inhibit the catalytic activity of a polypeptide. A modulator includes, without limitation, agents that increase or decrease the binding of a polypeptide to another agent. For example, a modulator may facilitate the binding of a polypeptide to another polypeptide. In some embodiments, the PDE3A/PDE3B polypeptide modulator is a compound of formula (I).

Solid tumors are, for example, cancers of the breast, brain, digestive tract, eyes, head and neck, liver, parathyroid, reproductive organs, respiratory tract, skin, thyroid, urinary tract and their distant metastases. These diseases also include lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and ductal carcinoma in situ.

Examples of brain cancers include, but are not limited to, brainstem glioma and hypophthalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, and neuroectodermal tumor and pineal tumor.

Tumors of the digestive tract include, but are not limited to, cancers of the anal canal, colon, colon and rectum, esophagus, gallbladder, stomach, pancreas, rectum, small intestine, and salivary glands.

Eye cancer includes, but is not limited to, intraocular melanoma and retinoblastoma.

Head and neck cancers include, but are not limited to, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, oral and lip cancer, and squamous cell cancer.

Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variant), cholangiocarcinoma (cancer of the intrahepatic bile duct), and mixed hepatocellular cholangiocarcinoma.

Examples of respiratory tract cancers include, but are not limited to, small cell and non-small cell lung cancer, as well as bronchial adenoma and pleuropulmonary blastoma.

The reproductive organs include the female and male reproductive organs.

Tumors of the female reproductive organs include, but are not limited to, cancer of the endometrium, cervix, ovary, vagina, and vulva, and uterine sarcoma. Tumors of the male genital organs include, without limitation, prostate and testicular cancer.

Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma (melanoma), Merkel cell skin cancer, and non-melanoma skin cancer.

Tumors of the urinary tract include, without limitation, cancer of the bladder, penis, kidney, renal pelvis, ureter, urethra, and human papillary kidney cancer.

Lymphomas include, but are not limited to, AIDS-associated lymphomas, non-Hodgkin's lymphomas, cutaneous T-cell lymphomas, Burkitt's lymphomas, Hodgkin's disease, and lymphomas of the central nervous system.

Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

Leukemias include, but are not limited to, acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

The term subject means a mammal, including, but not limited to, a human or non-human mammal such as, for example, a bull, horse, dog, sheep, or domestic cat.

As used herein, the terms treat, treatment, therapy, and the like. refer to the reduction or alleviation of a disease and/or associated symptoms. It is understood that, although not excluded, the treatment of a disease or condition does not require the complete elimination of the disease, condition or symptoms associated therewith.

Any compositions or methods presented herein may be combined with one or more of any other compositions and methods presented herein.

The term treatment or treat, as used herein, is used in a conventional manner, such as treating or caring for a subject for the purpose of combating, alleviating, reducing, curing, ameliorating a disease or illness, such as, for example, cancer. These diseases have been well characterized in humans but also exist with a similar etiology in other mammals and can be treated by administering the pharmaceutical compositions of the present invention.

The compounds according to the present invention can be used in particular for the treatment or prevention, i. prevention, hyperproliferative diseases, more particularly cancer diseases, eg hematological cancers, and tumor growth and metastasis, especially in the case of solid tumors and hematological cancers of all cases and stages with and without previous tumor treatment.

In general, the use of chemotherapeutic agents and/or anticancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to:

1) a more effective result in reducing tumor growth or even in eliminating the tumor compared to the administration of either agent alone,

2) ensuring the administration of smaller amounts of administered chemotherapeutic agents,

3) providing a chemotherapy treatment that is well tolerated by patients with fewer harmful pharmacological complications than seen with single agent chemotherapy and some other combination therapies,

4) provide treatment for a wider range of different types of cancer in mammals, especially humans,

5) providing a higher rate of treatment among patients to be treated,

6) providing a longer survival time among patients to be treated, compared with standard chemotherapy treatment,

7) providing a longer time for tumor progression, and/or

8) providing efficacy and tolerability of results at least as good as with agents used alone as compared to known cases where other combinations of anticancer agents produce an antagonistic effect.

In another aspect, the cell is in vitro. According to another embodiment, the cell is in vivo.

Optionally, the antitumor therapeutic agent (eg, compounds of general formula (I)) can be administered in combination with any other standard antitumor therapy or conventional chemotherapeutic agent, such as, for example, an alkylating agent; such methods are known to the person skilled in the art and are described in Remington's Pharmaceutical Sciences E. W. Martin. If desired, the agents of the present invention are administered in combination with any conventional anticancer therapy, including, but not limited to, surgery, radiation therapy, or chemotherapy for the treatment of neoplasia (eg, melanoma, lung adenocarcinoma, or cervical cancer).

The present invention also provides compounds of formula (I) for methods of treating hyperproliferative diseases, more particularly cancers, including hematologic cancers and solid tumors.

According to one embodiment, the present invention provides the methods of treatment mentioned above, wherein the tumors are selected from the list above, more specifically the tumors are: tumors of the anus, brain, breast, bones, central and peripheral nervous system, colon, eyes, kidneys , endocrine glands (eg, thyroid and adrenal cortex), endometrium, esophagus, gastrointestinal tract (including gastrointestinal stromal tumors), germ cells, head and neck, kidneys, liver, larynx and hypopharynx, lungs, mesothelioma, pancreas , prostate, rectum, reproductive organs (eg, cervix, ovaries, prostate), respiratory tract, small intestine, skin, soft tissue, stomach, testis, thyroid, parathyroid, ureter, urogenital tract, vagina, and vulva, and connective tissue and metastases of these tumors. Malignancies include hereditary cancers, exemplified by retinoblastoma and Wilms tumor.

According to another embodiment, the present invention provides methods for treating cancer or using compounds of formula (I) for treating cancer, wherein said disease is selected from brain cancer, eg glioma, more particularly astrocytoma or glioblastoma; breast cancer, more specifically ductal carcinoma, adenocarcinoma; cervical cancer; leukemias such as, for example, acute myeloid leukemia (AML); lung cancer, more specifically non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); skin cancer, more specifically melanoma; esophageal cancer, more specifically squamous cell carcinoma; ovarian cancer, more specifically teratocarcinoma, adenocarcinoma; pancreatic cancer and prostate cancer.

According to another embodiment, the present invention provides methods for treating cancer or using compounds of formula (I) for treating cancer, wherein said disease is selected from glioma, more specifically astrocytoma or glioblastoma; ductal carcinoma of the mammary gland, adenocarcinoma of the mammary gland; cervical cancer; acute myeloid leukemia (AML); non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), melanoma, squamous cell carcinoma,

- 142 041614 ovarian teratocarcinoma, ovarian adenocarcinoma, pancreatic cancer and prostate cancer.

In one embodiment, the present invention provides methods for treating cancer or using compounds of formula (I) for treating cancer, wherein said disease is selected from melanoma, AML, cervical cancer, and ovarian cancer, more particularly ovarian teratocarcinoma.

In one embodiment, the present invention provides methods for treating cancer or using compounds of formula (I) for treating cancer, wherein said cancer is selected from melanoma and cervical cancer.

According to one embodiment, the present invention provides methods for treating cancer or using compounds of formula (I) for treating cancer, said cancer being melanoma.

These diseases have been well characterized in humans but also exist with a similar etiology in other mammals and can be treated by administering the pharmaceutical compositions of the present invention.

The term treatment or therapy as used herein is used in a conventional manner, for example, to treat or care for a subject for the purpose of combating, alleviating, reducing, curing, ameliorating a disease or disorder, such as, for example, cancer.

The compounds according to the present invention are used in particular for the treatment and prevention, i. prevention of hyperproliferative diseases, more particularly cancers.

According to another aspect, the present invention provides compounds of formula (I) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate and salt thereof, in particular pharmaceutically acceptable salts thereof, or mixtures thereof, for use in the treatment or prevention of diseases, in particular hyperproliferative diseases.

The pharmaceutical activity of the compounds of the present invention can be explained by their activity by modulating phosphodiesterase 3A/B (PDE3A/B).

Thus, another aspect of the present invention is a method of treatment comprising administering a compound of formula (I) or a pharmaceutical composition thereof to a patient suffering from a cancer that is responding to treatment with a PDE3A/PDE3B modulator.

Another object of the present invention is a method of treatment comprising the steps of obtaining cancer cells from a patient, detecting co-expression of PDE3A and/or detecting co-expression of PDE3B and detecting co-expression of mRNA, polynucleotides or polypeptides Schlafen 12 (SLFN12) and/or SLFN12L, and/or the absence reducing the expression of CREB3L1 mRNA, polynucleotides or polypeptides in said cancer cells, summing up the total results to determine if the collected data indicate that said cancer cells are susceptible to treatment with a compound of formula (I), and administering a compound of formula (I) to said patient.

According to another aspect, the present invention provides the use of a compound of general formula (I) as described above, or its stereoisomer, tautomer, N-oxide, hydrate, solvate and salt, in particular its pharmaceutically acceptable salts, or mixtures thereof, for the treatment or prevention of diseases, in particular hyperproliferative diseases, in particular cancers.

According to another aspect, the present invention provides a compound of formula (I) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, in particular a pharmaceutically acceptable salt or mixture thereof, for prophylactic or therapeutic use. diseases, in particular hyperproliferative diseases, in particular cancers.

According to another aspect, the present invention provides the use of a compound of general formula (I) as described above, or its stereoisomer, tautomer, N-oxide, hydrate, solvate and salt, in particular its pharmaceutically acceptable salts, or mixtures thereof, in a process treatment or prevention of diseases, in particular hyperproliferative diseases, in particular cancers.

According to another aspect, the present invention provides the use of a compound of general formula (I) as described above, or its stereoisomer, tautomer, N-oxide, hydrate, solvate and salt, in particular its pharmaceutically acceptable salts, or mixtures thereof, for the preparation of a pharmaceutical compositions, preferably a drug, for the prevention or treatment of diseases, in particular hyperproliferative diseases, in particular cancers.

In accordance with another aspect, the present invention provides a method for the treatment or prevention of diseases, in particular hyperproliferative diseases, in particular cancer, comprising administering an effective amount of a compound of general formula (I) as described above, or its stereoisomer, tautomer, N-oxide, hydrate, solvate and salts, in particular its pharmaceutically acceptable salts, or mixtures thereof, to a patient in need thereof.

Pharmaceutical composition.

According to another aspect, the present invention provides pharmaceutical compositions, in particular a medicament, containing a compound of general formula (I) as described above, or its stereoisomer, tautomer, N-oxide, hydrate, solvate, salt, in particular a pharmaceutically acceptable salt, or a mixture thereof, and one or more excipients), in particular one or more pharmaceutically acceptable excipients. Conventional techniques for obtaining such pharmaceutical compositions in suitable dosage forms can be used.

In addition, the present invention relates to pharmaceutical compositions, in particular drugs, which contain at least one compound according to the invention, usually together with one or more pharmaceutically acceptable excipients, and their use for the above-mentioned purposes.

Compounds according to the present invention may have systemic and/or local activity. To this end, they can be administered in a suitable manner, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, auricular route, or as an implant or stent. For these routes of administration, the compounds of the present invention may be administered in suitable administration forms.

For oral administration, the compounds of the present invention can be prepared in dosage forms known in the art that deliver the compounds of the present invention rapidly and/or in a modified manner, such as, for example, tablets (tablets (uncoated tablets or coated tablets, for example with enteric coatings or controlled release coatings that are delayed or insoluble), orally disintegrating tablets, films/plates, films/lyophilisates, capsules (e.g. hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, chewing gums (eg soft chewing gums), powders, emulsions, suspensions, aerosols or solutions. You can include the compounds according to the present invention in crystalline and/or amorphous and/or dissolved form in these dosage forms.

Parenteral administration may be by preventing the absorption step (eg, intravenously, intraarterially, intracardiac, intraspinally, or endolumbally) or by including absorption (eg, intramuscularly, subcutaneously, intradermally, transdermally, or intraperitoneally). Administration forms suitable for parenteral administration include, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

Examples suitable for other routes of administration are pharmaceutical forms for inhalation (including powder inhalers, nebulizers), nasal drops, nasal solutions, nasal sprays; tablets/films/lozenges/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, lenses, ear drops, ear sprays, ear powders, ear rubs, ear swabs; vaginal capsules, aqueous suspensions (lotions, shaking potions), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milks, pastes, foams, topical preparations, powders, implants or stents.

Compounds according to the present invention can be included in these forms of administration. This can be done in a known manner by mixing with pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, but are not limited to, fillers and carriers (e.g. cellulose, microcrystalline cellulose (e.g. Avicel®), lactose, mannitol, starch, calcium phosphate (such as e.g. Di-Cafos®)), ointment bases (e.g. , petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), suppository bases (eg polyethylene glycol, coconut oil, tallow), solvents (eg water, ethanol, isopropanol, glycerin , propylene glycol, medium chain triglyceride fatty oils, liquid polyethylene glycols, paraffins), surfactants, emulsifiers, dispersants or wetting agents (e.g. sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as e.g. Lanette®) , sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol esters, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®), buffers, acids and bases (for example , phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), isotonic agents (eg glucose, sodium chloride),

- 144 041614 adsorbents (for example, highly dispersed silicas), viscosity-increasing agents, gelling agents, thickeners and/or binders (for example, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch, carbomers, polyacrylic acids (such as, 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®)), regulators flow rates, lubricants, glidants and demolding agents (e.g. magnesium stearate, stearic acid, talc, highly dispersed silicas (e.g. Aerosil®)), coating agents (e.g. sugars, shellac ) and film formers for films or diffusion membranes that dissolve are rapidly or modified (e.g. polyvinipyrrolidones (such as e.g. Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as e.g. Eudragit®) ), capsule materials (eg gelatin, hydroxypropyl methylcellulose), synthetic polymers (eg polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinipyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and block copolymers), plasticizers (e.g. polyethylene glycols, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate), penetration enhancers, stabilizers (e.g. antioxidants, such as e.g. ascorbic acid, ascorbyl palmitate, sodium ascorbate, butyl hydroxyanisole , butylhydroxyto luene, propyl gallate), preservatives (e.g. parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), dyes (e.g. inorganic pigments such as e.g. iron oxides, titanium dioxide), fragrances, sweeteners, fragrances and/or anti-odor agents.

In addition, the present invention relates to a pharmaceutical composition that contains at least one compound according to the present invention, usually together with one or more pharmaceutically acceptable excipients and their use according to the present invention.

Combinations.

According to another aspect, the present invention provides pharmaceutical combinations, in particular medicaments, containing at least one compound of general formula (I) according to the present invention and at least one or more additional active ingredients, in particular for the treatment and/or prevention of hyperproliferative diseases, cancer.

In particular, the present invention provides a pharmaceutical composition that contains:

one or more active ingredients, in particular compounds of general formula (I) as defined above, and one or more additional active ingredients, in particular for the treatment of hyperproliferative disease, cancer.

The term combination in the present invention is used as known to those skilled in the art and can be represented as a fixed combination, a non-fixed combination, or a set of components.

The term fixed combination in the present invention is used as known to those skilled in the art and is defined as a combination in which, for example, a first active ingredient, such as one or more compounds of general formula (I) according to the present invention, and the other active ingredient are present together in one single dosage form or in the form of a single whole. One example of the term fixed combination is a pharmaceutical composition in which the first active ingredient and the other active ingredient are present in a mixture for simultaneous administration, such as in a formulation. Another example of the term fixed combination is a pharmaceutical combination in which the first active ingredient and the other active ingredient are present in the same unit in an unmixed state.

The non-fixed combination or set of components in the present invention is used as known to those skilled in the art and is defined as a combination in which the first active ingredient and the second active ingredient are present in more than one unit. One example of a non-fixed combination or set of components is a combination in which the first active component and the second active component are present separately. The components of a non-fixed combination or set of components can be entered separately, sequentially, simultaneously, in parallel, or chronologically displaced.

The compounds of the present invention may be administered as a single pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients, so long as the combination does not cause unacceptable side effects. The present invention also provides such pharmaceutical combinations. For example, the compounds of the present invention may be combined with known anti-cancer agents, said anti-cancer agents including, but not limited to: 131I-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, алдеслейкин, алектиниб, алемтузумаб, алендроновая кислота, алитретиноин, алтретамин, амифостин, аминоглутетимид, гексил аминолевулинат, амрубицин, амсакрин, анастрозол, анцестим, анетол дитиолетион, анетумаб равтанзин, ангиотензин II, антитромбин IIII, апрепитант, арцитумомаб, арглабин, триоксид мышьяка, аспарагиназа , атезолизумаб, авелумаб, аксикабтаген целолейцел, акситиниб, азацитидин, базиликсимаб, белотекан, бендамустин, безилейзомаб, белиностат, бевацизумаб, бексаротен, бикалутамид, бисантрен, блеомицин, блинатумомаб, бортезомиб, босутиниб, бусерелин, брентуксимаб ведотин, бригатиниб, бусульфан, кабазитаксел, кабазитаксел , calcitonin, calcium folinate, levofol calcium inate, capecitabine, capromab, carbamazepine, carboplatin, carboquion, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celloleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, copanlifarabine, crisantaspas, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabin, degarelix, denileukin diphthitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxan, dibrospidium galactitol, dibrospidium dictiolactolab, dibrospidium diphenthol, dibrospidium diphthylactol , docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, enazidenib, endostatin, enocytabin, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epietin zetinta , erlotinib, esomeprazole, estradiol, estramustine, ethinyl estradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetyl acid, gan, gadoteric acid , gefitinib, gemcitabine, gemtuzumab, glucarpidas, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, grains I-125, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinibamide , imiquimod, improsulfan, inisetron, incadronic acid, mebulate ingenol, inotuzumab ozogamicin, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguan (123I), iomeprol, ipilimumab, irinotecan, itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lazocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisol , levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, lutetium Lu 177 dotatate, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxalene, methylaminolevulinate, methylprednisolone, methylprednisolone, methylaminolevulinate, methylprednisolone, methylprednisolone, , mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, mvasi, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartotumabib, necitumabib , nelarabin, neratinib, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, niraparib, nitracrin, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxin, mepesukcinate, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, o xymetholone, ozogamicin, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 grains, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargasa, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, perflubutan, perfosfamide, pertuzumab, picibanil, pilocarpine, pyrarubicin, pixantrone, plerixaphor, plicamycin, polyglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide , porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolid, rabeprazole, racotumumab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburikas, razoxane, refametinib, regorafenib, ribocyclic acid, etidronate rhenium-186, rituximab, rolapitant, romidepsin, romiplostim, romurtide, rucaparib, samarium (153 Sm) lexidronam, sargramostim, sarilumab, satumomab, secretin, siltuximab, sipuleucelT, sizofiran, sobuzoxan, glycididazole sodium, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, thalaporfin, talimogen laherparepvec, tamibarotene, tamoxifen, tapentadol, leukine, technetium (99mTc) nofetumomab-merpentan, 99mTc-HYNIC-[Tyr3]-oKTpeomug, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposid, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, thioguanine , tisagenleucleucel, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valdetanib, valrubicin, vapreotide, vemurafenib, vinblastine, vincristine, vindesin, vinflunin, vinorelbine, vismodegib, vorinostat, vorozol, yttrium-90 glass microspheres , zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

Based on standard laboratory methods known to evaluate compounds useful in the treatment of hyperproliferative diseases, more specifically cancers, standard toxicity tests and standard pharmacological assays to determine treatment for the conditions mentioned above in animals, and by comparing these results with those for known active ingredients or drugs that are used to treat these conditions, an effective dose of the compounds according to the present description can be easily determined for the treatment of each desired indication. The amount of active ingredient to be administered in the treatment of one of these conditions may vary widely according to conditions such as the particular compound and dosage unit employed, the route of administration, the period of treatment, the age and sex of the subject to be treated, and the nature and extent of the subject to be treated. states.

The total amount of active ingredient administered will typically be from about 0.001 mg/kg to about 500 mg/kg of body weight per day, in particular from about 0.001 mg/kg to about 200 mg/kg of body weight per day, and more specifically from about 0. 01 mg/kg to about 50 mg/kg of body weight per day. Clinically useful dosing regimens will range from once to three times a day to dosing once every four weeks. In addition, drug rest is possible, in which the subject does not receive a dose of drug for a certain period of time, which is useful for the overall balance between pharmacological effect and tolerability. A dosage unit may contain from about 0.5 mg to about 1500 mg of the active ingredient and may be administered one or more times per day, or less than once per day. The average daily dose for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and the use of infusion methods will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosing regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosing regimen will preferably be from 0.1 to 200 mg administered 1 to 4 times a day. The transdermal concentration will preferably be such as is necessary to maintain a daily dose of 0.01 to 200 mg/kg. The average daily dosage regimen by inhalation will preferably be from 0.01 to 100 mg/kg of total body weight. For oral administration, a dosing regimen of once or twice or three times a day and the dosage range is possible, as indicated above for total dosing.

Of course, the specific initial and ongoing dosing regimen for each subject will vary depending on the nature and severity of the condition as determined by the treating diagnostician, the activity of the particular compound used, the age and general condition of the subject, the time of administration, the route of administration, the rate of drug excretion, the combination of drugs and the like. The desired method of treatment and the number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be determined by those skilled in the art using conventional treatment tests.

Examples

Experimental part.

The shapes of the NMR peaks are indicated as they appear in the spectra; possible effects of a higher order were not considered.

1H NMR data of selected compounds are recorded as 1H NMR signal lists. For each signal peak, the δ-value in ppm is listed, followed by the signal intensity in parentheses. Between pairs of δ-values of the intensity of different peaks, there are semicolons as separators. Therefore, the list of peaks is described by the general form: δ1 (intensity ^, δ ₂ (intensity ^, ..., δ _i (intensity _i ), ..., δ _η (intensity ^.

The intensity of the sharp signal correlates with the height (in cm) of the signal in the printed NMR spectrum. When compared with other signals, these data can be correlated with real ratios of signal intensities. In the case of wide signals, more than one peak or the center of the signal is displayed along with their relative intensity compared to the most intense signal displayed in the spectrum. The list of 1H NMR peaks is similar to the classic 1H NMR reading and thus usually contains all the peaks listed in the classic NMR interpretation. In addition, as in classic 1H NMR printouts, peak lists can display solvent signals, signals derived from stereoisomers of a specific target compound, impurity peaks, satellite

- 147 041614 ¹³ C peaks and/or rotation side bands. Peaks of stereoisomers of the target compounds and/or peaks of impurities usually have an average lower intensity than the peaks of the target compounds (eg > 90% pure). Such stereoisomers and/or impurities may be typical of a particular production process. Therefore, their peaks can help identify the reproducibility of our by-product fingerprinting process. An expert who calculates target compound peaks using known methods (MestreC, ACD modeling, but also from empirically estimated averages) can highlight the target compound peaks, if necessary, using additional intensity filters. Such a selection will be similar to the corresponding peak of the classical 1H NMR interpretation. Further details on the description of NMR data with peak lists can be found in Citation of NMR Peaklist Data within Patent Applications (cf. http://www.researchdisclosure.com/searching-disclosures, Research Disclosure Database Number 605005, 2014, August 01, 2014) . During peak collection, as described in Research Disclosure Database Number 605005, the MinimumHeight parameter can be set from 1% to 4%. However, depending on the chemical structure and/or depending on the concentration of the measured compound, it may be appropriate to set the MinimumHeight <1%.

Chemical names were generated using the ACD/Name software from ACD/Labs. In some cases, common names for commercially available reagents have been used in place of the names generated by ACD/Name.

In the table below. 1 lists the abbreviations used in this part and in the Examples section, as they are not explained in the text. Other abbreviations have their usual meanings for a specialist.

Table 1

Abbreviations

[A] specific optical activity value EtOH ethanol THF Tetrahydrofuran DAD diode array detector δ NMR shift in rrsh d doublet (NMR interaction model) DMSO dimethyl sulfoxide M molar or molecular weight

- 148 041614

ESI electrospray ionization (MS) LiHMDS lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide LC-MS liquid chromatography with mass spectrometry m multiplet (NMR interaction model) MS mass spectrometry MHz megahertz NMR nuclear magnetic resonance q quartet (NMR interaction model) R _t , Rt retention time RT room temperature s singlet (NMR interaction model) t triplet (NMR interaction model) UPLC Ultra High Performance Liquid Chromatography UV ultraviolet WL wavelength DIPEA Ν,Ν-diisopropylethylamine UPLC-MS Ultra High Performance Liquid Chromatography - Mass Spectrometry pH hydrogen ion concentration index MTBE Methyl tert-butyl ether EtOAc, EA ethyl acetate MeCN, ACN Acetonitrile Et Ethyl Me Methyl Pr Propil AMC automated medical chemistry DMF Dimethylformamide MeOH methanol HOAC Acetic acid

RE Simple petroleum ether DCM dichloromethane J interaction constant (in NMR spectrum) NaOMe sodium methoxide NaOEt sodium ethoxide HC1 hydrochloric acid, hydrochloride aq water Pd/C Palladium on carbon IPA Isopropyl alcohol 06:06 volume ratio

Various aspects of the invention described in the present invention are illustrated by the following examples, which are not intended to limit the present invention in any way.

The example testing experiments described in the present invention serve to illustrate the present invention, and the present invention is not limited to the examples given.

The experimental part is the general part.

All reagents for which the synthesis is not described in the experimental part are either commercially available or known compounds, or can be obtained from known compounds by known methods by a person skilled in the art.

Compounds and intermediates prepared according to the methods of this

- 149 041614 of the invention may require cleaning. Purification of organic compounds is well known to the person skilled in the art, and there may be several ways to purify the same compound. In some cases, cleaning is not required. In some cases, compounds can be purified by crystallization. In some cases, impurities can be eliminated using a suitable solvent. In some cases, compounds can be purified by chromatography, in particular flash column chromatography, using, for example, pre-filled silica gel cartridges, such as Biotage SNAP KP-Sil® or KP-NH® cartridges, in combination with the Biotage autopurifier system ( SP4® or Isolera Four®) and eluents such as hexane/ethyl acetate or dichloromethane/methanol gradients. In some cases, compounds can be purified by preparative HPLC using, for example, a Waters autopurifier equipped with a diode array detector and/or a real-time sputter ionization mass spectrometer, in combination with a suitable prepacked reverse phase column and eluents such as a water gradient and acetonitrile, which may contain additives such as trifluoroacetic acid, formic acid, or aqueous ammonia.

In some cases, the purification methods as described above can provide those compounds of the present invention that have sufficiently basic or acidic functionality in salt form, such as in the case of a compound of the present invention that is sufficiently basic, a trifluoroacetate or formate salt, for example , or, in the case of a compound of the present invention which is sufficiently acidic, for example an ammonium salt. This type of salt can either be converted to its free base or free acid form, respectively, by various methods known to the person skilled in the art, or it can be used as salts in subsequent biological assays. It should be understood that the particular form (e.g., salt, free base, etc.) of the compound of the present invention, as isolated and as described in the present invention, is not necessarily the only form in which said compound may be used in a biological assay. to quantify a specific biological activity.

UPLC-MS standard methods.

Analytical UPLC-MS was performed as described below. Masses (m/z) are reported in positive ion electrospray mode unless negative mode (ESI-) is specified. In most cases, method 1 is used. If not, this is indicated.

Experimental part - general techniques.

Analytical LC-MS methods.

Method 1.

Device: Waters Acquity UPLC-MS SingleQuad; column: Acquity UPLC VEN C18 1.7 µm, 50x2.1 mm; eluent A: water + 0.1 vol.% formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 199% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60°C; DAD scan: 210-400 nm.

Method 2.

Device: Waters Acquity UPLC-MS SingleQuad; column: Acquity UPLC VEN C18 1.7 µm, 50x2.1 mm; eluent A: water + 0.2 vol% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 199% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60°C; DAD scan: 210-400 nm.

Method 3.

Device: SHIMADZU LCMS - UFLC 20-AD - LCMS 2020 MS detector; column: Waters Atlantis dC18 3 µm, 2.1x100 mm; eluent A: water + 0.1% formic acid (v/v), eluent B: acetonitrile + 0.1% formic acid (v/v); gradient: 0-5.00 min 5-100% B 5.00-5.40 min 100% B; flow: 0.6 ml/min; temperature: 40°C; PDA scan: 210-420 nm.

Method 4.

Waters Acquity UPLCMS SingleQuad device; column: Phenomenex Kinetix-XB C18 1.7 µm, 2.1x100mm; eluent A: water + 0.1% formic acid (v/v), eluent B: acetonitrile + 0.1% formic acid (v/v); gradient: 0-5.30 min 5-100% B, 5.30-5.80 min 100% B; flow: 0.6 ml/min; temperature: 40°C; PDA scan: 200-400nm.

Method 5.

Tandem liquid chromatography/mass spectrometry (LC/MS) was carried out on a Waters 2795 separation module and 3100 mass detector with a Waters Symmetry C18 column (3.5 µm, 4.6x100 mm) with a gradient of 0-100% CH3CN in water over 2.5 min with a constant 0.1% formic acid.

Preparative LC-MS methods.

Unless otherwise indicated, compounds were purified using mass triggered preparative HPLC (Waters Autopurifications System; column: Waters XBridge C18 5 µm 100x30 mm; DAD scan: 210-400 nm, flow: 150 ml/min) or UV triggered preparative HPLC (pump: Labomatic HD5000 or HD-3000, HDK 280 head, ND-B1000 low pressure gradient module, manual injection valve: Rheodyne 3725i038, detector: Knauer Azura UVD 2.15; manifold: Labomatic Labocol Vario-4000; column: Chromatorex RP C- 18 10 µm, 125x30 mm, flow: 70 ml/min).

- 150 041614

Acidic conditions: eluent A: water + 0.1 vol.% formic acid, eluent B: acetonitrile + 0.1 vol.% formic acid;

Basic conditions: eluent A: water + 0.2 vol.% aqueous ammonia (32%), eluent B: acetonitrile;

Experimental part - general techniques.

General details.

All reactions were carried out under a nitrogen (N ₂ ) atmosphere. All reagents and solvents were purchased from commercial suppliers and used as received. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker spectrometer (300 or 400 MHz Ή, 75 or 101 MHz ¹³ C). Chemical shifts of protons and carbon are given in ppm (δ) relative to the NMR solvent. Data are presented as follows: chemical shifts, multiplicity (br=extended, s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet; coupling constant(s) in Hz). Flash chromatography was performed using 40-60 µm Silica gel (60 A mesh) on a Teledyne Isco Combiflash Rf or Biotage Isolera. Analytical thin layer chromatography (TLC) was performed on EM Reagent 0.25 mm silica gel 60-F plates.

Experimental part - intermediate compounds.

Intermediate 1.

4-Chloro-X-methoxy-X-methyl-3-(trifluoromethyl)benzamide n ₃ c _x o ³ N CH ₃

_CF3

A mixture of 15 g (66.7 mmol) 4-chloro-3-trifluoromethyl-benzoic acid (CAS 1737-36-6) in 100 ml DCM was cooled in an ice bath before adding 6.73 ml (80 mmol) oxalyl chloride and a drop of DMF. The reaction mixture was stirred overnight, warming to room temperature before concentration, and the addition of CHCl ₃ was followed by concentration (twice) to remove oxalyl chloride. The crude product was dissolved in 100 ml CH ₂ C1 ₂ . In a separating funnel, 7.14 g of Ν,Οdimethylhydroxylamine HC1 (73.3 mmol) was added to 100 ml of CH ₂ C1 ₂ and 37 ml of Et ₃ N (266 mmol). After stirring for 15 minutes, the mixture was filtered and added to the acid chloride solution and the mixture was stirred for 3 days. The reaction mixture was then transferred to a separating funnel, and CH ₂ C1 ₂ was washed with water, then with aqueous NaHCO ₃ before drying and concentrating to an oil. Chromatography with 0-20% EtOAc in hexane gave 14.1 g of the title compound as an oil (79%).

*H NMR (300 MHz, CDC1 ₃ ) δ 8.08 (d, J=2.0 Hz, 1H), 7.85 (dd, J=8.1, 1.8 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 3.55 (s, 3H), 3.39 (s, 3H). Mass 268 (M + 1) ⁺ .

Intermediate 2.

-(4-Chloro-3-(trifluoromethyl)phenyl)propan-1-one

ci

4-Chloro-X-methoxy-X-methyl-3-(trifluoromethyl)benzamide (14.1 g, 52.6 mmol, intermediate 1) was dissolved in 200 ml THF and cooled in an ice bath before adding dropwise 44 ml of 3 M EtMgBr solution ( 132 mmol, ether). Immediately after completion of the addition, the ice bath was removed and the reaction mixture was stirred for 3 h before being cooled with an ice bath and quenched with a solution of NH ₄ C1. The mixture was transferred to a separating funnel, EtOAc and water were added. The organic layer was separated and dried and concentrated to a tan solid. Chromatography with 0-10% EtOAc in hexane gave 10.1 g of the product as a white solid (81%).

Ή NMR (400 MHz, CDC1 ₃ ) δ 8.29 (d, J=1.9 Hz, 1H), 8.08 (dd, J=8.3, 1.9 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 3.03 ( q, J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H). ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -62.87.

Intermediate 3.

1-[3,5-Difluoro-4-(morpholin-4-yl)phenyl]ethanone

A solution of morpholine (480 µl, 5.6 mmol) and 1-(3,4,5-trifluorophenyl)ethanone (440 mg, 2.53 mmol, CAS 220141-73-1) in Ν,N-diisopropylethylamine (660 µl, 3.8 mmol) was stirred at 100°C all night. The reaction mixture was concentrated in vacuo, diluted with water and extracted three times with ethyl acetate. The combined organic phases were concentrated in vacuo to give 560 mg (42% yield)

- 151 041614 the desired title compound, which was used in the next step without any further purification.

LC-MS (method 1): R _t = 1.06 min; MS (ESIpos): m/z = 242 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.491 (4.95), 2.496 (10.90), 2.500 (16.00), 2.505 (11.73), 2.509 (5.31), 2.597 (0.55), 3.224 (1.82) , 3.230 (1.81), 3.236 (2.59), 3.244 (1.94), 3.247 (2.03), 3.328 (4.68), 3.681 (3.37), 3.693 (3.40), 3.705 (3.03), 7.584 (2.54) , 7.589 (1.06), 7.609 (1.43), 7.612 (2.54).

Intermediate 4.

5-Acetyl-2-(morpholin-4-yl)benzonitrile

A solution of morpholine (5.3 ml) and 5-acetyl-2-fluorobenzonitrile (2.00 g, 12.3 mmol CAS: 288309-07-9) in N,N-diisopropylethylamine (6.4 ml) was stirred at 100°C overnight. For working up, the reaction mixture was concentrated in vacuo, diluted with water and extracted three times with ethyl acetate. The combined organic phases were concentrated in vacuo to give 3.00 g (quant) of the desired title compound, which was used in the next step without any further purification.

LC-MS (method 1): R _t = 0.90 min; MS (ESIpos): m/z = 231 [M+H] ⁺ .

Intermediate 5.

-(3-Fluoro-4-morpholinophenyl)propan-1-one

40 g of 3,4-difluoropropiophenone (235 mmol, CAS 2338472-7), 400 ml of CH3CN, 250 ml of morpholine (2.86 mol), and 50 ml of DIPEA (360 mmol) were added to a 1 L single-necked flask, and the solution was heated at 100 °C all night. The next day the reaction mixture was cooled and concentrated. The mixture was dissolved in CH ₂ Cl ₂ and washed several times with water, then brine, and dried (MgSO ₄ ), filtered and concentrated. Most of the crude product was dissolved in about 1 L of hot hexane and the resulting mixture was stirred overnight. After filtration, more crystals appeared in the mother liquors. The mother liquors were concentrated and recrystallized from hexane. A total of 52.5 g of a dry white solid was obtained (94%).

¹ H NMR (400 MHz, CDCl3) δ 7.72 (dd, J=8.4, 1.9 Hz, 1H), 7.66 (dd, J=14.0, 2.0 Hz, 1H), 6.93 (t, J=8.5 Hz, 1H), 3.94-3.85 (m, 4H), 3.26-3.17 (m, 4H), 2.94 (q, J=7.3 Hz, 2H), 1.23 (t, J=7.3 Hz, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -121.48. MS: 238 [M+H]+.

Intermediate 6.

1-(4-Morpholino-3-(trifluoromethyl)phenyl)propan-1-one

A solution of 10 g of 1-(4-fluoro-3-(trifluoromethyl)phenyl)propan-1-one (45 mmol, CAS 239107-27-8), 40 ml of morpholine (450 mmol) and 16 ml of DIPEA (90 mmol) was heated at reflux temperature all night. The next day another 20 ml of morpholine and 10 ml of DIPEA were added and heating was continued for several hours before cooling and concentration. Water was added to the crude reaction mixture, which was then washed several times with CH ₂ Cl ₂ , the combined CH ₂ Cl ₂ layers were washed with brine, dried and concentrated. Chromatography with 0-20% EtOAc in hexanes gave 6.0 g of the product as a white solid (46%).

¹ H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 3.87 (s, 4H), 3.05 ( s, 4H), 3.02-2.95 (m, 2H), 1.25 (t, J=7.2 Hz, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -60.02. MS: 288 (M+1) ⁺ .

Intermediate 7.

1-[4-Amino-3-fluoro-5-(trifluoromethyl)phenyl]ethan-1-one

- 152 041614

Tributyl(1-ethoxyvinyl)stannane, 45.35 g (125.6 mmol), and tetrakis(triphenylphosphine)palladium(0), 4.84 g (4.19 mmol). The resulting mixture was stirred at 120° C. overnight. After cooling to room temperature, 100 ml of hydrochloric acid solution (1M) was added. The resulting mixture was stirred at room temperature for another 4 hours. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EA = 5:1) to give 16.00 g (69.8%) of the product as a yellow solid. MS (ESIpos): m/z = 222 (M+H)+.

Intermediate 8.

1-[4-Chloro-3-fluoro-5-(trifluoromethyl)phenyl]ethan-1-one o ^f Y7 ^ch ' f—|—f F

Copper(II) chloride, 12.49 g ( 92.9 mmol), tert-butyl nitrite, 9.58 g (92.9 mmol). The resulting mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated ammonium chloride solution, brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:20) to give 16.0 g (83.8%) of the product as a yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.26 (d, 1H), 8.07 (s, 1H), 2.65 (s, 3H).

Intermediate 9.

1-[4-Bromo-3-fluoro-5-(trifluoromethyl)phenyl]ethan-1-one

To a solution of 1-(4-amino-3-fluoro-5-(trifluoromethyl)phenyl)ethanone, 15.00 g (67.8 mmol, intermediate 7), bromotrichloromethane, 26.90 g (135.7 mmol), and sodium nitrite, 23.40 g (339.1 mmol), in 300 ml dichloromethane/water (v:v=1:1) was added HOAc, 81.46 g (1.4 mol), in one portion. The resulting mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EA = 10:1) to give 16.70 g (86%) of the product as a yellow oil.

1H NMR (300 MHz, CDCl ₃ ): δ [ppm] = 8.09-8.03 (m, 1H), 7.86 (dd, 1H), 2.64 (s, 3H).

Intermediate 10.

(E)-tert-butyl (( 1 - (4-chloro-3- (trifluoromethyl) phenyl) prop-1 -en-1 -yl) oxy) dimethylsilane

1-(4-Chloro-3-(trifluoromethyl)phenyl)propan-1-one (10.1 g, 42.6 mmol, intermediate 2) was dissolved in 80 ml THF and cooled in a dry ice bath before adding 42.6 ml (42.6 mmol) 1N lithium hexamethyldisilazane (in THF). After 1 h, a solution of 6.42 g of tert-butyldimethylsilane (42.6 mmol) in 10 ml of THF was added dropwise, and the reaction mixture was stirred while warming to room temperature. After 3 days the reaction mixture was concentrated and hexane was added and the mixture was stirred for 30 minutes before being filtered and concentrated. Chromatography with hexane on silica gel pre-treated with Et ₃ N gave 11.2 g of product (75%).

1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=2.0 Hz, 1H), 7.55 (dd, J=8.4, 2.0 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 5.33 (q , J=6.9 Hz, 1H), 1.77 (d, J=6.9 Hz, 3H), 1.02 (s, 9H), 0.00 (s, 6H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -62.68.

Intermediate 11.

tert-butyl-[(E)-1-(3-fluoro-4-morpholino-phenyl)prop-1-enoxy]dimethylsilane

- 153 041614 c _nui Π \ Siz A x ^Si ^ ^Сн з Jj2j ° СнР ^{Нз СНe}

O^J ^F

A solution of 749 mg (3.16 mmol) of 1-(3-fluoro-4-morpholinophenyl)propan-1-one (intermediate 5) dissolved in 10 ml of TN was cooled to -78°C with a dry ice bath and 3.16 ml of (3.16 mmol) 1 N THF LiHMDS solution. After stirring cold for 1 h, a solution of 476 mg (3.16 mmol) tert-butyldimethylsilyl chloride (tBDMSCl) dissolved in 2 ml THF was added and the solution was stirred overnight while warming to room temperature. After 2 days about 50 ml of hexane was added, the mixture was filtered through a short plug of silica gel pre-treated with Et ₃ N in hexane. Elution with hexane and 5% EtOAc in hexane gave 670 mg of a clear oil (60%).

1H NMR (400 MHz, CDCl3) δ 7.19-7.09 (m, 2H), 6.86 (t, J=8.6 Hz, 1H), 5.16 (q, J=6.7 Hz, 1H), 3.95-3.80 (m, 4H) , 3.17-3.05 (m, 4H), 1.73 (d, J=6.8 Hz, 3H), 1.01 (s, 9H), 0.00 (s, 6H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ 123.51.

Intermediate 12.

tert-butyl-[(E)-1-(3,5-difluoro-4-morpholino-phenyl)prop-1-enoxy]dimethylsilane

A solution of 2.20 g (8.61 mmol) of 1-(3,5-difluoro-4-morpholinophenyl)propan-1-one (intermediate 3) was dissolved in 20 ml of THF and cooled with a -78°C ice bath. To this was added 8.61 ml (8.61 mmol) of a 1N (THF) LiHMDS solution. The solution was stirred cold for 1 h before adding 1.29 g (8.61 mmol) TBDMSCl dissolved in 10 ml THF and the ice bath was removed and stirring was continued overnight. The next day, hexane was added and the mixture was filtered through a short plug of silica gel pre-treated with Et ₃ N in hexane. Elution with hexane and 5% EtOAc in hexane gave 2.94 g of product (89%).

1H NMR (400 MHz, CDCl3) δ 6.94 (d, J=10.4 Hz, 2Н), 5.20 (q, J=6.8 Hz, 1H), 3.90-3.74 (m, 4H), 3.22 (s, 4H), 1.73 (d, J=6.9 Hz, 3H), 1.02 (s, 9H), 0.02 (s, 6H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -120.79.

Intermediate 13.

(E)-4-(4-(1-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-2-(trifluoromethyl)phenyl)morpholine

A solution of 5.00 g (17.4 mmol) of 1-(4-morpholino-3-(trifluoromethyl)phenyl)propan-1-one (intermediate 6) was dissolved in 30 ml of THF and cooled with a -78°C ice bath. To this was added 17.4 ml (17.4 mmol) of a 1N (THF) LiHMDS solution. The solution was stirred cold for 1 h before adding 2.62 g (17.4 mmol) TBDMSCl dissolved in 5 ml THF and the ice bath was removed and stirring was continued overnight. The next day, about 200 ml of hexane was added and the mixture was stirred for several hours before being filtered and concentrated. Chromatography with 0-10% EtOAc in hexane on a column pretreated with Et ₃ N gave 4.87 g of the product as a clear oil (70%).

1H NMR (400 MHz, CDCl ₃ ) δ 7.74 (s, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.28 (d, J=7.0 Hz, 1H), 5.27 (q, J=6.6 Hz, 1H), 3.85 (s, 4H), 2.95 (s, 4H), 1.76 (d, J=6.8 Hz, 3H), 1.02 (s, 9H), -0.00 (s, 6H).

Intermediate 14.

(E)-tert-butyl (( 1 - (4-fluoro-3- (trifluoromethyl) phenyl) prop-1 -en-1 -yl) oxy) dimethylsilane n ₃ C

7|H ₃ C CH ₃

A^S' ΌΗ ₃

_CF3

A solution of 4-fluoro-3-trifluoromethylpropiophenone (12 g, 55 mmol, CAS 239107-27-8) was dissolved in 60 ml THF and cooled in a dry ice bath before adding 60 ml (60 mmol) 1N lithium hexamethyldisilazane (in THF). After 1 h, a solution of 9.0 g of tert-butyldimethylsilane (60 mmol) in 15 ml of THF was added dropwise, and the reaction mixture was stirred, warming to room temperature overnight. The next day the reaction mixture was concentrated and stirred in 500 ml of hexane for 30 min before filtration and concentration.

Chromatography with hexane on silica gel pre-treated with Et ₃ N gave 15.3 g of product.

- 154 041614 (84%).

1H NMR (400 MHz, CDC13) δ 7.71 (dd, J=6.9, 2.1 Hz, 1H), 7.62 (ddd, J=7.3, 4.7, 2.2 Hz, 1H), 7.13 (t, J=9.4 Hz, 1H) , 5.26 (q, J=6.9 Hz, 1H), 1.76 (d, J=6.9 Hz, 3H), 1.02 (s, 9H), -0.00 (s, 6H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -61.49 (d, J=12.7 Hz), -116.85 (q, J=12.8 Hz).

Intermediate 15.

1-[3-Fluoro-4-(morpholin-4-yl)-5-(trifluoromethyl)phenyl]ethan-1-one o

Morpholine, 9.78 g (112.3 mmol), cesium carbonate, 54.87 g (168.4 mmol), tris(dibenzylideneacetone)dipalladium, 2.57 g (2.8 mmol), and 2,2'-bis(diphenylphosphino)-1,1'binaphthalene, 1.75 g (2.8 mmol).The resulting mixture was stirred at 80°C overnight under nitrogen atmosphere After cooling to room temperature, water was added and extracted with ethyl acetate The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EA = 5:1) to give 10.10 g (58%) of the product as a yellow oil MS (ESIpos): m/z = 292 (M+H)+.

Intermediate 16.

1-[4-Bromo-3-(difluoromethyl)phenyl]ethan-1-one ^CH 3 F

The title compound was synthesized analogously to intermediate 7 from 1bromo-4-iodo-2-(trifluoromethyl)benzene (CAS 1261496-16-5).

'H NMR (400 MHz, DMSO-d6): δ [ppm] = 8.18-8.10 (m, 1H), 8.07-8.00 (m, 1H), 8.00-7.90 (m, 1H), 7.407.03 (m, 1H), 2.63 (s, 3H).

Intermediate 17.

2-Bromo-1-[4-chloro-3-(trifluoromethyl)phenyl]ethanone

Br

1-[4-Chloro-3-(trifluoromethyl)phenyl]ethanone (3.76 g, 16.9 mmol, CAS 129825-11-2) was dissolved in acetic acid (15.5 mL) and bromine (870 μL, 17 mmol) and hydrogen bromide (46 µl, 840 µmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into ice water, adjusted to pH 5 with aqueous sodium hydrogen carbonate solution, the brown precipitate was filtered off, washed with water and dried to give 3.50 g of the crude title compound.

LC-MS (method 1): R _t = 1.29 min; MS (ESIpos): m/z = 301 [M+H]+.

Intermediate 18.

2-Bromo-1-[4-chloro-3-fluoro-5-(trifluoromethyl)phenyl]ethan-1-one

Hydrobromic acid, 0.03 g (0.3 mmol) , bromine, 8.97 g (56.1 mmol). The mixture was stirred at room temperature for 3 h. Upon completion of the reaction, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give 18 g (crude) product as a yellow oil.

'H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.43-8.35 (m, 1H), 8.23-8.14 (m, 1H), 5.07 (s, 2H).

Intermediate 19.

2-Bromo-1-[3,5-difluoro-4-(morpholin-4-yl)phenyl]ethanone

- 155 041614

1-[3,5-Difluoro-4-(morpholin-4-yl)phenyl]ethanone (540 mg, 2.24 mmol, intermediate 3) was dissolved in acetic acid (5.3 mL) and bromine (120 μL, 2.2 mmol) and hydrogen bromide (13 μl, 48% purity, 110 μmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into ice water, adjusted to pH 5 with aqueous sodium bicarbonate. The yellow precipitate was filtered off, washed with water and dried to give 580 mg (81% yield) of the crude title compound.

LC-MS (method 1): Rt = 1.18 min; MS (ESIpos): m/z = 320 [M+H]+.

Intermediate 20.

(rac)-2-Bromo-1-(3,4,5-trifluorophenyl)propan-1-one

1-(3,4,5-trifluorophenyl)propan-1-one (1.48 g, 7.87 mmol, CAS 220227-74-7) was dissolved in acetic acid (15 ml) and bromine (410 μl, 7.9 mmol) and hydrogen bromide (89 µl, 790 µmol, 48% purity) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into ice water, adjusted to pH 5 with aqueous sodium hydrogen carbonate solution and the aqueous phase was extracted with ethyl acetate with dichloromethane.

The organic phase was concentrated in vacuo to give 1.6 g (quant) of the crude title compound.

LC-MS (method 1): Rt = 1.33 min; MS (ESIpos): m/z = mass not detectable.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.78 (d, J=6.34 Hz, 3H) 5.85 (q, J=6.59 Hz, 1H) 7.88 - 8.06 (m, 2H).

Intermediate 21.

2-Bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone

1-[4-Fluoro-3-(trifluoromethyl)phenyl]ethanone (380 μl, 100% purity, 2.4 mmol, CAS 208173-24-4) was dissolved in acetic acid (3.7 ml) at room temperature. Bromine (120 μl, 100% purity, 2.4 mmol) was added dropwise to the reaction mixture, which was stirred overnight, it changed color from brown to orange. The mixture was concentrated under reduced pressure and used as a crude material in the next step.

Intermediate 22.

2-Bromo-1-[4-chloro-3-(trifluoromethoxy)phenyl]ethanone

1-[4-Chloro-3-(trifluoromethoxy)phenyl]ethanone (2.28 g, 9.56 mmol, CAS 886501-62-8) was dissolved in acetic acid (5.0 ml, 87 mmol) at room temperature. Bromine (490 µl, 9.6 mmol) and hydrobromic acid (54 µl, 48% purity, 480 µmol) were added dropwise to the reaction mixture, which was stirred overnight, it changed color from brown to orange. The mixture was poured into ice water, adjusted to pH 5 with aqueous sodium carbonate solution and extracted three times with dichloromethane. The combined organic phases were concentrated under reduced pressure to give the crude material (2.80 g, 92% yield).

Intermediate 23.

(rac)-2-Bromo-1-[4-chloro-3-(trifluoromethyl)phenyl]propan-1-one

- 156 041614

1-[4-Chloro-3-(trifluoromethyl)phenyl]propan-1-one (500 mg, 2.11 mmol, intermediate 2) was dissolved in acetic acid (5 mL) and bromine (109 μL, 2.11 mmol) and hydrogen bromide (23.9 µl, 0.21 mmol, 48% purity) was added. The reaction mixture was stirred overnight at room temperature. Then the reaction mixture was poured into ice water, brought to pH 5 with saturated aqueous NaHCO ₃ and the aqueous phase was extracted with DCM (3x20 ml). The organic phase was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give 605 mg (86% yield, 95% purity) of the title compound as a free flowing pale yellow oil. LCMS (method 3, 1.7 min) 95% at Rt = 1.34 min, MS (ESIpos): m/z = mass not detectable.

'H NMR (500 MHz, Chloroform-d) δ 1.92 (d, J=6.6 Hz, 3H), 5.21 (q, J=6.6 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 8.12 ( dd, J=2.0, 8.4 Hz, 1H), 8.35 (d, J=1.8 Hz, 1H).

Intermediate 24.

2-Bromo-1-[3-fluoro-4-(morpholin-4-yl)-5-(trifluoromethyl)phenyl]ethan-1-one

The title compound was synthesized analogously to intermediate 19 from intermediate 15.

MS (ESIpos): m/z = 370 (M+H)+.

Intermediate 25.

2-Bromo-1-[4-bromo-3-(difluoromethyl)phenyl]ethan-1-one o

The title compound was synthesized analogously to intermediate 19 from intermediate 16.

Intermediate 26.

2-Bromo-1-[4-bromo-3-(trifluoromethyl)phenyl]ethan-1-one o

The title compound was synthesized analogously to intermediate 19 from 1-(4-bromo-3-(trifluoromethyl)phenyl)ethanone (CAS 120077-70-5).

Intermediate 27.

-(3,4-Difluorophenyl)-2-hydroxyethanone

To a solution of 2-bromo-1-(3,4-difluorophenyl)ethanone (1.62 g, 6.89 mmol, CAS: 40706-98-7) in acetonitrile (9.3 ml), sodium formate (563 mg, 8.27 mmol), sodium bicarbonate (811 mg, 9.65 mmol) and water (4.4 ml) were added and the mixture was stirred for 24 h at 65°C. The organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. All collected organic phases were evaporated and dried in vacuo. Purification by column chromatography (silica gel, hexane/ethyl acetate, gradient: 12% ^ 93% ethyl acetate) gave the title compound (450 mg, 38% yield).

LC-MS (method 1): R _t =0.77 min; MS (ESIpos): m/z = 173 [M+H] ⁺ .

Intermediate 28.

1-[4-Chloro-3-(trifluoromethyl)phenyl]-2-hydroxyethanone

To a solution of 2-bromo-1-[4-chloro-3-(trifluoromethyl)phenyl]ethanone (8.00 g, 26.5 mmol, intermediate 17) in acetonitrile (23 ml), sodium formate (1.8 g, 26.5 mmol), bicarbonate sodium (2.23 g,

- 157 041614

26.5 mmol) and water (8 ml) were added and the mixture was stirred for 4 h at 65°C. The organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. All collected organic phases were evaporated and dried in vacuo. Purification by column chromatography (silica gel, hexane/ethyl acetate, gradient: 12% ^ 92% ethyl acetate) gave the title compound (700 mg, 11% yield) in 67% purity.

LC-MS (method 1): Rt = 1.03 min; MS (ESIpos): m/z = 239 [M+H]+.

Intermediate 29.

(rac)-2-Hidroxy-1-(3,4,5-trifluorophenyl)propan-1-one

To a solution of (rac)-2-bromo-1-(3,4,5-trifluorophenyl)propan-1-one (2.00 g, 7.49 mmol, intermediate 20) in acetonitrile (10 ml), sodium formate (611 mg, 8.99 mmol), sodium bicarbonate (881 mg, 10.5 mmol) and water (4.8 ml) were added and the mixture was stirred for 24 h at 65°C. The organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. All collected organic phases were evaporated and dried in vacuo. Purification by column chromatography (silica gel, hexane/ethyl acetate, gradient: 12% ^ 100% ethyl acetate) gave the title compound (1.62 g, quant.).

LC-MS (method 2): Rt = 0.94 min; MS (ESIneg): m/z = 203 [M-H] ^- .

Ή NMR (400 MHz, DMSO-d6) δ [ppm]: 1.261 (15.24), 1.278 (16.00), 2.518 (0.60), 2.523 (0.43), 4.981 (0.51), 4.998 (2.16), 5.015 (3.40), 5.031 (2.17), 5.048 (0.51), 5.579 (5.93), 5.595 (5.34), 7.899 (0.42), 7.909 (2.91), 7.916 (0.61), 7.926 (3.03), 7.931 (3.03), 7.941 (0.58), 7.948 (2.94), 7.958 (0.42).

Intermediate 30.

(rac)-1-(4-Bromophenyl)-2-hydroxypropan-1-one

To a solution of (rac)-2-bromo-1-(4-bromophenyl)propan-1-one (2.78 g, 9.52 mmol, CAS: 38786-67-3) in acetonitrile (13 ml), sodium formate (777 mg, 11.4 mmol), sodium bicarbonate (1.12 g, 13.3 mmol) and water (6.1 ml) were added and the mixture was stirred for 24 h at 65°C. The organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. All collected organic phases were evaporated and dried in vacuo. Purification by column chromatography (silica gel, hexane/ethyl acetate, gradient: 2% ^ 100% ethyl acetate) gave the title compound (1.15 g, 53% yield).

LC-MS (method 1): Rt = 0.98 min; MS (ESIpos): m/z = 229 [M+H] ⁺ .

Intermediate 31.

1-[3,5-Difluoro-4-(morpholin-4-yl)phenyl]-2-hydroxyethanone

A solution of 2-bromo-1-[3,5-difluoro-4-(morpholin-4-yl)phenyl]ethanone (580 mg, 50% purity, 0.90 mmol, intermediate 19) in acetonitrile (1.5 mL) and water ( 0.5 ml) was stirred for 1 h in a microwave vessel. Then sodium formate (61.6 mg, 0.906 mmol) and sodium bicarbonate (76.1 mg, 0.906 mmol) were added and stirred for 4 h at 65°С. The reaction mixture was diluted with water and extracted three times with ethyl acetate. All collected organic phases were evaporated and dried in vacuo. Purification by column chromatography (silica gel, hexane/ethyl acetate, gradient: 12% ^ 100% ethyl acetate) gave the title compound 60.0 mg (26% yield).

LC-MS (method 1): R _t = 0.87 min; MS (ESIpos): m/z = 258 [M+H] ⁺ .

Intermediate 32.

5-(Hydroxyacetyl)-2-(morpholin-4-yl)benzonitrile

Hydroxy(tosyloxy)iodo]benzene (18.1 g , 46.1 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were concentrated

- 158 041614 in vacuo and purified by column chromatography (silica gel, hexane/ethyl acetate, gradient:

15%^100% ethyl acetate) providing the title compound 570 mg (28% yield).

LC-MS (method 1): R _t = 0.73 min; MS (ESIpos): m/z = 247 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.34-3.39 (m, 4H), 3.71-3.81 (m, 4H), 4.73 (d, J=5.83 Hz, 2H), 5.12 (t, 1H) , 7.22 (d, J=8.87 Hz, 1H), 8.07 (dd, J=8.87, 2.03 Hz, 1H), 8.24 (d, J=2.03 Hz, 1H).

Intermediate 33.

(rac)-1-(3-Fluoro-4-morpholinophenyl)-2-hydroxypropan-1-one

According to the procedure described in the literature (Org. Lett. 2015, 17, 876), to 930 mg (3.91 mmol) of 1-(3fluoro-4-morpholinophenyl)propan-1-one (intermediate 5) dissolved in 6 ml of dry DMSO , 198 mg of iodine (0.782 mmol) was added, and the reaction mixture was heated at 60°C overnight. The next day the reaction mixture was cooled, water was added and the mixture was washed several times with EtOAc, the combined EtOAc layers were washed with brine, dried, concentrated and chromatographed with 0-40% EtOAc in hexanes to isolate 240 mg of the product as a yellow oil, which cured over time (24%).

1H NMR (400 MHz, CDCl ₃ ) δ 7.62-7.70 (m, 2H), 6.95 (t, J=8.4 Hz, 1H), 5.07 (p, J=6.7 Hz, 1H), 3.89 (s, 4H), 3.77 (d, J=6.3 Hz, 1H), 3.27 (s, 4H), 1.46 (d, J=6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -120.60. MS: 254 [M+H] ⁺ .

Intermediate 34.

(rac)-1 -[4-Chloro-3 -(trifluoromethyl)phenyl] -2-hydroxypropan-1 -one

To a solution of (rαc)-2-bromo-1-[4-chloro-3-(trifluoromethyl)phenyl]propan-1-one (605 mg, 1.82 mmol, intermediate 23) in MeCN (2.5 mL), sodium formate ( 149 mg, 2.19 mmol), sodium bicarbonate (214 mg, 2.55 mmol) and water (1.25 ml) were added and the mixture was stirred for 24 h at 65°C. The reaction mixture was diluted with water (10 ml) and then extracted with EtOAc (10 mlx3). The organic layers were combined, washed with sodium thiosulfate (50% saturated aqueous solution, diluted with H ₂ O), dried over anhydrous MgSO ₄ , filtered and dried in vacuo to give a crude solid. The crude residue was purified by Biotage Isolera™ chromatography (25 g KP-Sil eluting with 1:0-1:1 heptanes-EtOAc) to give 404.4 mg (67% yield, >75% NMR purity) of the title compound as free-flowing pale yellow oil. LCMS (method 3, 1.7 min) 87% at R _t = 1.10 min, MS (ESIpos): m/z = mass not detectable.

1H NMR (500 MHz, Chloroform-d) δ 1.46 (d, J=7.1 Hz, 3H), 3.55 (d, J=6.5 Hz, 1H), 5.08-5.18 (m, 1H), 7.67 (d, J= 8.4 Hz, 1H), 8.02 (dd, J=2.0, 8.3 Hz, 1H), 8.26 (d, J=1.7 Hz, 1H) [contains 10% w/w EtOAc and traces of heptane by NMR].

Intermediate 35.

2-(4-Chloro-3-methylphenyl)-2-oxoethyl acetate

Potassium acetate (294 mg, 2.99 mmol) and iodide potassium (166 mg, 998 μmol) and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were dried and concentrated in vacuo to give 200 mg (88% yield) of the crude title compound.

LC-MS (method 1): R _t = 1.16 min; MS (ESIpos): m/z = 227 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.147 (16.00), 2.408 (9.14), 2.728 (1.85), 2.888 (2.32), 5.444 (9.67), 7.597 (1.85), 7.618 (2.27) , 7.780 (0.91), 7.784 (0.96), 7.799 (0.71), 7.804 (0.79), 7.962 (1.48), 7.966 (1.38).

Intermediate 36.

(S)-1-(3-Fluoro-4-morpholinophenyl)-2-hydroxypropan-1-one

- 159 041614

According to the procedure described in the literature (J. Org. Chem. 1992, 57, 5067), 190 mg of methanesulfonamide and 2.7 g of AD-mix-α (Aldrich) were added to 10 ml of tert-butanol and 10 ml of water, and the mixture was cooled on ice bath before adding 670 mg of tert-butyl-[(E)-1-(3-fluoro-4-morpholino-phenyl)prop-1enoxy]dimethylsilane (intermediate 11). The mixture was kept cold for several hours and warmed to room temperature overnight. The next day, the mixture was cooled in an ice bath, 2 g of sodium sulfite was added and stirred for 30 minutes. Water and EtOAc were added and EtOAc was separated, dried and concentrated. Chromatography with 0-50% EtOAc gave 363 mg of a white solid (75%).

1Н NMR (400 MHz, CDCl ₃ ) δ 7.75-7.56 (m, 2Н), 6.95 (t, J=8.4 Hz, 1H), 5.08 (q, J=6.4 Hz, 1H), 3.90 (t, J=4.5 Hz, 4H), 3.77 (br s, 1H), 3.34-3.17 (m, 4H), 1.46 (d, J=7.0 Hz, 3H). ¹⁹ F NMR (376 MHz, CDC^) δ 120.60. MS: 254 [M+H] ⁺ .

Intermediate 37.

(S)-1-(3,5-Difluoro-4-morpholinophenyl)-2-hydroxypropan-1-one

According to a literature procedure (J. Org. Chem. 1992, 57, 5067), 11.2 g of AD-mix-α (Aldrich) and 760 mg of methanesulfonamide (8 mmol) were added to 40 ml of water and 40 ml of t-BuOH. The mixture was cooled in an ice bath and 2.94 g of tert-butyl-[(E)-1-(3,5-difluoro-4-morpholino-phenyl)prop-1enoxy]dimethylsilane (7.95 mmol, intermediate 12) was added to it . The mixture was kept in an ice bath for several hours before warming to room temperature overnight. Water and EtOAc were added, the EtOAc layer was dried, concentrated and chromatographed with 0-30% EtOAc in hexanes to give 1.68 g of an oil which solidified to settle (68%).

1H NMR (400 MHz, CDCU δ 7.45 (d, J=9.5 Hz, 2H), 5.02 (p, J=6.8 Hz, 1H), 3.83 (t, J=4.4 Hz, 4H), 3.65 (d, J= 6.5 Hz, 1H), 3.38 (s, 4H), 1.46 (d, J=7.0 Hz, 3H) ¹⁹ F NMR (376 MHz, CDCL) δ -119.20 MS: 272 [M+H] ⁺ .

Intermediate 38.

2-(4-Chloro-3-fluorophenyl)-2-oxoethyl acetate

Potassium acetate (4.06 g, 41.4 mmol) and iodide potassium (3.43 g, 20.7 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were dried and concentrated in vacuo to give 5.40 g (113% yield) of the crude title compound.

LC-MS (method 1): R _t = 1.07 min; MS (ESIpos): m/z = 189 [M+H]+.

Intermediate 39.

2-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl acetate

2-Bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (500 mg, 1.75 mmol, intermediate 21) was dissolved in dimethylformamide (2.6 ml) under nitrogen atmosphere, potassium acetate (516 mg, 5.26 mmol) and potassium iodide (291 mg, 1.75 mmol) were added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The crude material was used without further purification.

LC-MS (method 1): R _t = 1.14 min; MS (ESIneg): m/z = 263 [M-H] ^- .

- 160 041614

Intermediate 40.

(rac)-2-Hidroxy-1-(4-morpholino-3-(trifluoromethyl)phenyl)propan-1-one

A solution of 200 mg of 1-(4-morpholino-3-(trifluoromethyl)phenyl)propan-1-one (0.7 mmol, intermediate 6) and 35 mg of iodine (0.035 mmol) was heated at 60°C overnight in 2 ml of DMSO. After cooling, the reaction mixture was transferred to a separating funnel. Water and EtOAc were added, with the addition of sodium sulfite the solution lost most of the color. The EtOAc layer was washed with brine, dried, concentrated and chromatographed with 20-70% EtOAc in hexane to give 104 mg of a clear yellow oil (49%).

¹ H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 8.07 (d, J=10.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 5.13 (q, J=7.0 Hz, 1H), 3.93-3.81 (m, 4H), 3.74 (s, 1H), 3.10 (q, J=3.9 Hz, 4H), 1.47 (d, J=7.0 Hz, 3H). ¹⁹ F NMR (376 MHz, CDCl3) δ -59.94. Mass 304 (M+1)+.

Intermediate 41.

(S)-2-Hidroxy-1-(4-morpholino-3-(trifluoromethyl)phenyl)propan-1-one

According to a literature procedure (J. Org. Chem. 1992, 57, 5067), 1 g of methanesulfonamide and 14 g of AD-mix-α (Aldrich) were added to 50 ml of t-butanol and 50 ml of water, and the mixture was cooled with ice bath before adding 4.87 g of (E)-4-(4-(1-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-2(trifluoromethyl)phenyl)morpholine (intermediate 13). The mixture was kept cold for several hours and warmed to room temperature overnight. The next day, the mixture was cooled in an ice bath, 10 g of sodium sulfite was added and stirred for 30 minutes. Water and EtOAc were added and EtOAc was separated, dried and concentrated. Chromatography with 0-50% EtOAc gave 3.3 g of a white solid (90%).

1Н NMR (400 MHz, CDCl ₃ ) δ 8.24 (s, 1H), 8.08 (d, J=8.5 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 5.15 (s, 1H), 3.88 ( s, 4H), 3.71 (s, 1H), 3.17-3.03 (m, 4H), 1.48 (d, J=7.0 Hz, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -59.94. MS: 304 (M+1) ⁺ .

Intermediate 42.

(S)-1 - (4-Chloro-3 - (trifluoromethyl) phenyl) -2-hydroxypropan-1 -one

According to a literature procedure (J. Org. Chem. 1992, 57, 5067), 3 g of methanesulfonamide and 45 g of AD-mix-α (Aldrich) were added to 150 ml of t-butanol and 150 ml of water, and the mixture was cooled with ice bath before adding 11.2 g of (E)-tert-butyl ((1-(4-chloro-3-(trifluoromethyl)phenyl)prop-1-en-1yl)oxy)dimethylsilane (31.9 mmol, intermediate 10). The mixture was kept cold for several hours and warmed to room temperature overnight. The next day, the mixture was cooled in an ice bath, 30 g of sodium sulfite was added and stirred for 30 minutes. The mixture was filtered and water and EtOAc were added and the EtOAc was separated, dried and concentrated. Chromatography with 0-25% EtOAc gave 5.2 g of a pale yellow oil (65%). Weight 253 (M+1) ⁺ .

Intermediate 43.

(S)-1-(4-Fluoro-3-(trifluoromethyl)phenyl)-2-hydroxypropan-1-one

According to the procedure described in the literature (J. Org. Chem. 1992, 57, 5067), 1.8 g of methanesulfonamide and 26 g of AD-mix-α (Aldrich) were added to 90 ml of tert-butanol and 90 ml of water, and the mixture was cooled on ice bath before adding 6.0 g of (E)-tert-butyl ((1-(4-fluoro-3-(trifluoromethyl)phenyl)prop-1-en-1-161 041614 yl)oxy)dimethylsilane (18 mmol, intermediate 14). The mixture was kept cold for several hours and warmed to room temperature overnight. The next day, the mixture was cooled in an ice bath, 18 g of sodium sulfite was added and stirred for 30 minutes. Water and CH ₂ Cl ₂ were added and

CH ₂ Cl ₂ was separated, dried, and concentrated before chromatography with 0-30% EtOAc to give 3.5 g of product as an oil (82%).

¹ H NMR (400 MHz, CDCl3) δ 8.25 (dd, J=6.7, 1.7 Hz, 1H), 8.17 (ddd, J=8.3, 4.6, 2.2 Hz, 1H), 7.38 (t, J=9.2 Hz, 1H ), 5.15 (q, J=6.5 Hz, 1H), 3.62 (s, 1H), 1.48 (d, J=7.0 Hz, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -61.78 (d, J=12.5 Hz), -104.89 (q, J=12.5 Hz). Mass 237 (M+1)+.

Intermediate 44.

2-[4-Chloro-3-(trifluoromethoxy)phenyl]-2-oxoethyl acetate

2-bromo-1-[4-chloro-3-(trifluoromethoxy)phenyl]ethanone (2.80 g, 8.82 mmol, intermediate 22), was dissolved in acetonitrile (4.8 ml) under nitrogen atmosphere, potassium acetate (2.60 g, 26.5 mmol ) and potassium iodide (1.46 g, 8.82 mmol) were added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The crude material 2.50 g (96% yield) was used without further purification.

LC-MS (method 1): Rt = 1.14 min; MS (ESIneg): m/z = 263 [M-H] ^- .

Intermediate 45.

2-[4-Chloro-3-fluoro-5-(trifluoromethyl)phenyl]-2-oxoethyl acetate

Acetate was added to a solution of 2-bromo-1-[4-chloro-3-fluoro-5-(trifluoromethyl)phenyl]ethan-1-one (18 g, 56 mmol, intermediate 18) in 200 ml of N,N-dimethylformamide potassium, 11.1 g (113 mmol), potassium iodide, 9.4 g (56.3 mmol). The mixture was stirred at room temperature overnight. Upon completion of the reaction, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give 16.4 g (crude) product as a yellow oil.

L NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.39-8.31 (m, 1H), 8.13 (s, 1H), 5.54 (s, 2H), 2.16 (s, 3H).

Intermediate 46.

2-[3-Fluoro-4-(morpholin-4-yl)-5-(trifluoromethyl)phenyl]-2-oxoethyl acetate

The title compound was synthesized analogously to intermediate 45 from intermediate 24.

MS (ESIpos): m/z = 350 (M+H) ⁺ .

Intermediate 47.

2-[4-Bromo-3-(difluoromethyl)phenyl]-2-oxoethyl acetate

The title compound was synthesized analogously to Intermediate 45 from Intermediate 25.

¹ H NMR (400 MHz, DMSO-d6): δ [ppm] = 8.14 (s, 1H), 8.08-7.96 (m, 2H), 7.40-7.03 (m, 1H), 5.51 (s, 2H), 2.16 (s, 3H).

Intermediate 48.

2-[4-Bromo-3-(trifluoromethyl)phenyl]-2-oxoethyl acetate

- 162 041614

The title compound was synthesized analogously to Intermediate 45 from Intermediate 26.

Intermediate 49.

Methyl 2-[1-(3,4-difluorophenyl)-2-hydroxyethylidene]hydrazinecarboxylate

1-(3,4-Difluorophenyl)-2-hydroxyethanone (1.20 g, 6.97 mmol, intermediate 27) was dissolved in methanol. Methylhydrazinecarboxylate (1.13 g, 12.5 mmol) and aqueous hydrochloric acid (1Н) were added until pH 5.5 was reached. The reaction mixture was stirred 5 hours at room temperature and concentrated in vacuo to give the crude title compound (2.4 g, quant.) which was used in the next step without any further purification.

LC-MS (method 1): R _t =0.85 min; MS (ESIpos): m/z = 245 [M+H]+.

Intermediate 50.

Methyl 2-{1-[4-chloro-3-(trifluoromethyl)phenyl]-2-hydroxyethylidene}hydrazinecarboxylate

To a solution of 1-[4-chloro-3-(trifluoromethyl)phenyl]-2-hydroxyethanone (700 mg, 2.93 mmol, intermediate 28) in methanol (7.0 ml) was added methyl hydrazine carboxylate (396 mg, 4.40 mmol) and with the help aqueous hydrochloric acid (1N) gave pH 5.5. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was concentrated in vacuo to give 1.2 g of the crude title compound.

LC-MS (method 1): R _t = 1.04 min; MS (ESIpos): m/z = 311 [M+H] ⁺ .

Intermediate 51.

Methyl 2-[2-(acetyloxy)-1-(4-chloro-3-methylphenyl)ethylidene]hydrazinecarboxylate

To a solution of 2-(4-chloro-3-methylphenyl)-2-oxoethyl acetate (2.80 g, 12.4 mmol, intermediate 35) in methanol (32.0 ml) was added methyl hydrazine carboxylate (1.78 g, 19.8 mmol) and pH 5.5 was obtained with aqueous hydrochloric acid (1H). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give 3.6 g (98% yield) of the crude title compound, which was used in the next step without any further purification.

LC-MS (method 1): R _t = 1.17 min; MS (ESIpos): m/z = 299 [M+H] ⁺ .

Intermediate 52.

(rac)-Methyl 2-[2-hydroxy-1-(3,4,5-trifluorophenyl)propylidene]hydrazinecarboxylate

(rac)-2-Hydroxy-1-(3,4,5-trifluorophenyl)propan-1-one (1.62 g, 7.94 mmol, intermediate 29) was dissolved in methanol. Methyl hydrazine carboxylate (1.29 g, 14.3 mmol) and aqueous hydrochloric acid (1H) were added until a pH of 5.5 was reached. The reaction mixture was stirred 24 h at room temperature and concentrated in vacuo, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate, gradient: 12%^100% ethyl acetate) to provide the title compound (950 mg, 43% yield).

LC-MS (method 2): R _t = 1.03 min; MS (ESIneg): m/z = 275 [M-H] ^- .

Intermediate 53.

(rac)-Ethyl 2-[1-(4-bromophenyl)-2-hydroxypropylidene]hydrazinecarboxylate

(rac)-1-(4-Bromophenyl)-2-hydroxypropan-1-one (1.15 g, 5.02 mmol, intermediate 30) was dissolved in methanol. Methyl hydrazine carboxylate (814 mg, 9.04 mmol) and aqueous hydrochloric acid (1H) were added until a pH of 5.5 was reached. The reaction mixture was stirred 24 h at room temperature and concentrated in vacuo. Purification by column chromatography (silica gel, hexane/ethyl acetate, gradient: 2%^100% ethyl acetate) providing the title compound (600 mg, 40% yield).

LC-MS (method 1): R _t = 1.05 min; MS (ESIpos): m/z = 229 [M+H]+.

Intermediate 54.

Methyl 2-{1-[3,5-difluoro-4-(morpholin-4-yl)phenyl]-2-hydroxyethylidene}hydrazinecarboxylate

1-[3,5-Difluoro-4-(morpholin-4-yl)phenyl]-2-hydroxyethanone (460 mg, 1.79 mmol, intermediate 31) was dissolved in methanol (4.0 ml). Methylhydrazinecarboxylate (290 mg, 3.22 mmol) and aqueous hydrochloric acid (18 μl, 1.0 M, 18 μmol) were added until a pH of 5.5 was reached. The reaction mixture was stirred 5 hours at room temperature and concentrated in vacuo to give the crude title compound (30 mg, 5% yield) which was used in the next step without any further purification.

LC-MS (method 1): R _t = 0.91 min; MS (ESIpos): m/z = 330 [M+H] ⁺ .

Intermediate 55.

Methyl 2-{1-[3-cyano-4-(morpholin-4-yl)phenyl]-2-hydroxyethylidene}hydrazinecarboxylate

5-(Hydroxyacetyl)-2-(morpholin-4-yl)benzonitrile (570 mg, 2.31 mmol, intermediate 32) was dissolved in methanol. Methyl hydrazine carboxylate (375 mg, 4.17 mmol) and aqueous hydrochloric acid (1H) were added until a pH of 5.5 was reached. The reaction mixture was stirred 24 hours at room temperature and then concentrated in vacuo to give the crude title compound 600 mg (81% yield) which was used in the next step without any further purification.

LC-MS (method 1): Rt = 0.80 min; MS (ESIpos): m/z = 319 [M+H] ⁺ .

Intermediate 56.

Methyl 2-[2-(acetyloxy)-1-(4-chloro-3-fluorophenyl)ethylidene]hydrazinecarboxylate

- 164 041614

2-(4-Chloro-3-fluorophenyl)-2-oxoethyl acetate (5.40 g, 23.4 mmol, intermediate 38) was dissolved in methanol (16 ml, 380 mmol). Methyl hydrazine carboxylate (3.80 g, 42.1 mmol) and aqueous hydrochloric acid (1H) were added until a pH of 5.5 was reached. The reaction mixture was stirred 24 h at room temperature and concentrated in vacuo to give the crude title compound (7 g, quant.), which was used in the next step without any further purification.

LC-MS (method 1): R _t = 1.11 min; MS (ESIpos): m/z = 303 [M+H]+.

Intermediate 57.

Methyl (2)-2-{2-(acetyloxy)-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethylidene}hydrazinecarboxylate

2-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl acetate (95.0 mg, 360 µmol, intermediate 39) was dissolved in methanol (2.0 ml) and acidified to pH 5 using aqueous hydrochloric acid (1 M) . Then methyl hydrazine carboxylate (32.4 mg, 360 µmol) was added and the mixture was stirred for 72 hours at room temperature. The mixture was concentrated and the crude material was used without further purification.

LC-MS (method 1): Rt = 1.15 min; MS (ESIneg): m/z = 335 [M-H] ^- .

Intermediate 58.

Methyl (2)-2-{2-(acetyloxy)-1-[4-chloro-3-(trifluoromethoxy)phenyl]ethylidene}hydrazine carboxylate

2-[4-Chloro-3-(trifluoromethoxy)phenyl]-2-oxoethyl acetate (2.50 g, 8.43 mmol, intermediate 44) was dissolved in methanol (11 mL, 270 mmol) and acidified to pH 5 using aqueous hydrochloric acid (1M). Then methyl hydrazine carboxylate (1.37 g, 15.2 mmol) was added and the mixture was stirred for 1 hour at room temperature. The mixture was concentrated and the crude material 2.2 g (71% yield) was used without further purification.

LC-MS (method 1): R _t = 1.26 min; MS (ESIneg): m/z = 367 [M-H] ^- .

Intermediate 59.

Methyl (22)-2-{2-(acetyloxy)-1-[4-chloro-3-fluoro-5-(trifluoromethyl)phenyl]ethylidene}hydrazine-1carboxylate

The title compound was synthesized analogously to intermediate 58 from intermediate 45.

MS (ESIpos): m/z = 371 (M+H)+.

Intermediate 60.

Methyl (22)-2-{2-(acetyloxy)-1-[3-fluoro-4-(morpholin-4-yl)-5-(trifluoromethyl)phenyl]ethylidene}hydrazine-1-carboxylate

- 165 041614

The title compound was synthesized analogously to intermediate 58 from intermediate 46.

MS (ESIpos): m/z = 422 (M+H) ⁺ .

Intermediate 61.

Methyl (2E)-2-{2-(acetyloxy)-1-[4-bromo-3-(difluoromethyl)phenyl]ethylidene}hydrazine-1-carboxylate

The title compound was synthesized analogously to intermediate 58 from intermediate 47.

MS (ESIpos): m/z = 379 [M+H] ⁺ .

Intermediate 62.

Methyl (22)-2-{2-(acetyloxy)-1-[4-bromo-3-(trifluoromethyl)phenyl]ethylidene}hydrazine-1-carboxylate

The title compound was synthesized analogously to intermediate 58 from intermediate 48.

MS (ESIpos): m/z = 398 (M+H)+.

Intermediate 63.

5-(3,4-Difluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

Potassium carbonate (2.04 g, 14.7 mmol) was added to a solution of methyl 2-[1-(3,4-difluorophenyl)-2-hydroxyethylidene]hydrazinecarboxylate (2.40 g, 9.83 mmol, intermediate 49) in acetonitrile (20 mL), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated in vacuo and diluted with water. The precipitate was filtered off, washed with water and dried to give 1.20 g (58% yield) of the desired title compound.

LC-MS (method 1): Rt = 0.87 min; MS (ESIpos): m/z = 213 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-06) δ [ppm]: 2.074 (0.66), 2.518 (0.81), 2.523 (0.52), 5.354 (16.00), 7.514 (0.58), 7.535 (1.33), 7.539 (0.65), 7.555 (1.45), 7.561 (1.43), 7.568 (1.29), 7.572 (1.29), 7.580 (2.74), 7.585 (1.75), 7.595 (0.49), 7.607 (0.41), 7.747 (0.91), 7.752 (0.87), 7.767 (0.94), 7.772 (0.94), 7.778 (0.92), 7.782 (0.85), 7.798 (0.79), 7.801 (0.73), 11.168 (2.49).

Intermediate 64.

5-[4-Chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

Potassium carbonate (489 mg, 3.54 mmol), and the mixture was stirred for 3 h at 60°C. The reaction mixture was diluted with water and concentrated in vacuo. The precipitate was filtered off, washed with water and dried to give 700 mg (71% yield, 90% purity) of the desired title compound.

LC-MS (method 1): Rt = 1.11 min; MS (ESIpos): m/z = 279 [M+H] ⁺ .

- 166 041614 '11 NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (4.51), 2.518 (0.60), 2.523 (0.42), 5.427 (16.00), 7.827 (1.88), 7.848 (2.46), 7.979 (1.39), 7.984 (1.44), 8.000 (1.05), 8.005 (1.14), 8.081 (2.49), 8.087 (2.21), 11.267 (1.72).

Intermediate 65.

5-(4-Chloro-3-fluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

Sodium ethanolate (7.7 ml, 21% in EtOH, 21 mmol) and the mixture was stirred for 17 hours at room temperature. Water was added, the precipitate was filtered off and dried to give 1.60 g (51% yield) of the desired title compound.

LC-MS (method 1): R _t = 0.97 min; MS (ESIpos): m/z = 229 [M+H]+.

'll NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (0.57), 5.361 (16.00), 7.571 (1.23), 7.575 (1.31), 7.593 (1.77), 7.597 (1.79), 7.675 (2.38) , 7.695 (2.83), 7.716 (3.58), 7.720 (2.03), 7.742 (2.00), 7.747 (1.86), 11.223 (1.69).

Intermediate 66.

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

Methyl (2)-2-{2-(acetyloxy)-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethylidene}hydrazinecarboxylate (3.30 g, 9.81 mmol, intermediate 57) was suspended in ethanol (83 mL) in nitrogen atmosphere, and a solution of sodium ethoxide in ethanol (5.5 ml, 21% purity, 15 mmol) was added. Stirred at room temperature for 30 min. The reaction mixture was diluted with an aqueous saturated ammonium chloride solution and water and stirred for 1 hour. The precipitated product was filtered off. The filter cake was washed with water and dried in vacuo to give 2.50 g (95% pure) of the title compound.

LC-MS (method 1): Rt = 1.03 min; MS (ESIneg): m/z = 261 [M-H] ^- .

'll NMR (400 MHz, DMSO-d6) δ [ppm]: 1.228 (0.61), 1.246 (1.18), 1.264 (0.57), 2.327 (0.49), 2.669 (0.50), 4.164 (0.49), 4.181 (0.47) , 4.631 (1.19), 5.421 (16.00), 7.617 (1.38), 7.640 (2.05), 7.665 (1.50), 8.028 (2.22), 8.045 (2.02), 8.060 (1.16), 8.066 (1.06), 8.072 (1.26) , 8.081 (1.28), 8.088 (1.01), 8.094 (1.06), 11.215 (0.91).

Intermediate 67.

tert-butyl {2-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2(trifluoromethyl)anilino]ethyl}carbamate

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (150 mg, 572 µmol, intermediate 66) was dissolved in DMSO (500 µl) and tert-butyl (2-aminoethyl)carbamate (200 µl, 1.3 mmol) were added. The mixture was stirred at 100°C for 16 h. DMSO (2 ml) and water (0.5 ml) were added.

The mixture was extracted three times with MTBE and the combined organic phases were dried in vacuo. The precipitate was suspended in dichloromethane, filtered, and washed with MTBE. The precipitate was dissolved in ethyl acetate, washed with saturated aqueous ammonium chloride, the organic phases were then concentrated in vacuo. The precipitate was suspended in MTBE, filtered, and washed with MTBE and water. After drying in vacuo, 95.0 mg (95% purity, 39% yield) of the title compound was obtained.

LC-MS (method 1): R _t = 1.12 min; MS (ESIpos): m/z = 403 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.376 (16.00), 2.518 (0.78), 2.522 (0.49), 3.137 (0.54), 3.152 (0.62), 3.247 (0.60), 3.261 (0.54) , 5.299 (4.30), 6.043 (0.46), 6.916 (0.51), 6.939 (0.52), 7.051 (0.45), 7.733 (1.74), 7.752 (0.41), 10.884 (1.04).

- 167 041614

Intermediate 68.

(rac)-5-[4-Chloro-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

Methyl hydrazinocarboxylate (118 mg, 1.31 mmol) and 0.1 M aqueous hydrochloride solution (2 drops, 2.02 µmol). The resulting mixture was heated under reflux for 1 hour. The reaction mixture was concentrated in vacuo and the remaining material was azeotroped with MeOH (x2). A freshly prepared methanol solution of NaOMe [Na (109 mg, 4.75 mmol) in MeOH (3.1 ml)] was added and the mixture was stirred at room temperature for 2 h. MeOH (3.1 ml)] was added and the mixture was stirred at room temperature for another 2 h. AcOH (506 μl, 8.84 mmol) was added and the solution was concentrated and partitioned between EtOAc and water. The EtOAc was isolated, washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give a crude residue. The residue was purified by Biotage Isolera™ chromatography (25 g KP-Sil eluting with 1:0-1:1 heptanes-EtOAc). The resulting impure solid was repurified by Biotage Isolera™ chromatography (10 g KP-Sil eluting with 1:0-1:1 heptanes-EtOAc) to give the title compound (185.7 mg, 49% yield, 92% purity) as an off-white solid. LCMS (method 3, 2 min) 94% at R _t = 1.14 min, MS (ESIpos): m/z = 292.8 (M+H)+ [Weak ionization] LCMS (method 4, 7 min) 92% at R _t = 3.18 min, MS (ESIpos): m/z = 292.9 (M+H) ⁺ [Weak ionization] ¹ H NMR (500 MHz, Chloroform-d) δ 1.63 (d, J=7.0 Hz, 3H), 5.53 ( q, J=7.0 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.73 (dd, J=2.1, 8.4 Hz, 1H), 7.99 (d, J=1.9 Hz, 1H), 8.20 ( br. s, 1H). Chiral analysis: column: Cellulose-3.25 cm, Mobile phase: 20% IPA: 80% CO ₂ , Flow rate: 4 ml/min, UV at 280 nm, Run time: 7 min, neg. MS ion.

LC-MS (method 4, 7 min): R _t = 3.18 min; MS (ESIpos): m/z = 293 [M+H] ⁺ .

Intermediate 69.

5-[4-Chloro-3-fluoro-5-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

To a solution of methyl (22)-2-{2-(acetyloxy)-1-[4-chloro-3-fluoro-5-(trifluoromethyl)phenyl]ethylidene}hydrazine-1-carboxylate (20 g, 36% purity, intermediate compound 59) in 200 ml of ethanol, sodium hydride, 0.39 g (9.7 mmol, 60% purity), was added, then the resulting mixture was stirred at 0°C for 2 h under nitrogen atmosphere. Upon completion of the reaction, the mixture was acidified to pH=1 with HCl (1H). The solvent was removed in vacuo directly, the residue was purified by chromatography on a reverse phase C18 column: [mobile phase A: Waters (0.1% NH4HCO3), Mobile phase B: ACN; flow rate: 80 ml/min; gradient: 40% B - 70% B in 25 min] to give 2.01 g (34.4%) of the product as a white solid.

1H NMR (400 MHz, DMSO-d6): δ [ppm] = 11.35 (br s, 1H), 8.07 (dd, 1H), 7.97 (s, 1H), 5.43 (s, 2H).

Intermediate 70.

5-[4-Acetyl-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

H _tt N—N A /V// >° 7 \__/ V-0

H ₃ C

Λ

To a solution of 5-[4-bromo-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (500 mg, 1.5 mmol, intermediate 78), in 30 Tributyl(1ethoxyvinyl)stannan, 838 mg (2.3 mmol), and tetrakis(triphenylphosphine)palladium(0), 89 mg (0.08 mmol) were added in ml of 1,4-dioxane. The resulting mixture was stirred at 110° C. overnight. After cooling to room temperature, 15 ml of hydrochloric acid solution (1M) was added. The resulting mixture was stirred at room temperature for another 4 hours. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate.

The combined organic layers were washed with brine, water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EA = 3:1) to give 320 mg (65%) of the product as a yellow solid.

- 168 041614

MS (ESIpos): m/z = 287 (M+H)+.

Intermediate 71.

(gas)-6-Methyl-5-(3,4,5-trifluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

N _E S 0^,0

F

Potassium carbonate (143 mg, 1.03 mmol) and this mixture was stirred at 50°C overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with dichloromethane. The precipitate was filtered off and washed with dichloromethane. The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC to give 5.00 mg (95% pure, 6% yield) of the desired title compound.

LC-MS (method 1): Rt = 1.02 min; MS (ESIpos): m/z = 245 [M+H]+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.400 (16.00), 1.417 (15.92), 2.074 (1.45), 2.518 (9.20), 2.523 (6.26), 5.768 (1.18), 5.785 (4.51 ), 5.802 (4.43), 5.820 (1.15), 7.668 (0.50), 7.679 (3.67), 7.695 (3.93), 7.702 (4.09), 7.719 (3.89), 7.730 (0.53), 11.337 (5.65).

Intermediate 72.

(gas)-5-(4-Bromophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

(gas)-Methyl 2-[1-(4-bromophenyl)-2-hydroxypropylidene]hydrazinecarboxylate (600 mg, 1.99 mmol, intermediate 53) and potassium carbonate (826 mg, 5.98 mmol) were dissolved in acetonitrile (9 ml), and the mixture was stirred at 50° C. overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with dichloromethane. The precipitate was filtered off and the filtrate was concentrated in vacuo to give 430 mg (95% pure, 76% yield) of the desired title compound.

LC-MS (method 1): Rt = 1.04 min; MS (ESIneg): m/z = 269 [M-H] ^- .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.404 (14.54), 1.421 (14.87), 2.518 (1.89), 2.523 (1.26), 5.754 (1.10), 5.758 (0.51), 5.771 (4.34), 5.789 (4.17), 5.806 (1.06), 7.647 (0.53), 7.650 (2.93), 7.652 (2.17), 7.656 (1.32), 7.667 (2.22), 7.673 (16.00), 7.677 (3.81) 7.684 (15.37), 7.691 (2.09), 7.701 (1.39), 7.705 (2.06), 7.707 (2.93), 11.196 (1.47).

Intermediate 73.

5-[4-Chloro-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2Н-1,3,4-oxadiazin-2-one kVo UI ρφ ^N 'h ⁰

Methyl (2)-2-{2-(acetyloxy)-1-[4-chloro-3-(trifluoromethoxy)phenyl]ethylidene}hydrazine carboxylate (892 mg, 2.42 mmol, intermediate 58) was dissolved in ethanol (10 ml ) and cooled to 0°C. Sodium hydride (290 mg, 60% pure, 7.26 mmol) was added slowly and the mixture was stirred at 0°C for 10 min. The solvent was removed in vacuo and water was added. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were filtered with a waterproof filter and concentrated in vacuo. The residue was purified by chromatography to give 160 mg (90% pure, 20% yield) of the desired title compound.

LC-MS (method 1): Rt = 1.15 min; MS (ESIpos): m/z = 295 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.47), 1.172 (0.89), 1.190 (0.49), 1.987 (1.79), 2.518 (1.28), 2.523 (0.86), 4.034 (0.40), 5.393 (16.00), 7.734 (1.70), 7.739 (1.86), 7.755 (3.02), 7.760 (3.48), 7.803 (5.56), 7.825 (2.96) 11.245 (3.27).

Intermediate 74.

(6S)-5-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

To 5.0 g of (S)-1-(4-chloro-3-(trifluoromethyl)phenyl)-2-hydroxypropan-1-one (intermediate 42) in 20 ml of MeOH was added 1.94 g of methylhydrazinecarboxylate (21.6 mmol) and 12 drops of 0.1 N HCl solution (J. Med. Chem. 1992, 35, 163), and the mixture was heated at reflux temperature for 1 h. After cooling, the reaction mixture was concentrated, MeOH was added and concentrated to remove HCl and water (twice ). To this was added a solution of NaOMe (2.26 g Na (98.4 mmol) in 60 ml MeOH).

After 1 h 40 min, 5.9 ml HOAc (98 mmol) was added and the solution was concentrated and partitioned between

EtOAc and water. EtOAc was removed, dried and concentrated. Chromatography with 0-20% EtOAc in hexane followed by recrystallization from CH ₂ Cl ₂ and hexane gave 3.55 g of the product as a white solid (62%).

¹ H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 8.02 (d, J=1.7 Hz, 1H), 7.75 (dd, J=8.4, 2.0 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 5.56 (q, J=7.0 Hz, 1H), 1.65 (d, J=7.0 Hz, 3H). ¹⁹ F NMR (376 MHz, CDCl3) δ -62.93. LC-MS (method 5): mass 293 (M+1)+.

Chiral SFC analysis (Column: ChiralPak AS-H, 250 x 4.6 mm, 5 µm, Mobile phase modifier: 100% Methanol, gradient: 5-50% Methanol over 10 min, Flow rate: 4 ml/min, Back pressure: 100 bar, Column temperature: 40° C. UV detection range 200-400 nm) showed retention times of the separated enantiomers at 5.54 and 5.95 min at a ratio of 98.9:1.1.

Intermediate 75.

(6S)-5-(-[(4-Fluoro-3-(trifluoromethyl)phenyl)-)]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one n ₃ with Oh. ABOUT

_CF3

To 3.4 g of (S)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxynpropan-1-one (14 mmol, intermediate 43) in 15 ml of MeOH and 1.41 g of methylhydrazinecarboxylate (15.7 mmol) was added 9 drops of 0.1 N HCl solution (J. Med. Chem. 1992, 35, 163), and the mixture was heated under reflux for 1 h. After cooling, the reaction mixture was concentrated, MeOH was added and concentrated to remove HCl and water (twice). To this was added a solution of NaOMe (1.64 g Na (71.5 mmol) in 45 ml MeOH). After 2 h, 4.3 ml HOAc (72 mmol) was added and the solution was concentrated and partitioned between EtOAc and water. EtOAc was removed, dried and concentrated. Chromatography with 10-40% EtOAc in hexanes gave the product as an oil which solidified on standing overnight, 2.25 g (57%).

¹ H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.95 (dd, J=6.6, 2.0 Hz, 1H), 7.85 (ddd, J=8.3, 4.4, 2.3 Hz, 1H), 7.31 (t , J=9.2 Hz, 1H), 5.56 (q, J=7.0 Hz, 1H), 1.65 (d, J=7.0 Hz, 4H). ¹⁹ F NMR (376 MHz, CDCl3) δ -61.68 (d, J=12.6 Hz), -110.74 (q, J=12.7 Hz). LC-MS (method 5): mass 277 (M+1) ⁺ .

Intermediate 76.

5-(4-Chloro-3-methylphenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

Potassium carbonate (1.67 g, 12.1 mmol), and the mixture was stirred for 3 h at 50°C. The reaction mixture was diluted with water and concentrated in vacuo. The precipitate was filtered off, washed with water, stirred in MTBE, filtered and dried to give 500 mg (19% yield, 97% purity) of the desired title compound.

LC-MS (method 1): R _t = 1.04 min; MS (ESIpos): m/z = 225 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (0.97), 2.363 (14.47), 2.518 (0.67), 2.522 (0.51), 5.344 (16.00), 7.485 (2.22), 7.506 (4.13 ), 7.548 (1.82), 7.553 (1.83), 7.569 (0.93), 7.574 (1.01), 7.701 (2.51), 7.705 (2.30), 11.114 (1.64).

Intermediate 77.

5-[4-Bromo-3-(difluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

Sodium hydride, 0.8 g (33.3 mmol). The resulting mixture was stirred at 0° C. for 3 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give 4.2 g of product as a yellow solid. 100 mg was purified by preparative HPLC [Column: Xbridge prep C18

- 170 041614 µm 19x150 m; Mobile phase A: Waters (0.1% NH4HCO ₃ ), Mobile phase B: ACN; flow rate:

ml/min; gradient: 30% B - 55% B in 8 min; 254 and 220 nm; t = 7.12 min] to give 44.4 mg of the product as a white solid. MS (ESIpos): m/z = 303 (M-H) ⁺ .

Intermediate 78.

5-[4-Bromo-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one f

F _F

Sodium hydride, 0.2 g (4.1 mmol, 60% pure) at 0°C. The resulting mixture was stirred at 0° C. for 2 hours under nitrogen. Upon completion of the reaction, the pH was adjusted to 6~7 with 1N hydrochloride solution, then water was added, and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (EA/PE = 1/1) to give 0.43 g (49%) of the product as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 11.27 (s, 1H), 8.06 (d, 1H), 7.99 (d, 1H), 7.88 (dd, 1H), 5.43 (s, 2H ).

Experimental part - examples

Example 1

5-[4-(4,4-Difluoropiperidin-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

To a solution of 5-(3,4-difluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (160 mg, 754 µmol, intermediate 63) in N,N-diisopropylethylamine (530 µl, 3.1 mmol) 4,4difluoropiperidine hydrochloride (1:1) (357 mg, 2.26 mmol) and a small amount of calcium carbonate were added. The reaction mixture was stirred for 6 days at 110°C. Then water was added and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were filtered with a waterproof filter and concentrated in vacuo. The residue was purified by preparative HPLC to give 25.0 mg (95% pure, 10% yield) of the desired title compound.

LC-MS (method 1): R _t =1.09 min; MS (ESIpos): m/z = 314 [M+H] ⁺ .

Ή NMR (400 MHz, DMSO-d6) δ [ppm]: 2.069 (0.91), 2.074 (2.12), 2.082 (1.38), 2.104 (1.99), 2.118 (2.69), 2.132 (1.99), 2.153 (1.38), 2.166 (0.91), 2.518 (4.19), 2.523 (2.66), 3.206 (3.71), 3.221 (4.90), 3.234 (3.52), 5.307 (16.00), 7.126 (1.37), 7.148 (2.40), 7.170 (1.61), 7.448 (1.73), 7.453 (2.00), 7.469 (1.37), 7.475 (2.17), 7.482 (2.44), 7.487 (1.47), 7.517 (2.05), 7.523 (1.78), 11.025 (5.03).

Example 3

5-[4'-Fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

To 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (90.0 mg, 323 µmol, intermediate 64), (4- fluorophenyl)boronic acid (45.2 mg, 323 µmol), potassium carbonate (89.3 mg, 646 µmol) and 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (9.24 mg, 19.4 µmol) in 1,4- dioxane (830 µl) and water (250 µl) (nitrogen atmosphere) was added chlorine(2-dicyclohexylphosphino2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1 '-biphenyl)]palladium(II) (7.62 mg, 9.69 µmol) and the mixture was stirred for 2 h at 80°C. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were filtered with a waterproof filter and concentrated in vacuo. The residue was diluted with DMSO, filtered and purified by preparative HPLC to give 39.0 mg (90% pure, 32% yield) of the desired title compound.

LC-MS (method 1): Rt=1.25 min; MS (ESIpos): m/z = 339 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 11.25 (s, 1H), 8.10 (d, 1H), 8.01 (dd, 1H), 7.52 (d, 1H), 7.417.35 (m , 2H), 7.35-7.28 (m, 2H), 5.47 (s, 2H).

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Example 4

5-[3-Fluoro-4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

5-(3,4-difluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (160 mg, 754 µmol, intermediate 63) in morpholine (3.3 ml, 38 mmol) was stirred 18 h at 110°C. The reaction mixture was concentrated in vacuo and purified by column chromatography (silica gel, hexane/ethyl acetate, gradient: 25%^100% ethyl acetate) to give the title compound (47.0 mg, 21% yield) in 95% purity.

LC-MS (method 1): R _t = 0.84 min; MS (ESIpos): m/z = 280 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.988 (0.44), 2.518 (1.55), 2.523 (1.03), 3.063 (4.44), 3.075 (5.51), 3.087 (4.72), 3.730 (4.99 ), 3.741 (5.47), 3.752 (4.67), 5.304 (16.00), 5.759 (0.42), 7.052 (1.25), 7.075 (2.47), 7.097 (1.51), 7.457 (1.53), 7.463 (2.35), 7.470 (2.13 ), 7.475 (2.25), 7.480 (1.82), 7.483 (1.59), 7.507 (2.04), 7.512 (1.63), 11.017 (4.58).

Example 5

5-[3-Fluoro-4-(4-fluoro-4-methylpiperidin-1-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

To a solution of 5-(3,4-difluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (149 mg, 702 µmol, intermediate 63) in N,N-diisopropylethylamine (490 μl, 2.8 mmol) was added 4-fluoro-4methylpiperidine hydrochloride (1:1) (216 mg, 1.40 mmol) and the reaction mixture was stirred for days at 100°C. Then added and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were filtered with a waterproof filter and concentrated in vacuo. The residue was purified by preparative HPLC to give 39.0 mg (95% pure, 17% yield) of the desired title compound.

LC-MS (method 1): R _t = 1.12 min; MS (ESIpos): m/z = 310 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.38 (d, J=21.60 Hz, 3H) 1.87 (m, 4H) 2.90-3.06 (m, 2H) 3.27 (m, J=12.42 Hz, 2H) 5.30 (s, 2H) 7.05-7.18 (m, 1H) 7.40-7.54 (m, 2H) 11.00 (s, 1H).

Example 6

5-[3-Fluoro-4-(4-fluoropiperidin-1-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

To a solution of 5-(3,4-difluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (102 mg, 481 µmol, intermediate 63) in N,N-diisopropylethylamine (330 µl, 1.9 mmol) was added 4fluoropiperidine hydrochloride (1:1) (134 mg, 962 µmol) and the reaction mixture was stirred at 80°C over the weekend. Then acetonitrile was added and the mixture was stirred at 90° C. over the weekend. Then water was added and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were filtered with a waterproof filter and concentrated in vacuo. The residue was purified by preparative HPLC to give 20.0 mg (95% pure, 13% yield) of the desired title compound.

LC-MS (method 1): R _t = 1.03 min; MS (ESIpos): m/z = 296 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.809 (0.47), 1.818 (0.74), 1.826 (0.82), 1.835 (1.03), 1.843 (1.16), 1.851 (1.22), 1.860 (0.99), 1.868 (1.02), 1.877 (0.69), 1.886 (0.41), 1.950 (0.61), 1.960 (0.64), 1.971 (0.74), 1.981 (0.63), 1.993 (0.47), 2.004 (0.69), 2.014 (0.75), 2.024 (0.63), 2.036 (0.73), 2.045 (0.62), 2.058 (0.46), 2.075 (5.42), 2.518 (2.16), 2.523 (1.42), 3.026 (0.83), 3.036 (1.01), 3.044 (0.97), 3.055 (1.64),3.067 (1.34), 3.074 (1.35), 3.084 (1.06), 3.198 (1.12), 3.221 (1.46), 3.247 (0.76), 4.783 (0.50), 4.791 (0.63),4.800 (0.48), 4.905 (0.50), 4.913 (0.62), 4.922 (0.49), 5.299 (16.00), 7.083 (0.99), 7.107 (2.27), 7.129 (1.56), 7.435 (1.65), 7.440 (2.08), 7.459 (4.84), 7.492 (2.10), 7.497 (1.72), 11.007 (4.72).

Example 7

5-(4'-Fluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

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The title compound was synthesized analogously to Example 3 from intermediate 76 and 4-fluorophenyl)boronic acid.

LC-MS (method 1): R _t = 1.21 min; MS (ESIpos): m/z = 285 [M+H]+.

'H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 11.09 (s, 1H), 7.66 (d, 1H), 7.60 (dd, 1H), 7.41 (t, 2H), 7.327.26 ( m, 3H), 5.38 (s, 2H), 2.26 (s, 3H).

Example 8

5-(3',4'-Difluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2Н-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 76.

LC-MS (method 1): R _t = 1.24 min; MS (ESIpos): m/z = 303 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (0.85), 2.278 (15.36), 2.518 (1.87), 2.523 (1.22), 5.384 (16.00), 7.204 (0.69), 7.208 (0.73), 7.215 (0.75), 7.219 (0.89), 7.226 (0.88), 7.229 (0.87), 7.236 (0.80), 7.240 (0.65), 7.301 (3.13), 7.320 (3.58), 7.477 (0.97), 7.483 (1.70), 7.497 (1.08), 7.505 (2.78), 7.511 (1.94), 7.526 (1.78), 7.532 (2.39), 7.554 (0.81), 7.599 (1.61), 7.602 (1.77), 7.619 (1.34), 7.622 (1.60), 7.666 (3.03), 11.103 (4.86).

Example 9

5-(4'-Fluoro-2,2'-dimethylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 76.

LC-MS (method 1): R _t = 1.28 min; MS (ESIpos): m/z = 299 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.173 (0.74), 1.232 (0.71), 2.000 (16.00), 2.027 (14.86), 2.323 (0.49), 2.327 (0.66), 2.331 (0.50) , 2.522 (3.19) , 7.108 (2.77), 7.128 (0.46), 7.145 (2.99), 7.165 (3.29), 7.173 (1.61), 7.179 (1.47), 7.199 (1.43), 7.204 (1.39), 7.579 (1.67), 7.582 (1.73) , 7.599 (1.52), 7.602 (1.62), 7.672 (3.16), 11.082 (4.13).

Example 10

5-[4-(3,6-Dihydro-2H-pyran-4-yl)-3-methylphenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 76.

LC-MS (method 1): R _t = 0.94 min; MS (ESIpos): m/z = 273 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.266 (1.67), 2.273 (2.29), 2.278 (2.32), 2.284 (1.79), 2.291 (1.33), 2.304 (16.00), 2.518 (1.39) , 2.523 (0.91), 3.798 (2.85), 3.812 (6.11), 3.825 (2.73), 4.182 (1.67), 4.188 (4.45), 4.195 (4.45), 4.202 (1.71), 5.334 (15.96) , 5.678 (2.51), 5.682 (1.73), 7.174 (3.10), 7.193 (3.46), 7.495 (1.62), 7.499 (1.80), 7.515 (1.35), 7.520 (1.65), 7.553 (3.14), 11.038 (4.63) .

Example 11.

5-[3-Methyl-4-(1H-pyrazol-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

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The title compound was synthesized analogously to Example 3 from Intermediate 76.

LC-MS (method 2): Rt = 0.69 min; MS (ESIpos): m/z = 257 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (1.80), 2.327 (0.48), 2.425 (16.00), 2.522 (1.35), 2.539 (1.74), 2.669 (0.43), 5.356 (14.98), 7.490 (2.11), 7.511 (4.61), 7.538 (2.33), 7.542 (2.46), 7.559 (0.99), 7.562 (1.17), 7.606 (3.22), 13.065 (0.47).

Example 12.

5-[3-Methyl-4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 76.

LC-MS (method 2): Rt = 0.62 min; MS (ESIpos): m/z = 284 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.052 (0.76), 1.070 (0.42), 2.073 (4.95), 2.251 (0.91), 2.299 (15.80), 2.322 (0.85), 2.327 (1.18) 2.518 (3.08), 2.523 (2.05), 2.539 (1.31), 2.665 (0.58), 2.669 (0.82), 2.673 (0.58), 5.363 (16.00), 6.385 (3.14), 6.408 (3.19), 7.273 (3.32) , 7.293 (3.74), 7.392 (2.30), 7.398 (2.52), 7.504 (2.67), 7.511 (2.34), 7.528 (2.45), 7.535 (2.25), 7.555 (1.76), 7.559 (1.92), 7.576 (1.45) , 7.580 (1.67), 7.626 (3.23), 7.629 (2.90), 11.073 (5.50).

Example 13

5-[3-Methyl-4-(pyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 76.

LC-MS (method 1): Rt = 0.63 min; MS (ESIpos): m/z = 269 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.881 (0.51), 0.897 (0.57), 1.149 (0.58), 1.154 (0.62), 1.166 (0.64), 1.171 (0.76), 1.190 (0.46) , 1.232 (1.40), 1.237 (0.80), 1.245 (0.59), 1.249 (1.17), 1.254 (0.57), 1.987 (1.11), 2.286 (14.79), 2.518 (2.63) , 5.395 (16.00), 6.302 (0.81), 6.552 (0.70) . . , 8.609 (1.78), 11.112 (4.34).

Example 14

5-[3-Methyl-4-(pyrimidin-5-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 76.

LC-MS (method 2): Rt = 0.73 min; MS (ESIpos): m/z = 269 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.319 (12.30), 2.332 (0.49), 2.518 (1.72), 2.523 (1.21), 2.669 (0.43), 5.403 (12.20), 7.419 (2.41) , 7.439 (2.83), 7.663 (1.35), 7.667 (1.42), 7.683 (1.09), 7.686 (1.22), 7.730 (2.45), 8.899 (16.00), 9.229 (6.75), 11.138 (3.44).

Example 15

-(3'-Fluoro-2-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

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F

The title compound was synthesized analogously to Example 3 from Intermediate 76.

LC-MS (method 1): R _t = 1.21 min; MS (ESIpos): m/z = 285 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.075 (2.59), 2.281 (15.90), 2.518 (2.55), 2.523 (1.79), 5.387 (16.00), 7.195 (1.20), 7.197 (2.06) . , 7.257(0.46), 7.305(3.31), 7.325(3.65),7.476(0.88), 7.492(1.19), 7.494(1.03), 7.499(1.04), 7.503(0.54), 7.506(0.46), 7.511(1.00) , 7.514 (1.02), 7.517 (1.02), 7.533 (0.76), 7.603 (1.67), 7.607 (1.80), 7.623 (1.38), 7.627 (1.60), 7.670 (3.10), 11.099 (4.72).

Example 17.

(rac)-5-[3,5-Difluoro-4-(morpholin-4-yl)phenyl]-6-methyl-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 (50.0 mg, 205 µmol, intermediate 71) in morpholine (0.45 ml) was stirred at 100°C overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give the title compound 15.0 mg (95% pure, 22% yield).

LC-MS (method 1): R _t = 0.97 min; MS (ESIpos): m/z = 312 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (0.71), 1.380 (14.79), 1.397 (16.00), 1.411 (3.93), 2.075 (2.64), 2.332 (3.00), 2.336 (1.36), 2.518 (14.71) 2.523 (9.79) 2.673 (3.00) 2.678 (1.29) 3.069 (0.93) 3.079 (2.00) 3.090 (2.00) 3.170 (7.79) 3.181 (5.86) 3.686 (9.57) 3.698 (8.14) 3.735 (1.93) 3.747 (3.07) 3.758 (1.79) 5.730 (1.07) 5.748 (4.36) 5.765 (4.29) 5.783 (1.07) 5.823 (1.07), 7.167 (0.57), 7.185 (0.50), 7.386 (0.71), 7.394 (1.07), 7.409 (6.36), 7.437 (6.21), 7.452 (0.79), 7.460 (0.57), 11.198 (9.64).

Example 18.

5-{3,5-Difluoro-4-[2-methylmorpholin-4-yl]phenyl}-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (Mixture of stereoisomers)

(rac)-6-methyl-5-(3,4,5-trifluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (100 mg, 70% pure, 287 µmol, intermediate 71) and (rac)-2-methylmorpholine (87.0 mg, 860 μmol) were dissolved in acetonitrile (1.0 ml) and the mixture was stirred at 100°C overnight. The reaction mixture was concentrated in vacuo and the residue was extracted three times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by preparative HPLC to give 22.0 mg (95% pure, 22% yield) of the desired title compound.

LC-MS (method 1): R _t = 1.09 min; MS (ESIpos): m/z = 326 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.075 (15.75), 1.091 (16.00), 1.123 (3.56), 1.125 (3.68), 1.139 (3.64), 1.141 (3.72), 1.232 (0.45) , 1.379 (13.42), 1.396 (14.69), 1.409 (5.24), 1.417 (1.51), 2.336 (0.82), 2.518 (14.28), 2.523 (9.17), 2.539 (1.72), 2.563 (0.45) , 2.808 (1.06), 2.813 (0.94), 2.839 (1.84), 2.844 (1.35), 2.867 (1.47), 2.872 (1.39), 3.082 (0.70), 3.112 (2.21), 3.155 (2.91), 3.186 (1.88) , 3.259 (0.45), 3.290 (0.86), 3.582 (0.78), 3.590 (1.02), 3.609 (2.46), 3.618 (2.25), 3.628 (1.47), 3.636 (2.01), 3.645 (1.96) , 3.675 (1.23), 3.686 (0.53), 3.699 (0.82), 3.812 (1.96), 3.816 (1.64), 3.833 (1.27), 3.839 (1.60) , 5.748 (3.72), 5.765 (3.76), 5.782 (1.06), 5.809 (1.02), 5.827 (0.98), 7.165 (0.70), 7.181 (0.74), 7.362 (0.41), 7.384 (0.78), 7.391 (1.15) , 7.406 (5.77), 7.434 (5.57), 7.449 (0.74), 7.457 (0.49), 11.196 (9.70).

Example 20.

(rac)-6-Methyl-5-[4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

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To (gas)-5-(4-bromophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (78.0 mg, 290 µmol, intermediate 72) in THF ( 1.3 ml) morpholine (51 µl, 580 µmol), 2-dicyclohexylphosphino2',6'-diisopropoxybiphenyl (6.76 mg, 14.5 µmol) (argon atmosphere) and finally lithium bis(trimethylsilyl)amide (930 µl, 1.0 M, 930 µmol) and dicyclohexylphosphino-2',6'-diisopropyl-1,1'-biphenyl)(2-(2 aminoethyl)phenyl)palladium(II) (11.8 mg, 14.5 µmol) was added. The mixture was stirred for 4 hours at 80° C. in a microwave oven. The reaction mixture was diluted with methanol, filtered and concentrated in vacuo. The residue was diluted with DMSO, filtered and purified by preparative HPLC to give 15.0 mg (95% pure, 18% yield) of the desired title compound.

LC-MS (method 1): Rt = 0.83 min; MS (ESIpos): m/z = 276 [M+H]+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.357 (1.77), 1.384 (15.47), 1.402 (16.00), 1.419 (0.41), 2.318 (0.53), 2.456 (0.44), 2.461 (0.71 ), 2.466 (0.86), 2.470 (1.04), 2.518 (6.00), 2.523 (4.11), 2.660 (0.50), 3.140 (0.41), 3.152 (0.56), 3.164 (0.56), 3.186 (7.42), 3.198 (9.17 ), 3.211 (7.96), 3.718 (8.70), 3.731 (9.94), 3.743 (8.01), 5.695 (1.09), 5.712 (4.58), 5.729 (4.55), 5.746 (1.09), 6.973 (7.78), 6.996 (8.28 ), 7.596 (9.38), 7.619 (8.43), 10.895 (5.71).

Example 21.

5-[3,5-Difluoro-4-(morpholin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

Methyl 2-{1-[3,5-difluoro-4-(morpholin-4-yl)phenyl]-2-hydroxyethylidene}hydrazinecarboxylate (70.0 mg, 213 µmol, intermediate 54) and potassium carbonate (88.1 mg, 0.64 mmol ) was dissolved in acetonitrile (0.5 mL), and the mixture was stirred for 4 h at 65°C. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by preparative HPLC to give 49.0 mg (95% pure, 74% yield) of the desired title compound.

LC-MS (method 1): Rt = 0.93 min; MS (ESIpos): m/z = 298 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (2.47), 2.518 (7.37), 2.523 (5.54), 2.674 (0.72), 3.167 (5.67), 3.178 (4.32), 3.621 (0.42) 3.674 (6.41), 3.687 (7.16), 3.697 (5.99), 5.304 (16.00), 7.367 (0.58), 7.382 (3.99), 7.410 (3.94), 7.425 (0.58), 7.433 (0.42), 11.140 (4.55) .

Example 22.

2-(Morpholin-4-yl)-5-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)benzonitrile

Carbonate potassium (781 mg, 5.65 mmol) and the mixture was stirred at 60° C. overnight. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were concentrated in vacuo. The residue was treated with dichloromethane. The precipitate was filtered off to give the title compound 150 mg (95% pure, 26% yield).

LC-MS (method 1): Rt = 0.80 min; MS (ESIpos): m/z = 287 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (0.44), 2.518 (1.22), 2.523 (0.84), 2.994 (3.48), 3.238 (4.31), 3.250 (5.44), 3.262 (4.75), 3.752 (5.00), 3.764 (5.40), 3.775 (4.58), 5.338 (16.00), 7.215 (3.21), 7.238 (3.38), 7.933 (2.04), 7.938 (2.41), 7.954 (1.74), 7.960 (2.39), 7.990 (4.64), 7.995 (3.60), 11.083 (4.34).

Example 23.

3-Chloro-2-(morpholin-4-yl)-5-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)benzonitrile

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To a solution of 2-(morpholin-4-yl)-5-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)benzonitrile (60.0 mg, 210 µmol, Example 22) 1-chloropyrrolidine-2,5-dione (30.8 mg, 231 µmol) was added to THF (2.1 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give 14.0 mg (95% pure, 20% yield) of the desired title compound.

LC-MS (method 1): R _t = 0.94 min; MS (ESIpos): m/z = 321 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.518 (1.02), 2.523 (0.70), 3.323 (1.86), 3.328 (16.00), 3.345 (1.66), 3.730 (1.64), 3.741 (1.83) , 3.752 (1.47), 5.353 (4.79), 7.998 (1.28), 8.003 (2.14), 8.019 (2.05), 8.024 (1.33), 11.224 (1.46).

Example 24.

5-{4-[2,6-Dimethylmorpholin-4-yl]-3-fluorophenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

To a solution of 5-(3,4-difluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (70.0 mg, 330 µmol, intermediate 63) in X,X-diisopropylethylamine (570 µl) 2,6-dimethylmorpholine (57.0 mg, 495 µmol) was added and the reaction mixture was stirred for 5 days at 120°C. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give 6.00 mg (95% pure, 6% yield) of the desired title compound.

LC-MS (method 1): R _t = 1.04 min; MS (ESIpos): m/z = 308 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.115 (16.00), 1.131 (15.50), 1.209 (2.57), 1.225 (2.74), 2.075 (0.62), 2.336 (1.01), 2.383 (1.51) , 2.412 (2.18), 2.439 (1.79), 2.518 (11.75), 2.523 (8.39), 2.678 (0.95), 3.359 (2.07), 3.717 (0.90), 3.722 (1.01), 3.732 (1.06), 3.738 (1.23) 3.742 (1.23), 3.748 (1.12), 3.758 (1.01), 3.764 (0.84), 5.303 (14.10), 5.348 (0.39), 7.044 (1.01), 7.067 (2.01), 7.089 (1.23), 7.445 (1.45) , 7.450 (1.79), 7.463 (1.90), 7.467 (3.13), 7.499 (1.79), 7.504 (1.40), 11.010 (4.31).

Example 25-1.

(6S)-5-(3-Fluoro-4-morpholinophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

According to a literature procedure (J. Med. Chem. 1990, 35, 163), to 320 mg of 1-(3-fluoro-4-morpholinophenyl)-2-hydroxypropan-1-one (1.26 mmol, intermediate 36) in 2 ml EtOH and 2 drops of 0.1 N HCl were added 113 mg (1.26 mmol) of methylhydrazinecarboxylate and the reaction mixture was heated under reflux. After 40 minutes, another 11 mg of methylhydrazine carboxylate was added and heating was continued for another 20 minutes. After cooling, the mixture was concentrated and more MeOH was added, followed by concentration twice to remove residual water and acid. The crude product was dissolved in 1 ml EtOH and a solution of NaOEt (289 mg sodium in 4 ml EtOH) was added to the crude mixture and the mixture was stirred for 2 hours before being filtered. The solid was added to a mixture of slightly acidic (HCl) water and EtOAc. The EtOAc layer was separated, dried and concentrated to give 125 mg (34%) of the product as an off-white solid.

1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.44 (d, J=14.1 Hz, 1H), 7.30 (d, J=12.5 Hz, 1H), 6.94 (t, J=8.6 Hz, 1H ), 5.50 (q, J=6.9 Hz, 1H), 3.97-3.81 (m, 4H), 3.25-3.05 (m, 4H), 1.62 (d, J=7.0 Hz, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -120.67. LC-MS (method 5): 294 [M+H] ⁺ .

Chiral SCF chromatography separated enantiomers: column: ChiralPak AS-H, 250x4.6 mm, 5 µm, Mobile phase modifier: 100% Methanol, gradient: 5-50% Methanol over 10 min, Flow rate: 4 ml/min, Back pressure : 100 bar, Column temperature: 40°C. UV detection range 200-400nm. Retention times of separated enantiomers: 6.58 and 6.92 min. Analysis of the product from the enantioselective synthesis showed a ratio of 2.5 (6.58 min):97.5 (6.93 min).

Example 25-2.

(6S)-5-(3,5-Difluoro-4-morpholinophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

According to the method described in the literature (J. Med. Chem. 1990, 35, 163), to 1 g of (S)-1-(3,5-difluoro-4- 177 041614 morpholinophenyl)-2-hydroxypropan-1-one ( 5.34 mmol, Intermediate 37) in 5 ml MeOH and 3 drops of 0.1N HCl was added 481 mg methylhydrazinecarboxylate (5.34 mmol) and the reaction mixture was heated under reflux for 3 hours before cooling, concentrating and adding twice more MeOH and concentrating to remove residual water and HCl. A small amount of the crude product was dissolved in about 10 ml of MeOH, the solid was filtered and washed with MeOH, 935 mg of the solid was collected. This solid was stirred in 6 ml EtOH and a solution of NaOEt (600 mg Na in 15 ml EtOH) was added to it. All solids dissolve rapidly, but after 30 minutes a copious precipitate appears, which is filtered off and washed with cold EtOH. 490 mg of the solid was dissolved in EtOAc, washed with slightly acidified (HCl) water, the EtOAc layer was dried and concentrated to 433 mg of a white solid (51%).

¹ H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.17 (d, J=9.9 Hz, 2H), 5.44 (q, J=7.0 Hz, 1H), 3.92 - 3.75 (m, 4H), 3.29 (s, 4H), 1.62 (d, J=7.0 Hz, 3H). ¹⁹ F NMR (376 MHz, CDCl3) δ -118.99. LC-MS (method 5): 312 [M+H]+.

Chiral SCF chromatography separated the enantiomers: Column: ChiralPak AS-H, 250 x 4.6 mm, 5 µm, Mobile phase modifier: 100% Methanol, gradient: 5-50% Methanol over 10 minutes, Flow rate: 4 ml/min, Back pressure : 100 bar, Column temperature: 40°C. UV detection range 200-400nm. Retention times of separated enantiomers: 5.77 and 5.92 min. Analysis of the product from the enantioselective synthesis showed only a peak at 5.92 min.

Example 26.

5-[4-(3,3-Difluoropyrrolidin-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

To a solution of 5-(3,4-difluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (115 mg, 542 µmol, intermediate 63) in N,N-diisopropylethylamine (280 μl, 1.6 mmol) and acetonitrile (1.0 ml, 19 mmol) were added 3,3-difluoropyrrolidine hydrochloride (1:1) (233 mg, 1.63 mmol). The reaction mixture was stirred for 16 hours at 95°C, then 10 days at room temperature. Then water was added and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were filtered with a waterproof filter and concentrated in vacuo. The residue was purified by preparative HPLC to give 25.0 mg (95% pure, 15% yield) of the desired title compound.

LC-MS (method 1): R _t = 1.06 min; MS (ESIpos): m/z = 300 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (3.04), 2.440 (0.55), 2.459 (1.13), 2.477 (1.85), 2.518 (3.17), 2.522 (2.01), 2.530 (1.21), 2.549 (0.59), 3.593 (1.52), 3.596 (1.61), 3.611 (2.90), 3.615 (2.95), 3.629 (1.52), 3.632 (1.46), 3.802 (1.13), 3.808 (1.21), 3.835 (2.28), 3.842 (2.33), 3.869 (1.15), 3.875 (1.12), 5.283 (16.00), 6.811 (1.40), 6.833 (2.27), 6.856 (1.52), 7.407 (1.79), 7.412 (2.06), 7.428 (1.56), 7.433 (2.03), 7.450 (2.39), 7.455 (1.74), 7.488 (2.10), 7.493 (1.91), 10.945 (4.54).

Example 27.

5-(2-Methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 76.

LC-MS (method 1): R _t = 1.19 min; MS (ESIpos): m/z = 267 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.273 (14.45), 2.518 (2.88), 2.522 (1.87), 5.385 (16.00), 7.279 (2.96), 7.299 (3.38), 7.350 (2.25) , 7.353 (3.50), 7.357 (1.60), 7.364 (0.99), 7.370 (5.69), 7.374 (4.65) . , 7.599 (1.58), 7.615 (1.21), 7.619 (1.47), 7.661 (2.73), 7.665 (2.41), 11.083 (4.11).

Example 28.

5-[3-Methyl-4-(2-methylpyrimidin-5-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- 178 041614

The title compound was synthesized analogously to Example 3 from Intermediate 76.

LC-MS (method 1): R _t = 0.80 min; MS (ESIpos): m/z = 283 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.075 (0.60), 2.309 (14.06), 2.322 (0.90), 2.327 (1.04), 2.332 (0.75), 2.517 (3.94), 2.522 (2.64) , 2.665 (0.81), 2.669 (1.16), 2.674 (1.14), 2.684 (16.00), 5.396 (12.61), 7.384 (2.72), 7.404 (3.11), 7.645 (1.46), 7.649 (1.64), 7.665 (1.20) , 7.669 (1.43), 7.713 (2.82), 8.762 (14.78), 11.125 (4.23).

Example 29.

-[3-Methyl-4-(1-methyl-1 H-pyrazol-5 -yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 76.

LC-MS (method 1): Rt = 0.84 min; MS (ESIpos): m/z = 271 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.180 (10.00), 2.518 (1.44), 2.522 (0.92), 3.607 (16.00), 5.396 (9.67), 6.307 (3.52), 6.311 (3.58) 7.347 (1.98), 7.367 (2.26), 7.509 (3.43), 7.513 (3.50), 7.622 (1.08), 7.626 (1.14), 7.642 (0.91), 7.646 (1.00), 7.717 (1.97), 11.136 (2.85) .

Example 30.

5-(2,4'-Difluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 65.

LC-MS (method 1): R _t = 1.16 min; MS (ESIpos): m/z = 289 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.518 (1.62), 2.523 (1.13), 5.402 (16.00), 7.322 (3.02), 7.327 (0.94), 7.338 (1.15), 7.344 (6.59 ), 7.350 (1.08), 7.361 (0.99), 7.366 (3.44), 7.615 (0.62), 7.627 (1.86), 7.634 (4.89), 7.637 (3.92), 7.644 (5.15), 7.650 (6.98), 7.658 (1.19 ), 7.664 (3.32), 7.667 (3.42), 11.200 (4.60).

Example 31.

5-[4'-Chloro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

To 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (107 mg, 384 µmol, intermediate 64), 2-( 4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (137 mg, 576 µmol), potassium carbonate (106 mg, 768 µmol) and 2-(dicyclohexylphosphino)-2',4 ',6'triisopropylbiphenyl (11.0 mg, 23.0 µmol) in 1,4-dioxane (990 µl) and water (300 µl) (nitrogen atmosphere) 1,1'-biphenyl) [2-(2'-amino-1,1'biphenyl)]palladium(II) (9.06 mg, 11.5 µmol) and the mixture was stirred for 2 h at 80°C. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were filtered with a waterproof filter and concentrated in vacuo. The residue was diluted with DMSO, filtered and purified by preparative HPLC to give 41.0 mg (95% pure, 29% yield) of the desired title compound.

LC-MS (method 1): R _t = 1.33 min; MS (ESIpos): m/z = 355 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 11.26 (s, 1H), 8.11 (d, 1H), 8.02 (dd, 1H), 7.56-7.50 (m, 3H), 7.36 (d , 2H), 5.47 (s, 2H).

Example 32.

5-[4-(6-Methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- 179 041614

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (95.0 mg, 341 µmol, intermediate 64), 2 -methyl-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyridine (112 mg, 511 µmol), potassium carbonate (94.2 mg, 682 µmol) and 2(dicyclohexylphosphino)- 2',4',6'-triisopropylbiphenyl (9.75 mg, 20.5 µmol) was suspended in 870 µl 1,4-dioxane and 260 µl water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2dicyclohexylphosphino-2',4',6'-triisopropyl-1,G-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (8.05 mg, 10.2 µmol) added. Nitrogen was purged through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 21.0 mg (95% pure, 17% yield) of the title compound.

LC-MS (method 1): Rt = 0.78 min; MS (ESIpos): m/z = 336 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (3.23), 2.327 (0.93), 2.331 (0.67), 2.518 (3.71), 2.523 (2.56), 2.539 (16.00), 2.669 (0.92) , 2.673 (0.67), 5.477 (14.23), 7.357 (2.41), 7.377 (2.68), 7.545 (2.26), 7.566 (2.43), 7.660 (1.42), 7.666 (1.42), 7.680 (1.24), 7.686 (1.25) , 8.029 (1.51), 8.033 (1.59), 8.049 (1.34), 8.052 (1.48), 8.128 (3.04), 8.133 (2.84), 8.396 (2.36), 8.401 (2.32), 11.260 (4.73).

Example 33.

5-[4-(Pyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

F

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (86.0 mg, 309 µmol, intermediate 64), 3 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyridine (94.9 mg, 463 µmol), potassium carbonate (85.3 mg, 617 µmol) and 2-(dicyclohexylphosphino)2',4 ',6'-triisopropylbiphenyl (8.83 mg, 18.5 µmol) was suspended in 790 µl 1,4-dioxane and 240 µl water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (7.29 mg, 9.26 µmol) was added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 55.0 mg (95% pure, 53% yield) of the title compound.

LC-MS (method 2): Rt = 0.93 min; MS (ESIpos): m/z = 322 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (0.44), 2.327 (0.81), 2.331 (0.60), 2.518 (3.34), 2.522 (2.08), 2.669 (0.82), 2.673 (0.60), 5.485 (16.00) 7.502 (1.57) 7.504 (1.58) 7.514 (1.64) 7.516 (1.65) 7.600 (2.89), 7.791 (1.75), 7.811 (1.50),8.046 (1.84), 8.050 (1.92), 8.066 (1.64), 8.070 (1.77), 8.145 (3.63), 8.148 (3.42), 8.545 (2.93), 8.550 (2.86), 8.654 (2.67), 8.658 (2.74), 8.666 (2.69), 8.670 (2.53), 11.271 (5.14).

Example 34.

5-[4'-Amino-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (95.0 mg, 341 µmol, intermediate 64), 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)aniline (112 mg, 511 µmol), potassium carbonate (94.2 mg, 682 µmol) and 2-(cyclohexylphosphino)-2', 4',6'triisopropylbiphenyl (9.75 mg, 20.5 µmol) was suspended in 870 µl 1,4-dioxane and 260 µl water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (8.05 mg, 10.2 µmol) was added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 15.0 mg (95% pure, 12% yield) of the title compound.

LC-MS (method 2): Rt = 0.98 min; MS (ESIpos): m/z = 336 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (2.00), 2.522 (1.38), 5.314 (6.31), 5.444 (16.00), 6.589

- 180 041614 (0.68), 6.596 (5.91), 6.601 (1.80), 6.612 (1.95), 6.617 (6.48), 6.623 (0.68), 6.989 (4.19), 7.010 (3.67), 7.425 (2.50), 7.445 (2.66) ), 7.929 (1.64), 7.932 (1.70), 7.949 (1.45), 7.953 (1.59), 8.037 (3.39), 8.041 (3.14), 11.191 (5.48).

Example 35.

5-[3'-Hydroxy-4'-methyl-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (97.0 mg, 348 µmol, intermediate 64), ( 3-hydroxy-4-methylphenyl)boronic acid (79.4 mg, 522 µmol), potassium carbonate (96.2 mg, 696 µmol) and 2-(dicyclohexylphosphino)-2',4',6'triisopropylbiphenyl (9.96 mg, 20.9 µmol) suspended in 890 μl of 1,4-dioxane and 270 μl of water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6-triisopropyl1,G-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (8.22 mg, 10.4 µmol) was added . Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 41.0 mg (90% pure, 30% yield) of the title compound.

LC-MS (method 1): R _t = 1.12 min; MS (ESIpos): m/z = 351 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (1.11), 2.123 (1.92), 2.160 (15.29), 2.518 (1.75), 2.523 (1.16), 5.459 (16.00), 6.635 (1.73) , 6.654 (1.85), 6.737 (3.58), 6.948 (0.43), 6.952 (0.40), 7.110 (2.75), 7.129 (2.57), 7.447 (2.70), 7.467 (2.86), 7.964 (1.82), 7.968 (1.89) , 7.984 (1.62), 7.988 (1.75), 8.067 (3.65), 8.071 (3.42), 9.362 (0.76), 9.495 (7.97), 11.225 (5.99).

Example 36.

5-{3-(Trifluoromethyl)-4-[6-(trifluoromethyl)pyridin-3-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin2-one

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (95.0 mg, 341 µmol, intermediate 64), 5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2(trifluoromethyl)pyridine (140 mg, 511 µmol), potassium carbonate (94.2 mg, 682 µmol) and 2( dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (9.75 mg, 20.5 µmol) was suspended in 870 µl 1,4-dioxane and 260 µl water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2dicyclohexylphosphino-2',4',6'-triisopropyl-1,G-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (8.05 mg, 10.2 µmol) added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 59.0 mg (95% pure, 42% yield) of the title compound.

LC-MS (method 2): R _t = 1.20 min; MS (ESIpos): m/z = 390 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (2.93), 2.518 (1.68), 2.522 (1.10), 5.496 (16.00), 7.660 (2.40), 7.680 (2.60), 8.044 (2.01), 8.046 (2.07), 8.064 (3.56), 8.066 (3.56), 8.084 (1.65), 8.088 (1.73), 8.109 (2.17), 8.133 (0.98), 8.138 (0.97), 8.178 (3.24), 8.182 (3.03), 8.774 (2.61), 11.297 (4.59).

Example 37.

5-[4'-Fluoro-3'-hydroxy-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (90.0 mg, 323 µmol, intermediate 64), ( 4-fluoro-3-hydroxyphenyl)boronic acid (75.5 mg, 485 µmol), potassium carbonate (89.3 mg, 646 µmol) and 2-(dicyclohexylphosphino)-2',4',6'- 181 041614 triisopropylbiphenyl (9.24 mg, 19.4 µmol) were suspended in 1.5 ml of 1,4-dioxane and 500 µl of water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl1,G-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (7.62 mg, 9.69 µmol) added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 38.0 mg (95% pure, 32% yield) of the title compound.

LC-MS (method 1): Rt = 1.04 min; MS (ESIpos): m/z = 355 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (3.59), 2.461 (0.40), 2.466 (0.50), 2.471 (0.66), 2.518 (2.53), 2.522 (1.58), 5.462 (16.00) , 6.709 (0.76) , 6.909 (1.60), 6.914 (1.47), 7.189 (2.17), 7.210 (2.15), 7.217 (2.27), 7.238 (2.02), 7.483 (2.61), 7.503 (2.77), 7.975 (1.74), 7.980 (1.80) , 7.995 (1.55), 7.999 (1.65), 8.077 (3.52), 8.081 (3.23), 10.097 (2.17), 11.238 (5.47).

Example 38.

5-[5'-Amino-2',4'-difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

hh ₂

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (94.0 mg, 337 µmol, intermediate 64), ( 5-amino-2,4-difluorophenyl)boronic acid hydrochloride (1:1) (106 mg, 506 µmol), potassium carbonate (140 mg, 1.01 mmol) and 2(dicyclohexylphosphino)-2',4',6'- triisopropylbiphenyl (9.65 mg, 20.2 µmol) was suspended in 1.5 ml of 1,4-dioxane and 500 µl of water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2dicyclohexylphosphino-2',4',6'-triisopropyl-1,G-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (7.96 mg, 10.1 µmol) added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 62.0 mg (95% pure, 47% yield) of the title compound.

LC-MS (method 2): R _t = 1.08 min; MS (ESIpos): m/z = 372 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (9.18), 2.518 (1.73), 2.523 (1.22), 5.154 (5.11), 5.468 (16.00), 6.634 (1.32), 6.653 (1.50), 6.658 (1.44), 6.678 (1.30), 7.125 (1.76), 7.150 (1.95), 7.154 (1.94), 7.177 (1.76), 7.501 (2.48), 7.521 (2.63), 7.995 (1.70), 7.999 (1.76), 8.015 (1.51), 8.019 (1.66), 8.093 (3.39), 8.097 (3.16), 11.249 (4.52).

Example 39.

5-[4'-Amino-3'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

F

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (98.0 mg, 352 µmol, intermediate 64), 2 -fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)aniline (125 mg, 528 µmol), potassium carbonate (97.2 mg, 703 µmol) and 2-(dicyclohexylphosphino) 2',4',6'-triisopropylbiphenyl (10.1 mg, 21.1 µmol) was suspended in 900 µl 1,4-dioxane and 270 µl water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1,G-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (8.30 mg, 10.6 µmol ) were added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times.

The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 41.0 mg (90% pure, 30% yield) of the title compound.

LC-MS (method 2): Rt = 1.04 min; MS (ESIpos): m/z = 354 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.245 (5.29), 2.074 (13.20), 2.327 (1.00), 2.331 (0.72), 2.518 (3.88), 2.523 (2.65), 2.669 (1.01), 2.673 (0.74), 5.391 (6.65), 5.451 (16.00), 6.787 (1.32), 6.808 (2.68), 6.830

- 182 041614 (2.53), 6.852 (2.30), 6.856 (2.25), 6.872 (1.01), 6.877 (1.07), 6.968 (1.65), 6.973 (1.50), 6.999 (1.63), 7.469 (2.58), 7.489 (2.73) ), 7.694 (0.50), 7.949 (1.74), 7.953 (1.79), 7.969 (1.55), 7.973 (1.65), 8.054 (3.57), 8.058 (3.33), 11.213 (2.58).

Example 40.

5-[4-(6-Aminopyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (80.0 mg, 287 µmol, intermediate 64), 5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyridine-2-amine (94.8 mg, 431 µmol), potassium carbonate (79.4 mg, 574 µmol) and 2(dicyclohexylphosphino)- 2',4',6'-triisopropylbiphenyl (8.21 mg, 17.2 µmol) was suspended in 740 µl 1,4-dioxane and 220 µl water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (6.78 mg, 8.61 µmol) was added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 34.0 mg (95% pure, 33% yield) of the title compound.

LC-MS (method 2): R _t = 0.85 min; MS (ESIpos): m/z = 337 [M+H]+.

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (1.71), 2.518 (2.18), 2.522 (1.50), 5.454 (16.00), 6.179 (6.07), 6.487 (3.09), 6.489 (3.09) , 6.509 (3.08), 6.511 (3.03), 7.348 (1.30), 7.354 (1.31), 7.369 (1.22), 7.374 (1.23), 7.479 (2.34), 7.500 (2.49), 7.852 (2.54), 7.858 (2.51) , 7.967 (1.55), 7.971 (1.61), 7.988 (1.36), 7.991 (1.49), 8.072 (3.19), 8.076 (2.96), 11.216 (5.06).

Example 41.

5-[3'-Amino-4'-chloro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (94.0 mg, 337 µmol, intermediate 64), ( 3-amino-4-chlorophenyl)boronic acid (86.7 mg, 506 µmol), potassium carbonate (93.3 mg, 675 µmol) and 2-(dicyclohexylphosphino)-2',4',6'triisopropylbiphenyl (9.65 mg, 20.2 µmol) suspended in 870 μl of 1,4-dioxane and 260 μl of water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl1,G-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (7.96 mg, 10.1 µmol ) were added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 46.0 mg (95% pure, 35% yield) of the title compound.

LC-MS (method 2): R _t = 1.18 min; MS (ESIpos): m/z = 370 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (16.00), 5.460 (7.51), 5.512 (2.42), 6.452 (0.76), 6.457 (0.77), 6.473 (0.78), 6.478 (0.78) , 6.728 (1.65), 6.733 (1.55), 7.234 (2.26), 7.255 (2.09), 7.460 (1.24), 7.480 (1.31), 7.973 (0.83), 7.977 (0.87), 7.993 (0.74), 7.997 (0.80) , 8.071 (1.68), 8.075 (1.54), 11.234 (1.84).

Example 42.

5-[3'-Amino-4'-methyl-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (102 mg, 366 µmol, intermediate 64), ( 3-amino-4-methylphenyl)boronic acid (82.9 mg, 549 µmol), potassium carbonate (101 mg, 732 µmol) and 2-(dicyclohexylphosphino)-2',4',6'triisopropylbiphenyl (10.5 mg, 22.0 µmol) suspended in 940 μl of 1,4-dioxane and 280 μl of water.

- 183 041614

The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl1,G-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (8.64 mg, 11.0 µmol) added. Nitrogen was purged through the reaction mixture. Stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 81.0 mg (95% pure, 60% yield) of the title compound.

LC-MS (method 2): R _t = 1.10 min; MS (ESIpos): m/z = 350 [M+H]+.

'H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (2.86), 2.086 (13.85), 2.518 (1.16), 2.523 (0.79), 4.975 (4.73), 5.454 (16.00), 6.388 (1.53 ), 6.406 (1.61), 6.555 (3.24), 6.558 (3.06), 6.955 (2.54), 6.975 (2.44), 7.420 (2.52), 7.440 (2.64), 7.947 (1.68), 7.951 (1.73), 7.968 (1.48 ), 7.971 (1.62), 8.051 (3.40), 8.054 (3.14), 11.213 (5.28).

Example 43.

5-[3'-Amino-2'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (80.2 mg, 288 µmol, intermediate 64), 2 -fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)aniline (102 mg, 432 µmol), potassium carbonate (79.6 mg, 576 µmol) and 2-(dicyclohexylphosphino) 2',4',6'-triisopropylbiphenyl (8.23 mg, 17.3 µmol) was suspended in 740 µl 1,4-dioxane and 220 µl water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1,G-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (6.79 mg, 8.64 µmol ) were added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 51.0 mg (95% pure, 48% yield) of the title compound.

LC-MS (method 2): R _t = 1.04 min; MS (ESIpos): m/z = 354 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (16.00), 2.323 (0.46), 2.327 (0.60), 2.331 (0.45), 2.518 (2.03), 2.522 (1.33), 2.665 (0.44) , 2.669 (0.59), 2.673 (0.43), 5.253 (4.94), 5.472 (13.69), 6.369 (0.89) , 6.821(1.64), 6.838(1.19), 6.842(1.07),6.896(1.87), 6.916(2.66), 6.936(1.09), 7.493(2.29), 7.513(2.43), 7.992(1.64), 7.995(1.68) , 8.016 (1.57), 8.096 (3.24), 8.099 (3.06).

Example 44.

5-[4'-Amino-2'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (82.0 mg, 294 µmol, intermediate 64), 3 -fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)aniline (105 mg, 441 µmol), potassium carbonate (81.3 mg, 589 µmol) and 2-(dicyclohexylphosphino) 2',4',6'-triisopropylbiphenyl (8.42 mg, 17.7 µmol) was suspended in 760 µl 1,4-dioxane and 230 µl water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (6.95 mg, 8.83 µmol) was added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 9.00 mg (95% pure, 8% yield) of the title compound.

LC-MS (method 2): R _t = 1.00 min; MS (ESIneg): m/z = 352 [M-H] ^- .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (0.73), 2.332 (1.24), 2.336 (0.55), 2.518 (5.59), 2.522 (3.67), 2.539 (0.67), 2.673 (1.24) , 2.678 (0.55), 5.454 (16.00), 5.603 (5.98), 6.363 (1.85), 6.368 (2.13), 6.394 (1.58), 6.399 (2.43), 6.409 (2.88), 6.415 (1.70), 6.430 (2.52) , 6.435 (2.09), 6.882 (1.31), 6.905 (2.31), 6.925 (1.15), 7.441 (2.40), 7.461 (2.55), 7.951 (1.70), 7.955 (1.76), 7.971 (1.49), 7.975 (1.61) , 8.057 (3.49), 8.062 (3.22), 11.215 (5.56).

- 184 041614

Example 45.

5-[4-(1-Methyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (94.0 mg, 337 µmol, intermediate 64), 1 -methyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-pyrazole (105 mg, 506 µmol), potassium carbonate (93.3 mg, 675 µmol) and 2( dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (9.65 mg, 20.2 µmol) was suspended in 870 µl of 1,4-dioxane and 260 µl of water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2dicyclohexylphosphino-2',4',6'-triisopropyl-1,G-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (7.96 mg, 10.1 µmol) added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 47.0 mg (95% pure, 41% yield) of the title compound.

LC-MS (method 2): Rt = 0.91 min; MS (ESIpos): m/z = 325 [M+H]+.

'H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.522 (0.64), 3.888 (0.63), 3.903 (16.00), 5.441 (11.08), 7.621 (1.97), 7.636 (3.95), 7.949 (1.37) , 7.952 (1.44), 7.973 (4.85), 8.061 (2.56), 8.065 (2.43), 11.204 (2.04).

Example 46.

5-[4-(3-Methyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (80.0 mg, 287 µmol, intermediate 64), ( 3-methyl-1H-pyrazol-4-yl)boronic acid (54.2 mg, 431 µmol), potassium carbonate (79.4 mg, 574 µmol) and 2-(dicyclohexylphosphino)-2',4',6'triisopropylbiphenyl (8.21 mg , 17.2 µmol) were suspended in 740 µl of 1,4-dioxane and 220 µl of water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (6.78 mg, 8.61 µmol) was added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 17.0 mg (95% pure, 17% yield) of the title compound.

LC-MS (method 2): Rt = 0.83 min; MS (ESIpos): m/z = 325 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.050 (1.20), 2.074 (0.83), 2.137 (2.21), 2.322 (0.54), 2.327 (0.73), 2.331 (0.53), 2.518 (2.70) 2.522 (1.78), 2.539 (1.91), 2.665 (0.54), 2.669 (0.74), 2.673 (0.54), 5.453 (16.00), 7.376 (0.65), 7.473 (1.29), 7.493 (1.38), 7.952 (1.89) , 7.955 (1.96), 7.972 (1.69), 7.976 (1.81), 8.077 (3.55), 11.210 (4.03), 12.800 (0.50).

Example 47.

5-[4-( 1 H-Indazol-6-yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (115 mg, 413 µmol, intermediate 64), 1H -indazol-6-ylboronic acid (100 mg, 619 µmol), potassium carbonate (114 mg, 825 µmol) and 2-(dicyclohexylphosphino)-2',4',6'triisopropylbiphenyl (11.8 mg, 24.8 µmol) were suspended in 1.1 ml of 1,4-dioxane and 320 µl of water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (9.74 mg, 12.4 µmol) was added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. Due to incomplete conversion of 1H-indazol-6-ylboronic acid (66 mg, 408 µmol) and chlorine(2-dicyclohexylphosphino2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'- amino-1,1'-biphenyl)]palladium(II) (324.3 mg, 412.9 µmol) was added again and the mixture was heated at 80°C overnight. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 38.0 mg (95% pure, 24% yield) of the title compound.

LC-MS (method 2): Rt = 1.00 min; MS (ESIpos): m/z = 361 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (4.84), 2.518 (1.55), 2.523 (1.01), 5.489 (16.00), 7.051 (1.77), 7.072 (1.89), 7.468 (3.18) , 7.575 (2.44), 7.596 (2.61), 7.824 (2.77), 7.845 (2.62), 8.017 (1.64), 8.021 (1.68), 8.037 (1.41), 8.041 (1.54), 8.126 (3.35), 8.131 (3.20) , 8.147 (3.03), 11.252 (2.35), 13.190 (1.81).

Example 48.

5-[4-(5-Fluoro-6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (95.0 mg, 341 µmol, intermediate 64), ( 5-fluoro-6-methylpyridin-3-yl)boronic acid (79.2 mg, 511 µmol), potassium carbonate (94.2 mg, 682 µmol) and 2-(dicyclohexylphosphino)-2',4',6'triisopropylbiphenyl (9.75 mg , 20.5 µmol) were suspended in 1.5 ml of 1,4-dioxane and 510 µl of water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (8.05 mg, 10.2 µmol) was added. Nitrogen was purged through the reaction mixture. Stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 16.0 mg (95% pure, 13% yield) of the title compound.

LC-MS (method 2): R _t = 1.10 min; MS (ESIpos): m/z = 354 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (2.62), 2.518 (9.97), 2.522 (5.37), 2.526 (8.33), 2.673 (0.58), 5.428 (3.94), 5.482 (16.00) , 7.594 (2.25), 7.615 (2.41), 7.715 (1.42), 7.719 (1.42), 7.741 (1.41), 7.745 (1.42), 7.830 (0.46), 7.852 (0.60), 8.047 (1.49), 8.050 (1.57) , 8.067 (1.31), 8.071 (1.46), 8.083 (0.62), 8.089 (0.55), 8.142 (2.98), 8.146 (2.76), 8.281 (2.75), 11.276 (3.96).

Example 49.

5-[4-(1,2-Thiazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one o^o

A; .ΝΗ ifji ^N fH^f

F

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (108 mg, 388 µmol, intermediate 64), 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1,2-thiazole (123 mg, 581 µmol), potassium carbonate (107 mg, 775 µmol) and 2-( dicyclohexylphosphino)2',4',6'-triisopropylbiphenyl (11.1 mg, 23.3 µmol) was suspended in 1.7 ml of 1,4-dioxane and 580 µl of water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1,G-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (9.15 mg, 11.6 µmol ) were added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times.

The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 49.0 mg (95% pure, 37% yield) of the title compound.

LC-MS (method 2): R _t = 1.03 min; MS (ESIpos): m/z = 328 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (0.96), 2.518 (0.74), 2.523 (0.54), 5.477 (16.00), 7.648 (2.03), 7.668 (2.24), 8.029 (1.38) , 8.033 (1.43), 8.050 (1.22), 8.053 (1.32), 8.137 (2.69), 8.141 (2.50), 8.644 (4.81), 9.156 (5.87), 11.267 (1.51).

Example 50.

1-Methyl-5-[4-(2-oxo-3,6-dihydro-2Н-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]-1H-pyrrole2-carbonitrile

- 186 041614

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (133 mg, 476 µmol, intermediate 64), ( 5-cyano-1-methyl-1H-pyrrol-2-yl)boronic acid (107 mg, 714 µmol), potassium carbonate (132 mg, 953 µmol) and 2-(dicyclohexylphosphino)-2',4',6' triisopropylbiphenyl (13.6 mg, 28.6 µmol) was suspended in 2.1 ml of 1,4-dioxane and 710 µl of water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (11.2 mg, 14.3 µmol) was added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 100 mg (95% pure, 57% yield) of the title compound.

LC-MS (method 2): Rt = 1.11 min; MS (ESIneg): m/z = 347 [M-H] ^- .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (1.15), 2.518 (1.22), 2.522 (0.78), 3.330 (16.00), 3.635 (0.51), 5.482 (14.16), 6.264 (2.68 ), 6.274 (2.75), 7.064 (5.04), 7.074 (4.86), 7.673 (2.28), 7.693 (2.48), 8.060 (1.59), 8.064 (1.68), 8.080 (1.40), 8.083 (1.53), 8.159 (3.14 ), 8.162 (3.01), 11.303 (4.44).

Example 51.

5-[2,4'-Bis(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (118 mg, 424 µmol, intermediate 64), 4 ,4,5,5-tetramethyl-2-[4-(trifluoromethyl)phenyl]1,3,2-dioxaborolane (173 mg, 635 µmol), potassium carbonate (117 mg, 847 µmol) and 2(dicyclohexylphosphino)-2 ',4',6'-triisopropylbiphenyl (12.1 mg, 25.4 µmol) was suspended in 1.9 ml of 1,4-dioxane and 630 µl of water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10.0 mg, 12.7 µmol) was added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 41.0 mg (95% pure, 24% yield) of the title compound.

LC-MS (method 2): Rt = 1.34 min; MS (ESIneg): m/z = 387 [M-H] ^- .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (0.60), 2.518 (1.30), 2.522 (0.87), 5.485 (16.00), 7.558 (2.86), 7.573 (4.04), 7.578 (4.21 ), 7.592 (4.18), 7.840 (4.85), 7.861 (4.14), 8.040 (1.89), 8.044 (1.99), 8.064 (1.84), 8.139 (3.75), 8.142 (3.55), 11.272 (5.26).

Example 52.

5-[4-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (105 mg, 377 µmol, intermediate 64), 1 ,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-pyrazole (126 mg, 565 µmol), potassium carbonate (104 mg, 754 µmol) and 2(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (10.8 mg, 22.6 µmol) was suspended in 1.5 ml of 1,4-dioxane and 500 µl of water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (8.90 mg, 11.3 µmol) was added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 46.0 mg (95% pure, 34% yield) of the title compound.

LC-MS (method 2): R _t = 0.93 min; MS (ESIpos): m/z = 339 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.016 (16.00), 2.518 (0.93), 2.522 (0.63), 3.331 (14.15), 5.451 (11.97), 7.476 (1.92), 7.497 (2.06), 7.657 (3.25), 7.951 (1.30), 7.955 (1.34), 7.971 (1.16), 7.975 (1.25), 8.070 (2.59), 8.074 (2.44), 11.213 (3.27).

Example 53.

5-[4-(2-Methoxy-6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (150 mg, 538 µmol, intermediate 64), ( 2-methoxy-6-methylpyridin-3-yl)boronic acid (135 mg, 808 µmol), potassium carbonate (149 mg, 1.08 mmol) and 2-(dicyclohexylphosphino)-2',4',6'triisopropylbiphenyl (15.4 mg , 32.3 µmol) were suspended in 2.4 ml of 1,4-dioxane and 810 µl of water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (12.7 mg, 16.2 µmol) was added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 87.0 mg (95% pure, 42% yield) of the title compound.

LC-MS (method 2): Rt = 1.24 min; MS (ESIpos): m/z = 366 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.073 (2.23), 2.456 (14.29), 2.522 (0.48), 3.335 (16.00), 5.464 (12.60), 6.926 (2.62), 6.944 (2.85), 7.446 (2.39), 7.453 (2.89), 7.466 (2.72), 7.471 (2.82), 7.970 (1.51), 7.974 (1.61), 7.990 (1.37), 7.994 (1.51), 8.069 (3.06), 8.072 (2.92), 11.230 (4.14).

Example 54.

5-[4-(2-Methyl-1,3-thiazol-5-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (115 mg, 413 µmol, intermediate 64), 2 -methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)-1,3-thiazole (139 mg, 619 µmol), potassium carbonate (114 mg, 825 µmol) and 2(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (11.8 mg, 24.8 µmol) was suspended in 1.9 ml of 1,4-dioxane and 620 µl of water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(11) (9.74 mg, 12.4 µmol) was added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 31.0 mg (95% pure, 21% yield) of the title compound.

LC-MS (method 2): R _t = 1.02 min; MS (ESIpos): m/z = 342 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (3.55), 2.518 (1.43), 2.522 (0.95), 2.715 (16.00), 5.462 (12.09), 7.675 (5.53), 7.694 (2.05) , 8.007 (1.29), 8.012 (1.33), 8.028 (1.10), 8.032 (1.17), 8.125 (2.43), 8.130 (2.27), 11.280 (1.79).

Example 55.

5-[4'-(Methylamino)-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (167 mg, 599 µmol, intermediate 64), X -methyl-4-(4,4,5,5-tetramethyl-1,3,2- 188 041614 dioxaborolan-2-yl)aniline (210 mg, 899 µmol), potassium carbonate (166 mg, 1.20 mmol) and 2 (dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (17.1 mg, 36.0 µmol) was suspended in 2.7 ml 1,4-dioxane and 900 µl water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (14.1 mg, 18.0 µmol) was added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 41.0 mg (95% pure, 19% yield) of the title compound.

LC-MS (method 1): Rt = 1.08 min; MS (ESIpos): m/z = 350 [M+H]+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (1.18), 2.518 (1.55), 2.522 (1.04), 2.701 (10.67), 2.714 (10.49), 5.447 (16.00), 5.897 (0.58 ), 5.909 (1.81), 5.922 (1.81), 5.934 (0.57), 6.578 (5.57), 6.599 (6.07), 7.068 (4.60), 7.089 (4.12), 7.436 (2.75), 7.456 (2.97), 7.935 (1.84 ), 7.939 (1.91), 7.955 (1.71), 7.959 (1.79), 8.045 (3.75), 8.049 (3.51), 11.196 (6.11).

Example 56.

5-[3'-Amino-4'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

hh ₂

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (90.0 mg, 323 µmol, intermediate 64), ( 3-amino-4-fluorophenyl)boronic acid (75.1 mg, 485 µmol), potassium carbonate (89.3 mg, 646 µmol) and 2-(dicyclohexylphosphino)-2',4',6'triisopropylbiphenyl (9.24 mg, 19.4 µmol) suspended in 830 μl of 1,4-dioxane and 250 μl of water. The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (7.62 mg, 9.69 µmol) was added. Nitrogen was purged through the reaction mixture. It was stirred at 80°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 41.0 mg (95% pure, 34% yield) of the title compound.

LC-MS (method 2): Rt = 1.09 min; MS (ESIpos): m/z = 354 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.075 (1.25), 2.518 (1.63), 2.523 (1.10), 5.295 (5.00), 5.458 (16.00), 6.412 (0.70), 6.417 (0.82) , 6.422 (0.84), 6.432 (0.92), 6.438 (0.92), 6.442 (0.85), 6.448 (0.80), 6.694 (1.51), 6.699 (1.50), 6.715 (1.54), 6.720 (1.48), 7.017 (1.89) , 7.038 (1.92), 7.046 (2.02), 7.067 (1.81), 7.452 (2.49), 7.473 (2.66), 7.960 (1.65), 7.964 (1.75), 7.981 (1.48), 7.984 (1.64), 8.062 (3.35) , 8.066 (3.21), 11.226 (1.14).

Example 58.

5-[3',4',5'-Trifluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

F

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (115 mg, 413 µmol, intermediate 64), ( 3,4,5-trifluorophenyl)boronic acid (109 mg, 619 µmol), potassium carbonate (114 mg, 825 µmol) and dicyclohexyl[2',4',6'-tri(propan-2-yl)biphenyl-2yl ]phosphane (11.8 mg, 24.8 µmol) was suspended in 1,4-dioxane (1.9 mL) and water (620 µL). The mixture was degassed with nitrogen for 5 minutes. Then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (9.74 mg, 12.4 µmol) was added. Nitrogen was again passed through the reaction mixture. Stirred at 80°C overnight in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using a silica gel column, hexane/ethyl acetate gradient 12-100%. The resulting product fractions were concentrated and the residue was suspended in a mixture of 10 ml of hexane and 1 ml of tert-butyl methyl ether. The precipitated product was filtered. The filter cake was washed with haxane and dried in vacuo to give 96.0 mg (95% purity, 59% yield) of the title compound.

- 189 041614

LC-MS (method 1): R _t = 1.32 min; MS (ESIneg): m/z = 373 [M-H] ^- .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.48), 1.172 (0.93), 1.189 (0.47), 1.986 (1.46), 2.518 (1.55), 2.523 (1.01), 5.475 (16.00), 5.488 (0.51), 7.388 (1.93), 7.405 (2.31), 7.409 (2.33), 7.426 (2.00), 7.557 (2.42), 7.578 (2.58) 8.052 (1.62), 8.116 (3.22), 8.120 (2.98), 11.275 (4.90).

Example 59.

5-[2',5'-Difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (115 mg, 413 µmol, intermediate 64), ( 2,5-difluorophenyl)boronic acid (97.8 mg, 619 µmol), potassium carbonate (114 mg, 825 µmol) and dicyclohexyl[2',4',6'-tri(propan-2-yl)biphenyl-2yl]phosphane (11.8 mg, 24.8 µmol) was suspended in 1,4-dioxane (1.9 ml) and water (620 µl). The mixture was degassed with nitrogen for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (9.74 mg, 12.4 µmol) was added. Nitrogen was again passed through the reaction mixture. It was stirred at 80° C. overnight in a heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using a silica gel column, hexane/ethyl acetate gradient 12-100%. The resulting product fractions were concentrated and the residue was suspended in a mixture of 10 ml of hexane and 1 ml of tert-butyl methyl ether. The precipitated product was filtered. The filter cake was washed with haxane and dried in vacuo to give 95.0 mg (95% purity, 61% yield) of the title compound.

LC-MS (method 1): R _t = 1.23 min; MS (ESIpos): m/z = 357 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.518 (1.91), 2.523 (1.24), 5.482 (16.00), 7.284 (0.71), 7.293 (0.71), 7.299 (1.21), 7.313 (0.64) 7.320 (0.66), 7.370 (1.06), 7.376 (2.19), 7.381 (1.30), 7.388 (2.61), 7.393 (2.36), 7.397 (1.70), 7.408 (1.66), 7.588 (2.39), 7.608 (2.55) , 8.042 (1.66), 8.045 (1.74), 8.062 (1.47), 8.066 (1.61), 8.134 (3.31), 8.138 (3.06), 11.275 (4.91).

Example 60.

5-[3'-Amino-4'-fluoro-2-(trifluoromethoxy)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel, 5-[4-chloro-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (105 mg, 356 µmol, intermediate 73), ( 3-amino-4-fluorophenyl)boronic acid (82.8 mg, 535 µmol), potassium carbonate (98.5 mg, 713 µmol) and dicyclohexyl[2',4',6'-tri(propan-2yl)biphenyl-2-yl ]phosphane (10.2 mg, 21.4 µmol) was suspended in 1,4-dioxane (910 µL) and water (270 µL). The mixture was degassed with nitrogen for 5 minutes. Then chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1,G-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (8.41 mg, 10.7 µmol) added. Nitrogen was again passed through the reaction mixture. Stirred at 80°C overnight in a heating unit.

The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using a silica gel column, hexane/ethyl acetate gradient 12-100%. The resulting product fractions were concentrated and the residue was suspended in a mixture of 10 ml of hexane and 1 ml of tert-butyl methyl ether. The precipitated product was filtered. The filter cake was washed with haxane and dried in vacuo to give 51.0 mg (90% purity, 35% yield) of the title compound.

LC-MS (method 2): R _t = 1.12 min; MS (ESIpos): m/z = 370 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.172 (0.48), 1.987 (0.76), 2.518 (1.80), 2.523 (1.13), 5.306 (5.02), 5.419 (16.00), 6.591 (1.05), 6.596 (1.16), 6.601 (1.20), 6.607 (1.22), 6.611 (1.28), 6.617 (1.36), 6.622 (1.21), 6.628 (1.21), 6.870 (2.07), 6.875 (2.02), 6.891 (2.11), 6.897 (2.03), 7.063 (2.07), 7.084 (1.98), 7.091 (2.14), 7.112 (1.90), 7.545 (4.04), 7.555 (0.51), 7.566 (4.74), 7.745 (1.91), 7.750 (3.58), 7.756 (2.74), 7.760 (3.47), 7.764 (2.97), 7.766 (4.07), 7.771 (1.30), 11.205 (5.80).

- 190 041614

Example 61.

5-[3',4'-Difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (120 mg, 431 µmol, intermediate 64), ( 3,4-difluorophenyl)boronic acid (136 mg, 861 µmol), potassium carbonate (119 mg, 861 µmol) and dicyclohexyl[2',4',6'-tri(propan-2-yl)biphenyl-2yl]phosphane (12.3 mg, 25.8 µmol) was suspended in 1,4-dioxane (1.9 ml) and water (650 µl). The mixture was degassed with nitrogen for 5 minutes. Then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (10.2 mg, 12.9 µmol ) were added. Nitrogen was again passed through the reaction mixture. It was stirred at 80° C. overnight in a heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using a silica gel column, hexane/ethyl acetate gradient 12-100%. The resulting product fractions were concentrated and the residue was suspended in a mixture of 10 ml of hexane and 1 ml of tert-butyl methyl ether. The precipitated product was filtered. The filter cake was washed with haxane and dried in vacuo to give 103 mg (95% pure, 64% yield) of the title compound.

LC-MS (method 1): R _t = 1.27 min; MS (ESIpos): m/z = 357 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (1.54), 2.522 (0.94), 5.474 (16.00), 5.758 (0.65), 7.188 (0.95), 7.204 (0.99), 7.466 (0.85), 7.471 (0.86), 7.485 (0.95), 7.493 (1.14), 7.499 (0.95), 7.514 (1.84), 7.535 (2.22), 7.541 (3.81), 7.562 (4.67), 7.583 (0.86) 8.018 (1.97), 8.035 (1.65), 8.038 (1.80), 8.110 (3.71), 8.114 (3.49), 11.262 (5.28).

Example 62.

5-[4-( 1 H-Indol-6-yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (109 mg, 391 µmol, intermediate 64), 1H -indol-6-ylboronic acid (94.5 mg, 587 µmol), potassium carbonate (108 mg, 782 µmol) and dicyclohexyl[2',4',6'-tri(propan-2-yl)biphenyl-2yl]phosphane ( 11.2 mg, 23.5 µmol) were suspended in 1,4-dioxane (1.8 ml) and water (500 µl). The mixture was degassed with nitrogen for 5 minutes. Then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (9.23 mg, 11.7 µmol ) were added. Nitrogen was again passed through the reaction mixture. It was stirred at 80° C. overnight in a heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 69.0 mg (95% pure, 47% yield) of the title compound.

LC-MS (method 2): R _t = 1.17 min; MS (ESIneg): m/z = 358 [M-H] ^- .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (1.77), 2.518 (1.22), 2.522 (0.80), 5.480 (16.00), 6.478 (1.51), 6.480 (1.82), 6.483 (1.90), 6.485 (2.79), 6.488 (2.05), 6.490 (1.81), 6.493 (1.60), 6.944 (1.76), 6.946 (1.75), 6.964 (1.86), 6.966 (1.84), 7.351 (3.49), 7.421 (2.64), 7.428 (3.33) 7.435 (2.70) 7.539 (2.53) 7.559 (2.71) 7.587 (3.29) 7.608 (3.02) 8.102 (3.35), 8.107 (3.22), 11.227 (7.36).

Example 63.

5-[4-(2-Methylprop-1-en-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (112 mg, 402 µmol, intermediate 64), 4 ,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2dioxaborolane (110 mg, 603 µmol), potassium carbonate (111 mg, 804 µmol) and dicyclohexyl[ 2',4',6'

- 191 041614 tri(propan-2-yl)biphenyl-2-yl]phosphane (11.5 mg, 24.1 µmol) was suspended in 1,4-dioxane (1.8 ml) and water (600 µl). The mixture was degassed with nitrogen for 5 minutes. Then chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1,G-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (9.49 mg, 12.1 µmol) added. Nitrogen was again passed through the reaction mixture. It was stirred at 80° C. overnight in a heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 43.0 mg (95% pure, 34% yield) of the title compound.

LC-MS (method 2): R _t = 1.27 min; MS (ESIneg): m/z = 297 [M-H] ^- .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.700 (10.62), 1.703 (10.58), 1.912 (9.28), 1.915 (9.39), 2.518 (1.56), 2.522 (1.02), 5.422 (16.00), 6.379 (1.51), 7.457 (2.02), 7.478 (2.17), 7.916 (1.43), 7.920 (1.55), 7.940 (1.44), 7.988 (2.99), 7.992 (2.72), 11.182 (4.02).

Example 64.

5-[2',3'-Difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

F

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (130 mg, 467 µmol, intermediate 64), ( 2,3-difluorophenyl)boronic acid (111 mg, 700 µmol), potassium carbonate (129 mg, 933 µmol) and dicyclohexyl[2',4',6'-tri(propan-2-yl)biphenyl-2yl]phosphane (13.3 mg, 28.0 µmol) was suspended in 1,4-dioxane (2.1 ml) and water (700 µl). The mixture was degassed with nitrogen for 5 minutes. Then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (11.0 mg, 14.0 µmol) was added. Nitrogen was again passed through the reaction mixture. It was stirred at 80° C. overnight in a heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using a silica gel column, hexane/ethyl acetate gradient 12-100%. The resulting product fractions were concentrated and the residue was suspended in a mixture of 10 ml of hexane and 1 ml of tert-butyl methyl ether. The precipitated product was filtered. The filter cake was washed with haxane and dried in vacuo to give 81.0 mg (95% purity, 46% yield) of the title compound.

LC-MS (method 2): Rt = 1.22 min; MS (ESIneg): m/z = 355 [MH] ^- .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.172 (0.73), 1.986 (1.43), 2.518 (1.33), 2.523 (0.87), 5.486 (16.00), 7.168 (0.70), 7.187 (1.29) , 7.203 (0.90), 7.292 (0.55), 7.295 (0.52), 7.305 (0.63), 7.308 (0.67), 7.313 (1.02), 7.325 (1.01), 7.329 (0.91), 7.332 (0.62), 7.336 (0.50) 7.345 (0.54), 7.349 (0.47), 7.527 (0.47), 7.531 (0.49), 7.550 (0.94), 7.557 (0.62), 7.567 (0.56), 7.573 (0.95), 7.576 (0.86), 7.594 (0.49) , 7.597 (0.47), 7.612 (2.25), 7.633 (2.43), 8.052 (1.60), 8.056 (1.65), 8.073 (1.41), 8.077 (1.51), 8.149 (3.16), 8.153 (2.90), 11.280 (4.37) .

Example 65.

5-[4-(Morpholin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

F

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (100 mg, 381 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), and morpholine (170 μl, 1.9 mmol) was added. The mixture was stirred at 80°C overnight and then at 150°C overnight. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 20.0 mg (95% pure, 15% yield) of the title compound.

LC-MS (method 1): R _t = 1.03 min; MS (ESIpos): m/z = 330 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (0.49), 2.331 (0.67), 2.518 (4.11), 2.522 (2.52), 2.539 (0.51), 2.673 (0.68), 2.897 (4.65) 2.908 (5.70), 2.919 (4.90), 3.699 (5.05), 3.711 (5.60), 3.721 (4.98), 5.396 (16.00), 7.596 (1.76), 7.618 (1.98), 7.938 (1.29), 7.943 (1.97) , 7.962 (6.78), 11.134 (4.65).

Example 66.

5-[4-(Butylamino)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- 192 041614 o^o χ/' ^{ΝΗ n} 1 F^F

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (105 mg, 401 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), and butan-1-amine (44 μl, 440 μmol) was added. The mixture was stirred at 100° C. for 2 hours. More butan-1-amine (44 μl, 440 μmol) was added and stirring was continued at 100° C. overnight. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 77.0 mg (95% pure, 58% yield) of the title compound.

LC-MS (method 1): Rt = 1.27 min; MS (ESIpos): m/z = 316 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.879 (5.19), 0.897 (13.15), 0.915 (6.10), 1.297 (1.33), 1.315 (2.20), 1.334 (2.25), 1.353 (1.52) , 1.372 (0.43), 1.487 (0.71), 1.506 (1.67), 1.518 (1.27), 1.524 (2.25) . , 7.742 (1.52), 7.747 (1.15), 10.869 (4.91).

Example 67.

5-[4-(Ethylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

0^0 xY ³ n T

F^F

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (155 mg, 591 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), and ethanamine (330 μl, 2.0 M in tetrahydrofuran, 650 μmol) was added. The mixture was stirred at 60° C. overnight. Again, ethanamine (180 μl, 2.0 M in tetrahydrofuran, 355 μmol) was added and stirring continued at 60° C. overnight. A second time more ethanamine (180 μl, 2.0 M in tetrahydrofuran, 355 μmol) was added and heated at 60° C. overnight again. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 75.0 mg (95% pure, 42% yield) of the title compound.

LC-MS (method 1): Rt = 1.08 min; MS (ESIpos): m/z = 288 [M+H]+.

Ή NMR (400 MHz, DMSO-d6) δ [ppm]: 1.121 (5.12), 1.139 (12.23), 1.156 (5.23), 2.074 (1.79), 2.518 (2.25), 2.522 (1.36), 3.247 (0.59), 3.264 (1.98), 3.280 (2.39), 3.297 (1.97), 3.314 (0.66), 5.292 (16.00), 5.905 (0.72), 5.919 (1.42), 5.933 (0.71), 6.865 (2.11), 6.887 (2.22), 7.725 (3.88), 7.751 (1.46), 7.756 (1.12), 10.873 (4.44).

Example 68.

5-[4-(1-Methyl-1H-pyrazol-4-yl)-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel, 5-[4-chloro-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (135 mg, 458 µmol, intermediate 73), ( 1-methyl-1H-pyrazol-4-yl)boronic acid (86.6 mg, 687 µmol), potassium carbonate (127 mg, 916 µmol) and dicyclohexyl[2',4',6'-tri(propan-2yl)biphenyl -2-yl]phosphane (13.1 mg, 27.5 µmol) was suspended in 1,4-dioxane (1.5 ml) and water (500 µl). The mixture was degassed with nitrogen for 5 minutes. Then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10.8 mg, 13.7 µmol ) were added. Nitrogen was again passed through the reaction mixture. It was stirred at 60° C. for 2 hours in a heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 21.0 mg (95% pure, 13% yield) of the title compound.

LC-MS (method 1): Rt = 0.95 min; MS (ESIpos): m/z = 341 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.52), 1.172 (0.91), 1.190 (0.57), 1.231 (0.74), 1.987 (1.41), 2.323 (0.77), 2.326 (1.01), 2.331 (0.76), 2.539 (0.74), 2.665 (0.77), 2.669 (1.01), 2.673 (0.74), 3.910 (16.00), 5.397 (11.22), 7.686 (1.50), 7.690 (1.70) 7.710 (2.31), 7.731 (2.73), 7.847 (3.32), 7.867

- 193 041614 (2.56), 7.921 (5.07), 8.187 (4.85), 11.160 (4.16).

Example 69.

5-[4-(Propylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2Н-1,3,4-oxadiazin-2-one ⁿ XF^F

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (125 mg, 477 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), and propane-1-amine (43 μl, 520 μmol) was added. The mixture was stirred at 100°C for 18 hours. More propane-1-amine (43 μl, 520 μmol) was added and stirring was continued at 100°C for 2 hours. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to obtain 62.0 mg (95% pure, 41% yield) of title compound.

LC-MS (method 1): Rt = 1.18 min; MS (ESIpos): m/z = 302 [M+H]+.

1Н NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.866 (4.91), 0.885 (12.24), 0.903 (5.74), 1.525 (1.47), 1.543 (2.53), 1.561 (2.53), 1.579 (1.44) , 2.518 (2.77), 2.522 (2.03), 3.183 (1.10), 3.198 (2.27), 3.217 (2.34), 3.233 (1.14), 5.289 (16.00), 5.935 (0.76), 5.950 (1.51), 5.964 (0.79) , 6.865 (2.02), 6.887 (2.14), 7.717 (5.83), 7.740 (1.63), 7.745 (1.23), 10.871 (4.72).

Example 70.

5-[4-(6-Methylpyridin-3-yl)-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel, 5-[4-chloro-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (90.0 mg, 305 µmol, intermediate 73), ( 6-methylpyridin-3-yl)boronic acid (62.8 mg, 458 µmol), potassium carbonate (84.4 mg, 611 µmol) and dicyclohexyl[2',4',6'-tri(propan-2yl)biphenyl-2-yl ]phosphane (8.74 mg, 18.3 µmol) was suspended in 1,4-dioxane (780 µL) and water (240 µL). The mixture was degassed with nitrogen for 5 minutes. Then chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1,G-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (10.8 mg, 13.7 µmol) added.

Nitrogen was again passed through the reaction mixture. It was stirred at 60° C. for 2 hours in a heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 21.0 mg (95% pure, 19% yield) of the title compound.

LC-MS (method 1): R _t = 1.04 min; MS (ESIpos): m/z = 352 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.327 (0.93), 2.331 (0.69), 2.518 (4.00), 2.523 (2.78), 2.536 (16.00), 2.669 (0.96), 2.673 (0.70), 5.439 (14.58) 7.388 (2.55) 7.408 (2.74) 7.692 (3.17) 7.714 (4.28) 7.808 (2.01) 7.812 (3.15) 7.822 (2.47) 7.829 (6.74) 7.848 (1.94), 7.854 (2.01), 8.577 (2.82), 8.581 (2.84), 11.239 (4.67).

Example 71.

5-[4'-Chloro-2-(trifluoromethoxy)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel, 5-[4-chloro-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (135 mg, 458 µmol, intermediate 73), ( 4-chlorophenyl)boronic acid (107 mg, 687 µmol), potassium carbonate (127 mg, 916 µmol) and dicyclohexyl[2',4',6'-tri(propan-2-yl)biphenyl-2yl]phosphane (13.1 mg, 27.5 µmol) were suspended in 1,4-dioxane (1.5 ml) and water (500 µl). The mixture was degassed with nitrogen for 5 minutes. Then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10.8 mg, 13.7 µmol) was added. Nitrogen was again passed through the reaction mixture. Stirred at 60°C for 2 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved

- 194 041614 in DMSO, filtered and purified by preparative HPLC to give 44.0 mg (95% pure, 25% yield) of the title compound.

LC-MS (method 1): R _t = 1.37 min; MS (ESIpos): m/z = 371 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (0.80), 2.518 (3.98), 2.522 (2.72), 5.435 (16.00), 7.522 (0.44), 7.526 (3.04), 7.533 (1.36) , 7.543 (2.03), 7.549 (9.55), 7.554 (2.06), 7.565 (1.96), 7.569 (10.05), 7.575 (2.12), 7.586 (1.42), 7.592 (3.22), 7.651 (3.61), 7.661 (0.48) , 7.672 (4.83), 7.795 (1.81), 7.799 (3.79), 7.805 (2.72), 7.809 (3.36), 7.813 (2.75), 7.816 (3.69), 7.820 (1.38), 11.235 (4.85).

Example 72.

5-[4-(Azetidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one o^o ^F T ^F

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (100 mg, 381 µmol, intermediate 66) was dissolved in DMSO (1.0 ml) and azetidine (57 μl, 840 μmol) were added. The mixture was stirred at 100°C for 3 days. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 37.0 mg (95% pure, 31% yield) of the title compound.

LC-MS (method 1): R _t = 1.14 min; MS (ESIpos): m/z = 300 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (0.56), 2.260 (0.51), 2.278 (1.44), 2.297 (2.23), 2.316 (1.60), 2.322 (0.64), 2.327 (0.58) , 2.335 (0.65), 2.518 (1.50), 2.523 (1.06), 4.067 (2.57), 4.085 (4.57), 4.103 (2.46), 5.305 (16.00), 6.588 (2.04), 6.609 (2.12), 7.737 (1.31) , 7.742 (1.84), 7.764 (5.76), 10.908 (3.53).

Example 73.

5-[4-(1-Methyl-1 H-benzimidazol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (136 mg, 488 µmol, intermediate 64), ( 1-methyl-1H-benzimidazol-6-yl)boronic acid (129 mg, 732 µmol), potassium carbonate (135 mg, 976 µmol) and dicyclohexyl[2',4',6'-tri(propan-2yl)biphenyl -2-yl]phosphane (14.0 mg, 29.3 µmol) was suspended in 1,4-dioxane (2.2 ml) and water (730 µl). The mixture was degassed with nitrogen for 5 minutes. Then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl1,1'-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (11.5 mg, 14.6 µmol) added. Nitrogen was again passed through the reaction mixture. It was stirred at 80°C for 3 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 90.4 mg (50% yield) of the title compound.

LC-MS (method 2): R _t = 0.92 min; MS (ESIpos): m/z = 375 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.154 (0.66), 1.171 (1.28), 1.189 (0.61), 1.987 (2.41), 2.518 (1.12), 2.522 (0.72), 3.885 (1.32) , 4.017 (0.54), 4.034 (0.56), 4.061 (16.00), 5.494 (9.20), 7.074 (1.10), 7.095 (1.15), 7.587 (1.46), 7.607 (1.58), 7.630 (2.17), 7.808 (1.88) . , 8.142 (1.83), 11.258 (3.14).

Example 74.

5-[4-(Pentylamino)-3-(trifluoromethyl)phenyl]-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 (115 mg, 439 µmol, intermediate 66) was dissolved in DMSO (920 µl) and pentan-1-amine (55 µl, 480 µmol) was added. The mixture was stirred at 100°C for 18 hours. Again pentane-1-amine (55 μl, 480 μmol) was added and stirring was continued at 100°C for 2 hours. The reaction mixture was diluted

- 195 041614

DMSO, filtered and purified by preparative HPLC to give 71.0 mg (95% pure,

47% yield) indicated in the name of the compound.

LC-MS (method 1): Rt = 1.35 min; MS (ESIpos): m/z = 330 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.847 (2.92), 0.864 (9.07), 0.881 (3.05), 1.282 (2.81), 1.291 (4.88), 1.300 (3.93), 1.309 (2.93) , 1.331 (0.52), 1.504 (0.45), 1.522 (1.41), 1.539 (2.00), 1.557 (1.36), 2.518 (1.91), 2.522 (1.17), 3.206 (1.06), 3.223 (2.26), 3.240 (2.27) , 3.256 (1.03), 5.289 (16.00), 5.914 (0.82), 5.928 (1.62), 5.943 (0.80), 6.855 (2.16), 6.877 (2.28) .

Example 75.

5-[4-(1-Methyl-1 H-indazol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (114 mg, 409 µmol, intermediate 64), ( 1-methyl-1H-indazol-6-yl)boronic acid (108 mg, 614 µmol), potassium carbonate (113 mg, 818 µmol) and dicyclohexyl[2',4',6'-tri(propan-2yl)biphenyl -2-yl]phosphane (11.7 mg, 24.5 µmol) was suspended in 1,4-dioxane (1.8 ml) and water (610 µl). The mixture was degassed with nitrogen for 5 minutes. Then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl1,1'-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (9.66 mg, 12.3 µmol) added. Nitrogen was again passed through the reaction mixture. It was stirred at 80°C for 18 hours in a heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 63.0 mg (90% pure, 37% yield) of the title compound.

LC-MS method 1): Rt = 1.10 min; MS (ESIpos): m/z = 375 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.66), 1.171 (1.28), 1.189 (0.61), 1.987 (2.41), 2.518 (1.12), 2.522 (0.72), 3.885 (1.32), 4.017 (0.54), 4.034 (0.56), 4.061 (16.00), 5.494 (9.20), 7.074 (1.10), 7.095 (1.15), 7.587 (1.46), 7.607 (1.58), 7.630 (2.17), 7.808 (1.88), 7.810 (1.85), 7.829 (1.81), 7.830 (1.78),8.033 (0.99), 8.036 (1.03), 8.053 (0.85), 8.057 (0.93), 8.119 (3.84), 8.122 (3.57), 8.137 (1.94), 8.142 (1.83), 11.258 (3.14).

Example 76.

5-[4'-Fluoro-2-(trifluoromethoxy)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel, 5-[4-chloro-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (180 mg, 611 µmol, intermediate 73), ( 4-fluorophenyl)boronic acid (128 mg, 916 µmol), potassium carbonate (169 mg, 1.22 mmol) and dicyclohexyl[2',4',6'-tri(propan-2-yl)biphenyl-2yl]phosphane (17.5 mg, 36.7 µmol) were suspended in 1,4-dioxane (1.6 ml) and water (470 µl). The mixture was degassed with nitrogen for 5 minutes. Then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (14.4 mg, 18.3 µmol) was added. Nitrogen was again passed through the reaction mixture. It was stirred at 60° C. for 2 hours in a heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was taken up in DMSO, filtered and dried in vacuo. This was purified by chromatography to give 121 mg (95% pure, 53% yield) of the title compound.

LC-MS (method 1): Rt = 1.28 min; MS (ESIpos): m/z = 355 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.172 (0.72), 1.987 (1.44), 2.518 (1.57), 2.523 (1.10), 5.433 (16.00), 7.325 (2.97), 7.331 (0.88) 7.341 (1.10), 7.347 (6.45), 7.353 (1.07), 7.364 (1.01), 7.369 (3.40), 7.543 (3.25), 7.549 (1.30), 7.557 (3.71), 7.566 (3.07), 7.573 (1.08) , 7.579 (2.79), 7.640 (3.66), 7.661 (4.66), 7.785 (1.97), 7.789 (3.47), 7.794 (1.05), 7.797 (2.31), 7.801 (3.17), 7.806 (4.24), 11.225 (4.88) .

Example 77.

5-[3-Fluoro-4-(6-fluoropyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- 196 041614

The title compound was synthesized analogously to the procedure described in Example 3 from

5-(4-chloro-3-fluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (intermediate 65) and 4fluoropyridin-3-ylboronic acid.

LC-MS (method 11): R _t = 0.91 min; MS (ESIpos): m/z = 290 [M+H]+,

Example 78.

5-[3-Fluoro-4-(3-methylpyridin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

CH ₃

The title compound was synthesized analogously to Example 3 from Intermediate 65.

LC-MS (method 1): R _t = 0.53 min; MS (ESIpos): m/z = 286 [M+H] ⁺ .

Example 79.

5-[3-Fluoro-4-(2-methylpyridin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 65.

LC-MS (method 1): R _t = 0.50 min; MS (ESIpos): m/z = 286 [M+H] ⁺ .

Example 80.

5-(4'-Amino-2-fluorobiphenyl-4-yl)-3,6-dihydro-2Н-1,3,4-oxadiazin-2-one / /g ^1-1

The title compound was synthesized analogously to Example 3 from Intermediate 65.

LC-MS (method 1): R _t = 0.72 min; MS (ESIpos): m/z = 286 [M+H] ⁺ .

Example 81.

5-(2-Fluoro-2'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one CH ₃

The title compound was synthesized analogously to Example 3 from Intermediate 65.

LC-MS (method 1): R _t = 1.15 min; MS (ESIpos): m/z = 285 [M+H] ⁺ .

Example 82.

5-(2'-Chloro-2,4'-difluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 65.

LC-MS (method 1): R _t = 1.16 min; MS (ESIpos): m/z = 323 [M+H] ⁺ .

Example 83.

5-[4-(Cyclopent-1-en-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 65.

LC-MS (method 1): R _t = 1.19 min; MS (ESIpos): m/z = 261 [M+H] ⁺ .

Example 84.

5-(2'-Ethyl-2-fluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 65.

- 197 041614

LC-MS (method 1): R _t = 1.21 min; MS (ESIpos): m/z = 299 [M+H]+.

Example 85.

5-[3-Fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 65.

LC-MS (method 1): Rt = 0.97 min; MS (ESIpos): m/z = 302 [M+H] ⁺ .

Example 86.

5-(2,4'-Difluoro-3'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 65.

LC-MS (method 1): R _t = 1.20 min; MS (ESIpos): m/z = 303 [M+H]+.

Example 87.

5-(2-Fluoro-3'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 65.

LC-MS (method 1): R _t = 1.18 min; MS (ESIpos): m/z = 285 [M+H]+.

Example 88.

5-(2-Fluoro-4'-methylbiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 65.

LC-MS (method 1): R _t = 1.18 min; MS (ESIpos): m/z = 285 [M+H]+.

Example 89.

5-(2-Fluorobiphenyl-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 65.

LC-MS (method 1): R _t = 1.09 min; MS (ESIpos): m/z = 271 [M+H]+.

The following examples Example 90 - Example 118 was prepared according to Example 89 from Intermediate 65 by reaction of the appropriate boronic acid or the corresponding 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ester, which were obtained from commercial sources, unless otherwise specified.

Example 90.

5-[4-(2-Aminopyridin-4-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 0.47 min; MS (ESIpos): m/z = 287 [M+H]+.

Example 91.

5-[4-(3-Aminophenyl)-3-fluoro-phenyl]-3,6-dihydro-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 0.47 min; MS (ESIpos): m/z = 286 [M+H]+.

Example 92.

5-[4'-(Difluoromethyl)-2-fluoro[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- 198 041614

LC-MS (method 1): R _t = 1.10 min; MS (ESIpos): m/z = 321 [M+H]+.

Example 93.

5-[3-Fluoro-4-(pyridin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 0.50 min; MS (ESIpos): m/z = 272 [M+H]+.

Example 94.

5-[3-Fluoro-4-(2-methylpyrimidin-5-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 0.72 min; MS (ESIpos): m/z = 287 [M+H] ⁺ .

Example 95.

5-[3-Fluoro-4-(2-methoxypyridin-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one ^- <e-CH ₃

LC-MS (method 1): R _t = 0.95 min; MS (ESIpos): m/z = 302 [M+H]+.

Example 96.

5-[3-Fluoro-4-(2-methylpyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 0.51 min; MS (ESIpos): m/z = 286 [M+H] ⁺ .

Example 97.

5-[3-Fluoro-4-(6-methylpyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 0.56 min; MS (ESIpos): m/z = 286 [M+H] ⁺ .

Example 98.

5-(2,2',4',5'-tetrafluoro[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 1.14 min; MS (ESIpos): m/z = 325 [M+H]+.

Example 99.

5-(2,2',3',4'-tetrafluoro[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 1.15 min; MS (ESIpos): m/z = 325 [M+H] ⁺ .

Example 100.

5-(2,2',5'-Trifluoro[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 1.09 min; MS (ESIpos): m/z = 307 [M+H] ⁺ .

Example 101.

2'-Fluoro-4'-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5 -yl) [1,1'-biphenyl] -4-carbonitrile n-n /g-\ /=\

LC-MS (method 1): Rt = 0.98 min; MS (ESIpos): m/z = 296 [M+H] ⁺ .

- 199 041614

Example 102.

5-(2'-Amino-2-fluoro[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one n N-N

LC-MS (method 1): R _t = 0.89 min; MS (ESIpos): m/z = 286 [M+H]+.

Example 103.

5-(3'-Amino-2-fluoro-4'-methyl[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one n N-N

Gu (U ^SN nh ₂

LC-MS (method 1): Rt = 0.87 min; MS (ESIpos): m/z = 300 [M+H] ⁺ .

Example 104.

5-(2-Fluoro-3'-hydroxy[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 0.86 min; MS (ESIpos): m/z = 287 [M+H] ⁺ .

Example 105.

5-(2-Fluoro-4'-hydroxy[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 0.82 min; MS (ESIpos): m/z = 287 [M+H] ⁺ .

Example 106.

5-(2-Fluoro-2'-hydroxy[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 0.90 min; MS (ESIpos): m/z = 287 [M+H] ⁺ .

Example 107.

5-(2,3',4'-Trifluoro[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 1.14 min; MS (ESIpos): m/z = 307 [M+H] ⁺ .

Example 108.

5-[3-Fluoro-4-(pyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 0.59 min; MS (ESIpos): m/z = 272 [M+H] ⁺ .

Example 109.

5-(2,2',3'-Trifluoro[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 1.10 min; MS (ESIpos): m/z = 307 [M+H] ⁺ .

Example 110.

5-(2,3',5'-Trifluoro[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one n

N-N

0=( J o - ⁷

LC-MS (method 1): R _t = 1.15 min; MS (ESIpos): m/z = 307 [M+H] ⁺ .

Example 111.

5-(2,2',4'-Trifluoro[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): Rt= 1.11 min; MS (ESIpos): m/z = 307 [M+H] ⁺ .

- 200 041614

Example 112.

5-(2-Fluoro-2',4'-dimethyl[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): Rt = 1.23 min; MS (ESIpos): m/z = 299 [M+H]+.

Example 113.

5-(2,3'-Difluoro-4'-methyl[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 1.20 min; MS (ESIpos): m/z = 303 [M+H] ⁺ .

Example 114.

5-(2,2'-Difluoro[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): Rt = 1.07 min; MS (ESIpos): m/z = 289 [M+H] ⁺ .

Example 115.

5-(2,2',6'-Trifluoro[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 1.07 min; MS (ESIpos): m/z = 307 [M+H] ⁺ .

Example 116.

5-(2-Fluoro-2'-methoxy[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 1.07 min; MS (ESIpos): m/z = 301 [M+H] ⁺ .

Example 117.

5-(2,3'-Difluoro[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 1.11 min; MS (ESIpos): m/z = 289 [M+H] ⁺ .

Example 118.

5-[3-Fluoro-4-(4-methylpyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 0.55 min; MS (ESIpos): m/z = 286 [M+H] ⁺ .

Example 119.

(gas)-5-(3-Fluoro-4-morpholinophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

According to a literature procedure (J. Med. Chem. 1990, 35, 163), to 370 mg (gas)-1-(3-fluoro-4-morpholinophenyl)-2-hydroxypropan-1-one (1.46 mmol, intermediate 33 ) in 4 ml of EtOH and 56 drops of 0.1N HCl was added 131 mg (1.46 mmol) of methylhydrazinecarboxylate, and the reaction mixture was heated at reflux for 1 h. . NaOEt solution (350 mg sodium in 5 ml EtOH) was added to the crude mixture and the mixture was stirred overnight. The next day the solid was filtered off and added to a mixture of slightly acidic (HCl) water and EtOAc. The EtOAc layer was separated, dried and concentrated to give 107 mg (25%) of the product as an off-white solid.

1Н NMR (400 MHz, CDCl ₃ ) δ 8.19 (s, 1H), 7.44 (d, J=14.1 Hz, 1H), 7.30 (d, J=12.1 Hz, 1H), 6.94 (t, J=8.4 Hz, 1H), 5.50 (q, J=6.9 Hz, 1H), 3.90 (s, 4H), 3.19 (s, 4H), 1.62 (d, J=6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -120.66. LC-MS (method 5): 294 [M+H] ⁺ .

- 201 041614

Example 120.

(6S)-6-Methyl-5-[4-(morpholin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one n ₃ With ____. y---, )—O

O ⁴ N—σ υ—)=° \__/ \=/ N—N

F ₃ c' ^N

To 3.30 g of N)-2-hydroxy-1-(4-morpholino-3-(trifluoromethyl)phenyl)propan-1-one (10.8 mmol, intermediate 41) and 972 mg of methylhydrazinecarboxylate (10.8 mmol) in 10 ml of MeOH was added 6 drops of 0.1 N HCl (aq) and the reaction was heated at reflux temperature for 1 h. After cooling, the mixture was concentrated, MeOH was added and concentrated to remove water and HCl (twice). The crude reaction mixture was dissolved in about 20 ml EtOH and added to a solution of NaOEt (12.4 g sodium (54 mmol) in 30 ml EtOH). After 90 minutes, 3 ml of acetic acid was added resulting in abundant precipitation. The solids were filtered and washed with EtOH, dissolved in EtOAc and washed with water. The EtOAc was dried, concentrated to give 980 mg of the title compound as a white solid (26%) which was recrystallized from EtOH.

1H NMR (400 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 7.96 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 5.56 ( q, J=6.9 Hz, 1H), 3.87 (s, 4H), 3.01 (s, 4H), 1.65 (d, J=6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, CDCl3) δ -60.29. ¹³ C NMR (101 MHz, CDCl3) δ 153.72, 148.98, 146.92, 129.73, 127.71, 127.11 (q, J=29.4 Hz), 125.04 (q, J=5.0, 4.4 Hz), 123.83, 119.53, 71.87, 67.12 53.45, 17.36. MS: 344 (M+1)+.

Chiral SCF chromatography separated enantiomers: column: ChiralPak AD-H, 250 x 4.6 mm, 5 µm, Mobile phase modifier: 100% Methanol, gradient: 3 - 50% Methanol in 8 min, Flow rate: 4 ml/min, Back pressure : 100 bar, Column temperature: 40°C. UV detection range 200-400nm. The peak ratio corresponding to the enantiomers at 6.36 and 7.15 min was 99.61:0.39.

Example 121.

(6S)-5-(-[(3-Chloro-4-(morpholin-4-yl)-5-(trifluoromethyl)phenyl)-)]-6-methyl-3,6-dihydro-2H-1,3 ,4oxadiazin-2-one '/0^0

ΎΎ

_CF3

104 mg (0.304 mmol) solution of (S)-6-methyl-5-(4-morpholino-3-(trifluoromethyl)phenyl)-3,6-dihydro2H-1,3,4-oxadiazin-2-one (Example 120 ) was dissolved in 2 ml of HOAc, and the solution was cooled to 15-20°C using an ice bath. To this was added 0.295 ml NaOCl solution (10-15% available chlorine, Aldrich). About 30 min later, another 100 μl NaOCl solution was added. After another 30 min, the contents of the reaction were transferred to a separating funnel along with water and CH ₂ Cl ₂ . The CH ₂ Cl ₂ layer was separated and washed with Na ₂ SO ₃ solution, then brine, before drying and concentration. Chromatography with 20-40% EtOAc (twice) gave 19 mg of pure product (17%).

1H NMR (400 MHz, CDCl ₃ ) δ 8.25 (s, 1H), 7.86 (d, J=1.7 Hz, 1H), 7.83 (d, J=1.9 Hz, 1H), 5.53 (q, J=7.0 Hz, 1H), 3.88 (d, J=9.5 Hz, 2H), 3.84-3.63 (m, 4H), 2.74 (d, J=10.4 Hz, 2H), 1.65 (d, J=7.0 Hz, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -61.14. LC-MS (method 5): Mass 378 (M+1) ⁺ .

Example 126.

(rac)-6-Methyl-5-(4-morpholino-3-(trifluoromethyl)phenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

Solution of 100 mg of (rac)-2-hydroxy-1-(4-morpholino-3-(trifluoromethyl)phenyl)propan-1-one (0.33 mmol, intermediate 40), 33 mg of methylhydrazinecarboxylate (0.36 mmol) and 2 drops of 0.1 N HCl in 1 ml MeOH was heated at 60° C. for 1 hour. After cooling, the reaction mixture was concentrated, MeOH was added twice, followed by concentration to remove residual water and HCl. The crude product was dissolved in 1 ml MeOH and to this was added a solution of NaOMe (75 mg Na in 1 ml MeOH) and the solution was stirred for 2 hours before adding 200 μl of HOAc. The precipitates were dissolved with stirring and transferred to a separatory funnel with water and EtOAc. The EtOAc layer was separated, dried, concentrated and chromatographed with 20-50% EtOAc to give 39 mg of the product as a white solid (35%).

1H NMR (400 MHz, Chloroform-d) δ 8.22 (s, 1H), 7.96 (d, J=2.1 Hz, 1H), 7.80 (dd, J=8.5, 2.1 Hz, 1H), 7.39 (d, J= 8.5 Hz, 1H), 5.56 (q, J=7.0 Hz, 1H), 3.92 - 3.81 (m, 4H), 3.05 - 2.96 (m, 4H), 1.65 (d, J=7.0 Hz, 3H).

¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -60.29. LC-MS (method 5): 344 (M+1) ⁺ .

Chiral SCF chromatography separated the enantiomers of Example 126: column: ChiralPak AD-H, 250

- 202 041614 x 4.6 mm, 5 µm, Mobile phase modifier: 100% Methanol, gradient: 3 - 50% methanol in 8 min,

Flow rate: 4 ml/min, back pressure: 100 bar, Column temperature: 40°C. UV detection was in the range of 200-400 nm. Enantiomeric retention times: 6.30 and 7.10 min.

The following examples Example 127 to Example 130 were prepared analogously to Example 3 from Intermediate 64 by reaction with the appropriate boronic acid or the corresponding 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ester, which was prepared from commercial sources unless otherwise noted.

Example 127.

5-{4-[1 -Methyl-3 -(trifluoromethyl)-1 H-pyrazol-4-yl] -3 -(trifluoromethyl)phenyl} -3,6-dihydro-2H-1,3,4oxadiazin-2- He

LC-MS (method 2): R _t = 1.09 min; MS (ESIpos): m/z = 393 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.518 (2.02), 2.522 (1.30), 3.987 (14.22), 5.464 (16.00), 7.511 (2.16), 7.531 (2.32), 7.986 (1.57 ), 7.990 (1.64), 8.007 (1.39), 8.010 (1.52), 8.063 (3.50), 8.094 (3.14), 8.098 (2.96), 11.253 (4.82).

Example 128.

5-[4-(3,5 - Dimethyl-1 H-pyrazol-4-yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1, 3,4-oxadiazin-2one

LC-MS (method 2): Rt = 0.85 min; MS (ESIpos): m/z = 339 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.875 (1.00), 1.947 (0.99), 2.518 (1.20), 2.523 (0.87), 2.539 (16.00), 5.462 (6.32), 7.370 (0.92 ), 7.390 (0.95), 7.962 (0.61), 7.966 (0.62), 7.983 (0.54), 7.986 (0.58), 8.085 (1.23), 8.089 (1.15), 11.215 (1.68), 12.345 (0.47).

Example 129.

5-[4-(3,5-Dimethyl-1,2-oxazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 2): Rt = 1.04 min; MS (ESIpos): m/z = 340 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.966 (16.00), 2.074 (7.48), 2.169 (12.93), 2.518 (0.86), 2.523 (0.59), 5.476 (12.53), 7.542 (1.69 ), 7.562 (1.79), 8.045 (1.11), 8.048 (1.16), 8.065 (0.99), 8.068 (1.09), 8.143 (2.21), 8.148 (2.04).

Example 130.

5-{3-(Trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one

LC-MS (method 2): Rt = 0.95 min; MS (ESIneg): m/z = 377 [M-H] ^- .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (1.45), 2.518 (1.64), 2.523 (1.09), 5.466 (16.00), 7.513 (2.08), 7.533 (2.23), 7.984 (1.53 ), 7.988 (1.58), 8.004 (1.34), 8.008 (1.47), 8.081 (3.12), 8.094 (3.11), 8.098 (2.90), 11.248 (1.64).

Example 131.

- [4-(1-Ethyl-1 H-pyrazol-4-yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- 203 041614

In a reaction vessel, 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (120 mg, 431 µmol, intermediate 64), ( 1-ethyl-1H-pyrazol-4-yl)boronic acid (90.4 mg, 646 µmol), potassium carbonate (119 mg, 861 µmol) and dicyclohexyl[2',4',6'-tri(propan-2-yl )biphenyl2-yl]phosphane (12.3 mg, 25.8 µmol) was suspended in 1,4-dioxane (1.9 ml) and water (650 µl). The mixture was degassed with nitrogen for 5 minutes. Then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) (10.2 mg, 12.9 µmol ) were added. Nitrogen was again passed through the reaction mixture. It was stirred at 80° C. overnight in a heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 45.0 mg (95% pure, 29% yield) of the title compound.

LC-MS (method 1): Rt = 1.00 min; MS (ESIpos): m/z = 339 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.388 (6.84), 1.406 (14.43), 1.424 (6.92), 2.075 (1.76), 2.518 (3.48), 2.523 (2.49), 4.168 (1.84), 4.187 (5.81), 4.205 (5.52), 4.223 (1.78), 5.443 (16.00), 7.639 (2.44), 7.648 (4.66), 7.660 (2.64), 7.949 (1.60), 7.953 (1.67), 7.969 (1.37), 7.974 (1.48), 8.017 (4.66), 8.061 (3.08), 8.066 (2.91), 11.201 (3.48).

Example 132.

5-{4-[Cyclopentyl(methyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one a gL”

FromS

F

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (100 mg, 381 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), and N-methylcyclopentanamine (99 μl, 840 μmol) was added. The mixture was stirred at 100°C for 3 days. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 2.40 mg (95% pure, 2% yield) of the title compound.

LC-MS (method 2): R _t = 1.41 min; MS (ESIpos): m/z = 342 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.326 (0.78), 1.345 (1.03), 1.354 (1.09), 1.374 (1.03), 1.393 (0.48), 1.457 (0.54), 1.466 (0.74), 1.473 (1.26), 1.485 (1.36), 1.492 (1.20), 1.503 (1.05), 1.572 (0.50) 1.665 (0.99), 1.677 (1.14), 1.694 (1.05), 1.705 (0.76), 2.332 (0.80), 2.518 (4.29), 2.523 (3.01), 2.539 (0.78), 2.565 (16.00), 3.496 (0.68), 3.513 (0.97), 3.532 (0.62), 5.396 (14.95), 7.641 (1.63), 7.663 (1.88), 7.927 (4.79), 7.932 (2.46), 7.943 (1.61), 7.948 (0.85), 11.124 (3.94).

Example 133.

5-[4-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (109 mg, 391 µmol, intermediate 64), 1 -methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)-1,2,3,6-tetrahydropyridine (131 mg, 587 µmol), potassium carbonate (108 mg, 782 µmol) and dicyclohexyl[2',4',6'-tri(propan-2-yl)biphenyl-2-yl]phosphane (11.2 mg, 23.5 µmol) were suspended in 1,4dioxane (1.5 ml) and water (500 µl). The mixture was degassed with nitrogen for 5 minutes. Then chloro(2dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (9.23 mg, 11.7 µmol ) were added. Nitrogen was again passed through the reaction mixture. It was stirred at 80° C. overnight in a heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 61.0 mg (95% pure, 44% yield) of the title compound.

LC-MS (method 1): Rt = 0.56 min; MS (ESIpos): m/z = 340 [M+H] ⁺ .

- 204 041614

Ή NMR (400 MHz, DMSO-d6) δ [ppm]: 2.075 (0.64), 2.276 (15.55), 2.311 (2.18), 2.316 (2.25), 2.322 (1.96), 2.518 (1.45), 2.523 (1.12), 2.536 (2.66), 2.549 (4.64), 2.563 (1.94), 2.951 (3.63), 2.958 (3.57), 5.418 (16.00), 5.563 (1.89), 7.431 (2.37), 7.451 (2.55), 7.910 (1.67), 7.914 (1.76), 7.931 (1.43), 7.934 (1.64), 7.981 (3.40), 7.985 (3.07).

Example 134.

5-{4-[Butyl(methyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

X NH £jJ ^N

F

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (100 mg, 381 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), and N-methylbutan-1-amine (99 μl, 840 μmol) was added. The mixture was stirred at 100°C for 3 days. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 32.0 mg (95% pure, 24% yield) of the title compound.

LC-MS (method 1): R _t = 1.37 min; MS (ESIpos): m/z = 330 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.814 (4.69), 0.833 (11.78), 0.850 (5.68), 1.223 (1.11), 1.240 (1.92), 1.260 (2.01), 1.279 (1.38), 1.297 (0.42), 1.361 (0.68), 1.375 (0.99), 1.380 (1.33), 1.399 (1.84) 2.332 (0.52), 2.518 (2.56), 2.523 (1.91), 2.673 (16.00), 2.943 (2.08), 2.962 (2.58), 2.980 (1.98), 5.382 (15.03), 7.517 (1.94), 7.538 (2.11), 7.890 (1.22), 7.895 (1.63), 7.920 (3.73), 7.925 (1.96), 11.095 (4.03).

Example 135.

(6S)-5-[4'-Fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel, (6S)-5-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one (96.0 mg, 328 µmol , intermediate 74), (4-fluorophenyl)boronic acid (68.9 mg, 492 µmol), potassium carbonate (90.7 mg, 656 µmol) and dicyclohexyl[2',4',6'-tri(propan-2yl)biphenyl- 2-yl]phosphane (9.38 mg, 19.7 µmol) was suspended in 1,4-dioxane (1.5 ml) and water (500 µl). The mixture was degassed with nitrogen for 5 minutes. Then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl1,G-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (7.74 mg, 9.84 µmol) added. Nitrogen was again passed through the reaction mixture. It was stirred at 80° C. overnight in a heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 65.0 mg (95% pure, 53% yield) of the title compound.

Rotation angle: -303.9° (DMSO, 1.0000 g/100 ml, 20°C, 589 nm).

LC-MS (method 2): R _t = 1.28 min; MS (ESIneg): m/z = 351 [M-H] ^- .

1H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 11.32 (s, 1H), 8.15 (d, 1H), 8.05 (dd, 1H), 7.52 (d, 1H), 7.427.35 (m , 2H), 7.35-7.28 (m, 2H), 5.98-5.92 (m, 1H), 1.47 (d, 3H).

Example 136.

5-[4-(Cyclopentylamino)-3-(trifluoromethyl)phenyl]-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 (100 mg, 381 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), and cyclopentanamine (83 μl, 840 μmol) was added. The mixture was stirred at 100°C for 3 days. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 59.0 mg (95% pure, 45% yield) of the title compound.

LC-MS Method 1): R _t = 1.30 min; MS (ESIpos): m/z = 328 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.498 (0.84), 1.515 (1.31), 1.531 (1.56), 1.546 (2.28), 1.556 (2.19), 1.574 (1.62), 1.581 (1.20) 1.589 (1.27), 1.593 (1.23), 1.605 (0.51), 1.609 (0.52), 1.614 (0.67), 1.629 (0.56), 1.633 (0.49), 1.637 (0.49), 1.659 (1.46), 1.674 (1.72) , 1.688 (1.12), 1.959 (0.59), 1.976 (1.28), 1.988

- 205 041614 (1.45), 2.005 (1.58), 2.018 (0.99), 2.074 (0.98), 2.518 (4.95), 2.523 (3.46), 3.916 (0.51), 3.932 (0.97), 3.948 (1.00), 3.963 (0.57) ), 5.108 (1.49), 5.125 (1.44), 5.301 (16.00), 6.942 (2.14), 6.964 (2.28), 7.738 (3.92), 7.744 (2.52), 7.766 (1.60), 7.771 (1.31), 10.898 (4.59 ).

Example 137.

5-[4-(Propan-2-ylamino)-3-(trifluoromethyl)phenyl]-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 (100 mg, 381 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), and propane-2-amine (46 μl, 550 μmol) was added. The mixture was stirred at 100°C for 3 days. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 35.0 mg (95% pure, 22% yield) of the title compound.

LC-MS (method 1): Rt = 1.18 min; MS (ESIpos): m/z = 302 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.195 (15.78), 1.211 (16.00), 1.232 (0.44), 2.518 (2.46), 2.522 (1.54), 3.806 (0.43), 3.822 (0.66) 3.841 (0.67), 3.857 (0.44), 5.018 (1.03), 5.038 (1.00), 5.297 (12.01), 6.936 (1.55), 6.957 (1.64), 7.737 (3.71), 7.761 (1.17), 10.890 (3.44) .

Example 138.

5-[3'-Fluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In a reaction vessel 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (136 mg, 487 µmol, intermediate 64), 2 -(3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane (162 mg, 731 µmol), potassium carbonate (135 mg, 974 µmol) and dicyclohexyl[2',4',6' tri(propan-2-yl)biphenyl-2-yl]phosphane (13.9 mg, 29.2 µmol) was suspended in 1,4-dioxane (2.2 ml) and water (370 µl). The mixture was degassed with nitrogen for 5 minutes. Then chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (11.5 mg, 14.6 µmol) was added. Nitrogen was again passed through the reaction mixture. It was stirred at 80°C for 3 h in the heating unit. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 93.0 mg (95% pure, 54% yield) of the title compound.

LC-MS (method 2): Rt = 1.23 min; MS (ESIneg): m/z = 337 [MH] ^- .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.153 (0.76), 1.171 (1.52), 1.189 (0.73), 1.986 (2.93), 2.518 (1.50), 2.522 (0.92), 4.016 (0.63), 4.034 (0.63), 5.475 (16.00), 7.171 (1.74), 7.192 (2.71), 7.199 (1.44), 7.223 (1.29), 7.284 (0.68), 7.288 (0.65), 7.290 (0.67), 7.305 (1.39), 7.311 (1.34) 7.325 (0.83) 7.327 (0.83) 7.538 (2.61), 7.545 (1.03), 7.558 (2.72), 8.014 (1.67), 8.019 (1.78), 8.035 (1.49), 8.038 (1.66), 8.113 (3.37), 8.118 (3.19), 11.259 (4.93).

The following compounds Example 139 - Example 156 were prepared analogously to the procedure described in Example 3 from Intermediate 64 by reaction with the appropriate boronic acid or the corresponding 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl complex ether purchased from commercial sources unless otherwise noted.

Example 139.

5-[4-Methyl-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 2): Rt = 1.08 min; MS (ESIneg): m/z = 257 [MH] ^- .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (0.96), 2.474 (6.67), 2.478 (6.66), 2.518 (0.94), 2.522 (0.57), 5.403 (16.00), 7.538 (1.74) , 7.558 (1.96), 7.859 (1.42), 7.863 (1.50), 7.883 (1.33), 7.953 (2.78), 11.155 (3.34).

Example 140.

5-{4-[3-Methoxyprop-1-en-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- 206 041614

LC-MS (method 2): R _t = 1.08 min; MS (ESIneg): m/z = 313 [M-H] ^- .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.518 (1.27), 2.522 (0.83), 3.319 (16.00), 3.331 (13.80), 4.105 (1.72), 4.109 (1.86), 4.117 (1.86 ), 4.122 (1.83), 5.424 (7.79), 6.556 (0.61), 6.595 (0.81), 6.835 (0.54), 6.841 (0.55), 6.874 (0.42), 6.880 (0.42), 7.938 (4.05), 7.976 (1.82 ), 11.203(2.37).

Example 141.

(rac)-5-[4'-Hydroxy-2-(trifluoromethyl)-2',3',4',5'-tetrahydro[1,Γ-biphenyl]-4-yl]-3,6-dihydro- 2Н1,3,4-oxadiazin-2-one

LC-MS (method 2): R _t = 0.93 min; MS (ESIneg): m/z = 339 [M-H] ^- .

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.064 (1.48), 1.177 (0.71), 1.563 (0.63), 1.575 (0.49), 1.582 (0.52), 1.588 (0.73), 1.594 (0.86) , 1.606 (0.49), 1.618 (0.79), 1.836 (0.79), 1.845 (0.83), 1.855 (0.66), 1.865 (0.64), 1.876 (0.64), 1.949 (0.50), 1.956 (0.57), 1.968 (0.55) . . , 5.411 (16.00), 5.440 (1.74), 7.407 (2.63), 7.427 (2.78), 7.892 (1.82), 7.896 (1.93), 7.912 (1.60), 7.916 (1.79), 7.964 (3.75) , 11.178 (5.86).

Example 142.

5-[4-(5,6-Dihydro-2H-pyran-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 2): R _t = 1.06 min; MS (ESIneg): m/z = 325 [M-H] ^- .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (3.94), 2.204 (2.14), 2.214 (2.16), 2.518 (1.14), 2.523 (0.73), 3.753 (2.48), 3.767 (5.24 ), 3.780 (2.38), 4.151 (4.13), 4.156 (4.10), 5.421 (16.00), 5.763 (1.71), 7.497 (2.48), 7.518 (2.69), 7.922 (1.72), 7.925 (1.81), 7.942 (1.52 ), 7.946 (1.67), 8.009 (3.48), 8.013 (3.21), 11.206 (4.88).

Example 143.

5-[4-(Imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 2): R _t = 0.89 min; MS (ESIpos): m/z = 361 [M+H]+.

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (2.21), 2.522 (1.42), 5.491 (16.00), 7.180 (1.78), 7.204 (1.95), 7.630 (3.35), 7.649 (6.76) , 7.652 (9.28), 7.675 (2.96), 8.005 (5.24), 8.048 (1.88), 8.052 (1.96), 8.068 (1.65), 8.071 (1.79), 8.147 (3.72), 8.150 (3.50), 8.630 (3.88) , 11.276 (5.50).

Example 144.

5-{4-[3,3-Dimethylbut-1-en-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 1.43 min; MS (ESIpos): m/z = 327 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.112 (16.00), 2.074 (0.56), 5.420 (3.54), 6.553 (1.48), 7.877 (0.71), 7.922 (0.56), 7.943 (0.48) , 7.950 (0.91), 11.187 (1.16).

Example 145.

5-{3-(Trifluoromethyl)-4-[5-(trifluoromethyl)thiophen-3-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2one

- 207 041614

LC-MS (method 2): Rt = 1.34 min; MS (ESIneg): m/z = 393 [M-H] ^- .

Ή NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (3.07), 2.518 (1.51), 2.523 (0.90), 5.472 (16.00), 7.640 (2.38), 7.660 (2.58), 7.801 (2.85), 8.016 (1.70), 8.020 (1.81), 8.029 (4.25), 8.033 (4.41), 8.040 (1.69), 8.118 (3.18), 8.122 (2.97), 11.268 (5.08).

Example 146.

5-{4-[1 -(Difluoromethyl)-1 H-pyrazol-4-yl] -3 -(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one

To 5-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (900.0 mg, 3.2 mmol, intermediate 64), 1 -( difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H pyrazole (946 mg, 3.88 mmol, CAS 1206640-82-5), potassium carbonate (892 mg Chloro( 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2(2'-amino-1,1'-biphenyl)]palladium(II) (76 mg, 97 µmol), and the mixture was stirred for 15 hours at 80°C. The reaction mixture was poured into water and extracted four times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was diluted with DMSO, filtered and purified by preparative HPLC (acidic conditions) to give 766 mg (99% pure, 65% yield) of the desired title compound.

LC-MS (method 1): Rt = 1.04 min; MS (ESIpos): m/z = 361 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 11.25 (s, 1H), 8.49 (s, 1H), 8.11 (d, 1H), 8.02 (dd, 1H), 7.99 (s, 1H ), 7.90 (t, 1H), 7.69 (d, 1H), 5.46 (s, 2H).

Example 147.

5-[4-(Prop-1-en-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 2): Rt = 1.20 min; MS (ESIneg): m/z = 283 [M-H] ^- .

Ή NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.050 (11.86), 2.074 (0.50), 2.518 (1.27), 2.522 (0.78), 4.863 (3.04), 5.295 (2.22), 5.299 (3.26) , 5.303 (2.18), 5.424 (16.00), 7.474 (2.45), 7.494 (2.62), 7.928 (1.66), 7.932 (1.81), 7.948 (1.47), 7.952 (1.69), 7.992 (3.47) , 11.198 (4.16).

Example 148.

5-[4-(1-Benzothiophenyl-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): Rt = 1.36 min; MS (ESIpos): m/z = 377 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (0.57), 2.327 (0.51), 2.522 (1.96), 2.669 (0.51), 5.486 (16.00), 7.410 (0.44), 7.414 (0.74) , 7.428 (2.23), 7.434 (2.91), 7.443 (4.69), 7.451 (3.14), 7.457 (2.43), 7.471 (0.80), 7.475 (0.47), 7.525 (5.46), 7.774 (2.77), 7.794 (3.15) , 7.925 (2.05), 7.934 (1.26), 7.942 (1.75), 7.948 (1.82), 8.025 (1.93), 8.031 (1.79), 8.040 (1.11), 8.048 (3.61), 8.070 (1.77), 8.074 (1.90) , 8.162 (3.87), 8.166 (3.76), 11.297 (5.22).

Example 149.

5-[4-(2,5-Dihydrofuran-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- 208 041614

LC-MS (method 1): R _t = 1.00 min; MS (ESIpos): m/z = 313 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.327 (0.45), 2.518 (1.74), 2.523 (1.11), 2.669 (0.46), 4.746 (1.09), 4.757 (2.48), 4.760 (2.45) 4.764 (2.22), 4.770 (3.35), 4.792 (2.88), 4.805 (2.24), 4.815 (0.92), 5.433 (16.00), 5.437 (2.82), 6.102 (2.35), 7.597 (2.34), 7.617 (2.56) , 7.949 (1.69), 7.953 (1.74), 7.969 (1.46), 7.973 (1.56), 8.054 (3.27), 8.057 (3.02), 11.230 (4.55).

Example 150.

5-[4-(Cyclopent-1-en-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 1): R _t = 1.33 min; MS (ESIpos): m/z = 311 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.940 (0.63), 1.959 (2.02), 1.978 (2.99), 1.996 (2.24), 2.015 (0.77), 2.074 (4.02), 2.470 (1.87) . , 2.668 (0.50), 5.420 (16.00), 5.781 (2.28), 7.497 (2.46), 7.517 (2.66), 7.906 (1.75), 7.909 (1.81), 7.926 (1.54), 7.930 (1.66), 7.997 (3.48) , 8.000 (3.21), 11.191 (4.59).

Example 151.

5-[4-(1-Ethyl-1H-imidazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 2): Rt = 0.93 min; MS (ESIpos): m/z = 339 [M+H] ⁺ .

1H NMR (400 MHz, Chloroform-d) δ [ppm]: 0.000 (6.19), 1.438 (6.42), 1.456 (13.18), 1.475 (6.58), 1.555 (2.58), 1.942 (0.65), 3.969 (1.94), 3.987 (5.59), 4.005 (5.47), 4.024 (1.78), 5.213 (16.00), 7.520 (4.84), 7.711 (1.85), 7.715 (1.93), 7.732 (2.06), 7.736 (2.12), 7.922 (3.82), 8.055 (3.05), 8.076 (2.69), 8.284 (1.68).

Example 152.

3-Methyl-5-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]thiophene-2carbonitrile

LC-MS (method 1): R _t = 1.21 min; MS (ESIpos): m/z = 366 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (1.81), 2.442 (16.00), 2.518 (1.66), 2.523 (1.09), 5.470 (11.67), 7.264 (3.83), 7.713 (1.86), 7.734 (2.07), 8.040 (1.30), 8.044 (1.35), 8.060 (1.11), 8.064 (1.21), 8.149 (2.53), 8.152 (2.40), 11.311 (3.61).

Example 153.

5-{4-[1 -(Propan-2-yl)-1 H-pyrazol-4-yl] -3 -(trifluoromethyl)phenyl} -3,6-dihydro-2H-1,3,4oxadiazin-2- He

LC-MS (method 1): R _t = 1.08 min; MS (ESIpos): m/z = 353 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.442 (15.58), 1.459 (16.00), 2.074 (0.44), 2.326 (0.54), 2.331 (0.41), 2.522 (1.75), 2.668 (0.54), 2.673 (0.41), 4.551 (1.01), 4.568 (1.37), 4.584 (0.99), 5.444 (9.60), 7.644 (2.97), 7.653 (1.70), 7.674 (1.71), 7.947 (1.06), 7.951 (1.19), 7.968 (0.90), 7.972 (1.06), 8.033 (3.24), 8.059 (2.07), 8.063 (2.11), 11.200 (3.20).

- 209 041614

Example 154.

(rac)-5-[4-(Bicyclo[2.2.1]hept-2-en-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2 -He

LC-MS (method 2): Rt = 1.39 min; MS (ESIneg): m/z = 335 [MH] ^- .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.103 (1.01), 1.122 (0.42), 1.127 (0.42), 1.143 (1.33), 1.165 (1.23), 1.181 (1.16), 1.204 (1.33), 1.226 (0.57), 1.239 (1.91), 1.259 (2.01), 1.552 (1.41), 1.568 (1.00) 1.762 (1.94), 1.772 (0.88), 1.779 (1.17),1.787 (0.72), 2.327 (0.40), 2.518 (1.66), 2.523 (0.99), 2.669 (0.42), 3.014 (1.99), 3.017 (1.99), 3.115 (2.26), 5.416 (16.00), 6.148 (2.52), 6.155 (2.43), 7.420 (2.58), 7.440 (2.74), 7.899 (1.83), 7.902 (1.88), 7.919 (1.62), 7.923 (1.72), 7.999 (3.61), 8.003 (3.32), 11.193 (4.98).

Example 155.

- [2'-Fluoro-2-(trifluoromethyl) [1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

LC-MS (method 2): Rt = 1.20 min; MS (ESIneg): m/z = 337 [MH] ^- .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (2.38), 2.518 (1.38), 2.523 (0.93), 5.482 (16.00), 7.279 (0.79), 7.282 (0.85), 7.298 (1.94), 7.301 (2.29) 7.306 (1.21) 7.318 (2.17) 7.326 (2.53) 7.329 (2.48) 7.495 (0.54), 7.504 (0.72), 7.508 (1.04), 7.511 (0.90), 7.516 (0.66), 7.521 (0.73), 7.527 (0.82), 7.528 (1.00), 7.534 (0.55), 7.546 (2.33), 7.566 (2.26), 8.026 (1.43), 8.030 (1.52), 8.047 (1.29), 8.050 (1.41), 8.128 (2.88), 8.132 (2.71), 11.261 (0.84).

Example 156.

5-{3-(Trifluoromethyl)-4-[5-(trifluoromethyl)thiophen-2-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2 one

LC-MS (method 1): R _t = 1.36 min; MS (ESIneg): m/z = 393 [M-H]'.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.518 (2.71), 2.523 (1.80), 5.476 (16.00), 5.758 (0.90), 7.308 (1.89), 7.316 (1.94), 7.757 (2.58 ), 7.777 (3.04), 7.785 (2.32), 7.788 (2.37), 7.792 (1.65), 7.795 (2.22), 7.797 (2.14), 8.041 (1.87), 8.045 (1.91), 8.062 (1.57), 8.066 (1.68 ), 8.159 (3.53), 8.162 (3.35), 11.307 (4.85).

Example 157.

5-[4-(5-Methylpyridin-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

To a solution of 5-(4-bromo-3-(trifluoromethyl)phenyl)-3H-1,3,4-oxadiazin-2(6H)-one (100 mg, 0.3 mmol, intermediate 78) in 3 ml of N, N-dimethylformamide was added 5-methylpyridin-2ylboronic acid (85 mg, 0.6 mmol), cesium carbonate (303 mg, 0.9 mmol), palladium(II) acetate (7 mg, 0.03 mmol), 1,1'-bis(diphenylphosphino) ferrocene (34 mg, 0.03 mmol), and copper (I) chloride (31 mg, 0.3 mmol). The resulting mixture was stirred at 100° C. overnight under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous ammonium chloride, then with water, and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by preparative HPLC (Column: Xbridge prep C18 5 µm 19x150 mm; Mobile phase A: water (0.1% TFA), Mobile phase B: ACN; flow rate: 20 ml/min; gradient: 25% B - 52% B in 8 min; 254 & 220 nm; R _t : 7.23 min). The solvent was removed by lyophilization to give 11 mg (11%) of the title compound as a white solid. MS (ESIpos): m/z = 336 (M+H)+.

1H NMR (400 MHz, DMSO-d6): δ [ppm] = 11.26 (s, 1H), 8.51 (s, 1H), 8.12 (s, 1H), 8.05 (d, 1H), 7.74 (dd,

- 210 041614

1H), 7.63 (d, 1H), 7.43 (d, 1H), 5.49 (s, 2H), 2.38 (s, 3Н).

Example 158.

5-[4-(5-Fluoropyridin-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

nia nia nia

The title compound was prepared analogously to Example 157 from Intermediate 78.

MS (ESIpos): m/z = 340 (M+H) ⁺ .

Example 159.

5-[4-(5-Chloropyridin-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was prepared analogously to Example 157 from Intermediate 78.

MS (ESIpos): m/z = 356 (M+H) ⁺ .

Example 160.

5-[4-(Pyridin-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was prepared analogously to Example 157 from Intermediate 78.

MS (ESIpos): m/z = 322 (M+H) ⁺ .

Example 161.

5-[2'-(Difluoromethyl)-2-fluoro[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 65.

LC-MS (method 1): Rt = 1.15 min; MS (ESIpos): m/z = 321 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.327 (0.56), 2.332 (0.41), 2.518 (3.66), 2.522 (2.23), 2.539 (0.72), 2.673 (0.42), 5.420 (16.00) , 6.640 (1.33), 6.776 (2.59), 6.913 (1.22), 7.395 (1.43), 7.411 (1.68), 7.435 (1.39), 7.456 (2.95), 7.475 (1.80), 7.613 (0.51), 7.628 (1.57) , 7.631(1.66), 7.644(3.75), 7.647(4.44),7.651(7.09), 7.656(3.06), 7.668(2.39), 7.672(2.33), 7.680(2.78), 7.684(1.97), 7.749(1.67) , 7.754 (1.82), 7.770 (1.35), 11.225 (4.66).

Example 162.

5-(2,4'-Difluoro-2'-methyl[1,1'-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 65.

LC-MS (method 1): Rt = 1.21 min; MS (ESIpos): m/z = 303 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.145 (11.95), 2.327 (0.69), 2.331 (0.49), 2.518 (2.83), 2.523 (1.78), 2.669 (0.70), 2.673 (0.51) , 5.409 (16.00), 7.103 (0.60), 7.110 (0.70), 7.125 (1.41), 7.131 (1.66), 7.146 (1.37), 7.153 (0.94), 7.164 (0.43), 7.167 (0.41), (1.80), 7.262 (1.88), 7.269 (1.46), 7.284 (1.30), (1.36), 7.417 (2.96), 7.436 (1.60), 7.464 (0.83),

7.207 (1.43), 7.214 (1.29), 7.232 (1.48), 7.239 (1.33), 7.247

7.372 (0.66), 7.376 (0.51), 7.390 (0.52), 7.393 (0.64), 7.397

7.484 (0.55), 7.627 (4.67), 7.630 (2.19), 7.650 (4.12), 8.095

- 211 041614 (0.52), 8.115 (0.49), 11.198 (4.49).

Example 163.

2'-Fluoro-2-methyl-4'-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5 -yl) [1,1'-biphenyl]-4-carbonitrile

The title compound was synthesized analogously to Example 3 from Intermediate 65.

LC-MS (method 1): R _t = 1.09 min; MS (ESIpos): m/z = 310 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.186 (14.22), 2.326 (0.41), 2.522 (1.38), 2.669 (0.42), 5.416 (16.00), 7.440 (3.40), 7.447 (1.50), 7.460 (3.99), 7.467 (3.36), 7.487 (1.93), 7.665 (6.13), 7.684 (2.12), 7.687 (2.88), 7.691 (2.86) 7.782 (1.94), 7.866 (3.86), 11.224 (5.70).

Example 164.

5-[4-(2-Methylprop-1-en-1-yl)-3-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 73.

LC-MS (method 1): R _t = 1.31 min; MS (ESIpos): m/z = 315 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.765 (12.45), 1.767 (12.30), 1.922 (10.62), 1.925 (10.53), 2.075 (0.51), 2.518 (1.75), 2.523 (1.16) , 5.385 (16.00), 6.238 (2.53), 7.463 (2.46), 7.484 (3.00), 7.669 (5.19), 7.674 (3.38), 7.677 (2.32) .

Example 165.

(6S)-5-[4-(2-Aminopyridin-4-yl)-3 -(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one _ ^{H 2N} . __N-N

Τλ/ΓΑ// >0 \—/ \=/ y-o _F _/ H ₃ C FF (6S)-5-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3,6- dihydro-2H-1,3,4-oxadiazin-2-one (97%, 200 mg, 0.66 mmol, intermediate 74), 2-aminopyridine-4-boronic acid pinacol ester (219 mg, 0.66 mmol), 2 -(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl [XPhos] (19 mg, 39.78 µmol) and K ₂ CO ₃ (0.88 ml, 1.33 mmol) were stirred in 1,4-dioxane (2.65 ml). The mixture was degassed with nitrogen for 5 minutes. Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'amino-1,1'-biphenyl)]palladium(II), X-Phos aminobiphenylpalladium chloride [XPhos-Pd-G2] precatalyst (31 mg, 19.89 µmol) was then added and the resulting mixture was heated in a sealed tube at 80°C for 1 h. The mixture was allowed to cool to room temperature, then diluted with EtOAc (10 ml) and washed with saline (10 ml). The aqueous layer was washed with EtOAc (10 ml), the organic layers were combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by Biotage Isolera™ chromatography (10 g KP-Sil eluting with 1:0-0:1 heptanes-EtOAc) to give the title compound (146.3 mg, 61%, 97% pure) as a beige solid .

LCMS (method 4, 7 min) R _t = 1.33 min, MS (ESIPos): m/z = 351.1 (M+H) ⁺ 'll NMR (400 MHz, DMSO-d6): δ [ppm] = 11.32 (s , 1H), 8.14 (d, 1H), 8.04 (dd, 1H), 7.95 (d, 1H), 7.49 (d, 1H), 6.43 (d, 1H), 6.36 (s, 1H), 6.10 (s, 2H), 6.00-5.86 (m, 1H), 1.46 (d, 3H).

Example 166.

(6S)-6-Methyl-5-[4-(pyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one FF ^F X ^H '%O ^N / /—C

W7N- _NH

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): Rt = 0.74 min; MS (ESIpos): m/z = 336 [M+H] ⁺ .

Example 167.

(6S)-6-Methyl-5-[4-(6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

- 212 041614

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 0.78 min; MS (ESIpos): m/z = 350 [M+H]+.

Example 168.

(6S)-5-[2'-Fluoro-4'-methyl-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1, 3,4oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 1.27 min; MS (ESIpos): m/z = 367 [M+H] ⁺ .

Example 169.

(6S)-6-Methyl-5-[2',4',5'-trifluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1 ,3,4oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 1.25 min; MS (ESIpos): m/z = 389 [M+H] ⁺ .

Example 170.

(6S)-6-Methyl-5-[2',3',4'-trifluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1 ,3,4oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 1.26 min; MS (ESIpos): m/z = 389 [M+H] ⁺ .

Example 171.

(6S)-5-[2',5'-Difluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3, 4oxadiazin-2-one f _F y H ₃ c > ^o

N-N

F

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 1.21 min; MS (ESIpos): m/z = 371 [M+H] ⁺ .

Example 172.

4'-[(68)-6-Methyl-2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl]-2'-(trifluoromethyl)[1,G-biphenyl] -2 carbonitrile

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 1.09 min; MS (ESIpos): m/z = 360 [M+H] ⁺ .

Example 173.

(6S)-5-[4-(1H-Indol-5-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- 213 041614

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 1.09 min; MS (ESIpos): m/z = 374 [M+H] ⁺ .

Example 174.

(6S)-5-[4'-Hydroxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2 -He

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 0.96 min; MS (ESIpos): m/z = 351 [M+H] ⁺ .

Example 175.

(6S)-5-[3'-Hydroxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2 -He

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 1.00 min; MS (ESIpos): m/z = 351 [M+H] ⁺ .

Example 176.

(6S)-5-[3'-Amino-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazine2 -He

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): Rt = 0.94 min; MS (ESIpos): m/z = 350 [M+H] ⁺ .

Example 177.

(6S)-5-[2',4'-Difluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3, 4oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 1.23 min; MS (ESIpos): m/z = 371 [M+H] ⁺ .

Example 178.

(6S)-5-[3'-Fluoro-4'-methyl-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1, 3,4oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 1.31 min; MS (ESIpos): m/z = 367 [M+H] ⁺ .

Example 179.

(6S)-5-[2'-Fluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazine -2on

- 214 041614

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): Rt = 1.19 min; MS (ESIpos): m/z = 353 [M+H]+.

Example 180.

(6S)-5-[2'-Methoxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2 -He

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 1.19 min; MS (ESIpos): m/z = 365 [M+H] ⁺ .

Example 181.

(6S)-5-[3'-Fluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazine -2 he

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 1.23 min; MS (ESIpos): m/z = 353 [M+H] ⁺ .

Example 182.

(6S)-6-Methyl-5-[4-(4-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): Rt = 0.73 min; MS (ESIpos): m/z = 350 [M+H] ⁺ .

Example 183.

(6S)-6-Methyl-5-[4-(3-methylpyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R = 0.72 min; MS (ESIpos): m/z = 350 [M+H] ⁺ .

Example 184.

(6S)-6-Methyl-5-[4-(2-methylpyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): Rt = 0.68 min; MS (ESIpos): m/z = 350 [M+H]+.

Example 185.

(6S)-5-[4-(1H-Indol-6-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- 215 041614

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 1.15 min; MS (ESIpos): m/z = 374 [M+H]+.

Example 186.

(6S)-5-[2'-Ethyl-2-(trifluoromethyl)[1,Γ-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2Н-1,3,4-oxadiazin- 2on

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 1.32 min; MS (ESIpos): m/z = 363 [M+H] ⁺ .

Example 187.

(6S)-5-[4-(6-Methoxypyridin-3-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one

FF ^F Λ n ₃ s Ο-/~Λ-_/=\__/~°\ H ₃ s

H

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 1.12 min; MS (ESIpos): m/z = 366 [M+H] ⁺ .

Example 188.

(6S)-5-[4'-Methoxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2 -He

FF ^F A ⁿ z ^s , λ λ /—\ 7 ^- O

Η n ₃ s \=/ _N _ _N

Η

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 1.20 min; MS (ESIpos): m/z = 365 [M+H] ⁺ .

Example 189.

(6S)-6-Methyl-5-[4'-methyl-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazine -2 he

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LC-MS (method 1): R _t = 1.30 min; MS (ESIpos): m/z = 349 [M+H] ⁺ .

Example 190.

(6S)-5-{4-[1-(Difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-6-methyl-3,6-dihydro-2H1,3,4-oxadiazine -2-he

The title compound was synthesized analogously to Example 3 from Intermediate 74.

LCMS (method 3, 2 min) 100% at R _t = 1.10 min, MS (ESIPos): m/z = 374.90 (M+H) ⁺

LCMS (method 3, 7 min) 100% at R _t = 3.83 min, MS (ESIPos): m/z = 374.85 (M+n) ^{+ 1} H NMR (250 MHz, Chloroform-d) δ = 1.68 (d, J=7.0 Hz, 3H), 5.62 (q, J=7.0 Hz, 1H), 7.02-7.52 (m, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.76-7.90 (m, 1H), 7.99 (s, 1H), 8.10 (s, 1H), 8.35 (s, 1H).

- 216 041614

Example 191.

(rac)-5- {4-[1 -(Difluoromethyl)-1 H-pyrazol-4-yl] -3 -(trifluoromethyl)phenyl } -6-methyl-3,6-dihydro-2H1,3,4- oxadiazine-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 68.

LCMS (method 3, 7 min) 100% at Rt = 2.97 min, MS (ESIPos): m/z = 375.1 (M+H) + ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.45 (d, J =6.9 Hz, 3H), 5.93 (q, J=6.9 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.76-8.01 (m, 2H), 8.04 (dd, J=1.7, 8.2 Hz , 1H), 8.16 (d, J=1.5 Hz, 1H), 8.48 (s, 1H), 11.30 (br. s, 1H).

Example 192.

(rac)-5-[4'-Fluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazine -2 he

The title compound was synthesized analogously to Example 3 from Intermediate 68.

LCMS (method 4, 7 min) Rt= 3.62 min, MS (ESIPos): m/z = 353.1 (M+H)+

1H NMR (500 MHz, DMSO-d6) δ 1.44-1.50 (m, 3H), 5.94 (q, J=6.9 Hz, 1H), 7.28-7.33 (m, 2H), 7.37-7.41 (m, 2H), 7.52 (d, J=8.1 Hz, 1H), 8.04 (dd, J=1.4, 8.1 Hz, 1H), 8.15 (d, J=1.4 Hz, 1H), 11.30 (s, 1H).

Chiral analysis conditions: column: Cellulose-325 cm, Mobile phase: 25% Ethanol: 75% CO ₂ , Flow rate: 4 ml/min, UV at 280 nm, Run time: 5 min, Negative ionic MS.

Example 193.

5-{4-[1 -(Difluoromethyl)-1 H-pyrazol-4-yl]-3 -fluoro-5-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2- He

The title compound was synthesized analogously to Example 3 from Intermediate 69.

LC-MS (method 1): Rt = 1.06 min; MS (ESIpos): m/z = 379 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (2.77), 2.523 (2.01), 5.458 (16.00), 7.764 (1.60), 7.911 (3.39), 7.950 (4.30), 7.965 (1.44), 7.969 (1.74), 7.991 (7.30), 8.059 (1.39), 8.506 (5.10), 11.345 (4.91).

Example 195.

5-{3 -(Difluoromethyl)-4- [ 1 -(difluoromethyl)-1 H-pyrazol-4-yl]phenyl } -3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 77.

LC-MS (method 1): Rt = 0.98 min; MS (ESIpos): m/z = 343 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.323 (0.47), 2.327 (0.66), 2.522 (5.80), 2.665 (0.49), 2.669 (0.67), 5.442 (16.00), 7.007 (1.44) , 7.143 (3.09), 7.279 (1.29), 7.677 (2.23), 7.697 (2.73), 7.755 (1.76), 7.897 (2.13), 7.901 (4.21), 7.916 (1.69), 8.049 (4.88), 8.085 (6.78) , 8.505 (6.67), 11.194 (4.98).

Example 196.

(6S)-6-Methyl-5-{4-[(morpholin-4-yl)methyl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one

- 217 041614

Biphasic mixture of (6S)-5-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one (200 mg, 0.68 mmol, intermediate compound 74), potassium (morpholin-4yl)methyltrifluoroborate (212 mg, 1.03 mmol), potassium acetate (201 mg, 2.05 mmol), palladium (II) acetate (20.2 mg, 0.03 mmol), and 2-dicyclohexylphosphino-2',6 '-di-isopropoxy-1,1'-biphenyl//RuPhos (31.9 mg, 0.07 mmol) in toluene/water (12:1 v:v; 3.4 mL) was degassed via a nitrogen filled balloon for 5 min. The resulting mixture was heated at 100° C. for 16 hours. After this time, the reaction mixture was diluted with EtOAc and water and filtered through a pad of celite. The organic layer was isolated, washed with saturated aqueous sodium chloride, dried (MgSO ₄ ), filtered and concentrated in vacuo. The resulting material was purified by Biotage Isolera™ chromatography (silica gel, eluting with 1:0-0:1 heptanes-EtOAc), desired fractions were pooled and concentrated in vacuo. The resulting resin was dissolved in diethyl ether and concentrated in vacuo to give the desired compound (135 mg, 53%) as a yellow solid.

LCMS (method 3, 2 min) 100% at Rt = 0.79 min, MS (ESIpos): m/z = 358.05 (M+H)+.

LCMS (method 3, 7 min) 96% at R _t = 2.41 min, MS (ESIpos): m/z = 358.05 (M+H) ⁺ .

1H NMR (500 MHz, Chloroform-d) δ = 1.66 (d, J=7.0 Hz, 3Н), 2.49-2.54 (m, 4H), 3.71 (s, 2H), 3.73-3.79 (m, 4H), 5.58 (q, J=7.0 Hz, 1H), 7.78 (dd, J=8.2, 1.7 Hz, 1H), 7.87-7.99 (m, 2H), 8.18 (s, 1H); the material thus obtained contained 2.5% Et ₂ O (according to the summation of the NMR signals).

Example 197.

5-{4-[(Morpholin-4-yl)methyl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was prepared analogously to Example 196 from Intermediate 64.

LC-MS (method 1): R _t = 0.62 min; MS (ESIpos): m/z = 344 [M+H] ⁺ .

'll NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.388 (4.77), 2.399 (3.58), 2.518 (1.63), 2.523 (1.06), 3.581 (4.43), 3.592 (6.01), 3.604 (4.27 ), 3.640 (5.70), 5.416 (16.00), 7.858 (1.56), 7.879 (2.28), 7.959 (2.28), 7.977 (6.36), 11.182 (4.83).

Example 198.

5-[2-(Difluoromethyl)-4'-fluoro[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

To a solution of 5-(4-bromo-3-(difluoromethyl)phenyl)-3H-1,3,4-oxadiazin-2(6H)-one (100 mg, 0.3 mmol, intermediate 77) in dioxane/water (5 ml, vol:vol = 5:1) was added 1,1'bis(diphenylphosphino)ferrocene(II) chloride (26 mg (0.03 mmol), solid sodium carbonate (100 mg, 1.0 mmol) and 4-fluorophenylboronic acid ( 91 mg, 0.6 mmol) and the mixture was stirred at 100°C overnight under nitrogen atmosphere. After completion of the reaction, the solvent was removed in vacuo and the residue was diluted with water. The resulting mixture was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give 40 mg of the still impure title compound, which was then repurified by preparative HPLC [Column: XBridge C18 19x150; Movable phase A: water/10 mmol/l NH ₄ HCO ₃ , Mobile phase B: ACN, Flow rate: 2 0 ml/min; gradient: 35% B - 60% B over 8 min] to give 10.8 mg (10% yield) of the title compound as a white solid.

MS (ESIpos): m/z = 319 (M-H) ⁺ .

Example 199.

5-[4'-Chloro-2-(difluoromethyl)[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

F

The title compound was prepared analogously to Example 198 from Intermediate 77.

MS (ESIpos): m/z = 335 (M-H) ⁺ .

Example 200.

5-[3-(Difluoromethyl)-4-(6-methylpyridin-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

N=/ )-F

The title compound was prepared analogously to Example 198 from Intermediate 77.

MS (ESIpos): m/z = 318 (M+H) ⁺ .

Example 201.

5-[4-(Cyclopent-1-en-1-yl)-3-(difluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

F

The title compound was prepared analogously to Example 198 from Intermediate 77.

MS (ESIpos): m/z = 291 (M-H) ⁺ .

Example 202.

5-[3-(Difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one o

>°

F

The title compound was prepared analogously to Example 198 from Intermediate 77.

MS (ESIpos): m/z = 293 (M+H) ⁺ .

Example 203.

5-[4-(3-Hydroxy-3-methylazetidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazine

2nd

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (160 mg, 610 µmol, intermediate 66) was dissolved in DMSO (2.0 ml), and 3-methylazetidin-3-ol hydrochloride (113 mg, 915 µmol) and potassium carbonate (253 mg, 1.83 mmol) were added. The mixture was stirred at 100° C. overnight. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 69.0 mg (95% pure, 33% yield) of the title compound.

LC-MS (method 1): R _t = 0.92 min; MS (ESIpos): m/z = 330 [M+H] ⁺ .

Ή NMR (400 MHz, DMSO-d6) δ [ppm]: 1.439 (16.00), 2.074 (0.54), 2.323 (0.62), 2.326 (0.83), 2.331 (0.62), 2.665 (0.62), 2.669 (0.81), 2.673 (0.62), 3.892 (2.29), 3.912 (4.58), 3.946 (5.07), 3.967 (2.44), 5.311 (14.85), 5.639 (4.09), 6.619 (2.76), 6.642 (2.83), 7.736 (1.79), 7.742 (2.15), 7.764 (2.33), 7.778 (4.22), 7.782 (3.22), 10.918 (5.44).

Example 204.

(rac)-5-[4-{[3,3,3-trifluoro-2-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H1,3,4-oxadiazine-2- He

The title compound was prepared analogously to Example 203 from Intermediate 66.

LC-MS (method 1): R _t = 1.00 min; MS (ESIpos): m/z = 372 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (1.23), 2.522 (0.95), 3.366 (0.46), 3.380 (0.59), 3.385 (0.60), 3.400 (1.07), 3.419 (0.85 ), 3.434 (0.64), 3.547 (0.67), 3.559 (0.99), 3.572 (0.78), 3.581 (0.58), 3.593

- 219 041614 (0.68), 3.607 (0.47), 4.233 (0.69), 4.244 (0.79), 4.251 (0.77), 4.261 (0.70), 5.309 (16.00), 5.838 (0.83), 5.852 (1.62), 5.867 (0.82 ), 6.615 (3.02), 6.632 (3.00), 6.975 (2.08), 6.997 (2.16), 7.759 (7.02), 7.780 (1.72), 10.911 (5.36).

Example 205.

5-{4-[(Oxan-4-yl)amino]-3-(trifluoromethyl)phenyl}-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 (291 mg, 1.11 mmol, intermediate 66) was dissolved in DMSO (2.0 ml), and oxan-4-amine (225 mg, 2.22 mmol) was added. The mixture was stirred overnight at 100°C. Another part of oxan-4-amine (113 mg, 1.11 mmol) was added and stirred overnight at 100°C. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 139 mg (95% pure, 35% yield) of the title compound.

LC-MS (method 1): Rt = 1.01 min; MS (ESIpos): m/z = 344 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.535 (0.43), 1.546 (0.50), 1.567 (1.09), 1.575 (1.16), 1.594 (1.29), 1.606 (1.17), 1.624 (0.65) . . , 5.183 (1.37), 5.302 (16.00), 7.039 (1.85), 7.064 (1.98), 7.736 (4.97), 7.741 (2.83), 7.752 (1.74), 10.898 (5.13).

Example 206.

(cis/trans)-5-[4-{[3-hydroxycyclobutyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (130 mg, 496 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), N,N-diisopropylethylamine (260 μl, 1.5 mmol), and (cis/trans)-3-aminocyclobutan-1-ol hydrochloride (135 mg, 1.09 mmol) were added. The mixture was stirred at 100°C overnight and then another 2 days at 100°C. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 70.0 mg (95% pure, 41% yield) of the title compound.

LC-MS (method 1): Rt = 0.84 min; MS (ESIpos): m/z = 330 [M+H]+.

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.805 (0.77), 1.812 (0.59), 1.825 (1.72), 1.833 (1.60), 1.846 (1.64), 1.853 (1.84), 1.867 (0.64) , 1.874 (0.83), 2.254 (0.49), 2.518 (3.34), 2.523 (2.22), 2.539 (0.94), 2.696 (0.74), 2.703 (0.76), 2.713 (1.64), 2.720 (1.60), 2.725 (1.29) . . , 6.759 (1.96), 6.782 (2.04), 7.726 (1.87), 7.742 (5.61), 10.897 (4.98).

Example 207.

(rac)-5-{4-[2,4-Dimethylazetidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin2-one

5-[4-fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (150 mg, 572 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), and (rac)-2,4-dimethylazetidine hydrochloride (153 mg, 1.26 mmol) was added. The mixture was stirred at 100° C. overnight. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 34.0 mg (95% pure, 17% yield) of the title compound.

LC-MS (method 1): Rt = 1.28 min; MS (ESIpos): m/z = 328 [M+H]+.

Ή NMR (400 MHz, DMSO-d6) δ [ppm]: 1.180 (15.90), 1.196 (16.00), 1.331 (8.34), 1.346 (8.44), 1.371 (0.78), 1.452 (0.51), 1.467 (0.99), 1.478 (0.71), 1.482 (0.68), 1.493 (0.99), 1.508 (0.54), 1.905 (0.71) 2.665 (1.57), 2.669 (2.14), 2.674 (2.21), 2.696

- 220 041614 (0.68), 2.701 (0.95), 2.722 (0.48), 4.106 (0.58), 4.122 (0.99), 4.140 (0.99), 4.156 (0.61), 4.457 (2.35), 4.471 (2.31), 5.289 (1.19) ), 5.326 (14.33), 5.332 (13.92), 5.339 (9.02), 5.370 (1.06), 6.897 (4.09), 6.919 (4.26), 7.196 (1.19), 7.220 (1.23), 7.768 (2.76), 7.773 (3.06 ), 7.790 (2.45), 7.795 (3.00), 7.822 (3.03), 7.828 (7.76), 7.834 (5.79), 8.026 (0.68), 8.031 (0.61), 10.970 (8.10), 10.997 (2.55).

Example 208.

(cis or trans)-5-{4-[2,4-Dimethylazetidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one

by-product from Example 207, one stereoisomer: 32.0 mg (95% pure, 16% yield).

LC-MS (method 1): Rt = 1.30 min; MS (ESIpos): m/z = 328 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.180 (0.55), 1.196 (0.50), 1.330 (16.00), 1.346 (15.95), 1.452 (0.85), 1.467 (1.64), 1.478 (1.09), 1.482 (1.09), 1.493 (1.66), 1.508 (0.84), 2.323 (0.53), 2.326 (0.68),2.331 (0.50), 2.522 (2.13), 2.653 (0.82), 2.674 (2.18), 2.679 (1.27), 2.696 (1.18), 2.700 (1.66), 2.721 (0.76), 4.105 (1.18), 4.122 (2.02), 4.140 (1.94), 4.156 (1.10), 5.339 (15.37), 7.196 (2.28), 7.219 (2.38), 7.821 (4.79), 7.827 (3.48), 7.836 (2.35), 10.997 (4.38).

Example 209.

5-[4-{[3,3,3-Trifluoro-(2S)-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (530 mg, 1.86 mmol, intermediate 66) was dissolved in DMSO (9 ml), and (2S)-3-amino-1,1,1-trifluoropropan-2-ol hydrochloride (1:1) (1.4 g, 7.8 mmol) was added followed by calcium carbonate (0.8 g, 7.7 mmol). The mixture was stirred at 100°C for 3 days. The reaction mixture was filtered and purified by preparative HPLC (Basic, gradient: 0.00-0.50 min 17% B (40->70 ml/min), 0.51-5.50 min 33-34% B (70 ml/min)) to give 237 mg (99% purity, 16% yield) of the title compound.

LC-MS (method 1): R _t = 1.00 min; MS (ESIpos): m/z = 372 [M+H]+.

'll NMR (400 MHz, DMSC-d ₆ ): δ [ppm] = 10.91 (s, 1H), 7.76 (s, 1H), 7.77 (d, 1H), 6.99 (d, 1H), 6.64 (d, 1H), 5.85 (br t, 1H), 5.31 (s, 2H), 4.25 (br d, 1H), 3.58 (dt, 1H), 3.44–3.36 (m, 1H).

Example 210.

5-{4-[(2-Hidroxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (3.2 g, 12.3 mmol, intermediate 66) was dissolved in DMSO (22 ml), and 1-amino-2-methylpropan-2-ol (2.2 g, 24.6 mmol) was added, followed by calcium carbonate (1.23g, 12.3 mmol). The mixture was stirred at 100°C for 5 days. The reaction mixture was filtered and purified by preparative HPLC (acidic conditions) to give 3.1 g (99% pure, 76% yield) of the title compound.

LC-MS (method 1): Rt = 0.95 min; MS (ESIpos): m/z = 332 [M+H]+.

'll NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 10.89 (s, 1H), 7.74 (s, 1H), 7.75 (d, 1H), 6.94 (d, 1H), 5.40-5.34 ( m, 1H), 5.30 (s, 2H), 4.82 (s, 1H), 3.12 (d, 2H), 1.23–1.14 (m, 6H).

Example 211.

(trans)-5-[4-{[4-Hydroxycyclohexyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

- 221 041614

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (320 mg, 97% pure,

1.18 mmol, intermediate compound 66) was dissolved in DMSO (3.0 ml), and (trans)-4-aminocyclohexane-

1-ol (273 mg, 2.37 mmol) was added. The mixture was stirred at 100°C for 3 days. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 234 mg (97% pure, 54% yield) of the title compound.

LC-MS (method 2): Rt = 0.93 min; MS (ESIneg): m/z = 356 [M-H] ^- .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.290 (1.19), 1.297 (1.06), 1.322 (2.77), 1.352 (2.73), 1.378 (1.12), 1.384 (1.27), 1.416 (0.42), 1.802 (1.57), 1.828 (1.98), 1.880 (2.09), 1.906 (1.44), 2.073 (0.98),2.518 (1.45), 2.522 (0.91), 3.409 (0.73), 3.420 (1.09), 3.431 (1.29), 3.442 (1.17), 3.456 (1.01), 3.465 (0.85), 4.590 (3.68), 4.601 (3.59), 4.946 (1.58), 4.966 (1.54), 5.294 (16.00), 6.968 (2.28), 6.991 (2.43), 7.717 (4.14), 7.726 (2.26), 7.749 (1.67), 10.889 (6.00).

Example 212.

5-{4-[(Cyclopropylmethyl)amino]-3-(trifluoromethyl)phenyl}-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 (150 mg, 572 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), and 1-cyclopropylmethanamine (110 μl, 1.3 mmol) was added. The mixture was stirred at 100° C. overnight. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 102 mg (95% pure, 54% yield) of the title compound.

LC-MS (method 1): R _t = 1.19 min; MS (ESIpos): m/z = 314 [M+H]+.

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.233 (0.90), 0.245 (3.25), 0.248 (2.94), 0.257 (3.23), 0.260 (3.07), 0.271 (1.18), 0.422 (1.20) . . . , 10.879 (4.64).

Example 213.

5-[4-{[(3-Methyloxetan-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (120 mg, 458 µmol, intermediate 66) was dissolved in DMSO (800 µl), and 1-(3-methyloxetan-3-yl)methanamine (92.6 mg, 915 µmol) was added. The mixture was stirred at 100°C for 3 days. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 93.0 mg (95% pure, 56% yield) of the title compound.

LC-MS (method 1): R _t = 1.00 min; MS (ESIpos): m/z = 344 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.275 (16.00), 2.518 (1.01), 2.523 (0.62), 3.417 (3.57), 3.432 (3.59), 4.196 (6.36), 4.211 (6.95), 4.449 (5.85), 4.464 (5.27), 5.302 (13.69), 5.943 (0.63), 5.957 (1.27), 5.972 (0.63), 6.991 (1.48), 7.013 (1.59), 7.725 (1.51), 7.744 (5.58), 10.890 (4.43).

Example 214.

5-{4-[(3-Methoxypropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- 222 041614 o^o >n

Ir ^H 3 ^C ' ₀ ^^nA^ n X fH^f

F

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (260 mg, 992 µmol, intermediate 66) was dissolved in DMSO (2.0 ml), and 3-methoxypropan-1-amine (200 μl, 2.0 mmol) was added. The mixture was stirred at 100° C. for 64 hours. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 267 mg (99% pure, 80% yield) of the title compound.

LC-MS (method 1): Rt = 1.05 min; MS (ESIpos): m/z = 332 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.786 (0.98), 1.801 (1.53), 1.817 (1.01), 2.073 (0.41), 2.518 (0.61), 3.243 (16.00), 3.270 (0.53) , 3.286 (1.28), 3.301 (1.29), 3.316 (0.64), 3.410 (1.50), 3.425 (2.89), 3.439 (1.42), 5.293 (7.70), 6.066 (0.75), 6.852 (1.05), 6.874 (1.09) , 7.730 (2.05), 7.756 (0.75), 10.878 (2.38).

Example 215.

(rac)-5-[4-({[Oxolan-2-yl]methyl}amino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

XT'

Vo ^H 1 A

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (150 mg, 572 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), and (rac)-1-[oxolan-2-yl]methanamine (130 μl, 1.3 mmol) was added. The mixture was stirred at 100° C. overnight. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 108 mg (95% pure, 52% yield) of the title compound.

LC-MS (method 1): Rt = 1.09 min; MS (ESIpos): m/z = 344 [M+H]+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.591 (0.79), 1.603 (0.56), 1.611 (0.99), 1.619 (0.88), 1.628 (0.67), 1.636 (0.62), 1.641 (1.02 ), 1.657 (0.57), 1.783 (0.50), 1.798 (1.22), 1.815 (1.68), 1.819 (1.63), 1.829 (1.49), 1.836 (1.72), 1.846 (0.93), 1.850 (1.20), 1.866 (0.59 ), 1.885 (0.69), 1.902 (0.89), 1.906 (0.56), 1.914 (0.99), 1.923 (0.64), 1.931 (0.72), 1.934 (0.68), 1.945 (0.55), 2.327 (0.41), 2.518 (1.66 ), 2.523 (1.12), 2.669 (0.40), 3.212 (0.48), 3.226 (0.65), 3.245 (0.96), 3.261 (1.15), 3.275 (0.85), 3.352 (1.06), 3.359 (0.66), 3.372 (0.72 ), 3.386 (0.49), 3.610 (0.75), 3.630 (1.56), 3.647 (2.03), 3.664 (1.09), 3.732 (1.03), 3.748 (1.82), 3.765 (1.50), 3.768 (1.38), 3.785 (0.81 ), 4.026 (1.18), 4.038 (1.37), 4.042 (1.23), 4.054 (1.15), 5.298 (16.00), 5.690 (0.81), 5.703 (1.49), 5.717 (0.78), 6.965 (1.95), 6.987 (2.02 ), 7.731 (6.98), 7.752 (1.70), 10.890 (5.24).

Example 216.

5-[4-{[(2R)-2-Hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (260 mg, 992 µmol, intermediate 66) was dissolved in DMSO (2.5 ml), and (2K)-1-aminopropan-2-ol (160 μl, 2.0 mmol) was added. The mixture was stirred at 100° C. overnight. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 218 mg (95% pure, 66% yield) of the title compound.

LC-MS (method 1): Rt = 0.87 min; MS (ESIpos): m/z = 318 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.103 (10.18), 1.118 (10.29), 2.518 (1.03), 2.522 (0.64), 3.029 (0.52), 3.041 (0.61), 3.047 (0.62), 3.060 (1.03), 3.072 (0.84), 3.079 (0.87), 3.090 (0.74), 3.197 (0.72), 3.210 (1.13), 3.224 (0.93), 3.242 (0.79), 3.256 (0.52), 3.821 (0.41), 3.834 (0.85), 3.850 (1.11), 3.866 (0.78), 4.950 (3.78), 4.962 (3.73), 5.300 (16.00), 5.644 (0.86), 5.657 (1.44), 5.670 (0.84), 6.910 (1.93), 6.932 (1.99), 7.737 (7.21), 7.757 (1.77), 10.888 (5.40).

Example 217.

5-[4-{[(3R)-3-Hydroxybutyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one

- 223 041614

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (150 mg, 572 µmol, intermediate 66) was dissolved in DMSO (1000 μl), and (2R)-4-aminobutan-2-ol (102 mg, 1.14 mmol) was added. The mixture was stirred at 100° C. overnight. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 86.0 mg (95% pure, 43% yield) of the title compound.

LC-MS (method 1): R _t = 0.92 min; MS (ESIpos): m/z = 332 [M+H]+.

1H NMR (400 MHz, DMSO-06) δ [ppm]: 1.087 (10.42), 1.102 (10.69), 1.532 (0.62), 1.551 (0.91), 1.566 (1.16), 1.586 (1.04), 1.603 (0.41), 1.643 (0.40), 1.658 (0.96), 1.668 (1.02), 1.676 (0.77), 1.685 (0.73),1.693 (0.63), 1.702 (0.57), 2.327 (0.45), 2.522 (1.03), 2.669 (0.45), 3.268 (0.73), 3.284 (1.69), 3.299 (2.38),3.314 (1.99), 3.742 (0.91), 3.747 (0.91), 3.758 (0.91), 4.773 (3.53), 4.784 (3.42), 5.292 (16.00), 6.218 (0.94), 6.231 (1.79), 6.243 (0.92), 6.851 (2.46), 6.873 (2.55), 7.726 (4.84), 7.752 (1.77), 10.871 (5.39).

Example 218.

5-[4-{[(2S)-2-Hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2Н-1,3,4-oxadiαzin-2 one

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (150 mg, 97% pure, 555 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), and (2S)-1-aminopropan-2-ol (99 μl, 98% purity, 1.2 mmol) was added. The mixture was stirred at 100° C. for 18 hours. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 152 mg (98% pure, 85% yield) of the title compound.

LC-MS (method 1): Rt = 0.87 min; MS (ESIpos): m/z = 318 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.102 (10.45), 1.118 (10.65), 2.522 (0.80), 3.029 (0.54), 3.040 (0.63), 3.046 (0.65), 3.060 (1.08), 3.072 (0.87), 3.079 (0.90), 3.090 (0.77), 3.196 (0.73), 3.210 (1.18), 3.224 (0.95), 3.241 (0.81), 3.256 (0.54), 3.821 (0.44), 3.833 (0.89), 3.850 (1.17), 3.866 (0.83), 3.878 (0.41), 4.950 (4.60), 4.962 (4.59), 5.300 (16.00), 5.645 (0.89), 5.657 (1.48), 5.669 (0.87), 6.910 (2.00), 6.932 (2.06), 7.737 (7.43), 7.756 (1.82), 10.888 (5.53).

Example 219.

5-[4-{[(1-Hydroxycyclobutyl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (320 mg, 1.22 mmol, intermediate 66) was dissolved in DMSO (2.0 ml), and 1-(aminomethyl)cyclobutan-1-ol (247 mg, 2.44 mmol) was added. The mixture was stirred at 100° C. overnight. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 231 mg (95% pure, 52% yield) of the title compound.

LC-MS (method 1): R _t = 1.00 min; MS (ESIpos): m/z = 344 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.546 (0.74), 1.569 (1.05), 1.591 (0.73), 1.637 (0.72), 1.644 (0.54), 1.654 (0.80), 1.665 (0.53) , 1.976 (4.50), 1.993 (4.03), 1.998 (5.17), 2.015 (2.05), 2.074 (14.34), 2.518 (1.22), 2.522 (0.84), 3.279 (4.02), 3.291 (4.05), 5.278 (1.45) , 5.308 (16.00), 5.527 (3.57), 7.000 (2.21), 7.022 (2.34), 7.746 (3.95), 7.752 (2.30), 7.774 (1.55), 7.779 (1.23), 10.898 (5.51).

Example 220.

5-{4-[(3-Methylbutyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- 224 041614

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (150 mg, 572 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), and 3-methylbutan-1-amine (150 μl, 1.3 mmol) was added. The mixture was stirred at 100° C. overnight. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 106 mg (95% pure, 53% yield) of the title compound.

LC-MS (method 1): R _t = 1.34 min; MS (ESIpos): m/z = 330 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.898 (15.35), 0.914 (16.00), 1.413 (0.60), 1.430 (1.37), (1.39), 1.467 (0.77), 1.606 (0.67), 1.623 (0.77), 1.640 (0.58), 2.518 (1.24), 2.523 (0.87), 3.227 (0.56), (1.04), 3.263 (1.05), 3.278 (0.55), 5.289 (9.24), 5.866 (0.41), 5.880 (0.82), 5.894 (0.41), 6.849 (1.20), (1.25), 7.715 (1.22), 7.720 (2.09), 7.727 (1.19), 7.749 (0.82), 7.754 (0.65), 10.871 (2.70).

Example 221.

5-{4-[(2-Methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

1.449

3.242

6.871

5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (150 mg, 572 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), and 2-methylpropan-1-amine (130 μl, 1.3 mmol) was added. The mixture was stirred at 100° C. overnight. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 115 mg (95% pure, 61% yield) of the title compound.

LC-MS (method 1): R _t = 1.26 min; MS (ESIpos): m/z = 316 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.875 (15.59), 0.892 (16.00), 1.895 (0.77), 1.912 (0.95), 1.928 (0.73), 2.518 (2.28), 2.522 (1.46), 2.669 (0.50), 3.046 (1.72), 3.062 (2.63), 3.078 (1.65), 5.287 (12.60), 5.958 (0.63), 5.972 (1.23), 5.987 (0.61), 6.865 (1.49), 6.889 (1.55), 7.712 (5.25), 7.730 (1.38), 10.870 (3.92).

Example 222.

5-{4-[(2-Methoxyethyl)amino]-3-(trifluoromethyl)phenyl}-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 (1.05 g, 92% pure, 3.68 mmol, intermediate 66) was dissolved in DMSO (7.0 ml), and 2-methoxyethane-1-amine (710 μl, 99% purity, 8.1 mmol) was added. The mixture was stirred at 100° C. for 16 hours. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC (acidic conditions) to give 786 mg (100% pure, 67% yield) of the title compound.

LC-MS (method 1): R _t = 1.01 min; MS (ESIpos): m/z = 318 [M+H] ⁺ .

'H NMR (400 MHz, DMSC-d ₆ ): δ [ppm] = 10.89 (s, 1H), 7.73 (s, 1H), 7.75 (d, 1H), 6.95 (d, 1H), 5.76 (brt, 1H), 5.30 (s, 2H), 3.55-3.46 (m, 2H), 3.41 (q, 2H), 3.27 (s, 3H).

Example 223.

5-{4-[Ethyl(methyl)amino]-3-(trifluoromethyl)phenyl}-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 (150 mg, 572 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), and N-methylethanamine (110 μl, 1.3 mmol) was added. The mixture was stirred at 100° C. overnight. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 73.0 mg (95% pure, 40% yield) of the title compound.

LC-MS (method 1): R _t = 1.20 min; MS (ESIpos): m/z = 302 [M+H]+.

- 225 041614

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.964 (4.46), 0.981 (10.06), 0.999 (4.62), 2.074 (0.54), 2.518 (1.54), 2.523 (0.99), 2.666 (16.00), 2.967 (1.15), 2.985 (3.62), 3.002 (3.54), 3.020 (1.08), 5.387 (14.58), 7.533 (1.84), 7.554 (2.02), 7.904 (1.16), 7.910 (1.65), 7.931 (5.31), 11.105 (3.70).

Example 224.

5-[4-(tert-butylamino)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one ο _γ ο ⁿ ssl ^{H3 3} HI ^F F ^F

The title compound was prepared analogously to Example 205 from Intermediate 66.

LC-MS (method 1): R _t = 1.26 min; MS (ESIpos): m/z = 316 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.400 (16.00), 1.412 (1.99), 1.428 (2.69), 2.522 (1.01), 4.320 (0.50), 4.628 (0.62), 5.302 (4.05) , 7.153 (0.66), 7.176 (0.70), 7.740 (0.77), 7.745 (1.05), 7.750 (0.95), 7.757 (0.61), 10.918 (1.26).

Example 225.

5-[4-({[(2R)-Oxolan-2-yl]methyl}amino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one o^ o χΑ αχ

The title compound was prepared analogously to Example 205 from Intermediate 66.

LC-MS (method 1): R _t = 1.09 min; MS (ESIpos): m/z = 344 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.591 (0.72), 1.594 (0.54), 1.603 (0.49), 1.607 (0.56), 1.611 (0.92), 1.619 (0.83), 1.628 (0.62), 1.635 (0.55), 1.641 (0.98), 1.657 (0.54), 1.782 (0.47), 1.797 (1.10), 1.802 (0.80), 1.815 (1.49), 1.818 (1.44), 1.829 (1.32), 1.836 (1.57), 1.845 (0.82), 1.850 (1.09), 1.866 (0.56),1.885 (0.62), 1.901 (0.83), 1.906 (0.50), 1.914 (0.93), 1.919 (0.43), 1.923 (0.58), 1.928 (0.64), 1.930 (0.65), 1.934 (0.62), 1.945 (0.50), 1.950 (0.46), 2.518 (1.37), 2.522 (0.83), 3.212 (0.44), 3.225 (0.57), 3.245 (0.88), 3.261 (1.03), 3.275 (0.76), 3.352 (0.87), 3.359 (0.54), 3.371 (0.62), 3.386 (0.43), 3.609 (0.72), 3.630 (1.47), 3.647 (1.89), 3.664 (1.05), 3.732 (1.00), 3.749 (1.69), 3.752 (1.06), 3.765 (1.42), 3.768 (1.25), 3.785 (0.82) 5.422 (1.05), 5.690 (0.73), 5.704 (1.37), 5.718 (0.70), 6.965 (1.80), 6.987 (1.88), 7.731 (6.58), 7.752 (1.56), 10.890 (5.06).

Example 226.

5-[4-{[(Pyrazin-2-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-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 (39.3 mg, 150 µmol, intermediate 66) was dissolved in DMSO (2.0 ml), and 1-(pyrazin-2-yl)methanamine (32.7 mg, 300 µmol) and N,N-diisopropylethylamine (77.5 mg, 600 µmol) were added. The mixture was stirred at 120° C. overnight. The reaction mixture was filtered through a Celite pad and purified by preparative HPLC.

LC-MS (method 1): R _t = 0.88 min; MS (ESIneg): m/z = 350 [M-H]'.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (3.21), 2.083 (2.28), 2.458 (0.58), 2.518 (2.41), 2.522 (1.52), 2.539 (0.67), 4.667 (3.73) , 4.681 (3.71), 5.276 (16.00), 6.788 (2.49), 6.810 (3.40), 6.825 (1.81), 6.839 (0.85), 7.666 (1.52), 7.670 (1.62), 7.687 (1.41), 7.693 (1.52) , 7.782 (3.37), 7.787 (3.09), 8.541 (3.63), 8.547 (4.20), 8.589 (3.98), 8.593 (4.86), 8.616 (3.59), 8.620 (3.29), 8.623 (3.38), 8.626 (2.54) , 10.896 (5.03).

Example 227.

5-[4-(4-Hidroxypiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was prepared analogously to Example 226 from intermediate

- 226 041614 niya 66.

LC-MS (method 1): R _t = 0.90 min; MS (ESIpos): m/z = 344 [M+H] ⁺ .

Example 228.

5-[4-{[(2S)-1-Hidroxybutan-2-yl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

nia

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.95 min; MS (ESIpos): m/z = 332 [M+H]+.

Example 229.

(rac)-5-[4-(3-hydroxypiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2 one

nia

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.96 min; MS (ESIpos): m/z = 344 [M+H] ⁺ .

Example 230.

(rac)-1-[4-(2-Oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]piperidine-3 carboxamide

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.87 min; MS (ESIpos): m/z = 371 [M+H] ⁺ .

Example 231.

5-{4-[(3-Hydroxy-2,2-dimethylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.02 min; MS (ESIpos): m/z = 346 [M+H] ⁺ .

Example 232.

5-[4-(4,4-Difluoropiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.21 min; MS (ESIpos): m/z = 364 [M+H] ⁺ .

Example 233.

5-[4-{[(1 R,2R,4R)-Bicyclo[2.2.1]heptan-2-yl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H1,3,4 -oxadiazine-2-one

- 227 041614

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.38 min; MS (ESIpos): m/z = 354 [M+H]+.

Example 234.

5-{4-[(3S)-3-H-hydroxypyrrolidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): Rt = 0.87 min; MS (ESIpos): m/z = 330 [M+H]+.

Example 235.

(rac)-5-{4-[(2-Hydroxy-3-methoxypropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.84 min; MS (ESIpos): m/z = 348 [M+H]+.

Example 236.

5-[4-{[(1-Methyl-1 H-pyrazol-5-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2- He

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.88 min; MS (ESIpos): m/z = 354 [M+H]+.

Example 237.

5-[4-{[(1 H-Pyrazol-3 -yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.84 min; MS (ESIpos): m/z = 340 [M+H]+.

Example 238.

5-[4-{[2-(1H-Pyrazol-1-yl)ethyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.93 min; MS (ESIpos): m/z = 354 [M+H]+.

Example 239.

1-[4-(2-Oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]piperidine-4carbonitrile

F F

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.07 min; MS (ESIpos): m/z = 353 [M+H] ⁺ .

Example 240.

(rac)-5-{4-[(1-cyclopropylethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.24 min; MS (ESIpos): m/z = 328 [M+H] ⁺ .

Example 241.

(rac)-5-{4-[(2-Ethoxypropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2one

nN CH _3h

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.16 min; MS (ESIpos): m/z = 346 [M+H] ⁺ .

Example 242.

(rac)-5-{4-[(2-Methoxypropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2one

H

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.07 min; MS (ESIpos): m/z = 332 [M+H] ⁺ .

Example 243.

- [4-(3-Ethoxyazetidin-1 -yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

n

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.13 min; MS (ESIpos): m/z = 344 [M+H] ⁺ .

Example 244.

5-[4-{[(Pyrimidin-2-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one

- 229 041614

F F

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): Rt = 0.92 min; MS (ESIpos): m/z = 352 [M+H]+.

Example 245.

(rac)-5-[4-{[(Oxolan-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): Rt = 0.97 min; MS (ESIpos): m/z = 344 [M+H] ⁺ .

Example 246.

5-[4-{[(2 S)-4-Hydroxybutan-2-yl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.92 min; MS (ESIpos): m/z = 332 [M+H] ⁺ .

Example 247.

(rac)-5-[4-{[(6-Oxopiperidin-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

F F

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): Rt = 0.78 min; MS (ESIpos): m/z = 371 [M+H] ⁺ .

Example 248.

(rac)-5-[4-{[(2,2-Dimethylcyclopropyl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H1,3,4-oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.33 min; MS (ESIpos): m/z = 342 [M+H] ⁺ .

Example 249.

5-[4-({[ 1 -(Hydroxymethyl)cyclobutyl]methyl}amino)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H1,3,4-oxadiazin-2-one

F F

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.06 min; MS (ESIpos): m/z = 358 [M+H] ⁺ .

Example 250.

5-{4-[(2S)-2-(Hydroxymethyl)azetidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one

F F

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): Rt = 0.91 min; MS (ESIpos): m/z = 330 [M+H] ⁺ .

Example 251.

-Methyl-1 -[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]azetidine-3 carbonitrile

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): Rt = 1.03 min; MS (ESIpos): m/z = 339 [M+H] ⁺ .

Example 252.

5-[4-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one

F F

H

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.24 min; MS (ESIpos): m/z = 326 [M+H] ⁺ .

Example 253.

5-[4-(4-Ethyl-4-hydroxypiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

F F

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.12 min; MS (ESIpos): m/z = 372 [M+H] ⁺ .

Example 254.

4-[4-(2-Oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)anilino]butanenitrile

F F

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.92 min; MS (ESIpos): m/z = 327 [M+H] ⁺ .

Example 255.

6-[4-(2-Oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]-2λ ⁶ -thia-6azaspiro[3.3] heptane- 2,2-dione

- 231 041614

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.88 min; MS (ESIpos): m/z = 390 [M+H]+.

Example 256.

K ² -[4-(2-Oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]glycinamide _ΟγΟ ° ^H fXf

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.71 min; MS (ESIpos): m/z = 317 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (0.54), 2.323 (0.49), 2.327 (0.64), 2.331 (0.47), 2.522 (1.98), 2.665 (0.49), 2.669 (0.64) , 2.673 (0.46), 3.809 (4.91), 3.822 (4.81), 5.304 (16.00), 5.411 (1.30), 6.085 (1.06), 6.097 (2.01), 6.109 (1.01), 6.637 (2.32), 6.661 (2.34) , 7.301 (2.21), 7.528 (2.20), 7.763 (7.67), 7.781 (2.11), 7.992 (0.67), 10.907 (6.07).

Example 257.

- {4-[(3R)-3-Hydroxypyrrolidin-1 -yl] -3 -(trifluoromethyl)phenyl} -3,6-dihydro-2H-1,3,4oxadiazin-2-one ο _γ ο ^F F ^F

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 2): Rt = 0.88 min; MS (ESIpos): m/z = 330 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.845 (0.62), 1.855 (0.68), 1.877 (1.00), 1.884 (1.00), 1.892 (0.93), 1.939 (0.52), 1.950 (0.57 ), 1.959 (0.84), 1.969 (1.12), 1.981 (0.93), 1.993 (1.03), 2.003 (0.62), 2.012 (0.43), 2.074 (0.82), 2.331 (0.77), 2.518 (3.97), 2.523 (2.39 ), 2.673 (0.75), 3.153 (1.35), 3.179 (1.51), 3.367 (1.55), 3.551 (0.68), 3.575 (1.43), 3.593 (2.16), 3.611 (1.30), 4.368 (1.59), 5.021 (1.07 ), 5.320 (16.00), 7.009 (2.74), 7.032 (2.89), 7.727 (1.94), 7.733 (2.05), 7.749 (1.73), 7.755 (1.89), 7.855 (4.15), 7.861 (3.85), 8.335 (0.53 ), 10.925 (5.42).

Example 258.

5-{4-[(2-Methoxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.19 min; MS (ESIpos): m/z = 346 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.173 (16.00), 3.122 (11.15), 3.229 (2.00), 3.241 (1.94), 5.125 (0.66), 5.307 (6.19), 6.949 (0.91), 6.971 (0.95), 7.754 (2.50), 7.778 (0.71), 10.904 (2.14).

Example 259.

5-[4-({[(2S)-Oxolan-2-yl]methyl}amino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

- 232 041614

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.09 min; MS (ESIpos): m/z = 344 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.591 (0.74), 1.603 (0.50), 1.611 (0.95), 1.619 (0.85), 1.628 (0.64), 1.636 (0.58), 1.641 (1.00) , 1.657 (0.55), 1.782 (0.47), 1.797 (1.12), 1.815 (1.55), 1.819 (1.50), 1.829 (1.39), 1.836 (1.64), 1.850 (1.13), 1.866 (0.57), 1.885 (0.65) , 1.901 (0.85), 1.906 (0.52), 1.914 (0.96), 1.923 (0.60), 1.931 (0.68), 1.934 (0.65), 1.945 (0.52), 2.518 (1.86), 2.523 (1.15), 3.212 (0.45) . . 4.042 (1.21), 4.054 (1.12), 5.298 (16.00), 5.422 (0.75), 5.691 (0.77), 5.705 (1.44), 5.718 (0.74), 6.965 (1.88), 6.987 (1.97), 7.731 (6.79) , 7.752 (1.62), 10.890 (5.13).

Example 260.

- {4-[(2-Ethoxyethyl)amino] -3-(trifluoromethyl)phenyl} -3,6-dihydro-2H-1,3,4-oxadiazin-2-one o^o o ^{CH'n F} ^F

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.11 min; MS (ESIpos): m/z = 332 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.082 (6.73), 1.099 (13.49), 1.116 (6.96), 3.377 (1.78), 3.391 (4.78), 3.405 (5.37), 3.418 (2.53) , 3.431 (2.74), 3.449 (6.91), 3.466 (6.79), 3.483 (2.36), 3.534 (4.56), 3.548 (7.56), 3.563 (3.32), 5.300 (16.00), 5.739 (2.79) , 6.958 (3.43), 7.739 (8.49), 7.764 (2.77), 10.894 (6.48).

Example 261.

5-[4-{[(1S,2R)-2-Hydroxycyclopentyl]αmino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.01 min; MS (ESIpos): m/z = 344 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.336 (0.59), 1.347 (0.44), 1.358 (0.85), 1.367 (0.79), 1.378 (0.57), 1.389 (0.83), 1.409 (0.48), 1.489 (0.46), 1.497 (0.57), 1.510 (0.74), 1.518 (0.81), 1.530 (0.83), 1.539 (0.83), 1.549 (0.63), 1.560 (0.79), 1.578 (0.90), 1.592 (0.79), 1.599 (0.81), 1.604 (0.96), 1.612 (0.94), 1.624 (0.79), 1.631 (0.72), 1.637 (0.66), 1.644 (0.63), 1.715 (0.55), 1.722 (0.68) 1.740 (0.88), 1.747 (0.85), 1.758 (0.88), 1.770 (0.83), 1.776 (0.66), 1.787 (0.55), 1.796 (0.81) 1.831 (θ.81), 1.841 (0.66), 1.848 (0.68), 1.858 (0.48), 1.863 (0.46), 2.075 (0.44), 2.089 (0.59),2.100 (0.85), 2.107 (0.55), 2.119 (0.88 ), 2.130 (0.53), 2.332 (0.88), 2.518 (4.25), 2.523 (3.11), 2.540 (0.70), 2.673 (0.88), 3.727 (0.70), 3.742 (0.94), 3.758 (0.74), 4.124 (1.05 ), 5.302 (16.00), 5.355 (0.77), 5.677 (1.23), 5.693 (1.18), 6.911 (1.88), 6.933 (1.95), 7.740 (5.98), 7.762 (1.47), 8.354 (1.27), 10.889 (3.26 ).

Example 262.

5-{4-[(Oxetan-3-yl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was prepared analogously to Example 226 from intermediate

- 233 041614 niya 66.

LC-MS (method 1): Rt = 0.87 min; MS (ESIpos): m/z = 316 [M+H]+.

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (2.13), 2.523 (1.57), 2.539 (3.28), 4.554 (2.34), 4.570 (5.65), 4.585 (3.91), 4.660 (0.55) , 4.674 (0.90), 4.688 (0.90), 4.703 (0.56), 4.820 (3.06), 4.837 (5.21), 4.853 (2.56), 5.305 (16.00), 6.321 (1.57), 6.332 (1.54), 6.539 (2.11) , 6.561 (2.18), 7.713 (1.22), 7.719 (1.39), 7.736 (1.14), 7.741 (1.37), 7.782 (2.88), 7.787 (2.47), 10.925 (4.42).

Example 263.

-{3-(Difluoromethyl)-4-[1 -(propan-2-yl)-1 H-pyrazol-4-yl] phenyl} -3,6-dihydro-2H-1,3,4-oxadiazin2-one

To a solution of 5-(3-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl)-3H-1,3,4-oxadiazin-2(6H)-one (100 mg, 0.32 mmol, Example 202 ) in dioxane/water (5 ml, v:v = 5:1) was added 1,1'bis(diphenylphosphino)ferrocene(II) chloride (26 mg, 0.03 mmol), sodium carbonate (101 mg, 1.0 mmol) , 2-iodopropane (90 mg, 0.7 mmol), and the mixture was stirred at 100° C. overnight under nitrogen. Upon completion of the reaction, the solvent was removed in vacuo and the residue was diluted with water. The resulting mixture was extracted with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by preparative HPLC [Column: XBridge C18 19x150; Mobile phase A: water/10 mmol/L NH4HCO3, Mobile phase B: MeCN; flow rate: 20 ml/min; gradient: 20% B - 60% B over 8 min] to give 9.9 mg (8% yield) of the title compound as a white solid.

MS (ESIpos): m/z = 335 (M+H)+.

Example 264.

5-[3-Fluoro-4-(morpholin-4-yl)-5-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

Sodium hydride ( 28 mg, 0.7 mmol, 60% pure), then the resulting mixture was stirred at room temperature overnight. After the reaction, the solvent was removed in vacuo and water was added and the mixture was then extracted with ethyl acetate. The combined organic layers were washed with brine, water, and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by preparative HPLC (Column: Xbridge Prep C18, 5 µm, 19x150 mm; Mobile phase A: water (0.1% TFA), Mobile phase B: ACN; flow rate: 20 ml/min; gradient: 25% B - 64% B over 8 min; 254 nm and 220 nm; t: 7.18 min) to give 61.4 mg (25%) of the title compound as a white solid. MS (ESIpos): m/z = 348 (M+H)+.

Example 265.

(6S)-6-Methyl-5-{3-(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3,6-dihydro-2H1,3,4-oxadiazine -2-he

To (6S)-5-(4-fluoro-3-(trifluoromethyl)phenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (3.0 g, 11 mmol, intermediate compound 75) and 7.3 g of 3-trifluoromethyl pyrazole (54 mmol) dissolved in 20 ml of DMF were added 7.0 g of powdered Cs ₂ CO ₃ (22 mmol) and the mixture was heated at 60°C for 5 h and then stirred at room temperature all night. Water was added and the mixture was washed several times with EtOAc, the combined EtOAc layers were washed with water and brine, dried (MgSO ₄ ), concentrated and chromatographed on silica gel using 10-40% EtOAc in hexanes to isolate 3.7 g of product as a solid off-white substances (87%). The material was recrystallized from hot CH ₂ Cl ₂ /hexane to give white crystals. Chiral SFC analysis (Chiral Pak AD-H column, 3-50% MeOH in 8 min, flow 4 ml/min) showed the relationship

- 234 041614 enantiomers 0.06:99.94, retention time 4.18 and 4.74 min.

1H NMR (400 MHz, CDCl ₃ ) δ 8.81 (s, 1H), 8.17 (d, J=1.6 Hz, 1H), 7.95 (dd, J=8.4, 1.9 Hz, 1H), 7.79 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 6.77 (d, J=2.5 Hz, 1H), 5.63 (q, J=7.0 Hz, 1H), 1.68 (d, J=7.0 Hz, 3H). ¹⁹ F NMR (376 MHz, CDCl3) δ -59.33, -62.28. ¹³ C NMR (101 MHz, CDC^) δ 148.37, 145.71, 144.81 (q, J=38.7 Hz), 138.73, 133.45 - 133.21 (m), 133.13, 129.84, 129.53, 126.81 (q, J=32.2 Hz), 124.56 (q, J=5.2 Hz), 123.78 120.91 (m), 119.68 - 116.75 (m), 105.80,71.84, 17.38.

LC-MS (method 5): Mass 277 (M+1).

Example 266.

(6S)-6-Methyl-5-{3-(trifluoromethyl)-4-[4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}-3,6-dihydro-2H1,3,4-oxadiazine -2-he

F ^{H F} J , _k N—N y _o FV ⁿ zO

F F

K 100 mg (0.36 mmol) ^)-5-(4-fluoro-3-(trifluoromethyl)phenyl)-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one (intermediate 75 ) and 73 mg of 4-trifluoromethyl imidazole (0.54 mmol) dissolved in 2 ml of DMF were added 235 mg of powdered Cs ₂ CO ₃ (0.72 mmol) and the mixture was heated at 80°C for 5 h before cooling to room temperature. Water was added and the mixture was washed several times with EtOAc, the combined EtOAc was washed with water and brine, dried (MgSO ₄ ), and concentrated. Dichloromethane was added and the starting 4-trifluoromethyl imidazole was insoluble and filtered off. Chromatography with 0-70% EtOAc of the isolated crude product, which was dissolved in EtOAc and extracted with 1N HCl before drying and concentration, gave 53 mg of the title product as a white solid (38%).

1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.21 (s, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.70 (s, 1H), 7.54 (d, J=8.3 Hz , 1H), 7.48 (s, 1H), 5.63 (q, J=6.9 Hz, 1H), 1.70 (d, J=7.0 Hz, 3H). ¹⁹ F NMR (376 MHz, CDC^) δ -59.59, 63.01. Mass 393 (M+1).

Example 267.

5-[4-(3-Methoxypropyl)-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 (45.0 mg, 143 µmol, Example 140) was dissolved in ethanol (2.0 ml) under argon atmosphere, then Pd/C (8.59 mg, 14.3 µmol) was added and the mixture was stirred for 4 h under hydrogen atmosphere. The catalyst was removed through Celite, washed with dichloromethane and the organic phase was evaporated in vacuo to give 37.3 mg (95% pure, 78% yield) of the title compound.

LC-MS (method 1): Rt=1.11 min; MS (ESIpos): m/z = 317 [M+H]+.

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.764 (0.51), 1.780 (1.40), 1.799 (1.64), 1.819 (1.46), 1.835 (0.56), 2.669 (0.41), 2.787 (1.49) , 2.807 (1.97), 2.826 (1.37), 3.331 (16.00), 3.357 (2.50), 3.372 (4.84), 3.388 (2.33), 5.406 (11.07), 7.576 (1.87), 7.597 (2.10), 7.902 (1.69) , 7.923 (1.55), 7.950 (3.05), 11.160 (3.49).

Example 268.

5-[4-(2-Methylpropyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 267 of Example 63.

LC-MS (method 1): R _t = 1.33 min; MS (ESIpos): m/z = 301 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.879 (14.98), 0.896 (15.48), 1.928 (0.57), 1.945 (0.70), 1.962 (0.56), 2.518 (1.14), 2.523 (0.79), 2.646 (2.31), 2.664 (2.39), 5.411 (16.00), 7.554 (1.79), 7.574 (2.00), 7.897 (1.28), 7.901 (1.42), 7.962 (2.39), 11.162 (3.15).

Example 269.

5-[4-(3,3-Dimethylbutyl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- 235 041614

The title compound was synthesized analogously to Example 267 of Example 144.

LC-MS (method 1): R _t = 1.47 min; MS (ESIpos): m/z = 329 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.939 (1.27), 0.948 (16.00), 1.399 (0.56), 1.411 (0.41), 1.421 (0.48), 1.432 (0.41), 1.443 (0.58) , 2.518 (0.41), 2.698 (0.44), 5.404 (4.21), 7.552 (0.60), 7.573 (0.67), 7.891 (0.50), 7.911 (0.46), 7.935 (0.95), 11.151 (1.28).

Example 270.

5-[4-(Propan-2-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 (90.0 mg, 317 µmol , Example 147) was dissolved in ethanol (4.0 mL) under argon, then Pd/C (19.0 mg, 31.7 µmol) was added and the mixture was stirred for 2 h under hydrogen. The catalyst was removed through celite, washed with dichloromethane and the organic phase was evaporated in vacuo to give 72.0 mg (95% pure, 75% yield) of the title compound.

LC-MS (method 1): R _t = 1.25 min; MS (ESIpos): m/z = 287 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.241 (15.87), 1.258 (16.00), 2.518 (1.04), 2.523 (0.68), 3.224 (0.69), 3.240 (0.90), 3.256 (0.66), 5.406 (15.12), 7.740 (2.07), 7.760 (2.48), 7.926 (4.00), 7.932 (2.51), 7.953 (1.55), 11.150 (3.85).

Example 271.

(rac)-5 - {4-[Oxan-3 -yl] -3 - (trifluoromethyl) phenyl} -3,6-dihydro-2H-1,3,4-oxadiazin-2-one

In the autoclave vessel 5-[4-(5,6-dihydro-2H-pyran-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H1,3,4-oxadiazin-2-one ( 40.0 mg, 123 µmol, Example 142) was dissolved in ethanol (2.0 ml) and THF (0.4 ml) under argon, then Pd/C (15.0 mg, 31.7 µmol) was added. The vessel was pressurized with hydrogen (26.2 bar) and stirred for 21 hours at room temperature. The catalyst was filtered off and the organic phase was evaporated in vacuo. The crude product was purified by mass triggered preparative HPLC to give 16.0 mg (95% pure, 38% yield) of the title compound.

LC-MS (method 1): R _t = 1.09 min; MS (ESIpos): m/z = 329 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.307 (0.41), 1.324 (0.40), 1.674 (1.60), 1.843 (1.21), 1.863 (1.70), 2.518 (2.74), 2.523 (1.86) 3.082 (0.63), 3.435 (0.66), 3.445 (0.62), 3.463 (2.10), 3.471 (1.19), 3.489 (2.63), 3.499 (0.69), 3.516 (1.19), 3.702 (1.10), 3.711 (0.97) . , 11.172 (4.69).

Example 272.

(trans)-5-{4-[4-hydroxycyclohexyl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2one

The title compound was synthesized analogously to Example 271 of Example 141.

LC-MS (method 1): R _t = 0.93 min; MS (ESIpos): m/z = 343 [M+H]+.

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.206 (0.45), 1.225 (1.07), 1.236 (1.26), 1.253 (1.14), 1.265 (1.22), 1.284 (0.52), 1.295 (0.48) , 1.615 (1.03), 1.652 (1.96), 1.670 (2.65), 1.933 (1.39), 1.957 (1.34),2.331 (0.91), 2.336 (0.43), 2.518 (4.32), 2.523 (2.73), 2.673 (0.89) . , 7.721 (2.23), 7.897 (1.57), 7.902 (1.86), 7.925 (4.57), 11.146 (5.52).

- 236 041614

Example 273.

(cis)-5-{4-[4-Hydroxycyclohexyl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2one

The title compound was isolated during the synthesis according to Example 272 as a by-product.

LC-MS (method 1): Rt = 1.04 min; MS (ESIpos): m/z = 343 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.408 (1.39), 1.436 (1.46), 1.487 (0.67), 1.521 (1.58), 1.555 (1.02), 1.762 (1.69), 1.793 (1.28) , 1.892 (0.53), 1.923 (1.32), 1.949 (1.23), 1.980 (0.46), 2.331 (0.97), 2.336 (0.46), 2.518 (5.45), 2.522 (3.25), 2.669 (1.37), 2.673 (1.00) . , 7.929 (3.83), 7.938 (2.13), 7.959 (1.51), 11.150 (5.15).

Example 274.

5-{4-[(2-Aminoethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one - hydrochloric acid salt

H' ^{C1 m} D II N ⁿ X tert-butyl ]ethyl} carbamate (86.0 mg, 214 µmol, intermediate 67) was dissolved in 1,4-dioxane (3.0 ml), then hydrochloric acid in 1,4-dioxane (530 µl, 4.0 M, 2.1 mmol) was added and stirred in within 3 days. Then other parts of 1,4-dioxane (2.0 ml) and hydrochloric acid in 1,4-dioxane (270 μl, 4.0 M, 1.1 mmol) were added and the mixture was stirred overnight. The reaction mixture was dried in vacuo to give 72.0 mg (95% pure, 94% yield).

LC-MS (method 1): R _t = 0.56 min; MS (ESIpos): m/z = 303 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (1.33), 2.523 (0.83), 2.933 (0.66), 2.948 (0.67), 3.513 (0.85), 3.529 (0.83), 3.565 (16.00) , 5.317 (5.64), 6.183 (0.59), 7.003 (0.74), 7.027 (0.78), 7.767 (1.39), 7.772 (1.21), 7.780 (0.74), 7.949 (0.78), 10.922 (2.06).

Example 275.

(rac)-5-{4-[1-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazine -2-one - salt of hydrochloric acid o^o Jk .nh Jlj ^N nh ₂ ^f

Stage 1: tert-butyl {3-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]3-azabicyclo[3.1 .0]hexan-1-yl}carbamate was prepared analogously to Example 205 from Intermediate 66.

Stage 2: tert-butyl {3-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]3-azabicyclo[3.1 .0]hexan-1-yl}carbamate was deprotected analogously to Example 274 to give the title compound.

LC-MS (method 2): R _t = 0.92 min; MS (ESIpos): m/z = 341 [M+H] ⁺ .

'H NMR (400 MHz, DMSO-d6) δ [ppm]: 3.328 (0.40), 3.351 (0.77), 3.435 (0.55), 3.458 (0.55), 3.565 (16.00), 3.618 (0.46), 5.363 (2.05) , 7.906 (0.57), 7.912 (0.46), 8.789 (0.70), 11.078 (0.83).

Example 276.

5-[4-(Methylamino)-3-(trifluoromethyl)phenyl]-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 (150 mg, 572 µmol, intermediate 66) was dissolved in DMSO (1.0 ml), and (methylamino)acetonitrile (96 µl, 1.3

- 237041614 mmol) was added. The mixture was stirred overnight at 100°C. (Methylamino)acetonitrile (96 μl, 1.3 mmol) was added again and stirred overnight at 100°C. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a waterproof filter and the filtrate was concentrated under reduced pressure. The residue was diluted with DMSO, filtered and purified by preparative HPLC to give 5.60 mg (95% pure, 3% yield) of the title compound.

LC-MS (method 1): Rt = 0.96 min; MS (ESIpos): m/z = 274 [M+H]+.

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (1.46), 2.523 (1.03), 2.808 (8.32), 2.820 (8.21), 5.297 (16.00), 6.160 (1.14), 6.172 (1.13) , 6.782 (2.23), 6.805 (2.34), 7.725 (2.45), 7.730 (3.10), 7.754 (1.58), 7.759 (1.18), 7.777 (1.40), 7.782 (1.18), 10.873 (4.35).

Example 277.

(6S)-6-Methyl-5-[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

H ₃ C, O^O h ₃ c' ^N ^ p-Lf

A solution of (6S)-5-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (200 mg, 0.68 mmol, intermediate compound 74) and 1-methylpiperazine (1.52 ml, 13.67 mmol) in N,N-dimethylacetamide (0.6 ml) were heated at 140°C for 16 h. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium chloride solution, the organic layer was isolated and washed saturated aqueous sodium chloride solution (x4), dried (MgSO ₄ ), filtered and concentrated in vacuo. The resulting material was purified by Biotage Isolera™ chromatography (silica gel eluting with 0:1-1:9 MeOH/DCM), desired fractions were combined and concentrated in vacuo to give the crude desired compound (66 mg @ 83% pure). This material was then purified by reverse phase Biotage Isolera™ chromatography (C18 eluting with MeCN-Water, 1:9-1:0), the desired fractions were pooled and lyophilized to give the title compound (9.8 mg, 4%) as a solid pale pink substance.

LCMS (method 3, 2 min) 92% at R _t = 0.83 min, MS (ESIpos): m/z = 357.10 (M+H)+.

LCMS (mS18, 7 min) 92% at Rt = 2.60 min, MS (ESIpos): m/z = 357.45 (M+H) ⁺ .

'H NMR (500 MHz, DMSO-d6) δ = 1.43 (d, J=6.9 Hz, 3H), 2.23 (s, 3H), 2.46 (s, 2H), 2.93 (t, J=4.7 Hz, 4H) , 5.85 (q, J=6.9Hz, 1H), 7.56 (d, J=8.5Hz, 1H), 7.95 (dd, J=8.5, 2.0Hz, 1H), 8.00 (d, J=2.1Hz, 1H) , 11.17 (s, 1H) - 2 missing piperazine ring proton signals covered by the solvent peak.

Example 278.

5-[4-(2-Hydroxypropan-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

To a solution of 5-[4-acetyl-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (100 mg, 0.35 mmol, intermediate 70) in 15 ml tetrahydrofuran was added methylmagnesium bromide, 0.12 ml (3.5 mmol, 3 mol/l in diethyl ether) at 0°C. The resulting mixture was stirred at 0° C. for 1 hour under nitrogen. Upon completion of the reaction, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, the residue was purified by preparative HPLC [Column: XBridge, RP18 OBD 19x150 mm; Mobile phase A: water (0.1% NH4HCO3), Mobile phase B: ACN; flow rate: 20 ml/min; gradient: 25% B - 40% B over 8 min, held 1.5 min; 254 and 220 nm, R _t : 6.28 min] to give 35.4 mg (33%) of the title compound as a white solid.

MS (ESIpos): m/z = 303 (M+H) ⁺ .

'H NMR (400 MHz, DMSO-d6): δ[ppm] = 11.16 (s, 1H), 8.05 (d, 1H), 7.87 (dd, 1H), 7.80 (d, 1H), 5.41 (s, 2H ), 5.23 (s, 1H), 1.55 (s, 6H).

Example 279.

(6S)-5-[4-(3,3-Difluoroazetidin-1 -yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one

- 238 041614

Suspension of (6S)-5-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (100 mg, 0.34 mmol, intermediate 74), 3,3-difluoroazetidine hydrochloride (60.3 mg, 0.47 mmol), potassium phosphate (197 mg, 0.93 mmol), tris(dibenzylideneacetone)dipalladium(0) (14.2 mg, 0.02 mmol), and 2-(dicyclohexylphosphino) -2',4',6'-tri-iso-propyl-1,1'-biphenyl//XPhos (29.6 mg, 0.06 mmol) in

1,4-dioxane (1.5 ml) was degassed with a nitrogen-filled balloon and heated at 100°C for 20 h. After this time, the reaction mixture was cooled to room temperature and partitioned between IPA/DCM (1:4 vol:vol. ) and water, the organic layer was separated by means of a phase separation cartridge and concentrated in vacuo. The resulting material was purified by Biotage Isolera™ chromatography (silica gel eluting with EtOAc/heptane (0:1 - 1:1 - 1:0), desired fractions were combined and concentrated in vacuo to give 70 mg (54% yield) of the title compound in as a pale yellow solid.

LCMS (method 3, 2 min) 99% at R _t = 1.17 min, MS (ESIpos): m/z = 390.95 (M+MeCN+H)+.

LCMS (method 3, 7 min) 92% at R _t = 4.02 min, MS (ESIpos): m/z = 390.95 (M+MeCN+H)+.

¹ H NMR (500 MHz, DMSO-d6) δ = 1.40 (d, J=6.9 Hz, 3H), 4.51 (t, J=12.3 Hz, 4H), 5.83 (q, J=6.9 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H), 7.85 (dd, J=8.8, 2.1 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 11.03 (s, 1H).

Example 280.

(6S)-5-[4-(3-Hydroxy-3-methylazetidin-1-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H1,3,4-oxadiazin-2 -He

The title compound was synthesized analogously to Example 280 from Intermediate 74 and 3-hydroxy-3-methylazetidine.

LCMS (method 3, 2 min) 97% at R _t = 1.04 min, MS (ESIpos): m/z = 334.00 (M+H)+.

LCMS (method 3, 7 min) 100% at R _t = 3.52 min, MS (ESIpos): m/z = 334.00 (M+H)+.

1H NMR (500 MHz, DMSO-d6) δ = 1.40 (d, J=6.9 Hz, 3H), 1.45 (s, 3H), 3.91 (d, J=8.2 Hz, 2H), 3.96 (d, J=8.2 Hz, 2H), 5.62 (s, 1H), 5.78 (q, J=6.9 Hz, 1H), 6.63 (d, J=8.9 Hz, 1H), 7.76 (dd, J=8.9, 2.1 Hz, 1H), 7.83 (d, J=2.1 Hz, 1H), 10.95 (s, 1H).

Example 281.

5-{4-[(2-methoxybutyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

H ⁿ sC' ° x ^

G nA4

HgC' ⁿ / ^F A

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.17 min; MS (ESIpos): m/z = 346 [M+H]+.

Example 282.

5-[4-{[3-(1H-imidazol-1-yl)propyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.51 min; MS (ESIpos): m/z = 368 [M+H]+.

Example 283.

5-{4-[(2-Hydroxy-2-methylpropyl)(methyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one

- 239 041614

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.00 min; MS (ESIpos): m/z = 346 [M+H] ⁺ .

Example 284.

5-[4-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one

nia

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.08 min; MS (ESIpos): m/z = 370 [M+H]+.

Example 285.

5-{4-[(1-hydroxypentan-2-yl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2 one

nia

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.04 min; MS (ESIpos): m/z = 346 [M+H] ⁺ .

Example 286.

5-[4-{[(1 -methyl-1 H-pyrazol-3 -yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4 oxadiazin-2 -He

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): Rt = 0.93 min; MS (ESIpos): m/z = 354 [M+H] ⁺ .

Example 287.

1-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]azetidine-3carboxamide

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.74 min; MS (ESIpos): m/z = 343 [M+H] ⁺ .

Example 288.

5-[4-{[(pyridin-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.61 min; MS (ESIpos): m/z = 351 [M+H] ⁺ .

Example 289.

- 240 041614

5-{4-[(4-Hidroxycyclohexyl)(methyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.00 min; MS (ESIpos): m/z = 372 [M+H]+.

Example 290.

5-[4-{[(5-oxopyrrolidin-2-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.76 min; MS (ESIpos): m/z = 357 [M+H]+.

Example 291.

5-[4-{[2-(1H-imidazol-5-yl)ethyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.49 min; MS (ESIpos): m/z = 354 [M+H]+.

Example 292.

5-[4-{[(2R,3R)-1,3-dihydroxybutan-2-yl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2- He

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.76 min; MS (ESIpos): m/z = 348 [M+H]+.

Example 293.

5-[4-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2- He

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): Rt= 1.11 min; MS (ESIpos): m/z = 360 [M+H]+.

Example 294.

5-[4-{[(oxan-4-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- 241 041614

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.02 min; MS (ESIpos): m/z = 358 [M+H]+.

Example 295.

5-[4-{[(1 -methyl-1 H-imidazol-2-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2- He

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.45 min; MS (ESIpos): m/z = 354 [M+H] ⁺ .

Example 296.

5-{4-[(dicyclopropylmethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazine-2-

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.32 min; MS (ESIpos): m/z = 354 [M+H] ⁺ .

Example 297.

5-[4-{[2-(1H-1,2,3-triazol-1-yl)ethyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazine -2-he n

An ^ ^N V°

N / ^F F ^F

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.78 min; MS (ESIpos): m/z = 355 [M+H] ⁺ .

Example 298.

5-[4-{[(4-methyloxan-4-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.11 min; MS (ESIpos): m/z = 372 [M+H] ⁺ .

Example 299.

5-[4-{[(pyrimidin-5-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

- 242 041614

LC-MS (method 1): Rt = 0.80 min; MS (ESIpos): m/z = 352 [M+H]+.

Example 300.

5-[4-{[(1 -methyl-1 H-pyrazol-4-yl)methyl] amino } -3 -(trifluoromethyl)phenyl] -3,6-dihydro-2H-1,3,4oxadiazin-2- He

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): Rt = 0.89 min; MS (ESIpos): m/z = 354 [M+H]+.

Example 301.

5-{4-[(1-methylazepan-4-yl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): Rt = 0.53 min; MS (ESIpos): m/z = 371 [M+H]+.

Example 302.

5-[4-(4,6-dimethyl-1,4-diazepan-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): Rt = 0.55 min; MS (ESIpos): m/z = 371 [M+H] ⁺ .

Example 303.

K-methyl-N ³ -[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]-beta alanine amide

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.76 min; MS (ESIpos): m/z = 345 [M+H] ⁺ .

Example 304.

N-methyl-1-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]prolinamide

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): Rt = 0.90 min; MS (ESIpos): m/z = 371 [M+H] ⁺ .

Example 305.

5-[4-{[(1-methyl-5-oxopyrrolidin-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H1,3,4-oxadiazin-2-one

- 243 041614

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.81 min; MS (ESIpos): m/z = 371 [M+H] ⁺ .

Example 306.

Ethyl-N ² -[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]glycinamide

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): Rt = 0.81 min; MS (ESIpos): m/z = 345 [M+H] ⁺ .

Example 307.

N,N-dimethyl-N ² -[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]glycinamide

LC-MS (method 1): Rt = 0.88 min; MS (ESIpos): m/z = 345 [M+H]+.

Example 308.

5-[4-{[(pyridazin-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2onium

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.79 min; MS (ESIpos): m/z = 352 [M+H] ⁺ .

Example 309.

5-{4-[(1-methylpiperidin-4-yl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2 one

nia

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): Rt = 0.48 min; MS (ESIpos): m/z = 357 [M+H] ⁺ .

Example 310.

- {4-[3-(dimethylamino)pyrrolidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4 oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.50 min; MS (ESIpos): m/z = 357 [M+H] ⁺ .

Example 311.

5-{4-[(2-methylpiperidin-4-yl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2one

- 244 041614

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.52 min; MS (ESIpos): m/z = 357 [M+H]+.

Example 312.

5-[4-{[3-(4H-1,2,4-triazol-4-yl)propyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazine -2-he

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.71 min; MS (ESIpos): m/z = 369 [M+H] ⁺ .

Example 313.

5-[4-{[2-(2-oxoimidazolidin-1-yl)ethyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): Rt = 0.77 min; MS (ESIpos): m/z = 372 [M+H] ⁺ .

Example 314.

3-{ethyl[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2(trifluoromethyl)phenyl]amino}propanenitrile

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 1.15 min; MS (ESIpos): m/z = 341 [M+H] ⁺ .

Example 315.

5-[4-{[(1-ethylpyrrolidin-2-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.50 min; MS (ESIpos): m/z = 371 [M+H] ⁺ .

Example 316.

N-{2-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)anilino]ethyl}acetamide

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.75 min; MS (ESIpos): m/z = 345 [M+H] ⁺ .

Example 317.

5-[4-{[2-(piperidin-1-yl)ethyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.51 min; MS (ESIpos): m/z = 371 [M+H]+.

Example 318.

5-[4-{[2-(1-methylpyrrolidin-2-yl)ethyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was prepared analogously to Example 226 from Intermediate 66.

LC-MS (method 1): R _t = 0.52 min; MS (ESIpos): m/z = 371 [M+H] ⁺ .

Example 319.

5-{4-[(3-hydroxy-3-methylbutyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin2-one

The title compound was prepared analogously to Example 132 from Intermediate 66.

LC-MS (method 1): R _t = 0.99 min; MS (ESIpos): m/z = 346 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.157 (16.00), 1.663 (0.83), 1.681 (1.79), 1.698 (0.85), 2.518 (0.61), 3.273 (0.44), 3.290 (1.02), 3.302 (1.01), 3.320 (0.55), 4.668 (3.46), 5.293 (7.07), 6.407 (0.73), 6.832 (0.98), 6.855 (1.03), 7.723 (1.11), 7.728 (1.73), 7.735 (0.96), 7.757 (0.70), 7.762 (0.56), 10.870 (2.45).

Example 320.

5-[4-{[4-aminocyclohexyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (mixture of stereoisomers)

The title compound was prepared analogously to Example 132 from Intermediate 66.

LC-MS (method 2): R _t = 0.96 min; MS (ESIpos): m/z = 357 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.311 (0.95), 1.338 (1.33), (2.17), 1.597 (2.32), 1.611 (1.90), 1.621 (1.94), 1.630 (1.54), 1.748 (1.66), (1.14), 1.880 (0.48), 1.907 (0.51), 2.518 (2.24), 2.523 (1.56), 2.539 (0.82),

1.566 (1.33), 1.575 (1.72), 1.587

1.759 (1.27), 1.768 (1.26), 1.777

2.836 (0.86), 3.324 (1.17), 3.627 (0.62), 4.882 (0.98), 4.903 (0.97), 5.293 (4.48), 5.300 (16.00), 6.953 (1.71), 6.975 (1.87), 7.718 (0.92), 7.727 (0.59), 7.741 (6.05), 7.761 (1.52), 10.894 (0.40).

Example 321.

5-{4-[(2-amino-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin2-one

- 246 041614

The title compound was prepared analogously to Example 132 from Intermediate 66.

LC-MS (method 2): Rt = 0.96 min; MS (ESIpos): m/z = 331 [M+H]+.

'H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.092 (16.00), 1.621 (0.70), 2.518 (1.01), 2.523 (0.65), 2.971 (1.78), 2.983 (1.77), 5.299 (7.03 ), 5.857 (0.60), 6.867 (0.81), 6.891 (0.86), 7.737 (2.42), 7.754 (0.74), 10.880 (1.18).

Example 322.

5-[4-{[3-aminocyclohexyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (mixture of stereoisomers)

The title compound was prepared analogously to Example 132 from Intermediate 66.

LC-MS (method 1): Rt = 0.72 min; MS (ESIpos): m/z = 357 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.147 (0.69), 1.170 (0.75), 1.195 (0.50), 1.239 (0.68), 1.261 (1.15), 1.292 (1.73), 1.314 (1.43) , 1.337 (1.03), 1.357 (1.07), 1.382 (0.92), 1.404 (0.64), 1.457 (0.43) . , 4.871 (0.42), 5.289 (16.00), 5.300 (5.89), 6.897 (1.75), 6.920 (1.84), 6.956 (0.72), 6.979 (0.78), 7.713 (7.13), 7.732 (2.73), 7.738 (2.60) , 7.748 (0.88), 7.770 (0.58), 10.877 (0.75).

Example 323.

5-[4-{[2-(dimethylamino)ethyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one

The title compound was prepared analogously to Example 132 from Intermediate 66.

LC-MS (method 1): R _t = 0.58 min; MS (ESIpos): m/z = 331 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.186 (16.00), 2.467 (0.79), 2.483 (2.15), 2.518 (0.97), 2.522 (0.61), 3.252 (0.87), 3.264 (0.85 ), 5.302 (5.87), 5.779 (0.49), 6.877 (0.75), 6.899 (0.78), 7.740 (0.81), 7.744 (1.20), 7.756 (0.61), 7.778 (0.50), 7.784 (0.41), 10.894 (1.17 ).

Example 324.

5-[4-{[2-(dimethylamino)ethyl](methyl)amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one

The title compound was prepared analogously to Example 132 from Intermediate 66.

LC-MS (method 2): R _t = 1.06 min; MS (ESIpos): m/z = 345 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.083 (16.00), 2.285 (0.78), 2.304 (0.89), 2.308 (0.61), 2.322 (0.99), 2.518 (0.86), 2.523 (0.55), 2.720 (5.24), 3.062 (0.75), 3.081 (0.82), 3.098 (0.69), 5.383 (5.03), 7.549 (0.60), 7.569 (0.66), 7.892 (0.42), 7.897 (0.61), 7.918 (2.09), 11.100 (0.79).

Example 325.

5-[4-(2-methyl-1,3-benzothiazol-5-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- 247 041614

The title compound was prepared analogously to Example 3 from intermediate

64.

LC-MS (method 2): Rt = 1.19 min; MS (ESIpos): m/z = 392 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.154 (1.24), 1.171 (2.57), 1.189 (1.26), 1.987 (4.28), 2.518 (1.06), 2.523 (0.71), 2.831 (16.00) 4.017 (0.97), 4.034 (0.97), 5.489 (10.98), 7.341 (1.21), 7.344 (1.21), 7.361 (1.26), 7.364 (1.26), 7.582 (1.81), 7.603 (1.95), 7.848 (2.36) , 8.029 (1.22), 8.033 (1.26), 8.049 (1.08), 8.053 (1.18), 8.112 (2.79), 8.135 (4.89), 11.257 (4.10).

Example 326.

5-[4-(2-methyl-1H-benzimidazol-5-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one

The title compound was prepared analogously to Example 3 from Intermediate 64.

LC-MS (method 2): R _t = 0.87 min; MS (ESIpos): m/z = 375 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (3.86), 2.518 (2.91), 2.523 (1.64), 5.478 (16.00), 7.042 (1.26), 7.062 (2.20), 7.083 (1.18), 7.346 (2.05) 7.430 (2.27) 7.450 (2.16) 7.471 (1.90) 7.524 (1.62) 7.540 (3.42) 7.560 (2.98) 7.988 (2.21) 8.008 (2.00) 11.231 (4.23), 11.235 (3.86), 12.311 (1.82), 12.342 (1.57).

Example 327.

5-[4-(3-methyl-1H-indazol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was prepared analogously to Example 3 from Intermediate 64.

LC-MS (method 2): Rt = 1.04 min; MS (ESIpos): m/z = 375 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.524 (16.00), 5.486 (11.79), 5.758 (0.87), 7.007 (1.57), 7.028 (1.65), 7.371 (3.17), 7.557 (2.09) , 7.578 (2.25), 7.754 (2.38), 7.774 (2.27), 8.011 (1.48), 8.015 (1.50), 8.032 (1.32), 8.035 (1.39), 8.120 (2.90), 8.123 (2.68), 11.251 (4.44) , 12.748 (3.12).

Example 328.

5-[4-(1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one

F F

The title compound was prepared analogously to Example 3 from Intermediate 64.

LC-MS (method 2): Rt = 0.89 min; MS (ESIpos): m/z = 326 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.074 (0.93), 2.162 (1.73), 2.518 (2.42), 2.522 (1.40), 2.539 (0.52), 2.890 (2.15), 3.362 (1.06) , 3.537 (0.43), 5.418 (16.00), 5.601 (1.78), 7.409 (1.05), 7.429 (1.21), 7.916 (1.72), 7.936 (1.59), 7.982 (2.87), 11.188 (0.95).

Example 329.

5-[3-(difluoromethyl)-4-(2,5-dihydrofuran-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

- 248 041614

The title compound was prepared analogously to Example 198 from Intermediate 77.

MS (ESIpos): m/z = 293 (M-H) ⁺ .

Example 330.

5-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

The title compound was synthesized analogously to Example 3 from Intermediate 65.

LC-MS (method 1): R _t = 0.75 min; MS (ESIpos): m/z = 288 [M+H] ⁺ .

Experimental part - biological analyses.

Examples were tested in selected biological assays one or more times. When tested more than once, the data is reported as either means or averages, where the mean, also called the arithmetic mean, is the sum of the values obtained divided by the number of times tested, and the mean is the mean of the group of values when ranked in ascending or descending order. If the number of values in the dataset is odd, the average is the average. If the number of values in the dataset is even, the average is the arithmetic mean of the two averages.

The examples have been synthesized one or more times. When synthesizing more than once, biological assay data are averages or averages calculated using datasets from testing one or more batches of synthesis.

The in vitro activity of the compounds of the present invention can be demonstrated in the following assays.

Analysis 1.

Measurements of cell proliferation.

The antiproliferative activity of the compounds of general formula (I) was investigated in vitro in human cancer cells. For this, an appropriate number of cells (Hela: 800; SK-MEL-3: 1000; A549: 800) were plated in 384-well plates with the appropriate growth medium ((A549: DMEM/Ham's F12 (Biochrom; # FG 4815 with stable glutamine) , FCS 10% ultimate (Biochrom; # S 0415); Hela: DMEM/Ham's F12 (Biochrom; # FG 4815 with stable glutamine), FCS 10% ultimate (Biochrom; # S 0415); SK-MEL-3: McCoy's 5A (Biochrom; # F 1015), FCS 10% final (Biochrom; # S 0415), L-alanyl-L-glutamine final: 2 mM, (Biochrom; # K 0302)) and incubated at 37° C. overnight. h cells on one plate (0 hour plate) were treated with 30 µl/cavity of CTG solution (Promega Cell Titer Glo (catalog nos G755B and G756B)) and incubated at room temperature for 10 minutes and luminescence measured with VICTOR V ( Perkin Elmer) to determine cell viability at the start of treatment.Cells on a test plate were treated with compounds of general formula (I) and incubated at 37°C for 72 hours. to cells using the digital pipette HP D300 in a series of 10 (or more) 2.5-fold dilutions, generally starting at a maximum final drug concentration of 100nM. As a control, cells were treated with medium (DMSO at a final concentration of 0.3%). After 72 h, cells were treated with 20 µl/density of CTG solution (Promega Cell Titer Glo (catalog nos G755B and G756B)) and incubated at room temperature for 10 min, and luminescence measured with VICTOR V (Perkin Elmer) to determine cell viability at the end of processing. The percentage effect on cell growth and their resulting IC ₅₀ were determined for each test substance using values from 0 h plate (=maximum inhibition) and DMSO control (=minimum inhibition). IC ₅₀ values were calculated using 4-way fitting.

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table 2

Antiproliferation IC ₅₀ values of some in vitro examples in various cell lines

Example (Intermediate connection where indicated) HeLa SK-MEL-3 IGR37 1C ₅₀ [nM] IC50 [nM] IC50 [nM] (Cervical cancer) (melanoma) (melanoma) 1 2 3 3 3 7 4 7 16 5 3 5 6 5 9 7 5 13 8 6 18 16 9 15 33 10 15 43 AND 19 49 13 27 82 15 8 16 17 7 17 18 18 74 20 15 41 21 15 >67 23 45 >100

- 250 041614

24 55 >100 25-1 2 3 25-2 3 5 26 9 29 27 2 6 29 46 >100 thirty 1 4 31 4 AND 14 32 5 7 33 6 10 34 3 765 36 23 39 37 37 12 38 83 >100 39 4 6 40 5 7 41 10 21 42 55 64 43 34 48 44 14 9 45 3 4 47 2 2 48 8 16 49 6 13 50 81 19800

- 251 041614

51 thirty 49 53 36 13000 54 1 3 55 7 14 56 5 10 58 40 64 59 18 38 60 13 20 61 10 16 62 6 14 63 1 3 64 17 41 65 2 3 66 2 3 67 3 5 68 4 6 69 1 1 70 15 29 71 20 38 72 2 5 74 AND 23 76 6 13 13 77 8 16 78 10 21 79 12 25

- 252 041614

80 2 6 81 4 9 82 4 9 83 3 6 84 19 48 85 7 13 86 6 25 87 10 32 88 2 6 89 2 5 90 16 thirty 91 14 17 92 2 4 4 93 7 13 94 16 36 96 18 40 97 5 8 98 5 8 99 5 eleven 100 5 9 101 2 4 102 23 40 103 3 6 105 8 15 106 9 16

- 253 041614

107 6 12 108 6 13 109 4 9 BY 8 14 111 2 4 112 6 10 FROM 2 6 114 4 7 115 4 7 116 16 35 117 5 9 118 3 6 119 5 7 120 0.3 1 121 5 10 12 126 1 1 2 131 2 6 132 16 38 133 32 51 134 12 26 135 1 3 3 136 0.3 1 137 1 3 138 7 19 139 14 29 40

- 254 041614

140 1 1 141 2 3 142 3 4 143 15 thirty 144 6 13 145 27 47 146 1 2 2 147 22 39 148 53 >100 149 2 4 150 2 5 151 5 5 152 21 56 153 4 7 154 2 4 155 9 17 156 55 68 157 44 71 158 22 40 159 AND 22 160 27 47 161 6 10 12 162 4 7 163 8 14 164 6 8

- 255 041614

165 1 1 1 166 1 1 1 167 4 6 168 14 25 169 20 32 170 27 40 171 18 31 172 37 48 173 15 27 174 1 1 1 175 6 3 176 2 4 177 12 17 178 13 19 179 8 15 180 36 48 181 3 6 182 39 54 183 15 22 184 5 6 185 4 6 187 23 40 188 22 38 189 6 12 190 0.2 0.4 0.4

- 256 041614

191 0.4 1 1 192 2 6 7 193 5 9 195 2 5 196 15 31 33 197 5 10 198 6 14 199 2 5 200 10 22 201 3 9 202 5 12 203 1 2 204 1 2 205 4 5 206 0.5 1 207 9 14 208 5 7 209 7 7 210 6 8 211 2 2 212 1 2 213 14 21 214 1 2 215 2 3 216 6 7

- 257 041614

217 14 16 218 3 4 219 8 13 220 6 14 221 1 2 222 1 1 223 6 9 224 2 3 225 3 5 226 1 2 2 227 1 228 7 229 1 230 7 231 2 232 2 5 4 233 8 234 2 235 4 236 4 237 0.4 238 7 239 0.3 1 1 240 3 12 10 241 6

- 258 041614

242 2 243 6 244 3 245 3 246 12 247 10 248 6 249 1 250 2 251 2 5 4 252 1 253 1 40 5 254 2 255 5 256 37 63 257 6 9 258 3 6 259 1 3 260 1 3 261 38 >100 262 2 5 263 9 32 264 2 2 265 2 5 7 266 19 35 65

- 259 041614

267 2 5 7 268 1 3 269 6 17 24 270 9 15 271 1 3 272 1 1 273 1 1 274 19 31 275 5 7 276 27 49 50 277 0.3 1 1 278 58 80 279 1 2 2 280 0.1 0.4 0.4 Intermediate 64 29 53 Intermediate 66 56 >100 Intermediate 72 78 260 Intermediate 73 58 >100 Intermediate 74 6 AND Intermediate 75 22 45

- 260 041614

Intermediate 76 40 75 Intermediate 77 40 65 Intermediate 78 8 20 Intermediate 67 >100 >100 12 20 58 14 49 64 22 26 51 28 14 28 35 39 25 46 21 34 52 48 >100 73 25 46 75 22 44 95 33 >100 104 37 17 127 >100 >100 128 >100 >100 129 >100 >100 130 >100 25600 186 61 71 281 12

- 261 041614

282 13 283 13 284 14 285 14 286 23 287 23 288 26 289 26 290 32 291 35 292 43 293 43 294 45 295 47 296 59 297 59 298 62 299 69 300 90 301 >100 302 >100 303 >100 304 >100 305 >100 306 >100

- 262 041614

307 >100 308 >100 309 >100 310 >100 311 >100 312 >100 313 >100 314 >100 315 >100 316 >100 317 >100 318 >100 319 61 >100 320 >100 >100 321 >100 54 322 >100 >100 323 >84 >100 324 >100 >100 325 >100 >100 326 >100 >100 327 >100 >100 328 47 >100 329 41 64 330 >100 >100

One aspect of the present invention is the use of compounds of formula (I) for the treatment of cervical cancer.

Another aspect of the present invention is the use of compounds of formula (I) for the treatment of skin cancer, especially melanoma.

Another aspect of the present invention is the use of compounds of formula (I) for the treatment of skin cancer, especially melanoma, and cervical cancer.

Another aspect of the present invention are compounds of formula (I) which are effective in inhibiting tumor cell proliferation (eg on HeLa cells) with IC ₅₀ values < 100 nM.

Table 3-1

Antiproliferation IC ₅₀ values of some in vitro examples on various cell lines

Example 31 92 139 146 267 269 277 cell line 1C ₅₀ [nM] mammary gland Hs 578T >100 31 >100 28 34 66 >100 erythroleukemia HEL 92.1.7 47 9 >100 13 26 44 >100 glioblastoma DK-MG 39 17 61 12 18 49 >100 glioblastoma DBTRG05-MG 56 18 >100 14 35 50 >100 Melanoma CHL-1 28 AND 58 8 16 47 >100 Melanoma A-2058 51 18 >100 16 40 61 >100 teratocarcinoma of the ovary RA-1 39 17 >100 12 44 49 >100

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Table 3-2

Antiproliferation IC ₅₀ values of some in vitro examples on various cell lines

Example 1 3 4 7 8 135 cell line IC ₅ o [nM] Astrocytoma H4 thirty 25 47 44 50 dairy gland Hs 578T 29 erythroleukemia I HEL 92.1.7 20 25 glioblastoma DK-MG 21 lung NCI- H1734 19 13 40 26 42 Melanoma IGR-1 89 99 >100 Melanoma CHL-1 9 Melanoma HMCB 19 26 13 Melanoma COLO741 1 Melanoma C32 15 Melanoma A-2058 24 ovarian teratocarcinoma PA-1 22

Analysis 2.

Measurement of cell proliferation.

The antiproliferative activity of the compounds of general formula (I) was found in vitro in human cancer cells. For this, 500 cells including HeLa cells, A2058 cells, DU145 cells, HMCB cells, IGR37 cells, NCIH1734 cells, 0SRC2 cells, or 750 cells including CAL51 cells, COLO741 cells, DBTRG05MG cells, DKMG cells, G292CLONEA141B1 cells, GB1 cells, HEL cells, HEL9217 cells, JHUEM1 cells, L3.3 cells, LI7 cells, TE4 cells, or 1000 cells, including 8505C cells, HUT78 cells, NCIH1563 cells, NCIH2122 cells, NCIH2172 cells, RVH421 cells, SKMEL3 cells, or 1500 cells, including C32 cells, HS578T cells, JHOM1 cells, NCIH196 cells, OVKATE cells, were plated in 384-well plates with suitable growth medium and incubated at 37°C overnight. After 24 hours, the cells on the test plate were treated with compounds of general formula (I) and incubated at 37°C for 72 hours. The compounds were added to the cells using a digital dispenser HP D300 in a series of 10 (or more) step dilutions. As a control, cells were treated with medium (DMSO at a final concentration of 0.3%). After 72 hours, cells were treated with 20 µl/density of a 50% CTG solution in PBS (Promega Cell Titer Glo (catalog nos. G755B and G756B)) and incubated at room temperature for 10 minutes, and luminescence measured with a VICTOR V (Perkin Elmer ) to determine cell viability at the end of treatment. The percentage effect on cell growth and their resulting IC ₅₀ were determined for each test substance using values from untreated wells (=percent viability). IC ₅₀ values were calculated using 4-way fitting.

Table 4

Antiproliferation IC ₅₀ values of some in vitro examples in various cell lines

Example number Example 135 146 265 cell line 1C ₅₀ [nM] mammary gland, ductal carcinoma HS578T 33 20 116 breast NS CAL51 37 cervix HeLa 2 2 5

- 264 041614

glioma_astrocytoma DKMG 22 13 59 lung adenocarcinoma NCIH1563 18 46 lung adenocarcinoma NCIH2122 3 Non-small cell lung cancer H2172 38 37 101 Small cell lung cancer H196 150 32 355 Melanoma A2058 38 25 96 Melanoma C32 58 52 132 Melanoma RVH421 140 47 262 Melanoma SKMEL3 5 3 10 squamous cell carcinoma esophagus TE4 15 41 ovarian adenocarcinoma JHOM1 8 NS pancreas L3.3 82 15 312 prostate NS DU145 14

Thus, one aspect of the present invention is the use of compounds of formula (I) for the treatment of brain cancer (especially glioma, more specifically glioblastoma, astrocytoma), breast cancer (especially ductal carcinoma and adenocarcinoma), cervical cancer, AML (especially erythroleukemia) , lung cancer (especially NSCLC adenocarcinoma and SCLC), skin cancer (especially melanoma), esophageal cancer (especially squamous cell carcinoma), ovarian cancer (especially teratocarcinoma, adenocarcinoma), pancreatic cancer and prostate cancer.

Analysis 3.

In vivo xenograft models.

The antitumor activities of the compounds of examples 135 and 146 were investigated in murine xenograft models of human cancer. To do this, tumor cells were implanted subcutaneously in mice. With an average tumor size of 20-40 mm ^{2 ,} animals were randomized into treatment and control groups (at least n = 10 animals/group, and treatment was started with vehicle alone or with the appropriate compound (composition: 90% PEG400/10% ethanol; route of administration: in Oral volume was 10 ml/kg In the case of double daily treatments, the interval between two applications per day was 6-7 hours Tumor size and body weight were determined at least weekly. was determined using an electronic caliper [length (mm) x width (mm)].The experiment was terminated when the study reached a predetermined ethical endpoint based on German and European guidelines for animal husbandry.In vivo antitumor efficacy is presented as the ratio T/ C at the end of the study (Treatment/Control; mean tumor weight of the treatment group/mean tumor weight of the control group) in Table 8. A compound having a T/C below 0.5 determines as active (i.e. efficient). Statistical analysis was carried out using the SigmaStat software. A one-way analysis of variance was performed and differences with controls were compared using a pairwise comparison procedure (Dune's method).

The compounds of examples 135 and 146 showed strong antitumor efficacy in various xenograft models of human tumors when used alone. In particular, the Compound of Example 135 and/or Example 146 was effective in reducing the tumor area of cervical cancer, ovarian teratocarcinoma, AML and melanoma.

- 265 041614

Table 5

Antitumor Activity of Example 135, Example 146, and Example 265 in Various Mouse Xenograft Human Cancer Models

Xenograft model A cell line isolated from a patient with Example Dose and regimen T/C IGR-37 Melanoma 146 10 mg/kg 2QD po 0.05* IGR-37 Melanoma 135 10 mg/kg 2QD po 0.06* HEL92.1.7 AML 146 40 mg/kg 2QD po 0.08* HeLa cervical cancer uterus 146 5 mg/kg 2QD po 0.08* A2058 Melanoma 146 10 mg/kg 2QD po 0.23* RA-1 Teratocarcinoma of the ovaries 146 20 mg/kg 2QD po 0.49* RA-1 Teratocarcinoma of the ovaries 135 5 mg/kg 2QD po 0.63 IGR-37 Melanoma 265 10 mg/kg 2QD po 0.27*

* P < 0.05 treatment versus control at end of study

T/S = ratio of mean final tumor weight in the treatment group to mean final tumor weight in the control group

The abbreviation 2QD means twice a day, r.o. means by mouth or orally.

Analysis 4.

A method for inhibiting the PDE3A enzyme.

A commercially available 3H-cAMP proximity scintillation assay system (SPA, Perkin Elmer) was used for enzyme inhibition studies. To determine the in vitro effect of the compounds of Example on the PDE3A reaction, 2 μl of the appropriate solution of the compound of Example in DMSO (serial dilutions) were placed in the wells of microtiter plates (Isoplate-96/200W; Perkin Elmer). 50 µl dilution of PDE3A cell extract from Sf9 cells overexpressing full-length human PDE3 A (SB Drug Discovery, UK) in buffer A (50 mM Tris/HCl pH 7.5, 8.3 mM MgCl ₂ , 1.7 mM EDTA, 0 .2% BSA) was added. The dilution of the PDE3A cell extract was chosen such that the reaction kinetics were linear and less than 70% of the substrate was consumed (typical dilution 1:5000). The reaction was started by adding 50 µl (0.025 µFU) 1:2000 in buffer A without BSA diluted substrate [8-3H]adenosine-3',5'-cyclic phosphate (1 µFU/µL; Perkin Elmer). After incubation at room temperature for 60 minutes, the reaction was stopped by adding 25 μl of a suspension containing 18 mg/ml of yttrium scintillation proximity beads (Perkin Elmer) in water. Microtiter plates were sealed and counted in a Microbeta scintillation counter (PerkinElmer Wallac). IC ₅₀ values were determined from sigmoid curves by plotting percent PDE3A activity versus log compound concentration.

Analysis 5.

Inhibition of the PDE3B enzyme.

A commercially available 3H-cAMP proximity scintillation assay system (SPA, Perkin Elmer) was used for enzyme inhibition studies. To determine the in vitro effect of the compounds of Example on the PDE3B reaction, 2 μl of the appropriate solution of the compound of Example in DMSO (serial dilutions) were placed in the wells of microtiter plates (Isoplate-96/200W; Perkin Elmer). 50 µl dilution of PDE3B cell extract from Sf9 cells overexpressing full-length human PDE3B (SB Drug Discovery, UK) in buffer A (50 mM Tris/HCl pH 7.5,

- 266 041614 .3 mM MgCl2, 1.7 mM EDTA, 0.2% BSA) was added. The dilution of the PDE3B cell extract was chosen such that the reaction kinetics were linear and less than 70% of the substrate was consumed (typical dilution 1:6000). The reaction was started by adding 50 µl (0.025 µFU) 1:2000 in buffer A without BSA diluted substrate [8-3H]adenosine-3',5'-cyclic phosphate (1 µFU/µL; Perkin Elmer). After incubation at room temperature for 60 minutes, the reaction was stopped by adding 25 μl of a suspension containing 18 mg/ml of yttrium scintillation proximity beads (Perkin Elmer) in water. Microtiter plates were sealed and measured in a Microbeta scintillation counter (PerkinElmer Wallac). IC ₅₀ values were determined from sigmoid curves by plotting percent PDE3B activity versus log compound concentration.

One aspect of the present invention are compounds of formula (I) which effectively inhibit tumor cell proliferation with IC ₅₀ values < 100 nM in, for example, HeLa cells, while IC ₅₀ values for enzymatic inhibition of PDE3A or PDE3B are often >2.5 times higher than IC ₅₀ values. for tumor cell proliferation.

Another aspect of the present invention are compounds of _formula (I) which effectively inhibit tumor cell proliferation with IC ₅₀ values < 100 nM in e.g. proliferation of tumor cells.

One aspect of the present invention are compounds of formula (I) which effectively inhibit tumor cell proliferation with IC ₅₀ values < 100 nM in, for example, HeLa cells, while IC ₅₀ values for enzymatic inhibition of PDE3A or PDE3B are often >30 times higher than IC ₅₀ values. for tumor cell proliferation.

Table 6

- 267 041614

23 380 270 24 180 110 25-1 44 22 25-2 17 15 26 700 270 27 75 110 29 300 160 thirty 99 79 31 310 603 32 67 110 33 65 80 34 100 100 36 280 320 37 150 130 38 210 260 39 72 75 40 42 39 41 31 31 42 170 250 43 96 85 44 190 200 45 43 34 47 53 33 48 240 240 49 230 190 50 260 210 51 >1000 >1000 53 580 390 54 100 89

- 268 041614

55 280 250 56 180 80 58 310 570 59 150 250 60 270 510 61 230 320 62 85 180 63 31 33 64 221 193 65 25 thirty 66 65 95 67 47 63 68 81 152 69 31 47 70 75 170 71 >1000 >1000 72 74 180 74 42 100 76 225 250 77 33 83 78 29 48 79 29 71 80 34 87 81 130 270 82 200 320 83 100 250 84 150 320 85 33 78 86 84 210

- 269 041614

87 81 230 88 110 250 89 110 140 90 43 100 91 68 85 92 68 130 93 50 100 94 91 280 96 50 110 97 65 130 98 100 120 99 88 100 100 48 66 101 28 39 102 170 280 103 66 140 105 48 100 106 120 240 107 150 160 108 26 22 109 46 32 110 100 140 111 72 81 112 170 230 FROM 210 215 114 92 100 115 92 100 116 79 76 117 77 95

- 270 041614

118 60 64 119 36 13 120 6 4 121 150 299 126 12 8 131 32 42 132 260 450 133 >1000 >1000 134 270 580 135 87 50 136 32 27 137 52 88 138 150 200 139 140 310 140 58 80 141 13 27 142 25 47 143 38 83 144 55 100 145 240 410 146 40 80 147 140 310 148 190 210 149 163 132 150 240 250 151 69 159 152 63 76 153 15 26 154 70 120

- 271 041614

155 92 110 156 440 650 157 >1000 >1000 158 500 720 159 >1000 >1000 160 >1000 >1000 161 66 49 162 210 120 163 35 51 164 300 200 165 77 66 166 69 42 167 34 66 168 170 220 169 180 240 170 190 180 171 150 210 172 290 520 173 58 58 174 27 16 175 26 24 176 37 35 177 160 130 178 140 130 179 140 110 180 250 250 181 74 77 182 220 260 183 200 170

- 272 041614

184 66 57 185 49 48 187 81 100 188 90 100 189 190 200 190 38 25 191 48 57 192 320 120 193 195 215 195 58 77 196 810 790 197 650 803 198 170 130 199 210 200 200 34 66 201 86 77 202 76 63 203 37 88 204 80 110 205 53 123 206 15 20 207 74 180 208 BY 140 209 275 533 210 140 363 211 29 54 212 26 24 213 68 71 214 59 73

- 273 041614

215 66 100 216 103 167 217 65 210 218 35 89 219 58 97 220 90 131 221 28 56 222 76 120 223 140 100 224 165 200 225 45 220 226 128 187 227 13 9 228 400 920 229 82 67 230 58 100 231 100 110 232 145 145 233 86 250 234 78 73 235 170 180 236 45 54 237 120 140 238 88 300 239 27 26 240 180 260 241 66 130 242 92 130 243 48 100

- 274 041614

244 120 150 245 75 100 246 95 210 247 65 180 248 61 140 249 100 110 250 120 120 251 61 97 252 BY 86 253 190 155 254 45 31 255 100 76 256 240 480 257 75 120 258 41 130 259 34 110 260 48 170 261 550 600 262 18 20 263 50 46 264 75 112 265 657 383 266 >1000 930 267 145 185 268 138 110 269 695 790 270 55 170 271 27 25 272 19 10

- 275 041614

273 44 53 274 300 400 275 29 64 276 79 240 277 100 87 278 >1000 >1000 279 20 23 280 AND 9 Intermediate 64 610 490 Intermediate 66 >1000 >1000 Intermediate 72 320 400 Intermediate 73 720 >1000 Intermediate 74 34 100 Intermediate 75 240 710 Intermediate 76 375 130 Intermediate 77 150 330 Intermediate 78 140 180 Intermediate 67 6 7 12 31 thirty 14 63 71

- 276 041614

22 52 33 28 31 40 35 79 75 46 27 17 52 65 thirty 73 18 41 75 31 78 95 37 79 104 35 58 127 78 31 128 280 270 129 970 770 130 200 160 319 70 180 320 76 220 321 290 500 322 580 780 323 >280 >910 324 >1000 >1000 325 56 150 326 17 thirty 327 AND 16 328 74 91 329 100 93

Analysis 6.

Method for human cryo-hepatocytes.

In vitro metabolic stability study on cryopreserved human hepatocytes (including calculation of in vivo hepatic clearance (CL) and maximum oral bioavailability (Fmax)).

Cryopreserved hepatocytes (eg, purchased from Celsis In VitroTechnologies) were briefly thawed, washed with 45 ml prewarmed GRO HT in vitro medium, and centrifuged for 5 min at 50 x g. The cell pellet was resuspended in 5 ml Krebs-Henseleit Butter(KHB). Cell viability was determined by trypan blue exclusion.

For metabolic stability analysis, liver cells were dispensed in WME containing 5% FCS into glass vials at a density of 1.0 x 16 viable cells/mL. The test compound was added to a final concentration of 1 μM. During the incubation, hepatocyte suspensions were continuously shaken at 580 rpm and aliquots were taken at 2, 8, 16, 30, 45, and 90 minutes, to which equal volumes of cold methanol were immediately added. The samples were frozen at -20°C overnight, after which they were centrifuged for 15 min at 3000 rpm, and the supernatant was analyzed using an Agilent 1290 HPLC system with LCMS/MS detection.

The half-life of the test compound was determined from a concentration-time plot. Based on the half-life, own clearances were calculated. Together with additional parameters: hepatic blood flow, the number of liver cells in vivo and in vitro. In vivo hepatic clearance (CL) and maximum oral bioavailability (Fmax) were calculated. In vivo hepatic clearance (CLblood) and maximum oral bioavailability (Fmax) were calculated using the following formula: CL'intrinsic [mL/(min*kg)] = kel [L/min]/((cellno/incubation volume [mL]) * fu,inc) * (cellno/liver weight [g]) * (specific liver mass [g liver/kg body weight]); CLblood thoroughly mixed [l/(h*kg)] = (QH [l/(h*kg)] * fu,blood * CL'intrinsic [l/(h*kg)] )/(QH [l/(h *kg] + fu,blood * CL'intrinsic [l/(h*kg]); Fmax = 1CLblood/QH, and using the following parameter values: hepatic blood flow - 1.32 l/h/kg human; liver specific gravity - 21 g /kg of body weight; liver cells in vivo - 1.1 x 10 ⁸ cells / g of liver, liver cells in vitro - 1.0x10 ⁶ /ml; fu, inc and fu, blood are taken as 1.

- 277 041614

Table 7

Test results of human cryo-hepatocytes

Sample Fmax [%] Ciblood [l/h/kg] 1 82 0.24 3 70 0.39 4 100 <0.01 7 75 0.33 9 85 0.19 31 52 0.64 71 86 0.19 76 80 0.27 111 76 0.32 121 90 0.13 135 26 0.98 140 61 0.51 146 60 0.53 161 59 0.55 162 53 0.62 1 82 0.24 3 70 0.39 4 100 <0.01 7 75 0.33 165 33 0.88 190 32 0.90 195 100 <0.01 198 67 0.44 199 29 0.94 203 54 0.61 224 74 0.35 256 95 0.07 260 35 0.86 265 61 0.51 267 80 0.27 268 78 0.30 269 69 0.41 270 100 <0.01 281 35 0.85

Analysis 7.

In vivo pharmacokinetics in non-rodent animals (eg dogs).

For in vivo pharmacokinetic experiments, test compounds were administered to non-rodent animals (e.g., female beagle dogs) intravenously (i.v.) at doses of 0.1 to 1 mg/kg and intragastrically (i.g.) at doses of 0.3 to 3 mg/kg in the form solutions using solubilizers such as, for example, PEG400 in well-tolerated amounts and usually as a short-term infusion (15 min).

Blood samples were taken, for example, at 2, 8, 15, 30, 45 minutes, 1 hour, 2, 4, 6, 8 and 24 hours post dosing from the great saphenous vein. Depending on the expected half-life, additional samples were taken at later time points (eg, 48, 72 h).

For pharmacokinetics after intragastric administration, test compounds were administered intragastrically to fasted non-rodents (eg, dogs). Blood samples were taken, for example, after 5,

- 278 041614 , 30, 45 min, 1 h, 2, 4, 6, 8 and 24 h after dosing. Depending on the expected half-life, additional samples were taken at later time points (eg, 48, 72 h). Blood was collected in lithium heparin tubes (Monovetten®, Sarstedt) and centrifuged for 15 min at 3000 rpm. A small aliquot (eg 100 μl) from the supernatant (plasma) was withdrawn and precipitated by adding an aliquot of ice-cold acetonitrile (eg 400 μl) and frozen at -20° C. overnight. Samples were subsequently thawed and centrifuged at 3000 rpm, 4°C for 20 min. Aliquots of the supernatants were taken for analytical testing using an Agilent HPLC system with LCMS/MS detection. PK parameters were calculated by non-compartmental analysis using PK calculation software.

PK parameters calculated from concentration time profiles after intravenous administration: CLplasma: total plasma clearance of the test compound (in L/kg/h); CLblood: total blood clearance of the test compound: CLplasma * Cp/Cb (abbreviation: CLp;) in l/kg/h), with Cp/Cb being the ratio of plasma to blood concentrations.

PK parameters calculated from concentration time profiles after intragastric administration: Cmax: maximum plasma concentration (in mg/l); Cmaxnorm: Cmax divided by the administered dose (in kg/l); Tmax: point in time at which Cmax was observed (in hours). Parameters calculated from both intravenous and intragastric administration, such as concentration-time profiles: AUCnorm: area under the concentration-time curve from t = 0 h to infinity (extrapolated) divided by the administered dose (in kg*h/l); AUC norm (0-tlast): area under the concentration-time curve from t = 0 h to the last time point for which plasma concentrations can be measured, divided by the administered dose (in kg * h / l); t1/2: terminal half-life (in hours); F: oral bioavailability: AUCnorm after intragastric administration divided by AUCnorm after intravenous administration (in%).

Table 8

Results of an in vivo pharmacokinetic test

Analysis 8.

In vivo pharmacokinetics in rodents (eg mice).

The maintenance and care of the animals was carried out in strict accordance with the European and German guidelines for the protection of laboratory animals. Animals received food and water as much as they wanted. To quantify circulating plasma compounds, a specific dose (1-100 mg/kg) was orally administered to female NMRInu/nu mice aged 6-8 weeks in solubilized form (n=3 mice at time).

Blood was collected in lithium heparin tubes (Monovetten®, Sarstedt) and centrifuged for 15 minutes at 3000 rpm. A small aliquot (eg 100 μl) from the supernatant (plasma) was withdrawn and precipitated by adding an aliquot of ice-cold acetonitrile (eg 400 μl) and frozen at -20° C. overnight. Samples were subsequently thawed and centrifuged at 3000 rpm, 4°C for 20 min. Aliquots of the supernatants were taken for analytical testing using an Agilent HPLC system with LCMS/MS detection. PK parameters were calculated by non-compartmental analysis using PK calculation software.

Analysis 9.

Validation of PDE3A modulator-induced PDE3A protein interactions using immunoprecipitation and immunoblotting.

HeLa cells were transfected with ORF overexpression constructs expressing V5-tagged SLFN12 or V5-tagged GFP. ORF expression constructs were derived from TRC (clone IDs: TRCN0000468231, TRCN0000476272, ccsbBroad304_99997). 72 hours after transfection, cells were treated with 10 μM DNMDP or trequinsin for 4 hours, followed by lysis using ModRipa lysis buffer and PDE3A immunoprecipitation. For each condition, 2 mg of total protein lysate was incubated with 1 μg of anti-PDE3A antibody at 4°C overnight, after which 7.5 μl of Dinabeads paramagnetic microparticles each of protein A and protein G (Life Technologies 10001D and 10003D) were added and incubated 1 more hour. The microparticles were washed and the bound proteins were eluted with 30 μl of LDS PAGE gel loading buffer. Injections (~60 μg total protein lysate) and IP products were separated on 4-12% Tris-glycine PAGE gels and immunoblotted with anti-V5 antibody (Life Technologies R96205, 1:5000), anti-PDE3A antibody from Bethyl (1:5000). 1000) and secondary antibodies from LiCOR Biosciences (Cat. # 926-32210 and 926068021, each at 1:10000). Blots

- 279 041614 washed and visualized using an infrared imaging device

Licor Odyssey.

Other embodiments

It will be apparent from the foregoing description that changes and modifications can be made to the present invention described herein to accommodate various applications and conditions. Such embodiments are also within the scope of the following claims.

The statement of a list of elements in any definition of a variable herein includes definitions of that variable as any single element or combination (or subcombination) of the listed elements. The exposition of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or parts thereof.

Claims (27)

CLAIM 1. Compound of formula (I) formula (I) wherein R ¹ is selected from a halogen atom, a cyano group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, and a C ₁ -C ₃ haloalkoxy group; R ² is selected from a hydrogen atom and a halogen atom; R ³ is selected from a C ₁ -C ₆ alkyl group which is unsubstituted or substituted with one or two substituents, and each substituent is independently selected from a hydroxy group, a C ₁ -C 4 alkoxy group, and a 3-7 membered heterocycloalkyl group containing one or two identical or different ring a heteroatom selected from N, O; a C ₂ -C6-alkenyl group which is unsubstituted or substituted by a C ₁ -C4 alkoxy group; C ₃ -C ₉ -cycloalkyl group, which is not substituted or substituted by hydroxy; a C ₅ -C ₉ -cycloalkenyl group which is unsubstituted or substituted by a hydroxy group; a 3-9 membered heterocycloalkyl group containing one, two or three heteroatoms independently selected from -O-, S(O) ₂ and -NR ⁹ - and said heterocycloalkyl group is unsubstituted or substituted with one or two substituents, and each the substituent is independently selected from a halogen atom; cyano groups; hydroxy groups; C ₁ -C ₃ -alkyl group, which is not substituted or additionally substituted by hydroxy; C ₁ -C ₃ alkoxy groups; C(O)NR ⁵ R ⁶ groups, and NR5R ⁶ groups; 3-9-membered heterocycloalkyl group containing one, two or three heteroatoms, which are independently selected from -O-, S(O) ₂ and -NR ⁹ -, and the specified heterocycloalkyl group additionally contains a bridging -CH ₂ -group, A 5-9 membered heterocycloalkyl group containing one or two identical or different ring heteroatoms selected from N, O, which is partially unsaturated and unsubstituted or substituted with one substituent, and each substituent is independently selected from an oxo group (=O) and C ₁ -C ₃ -alkyl group; a phenyl group that is unsubstituted or substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ -alkoxy groups and NR5R ⁶ groups; a mono- or bicyclic heteroaryl group which is a mono- or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms containing at least one ring heteroatom selected from N, O and/or S, which is unsubstituted or substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, a hydroxy group, and an NR ⁵ R ⁶ group, with the proviso that said monocyclic heteroaryl group is not 4-pyridyl; a mono- or bicyclic heteroaryl group which is a monocyclic - 280 041614 or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms, containing at least one ring heteroatom and one, two or three additional ring heteroatoms selected from N, O and/or S, which is not substituted or substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C^Q haloalkyl group, a C ₁ -C ₃ alkoxy group, a hydroxy group, and an NR5R ⁶ group; and NR7R group ⁸ ; R ⁴ is selected from a hydrogen atom and a C ₁ -C ₃ alkyl group; R5/R ⁶ are independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group; R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded, C ₁ -C ₆ -alkyl group, which is not substituted or substituted by one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, C(O)NR5R ⁶ groups, NR5R ⁶ groups, C ₁ -C ₃ -alkoxy groups, C ₃ -C ₇ cycloalkyl group which is unsubstituted or substituted with one or two substituents, and said substituents are independently selected from C 1 -C ₃ alkyl group, hydroxy group and C ₁ -C ₃ hydroxyalkyl group; a 3-7 membered heterocycloalkyl group containing one heteroatom selected from -O- or -NR ⁹ - which itself is unsubstituted or substituted with a C ₁ -C ₃ -alkyl group or an oxo (=O) group; a heteroaryl group which is a mono- or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms containing at least one ring heteroatom selected from N, O and/or S and which is itself unsubstituted or substituted With ₁ -C ₃ -alkyl group; C ₃ -C ₆ -cycloalkyl group, which is not substituted or substituted by hydroxy; And a 3-6 membered heterocycloalkyl group containing one oxygen atom; R ⁹ represents a hydrogen atom; or its salt, or a mixture thereof. 2. The compound according to claim 1, where R ¹ is selected from a halogen atom, a cyano group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ haloalkoxy group; R ² is selected from a hydrogen atom and a halogen atom; R ³ is selected from A C ₁ -C ₆ alkyl group which is optionally substituted with a substituent selected from hydroxy, C ₁ -C ₄ alkoxy and a 3-7 membered heterocycloalkyl group containing one or two identical or different ring heteroatoms selected from N, O ; C ₂ -C ₆ alkenyl group which is optionally substituted with C ₁ -C ₄ alkoxy group; C ₃ -C ₇ -cycloalkyl group, which is optionally substituted by hydroxy; C ₅ -C ₇ -cycloalkenyl group, which is optionally substituted by hydroxy group; a 3-7 membered heterocycloalkyl group containing one or two heteroatoms that are independently selected from -O-, S(O) ₂ and -NR ⁹ - and said heterocycloalkyl group is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom; cyano groups; hydroxy groups; C ₁ -C ₃ -alkyl group, which is optionally further substituted by hydroxy; C ₁ -C ₃ alkoxy groups; C(O)NR5R ⁶ groups and NR5R ⁶ groups; a 5-7 membered heterocycloalkyl group containing a heteroatom selected from -O- and -NR ⁹ - which is partially unsaturated and optionally substituted with a C ₁ -C ₃ alkyl group; a phenyl group which is optionally substituted with one, two or three substituents, and each substituent is independently selected from halogen, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy and NR5R ⁶ groups; a mono- or bicyclic heteroaryl group which is a mono- or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms containing at least one ring heteroatom selected from N, O and/or S and which is optionally substituted a substituent selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, and an NR5R ⁶ group, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group; - 281 041614 mono - or bicyclic heteroaryl group, which is a monocyclic or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms, containing at least one ring heteroatom and one, two or three additional ring heteroatoms selected from N, O and/or S, and which is optionally substituted with a substituent selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, and NR5R ⁶ groups; And NR7R ⁸ groups; R ⁴ is selected from a hydrogen atom and a C ₁ -C ₃ alkyl group; R5/R ⁶ are independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group; R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded, C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom; cyano groups; hydroxy groups; C(O)NR5R ⁶ groups; NR5R ⁶ groups; C ₁ -C ₃ alkoxy groups; C ₃ -C ₇ -cycloalkyl group, which is optionally further substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group, hydroxy group and C ₁ -C ₃ -hydroxyalkyl group; a 3-7 membered heterocycloalkyl group containing one heteroatom selected from -O- and -NR ⁹ - which is optionally further substituted with a C ₁ -C ₃ alkyl group; a heteroaryl group which is a mono- or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms containing at least one ring heteroatom selected from N, O and/or S and which is optionally further substituted with C ₁ -C ₃ -alkyl group; C ₃ -C ₇ -cycloalkyl group, which is optionally substituted by hydroxy group or C ₁ -C ₃ alkyl group, and a 3-6 membered heterocycloalkyl group containing one oxygen atom; R ⁹ represents a hydrogen atom; or its salt, or a mixture thereof. 3. The compound according to claim 1, where R ¹ is selected from a halogen atom, C ₁ -C ₃ -alkyl group, C ₁ -C ₃ haloalkyl group and C ₁ -C ₃ haloalkoxygroup; R ² is selected from a hydrogen atom and a halogen atom; R ³ is selected from A C ₁ -C ₆ alkyl group which is optionally substituted with a substituent selected from hydroxy, C ₁ -C ₄ alkoxy and a 3-7 membered heterocycloalkyl group containing one or two identical or different ring heteroatoms selected from N, O ; C ₂ -C ₆ alkenyl group which is optionally substituted with C ₁ -C ₄ alkoxy group; C ₃ -C ₇ -cycloalkyl group, which is optionally substituted by hydroxy; C ₅ -C ₇ -cycloalkenyl group; a 3-7 membered heterocycloalkyl group containing one or two heteroatoms independently selected from -O- and -NR ⁹ -, and said heterocycloalkyl group is optionally further substituted with one or two substituents, and each substituent is independently selected from a halogen atom; cyano groups; hydroxy groups; C ₁ -C ₃ -alkyl group, which is optionally further substituted by hydroxy; C ₁ -C ₃ -alkoxy groups and C(O)NR5R ⁶ groups; a 5-7 membered heterocycloalkyl group containing a heteroatom selected from -O- and -NR ⁹ - which is partially unsaturated and optionally substituted with a substituent selected from a C ₁ -C ₃ -alkyl group, a phenyl group which is optionally substituted one, two or three substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, and an NR5R ⁶ group; a mono- or bicyclic heteroaryl group which is a mono- or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms containing at least one ring heteroatom selected from N, O and/or S and which is optionally substituted - 282 041614 with a substituent selected from a halogen atom, a C1- _C3 alkyl group, a C1- _C3 haloalkyl group, C1- _C3 alkoxy groups and ^NR5R6 groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group; a mono- or bicyclic heteroaryl group which is a mono- or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms, containing at least one ring heteroatom and one, two or three additional ring heteroatoms selected from N, O and/or S, and which is optionally substituted with a substituent selected from a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, and an NR5R ⁶ group; and NR7R group ⁸ ; R ⁴ is selected from a hydrogen atom and a C ₁ -C ₃ alkyl group; R5/R ⁶ are independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group; R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded, C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom; cyano groups; hydroxy groups; NR ⁵ R ⁶ groups; Ci-C ₃ alkoxy groups; a C3-C7 cycloalkyl group which is optionally further substituted with one or two substituents, and said substituents are independently selected from a C1- _C3 alkyl group, a hydroxy group and a C1- _C3 hydroxyalkyl group; a 3-7 membered heterocycloalkyl group containing one heteroatom selected from -O- and -NR ⁹ -, which is optionally further substituted with a C1- _C3 alkyl group; a heteroaryl group which is a mono- or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms containing at least one ring heteroatom selected from N, O and/or S and which is optionally further substituted with C1- With ₃ -alkyl group; C ₃ -C ₇ -cycloalkyl group, which is optionally substituted by hydroxy group, 3-6-membered heterocycloalkyl group, which contains one oxygen atom; R ⁹ represents a hydrogen atom; or its salt, or a mixture thereof. 4. Connection according to claim 1, where R ¹ is selected from 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 is selected from a C1- _C6 alkyl group which is optionally substituted with a substituent selected from hydroxy, C1- _C4 alkoxy and a 3-7 membered heterocycloalkyl group containing one or two identical or different ring heteroatoms selected from N, O; C ₂ -C ₆ alkenyl group which is optionally substituted with C 1 -C ₄ alkoxy group; C ₄ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy; C ₅ -C ₇ -cycloalkenyl group; a 3-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from —O— and —NR ⁹ —, and said heterocycloalkyl group is optionally further substituted with one or two substituents, and each substituent is independently selected from a halogen atom; cyano groups; hydroxy groups; a C1- _C3 alkyl group which is optionally further substituted with hydroxy; a 5-6 membered heterocycloalkyl group containing a heteroatom selected from -O- and -NR ⁹ - which is partially unsaturated and optionally substituted with a substituent selected from a C1- _C3 alkyl group; a phenyl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C1- _C3 alkyl group, a C1- _C3 haloalkyl group, and an ^NR5R6 group; a mono- or bicyclic heteroaryl group which is a mono- or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms containing at least one ring heteroatom selected from N, O and/or S and which is unsubstituted or substituted with a substituent selected from a halogen atom, a C1- _C3 alkyl group, a C1- _C3 haloalkyl group, - 283 041614 C1-C3 alkoxy groups and NR5R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group; a mono- or bicyclic heteroaryl group which is a monocyclic or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms, containing at least one ring heteroatom and one, two or three additional ring heteroatoms selected from N, O and/or S, and which is optionally substituted with a substituent selected from a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, and an NR5R ⁶ group; and NR7R group ⁸ ; R ⁴ is selected from a hydrogen atom and a C ₁ -C ₃ alkyl group; R5/R ⁶ are independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group; R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded, C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom; hydroxy groups; C ₁ -C ₃ alkoxy groups; C ₃ -C ₆ -cycloalkyl group, which is optionally additionally substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group and C ₁ -C ₃ hydroxyalkyl group; a 4-6 membered heterocycloalkyl group containing one heteroatom selected from —O— and —NR ⁹ —, which is optionally further substituted with a C ₁ -C ₃ alkyl group; a heteroaryl group which is a mono- or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms containing at least one ring heteroatom selected from N, O and/or S and which is optionally further substituted with C ₁ -C ₃ -alkyl group; C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy or C ₁ -C ₃ alkyl group; 3-6 membered heterocycloalkyl group containing one oxygen atom, R ⁹ represents a hydrogen atom; or its salt, or a mixture thereof. 5. Connection according to claim 1, where R ¹ is selected from a halogen atom, a C ₁ -C ₃ alkyl group and a C ₁ -C ₃ haloalkyl group; R ² is selected from a hydrogen atom and a halogen atom; R ³ is selected from C ₁ -C ₆ -alkyl group, which is optionally substituted with one or two substituents, and each substituent is independently selected from hydroxy group, C ₁ -C ₄ -alkoxy group and 3-7 membered heterocycloalkyl group containing one or two identical or different ring heteroatoms selected from N, O; C ₂ -C ₆ -alkenyl group, which is optionally substituted with C ₁ -C ₃ -alkoxy group; C ₃ -C ₇ -cycloalkyl group, which is optionally substituted by hydroxy; C ₅ -C ₆ -cycloalkenyl group, which is optionally substituted by hydroxy; a 3-6 membered heterocycloalkyl group containing one, two or three heteroatoms which are independently selected from -O- and -NR ⁹ - and said heterocycloalkyl group is optionally substituted with one or two substituents and each substituent is independently selected from a halogen atom; cyano groups; hydroxy groups; a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy; a 5-7 membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one or two substituents, and each substituent is independently selected from a C ₁ -C ₃ alkyl group; a phenyl group which is optionally substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a C ₁ C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ -alkoxy groups, C ₁ -C ₃ -haloalkoxy groups and NR ⁵ R ⁶ groups; a mono- or bicyclic heteroaryl group which is a mono- or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms containing at least one ring heteroatom selected from N, O and/or S and which is optionally substituted one or two substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, a hydroxy group, and an NR ⁵ R ⁶ group, with provided that said monocyclic heteroaryl group is not a co-pyridin-4-yl group; a mono- or bicyclic heteroaryl group which is a monocyclic or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms, containing at least one ring heteroatom and one, two or three additional ring heteroatoms selected from N, O and/or S, and which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C 1 -C 3 haloalkyl group, a C ₁ -C ₃ alkoxy group, a hydroxy group, and NR5R ⁶ groups; and NR7R group ⁸ ; R ⁴ is selected from a hydrogen atom and a C ₁ -C ₃ alkyl group; R5/R ⁶ are independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group; R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded, C ₁ -C ₆ -alkyl group, which is optionally substituted with one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, C ₁ -C ₃ -alkoxy groups, C ₃ -C ₇ -cycloalkyl group, which is optionally substituted with one or two substituents, and these substituents are independently selected from C 1 -C ₃ -alkyl group, hydroxy group and C ₁ -C ₃ hydroxyalkyl group; a 3-7 membered heterocycloalkyl group which itself is optionally substituted with a C ₁ -C ₃ alkyl group; and a heteroaryl group which is a mono- or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms containing at least one ring heteroatom selected from N, O and/or S and which is optionally further substituted with C ₁ -C ₃ -alkyl group; C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy group, and 3-6 membered heterocycloalkyl group containing one oxygen atom, R ⁹ represents a hydrogen atom; or its salt, or a mixture thereof. 6. Connection according to claim 1, where R ¹ is selected from a halogen atom, a C ₁ -C ₃ alkyl group and a C ₁ -C ₃ haloalkyl group; R ² is selected from a hydrogen atom and a halogen atom; R ³ is selected from a 3-6 membered heterocycloalkyl group containing one or two heteroatoms independently selected from —O— and —NR ⁹ —, and said heterocycloalkyl group is optionally further substituted with one or two substituents, and each substituent is independently selected from a halogen atom; hydroxy groups; and a C ₁ -C ₃ alkyl group which is optionally further substituted with hydroxy; a phenyl group which is optionally substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a hydroxy group, and a C ₁ -C ₃ haloalkyl group; a mono- or bicyclic heteroaryl group which is a mono- or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms containing at least one ring heteroatom selected from N, O and/or S and which is optionally substituted a substituent selected from a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group and an NR5R ⁶ group, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group; a mono- or bicyclic heteroaryl group which is a monocyclic or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms, containing at least one ring heteroatom and one, two or three additional ring heteroatoms selected from N, O and/or S, and which is optionally substituted with a substituent selected from a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, and an NR5R ⁶ group; and NR ⁷ R ⁸ groups; R ⁴ is selected from a hydrogen atom and a C ₁ -C ₃ alkyl group; R5/R ⁶ are independently selected from a hydrogen atom and a C ₁ -C ₃ alkyl group; R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded, C ₁ -C ₆ -alkyl group, which is optionally substituted with one or two, three or four substituents, and the specified substituent is independently selected from - 285 041614 halogen atoms; hydroxy groups; C ₁ -C ₃ alkoxy groups; C ₃ -C ₅ -cycloalkyl group, which is optionally additionally substituted with one or two substituents, and these substituents are independently selected from C ₁ -C ₃ -alkyl group and C1-C ₃ hydroxyalkyl group; a 5-6 membered heterocycloalkyl group containing one heteroatom which is selected from -O- and -NR ⁹ -, which is optionally further substituted with a C ₁ -C ₃ -alkyl group, a heteroaryl group which is a mono- or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms, containing at least one ring heteroatom selected from N, O and/or S, and which is optionally further substituted with a C ₁ -C ₃ alkyl group; C ₃ -C ₆ -cycloalkyl group, which is optionally substituted by hydroxy or C ₁ -C ₃ alkyl group; a 4-5 membered heterocycloalkyl group containing one oxygen atom; R ⁹ represents a hydrogen atom; or its salt, or a mixture thereof. 7. Connection according to claim 1, where R ¹ is selected from CF ₃ and a fluorine atom; R ² represents a hydrogen atom; R ³ is selected from a phenyl group which is optionally substituted with a substituent which is selected from a halogen atom and a C1- _C3 haloalkyl group, a monocyclic heteroaryl group which is a mono- or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms containing at least one ring heteroatom selected from N, O and/or S and substituted by a substituent selected from C ₁ -C ₃ haloalkyl group and NR5R ⁶ group; and NR7R group ⁸ ; R ⁴ is selected from a hydrogen atom and a methyl group; R5/R ⁶ are independently selected from a hydrogen atom and a methyl group; R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded, a C1- _C3 alkyl group which is optionally substituted with one, two or four substituents, and said substituent is independently selected from a halogen atom, a hydroxy group and a methoxy group, or a salt thereof, or a mixture thereof. 8. The compound according to claim 1, which is selected from the group: 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)-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 -[2-methylmorpholin-4-yl]phenyl}-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2one, (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, - 286 041614 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-1 H-pyrazol-5-yl)phenyl]-3,6-dihydro-2H-1 ,3,4-oxadiazin-2-one, 5-(2,4'-difluorobiphenyl-4-yl)-3,6-dihydro-2Н-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-oxadiazine -2-one, 5-{3-(trifluoromethyl)-4-[6-(trifluoromethyl)pyridin-3-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2one, 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-1 H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H- 1,3 ,4-oxadiazin-2-one, 5-[4-(3-methyl-1 H-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-f tor-6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1,2-thiazole -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-2carbonitrile, 5-[2,4'-bis(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1,3-dimethyl-1 H-pyrazol-4-yl)-3 -(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one, 5-[4-(2-methoxy-6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-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-oxadiazine -2-one, 5-[3',4'-difluoro-2-(trifluoromethyl)biphenyl-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5- [4-(1 H-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-d ihydro-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- 1 H-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-1 H-benzimidazol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one, 5-[4-(pentylamino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-(1-methyl-1 H-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, - 287 041614 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-(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-oxadiazine -2-one, 5-[3-fluoro-4-(6-methylpyride in-3-yl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-(2,2',4',5'-tetrafluorobiphenyl-4-yl)- 3,6-dihydro-2Н-1,3,4-oxadiazin-2-one, 5-(2,2',3',4'-tetrafluorobiphenyl-4-yl)-3,6-dihydro-2Н-1 ,3,4-oxadiazin-2-one, 5-(2,2',5'-trifluorobiphenyl-4-yl)-3,6-dihydro-2Н-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-oxadiazine -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-2Н-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-2Н-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-1,3,4oxadiazin-2 -one, (6S)-5-(-[(4-chloro-3-(trifluoromethyl)phenyl)-)]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazine-2- he, (6S)-5-(-[(4-fluoro-3-(trifluoromethyl)phenyl)-)]-6-meth yl-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-1,3,4oxadiazin-2-one, 5-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one, 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-1,3,4oxadiazin-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-1,3,4oxadiazin-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-[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 - 288 041614 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-2one, 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-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-2carbonitrile, 5-{4-[1 -(propan-2-yl)-1 H-pyrazol-4-yl] -3 -(trifluoromethyl)phenyl} -3,6-dihydro-2H-1,3,4-oxadiazine2- he, (gas)-5-[4-(bicyclo[2.2.1]hept-2-en-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4 -oxadiazine2-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-2one, 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-1,3,4oxadiazin-2-one, (6S)- 6-methyl-5-[4-(6-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one, (6S)-5 -[2'-fluoro-4'-methyl-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2 -one, (6S)-6-methyl-5-[2',4',5'-trifluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-3,6-dihydro- 2H-1,3,4oxadiazin-2-one, (6S)-6-methyl-5-[2',3',4'-trifluoro-2-(trifluoromethyl)[1,1'-biphenyl] -4- yl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one, (6S)-5-[2',5'-difluoro-2-(trifluoromethyl)[1,1'-biphenyl] - 4-yl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one, 4'-[(6S)-6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5 -yl]-2'-(trifluoromethyl)[1,1'-biphenyl ]-2carbonitrile, (6S)-5-[4-(1H-indol-5-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazine -2-one, (6S)-5-[4'-hydroxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1, 3,4oxadiazin-2-one, (6S)-5-[3'-hydroxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H -1,3,4oxadiazin-2-one, (6S)-5-[3'-amino-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6- dihydro-2H-1,3,4-oxadiazin-2one, (6S)-5-[2',4'-difluoro-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6- methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one, (6S)-5-[3'-fluoro-4'-methyl-2-(trifluoromethyl)[1,1'-biphenyl] -4-yl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one, (6S)-5-[2'-fluoro-2-(trifluoromethyl)[1,1' -biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2one, (6S)-5-[2'-methoxy-2-(trifluoromethyl)[1 ,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin2-one, (6S)-5-[3'-fluoro-2-(trifluoromethyl )[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H -1,3,4-oxadiazin-2one, (6S)-6-methyl-5-[4-(4-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2Н- 1,3,4oxadiazin-2-one, - 289 041614 (6S)-6-methyl-5-[4-(3-methylpyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2- he, (6S)-6-methyl-5-[4-(2-methylpyridin-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one , (6S)-5-[4-(1H-indol-6-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2- he, (6S)-5-[4-(6-methoxypyridin-3-yl)-3 -(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one , (6S)-5-[4'-methoxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4- oxadiazin2-one, (6S)-6-methyl-5-[4'-methyl-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-3,6-dihydro-2H-1,3 ,4-oxadiazin-2one, (6S)-5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)-phenyl}-6-methyl-3,6-dihydro -2H1,3,4-oxadiazin-2-one, 5-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-(trifluoromethyl)-phenyl}-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2- He, 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-1,3,4oxadiazin-2-one , 5-{3-(difluoromethyl)-4-[ 1 -(difluoromethyl)-1 H-pyrazol-4-yl]phenyl} -3,6-dihydro-2H-1,3,4-oxadiazin2-one )-6-methyl-5-{4-[(morpholin-4-yl)methyl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-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-oxadiazin2-one, (rac)-5 -[4-{[3,3,3-trifluoro-2-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H1,3,4-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-1,3,4oxadiazin-2-one, 5-{4-[(rac)-2,4-dimethylazetudin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2one, 5-{4-[(cis or trans)-2,4-dimethylazetidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one, 5-[4-{[3,3,3-trifluoro-2(S)-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one , 5-{4-[(2-hydroxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one, 5-[4-{[(trans)-4-hydroxycyclohexyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-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-1,3,4oxadiazin-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-oxadiazin2-one, 5-[4-{[2(R)-2-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one, 5-[4-{[(3R)-3-hydroxybutyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one, 5-[4-{[(2S)-2-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one, 5-[4-{[(1-hydroxycyclobutyl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-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, - 290 041614 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)-oxolαn-2-yl]methyl}αmino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxαdiαzin2-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-1,3,4oxadiazin-2-one, 5-[4-(3-hydroxypiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (racemic mixture), (gas) -1-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]piperidine-3carboxamide, 5-{4-[(3-hydroxy-2,2-dimethylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-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-2H1,3,4-oxadiazin-2-one , 5-{4-[(3S)-3-hydroxypyrrolidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin2-one, (rac)-5 -{4-[(2-hydroxy-3-methoxypropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one, 5-[4-{[(1-methyl-1H-pyrazol-5-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one , 5-[4-{[(1 H-pyrazol-3 -yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one, 5-[4-{[2-(1 H-pyrazol-1-yl)ethyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one, 1-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]piperidine-4carbonitrile, (rac)-5-{4 -[(1-cyclopropylethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin2-one, (rac)-5-{4-[(2-ethoxypropyl )amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2one, (rac)-5-{4-[(2-methoxypropyl)amino]-3- (trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2one, 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-oxadiazin2-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-1,3,4oxadiazin-2-one, (rac )-5-[4-{[(6-oxopiperidin-3-yl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one, ( rac)-5-[4-{[(2,2-dimethylcyclopropyl)methyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H1,3,4-oxadiazin-2-one, 5-[4-({[1-(hydroxymethyl)cyclobutyl]methyl}amino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one, 5-{4-[(2S)-2-(hydroxymethyl)azetidin-1-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one, 3-methyl-1-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]azetidine-3carbonitrile, 5-[4-(3-azabicyclo[3.1.0]hexan-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2one, 5-[4-(4-ethyl-4-hydroxypiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-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]-2lambda ⁶ -thia-6azaspiro[3.3]heptan-2,2-dione, K 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-oxadiazin2-one, - 291 041614 5-{4-[(2-methoxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2-one, 5-[4-({[(2S)-oxolan-2-yl]methyl}amino)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin2-one, 5-{4-[(2-ethoxyethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one, 5-[4-{[(1S,2R)-2-hydroxucyclolonentyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-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)-1 H-pyrazol-4-yl]phenyl} -3,6-dihydro-2H-1,3,4-oxadiazin2- He, 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-2H1,3,4-oxadiazin-2-one, (6S)-6-methyl-5-{3-(trifluoromethyl)-4-[4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}-3,6-dihydro-2H1,3,4-oxadiazine -2-he, 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, (gas)-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-2one (trans isomer), (cis)-5-{4-[4-hydroxycyclohexyl]-3-(trifluoromethyl )phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2one, 5-{4-[(2-aminoethyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one-hydrochloric acid salt, 5-{4-[1-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-(trifluoromethyl)-phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-2- he is a salt of hydrochloric acid, 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-1,3,4oxadiazin-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-1,3,4oxadiazin-2-one and (6S)-5- [4-(3-hydroxy-3-methylazetidin-1-yl)-3-(trifluoromethyl)-phenyl]-6-methyl-3,6-dihydro-2H1,3,4-oxadiazin-2-one, or its salt, or a mixture thereof. 9. The connection according to claim 8, which is selected from 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-2H1,3,4-oxadiazin-2-one, 5-[4-{[3,3,3-trifluoro-2(S)-hydroxypropyl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4oxadiazin-2-one , 5-{4-[(2-hydroxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4oxadiazin-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-1,3,4oxadiazin-2-one, (6S)-5-[4-(2-aminopyridin- 4-yl)-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4oxadiazin-2-one, (6S)-6-methyl-5-{3-(trifluoromethyl )-4[3-(trifluoromethyl)-1H-pyrosol-1-yl]phenyl}-3,6-dihydro-2H1,3,4-oxadiazin-2-one, or a salt thereof, or a mixture thereof. 10. A process for preparing a compound of general formula (I) according to any one of claims 1 to 9, said method comprising the step A of providing for the reaction of an intermediate compound of general formula (II) - 292 041614 r ₂ (I), where X represents Cl, Br, I or a leaving group selected from (C1-C4 alkylsulfonyl)oxy, (C1-C ₄ -fluoroalkylsulfonyl)oxy and (phenylsulfonyl)oxy, and the phenyl present in (phenylsulfonyl) )oxy, unsubstituted or substituted with one, two, three, four or five substituents each independently selected from halo, nitro, cyano, C1- _C4 alkyl, and _C1C4 alkoxy; R ¹ is selected from a fluorine atom, a cyano group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C1C ₃ haloalkoxy group; R ² is selected from a hydrogen atom, a fluorine atom; R ⁴ is selected from a hydrogen atom and a C ₁ -C ₃ alkyl group; under transition metal-catalyzed coupling reaction conditions such as Suzuki coupling reaction, Negishi coupling reaction, Kumada coupling reaction, Stille coupling reaction with an organoboron compound selected from boronic acid of formula (IIIa) (R ^X )B(OH) ₂ (Sha ), a boronic acid ester of the formula (R ^X )B(OR ^Y ) ₂ (SHb), and a tetrafluoroborate salt of the formula (R ^x )BF ₄ (H1O), wherein R ^x is a C ₁ -C ₆ alkyl group which unsubstituted or substituted with one or two substituents, and each substituent is independently selected from hydroxy, C ₁ -C ₄ alkoxy, and a 3-7 membered heterocycloalkyl group containing one or two identical or different ring heteroatoms selected from N, O; C ₂ -C ₆ alkenyl group which is unsubstituted or substituted by C 1 -C ₄ alkoxy group; a C5-C9 cycloalkenyl group which is unsubstituted or substituted by hydroxy; A 3-9 membered heterocycloalkyl group containing one, two or three heteroatoms that are independently selected from -O-, S(O) ₂ and -NR ⁹ -, and said heterocycloalkyl group is unsubstituted or additionally contains a bridging group selected from - CH2-, and said heterocycloalkyl group is unsubstituted or substituted with one, two or three substituents, and each substituent is independently selected from a halogen atom; cyano groups; hydroxy groups; C ₁ -C ₃ -alkyl group, which is not substituted or additionally substituted by hydroxy; C 1 -C ₃ alkoxy groups; C(O)NR5R ⁶ groups, and NR5R ⁶ groups; A 5-9 membered heterocycloalkyl group containing one or two identical or different heteroatoms selected from N, O, which is partially unsaturated and unsubstituted or substituted with one, two or three substituents, and each substituent is independently selected from an oxo group (=O ), and C ₁ -C ₃ -alkyl group; a phenyl group that is unsubstituted or substituted with one, two, three or four substituents, and each substituent is independently selected from a halogen atom, hydroxy group, cyano group, C1C ₃ alkyl group, C ₁ -C ₃ haloalkyl group, C ₁ -C ₃ -alkoxy groups and NR5R ⁶ groups, a mono- or bicyclic heteroaryl group which is a monocyclic or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms containing at least one ring heteroatom selected from N, O and/ or S, and which is unsubstituted or substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, hydroxy groups and NR ⁵ R ⁶ groups, provided that said monocyclic heteroaryl group is not a pyridin-4-yl group; a mono- or bicyclic heteroaryl group which is a monocyclic - 293 041614 or a bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms containing at least one ring heteroatom and one, two or three additional ring heteroatoms selected from N, O and/or S, and which is not substituted or substituted with one or two substituents, and each substituent is independently selected from a halogen atom, a C ₁ -C ₃ alkyl group, a cyano group, a C 1 -C 3 haloalkyl group, a C ₁ -C ₃ alkoxy group, a hydroxy group, and an NR5R ⁶ group; R ^y is C ₁ -C ₆ alkyl, or the two R ^y residues together represent a C 2 -C 6 alkylene group, in the presence of a base, and a palladium catalyst which is selected from: dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(0), palladium acetate (P)/triscyclohexylphosphine, tris(dibenzylideneacetone)dipalladium, bis(diphenylphosphineferrocenyl)palladium(II) chloride, dimer 1,3-bis(2,6-diisopropylphenyl)imidazole2- ylidene(1,4-naphthoquinone)palladium, allyl(chlorine)(1,3-dimesityl-1,3-dihydro-2H-imidazole-2ylidene)palladium, palladium acetate (P)/dicyclohexyl(2',4',6 '-triisopropyl-biphenyl-2-yl)phosphine, [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride monodichloromethane adduct, [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II), chlorine(2 -dicyclohexylphosphino-2',4',6'triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(11), palladium (II) acetate and (2dicyclohexylphosphino -2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II). 11. The method of claim 10 wherein an organoboron compound selected from boronic acid of formula (IIIa) is used. I(R ^x )B(OH) ₂ (Illa), a boronic acid ester of the formula (R ^x )B(OR ^y ) ₂ (SHb), and a tetrafluoroborate salt of the formula I(R ^x )BF ₄ x ^(ШС) ' and R ^x is a methyl group that is not substituted or substituted by a 3-7-membered heterocycloalkyl group containing one or two identical or different ring heteroatoms selected from N, O. 12. The process of claim 10, wherein a palladium catalyst selected from dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(0), palladium(11) acetate/triscyclohexylphosphine, tris(dibenzylideneacetone)dipalladium, bis(diphenylphosphineferrocenyl)palladium(II) chloride is used. , 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene(1,4-naphthoquinone)palladium dimer, allyl(chlorine)(1,3-dimesityl-1,3-dihydro-2H-imidazole-2 -ylidene)palladium, palladium (P) acetate/dicyclohexyl(2',4',6'-triisopropyl-biphenyl-2-yl)phosphine, [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride monodichloromethane adduct , [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino -1,1'-biphenyl)]palladium(II), palladium(II) acetate and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'amino -1,1'-biphenyl)]palladium(II), and an additional ligand. 13. A method for preparing a compound of general formula (I) according to claim 10, said method comprising, for compound (II): R ¹ is trifluoromethyl and R ² is a hydrogen atom, for step A: Suzuki coupling reaction conditions, and palladium the catalyst is chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'biphenyl)]palladium(H), and the ligand is 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl. 14. A process for the preparation of a compound of general formula (I) according to any one of claims 1 to 9, said method comprising the step B of providing for the reaction of an intermediate compound of general formula (II) r ₂ (P), where X is F or Cl, with the proviso that if X is Cl, R ¹ or R ² cannot be F; preferably X is F; R ¹ is selected from a halogen atom, a cyano group, a C1- _C3 alkyl group, a C1- _C3 haloalkyl group, and a C1- _C3 haloalkoxy group; with the proviso that if X is Cl, R ¹ cannot be a fluorine atom; R ² is selected from a hydrogen atom and a halogen atom; - 294 041614 with the proviso that if X is Cl, R ² cannot be a fluorine atom; with the proviso that at least one of R ¹ and R ² exhibits an electron-withdrawing effect; R ⁴ is selected from a hydrogen atom and a C1- _C3 alkyl group; with the corresponding amine, in free base or salt form, selected from HNR ⁷ R ⁸ , and a cyclic amine having one NH as ring atom, the cyclic amine being selected from 3-9-membered heterocycloalkane containing one, two or three heteroatoms independently selected from -O-, S(O) ₂ and NR ⁹ -, wherein said heterocycloalkyl group is unsubstituted or additionally substituted with a substituent containing a bridging group -CH ₂ -, a partially unsaturated 5-9 membered heterocycloalkane containing one or two identical or different heteroatoms selected from N, O, and unsubstituted or substituted with one substituent, and each substituent is independently selected from an oxo group (=O), and C ₁ -C ₃ -alkyl group, heteroarene, which is a monocyclic or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms, containing at least one ring heteroatom selected from N, O and/or S, and which unsubstituted or substituted with a substituent selected from a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, and an NR5R ⁶ group, provided that said monocyclic heteroaryl group is not etc is a pyridin-4yl group; containing one NH as a ring atom, respectively, heteroarene, which is a monocyclic or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms, containing at least one ring heteroatom and one, two or three additional ring heteroatoms, selected from N, O and/or S and which is unsubstituted or substituted with a substituent selected from a halogen atom, a C ₁ -C ₃ alkyl group, a Ci-C ₃ haloalkyl group, a C ₁ -C ₃ alkoxy group, and an NR5R ⁶ group ; containing one NH as ring atom, respectively, where R ⁷ /R ⁸ are independently selected from a hydrogen atom, with the proviso that R ⁷ = R ⁸ = hydrogen is excluded, C ₁ -C ₆ -alkyl group, which is not substituted or substituted by one, two, three or four substituents, and the specified substituent is independently selected from a halogen atom, cyano group, hydroxy group, C(O)NR5R ⁶ groups, NR5R ⁶ groups, Ci-C ₃ -alkoxy groups, C ₃ -C ₇ -cycloalkyl group, which is not substituted or substituted by one or two substituents, and these substituents are independently selected from C1-C ₃ -alkyl group, hydroxy group and C1-C ₃ hydroxyalkyl group; 3-7 membered heterocycloalkyl group containing one oxygen atom, heteroaryl group which is a monocyclic or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms containing at least one ring heteroatom selected from N, O and/or S and which is itself unsubstituted or substituted with a _{C 1} -C ₃ alkyl group; C ₃ -C ₆ -cycloalkyl group, which is not substituted or substituted by hydroxy group, and 3-6-membered heterocycloalkyl group containing an oxygen atom, while the 3-9-membered heterocycloalkane containing one NH as a ring atom is a cyclic amine corresponding to a 3-9-membered heterocycloalkyl group R ³ according to claim 1, when provided that it contains one NH as a ring atom, a partially unsaturated 3-9 membered heterocycloalkane containing one NH as a ring atom is a cyclic amine corresponding to a partially unsaturated 3-9 membered heterocycloalkyl group R ³ according to claim 1, when provided that it contains one NH as a ring atom, and a heteroarene containing one NH as a ring atom is a cyclic amine corresponding to the heteroaryl group R ³ according to claim 1, provided that it contains one NH as a ring atom , and at a temperature from room temperature to 160°C, to obtain a compound of formula (I). 15. The method of claim 14, wherein the reaction is carried out in the presence of a base. 16. The method of claim 14 wherein the reaction is carried out in an inert solvent. 17. A method for preparing a compound of general formula (I) according to claim 14, said method comprising, for compound (II): R ¹ is trifluoromethyl and R ² is a hydrogen atom, for step B: the two R ^y residues together are - C(CH ₃ ) ₂ -C(CH ₃ ) ₂ - to form a pinacol ester, the base is potassium carbonate or potassium acetate. 18. A method for obtaining a compound of general formula (I) according to any one of claims 1 to 9, - 295 041614 said method includes the step C of providing the reaction of an intermediate compound of general formula (II) r ₂ (P), where X represents Cl, Br, I or a leaving group selected from (C1-C4 alkylsulfonyl)oxy, (C ₁ -C ₄ -fluoroalkylsulfonyl)oxy and (phenylsulfonyl)oxy, and phenyl present in ( phenylsulfonyl)oxy, unsubstituted or substituted with one, two, three, four or five substituents, each independently selected from halogen, nitro, cyano, C ₁ -C ₄ -alkyl and C1C ₄ -alkoxy; R ¹ is selected from a fluorine atom, a cyano group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C1C ₃ haloalkoxy group; R ² is selected from a hydrogen atom, a fluorine atom; R ⁴ is selected from a hydrogen atom and a C1- _C3 alkyl group; with the corresponding amine, optionally in free base or salt form, selected from HNR7R ⁸ , and a cyclic amine having one NH as ring atom, the cyclic amine being selected from 3-9-membered heterocycloalkane containing one, two or three heteroatoms, which are independently selected from -O-, S(O) ₂ and NR ⁹ -, and the specified heterocycloalkyl group is additionally substituted by a substituent containing a bridge group -CH ₂ -; a partially unsaturated 3-9 membered heterocycloalkane containing one or two identical or different heteroatoms selected from N, O, and unsubstituted or substituted with one substituent, and each substituent is independently selected from an oxo group (=O), and C1-C ₃ - an alkyl group, and a heteroarene which is a monocyclic or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms containing at least one ring heteroatom selected from N, O and/or S and which is unsubstituted or substituted with a substituent selected from a halogen atom, a C1- _C3 alkyl group, a C1- _C3 haloalkyl group, a C _{g C3} alkoxy group, and an ^NR5R6 group, provided that said monocyclic heteroaryl group is not a pyridin-4yl group ; containing one NH as the ring atom, respectively, and a heteroarene, which is a monocyclic or bicyclic aromatic ring with 5, 6, 8, 9, or 10 ring atoms, containing at least one ring heteroatom and one, two, or three additional ring heteroatoms selected from N, O and/or S and which is unsubstituted or substituted with a substituent selected from a halogen atom, a C1- _C3 alkyl group, a C1- _C3 haloalkyl group, a C1- _C3 alkoxy group, and an ^NR5R6 group; containing one NH as ring atom, respectively, where R7/ ^R8 are independently selected from a hydrogen atom, with the proviso that ^R7 = ^R8 =hydrogen is excluded, a C1- _C6 alkyl group which is unsubstituted or substituted with one, two, three or four substituents, and said substituent is independently selected from halogen atom, cyano group, hydroxy group, C(O)NR ⁵ R ⁶ group, NR5R ⁶ group, C1-C ₃ -alkoxy groups, C ₃ -C ₇ -cycloalkyl group, which is not substituted or substituted by one or two substituents, and these substituents are independently selected from C1-C ₃ -alkyl group, oxo (=O) group, hydroxy group and C1-C ₃ -hydroxyalkyl group; a 3-7 membered heterocycloalkyl group which is itself unsubstituted or substituted by a C1- _C3 alkyl group or an oxo (=O) group, a heteroaryl group which is a mono- or bicyclic aromatic ring with 5, 6, 8, 9 or 10 ring atoms, containing at least one ring heteroatom, and which itself is not substituted or substituted with a C1- _C3 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 ₁ -C ₅ -alkylene-NR ⁵ -C ₁ -C ₅ -alkyl group, C ₃ -C ₆ -cycloalkyl group, which is not substituted or substituted by hydroxy group, and a 3-6 membered heterocycloalkyl group which is unsubstituted or substituted with one or two substituents, said substituent being independently selected from a C1- _C3 alkyl group and a hydroxy group, wherein a 3-9 membered heterocycloalkane containing one NH as ring atom , is a cyclic amine corresponding to a 3-9-membered heterocycloalkyl group R ³ according to claim 1, provided that it contains one NH as a ring atom, a partially unsaturated 3-9-membered heterocycloalkane containing one NH as a ring 296 041614 of the first atom, is a cyclic amine corresponding to a partially unsaturated 3-9 membered heterocycloalkyl group R ³ according to claim 1, provided that it contains one N-H as a ring atom, and a heteroarene containing one N-H as ring atom, is a cyclic amine corresponding to the heteroaryl group R ³ according to claim 1, provided that it contains one N-H as a ring atom, in the presence of a base ion and a palladium catalyst, ligand, in an inert solvent, and in the presence of an inert solvent, and at a temperature in the range from 60 to 160°C, to obtain a compound of formula (I). 19. The method according to claim 14 or 18, wherein the hydrochloride salt is used as the corresponding amine. 20. A process for the preparation of a compound of general formula (I) according to claim 18, said process comprising, for compound (II): R ¹ is trifluoromethyl and R ² is a hydrogen atom, for step C: the palladium catalyst is tris(dibenzyl pdenacetone) dipalladium(0), and the ligand is 2-(dicyclohexylphosphino)2',4',6'-triisopropyl-1,1'-biphenyl or 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene. 21. Pharmaceutical composition containing a compound of General formula (I) according to any one of paragraphs. 1 9 and one or more pharmaceutically acceptable excipients. 22. Pharmaceutical combination for the treatment or prevention of a hyperproliferative disease, containing: one or more compounds of general formula (I) according to any one of claims 1 to 9, and one or more additional anticancer agents. 23. The use of a compound of general formula (I) according to any one of claims 1 to 9 for the treatment or prevention of a hyperproliferative disease. 24. Use according to claim 23, wherein the hyperproliferative disease is a cancerous disease. 25. Use according to claim 24, wherein the cancer is brain cancer, breast cancer, cervical cancer, AML, lung cancer, skin cancer, esophageal cancer, ovarian cancer, pancreatic cancer and prostate cancer. 26. A compound having the structure of the general formula (II) _r2 1 ⁽¹¹⁾ ' 2 where R ¹ is a fluorine atom or a trifluoromethyl group, R ² is a hydrogen atom or a methyl group, and R ⁴ is as defined for a compound of general formula (I) according to any one of claims 19, and X is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. 27. Use of a compound of general formula (II) (H), where R ¹ , R ² and R ⁴ have the meaning as defined for the compound of general formula (I) according to any one of claims 1 to 7, and X represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, or a leaving group to obtain a compound of general formula (I) according to any one of claims 1 to 7.