DIHYDROOXADIAZINONES

Abstract

The present invention provides dihydrooxydiazinone compounds of general formula (I)

##STR00001##

in which R.sup.1, R.sup.2, R.sup.3, and R.sup.4, are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative diseases, as a sole agent or in combination with other active ingredients.

Claims

1. A compound having the structure ##STR00436## (6S)-5-[4′-fluoro-2-(trifluoromethyl)biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

2-11. (canceled)

12. A pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable excipients.

13. A pharmaceutical combination comprising: the compound of claim 1, and one or more further anti-cancer agents.

14. A method for the treatment of a disease in a subject, comprising administering to the subject the compound of claim 1.

15. (canceled)

16. The method according to claim 14, wherein the disease is a hyperproliferative disease.

17. The method according to claim 16, wherein the hyperproliferative disease is a cancer disease.

18. The method according to claim 17, wherein the cancer disease is selected from brain cancer, breast cancer, cervical cancer, AML, lung cancer, skin cancer, esophageal carcinoma, ovarian cancer, pancreas cancer and prostate cancer.

19-22. (canceled)

23. The method according to claim 17, wherein the cancer disease is selected from glioma, glioblastoma, and ovarian cancer.

Description

EXAMPLES

Experimental Section

[3052] NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.

[3053] The .sup.1H-NMR data of selected compounds are listed in the form of .sup.1H-NMR peaklists. Therein, for each signal peak the b value in ppm is given, followed by the signal intensity, reported in round brackets. The b value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: δ.sub.1 (intensity.sub.1), δ.sub.2 (intensity.sub.2), . . . , δ.sub.i (intensity.sub.i), . . . , δ.sub.n (intensity.sub.n).

[3054] The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A .sup.1H-NMR peaklist is similar to a classical .sup.1H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical .sup.1H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of the particular target compound, peaks of impurities, .sup.13C satellite peaks, and/or spinning sidebands. The peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compound (e.g., with a purity of >90%). Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify a reproduction of the manufacturing process on the basis of “by-product fingerprints”. An expert who calculates the peaks of the target compound by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of the target compound as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical

[3055] .sup.1H-NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication “Citation of NMR Peaklist Data within Patent Applications” (cf. http://www.researchdisclosure.com/searching-disclosures, Research Disclosure Database Number 605005, 2014, 1 Aug. 2014). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter “MinimumHeight” can be adjusted between 1% and 4%. However, depending on the chemical structure and/or depending on the concentration of the measured compound it may be reasonable to set the parameter “MinimumHeight”<1%.

[3056] Chemical names were generated using the AC/Name software from ACD/Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names.

[3057] The following table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person.

TABLE-US-00001 TABLE 1 Abbreviations [α] specific rotation value EtOH Ethanol THF Tetrahydrofurane DAD Diode array detector δ NMR shift in ppm d doublet (NMR coupling pattern) DMSO dimethylsulfoxide M Molar or molecular Mass ESI electrospray ionisation (MS) LiHMDS Lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide LC-MS liquid chromatography coupled to mass spectrometry m multiplet (NMR coupling pattern) MS mass spectrometry MHz Megahertz NMR nuclear magnetic resonance q quartet (NMR coupling pattern) R.sub.t, Rt retention time RT room temperature s singlet (NMR coupling pattern) t triplet (NMR coupling pattern) UPLC Ultra Performance Liquid Chromatography UV ultraviolet WL wavelength DIPEA N,N-diisopropylethylamine UPLC-MS Ultra High Preformance Liquid Chromatography Mass Spectroscopy pH Potential of Hydrogen MTBE Methyl tert-butyl ether EtOAc, EA Ethyl acetate MeCN, ACN Acetonitrile Et Ethyl Me Methyl Pr Propyl AMC Automated Medicinal Chemistry DMF Dimethylformamide MeOH methanol HOAc Acetic Acid PE Petroleum Ether DCM dichloromethane J coupling constant (in NMR spectra) NaOMe sodium methoxide NaOEt sodium ethoxide HCl hydrochloric acid, hydrogen chloride aq aqueous Pd/C Palladium on carbon IPA Isopropyl alcohol v:v ratio by volume

[3058] The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.

[3059] The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

Experimental Section—General Part

[3060] All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.

[3061] The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartridges KP-Sil® or KP-NH® in combination with a Biotage autopurifier system (SP4® or Isolera Four®) and eluents such as e.g. gradients of hexane/ethyl acetate or DCM/methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as e.g. gradients of water and acetonitrile which may contain additives such as e.g. trifluoroacetic acid, formic acid or aqueous ammonia.

[3062] In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as e.g., in the case of a compound of the present invention which 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, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

UPLC-MS Standard Procedures

[3063] Analytical UPLC-MS was performed as described below. The masses (m/z) are reported from the positive mode electrospray ionisation unless the negative mode is indicated (ESI-). In most of the cases method 1 is used. If not, it is indicated.

Experimental Section—General Procedures

Analytical LC-MS Methods:

Method 1:

[3064] Instrument: Waters Acquity UPLC-MS SingleQuad; column: Acquity UPLC BEH C18 1.7 μm, 50×2.1 mm; eluent A: water+0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60° C.; DAD scan: 210-400 nm.

Method 2:

[3065] Instrument: Waters Acquity UPLC-MS SingleQuad; Column: Acquity UPLC BEH C18 1.7 μm, 50×2.1 mm; eluent A: water+0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60° C.; DAD scan: 210-400 nm.

Method 3:

[3066] Instrument: SHIMADZU LCMS-UFLC 20-AD-LCMS 2020 MS detector; Column: Waters Atlantis dC18 3 μm, 2.1×100 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:

[3067] Instrument Waters Acquity UPLCMS SingleQuad; Column: Phenomenex Kinetix-XB C18 1.7 μm, 2.1×100 mm; 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: 200-400 nm.

Method 5:

[3068] Tandem Liquid Chromatography/Mass Spectrometry (LC/MS) was performed on a Waters 2795 separations module and 3100 mass detector with a Waters Symmetry C18 column (3.5 μm, 4.6×100 mm) with a gradient of 0-100% CH.sub.3CN in water over 2.5 min with constant 0.1% formic acid.

Preparative LC-MS Methods:

[3069] Unless otherwise noted compounds were purified using mass-triggered preparative HPLC (Waters Autopurificationsystem; Column: Waters XBridge C18 5p 100×30 mm; DAD scan: 210-400 nm, flow: 150 mL/min) or UV triggered preparative HPLC (pump: Labomatic HD-5000 or HD-3000, head HDK 280, lowpressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 μm, 125×30 mm, flow: 70 mL/min)

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 Section—General Procedures

General Details

[3070] All reactions were carried out under nitrogen (N.sub.2) atmosphere. All reagents and solvents were purchased from commercial vendors and used as received. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker (300 or 400 MHz .sup.1H, 75 or 101 MHz .sup.13C) spectrometer. Proton and carbon chemical shifts are reported in ppm (δ) referenced to the NMR solvent. Data are reported as follows: chemical shifts, multiplicity (br=broad, 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 a Biotage Isolera. Analytical thin layer chromatography (TLC) was performed on EM Reagent 0.25 mm silica gel 60-F plates.

Experimental Section—Intermediates

Intermediate 1

4-Chloro-N-methoxy-N-methyl-3-(trifluoromethyl)benzamide

[3071] ##STR00036##

[3072] A mixture of 15 g (66.7 mmol) of 4-chloro-3-trifluoromethyl benzoic acid (CAS 1737-36-6) in 100 ml of DCM was cooled in an ice bath before addition of 6.73 mL (80 mmol) of oxalyl chloride and a drop of DMF. The reaction was stirred overnight, warming to room temperature before concentration, and addition of CHCl.sub.3 followed by concentration (twice) to remove oxalyl chloride. The crude product was dissolved in 100 mL of CH.sub.2Cl.sub.2. In a separate flask, 7.14 g of N,O-dimethylhydroxylamine HCl (73.3 mmol) was added to 100 mL of CH.sub.2Cl.sub.2 and 37 mL of Et.sub.3N (266 mmol). After stirring 15 min the mixture was filtered and added to the acid chloride solution and the mixture was stirred 3 d. The reaction mixture was then transferred to a separatory funnel and the CH.sub.2Cl.sub.2 was rinsed with water, then aqueous NaHCO.sub.3 solution, before drying and concentrating to an oil. Chromatography with 0-20% EtOAc in hexane yielded 14.1 g of the title compound as an oil (79%).

[3073] .sup.1H NMR (300 MHz, CDCl.sub.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

1-(4-Chloro-3-(trifluoromethyl)phenyl)propan-1-one

[3074] ##STR00037##

[3075] 4-chloro-N-methoxy-N-methyl-3-(trifluoromethyl)benzamide (14.1 g, 52.6 mmol, Intermediate 1) was dissolved in 200 mL of THF and cooled in an ice bath before dropwise addition of 44 mL of 3 M EtMgBr solution (132 mmol, ether). Once addition was complete the ice bath was removed and the reaction stirred 3 h before cooling with an ice bath and quenching with NH.sub.4Cl solution. The mixture was transferred to a separatory 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 yielded 10.1 g of product as a white solid (81%).

[3076] .sup.1H NMR (400 MHz, CDCl.sub.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). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −62.87.

Intermediate 3

1-[3,5-Difluoro-4-(morpholin-4-yl)phenyl]ethanone

[3077] ##STR00038##

[3078] 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 N,N-diisopropylethylamine (660 μL, 3.8 mmol) was stirred at 100° C. overnight. 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 obtain 560 mg (42% yield) of the desired title compound, which was used in the next step without any further purification.

[3079] LC-MS (Method 1): R.sub.t=1.06 min; MS (ESIpos): m/z=242 [M+H].sup.+

[3080] .sup.1H-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), 7.587 (1.37), 7.589 (1.06), 7.609 (1.43), 7.612 (2.54).

Intermediate 4

5-Acetyl-2-(morpholin-4-yl)benzonitrile

[3081] ##STR00039##

[3082] 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 work 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 obtain 3.00 g (quant.) of the desired title compound, which was used in the next step without any further purification.

[3083] LC-MS (Method 1): R.sub.t=0.90 min; MS (ESIpos): m/z=231 [M+H].sup.+

Intermediate 5

1-(3-Fluoro-4-morpholinophenyl)propan-1-one

[3084] ##STR00040##

[3085] To a 1 L one-neck flask was added 40 g of 3,4-difluoropropiophenone (235 mmol, CAS 23384-72-7), 400 mL of CH.sub.3CN, 250 mL of morpholine (2.86 mol), and 50 mL of DIPEA (360 mmol) and the solution was heated at 100° C. overnight. The next day the reaction was cooled and concentrated. The mixture was dissolved in CH.sub.2Cl.sub.2 and rinsed several times with water, then brine, and was dried (MgSO.sub.4), filtered and concentrated. Most of the crude product dissolved in approx. 1 L of hot hexane and was cooled overnight. Upon filtration, more crystals appeared in the mother liquors. The mother liquors were concentrated and recrystallized from hexane. A total of 52.5 g of dry white solid was obtained (94%).

[3086] .sup.1H NMR (400 MHz, CDCl.sub.3) 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). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −121.48. MS: 238 [M+H].sup.+

Intermediate 6

1-(4-Morpholino-3-(trifluoromethyl)phenyl)propan-1-one

[3087] ##STR00041##

[3088] 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) were heated at reflux temperature overnight. The next day another 20 mL of morpholine and 10 mL of DIPEA were added and heating continued several hours before cooling and concentrating. Water was added to the crude reaction mixture which was then rinsed several times with CH.sub.2Cl.sub.2, the combined CH.sub.2Cl.sub.2 layers were rinsed with brine, dried and concentrated. Chromatography with 0-20% EtOAc in hexane yielded 6.0 g of product as a white solid (46%).

[3089] .sup.1H NMR (400 MHz, CDCl.sub.3) 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). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −60.02. MS: 288 (M+1)+.

Intermediate 7

1-[4-Amino-3-fluoro-5-(trifluoromethyl)phenyl]ethan-1-one

[3090] ##STR00042##

[3091] To a solution of 4-bromo-2-fluoro-6-(trifluoromethyl)benzenamine (21.60 g, 83.7 mmol, CAS 875664-46-3), in 250 mL of 1,4-dioxane were added 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. for overnight. After cooled to room temperature, 100 mL of the hydrochloric acid solution (1 M) was added. The resulting mixture was stirred at room temperature for further 4 hours. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue purified with 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

[3092] ##STR00043##

[3093] To a solution of 1-[4-amino-3-fluoro-5-(trifluoromethyl)phenyl]ethan-1-one (15.80 g, 71.4 mmol, Intermediate 7) in 200 mL of acetonitrile was added 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 layer was washed with saturated ammonium chloride solution, brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, the residue was purified with silica gel column chromatography (ethyl acetate: petroleum ether=1:20) to give 16.0 g (83.8%) of the product as a yellow oil.

[3094] .sup.1H-NMR (400 MHz, DMSO-d.sub.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

[3095] ##STR00044##

[3096] 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 of 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 layer was washed with brine, water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified with silica gel column chromatography (PE/EA=10:1) to give 16.70 g (86%) of the product as a yellow oil.

[3097] .sup.1H-NMR (300 MHz, CDCl.sub.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

[3098] ##STR00045##

[3099] 1-(4-chloro-3-(trifluoromethyl)phenyl)propan-1-one (10.1 g, 42.6 mmol, Intermediate 2) was dissolved in 80 mL of THF and cooled in a dry ice bath before addition of 42.6 mL (42.6 mmol) of 1 N lithium hexamethyldisilazane (in THF). After 1 h, a solution of 6.42 g of tert-butyldimethylsilane (42.6 mmol) in 10 mL THF was added dropwise and the reaction was stirred, warming to room temperature. After 3 d, the reaction mixture was concentrated and hexane was added and the mixture was stirred 30 min before filtering and concentrating. Chromatography with hexane on silica gel pretreated with Et.sub.3N yielded 11.2 g of product (75%).

[3100] .sup.1H NMR (400 MHz, CDCl.sub.3) 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). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −62.68.

Intermediate 11

tert-Butyl-[(E)-1-(3-fluoro-4-morpholino-phenyl)prop-1-enoxy]-dimethyl-silane

[3101] ##STR00046##

[3102] A solution of 749 mg (3.16 mmol) 1-(3-fluoro-4-morpholinophenyl)propan-1-one (Intermediate 5) dissolved in 10 mL THF was cooled in a −78° C. dry ice bath and to it was added 3.16 mL (3.16 mmol) of a 1 N THF solution of LiHMDS. After stirring cold for 1 h, a solution of 476 mg (3.16 mmol) of tert-butyldimethylsilyl chloride (tBDMSCI), dissolved in 2 mL of THF, was added and the solution was stirred overnight, warming to room temperature. After 2 d, ca. 50 mL of hexane was added, the mixture was filtered over a short plug of silica gel pretreated with some Et.sub.3N in hexane. Elution with hexane and 5% EtOAc in hexane isolated 670 mg clear oil (60%).

[3103] .sup.1H NMR (400 MHz, CDCl.sub.3) 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). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −123.51.

Intermediate 12

tert-Butyl-[(E)-1-(3,5-difluoro-4-morpholino-phenyl)prop-1-enoxy]-dimethyl-silane

[3104] ##STR00047##

[3105] 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 THF and cooled with a −78° C. ice bath. To this was added 8.61 mL (8.61 mmol) of a 1 N (THF) LiHMDS solution. The solution was stirred cold 1 h before addition of 1.29 g (8.61 mmol) TBDMSCI, dissolved in 10 mL THF, and the ice bath was removed and stirring continued overnight. The next day hexane was added and the mixture was filtered over a short plug of silica gel pretreated with Et.sub.3N in hexane. Elution with hexane and 5% EtOAc in hexane isolated 2.94 g of product (89%).

[3106] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.94 (d, J=10.4 Hz, 2H), 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). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −120.79.

Intermediate 13

(E)-4-(4-(1-((tert-Butyldimethylsilyl)oxy)prop-1-en-1-yl)-2-(trifluoromethyl)phenyl)morpholine

[3107] ##STR00048##

[3108] 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 THF and cooled with a −78° C. ice bath. To this was added 17.4 mL (17.4 mmol) of a 1 N (THF) LiHMDS solution. The solution was stirred cold 1 h before addition of 2.62 g (17.4 mmol) TBDMSCI, dissolved in 5 mL THF, and the ice bath was removed and stirring continued overnight. The next day ca. 200 mL of hexane was added and the mixture was stirred several hours before filtering and concentration. Chromatography with 0-10% EtOAc in hexane on a column pretreated with Et.sub.3N yielded 4.87 g of product as a clear oil (70%).

[3109] .sup.1H NMR (400 MHz, CDCl.sub.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

[3110] ##STR00049##

[3111] A solution of 4-fluoro-3-trifluoromethylpropiophenone (12 g, 55 mmol, CAS 239107-27-8) was dissolved in 60 mL of THF and cooled in a dry ice bath before addition of 60 mL (60 mmol) of 1 N lithium hexamethyldisilazane (in THF). After 1 h, a solution of 9.0 g of tert-butyldimethylsilane (60 mmol) in 15 mL THF was added dropwise and the reaction 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 filtering and concentrating. Chromatography with hexane on silica gel pretreated with Et.sub.3N yielded 15.3 g product (84%).

[3112] .sup.1H NMR (400 MHz, CDCl.sub.3) 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). .sup.19F NMR (376 MHz, CDCl.sub.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

[3113] ##STR00050##

[3114] To a solution of 1-(4-bromo-3-fluoro-5-(trifluoromethyl)phenyl)ethanone, 16.00 g (56.1 mmol, Intermediate 9, in 300 mL of toluene were added 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. for overnight under nitrogen atmosphere. After cooled to room temperature, water was added, and extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate, the solvent was removed in vacuo, and the residue was purified with 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

[3115] ##STR00051##

[3116] The title compound was synthesized analogously to Intermediate 7 from 1-bromo-4-iodo-2-(trifluoromethyl)benzene (CAS 1261496-16-5).

[3117] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.18-8.10 (m, 1H), 8.07-8.00 (m, 1H), 8.00-7.90 (m, 1H), 7.40-7.03 (m, 1H), 2.63 (s, 3H)

Intermediate 17

2-Bromo-1-[4-chloro-3-(trifluoromethyl)phenyl]ethanone

[3118] ##STR00052##

[3119] 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) were added. The reaction mixture was stirred overnight at room temperature. Then the reaction was poured into iced water, adjusted to pH 5 with aqueous sodium hydrogencarbonate solution, the brown precipitate was filtered off, washed with water and dried, to obtain 3.50 g of the crude title compound

[3120] LC-MS (Method 1): R.sub.t=1.29 min; MS (ESIpos): m/z=301 [M+H].sup.+

Intermediate 18

2-Bromo-1-[4-chloro-3-fluoro-5-(trifluoromethyl)phenyl]ethan-1-one

[3121] ##STR00053##

[3122] To a solution of 1-[4-chloro-3-fluoro-5-(trifluoromethyl)phenyl]ethan-1-one (15.00 g, 62 mmol, Intermediate 8) in 300 mL of HOAc was added hydrobromic acid, 0.03 g (0.3 mmol), bromine, 8.97 g (56.1 mmol), The mixture was stirred at room temperature for 3 hours.

[3123] Upon completion of the reaction, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give 18 g (crude) of the product as a yellow oil.

[3124] .sup.1H-NMR (400 MHz, DMSO-d.sub.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

[3125] ##STR00054##

[3126] 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) were added. The reaction mixture was stirred overnight at room temperature. Then the reaction was poured into iced water, adjusted to pH 5 with aqueous sodium hydrogencarbonate solution. The yellow precipitate was filtered off, washed with water and dried, to obtain 580 mg (81% yield) of the crude title compound.

[3127] LC-MS (Method 1): R.sub.t=1.18 min; MS (ESIpos): m/z=320 [M+H].sup.+

Intermediate 20

(rac)-2-Bromo-1-(3,4,5-trifluorophenyl)propan-1-one

[3128] ##STR00055##

[3129] 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) were added. The reaction mixture was stirred overnight at room temperature. Then the reaction was poured into iced water, adjusted to pH 5 with aqueous sodium hydrogencarbonate solution and the aqueous phase was extracted with dichloromethane. The organic phase was concentrated in vacuo, to obtain 1.6 g (quant.) of the crude title compound.

[3130] LC-MS (Method 1): R.sub.t=1.33 min; MS (ESIpos): m/z=mass not detectable.

[3131] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78 (d, J=6.34 Hz, 3H) 5.85 (q, J=6.59 Hz, 1H) 7.88-8.06 (in, 2H).

Intermediate 21

2-Bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone

[3132] ##STR00056##

[3133] 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 into the reaction mixture, which was stirred overnight, its colour turned from brown to orange. The mixture was concentrated under reduced pressure and used as crude material in the next step.

Intermediate 22

2-Bromo-1-[4-chloro-3-(trifluoromethoxy)phenyl]ethanone

[3134] ##STR00057##

[3135] 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 into the reaction mixture, which was stirred overnight, its colour turned from brown to orange. The mixture was poured on ice water, set to pH5 with aqueous sodium carbonate solution and extracted three times with dichloromethane. The combined organic phases were concentrated under reduced pressure and obtained as crude material (2.80 g, 92% yield).

Intermediate 23

(rac)-2-Bromo-1-[4-chloro-3-(trifluoromethyl)phenyl]propan-1-one

[3136] ##STR00058##

[3137] 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) were added. The reaction mixture was stirred overnight at RT. Then the reaction was poured into iced water, adjusted to pH 5 with sat. aq. NaHCO.sub.3 and the aqueous phase was extracted with DCM (3×20 mL). The organic phase was dried over anhydrous MgSO.sub.4, filtered and concentrated in vacuo to afford 605 mg (86% yield, 95% purity) of the title compound as a pale yellow free-flowing oil. LCMS (Method 3, 1.7 min) 95%@Rt=1.34 min, MS (ESIpos): m/z=mass not detectable .sup.1H 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

[3138] ##STR00059##

[3139] The title compound was synthesized analogously to Intermediate 19 from Intermediate 15.

[3140] MS(ESIpos): m/z=370 (M+H)+.

Intermediate 25

2-Bromo-1-[4-bromo-3-(difluoromethyl)phenyl]ethan-1-one

[3141] ##STR00060##

[3142] 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

[3143] ##STR00061##

[3144] The title compound was synthesized analogously to Intermediate 19 from 1-(4-bromo-3-(trifluoromethyl)phenyl)ethanone (CAS 120077-70-5).

Intermediate 27

1-(3,4-Difluorophenyl)-2-hydroxyethanone

[3145] ##STR00062##

[3146] 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 via column chromatography (silica gel, hexane/ethyl acetate, gradient: 12%->93% ethyl acetate) afforded the title compound (450 mg, 38% yield).

[3147] LC-MS (Method 1): R.sub.t=0.77 min; MS (ESIpos): m/z=173 [M+H].sup.+

Intermediate 28

1-[4-Chloro-3-(trifluoromethyl)phenyl]-2-hydroxyethanone

[3148] ##STR00063##

[3149] 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), sodium hydrogencarbonate (2.23 g, 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 via column chromatography (silica gel, hexane/ethyl acetate, gradient: 12%->92% ethyl acetate) afforded the title compound (700 mg, 11% yield) in a purity of 67%.

[3150] LC-MS (Method 1): R.sub.t=1.03 min; MS (ESIpos): m/z=239 [M+H].sup.+

Intermediate 29

(rac)-2-Hydroxy-1-(3,4,5-trifluorophenyl)propan-1-one

[3151] ##STR00064##

[3152] 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 hydrogencarbonate (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 via column chromatography (silica gel, hexane/ethyl acetate, gradient: 12%->100% ethyl acetate) afforded the title compound (1.62 g, quant.).

[3153] LC-MS (Method 2): R.sub.t=0.94 min; MS (ESIneg): m/z=203 [M−H].sup.−

[3154] .sup.1H-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

[3155] ##STR00065##

[3156] 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 hydrogencarbonate (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 via column chromatography (silica gel, hexane/ethyl acetate gradient: 2%->100% ethyl acetate) afforded the title compound (1.15 g, 53% yield).

[3157] LC-MS (Method 1): R.sub.t=0.98 min; MS (ESIpos): m/z=229 [M+H].sup.+

Intermediate 31

1-[3,5-Difluoro-4-(morpholin-4-yl)phenyl]-2-hydroxyethanone

[3158] ##STR00066##

[3159] 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 1 h in a microwave vial. Then sodium formate (61.6 mg, 0.906 mmol) and sodium hydrogencarbonate (76.1 mg, 0.906 mmol) were added and stirred 4 h at 65° C. 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 via column chromatography (silica gel, hexane/ethyl acetate, gradient: 12%->100% ethyl acetate) afforded the title compound 60.0 mg (26% yield).

[3160] LC-MS (Method 1): R.sub.t=0.87 min; MS (ESIpos): m/z=258 [M+H].sup.+

Intermediate 32

5-(Hydroxyacetyl)-2-(morpholin-4-yl)benzonitrile

[3161] ##STR00067##

[3162] To a solution of 5-acetyl-2-(morpholin-4-yl)benzonitrile (1.77 g, 7.68 mmol, Intermediate 4) in DMSO (36 mL) and water (7.4 mL) was added hydroxy(tosyloxy)iodo]benzene (18.1 g, 46.1 mmol) and the mixture was stirred at room temperature over night. The reaction mixture was diluted with water and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were concentrated in vacuo and purified by column chromatography (silica gel, hexane/ethyl acetate, gradient: 15%->100% ethyl acetate) afforded the title compound 570 mg (28% yield).

[3163] LC-MS (Method 1): R.sub.t=0.73 min; MS (ESIpos): m/z=247 [M+H].sup.+

[3164] 1H NMR (400 MHz, DMSO-d6) 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

[3165] ##STR00068##

[3166] Following a literature procedure (Org. Lett. 2015, 17, 876), to 930 mg (3.91 mmol) of 1-(3-fluoro-4-morpholinophenyl)propan-1-one (Intermediate 5) dissolved in 6 mL of dry DMSO was added 198 mg of iodine (0.782 mmol) and the reaction was heated at 60° C. overnight. The next day the reaction was cooled, water was added and the mixture was rinsed several times with EtOAc, the combined EtOAc layers were rinsed with brine, dried, concentrated and chromatographed with 0-40% EtOAc in hexane to isolate 240 mg of product as a yellow oil which solidified with time (24%).

[3167] .sup.1H NMR (400 MHz, CDCl.sub.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). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −120.60. MS: 254 [M+H].sup.+

Intermediate 34

(rac)-1-[4-Chloro-3-(trifluoromethyl)phenyl]-2-hydroxypropan-1-one

[3168] ##STR00069##

[3169] To a solution of (rac)-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 hydrogencarbonate (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 mL×3). The organic layers were combined, washed with sodium thiosulfate (sat. aq. sol. 50% diluted in H.sub.2O), dried over anhydrous MgSO.sub.4, filtered and dried in vacuo to obtain a crude residue. The crude residue was purified by Biotage Isolera™ chromatography (25 g KP-Sil, eluting with heptanes-EtOAc, 1:0 to 1:1) to afford 404.4 mg (67% yield, >75% purity by NMR) of the title compound as a pale yellow free-flowing oil. LCMS (Method 3, 1.7 min) 87%@Rt=1.10 min, MS (ESIpos): m/z=mass not detectable .sup.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 trace heptane by NMR].

Intermediate 35

2-(4-Chloro-3-methylphenyl)-2-oxoethyl acetate

[3170] ##STR00070##

[3171] To a solution of 2-bromo-1-(4-chloro-3-methylphenyl)ethanone (247 mg, 998 μmol, CAS 205178-80-9) in DMF (4.0 mL) were added potassium acetate (294 mg, 2.99 mmol) and potassium iodide (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 obtain 200 mg (88% yield) of the crude title compound.

[3172] LC-MS (Method 1): R.sub.t=1.16 min; MS (ESIpos): m/z=227 [M+H].sup.+

[3173] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3174] ##STR00071##

[3175] Following a literature procedure (J. Org. Chem. 1992, 57, 5067), to 10 mL of tert-butanol and 10 mL water was added 190 mg methanesulfonamide, and 2.7 g AD-mix-α (Aldrich) and the mixture was cooled on an ice bath before addition of the 670 mg of tert-butyl-[(E)-1-(3-fluoro-4-morpholino-phenyl)prop-1-enoxy]-dimethyl-silane (Intermediate 11). The mixture was kept cold for several hours and warmed to room temperature overnight. The next day the mixture was cooled on an ice bath, 2 g of sodium sulfite was added and stirred 30 min. Water and EtOAc were added and the EtOAc separated, dried, and concentrated. Chromatography with 0-50% EtOAc yielded 363 mg white solid (75%).

[3176] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.75-7.56 (m, 2H), 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). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −120.60. MS: 254 [M+H].sup.+

Intermediate 37

(S)-1-(3,5-Difluoro-4-morpholinophenyl)-2-hydroxypropan-1-one

[3177] ##STR00072##

[3178] Following a literature procedure (J. Org. Chem. 1992, 57, 5067), to 40 mL of water and 40 mL of tert-BuOH was added 11.2 g of AD-mix-α (Aldrich) and 760 mg of methanesulfonamide (8 mmol). The mixture was cooled in an ice bath and to this was added the 2.94 g of tert-butyl-[(E)-1-(3,5-difluoro-4-morpholino-phenyl)prop-1-enoxy]-dimethyl-silane (7.95 mmol, Intermediate 12). The mixture was kept on 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 hexane to yield 1.68 g of oil which solidified with sitting (68%).

[3179] .sup.1H NMR (400 MHz, CDCl.sub.3) 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). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −119.20. MS: 272 [M+H].sup.+

Intermediate 38

2-(4-Chloro-3-fluorophenyl)-2-oxoethyl acetate

[3180] ##STR00073##

[3181] To a solution of 2-bromo-1-(4-chloro-3-fluorophenyl)ethanone (5.20 g, 20.7 mmol, CAS 231297-62-4) in DMF (31 mL) were added potassium acetate (4.06 g, 41.4 mmol) and potassium iodide (3.43 g, 20.7 mmol) and the mixture was stirred at room temperature over night. 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 obtain 5.40 g (113% yield) of the crude title compound.

[3182] LC-MS (Method 1): R.sub.t=1.07 min; MS (ESIpos): m/z=189 [M+H].sup.+

Intermediate 39

2-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl acetate

[3183] ##STR00074##

[3184] 2-Bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (500 mg, 1.75 mmol, Intermediate 21) was dissolved in dimethyl formamide (2.6 mL) under nitrogen, 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 water-resistant filter and the filtrate was concentrated under reduced pressure. The crude material was used without further purification.

[3185] LC-MS (Method 1): R.sub.t=1.14 min; MS (ESIneg): m/z=263 [M−H].sup.−

Intermediate 40

(rac)-2-Hydroxy-1-(4-morpholino-3-(trifluoromethyl)phenyl)propan-1-one

[3186] ##STR00075##

[3187] 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) were heated at 60° C. overnight in 2 mL of DMSO. After cooling, the reaction mixture was transferred to a separatory funnel. Water and EtOAc were added, addition of sodium sulfite solution dissipated most of the color. The EtOAc layer was rinsed with brine, dried, concentrated and chromatographed with 20-70% EtOAc in hexane to yield 104 mg of a clear yellow oil (49%).

[3188] .sup.1H NMR (400 MHz, CDCl.sub.3) 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). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −59.94. Mass 304 (M+1)+.

Intermediate 41

(S)-2-Hydroxy-1-(4-morpholino-3-(trifluoromethyl)phenyl)propan-1-one

[3189] ##STR00076##

[3190] Following a literature procedure (J. Org. Chem. 1992, 57, 5067), to 50 mL of tert-butanol and 50 mL water was added 1 g methanesulfonamide, and 14 g AD-mix-α (Aldrich) and the mixture was cooled on an ice bath before addition of the 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 on an ice bath, 10 g of sodium sulfite was added and stirred 30 min. Water and EtOAc were added and the EtOAc separated, dried, and concentrated. Chromatography with 0-50% EtOAc yielded 3.3 g white solid (90%).

[3191] .sup.1H NMR (400 MHz, CDCl.sub.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). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −59.94. MS: 304 (M+1)+.

Intermediate 42

(S)-1-(4-Chloro-3-(trifluoromethyl)phenyl)-2-hydroxypropan-1-one

[3192] ##STR00077##

[3193] Following a literature procedure (J. Org. Chem. 1992, 57, 5067), to 150 mL of tert-butanol and 150 mL of water was added 3 g methanesulfonamide, and 45 g AD-mix-α (Aldrich) and the mixture was cooled on an ice bath before addition of the 11.2 g of (E)-tert-Butyl((1-(4-chloro-3-(trifluoromethyl)phenyl)prop-1-en-1-yl)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 on an ice bath, 30 g of sodium sulfite was added and stirred 30 min. The mixture was filtered and water and EtOAc were added and the EtOAc was separated, dried, and concentrated. Chromatography with 0-25% EtOAc yielded 5.2 g of pale yellow oil (65%). Mass 253 (M+1)+.

Intermediate 43

(S)-1-(4-Fluoro-3-(trifluoromethyl)phenyl)-2-hydroxypropan-1-one

[3194] ##STR00078##

[3195] Following a literature procedure (J. Org. Chem. 1992, 57, 5067), to 90 mL of tert-butanol and 90 mL water was added 1.8 g methanesulfonamide, and 26 g AD-mix-α (Aldrich) and the mixture was cooled on an ice bath before addition of the 6.0 g of (E)-tert-Butyl((1-(4-fluoro-3-(trifluoromethyl)phenyl)prop-1-en-1-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 on an ice bath, 18 g of sodium sulfite was added and stirred 30 min. Water and CH.sub.2Cl.sub.2 were added and the CH.sub.2Cl.sub.2 was separated, dried, and concentrated before chromatography with 0-30% EtOAc yielded 3.5 g of product as an oil (82%).

[3196] .sup.1H NMR (400 MHz, CDCl.sub.3) 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). .sup.19F NMR (376 MHz, CDCl.sub.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

[3197] ##STR00079##

[3198] 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, 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 water-resistant filter and the filtrate was concentrated under reduced pressure. The crude material 2.50 g (96% yield) was used without further purification.

[3199] LC-MS (Method 1): R.sub.t=1.14 min; MS (ESIneg): m/z=263 [M−H].sup.−

Intermediate 45

2-[4-Chloro-3-fluoro-5-(trifluoromethyl)phenyl]-2-oxoethyl acetate

[3200] ##STR00080##

[3201] 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 was added potassium acetate, 11.1 g (113 mmol), potassium iodide, 9.4 g (56.3 mmol), The mixture was stirred at room temperature for overnight. Upon completion of the reaction, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give 16.4 g (crude) of the product as a yellow oil.

[3202] .sup.1H-NMR (400 MHz, DMSO-d.sub.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

[3203] ##STR00081##

[3204] The title compound was synthesized analogously to Intermediate 45 from Intermediate 24.

[3205] MS(ESIpos): m/z=350 (M+H)+.

Intermediate 47

2-[4-Bromo-3-(difluoromethyl)phenyl]-2-oxoethyl acetate

[3206] ##STR00082##

[3207] The title compound was as synthesized analogously to Intermediate 45 from Intermediate 25.

[3208] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 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

[3209] ##STR00083##

[3210] The title compound was as synthesized analogously to Intermediate 45 from Intermediate 26.

Intermediate 49

Methyl 2-[1-(3,4-difluorophenyl)-2-hydroxyethylidene]hydrazinecarboxylate

[3211] ##STR00084##

[3212] 1-(3,4-difluorophenyl)-2-hydroxyethanone (1.20 g, 6.97 mmol, Intermediate 27) was dissolved in methanol. Methyl hydrazinecarboxylate (1.13 g, 12.5 mmol) and aqueous hydrochloric acid (1N) were added until pH value 5.5 was reached. The reaction mixture was stirred 5 h at room temperature and concentrated in vacuo, to obtain the crude title compound (2.4 g, quant.), which was used in the next step without any further purification.

[3213] LC-MS (Method 1): R.sub.t=0.85 min; MS (ESIpos): m/z=245 [M+H].sup.+

Intermediate 50

Methyl 2-{1-[4-chloro-3-(trifluoromethyl)phenyl]-2-hydroxyethylidene}hydrazinecarboxylate

[3214] ##STR00085##

[3215] 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 hydrazinecarboxylate (396 mg, 4.40 mmol) and with aqueous hydrochloric acid (1N) a pH of 5.5 was adjusted. The reaction mixture was stirred 24 h at room temperature. The reaction mixture was concentrated in vacuo, to obtain 1.2 g of the crude title compound.

[3216] LC-MS (Method 1): R.sub.t=1.04 min; MS (ESIpos): m/z=311 [M+H].sup.+

Intermediate 51

Methyl 2-[2-(acetyloxy)-1-(4-chloro-3-methylphenyl)ethylidene]hydrazinecarboxylate

[3217] ##STR00086##

[3218] 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 hydrazinecarboxylate (1.78 g, 19.8 mmol) and a pH of 5.5 was adjusted with aqueous hydrochloric acid (1N). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, to obtain 3.6 g (98% yield) of the crude title compound, which was used in the next step without any further purification.

[3219] LC-MS (Method 1): R.sub.t=1.17 min; MS (ESIpos): m/z=299 [M+H].sup.+

Intermediate 52

(rac)-Methyl 2-[2-hydroxy-1-(3,4,5-trifluorophenyl)propylidene]hydrazinecarboxylate

[3220] ##STR00087##

[3221] (rac)-2-Hydroxy-1-(3,4,5-trifluorophenyl)propan-1-one (1.62 g, 7.94 mmol, Intermediate 29) was dissolved in methanol. Methyl hydrazinecarboxylate (1.29 g, 14.3 mmol) and aqueous hydrochloric acid (1N) was added until pH value 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) afforded the title compound (950 mg, 43% yield).

[3222] LC-MS (Methode 2): R.sub.t=1.03 min; MS (ESIneg): m/z=275 [M−H].sup.−

Intermediate 53

(rac)-Ethyl 2-[-1-(4-bromophenyl)-2-hydroxypropylidene]hydrazinecarboxylate

[3223] ##STR00088##

[3224] (rac)-1-(4-Bromophenyl)-2-hydroxypropan-1-one (1.15 g, 5.02 mmol, Intermediate 30) was dissolved in methanol. Methyl hydrazinecarboxylate (814 mg, 9.04 mmol) and aqueous hydrochloric acid (1N) was added until pH value 5.5 was reached. The reaction mixture was stirred 24 h at room temperature and concentrated in vacuo. Purification via column chromatography (silica gel, hexane/ethyl acetate gradient: 2%->100% ethyl acetate) afforded the title compound (600 mg, 40% yield).

[3225] LC-MS (Method 1): R.sub.t=1.05 min; MS (ESIpos): m/z=229 [M+H].sup.+

Intermediate 54

Methyl 2-{1-[3,5-difluoro-4-(morpholin-4-yl)phenyl]-2-hydroxyethylidene}hydrazinecarboxylate

[3226] ##STR00089##

[3227] 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). Methyl hydrazinecarboxylate (290 mg, 3.22 mmol) and aqueous hydrochloric acid (18 μl, 1.0 M, 18 μmol) was added until pH value 5.5 was reached. The reaction mixture was stirred 5 h at room temperature and concentrated in vacuo, to obtain the crude title compound (30 mg, 5% yield), which was used in the next step without any further purification.

[3228] LC-MS (Method 1): R.sub.t=0.91 min; MS (ESIpos): m/z=330 [M+H].sup.+

Intermediate 55

Methyl 2-{1-[3-cyano-4-(morpholin-4-yl) phenyl]-2-hydroxyethylidene}hydrazinecarboxylate

[3229] ##STR00090##

[3230] 5-(Hydroxyacetyl)-2-(morpholin-4-yl)benzonitrile (570 mg, 2.31 mmol, Intermediate 32) was dissolved in methanol. Methyl hydrazinecarboxylate (375 mg, 4.17 mmol) and aqueous hydrochloric acid (1N) was added until pH value 5.5 was reached. The reaction mixture was stirred 24 h at room temperature and then concentrated in vacuo, to obtain the crude title compound 600 mg (81% yield), which was used in the next step without any further purification.

[3231] LC-MS (Method 1): R.sub.1=0.80 min, MS (ESIpos): m/z=319 [M+H].sup.+

Intermediate 56

Methyl 2-[2-(acetyloxy)-1-(4-chloro-3-fluorophenyl)ethylidene]hydrazinecarboxylate

[3232] ##STR00091##

[3233] 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 hydrazinecarboxylate (3.80 g, 42.1 mmol) and aqueous hydrochloric acid (1N) was added until pH value 5.5 was reached. The reaction mixture was stirred 24 h at room temperature and concentrated in vacuo, to obtain the crude title compound (7 g, quant.), which was used in the next step without any further purification.

[3234] LC-MS (Method 1): R.sub.t=1.11 min; MS (ESIpos): m/z=303 [M+H].sup.+

Intermediate 57

Methyl (2)-2-{2-(acetyloxy)-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethylidene}hydrazinecarboxylate

[3235] ##STR00092##

[3236] 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 (1M). Then methyl hydrazinecarboxylate (32.4 mg, 360 μmol) was added and the mixture was stirred 72 hours at room temperature. The mixture was concentrated and the crude material was used without further purification.

[3237] LC-MS (Method 1): R.sub.t=1.15 min; MS (ESIneg): m/z=335 [M−H].sup.−

Intermediate 58

Methyl (2)-2-{2-(acetyloxy)-1-[4-chloro-3-(trifluoromethoxy)phenyl]ethylidene}hydrazinecarboxylate

[3238] ##STR00093##

[3239] 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 hydrazinecarboxylate (1.37 g, 15.2 mmol) was added and the mixture was stirred 1 hour at room temperature. The mixture was concentrated and the crude material 2.2 g (71% yield) was used without further purification.

[3240] LC-MS (Method 1): R.sub.t=1.26 min; MS (ESIneg): m/z=367 [M−H].sup.−

Intermediate 59

Methyl (2Z)-2-{2-(acetyloxy)-1-[4-chloro-3-fluoro-5-(trifluoromethyl)phenyl]ethylidene}hydrazine-1-carboxylate

[3241] ##STR00094##

[3242] The title compound was synthesized analogously to Intermediate 58 from Intermediate 45.

[3243] MS (ESIpos):m/z=371 (M+H)+

Intermediate 60

Methyl (2Z)-2-{2-(acetyloxy)-1-[3-fluoro-4-(morpholin-4-yl)-5-(trifluoromethyl)phenyl]ethylidene}hydrazine-1-carboxylate

[3244] ##STR00095##

[3245] The title compound was synthesized analogously to Intermediate 58 from Intermediate 46.

[3246] MS(ESIpos): m/z=422 (M+H)+.

Intermediate 61

Methyl (2E)-2-{2-(acetyloxy)-1-[4-bromo-3-(difluoromethyl)phenyl]ethylidene}hydrazine-1-carboxylate

[3247] ##STR00096##

[3248] The title compound was synthesized analogously to Intermediate 58 from Intermediate 47.

[3249] MS (ESIpos): m/z=379 [M+H].sup.+.

Intermediate 62

Methyl (2Z)-2-{2-(acetyloxy)-1-[4-bromo-3-(trifluoromethyl)phenyl]ethylidene}hydrazine-1-carboxylate

[3250] ##STR00097##

[3251] The title compound was synthesized analogously to Intermediate 58 from Intermediate 48.

[3252] MS(ESIpos): m/z=398 (M+H)+.

Intermediate 63

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

[3253] ##STR00098##

[3254] 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) was added potassium carbonate (2.04 g, 14.7 mmol) 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 obtain 1.20 g (58% yield) of the desired title compound.

[3255] LC-MS (Method 1): R.sub.t=0.87 min; MS (ESIpos): m/z=213 [M+H].sup.+

[3256] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3257] ##STR00099##

[3258] To a solution of methyl 2-{1-[4-chloro-3-(trifluoromethyl)phenyl]-2-hydroxyethylidene}hydrazinecarboxylate (1.10 g, 3.54 mmol, Intermediate 50) in acetonitrile (9 mL) was added potassium carbonate (489 mg, 3.54 mmol) and the mixture was stirred 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 obtain 700 mg (71% yield, 90% purity) of the desired title compound.

[3259] LC-MS (Method 1): R.sub.t=1.11 min; MS (ESIpos): m/z=279 [M+H].sup.+

[3260] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3261] ##STR00100##

[3262] To a solution of methyl 2-[2-(acetyloxy)-1-(4-chloro-3-fluorophenyl)ethylidene]hydrazinecarboxylate (4.15 g, 13.7 mmol, Intermediate 56) in ethanol (21 ml) was added sodium ethanolate (7.7 ml, 21% in EtOH, 21 mmol) and the mixture was stirred 17 h at RT. Water was added, the precipitate was filtered off and dried to obtain 1.60 g (51% yield) of the desired title compound.

[3263] LC-MS (Method 1): R.sub.t=0.97 min; MS (ESIpos): m/z=229 [M+H].sup.+

[3264] .sup.1H-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

[3265] ##STR00101##

[3266] Methyl (2)-2-{2-(acetyloxy)-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethylidene}hydrazinecarboxy-late (3.30 g, 9.81 mmol, Intermediate 57) was suspended in ethanol (83 mL) under nitrogen and sodium ethylate solution in ethanol (5.5 mL, 21% purity, 15 mmol) was added. It was stirred at room temperature for 30 min. The reaction mixture was diluted with aqueous saturated ammonium chloride solution and water and stirred for 1 hour. Precipitated product was filtered off. The filter cake was washed with water and dried under vacuo to give 2.50 g (95% purity) of the title compound.

[3267] LC-MS (Method 1): R.sub.t=1.03 min; MS (ESIneg): m/z=261 [M−H].sup.−

[3268] .sup.1H-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

[3269] ##STR00102##

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) was 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 aqueous saturated ammonium chloride solution, 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.

[3270] LC-MS (Method 1): R.sub.t=1.12 min; MS (ESIpos): m/z=403 [M+H].sup.+

[3271] .sup.1H-NMR (400 MHz, DMSO-d6) 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).

Intermediate 68

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

[3272] ##STR00103##

[3273] To a solution of (rac)-1-[4-chloro-3-(trifluoromethyl)phenyl]-2-hydroxypropan-1-one (400 mg, 1.19 mmol, Intermediate 34) in MeOH (1.2 mL) was added methyl hydrazinocarboxylate (118 mg, 1.31 mmol) and 0.1M aqueous hydrogen chloride solution (2 drops, 2.02 μmol). The resulting mixture was heated at reflux for 1 h. The reaction mixture was concentrated in vacuo and the residual material azeotroped with MeOH (×2). Freshly prepared methanolic NaOMe solution [Na (109 mg, 4.75 mmol) consumed in MeOH (3.1 mL)] was added and the mixture stirred at RT for 2 h. Additional freshly prepared methanolic NaOMe solution [Na (109 mg, 4.75 mmol) consumed in MeOH (3.1 mL)] was added and the mixture stirred at RT for a further 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.sub.4, filtered and concentrated in vacuo to obtain a crude residue. The residue was purified by Biotage Isolera™ chromatography (25 g KP-Sil, eluting with heptanes-EtOAc, 1:0 to 1:1). The obtained impure solid was re-purified by Biotage Isolera™ chromatography (10 g KP-Sil, eluting with heptanes-EtOAc, 1:0 to 1:1) to afford the title compound (185.7 mg, 49% yield, 92% purity) as a off-white solid. LCMS (Method 3, 2 min) 94%@Rt=1.14 min, MS (ESIpos): m/z=292.8 (M+H)+ [Weak ionisation] LCMS (Method 4, 7 min) 92%@Rt=3.18 min, MS (ESIpos): m/z=292.9 (M+H)+ [Weak ionisation] .sup.1H 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.sub.2, Flow rate: 4 mL/min, UV at 280 nm, Runtime: 7 min, Neg ion MS

[3274] LC-MS (Method 4, 7 min): R.sub.t=3.18 min; MS (ESIpos): m/z=293 [M+H].sup.+

Intermediate 69

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

[3275] ##STR00104##

[3276] To a solution of methyl (2Z)-2-{2-(acetyloxy)-1-[4-chloro-3-fluoro-5-(trifluoromethyl)phenyl]ethylidene}hydrazine-1-carboxylate (20 g, 36% purity, Intermediate 59), in 200 mL of ethanol, was added sodium hydride, 0.39 g (9.7 mmol, 60% purity), then the resulting mixture was stirred at 0° C. for 2 hours under nitrogen. Upon completion of the reaction, the mixture was acidified to pH=1 with HCl (1N). The solvent was removed in vacuo directly, the residue was purified by C18 reversed phase column chromatography: [Mobile Phase A: Waters (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 40% B to 70% B in 25 min] to give 2.01 g (34.4%) of the product as a white solid.

[3277] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 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

[3278] ##STR00105##

[3279] 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 mL of 1,4-dioxane were added tributyl(1-ethoxyvinyl)stannane, 838 mg (2.3 mmol), and tetrakis(triphenylphosphine)palladium(0), 89 mg (0.08 mmol). The resulting mixture was stirred at 110° C. for overnight. After cooled to room temperature, 15 mL of the hydrochloric acid solution (1 M) was added. The resulting mixture was stirred at room temperature for further 4 hours. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue purified with silica gel column chromatography (PE/EA=3:1) to give 320 mg (65%) of the product as a yellow solid.

[3280] MS(ESIpos): m/z=287 (M+H)+.

Intermediate 71

(rac)-6-Methyl-5-(3,4,5-trifluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3281] ##STR00106##

[3282] To a solution of (rac)-methyl 2-[2-hydroxy-1-(3,4,5-trifluorophenyl)propylidene]hydrazinecarboxylate (95.0 mg, 344 μmol, Intermediate 52) in toluene (2.0 mL) was added 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 obtain 5.00 mg (95% purity, 6% yield) of the desired title compound.

[3283] LC-MS (Method 1): R.sub.t=1.02 min; MS (ESIpos): m/z=245 [M+H].sup.+

[3284] .sup.1H-NMR (400 MHz, DMSO-d6) 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

(rac)-5-(4-Bromophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3285] ##STR00107##

[3286] (rac)-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 obtain 430 mg (95% purity, 76% yield) of the desired title compound.

[3287] LC-MS (Method 1): R.sub.t=1.04 min; MS (ESIneg): m/z=269 [M−H].sup.−

[3288] .sup.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), 7.681 (3.98), 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-2H-1,3,4-oxadiazin-2-one

[3289] ##STR00108##

[3290] Methyl (2)-2-{2-(acetyloxy)-1-[4-chloro-3-(trifluoromethoxy)phenyl]ethylidene}hydrazinecarboxylate (892 mg, 2.42 mmol, Intermediate 58) was dissolved in ethanol (10 ml) and cooled to 0° C. Sodium hydride (290 mg, 60% purity, 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 water-resistant filter and concentrated in vacuo. The residue was purified by chromatography to obtain 160 mg (90% purity, 20% yield) of the desired title compound.

[3291] LC-MS (Method 1): Rt=1.15 min; MS (ESIpos): m/z=295 [M+H].sup.+

[3292] .sup.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), 7.844 (1.95), 7.848 (2.51), 7.851 (1.79), 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

[3293] ##STR00109##

[3294] 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 methyl hydrazinecarboxylate (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 was concentrated, MeOH was added and concentrated to remove HCl and water (twice). To this was added a NaOMe solution (2.26 g Na (98.4 mmol) consumed in 60 mL MeOH). After 1 h 40 min, 5.9 mL of HOAc (98 mmol) was added and the solution was concentrated and partitioned between EtOAc and water. The EtOAc was removed, dried, and concentrated. Chromatography with 0-20% EtOAc in hexane followed by recrystallization from CH.sub.2Cl.sub.2 and hexane yielded 3.55 g of product as a white solid (62%).

[3295] .sup.1H NMR (400 MHz, CDCl.sub.3) 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). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −62.93. LC-MS (Method 5): Mass 293 (M+1)+. Chiral SFC analysis (Column: ChiralPak AS-H, 250×4.6 mm, 5 μm, Mobile Phase Modifier: 100% Methanol, Gradient: 5 to 50% Methanol over 10 min, Flow Rate: 4 mL/min, Back Pressure: 100 bar, Column Temperature: 40° C. UV detection was from 200-400 nm) showed retention times of separated enantiomers at 5.54 and 5.95 min in 98.9:1.1 ratio.

Intermediate 75

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

[3296] ##STR00110##

[3297] To 3.4 g of (S)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxypropan-1-one (14 mmol, Intermediate 43) in 15 mL of MeOH and 1.41 g of methyl hydrazinecarboxylate (15.7 mmol) was added 9 drops of 0.1 N HCl solution (J. Med. Chem. 1992, 35, 163) and the mixture was heated at reflux 1 h. After cooling, the reaction was concentrated, MeOH was added and concentrated to remove HCl and water (twice). To this was added a NaOMe solution (1.64 g Na (71.5 mmol) consumed in 45 mL MeOH). After 2 h, 4.3 mL of HOAc (72 mmol) was added and the solution was concentrated and partitioned between EtOAc and water. The EtOAc was removed, dried, and concentrated. Chromatography with 10-40% EtOAc in hexane yielded the product as an oil which solidified upon standing overnight, 2.25 g (57%). .sup.1H NMR (400 MHz, CDCl.sub.3) 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). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −61.68 (d, J=12.6 Hz),-110.74 (q, J=12.7 Hz).

[3298] 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

[3299] ##STR00111##

[3300] To a solution of methyl 2-[2-(acetyloxy)-1-(4-chloro-3-methylphenyl)ethylidene]hydrazinecarboxylate (3.60 g, 12.1 mmol, Intermediate 51) in acetonitrile (63 mL) was added 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 off and dried, to obtain 500 mg (19% yield, 97% purity) of the desired title compound.

[3301] LC-MS (Method 1): R.sub.t=1.04 min; MS (ESIpos): m/z=225 [M+H].sup.+

[3302] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3303] ##STR00112##

[3304] To a solution of methyl 2-(2-acetoxy-1-(4-bromo-3-(difluoromethyl)phenyl)ethylidene)-hydrazinecarboxylate, 8 g (21.0 mmol, Intermediate 61), in 100 mL of ethanol, was added sodium hydride, 0.8 g (33.3 mmol). The resulting mixture was stirred at 0° C. for 3 hours.

[3305] Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified with silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give 4.2 g of the product, as a yellow solid. 100 mg was purified by Prep-HPLC [Column: Xbridge prep C18 5 um 19*150 m; Mobile phase A: Waters (0.1% NH4HCO3), Mobile phase B: ACN; Flow rate: 20 ml/min; Gradient: 30% B to 55% B in 8 min; 254 & 220 nm; t=7.12 min] to give 44.4 mg of 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

[3306] ##STR00113##

[3307] To a solution of methyl 2-(2-acetoxy-1-(4-bromo-3-(trifluoromethyl)phenyl)ethylidene)-hydrazinecarboxylate, 1.4 g (2.7 mmol, Intermediate 62), in 50 mL of ethanol, was added sodium hydride, 0.2 g (4.1 mmol, 60% purity) at 0° C. The resulting mixture was stirred at 0° C. for 2 hours under nitrogen atmosphere. Upon completion of the reaction, the pH value was adjusted to 6˜7 with 1N hydrogen chloride solution, then, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium. The solvent was removed in vacuo and the residue was purified with silica gel column chromatography (EA/PE=1/1) to give 0.43 g (49%) of the product as a yellow solid.

[3308] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=11.27 (s, 1H), 8.06 (d, 1H), 7.99 (d, 1H), 7.88 (dd, 1H), 5.43 (s, 2H)

Experimental Section—Examples

Example 1

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

[3309] ##STR00114##

[3310] 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) were added 4,4-difluoropiperidine hydrochloride (1:1) (357 mg, 2.26 mmol) and a small amount of calcium carbonate. 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 water-resistant filter and concentrated in vacuo. The residue was purified by preparative HPLC to obtain 25.0 mg (95% purity, 10% yield) of the desired title compound.

[3311] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=314 [M+H].sup.+

[3312] .sup.1H-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

[3313] ##STR00115##

[3314] 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 chloro(2-dicyclohexylphosphino-2′,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 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 water-resistant filter and concentrated in vacuo. The residue was diluted with DMSO, filtered and purified by preparative HPLC, to obtain 39.0 mg (90% purity, 32% yield) of the desired title compound.

[3315] LC-MS (Method 1): R.sub.t=1.25 min; MS (ESIpos): m/z=339 [M+H].sup.+

[3316] 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=11.25 (s, 1H), 8.10 (d, 1H), 8.01 (dd, 1H), 7.52 (d, 1H), 7.41-7.35 (m, 2H), 7.35-7.28 (m, 2H), 5.47 (s, 2H)

Example 4

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

[3317] ##STR00116##

[3318] 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 afford the title compound (47.0 mg, 21% yield) in a purity of 95%.

[3319] LC-MS (Method 1): Rt=0.84 min; MS (ESIpos): m/z=280 [M+H].sup.+

[3320] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3321] ##STR00117##

[3322] 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-4-methylpiperidine hydrochloride (1:1) (216 mg, 1.40 mmol) and the reaction mixture was stirred for 3 days at 100° C. Then water was added and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were filtered with a water-resistant filter and concentrated in vacuo. The residue was purified by preparative HPLC to obtain 39.0 mg (95% purity, 17% yield) of the desired title compound.

[3323] LC-MS (Method 1): R.sub.t=1.12 min; MS (ESIpos): m/z=310 [M+H].sup.+

[3324] .sup.1H NMR (400 MHz, DMSO-d6) 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

[3325] ##STR00118##

[3326] 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 4-fluoropiperidine 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 a weekend again. Then water was added and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were filtered with a water-resistant filter and concentrated in vacuo. The residue was purified by preparative HPLC to obtain 20.0 mg (95% purity, 13% yield) of the desired title compound.

[3327] LC-MS (Method 1): R.sub.t=1.03 min; MS (ESIpos): m/z=296 [M+H].sup.+

[3328] .sup.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

[3329] ##STR00119##

[3330] The title compound was synthesized analogously to Example 3 from Intermediate 76 from 4-fluorophenyl)boronic acid.

[3331] LC-MS (Method 1): R.sub.t=1.21 min; MS (ESIpos): m/z=285 [M+H].sup.+

[3332] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=11.09 (s, 1H), 7.66 (d, 1H), 7.60 (dd, 1H), 7.41 (t, 2H), 7.32-7.26 (m, 3H), 5.38 (s, 2H), 2.26 (s, 3H)

Example 8

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

[3333] ##STR00120##

[3334] The title compound was synthesized analogously to Example 3 from Intermediate 76.

[3335] LC-MS (Method 1): R.sub.1=1.24 min; MS (ESIpos): m/z=303 [M+H].sup.+

[3336] .sup.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

[3337] ##STR00121##

[3338] The title compound was synthesized analogously to Example 3 from Intermediate 76.

[3339] LC-MS (Method 1): R.sub.1=1.28 min; MS (ESIpos): m/z=299 [M+H].sup.+

[3340] .sup.1H-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), 2.665 (0.49), 2.669 (0.66), 2.673 (0.50), 5.389 (13.67), 7.076 (1.45), 7.082 (1.74), 7.092 (2.67), 7.097 (1.77), 7.103 (2.09), 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

[3341] ##STR00122##

[3342] The title compound was synthesized analogously to Example 3 from Intermediate 76.

[3343] LC-MS (Method 1): R.sub.t=0.94 min; MS (ESIpos): m/z=273 [M+H].sup.+

[3344] .sup.1H-NMR (400 MHz, DMSO-d6) 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), 5.675 (1.70), 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

[3345] ##STR00123##

[3346] The title compound was synthesized analogously to Example 3 from Intermediate 76.

[3347] LC-MS (Method 2): R.sub.t=0.69 min; MS (ESIpos): m/z=257 [M+H].sup.+

[3348] .sup.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), 7.811 (0.62), 8.060 (0.61), 11.033 (5.10), 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

[3349] ##STR00124##

[3350] The title compound was synthesized analogously to Example 3 from Intermediate 76.

[3351] LC-MS (Method 2): R.sub.t=0.62 min; MS (ESIpos): m/z=284 [M+H].sup.+

[3352] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3353] ##STR00125##

[3354] The title compound was synthesized analogously to Example 3 from Intermediate 76.

[3355] LC-MS (Method 1): R.sub.t=0.63 min; MS (ESIpos): m/z=269 [M+H].sup.+

[3356] .sup.1H-NMR (400 MHz, DMSO-d6) 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), 2.522 (1.86), 3.565 (14.67), 5.395 (16.00), 6.302 (0.81), 6.552 (0.70), 6.926 (0.50), 7.339 (3.03), 7.359 (3.43), 7.478 (1.32), 7.480 (1.35), 7.490 (1.34), 7.492 (1.40), 7.498 (1.50), 7.500 (1.52), 7.510 (1.45), 7.512 (1.47), 7.632 (1.61), 7.636 (1.75), 7.652 (1.35), 7.656 (1.55), 7.700 (2.93), 7.703 (2.67), 7.821 (1.27), 7.825 (1.67), 7.831 (1.30), 7.841 (1.16), 7.846 (1.52), 7.851 (1.09), 8.589 (2.72), 8.594 (4.18), 8.598 (2.45), 8.606 (1.96), 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

[3357] ##STR00126##

[3358] The title compound was synthesized analogously to Example 3 from Intermediate 76.

[3359] LC-MS (Method 2): R.sub.t=0.73 min; MS (ESIpos): m/z=269 [M+H].sup.+

[3360] .sup.1H-NMR (400 MHz, DMSO-d6) 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

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

[3361] ##STR00127##

[3362] The title compound was synthesized analogously to Example 3 from Intermediate 76.

[3363] LC-MS (Method 1): R.sub.t=1.21 min; MS (ESIpos): m/z=285 [M+H].sup.+

[3364] .sup.1H-NMR (400 MHz, DMSO-d6) 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), 7.200 (1.75), 7.212 (1.77), 7.215 (3.98), 7.219 (3.51), 7.228 (1.73), 7.234 (1.62), 7.237 (1.60), 7.240 (1.45), 7.245 (1.67), 7.250 (1.96), 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

[3365] ##STR00128##

[3366] (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 afforded the title compound 15.0 mg (95% purity, 22% yield).

[3367] LC-MS (Method 1): R.sub.t=0.97 min; MS (ESIpos): m/z=312 [M+H].sup.+

[3368] .sup.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), 3.675 (8.79), 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), 5.805 (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)

[3369] ##STR00129##

[3370] (rac)-6-methyl-5-(3,4,5-trifluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (100 mg, 70% purity, 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.

[3371] 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 obtain 22.0 mg (95% purity, 22% yield) of the desired title compound.

[3372] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=326 [M+H].sup.+

[3373] .sup.1H-NMR (400 MHz, DMSO-d6) 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), 2.678 (0.82), 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), 3.669 (1.23), 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), 3.865 (0.74), 3.892 (0.57), 5.731 (0.94), 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

[3374] ##STR00130##

[3375] To (rac)-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-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (6.76 mg, 14.5 μmol) (argon atmosphere) and finally lithium bis (trimethylsilyl)amide (930 μL, 1.0 M, 930 μmol) and dicyclolhexylphosphino-2′,6′-diisopropyl-1,1′-biphenyl)(2-(2-aminoethyl)phenyl)palladium(II) (11.8 mg, 14.5 μmol) were added. The mixture was stirred 4 h at 80° C. in a microwave oven. The reaction mixture was diluted with methanol, filtered off and concentrated in vacuo. The residue was diluted with DMSO, filtered and purified by preparative HPLC to obtain 15.0 mg (95% purity, 18% yield) of the desired title compound.

[3376] LC-MS (Method 1): R.sub.t=0.83 min; MS (ESIpos): m/z=276 [M+H].sup.+

[3377] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3378] ##STR00131##

[3379] 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) were dissolved in acetonitrile (0.5 mL) and the mixture was stirred 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 obtain 49.0 mg (95% purity, 74% yield) of the desired title compound.

[3380] LC-MS (Method 1): R.sub.t=0.93 min; MS (ESIpos): m/z=298 [M+H].sup.+

[3381] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3382] ##STR00132##

[3383] To a solution of methyl 2-{1-[3-cyano-4-(morpholin-4-yl)phenyl]-2-hydroxyethylidene}hydrazinecarboxylate (600 mg, 1.88 mmol, Intermediate 55) in acetonitrile (5 mL) was added potassium carbonate (781 mg, 5.65 mmol) and the mixture was stirred at 60° C. over night. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were concentrated in vacuo.

[3384] The residue was treated with dichloromethane. The precipitate was filtered off to obtain the title compound 150 mg (95% purity, 26% yield).

[3385] LC-MS (Method 1): R.sub.t=0.80 min; MS (ESIpos): m/z=287 [M+H].sup.+

[3386] .sup.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

[3387] ##STR00133##

[3388] 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) in THF (2.1 mL) was added 1-chloropyrrolidine-2,5-dione (30.8 mg, 231 μmol) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to obtain 14.0 mg (95% purity, 20% yield) of the desired title compound.

[3389] LC-MS (Method 1): R.sub.t=0.94 min; MS (ESIpos): m/z=321 [M+H].sup.+

[3390] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3391] ##STR00134##

[3392] 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 N,N-diisopropylethylamine (570 μL) was added 2,6-dimethylmorpholine (57.0 mg, 495 μmol) 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 obtain 6.00 mg (95% purity, 6% yield) of the desired title compound.

[3393] LC-MS (Method 1): R.sub.t=1.04 min; MS (ESIpos): m/z=308 [M+H].sup.+

[3394] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3395] ##STR00135##

[3396] Following 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 methyl hydrazinecarboxylate and the reaction mixture was heated at reflux. After 40 min another 11 mg of methyl hydrazinecarboxylate was added and heat was continued another 20 min. After cooling, the mixture was concentrated, and more MeOH followed by concentration was done twice to remove residual water and acid. The crude product was dissolved in 1 mL EtOH and to the crude mixture was added a NaOEt solution (289 mg of sodium consumed in 4 mL EtOH) and the mixture was stirred 2 h 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.

[3397] .sup.1H NMR (400 MHz, CDCl.sub.3) 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). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −120.67. LC-MS (Method 5): 294 [M+H].sup.+

[3398] Chiral SCF chromatography separated the enantiomers: Column: ChiralPak AS-H, 250×4.6 mm, 5 um, Mobile Phase Modifier: 100% Methanol, Gradient: 5 to 50% Methanol over 10 minutes, Flow Rate: 4 mL/min, Back Pressure: 100 bar, Column Temperature: 40° C. UV detection was from 200-400 nm. Retention times of separated enantiomers: 6.58 and 6.92 min. Analysis of product from 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

[3399] ##STR00136##

[3400] Following a literature procedure (J. Med. Chem. 1990, 35, 163), to 1 g of (S)-1-(3,5-difluoro-4-morpholinophenyl)-2-hydroxypropan-1-one (5.34 mmol, Intermediate 37) in 5 mL of MeOH and 3 drops of 0.1 N HCl was added 481 mg of methyl hydrazinecarboxylate (5.34 mmol) and the reaction mixture was heated at reflux 3 h before cooling, concentrating and twice adding more MeOH and concentrating to remove residual water and HCl. Little of the crude product dissolved in ca. 10 mL MeOH, the solid was filtered and rinsed with MeOH, 935 mg of solid was collected. This solid was stirred in 6 mL EtOH and to it was added a NaOEt solution (600 mg Na consumed in 15 mL EtOH). All solids quickly dissolved but after 30 min copious precipitate appeared and was filtered and rinsed with cold EtOH. The 490 mg solid was dissolved in EtOAc, rinsed with slightly acidic (HCl) water, the EtOAc layer is dried and concentrated to 433 mg white solid product (51%).

[3401] .sup.1H NMR (400 MHz, CDCl.sub.3) 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). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −118.99. LC-MS (Method 5): 312 [M+H].sup.+

[3402] Chiral SCF chromatography separated the enantiomers: Column: ChiralPak AS-H, 250×4.6 mm, 5 um, Mobile Phase Modifier: 100% Methanol, Gradient: 5 to 50% Methanol over 10 minutes, Flow Rate: 4 mL/min, Back Pressure: 100 bar, Column Temperature: 40° C. UV detection was from 200-400 nm. Retention times of separated enantiomers: 5.77 and 5.92 min. Analysis of product from enantioselective synthesis showed only the 5.92 min peak.

Example 26

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

[3403] ##STR00137##

[3404] To a solution of 5-(3,4-difluorophenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one 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 h at 95° C., then 10 d at RT. Then water was added and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were filtered with a water-resistant filter and concentrated in vacuo. The residue was purified by preparative HPLC to obtain 25.0 mg (95% purity, 15% yield) of the desired title compound.

[3405] LC-MS (Method 1): R.sub.t=1.06 min; MS (ESIpos): m/z=300 [M+H].sup.+

[3406] .sup.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

[3407] ##STR00138##

[3408] The title compound was synthesized analogously to Example 3 from Intermediate 76.

[3409] LC-MS (Method 1): R.sub.t=1.19 min; MS (ESIpos): m/z=267 [M+H].sup.+

[3410] .sup.1H-NMR (400 MHz, DMSO-d6) 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), 7.383 (0.75), 7.388 (2.34), 7.395 (0.58), 7.404 (1.42), 7.407 (1.78), 7.411 (0.82), 7.445 (3.64), 7.449 (1.40), 7.461 (2.34), 7.464 (4.34), 7.469 (1.00), 7.478 (0.65), 7.482 (1.54), 7.485 (0.91), 7.596 (1.46), 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

[3411] ##STR00139##

[3412] The title compound was synthesized analogously to Example 3 from Intermediate 76.

[3413] LC-MS (Method 1): R.sub.t=0.80 min; MS (ESIpos): m/z=283 [M+H].sup.+

[3414] .sup.1H-NMR (400 MHz, DMSO-d6) 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

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

[3415] ##STR00140##

[3416] The title compound was synthesized analogously to Example 3 from Intermediate 76.

[3417] LC-MS (Method 1): R.sub.t=0.84 min; MS (ESIpos): m/z=271 [M+H].sup.+

[3418] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3419] ##STR00141##

[3420] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[3421] LC-MS (Method 1): R.sub.t=1.16 min; MS (ESIpos): m/z=289 [M+H].sup.+

[3422] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3423] ##STR00142##

[3424] 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) was added chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (9.06 mg, 11.5 μmol) and the mixture was stirred 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 off a water-resistant filter and concentrated in vacuo. The residue was diluted with DMSO, filtered and purified by preparative HPLC, to obtain 41.0 mg (95% purity, 29% yield) of the desired title compound.

[3425] LC-MS (Method 1): Rt=1.33 min; MS (ESIpos): m/z=355 [M+H].sup.+

[3426] 1H-NMR (400 MHz, DMSO-d6): 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

[3427] ##STR00143##

[3428] 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-1,3,2-dioxaborolan-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) were suspended in 870 μL 1,4-dioxane and 260 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (8.05 mg, 10.2 μmol) was added. Nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 17% yield) of the title compound.

[3429] LC-MS (Method 1): R.sub.t=0.78 min; MS (ESIpos): m/z=336 [M+H].sup.+

[3430] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3431] ##STR00144##

[3432] 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-2-yl)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) were suspended in 790 μL 1,4-dioxane and 240 μL water. The mixture was degassed with nitrogen for 5 min. 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 passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 53% yield) of the title compound.

[3433] LC-MS (Method 2): R.sub.t=0.93 min; MS (ESIpos): m/z=322 [M+H].sup.+

[3434] .sup.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), 7.521 (1.79), 7.523 (1.76), 7.533 (1.79), 7.535 (1.79), 7.580 (2.69), 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

[3435] ##STR00145##

[3436] 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-2-yl)aniline (112 mg, 511 μmol), potassium carbonate (94.2 mg, 682 μmol) and 2-(icyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (9.75 mg, 20.5 μmol) were suspended in 870 μL 1,4-dioxane and 260 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (8.05 mg, 10.2 μmol) was added. Nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 12% yield) of the title compound.

[3437] LC-MS (Method 2): R.sub.t=0.98 min; MS (ESIpos): m/z=336 [M+H].sup.+

[3438] .sup.1H-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 (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

[3439] ##STR00146##

[3440] 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) were suspended in 890 μL 1,4-dioxane and 270 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (8.22 mg, 10.4 μmol) was added. Nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 30% yield) of the title compound.

[3441] LC-MS (Method 1): R.sub.t=1.12 min; MS (ESIpos): m/z=351 [M+H].sup.+

[3442] .sup.1H-NMR (400 MHz, DMSO-d6) 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-oxadiazin-2-one

[3443] ##STR00147##

[3444] 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) were suspended in 870 μL 1,4-dioxane and 260 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (8.05 mg, 10.2 μmol) was added. Nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 42% yield) of the title compound.

[3445] LC-MS (Method 2): R.sub.t=1.20 min; MS (ESIpos): m/z=390 [M+H].sup.+

[3446] .sup.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

[3447] ##STR00148##

[3448] 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′-triisopropylbiphenyl (9.24 mg, 19.4 μmol) were suspended in 1.5 mL 1,4-dioxane and 500 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (7.62 mg, 9.69 μmol) was added. Nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 32% yield) of the title compound.

[3449] LC-MS (Method 1): R.sub.t=1.04 min; MS (ESIpos): m/z=355 [M+H].sup.+

[3450] .sup.1H-NMR (400 MHz, DMSO-d6) 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), 6.714 (0.90), 6.719 (0.91), 6.725 (0.90), 6.730 (0.96), 6.735 (1.01), 6.740 (0.91), 6.746 (0.85), 6.887 (1.58), 6.893 (1.52), 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

[3451] ##STR00149##

[3452] 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) were suspended in 1.5 mL 1,4-dioxane and 500 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (7.96 mg, 10.1 μmol) was added. Nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 47% yield) of the title compound.

[3453] LC-MS (Method 2): R.sub.t=1.08 min; MS (ESIpos): m/z=372 [M+H].sup.+

[3454] .sup.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

[3455] ##STR00150##

[3456] 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-dioxaborolan-2-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) were suspended in 900 μL 1,4-dioxane and 270 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (8.30 mg, 10.6 μmol) was added. Nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 30% yield) of the title compound.

[3457] LC-MS (Method 2): R.sub.t=1.04 min; MS (ESIpos): m/z=354 [M+H].sup.+

[3458] .sup.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 (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

[3459] ##STR00151##

[3460] 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-2-yl)pyridin-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) were suspended in 740 μL 1,4-dioxane and 220 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-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 passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 33% yield) of the title compound.

[3461] LC-MS (Method 2): R.sub.t=0.85 min; MS (ESIpos): m/z=337 [M+H].sup.+

[3462] .sup.1H-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

[3463] ##STR00152##

[3464] 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) were suspended in 870 μL 1,4-dioxane and 260 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (7.96 mg, 10.1 μmol) was added. Nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 35% yield) of the title compound.

[3465] LC-MS (Method 2): R.sub.t=1.18 min; MS (ESIpos): m/z=370 [M+H].sup.+

[3466] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3467] ##STR00153##

[3468] 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) were suspended in 940 μL 1,4-dioxane and 280 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (8.64 mg, 11.0 μmol) was added. Nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 60% yield) of the title compound.

[3469] LC-MS (Method 2): R.sub.t=1.10 min; MS (ESIpos): m/z=350 [M+H].sup.+

[3470] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3471] ##STR00154##

[3472] 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-dioxaborolan-2-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) were suspended in 740 μL 1,4-dioxane and 220 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (6.79 mg, 8.64 μmol) was added. Nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 48% yield) of the title compound.

[3473] LC-MS (Method 2): R.sub.t=1.04 min; MS (ESIpos): m/z=354 [M+H].sup.+

[3474] .sup.1H-NMR (400 MHz, DMSO-d6) 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), 6.385 (1.64), 6.401 (0.86), 6.797 (0.79), 6.801 (0.82), 6.817 (1.69), 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

[3475] ##STR00155##

[3476] 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-dioxaborolan-2-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) were suspended in 760 μL 1,4-dioxane and 230 μL water. The mixture was degassed with nitrogen for 5 min. 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 passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 8% yield) of the title compound.

[3477] LC-MS (Method 2): R.sub.t=1.00 min; MS (ESIneg): m/z=352 [M−H].sup.−

[3478] .sup.1H-NMR (400 MHz, DMSO-d6) 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).

Example 45

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

[3479] ##STR00156##

[3480] 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-1,3,2-dioxaborolan-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) were suspended in 870 μL 1,4-dioxane and 260 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (7.96 mg, 10.1 μmol) was added. Nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 41% yield) of the title compound.

[3481] LC-MS (Method 2): R.sub.t=0.91 min; MS (ESIpos): m/z=325 [M+H].sup.+

[3482] .sup.1H-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

[3483] ##STR00157##

[3484] 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 1,4-dioxane and 220 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-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 passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 17% yield) of the title compound.

[3485] LC-MS (Method 2): R.sub.t=0.83 min; MS (ESIpos): m/z=325 [M+H].sup.+

[3486] .sup.1H-NMR (400 MHz, DMSO-d6) 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-(1H-Indazol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3487] ##STR00158##

[3488] 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 1,4-dioxane and 320 μL water. The mixture was degassed with nitrogen for 5 min. 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 passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. Because of incomplete conversion 1H-indazol-6-ylboronic acid (66 mg, 408 μmol) and chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (324.3 mg, 412.9 μmol) were 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 water-resistant 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% purity, 24% yield) of the title compound.

[3489] LC-MS (Method 2): R.sub.t=1.00 min; MS (ESIpos): m/z=361 [M+H].sup.+

[3490] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3491] ##STR00159##

[3492] 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 1,4-dioxane and 510 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (8.05 mg, 10.2 μmol) was added. Nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 13% yield) of the title compound.

[3493] LC-MS (Method 2): R.sub.t=1.10 min; MS (ESIpos): m/z=354 [M+H].sup.+

[3494] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3495] ##STR00160##

[3496] 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) were suspended in 1.7 mL 1,4-dioxane and 580 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (9.15 mg, 11.6 μmol) was added. Nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 37% yield) of the title compound.

[3497] LC-MS (Method 2): R.sub.t=1.03 min; MS (ESIpos): m/z=328 [M+H].sup.+

[3498] .sup.1H-NMR (400 MHz, DMSO-d6) 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-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]-1H-pyrrole-2-carbonitrile

[3499] ##STR00161##

[3500] 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) were suspended in 2.1 mL 1,4-dioxane and 710 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (11.2 mg, 14.3 μmol) was added. Nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 57% yield) of the title compound.

[3501] LC-MS (Method 2): R.sub.t=1.11 min; MS (ESIneg): m/z=347 [M−H].sup.−

[3502] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3503] ##STR00162##

[3504] 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) were suspended in 1.9 mL 1,4-dioxane and 630 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-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 passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 24% yield) of the title compound.

[3505] LC-MS (Method 2): R.sub.t=1.34 min; MS (ESIneg): m/z=387 [M−H].sup.−

[3506] .sup.1H-NMR (400 MHz, DMSO-d6) 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-2-one

[3507] ##STR00163##

[3508] 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-1,3,2-dioxaborolan-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) were suspended in 1.5 mL 1,4-dioxane and 500 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-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 passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 34% yield) of the title compound.

[3509] LC-MS (Method 2): R.sub.t=0.93 min; MS (ESIpos): m/z=339 [M+H].sup.+

[3510] .sup.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-oxadiazin-2-one

[3511] ##STR00164##

[3512] 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 1,4-dioxane and 810 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (12.7 mg, 16.2 μmol) was added. Nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 42% yield) of the title compound.

[3513] LC-MS (Method 2): R.sub.t=1.24 min; MS (ESIpos): m/z=366 [M+H].sup.+

[3514] .sup.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

[3515] ##STR00165##

[3516] 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-dioxaborolan-2-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) were suspended in 1.9 mL 1,4-dioxane and 620 μL water. The mixture was degassed with nitrogen for 5 min. 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 passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 21% yield) of the title compound.

[3517] LC-MS (Method 2): R.sub.t=1.02 min; MS (ESIpos): m/z=342 [M+H].sup.+

[3518] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3519] ##STR00166##

[3520] 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), N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-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) were suspended in 2.7 mL 1,4-dioxane and 900 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-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 passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 19% yield) of the title compound.

[3521] LC-MS (Method 1): R.sub.t=1.08 min; MS (ESIpos): m/z=350 [M+H].sup.+

[3522] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3523] ##STR00167##

[3524] 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) were suspended in 830 μL 1,4-dioxane and 250 μL water. The mixture was degassed with nitrogen for 5 min. Then, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (7.62 mg, 9.69 μmol) was added. Nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 2 hours in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 34% yield) of the title compound.

[3525] LC-MS (Method 2): R.sub.1=1.09 min, MS (ESIpos): m/z=354 [M+H].sup.+

[3526] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3527] ##STR00168##

[3528] 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-2-yl]phosphane (11.8 mg, 24.8 μmol) were suspended in 1,4-dioxane (1.9 mL) and water (620 μL). The mixture was degassed with nitrogen for 5 min.

[3529] Afterwards 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. Again nitrogen was passed through the reaction mixture. It was stirred at 80° C. overnight in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant filter and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using a silica column, gradient hexane/ethyl acetate 12-100%. Obtained product fractions were concentrated and the residue was suspended in a mixture of 10 mL hexane and 1 mL tert-butyl methyl ether. The precipitated product was filtered. The filter cake was washed with hexane and dried under vacuo to give 96.0 mg (95% purity, 59% yield) of the title compound.

[3530] LC-MS (Method 1): R.sub.t=1.32 min; MS (ESIneg): m/z=373 [M−H].sup.−

[3531] .sup.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), 8.028 (1.60), 8.032 (1.69), 8.049 (1.42), 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

[3532] ##STR00169##

[3533] 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-2-yl]phosphane (11.8 mg, 24.8 μmol) were suspended in 1,4-dioxane (1.9 mL) and water (620 μL). The mixture was degassed with nitrogen for 5 min. Afterwards, 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. Again nitrogen was passed through the reaction mixture. It was stirred at 80° C. overnight in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant filter and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using a silica column, gradient hexane/ethyl acetate 12-100%. The obtained product fractions were concentrated and the residue was suspended in a mixture of 10 mL hexane and 1 mL tert-butyl methyl ether. The precipitated product was filtered. The filter cake was washed with hexane and dried under vacuo to give 95.0 mg (95% purity, 61% yield) of the title compound.

[3534] LC-MS (Method 1): R.sub.t=1.23 min; MS (ESIpos): m/z=357 [M+H].sup.+

[3535] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3536] ##STR00170##

[3537] 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-2-yl)biphenyl-2-yl]phosphane (10.2 mg, 21.4 μmol) were suspended in 1,4-dioxane (910 μL) and water (270 μL). The mixture was degassed with nitrogen for 5 min. Afterwards chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (8.41 mg, 10.7 μmol) was added. Again nitrogen was passed through the reaction mixture. It was stirred at 80° C. overnight in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant filter and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using a silica column, gradient hexane/ethyl acetate 12-100%. The obtained product fractions were concentrated and the residue was suspended in a mixture of 10 mL hexane and 1 mL tert-butyl methyl ether. The precipitated product was filtered. The filter cake was washed with hexane and dried under vacuo to give 51.0 mg (90% purity, 35% yield) of the title compound.

[3538] LC-MS (Method 2): R.sub.t=1.12 min; MS (ESIpos): m/z=370 [M+H].sup.+

[3539] .sup.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).

Example 61

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

[3540] ##STR00171##

[3541] 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-2-yl]phosphane (12.3 mg, 25.8 μmol) were suspended in 1,4-dioxane (1.9 mL) and water (650 μL). The mixture was degassed with nitrogen for 5 min. Afterwards chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (10.2 mg, 12.9 μmol) was added. Again nitrogen was passed through the reaction mixture. It was stirred at 80° C. overnight in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant filter and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using a silica column, gradient hexane/ethyl acetate 12-100%. The obtained product fractions were concentrated and the residue was suspended in a mixture of 10 mL hexane and 1 mL tert-butyl methyl ether. The precipitated product was filtered off. The filter cake was washed with hexane and dried under vacuo to give 103 mg (95% purity, 64% yield) of the title compound.

[3542] LC-MS (Method 1): R.sub.t=1.27 min; MS (ESIpos): m/z=357 [M+H].sup.+

[3543] .sup.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), 8.015 (1.87), 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

[3544] ##STR00172##

[3545] 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-2-yl]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 min. Afterwards chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (9.23 mg, 11.7 μmol) was added. Again, nitrogen was passed through the reaction mixture. It was stirred at 80° C. overnight in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 47% yield) of the title compound.

[3546] LC-MS (Method 2): R.sub.t=1.17 min; MS (ESIneg): m/z=358 [M−H].sup.−

[3547] .sup.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), 7.986 (1.66), 7.989 (1.76), 8.006 (1.46), 8.010 (1.62), 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

[3548] ##STR00173##

[3549] 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)-1,3,2-dioxaborolane (110 mg, 603 μmol), potassium carbonate (111 mg, 804 μmol) and dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane (11.5 mg, 24.1 μmol) were suspended in 1,4-dioxane (1.8 mL) and water (600 μL). The mixture was degassed with nitrogen for 5 min. Afterwards chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (9.49 mg, 12.1 μmol) was added. Again, nitrogen was passed through the reaction mixture. It was stirred at 80° C. overnight in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 34% yield) of the title compound.

[3550] LC-MS (Method 2): R.sub.t=1.27 min; MS (ESIneg): m/z=297 [M−H].sup.−

[3551] .sup.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

[3552] ##STR00174##

[3553] 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-2-yl]phosphane (13.3 mg, 28.0 μmol) were suspended in 1,4-dioxane (2.1 mL) and water (700 μL). The mixture was degassed with nitrogen for 5 min. Afterwards 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. Again, nitrogen was passed through the reaction mixture. It was stirred at 80° C. overnight in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant filter and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography using a silica column, gradient hexane/ethyl acetate 12-100%. The obtained product fractions were concentrated and the residue was suspended in a mixture of 10 mL hexane and 1 mL tert-butyl methyl ether. The precipitated product was filtered. The filter cake was washed with hexane and dried under vacuo to give 81.0 mg (95% purity, 46% yield) of the titled compound.

[3554] LC-MS (Method 2): R.sub.t=1.22 min; MS (ESIneg): m/z=355 [M−H].sup.−

[3555] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3556] ##STR00175##

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% purity, 15% yield) of the title compound.

[3557] LC-MS (Method 1): R.sub.t=1.03 min; MS (ESIpos): m/z=330 [M+H].sup.+

[3558] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3559] ##STR00176##

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% purity, 58% yield) of the title compound.

[3560] LC-MS (Method 1): R.sub.t=1.27 min; MS (ESIpos): m/z=316 [M+H].sup.+

[3561] .sup.1H-NMR (400 MHz, DMSO-d6) 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), 1.542 (1.41), 1.560 (0.50), 2.518 (1.62), 2.522 (1.02), 3.216 (1.04), 3.233 (2.23), 3.249 (2.24), 3.265 (1.01), 5.289 (16.00), 5.903 (0.75), 5.917 (1.49), 5.931 (0.73), 6.861 (2.11), 6.882 (2.20), 7.719 (4.74), 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

[3562] ##STR00177##

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 was continued at 60° C. overnight. A second time more ethanamine (180 μL, 2.0 M in tetrahydrofuran, 355 μmol) was added and it was 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% purity, 42% yield) of the title compound.

[3563] LC-MS (Method 1): R.sub.t=1.08 min; MS (ESIpos): m/z=288 [M+H].sup.+

[3564] .sup.1H-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

[3565] ##STR00178##

[3566] 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-2-yl)biphenyl-2-yl]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 min. Afterwards 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. Again, nitrogen was passed through the reaction mixture. It was stirred at 60° C. for 2 h in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 13% yield) of the title compound.

[3567] LC-MS (Methode 1): Rt=0.95 min; MS (ESIpos): m/z=341 [M+H].sup.+

[3568] .sup.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), 7.706 (1.73), 7.710 (2.31), 7.731 (2.73), 7.847 (3.32), 7.867 (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-2H-1,3,4-oxadiazin-2-one

[3569] ##STR00179##

[3570] 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 propan-1-amine (43 μl, 520 μmol) was added. The mixture was stirred at 100° C. for 18 h. Again propan-1-amine (43 μl, 520 μmol) was added and stirring was continued at 100° C. for 2 h. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 62.0 mg (95% purity, 41% yield) of the title compound.

[3571] LC-MS (Method 1): Rt=1.18 min; MS (ESIpos): m/z=302 [M+H].sup.+

[3572] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3573] ##STR00180##

[3574] 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-2-yl)biphenyl-2-yl]phosphane (8.74 mg, 18.3 μmol) were suspended in 1,4-dioxane (780 μl) and water (240 μl). The mixture was degassed with nitrogen for 5 min. Afterwards 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. Again, nitrogen was passed through the reaction mixture. It was stirred at 60° C. for 2 h in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 19% yield) of the title compound.

[3575] LC-MS (Methode 1): Rt=1.04 min; MS (ESIpos): m/z=352 [M+H].sup.+

[3576] .sup.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), 7.834 (3.20), 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

[3577] ##STR00181##

[3578] 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-2-yl]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 min. Afterwards 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. Again, nitrogen was passed through the reaction mixture. It was stirred at 60° C. for 2 h in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and purified by preparative HPLC to give 44.0 mg (95% purity, 25% yield) of the title compound.

[3579] LC-MS (Methode 1): Rt=1.37 min; MS (ESIpos): m/z=371 [M+H].sup.+

[3580] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3581] ##STR00182##

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) was added. The mixture was stirred at 100° C. for 3 d. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 37.0 mg (95% purity, 31% yield) of the title compound.

[3582] LC-MS (Methode 1): Rt=1.14 min; MS (ESIpos): m/z=300 [M+H].sup.+

[3583] .sup.1H-NMR (400 MHz, DMSO-d6) 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-1H-benzimidazol-6-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3584] ##STR00183##

[3585] 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-2-yl)biphenyl-2-yl]phosphane (14.0 mg, 29.3 μmol) were suspended in 1,4-dioxane (2.2 ml) and water (730 μl). The mixture was degassed with nitrogen for 5 min. Afterwards 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. Again, nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 3 h in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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 titled compound.

[3586] LC-MS (Methode 2): Rt=0.92 min; MS (ESIpos): m/z=375 [M+H].sup.+

[3587] 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 74

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

[3588] ##STR00184##

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 h. Again pentan-1-amine (55 μl, 480 μmol) was added and stirring was continued at 100° C. for 2 h. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 71.0 mg (95% purity, 47% yield) of the title compound.

[3589] LC-MS (Methode 1): Rt=1.35 min; MS (ESIpos): m/z=330 [M+H].sup.+

[3590] .sup.1H-NMR (400 MHz, DMSO-d6) 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), 7.718 (5.77), 7.742 (1.64), 10.870 (5.21).

Example 75

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

[3591] ##STR00185##

[3592] 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-2-yl)biphenyl-2-yl]phosphane (11.7 mg, 24.5 μmol) were suspended in 1,4-dioxane (1.8 ml) and water (610 μl). The mixture was degassed with nitrogen for 5 min. Afterwards chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (9.66 mg, 12.3 μmol) was added. Again, nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 18 h in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 37% yield) of the title compound.

[3593] LC-MS Methode 1): Rt=1.10 min; MS (ESIpos): m/z=375 [M+H].sup.+

[3594] .sup.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

[3595] ##STR00186##

[3596] 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-2-yl]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 min.

[3597] Afterwards 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. Again, nitrogen was passed through the reaction mixture. It was stirred at 60° C. for 2 h in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant filter and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO, filtered and dried in vacuo. It was purified by chromatography to give 121 mg (95% purity, 53% yield) of the title compound.

[3598] LC-MS (Methode 1): Rt=1.28 min; MS (ESIpos): m/z=355 [M+H].sup.+

[3599] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3600] ##STR00187##

[3601] 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 4-fluoropyridin-3-yl boronic acid.

[3602] LC-MS (Method 11): R.sub.t=0.91 min; MS (ESIpos): m/z=290 [M+H].sup.+

Example 78

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

[3603] ##STR00188##

[3604] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[3605] LC-MS (Method 1): R.sub.t=0.53 min; MS (ESIpos): m/z=286 [M+H].sup.+

Example 79

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

[3606] ##STR00189##

[3607] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[3608] LC-MS (Method 1): R.sub.t=0.50 min; MS (ESIpos): m/z=286 [M+H].sup.+

Example 80

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

[3609] ##STR00190##

[3610] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[3611] LC-MS (Method 1): R.sub.t=0.72 min; MS (ESIpos): m/z=286 [M+H].sup.+

Example 81

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

[3612] ##STR00191##

[3613] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[3614] LC-MS (Method 1): R.sub.t=1.15 min; MS (ESIpos): m/z=285 [M+H].sup.+

Example 82

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

[3615] ##STR00192##

[3616] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[3617] LC-MS (Method 1): R.sub.t=1.16 min; MS (ESIpos): m/z=323 [M+H].sup.+

Example 83

5-[4-(Cyclopent-1-en-1-yl)-3-fluorophenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3618] ##STR00193##

[3619] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[3620] LC-MS (Method 1): R.sub.t=1.19 min; MS (ESIpos): m/z=261 [M+H].sup.+

Example 84

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

[3621] ##STR00194##

[3622] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[3623] LC-MS (Method 1): R.sub.t=1.21 min; MS (ESIpos): m/z=299 [M+H].sup.+

Example 85

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

[3624] ##STR00195##

[3625] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[3626] LC-MS (Method 1): R.sub.t=0.97 min; MS (ESIpos): m/z=302 [M+H].sup.+

Example 86

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

[3627] ##STR00196##

[3628] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[3629] LC-MS (Method 1): R.sub.t=1.20 min; MS (ESIpos): m/z=303 [M+H].sup.+

Example 87

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

[3630] ##STR00197##

[3631] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[3632] LC-MS (Method 1): R.sub.t=1.18 min; MS (ESIpos): m/z=285 [M+H].sup.+

Example 88

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

[3633] ##STR00198##

[3634] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[3635] LC-MS (Method 1): R.sub.t=1.18 min; MS (ESIpos): m/z=285 [M+H].sup.+

Example 89

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

[3636] ##STR00199##

[3637] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[3638] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=271 [M+H].sup.+

[3639] The following examples Example 90—Example 118 were prepared in analogy to example 89 from Intermediate 65 by reacting with the respective corresponding boronic acid or the corresponding 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ester which were purchased from commercial sources unless stated otherwise

Example 90

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

[3640] ##STR00200##

[3641] LC-MS (Method 1): R.sub.t=0.47 min; MS (ESIpos): m/z=287 [M+H].sup.+

Example 91

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

[3642] ##STR00201##

[3643] LC-MS (Method 1): R.sub.t=0.47 min; MS (ESIpos): m/z=286 [M+H].sup.+

Example 92

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

[3644] ##STR00202##

[3645] LC-MS (Method 1): R.sub.t=1.10 min; MS (ESIpos): m/z=321 [M+H].sup.+

Example 93

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

[3646] ##STR00203##

[3647] LC-MS (Method 1): R.sub.t=0.50 min; MS (ESIpos): m/z=272 [M+H].sup.+

Example 94

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

[3648] ##STR00204##

[3649] LC-MS (Method 1): R.sub.t=0.72 min; MS (ESIpos): m/z=287 [M+H].sup.+

Example 95

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

[3650] ##STR00205##

[3651] LC-MS (Method 1): R.sub.t=0.95 min; MS (ESIpos): m/z=302 [M+H].sup.+

Example 96

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

[3652] ##STR00206##

[3653] LC-MS (Method 1): R.sub.t=0.51 min; MS (ESIpos): m/z=286 [M+H].sup.+

Example 97

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

[3654] ##STR00207##

[3655] LC-MS (Method 1): R.sub.t=0.56 min; MS (ESIpos): m/z=286 [M+H].sup.+

Example 98

5-(2,2′,4′,5′-Tetrafluoro[1,1′-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3656] ##STR00208##

[3657] LC-MS (Method 1): R.sub.t=1.14 min; MS (ESIpos): m/z=325 [M+H].sup.+

Example 99

5-(2,2′,3′,4′-Tetrafluoro[1,1′-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3658] ##STR00209##

[3659] LC-MS (Method 1): R.sub.t=1.15 min; MS (ESIpos): m/z=325 [M+H].sup.+

Example 100

5-(2,2′,5′-Trifluoro[1,1′-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3660] ##STR00210##

[3661] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=307 [M+H].sup.+

Example 101

2′-Fluoro-4′-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)[1,1′-biphenyl]-4-carbonitrile

[3662] ##STR00211##

[3663] LC-MS (Method 1): R.sub.t=0.98 min; MS (ESIpos): m/z=296 [M+H].sup.+

Example 102

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

[3664] ##STR00212##

[3665] LC-MS (Method 1): R.sub.t=0.89 min; MS (ESIpos): m/z=286 [M+H].sup.+

Example 103

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

[3666] ##STR00213##

[3667] LC-MS (Method 1): R.sub.t=0.87 min; MS (ESIpos): m/z=300 [M+H].sup.+

Example 104

5-(2-Fluoro-3′-hydroxy[1,1′-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3668] ##STR00214##

[3669] LC-MS (Method 1): R.sub.t=0.86 min; MS (ESIpos): m/z=287 [M+H].sup.+

Example 105

5-(2-Fluoro-4′-hydroxy[1,1′-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3670] ##STR00215##

[3671] LC-MS (Method 1): Rt=0.82 min; MS (ESIpos): m/z=287 [M+H].sup.+

Example 106

5-(2-Fluoro-2′-hydroxy[1,1′-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3672] ##STR00216##

[3673] LC-MS (Method 1): R.sub.t=0.90 min; MS (ESIpos): m/z=287 [M+H].sup.+

Example 107

5-(2,3′,4′-Trifluoro[1,1′-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3674] ##STR00217##

[3675] LC-MS (Method 1): R.sub.t=1.14 min; MS (ESIpos): m/z=307 [M+H].sup.+

Example 108

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

[3676] ##STR00218##

[3677] LC-MS (Method 1): R.sub.t=0.59 min; MS (ESIpos): m/z=272 [M+H].sup.+

Example 109

5-(2,2′,3′-Trifluoro[1,1′-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3678] ##STR00219##

[3679] LC-MS (Method 1): R.sub.t=1.10 min; MS (ESIpos): m/z=307 [M+H].sup.+

Example 110

5-(2,3′,5′-Trifluoro[1,1′-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3680] ##STR00220##

[3681] LC-MS (Method 1): R.sub.t=1.15 min; MS (ESIpos): m/z=307 [M+H].sup.+

Example 111

5-(2,2′,4′-Trifluoro[1,1′-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3682] ##STR00221##

[3683] LC-MS (Method 1): R.sub.t=1.11 min; MS (ESIpos): m/z=307 [M+H].sup.+

Example 112

5-(2-Fluoro-2′,4′-dimethyl[1,1′-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3684] ##STR00222##

[3685] LC-MS (Method 1): R.sub.t=1.23 min; MS (ESIpos): m/z=299 [M+H].sup.+

Example 113

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

[3686] ##STR00223##

[3687] LC-MS (Method 1): R.sub.t=1.20 min; MS (ESIpos): m/z=303 [M+H].sup.+

Example 114

5-(2,2′-Difluoro[1,1′-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3688] ##STR00224##

[3689] LC-MS (Method 1): R.sub.t=1.07 min; MS (ESIpos): m/z=289 [M+H].sup.+

Example 115

5-(2,2′,6′-Trifluoro[1,1′-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3690] ##STR00225##

[3691] LC-MS (Method 1): R.sub.t=1.07 min; MS (ESIpos): m/z=307 [M+H].sup.+

Example 116

5-(2-Fluoro-2′-methoxy[1,1′-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3692] ##STR00226##

[3693] LC-MS (Method 1): R.sub.t=1.07 min; MS (ESIpos): m/z=301 [M+H].sup.+

Example 117

5-(2,3′-Difluoro[1,1′-biphenyl]-4-yl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3694] ##STR00227##

[3695] LC-MS (Method 1): R.sub.t=1.11 min; MS (ESIpos): m/z=289 [M+H].sup.+

Example 118

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

[3696] ##STR00228##

[3697] LC-MS (Method 1): R.sub.t=0.55 min; MS (ESIpos): m/z=286 [M+H].sup.+

Example 119

(rac)-5-(3-Fluoro-4-morpholinophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3698] ##STR00229##

[3699] Following a literature procedure (J. Med. Chem. 1990, 35, 163), to 370 mg of (rac)-1-(3-fluoro-4-morpholinophenyl)-2-hydroxypropan-1-one (1.46 mmol, Intermediate 33) in 4 mL EtOH and 5-6 drops of 0.1 N HCl were added 131 mg (1.46 mmol) of methyl hydrazinecarboxylate and the reaction was heated at reflux 1 h. After cooling, the mixture was concentrated, and more EtOH followed by concentration was done twice to remove residual water and acid. To the crude mixture was added a NaOEt solution (350 mg of sodium consumed in 5 mL EtOH) 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 product as an off-white solid.

[3700] 1H NMR (400 MHz, CDCl.sub.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). 19F NMR (376 MHz, CDCl.sub.3) δ −120.66. LC-MS (Method 5): 294 [M+H].sup.+

Example 120

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

[3701] ##STR00230##

[3702] To 3.30 g of (S)-2-hydroxy-1-(4-morpholino-3-(trifluoromethyl)phenyl)propan-1-one (10.8 mmol, Intermediate 41) and 972 mg of methyl hydrazinecarboxylate (10.8 mmol) in 10 mL MeOH were added 6 drops of 0.1 N HCl (aq), and the reaction was heated at reflux temperature 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 ca. 20 mL EtOH and added to a solution of NaOEt (12.4 g of sodium (54 mmol) consumed in 30 mL EtOH). After 90 min, 3 mL of acetic acid were added resulting in copious precipitation. The solids were filtered and rinsed with EtOH, dissolved in EtOAc and washed with water. The EtOAc was dried, concentrated, to give 980 mg of the title compound as white solid (26%) which was recrystallized from EtOH.

[3703] .sup.1H NMR (400 MHz, CDCl.sub.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). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −60.29. .sup.13C NMR (101 MHz, CDCl.sub.3) 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)+.

[3704] Chiral SCF chromatography separated the enantiomers: Column: ChiralPak AD-H, 250×4.6 mm, 5 um, Mobile Phase Modifier: 100% Methanol, Gradient: 3 to 50% Methanol over 8 minutes, Flow Rate: 4 mL/min, Back Pressure: 100 bar, Column Temperature: 40° C. UV detection was from 200-400 nm. Ratio of peaks corresponding to 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-1,3,4-oxadiazin-2-one

[3705] ##STR00231##

[3706] A solution of 104 mg (0.304 mmol) of (S)-6-methyl-5-(4-morpholino-3-(trifluoromethyl)phenyl)-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (Example 120) was dissolved in 2 mL HOAc and the solution was cooled to 15-20° C. with an ice bath. To this was added 0.295 mL of a NaOCl solution (10-15% available chlorine, Aldrich). After ca. 30 min another 100 μL of NaOCl solution was added. After another 30 min the reaction contents were transferred to a separatory funnel along with water and CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2 layer was separated and rinsed with a Na.sub.2SO.sub.3 solution, then brine, before drying and concentrating. Chromatography with 20-40% EtOAc (twice) yielded 19 mg of clean product (17%).

[3707] .sup.1H NMR (400 MHz, CDCl.sub.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). .sup.19F NMR (376 MHz, CDCl.sub.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

[3708] ##STR00232##

[3709] A 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 methyl hydrazinecarboxylate (0.36 mmol) and 2 drops of 0.1 N HCl in 1 mL MeOH was heated at 60° C. for 1 h. After cooling, the reaction was concentrated, MeOH was twice added followed by concentration to remove residual water and HCl. The crude product was dissolved in 1 mL MeOH and to it was added a NaOMe solution (75 mg Na consumed in 1 mL MeOH) and the solution was stirred 2 h before addition of 200 μL of HOAc. The precipitates dissolve with stirring and were transferred to a separatory funnel with water and EtOAc. The EtOAc layer was separated, dried, concentrated and chromatographed with 20-50% EtOAc to yield 39 mg of product as a white solid (35%).

[3710] .sup.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).

[3711] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −60.29. LC-MS (Method 5): 344 (M+1)+.

[3712] Chiral SCF chromatography separated the enantiomers of example 126: Column: ChiralPak AD-H, 250×4.6 mm, 5 um, Mobile Phase Modifier: 100% Methanol, Gradient: 3 to 50% Methanol over 8 minutes, Flow Rate: 4 mL/min, Back Pressure: 100 bar, Column Temperature: 40° C. UV detection was from 200-400 nm. Retention time of enantiomers: 6.30 and 7.10 min.

[3713] The following examples Example 127—Example 130 were prepared in analogy to Example 3 from Intermediate 64 by reacting with the respective corresponding boronic acid or the corresponding 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ester which were purchased from commercial sources unless stated otherwise.

Example 127

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

[3714] ##STR00233##

[3715] LC-MS (Method 2): R.sub.t=1.09 min; MS (ESIpos): m/z=393 [M+H].sup.+

[3716] .sup.1H-NMR (400 MHz, DMSO-d6) 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-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3717] ##STR00234##

[3718] LC-MS (Method 2): R.sub.t=0.85 min; MS (ESIpos): m/z=339 [M+H].sup.+

[3719] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3720] ##STR00235##

[3721] LC-MS (Method 2): R.sub.t=1.04 min; MS (ESIpos): m/z=340 [M+H].sup.+

[3722] .sup.1H-NMR (400 MHz, DMSO-d6) 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-1,3,4-oxadiazin-2-one

[3723] ##STR00236##

[3724] LC-MS (Method 2): R.sub.t=0.95 min; MS (ESIneg): m/z=377 [M−H].sup.−

[3725] .sup.1H-NMR (400 MHz, DMSO-d6) 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

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

[3726] ##STR00237##

[3727] 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)biphenyl-2-yl]phosphane (12.3 mg, 25.8 μmol) were suspended in 1,4-dioxane (1.9 mL) and water (650 μL). The mixture was degassed with nitrogen for 5 min. Afterwards chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (10.2 mg, 12.9 μmol) was added. Again, nitrogen was passed through the reaction mixture. It was stirred at 80° C. overnight in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 29% yield) of the title compound.

[3728] LC-MS (Method 1): Rt=1.00 min; MS (ESIpos): m/z=339 [M+H].sup.+

[3729] .sup.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

[3730] ##STR00238##

[3731] 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 d. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 2.40 mg (95% purity, 2% yield) of the title compound.

[3732] LC-MS (Methode 2): Rt=1.41 min; MS (ESIpos): m/z=342 [M+H].sup.+

[3733] .sup.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), 1.586 (0.99), 1.603 (1.42), 1.613 (1.14), 1.624 (0.76), 1.647 (0.76), 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-1,3,4-oxadiazin-2-one

[3734] ##STR00239##

[3735] 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-dioxaborolan-2-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 1,4-dioxane (1.5 mL) and water (500 μL). The mixture was degassed with nitrogen for 5 min. Afterwards chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (9.23 mg, 11.7 μmol) was added. Again, nitrogen was passed through the reaction mixture. It was stirred at 80° C. overnight in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 44% yield) of the title compound.

[3736] LC-MS (Method 1): Rt=0.56 min; MS (ESIpos): m/z=340 [M+H].sup.+

[3737] .sup.1H-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

[3738] ##STR00240##

[3739] 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 d. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 32.0 mg (95% purity, 24% yield) of the title compound.

[3740] LC-MS (Method 1): Rt=1.37 min; MS (ESIpos): m/z=330 [M+H].sup.+

[3741] .sup.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), 1.413 (0.85), 1.418 (1.11), 1.435 (0.42), 2.323 (0.49), 2.327 (0.72), 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

[3742] ##STR00241##

[3743] In a reaction vessel, (6S)-5-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-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-2-yl)biphenyl-2-yl]phosphane (9.38 mg, 19.7 μmol) were suspended in 1,4-dioxane (1.5 mL) and water (500 μL). The mixture was degassed with nitrogen for 5 min. Afterwards chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (7.74 mg, 9.84 μmol) was added. Again, nitrogen was passed through the reaction mixture. It was stirred at 80° C. overnight in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 53% yield) of the title compound.

[3744] Rotational angle: −303.9° (DMSO, 1.0000 g/100 ml, 200° C., 589 nm)

[3745] LC-MS (Method 2): Rt=1.28 min, MS (ESIneg): m/z=351 [M−H].sup.−

[3746] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=11.32 (s, 1H), 8.15 (d, 1H), 8.05 (dd, 1H), 7.52 (d, 1H), 7.42-7.35 (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

[3747] ##STR00242##

[3748] 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 d. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 59.0 mg (95% purity, 45% yield) of the title compound.

[3749] LC-MS Method 1): Rt=1.30 min; MS (ESIpos): m/z=328 [M+H].sup.+

[3750] .sup.1H-NMR (400 MHz, DMSO-d6) 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 (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

[3751] ##STR00243##

[3752] 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 propan-2-amine (46 μl, 550 μmol) was added. The mixture was stirred at 100° C. for 3 d. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 35.0 mg (95% purity, 22% yield) of the title compound.

[3753] LC-MS (Method 1): Rt=1.18 min; MS (ESIpos): m/z=302 [M+H].sup.+

[3754] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3755] ##STR00244##

[3756] 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-1,3,2-dioxaborolane (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) were suspended in 1,4-dioxane (2.2 mL) and water (370 μL). The mixture was degassed with nitrogen for 5 min. Afterwards 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. Again, nitrogen was passed through the reaction mixture. It was stirred at 80° C. for 3 h in a heating block. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried using a water-resistant 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% purity, 54% yield) of the title compound.

[3757] LC-MS (Method 2): Rt=1.23 min; MS (ESIneg): m/z=337 [M−H].sup.−

[3758] .sup.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), 7.331 (0.80), 7.334 (0.73), 7.490 (1.02), 7.505 (1.32), 7.509 (1.45), 7.524 (1.55), 7.530 (1.08), 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).

[3759] The following compounds of Example 139 to Example 156 were prepared in analogy to the procedure described in Example 3 from Intermediate 64 by reacting with the respective corresponding boronic acid or the corresponding 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ester which were purchased from commercial sources unless stated otherwise.

Example 139

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

[3760] ##STR00245##

[3761] LC-MS (Method 2): R.sub.t=1.08 min; MS (ESIneg): m/z=257 [M−H].sup.−

[3762] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3763] ##STR00246##

[3764] LC-MS (Method 2): R.sub.t=1.08 min; MS (ESIneg): m/z=313 [M−H].sup.−

[3765] .sup.1H-NMR (400 MHz, DMSO-d6) 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[1,1′-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3766] ##STR00247##

[3767] LC-MS (Method 2): R.sub.t=0.93 min; MS (ESIneg): m/z=339 [M−H].sup.−

[3768] .sup.1H-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), 1.975 (0.55), 1.993 (0.63), 2.000 (0.66), 2.012 (0.68), 2.019 (0.62), 2.278 (2.23), 2.327 (0.73), 2.331 (0.71), 2.340 (0.87), 2.384 (0.68), 2.518 (0.85), 2.522 (0.55), 2.539 (0.51), 3.771 (0.43), 3.782 (0.68), 3.790 (0.85), 3.796 (0.78), 3.801 (0.82), 4.724 (4.22), 4.735 (3.92), 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), 7.968 (3.41), 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

[3769] ##STR00248##

[3770] LC-MS (Method 2): R.sub.t=1.06 min; MS (ESIneg): m/z=325 [M−H].sup.−

[3771] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3772] ##STR00249##

[3773] LC-MS (Method 2): R.sub.t=0.89 min; MS (ESIpos): m/z=361 [M+H].sup.+

[3774] .sup.1H-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

[3775] ##STR00250##

[3776] LC-MS (Method 1): R.sub.t=1.43 min; MS (ESIpos): m/z=327 [M+H].sup.+

[3777] .sup.1H-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-2-one

[3778] ##STR00251##

[3779] LC-MS (Method 2): R.sub.t=1.34 min; MS (ESIneg): m/z=393 [M−H].sup.−

[3780] .sup.1H-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)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3781] ##STR00252##

[3782] 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, 6.5 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (92 mg, 194 μmol) in 1,4-dioxane (15 mL) and water (5 mL) (nitrogen atmosphere) was added 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 15 h 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 obtain 766 mg (99% purity, 65% yield) of the desired title compound.

[3783] LC-MS (Method 1): R.sub.t=1.04 min; MS (ESIpos): m/z=361 [M+H].sup.+

[3784] .sup.1H-NMR (400 MHz, DMSO-d.sub.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

[3785] ##STR00253##

[3786] LC-MS (Method 2): R.sub.t=1.20 min; MS (ESIneg): m/z=283 [M−H].sup.−

[3787] .sup.1H-NMR (400 MHz, DMSO-d6) 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), 7.995 (3.05), 11.198 (4.16).

Example 148

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

[3788] ##STR00254##

[3789] LC-MS (Method 1): R.sub.t=1.36 min; MS (ESIpos): m/z=377 [M+H].sup.+

[3790] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3791] ##STR00255##

[3792] LC-MS (Method 1): R.sub.t=1.00 min; MS (ESIpos): m/z=313 [M+H].sup.+

[3793] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3794] ##STR00256##

[3795] LC-MS (Method 1): R.sub.t=1.33 min; MS (ESIpos): m/z=311 [M+H].sup.+

[3796] .sup.1H-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), 2.477 (2.41), 2.518 (2.20), 2.522 (1.26), 2.615 (1.28), 2.620 (1.39), 2.634 (2.18), 2.639 (2.08), 2.652 (1.26), 2.658 (1.13), 2.664 (0.69), 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

[3797] ##STR00257##

[3798] LC-MS (Method 2): R.sub.t=0.93 min; MS (ESIpos): m/z=339 [M+H].sup.+

[3799] .sup.1H-NMR (400 MHz, CHLOROFORM-d) 5 [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-2-carbonitrile

[3800] ##STR00258##

[3801] LC-MS (Method 1): R.sub.t=1.21 min; MS (ESIpos): m/z=366 [M+H].sup.+

[3802] .sup.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)-1H-pyrazol-4-yl]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3803] ##STR00259##

[3804] LC-MS (Method 1): R.sub.t=1.08 min; MS (ESIpos): m/z=353 [M+H].sup.+

[3805] .sup.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).

Example 154

(rac)-5-[4-(Bicyclo[2.2.1]hept-2-en-2-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3806] ##STR00260##

[3807] LC-MS (Method 2): R.sub.t=1.39 min; MS (ESIneg): m/z=335 [M−H].sup.−

[3808] .sup.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), 1.573 (1.23), 1.728 (0.77), 1.736 (1.30), 1.743 (0.97), 1.755 (1.97), 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

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

[3809] ##STR00261##

[3810] LC-MS (Method 2): R.sub.t=1.20 min; MS (ESIneg): m/z=337 [M−H].sup.−

[3811] .sup.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), 7.344 (1.32), 7.350 (2.10), 7.362 (0.54), 7.367 (0.44), 7.490 (0.61), 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

[3812] ##STR00262##

[3813] LC-MS (Method 1): R.sub.t=1.36 min; MS (ESIneg): m/z=393 [M−H].sup.−

[3814] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3815] ##STR00263##

[3816] 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 were added 5-methylpyridin-2-ylboronic 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 nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer were washed with saturated aq. ammonium chloride solution, followed by water, and were then dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by prep-HPLC (Column: Xbridge prep C18 5 μm 19*150 mm; Mobile phase A: Water (0.1% TFA), Mobile phase B: ACN; Flow rate: 20 ml/min; Gradient: 25% B to 52% B in 8 min; 254 & 220 nm; Rt:7.23 min). The solvent was removed by lyophilization to give 11 mg (11%) of the title compound as a white solid.

[3817] MS(ESIpos): m/z=336 (M+H)+.

[3818] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=11.26 (s, 1H), 8.51 (s, 1H), 8.12 (s, 1H), 8.05 (d, 1H), 7.74 (dd, 1H), 7.63 (d, 1H), 7.43 (d, 1H), 5.49 (s, 2H), 2.38 (s, 3H)

Example 158

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

[3819] ##STR00264##

[3820] The title compound was prepared in analogy to Example 157 from Intermediate 78.

[3821] MS(ESIpos): m/z=340 (M+H).sup.+.

Example 159

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

[3822] ##STR00265##

[3823] The title compound was prepared in analogy to Example 157 from Intermediate 78.

[3824] MS(ESIpos): m/z=356 (M+H).sup.+.

Example 160

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

[3825] ##STR00266##

[3826] The title compound was prepared in analogy to Example 157 from Intermediate 78.

[3827] MS(ESIpos): m/z=322 (M+H).sup.+.

Example 161

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

[3828] ##STR00267##

[3829] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[3830] LC-MS (Method 1): R.sub.t=1.15 min; MS (ESIpos): m/z=321 [M+H].sup.+

[3831] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3832] ##STR00268##

[3833] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[3834] LC-MS (Method 1): R.sub.t=1.21 min; MS (ESIpos): m/z=303 [M+H].sup.+

[3835] .sup.1H-NMR (400 MHz, DMSO-d6) 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), 7.207 (1.43), 7.214 (1.29), 7.232 (1.48), 7.239 (1.33), 7.247 (1.80), 7.262 (1.88), 7.269 (1.46), 7.284 (1.30), 7.372 (0.66), 7.376 (0.51), 7.390 (0.52), 7.393 (0.64), 7.397 (1.36), 7.417 (2.96), 7.436 (1.60), 7.464 (0.83), 7.484 (0.55), 7.627 (4.67), 7.630 (2.19), 7.650 (4.12), 8.095 (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

[3836] ##STR00269##

[3837] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[3838] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=310 [M+H].sup.+

[3839] .sup.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), 7.759 (2.10), 7.762 (2.17), 7.779 (1.83), 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

[3840] ##STR00270##

[3841] The title compound was synthesized analogously to Example 3 from Intermediate 73.

[3842] LC-MS (Method 1): R.sub.t=1.31 min; MS (ESIpos): m/z=315 [M+H].sup.+

[3843] .sup.1H-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), 7.686 (2.32), 7.690 (1.32), 11.160 (4.38).

Example 165

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

[3844] ##STR00271##

[3845] (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.sub.2CO.sub.3 (0.88 mL, 1.33 mmol) were stirred in 1,4-Dioxane (2.65 mL). The mixture was thoroughly degassed with nitrogen for 5 mins. Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II), X-Phos aminobiphenyl palladium chloride precatalyst [XPhos-Pd-G2] (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 RT then was diluted with EtOAc (10 mL) and washed with brine (10 mL). The aqueous layer was washed with EtOAc (10 mL), the organics combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by Biotage Isolera™ chromatography (10 g KP-Sil, eluting with heptanes-EtOAc, 1:0 to 0:1) to afford the title compound (146.3 mg, 61%, 97% purity) as a beige solid.

[3846] LCMS (Method 4, 7 min) Rt=1.33 min, MS (ESIPos): m/z=351.1 (M+H)+

[3847] .sup.1H-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

[3848] ##STR00272##

[3849] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3850] LC-MS (Method 1): R.sub.t=0.74 min; MS (ESIpos): m/z=336 [M+H].sup.+

Example 167

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

[3851] ##STR00273##

[3852] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3853] LC-MS (Method 1): R.sub.t=0.78 min; MS (ESIpos): m/z=350 [M+H].sup.+

Example 168

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

[3854] ##STR00274##

[3855] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3856] LC-MS (Method 1): R.sub.t=1.27 min; MS (ESIpos): m/z=367 [M+H].sup.+

Example 169

(6S)-6-Methyl-5-[2′,4′,5′-trifluoro-2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3857] ##STR00275##

[3858] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3859] LC-MS (Method 1): R.sub.t=1.25 min; MS (ESIpos): m/z=389 [M+H].sup.+

Example 170

(6S)-6-Methyl-5-[2′,3′,4′-trifluoro-2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3860] ##STR00276##

[3861] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3862] LC-MS (Method 1): R.sub.t=1.26 min; MS (ESIpos): m/z=389 [M+H].sup.+

Example 171

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

[3863] ##STR00277##

[3864] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3865] LC-MS (Method 1): R.sub.t=1.21 min; MS (ESIpos): m/z=371 [M+H].sup.+

Example 172

4′-[(6S)-6-Methyl-2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl]-2′-(trifluoromethyl)[1,1′-biphenyl]-2-carbonitrile

[3866] ##STR00278##

[3867] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3868] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=360 [M+H].sup.+

Example 173

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

[3869] ##STR00279##

[3870] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3871] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=374 [M+H].sup.+

Example 174

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

[3872] ##STR00280##

[3873] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3874] LC-MS (Method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=351 [M+H].sup.+

Example 175

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

[3875] ##STR00281##

[3876] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3877] LC-MS (Method 1): R.sub.t=1.00 min; MS (ESIpos): m/z=351 [M+H].sup.+

Example 176

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

[3878] ##STR00282##

[3879] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3880] LC-MS (Method 1): R.sub.t=0.94 min; MS (ESIpos): m/z=350 [M+H].sup.+

Example 177

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

[3881] ##STR00283##

[3882] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3883] LC-MS (Method 1): R.sub.t=1.23 min; MS (ESIpos): m/z=371 [M+H].sup.+

Example 178

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

[3884] ##STR00284##

[3885] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3886] LC-MS (Method 1): R.sub.t=1.31 min; MS (ESIpos): m/z=367 [M+H].sup.+

Example 179

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

[3887] ##STR00285##

[3888] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3889] LC-MS (Method 1): R.sub.t=1.19 min; MS (ESIpos): m/z=353 [M+H].sup.+

Example 180

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

[3890] ##STR00286##

[3891] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3892] LC-MS (Method 1): R.sub.t=1.19 min; MS (ESIpos): m/z=365 [M+H].sup.+

Example 181

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

[3893] ##STR00287##

[3894] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3895] LC-MS (Method 1): R.sub.t=1.23 min; MS (ESIpos): m/z=353 [M+H].sup.+

Example 182

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

[3896] ##STR00288##

[3897] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3898] LC-MS (Method 1): R.sub.t=0.73 min; MS (ESIpos): m/z=350 [M+H].sup.+

Example 183

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

[3899] ##STR00289##

[3900] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3901] LC-MS (Method 1): R.sub.t=0.72 min; MS (ESIpos): m/z=350 [M+H].sup.+

Example 184

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

[3902] ##STR00290##

[3903] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3904] LC-MS (Method 1): R.sub.t=0.68 min; MS (ESIpos): m/z=350 [M+H].sup.+

Example 185

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

[3905] ##STR00291##

[3906] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3907] LC-MS (Method 1): R.sub.t=1.15 min; MS (ESIpos): m/z=374 [M+H].sup.+

Example 186

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

[3908] ##STR00292##

[3909] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3910] LC-MS (Method 1): R.sub.t=1.32 min; MS (ESIpos): m/z=363 [M+H].sup.+

Example 187

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

[3911] ##STR00293##

[3912] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3913] LC-MS (Method 1): R.sub.t=1.12 min; MS (ESIpos): m/z=366 [M+H].sup.+

Example 188

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

[3914] ##STR00294##

[3915] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3916] LC-MS (Method 1): R.sub.t=1.20 min; MS (ESIpos): m/z=365 [M+H].sup.+

Example 189

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

[3917] ##STR00295##

[3918] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3919] LC-MS (Method 1): R.sub.t=1.30 min; MS (ESIpos): m/z=349 [M+H].sup.+

Example 190

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

[3920] ##STR00296##

[3921] The title compound was synthesized analogously to Example 3 from Intermediate 74.

[3922] LCMS (Method 3, 2 min) 100%@Rt=1.10 mins, MS (ESIPos): m/z=374.90 (M+H).sup.+

[3923] LCMS (Method 3, 7 min) 100%@Rt=3.83 mins, MS (ESIPos): m/z=374.85 (M+H).sup.+

[3924] .sup.1H 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).

Example 191

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

[3925] ##STR00297##

[3926] The title compound was synthesized analogously to Example 3 from Intermediate 68.

[3927] LCMS (Method 3, 7 min) 100%@Rt=2.97 mins, MS (ESIPos): m/z=375.1 (M+H).sup.+

[3928] .sup.1H NMR (500 MHz, DMSO-d6) 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-oxadiazin-2-one

[3929] ##STR00298##

[3930] The title compound was synthesized analogously to Example 3 from Intermediate 68.

[3931] LCMS (Method 4, 7 min) Rt=3.62 min, MS (ESIPos): m/z=353.1 (M+H).sup.+

[3932] .sup.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).

[3933] Chiral Analysis conditions: Column: Cellulose-3 25 cm, Mobile phase: 25% Ethanol: 75% CO.sub.2, Flow rate: 4 mL/min, UV at 280 nm, Runtime: 5 min, Neg ion MS

Example 193

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

[3934] ##STR00299##

[3935] The title compound was synthesized analogously to Example 3 from Intermediate 69.

[3936] LC-MS (Method 1): R.sub.t=1.06 min; MS (ESIpos): m/z=379 [M+H].sup.+

[3937] .sup.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)-1H-pyrazol-4-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3938] ##STR00300##

[3939] The title compound was synthesized analogously to Example 3 from Intermediate 77.

[3940] LC-MS (Method 1): R.sub.t=0.98 min; MS (ESIpos): m/z=343 [M+H].sup.+

[3941] .sup.1H-NMR (400 MHz, DMSO-d6) 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-1,3,4-oxadiazin-2-one

[3942] ##STR00301##

[3943] A biphasic mixture 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 74), potassium (morpholin-4-yl)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-i-propoxy-1,1′-biphenyl/RuPhos (31.9 mg, 0.07 mmol) in toluene/water (12:1 v:v; 3.4 mL) was degassed via nitrogen-filled balloon for 5 minutes. The resulting mixture was heated at 100° C. for 16 hours. After this time, the reaction mixture was diluted with EtOAc and water and was filtered through a pad of Celite. The organic layer was isolated, washed with saturated aqueous sodium chloride solution, dried (MgSO.sub.4), filtered and concentrated in vacuo. The residual material was purified by Biotage Isolera™ chromatography (silica gel, eluting with heptanes-EtOAc, 1:0 to 0:1), with the desired fractions combined and concentrated in vacuo. The resulting gum was dissolved in diethyl ether and concentrated in vacuo to afford the desired compound (135 mg, 53%) as a yellow solid.

[3944] LCMS (Method 3, 2 min) 100%@Rt=0.79 min, MS (ESIpos): m/z=358.05 (M+H).sup.+.

[3945] LCMS (Method 3, 7 min) 96%@Rt=2.41 min, MS (ESIpos): m/z=358.05 (M+H).sup.+.

[3946] .sup.1H NMR (500 MHz, Chloroform-d) δ=1.66 (d, J=7.0 Hz, 3H), 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.sub.2O (by NMR signal integration)

Example 197

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

[3947] ##STR00302##

[3948] The title compound was prepared in analogy to Example 196 from Intermediate 64.

[3949] LC-MS (Method 1): R.sub.t=0.62 min; MS (ESIpos): m/z=344 [M+H].sup.+

[3950] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[3951] ##STR00303##

[3952] 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, v:v=5:1) were added 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride (26 mg (0.03 mmol), sodium carbonate solid (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. 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 with silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to give 40 mg of the still impure title compound, which was then re-purified by Prep-HPLC [Column:XBridge C18 19*150; Mobile Phase A: Water/10 mmol/L NH.sub.4HCO.sub.3, Mobile Phase B: ACN, Flow rate: 20 mL/min; Gradient: 35% B to 60% B in 8 min] to give 10.8 mg (10% yield) of the title compound as a white solid.

[3953] 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

[3954] ##STR00304##

[3955] The title compound was prepared in analogy to Example 198 from Intermediate 77.

[3956] 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

[3957] ##STR00305##

[3958] The title compound was prepared in analogy to Example 198 from Intermediate 77.

[3959] MS(ESIpos): m/z=318 (M+H).sup.+.

Example 201

5-[4-(Cyclopent-1-en-1-yl)-3-(difluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3960] ##STR00306##

[3961] The title compound was prepared in analogy to Example 198 from Intermediate 77.

[3962] MS(ESIpos): m/z=291(M−H)+.

Example 202

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

[3963] ##STR00307##

[3964] The title compound was prepared in analogy to Example 198 from Intermediate 77.

[3965] MS(ESIpos): m/z=293 (M+H).sup.+.

Example 203

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

[3966] ##STR00308##

[3967] 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 hydrogen chloride (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% purity, 33% yield) of the title compound.

[3968] LC-MS (Method 1): R.sub.t=0.92 min; MS (ESIpos): m/z=330 [M+H].sup.+

[3969] .sup.1H-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-2H-1,3,4-oxadiazin-2-one

[3970] ##STR00309##

[3971] The title compound was prepared analogously to Example 203 from Intermediate 66.

[3972] LC-MS (Method 1): R.sub.t=1.00 min; MS (ESIpos): m/z=372 [M+H].sup.+

[3973] .sup.1H-NMR (400 MHz, DMSO-d6) 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 (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

[3974] ##STR00310##

[3975] 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 portion 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% purity, 35% yield) of the title compound.

[3976] LC-MS (Method 1): R.sub.t=1.01 min; MS (ESIpos): m/z=344 [M+H].sup.+

[3977] .sup.1H-NMR (400 MHz, DMSO-d6) 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), 1.634 (0.56), 1.818 (1.67), 1.824 (1.69), 1.850 (1.33), 1.855 (1.31), 2.518 (1.10), 2.522 (0.69), 3.401 (1.24), 3.406 (1.50), 3.430 (2.82), 3.434 (2.82), 3.459 (1.61), 3.463 (1.33), 3.731 (0.61), 3.741 (0.56), 3.750 (0.60), 3.845 (1.68), 3.865 (1.26), 3.871 (1.50), 5.162 (1.41), 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-1,3,4-oxadiazin-2-one

[3978] ##STR00311##

[3979] 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 hydrogen chloride (135 mg, 1.09 mmol) were added. The mixture was stirred at 100° C. overnight and then 2 another days at 100° C. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 70.0 mg (95% purity, 41% yield) of the title compound.

[3980] LC-MS (Method 1): R.sub.t=0.84 min; MS (ESIpos): m/z=330 [M+H].sup.+

[3981] .sup.1H-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), 2.730 (1.35), 2.735 (1.63), 2.742 (1.61), 2.752 (0.76), 2.759 (0.77), 3.449 (0.46), 3.468 (0.85), 3.484 (0.83), 3.501 (0.44), 3.855 (0.59), 3.873 (1.13), 3.890 (1.13), 3.907 (0.56), 5.095 (2.90), 5.103 (0.87), 5.111 (2.78), 5.271 (0.50), 5.296 (16.00), 5.621 (1.65), 5.636 (1.87), 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-oxadiazin-2-one

[3982] ##STR00312##

[3983] 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 hydrogen chloride (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% purity, 17% yield) of the title compound.

[3984] LC-MS (Method 1): R.sub.t=1.28 min; MS (ESIpos): m/z=328 [M+H].sup.+

[3985] .sup.1H-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), 2.037 (1.87), 2.327 (1.97), 2.331 (1.43), 2.518 (8.14), 2.523 (5.45), 2.665 (1.57), 2.669 (2.14), 2.674 (2.21), 2.696 (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-1,3,4-oxadiazin-2-one

[3986] ##STR00313##

[3987] Byproduct from example 207, single stereoisomer: 32.0 mg (95% purity, 16% yield).

[3988] LC-MS (Method 1): R.sub.t=1.30 min; MS (ESIpos): m/z=328 [M+H].sup.+

[3989] .sup.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-1,3,4-oxadiazin-2-one

[3990] ##STR00314##

[3991] 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.

[3992] LC-MS (Method 1): R.sub.t=1.00 min; MS (ESIpos): m/z=372 [M+H].sup.+

[3993] .sup.1H-NMR (400 MHz, DMSO-d.sub.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-Hydroxy-2-methylpropyl)amino]-3-(trifluoromethyl)phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[3994] ##STR00315##

[3995] 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 (1.23 g, 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% purity, 76% yield) of the title compound.

[3996] LC-MS (Method 1): R.sub.t=0.95 min; MS (ESIpos): m/z=332 [M+H].sup.+

[3997] .sup.1H-NMR (400 MHz, DMSO-d.sub.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-1,3,4-oxadiazin-2-one

[3998] ##STR00316##

[3999] 5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (320 mg, 97% purity, 1.18 mmol, Intermediate 66) was dissolved in DMSO (3.0 ml), and (trans)-4-aminocyclohexan-1-ol (273 mg, 2.37 mmol) was added. The mixture was stirred at 100° C. for 3 d. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 234 mg (97% purity, 54% yield) of the title compound.

[4000] LC-MS (Method 2): R.sub.t=0.93 min; MS (ESIneg): m/z=356 [M−H].sup.−

[4001] .sup.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

[4002] ##STR00317##

[4003] 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% purity, 54% yield) of the title compound.

[4004] LC-MS (Method 1): R.sub.t=1.19 min; MS (ESIpos): m/z=314 [M+H].sup.+

[4005] .sup.1H-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), 0.432 (2.85), 0.436 (3.03), 0.442 (1.50), 0.447 (1.41), 0.452 (3.06), 0.457 (2.84), 0.467 (0.95), 1.084 (0.61), 1.088 (0.61), 1.092 (0.62), 1.096 (0.52), 1.104 (1.00), 1.112 (0.51), 1.116 (0.58), 1.121 (0.58), 1.124 (0.54), 2.518 (2.09), 2.523 (1.38), 3.118 (2.18), 3.133 (3.59), 3.149 (2.08), 5.295 (16.00), 5.888 (0.75), 5.902 (1.47), 5.916 (0.72), 6.936 (2.04), 6.958 (2.15), 7.729 (5.36), 7.752 (1.52), 7.757 (1.12), 10.879 (4.64).

Example 213

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

[4006] ##STR00318##

[4007] 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 d. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 93.0 mg (95% purity, 56% yield) of the title compound.

[4008] LC-MS (Method 1): R.sub.t=1.00 min; MS (ESIpos): m/z=344 [M+H].sup.+

[4009] .sup.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

[4010] ##STR00319##

[4011] 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 h. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 267 mg (99% purity, 80% yield) of the title compound.

[4012] LC-MS (Method 1): R.sub.t=1.05 min; MS (ESIpos): m/z=332 [M+H].sup.+

[4013] .sup.1H-NMR (400 MHz, DMSO-d6) 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-1,3,4-oxadiazin-2-one

[4014] ##STR00320##

[4015] 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% purity, 52% yield) of the title compound.

[4016] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=344 [M+H].sup.+

[4017] .sup.1H-NMR (400 MHz, DMSO-d6) 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-2-one

[4018] ##STR00321##

[4019] 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 (2R)-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% purity, 66% yield) of the title compound.

[4020] LC-MS (Method 1): R.sub.t=0.87 min; MS (ESIpos): m/z=318 [M+H].sup.+

[4021] .sup.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-2-one

[4022] ##STR00322##

[4023] 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% purity, 43% yield) of the title compound.

[4024] LC-MS (Method 1): R.sub.t=0.92 min; MS (ESIpos): m/z=332 [M+H].sup.+

[4025] .sup.1H-NMR (400 MHz, DMSO-d6) 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-2H-1,3,4-oxadiazin-2-one

[4026] ##STR00323##

[4027] 5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (150 mg, 97% purity, 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 h. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC to give 152 mg (98% purity, 85% yield) of the title compound.

[4028] LC-MS (Method 1): R.sub.t=0.87 min; MS (ESIpos): m/z=318 [M+H].sup.+

[4029] .sup.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-1,3,4-oxadiazin-2-one

[4030] ##STR00324##

[4031] 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% purity, 52% yield) of the title compound.

[4032] LC-MS (Method 1): Rt=1.00 min; MS (ESIpos): m/z=344 [M+H].sup.+

[4033] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[4034] ##STR00325##

[4035] 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% purity, 53% yield) of the title compound.

[4036] LC-MS (Method 1): R.sub.t=1.34 min; MS (ESIpos): m/z=330 [M+H].sup.+

[4037] .sup.1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.898 (15.35), 0.914 (16.00), 1.413 (0.60), 1.430 (1.37), 1.449 (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), 3.242 (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), 6.871 (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

[4038] ##STR00326##

[4039] 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% purity, 61% yield) of the title compound.

[4040] LC-MS (Method 1): R.sub.t=1.26 min; MS (ESIpos): m/z=316 [M+H].sup.+

[4041] .sup.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

[4042] ##STR00327##

[4043] 5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (1.05 g, 92% purity, 3.68 mmol, Intermediate 66) was dissolved in DMSO (7.0 ml), and 2-methoxyethan-1-amine (710 μl, 99% purity, 8.1 mmol) was added. The mixture was stirred at 100° C. for 16 h. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC (acidic conditions) to give 786 mg (100% purity, 67% yield) of the title compound.

[4044] LC-MS (Method 1): R.sub.t=1.01 min; MS (ESIpos): m/z=318 [M+H].sup.+

[4045] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.89 (s, 1H), 7.73 (s, 1H), 7.75 (d, 1H), 6.95 (d, 1H), 5.76 (br t, 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

[4046] ##STR00328##

[4047] 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% purity, 40% yield) of the title compound.

[4048] LC-MS (Method 1): R.sub.t=1.20 min; MS (ESIpos): m/z=302 [M+H].sup.+

[4049] .sup.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

[4050] ##STR00329##

[4051] The title compound was prepared analogously to Example 205 from Intermediate 66.

[4052] LC-MS (Method 1): R.sub.t=1.26 min; MS (ESIpos): m/z=316 [M+H].sup.+

[4053] .sup.1H-NMR (400 MHz, DMSO-d6) 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-1,3,4-oxadiazin-2-one

[4054] ##STR00330##

[4055] The title compound was prepared analogously to Example 205 from Intermediate 66.

[4056] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=344 [M+H].sup.+

[4057] .sup.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), 4.026 (1.09), 4.038 (1.26), 4.042 (1.15), 4.054 (1.08), 5.298 (16.00), 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

[4058] ##STR00331##

[4059] 5-[4-Fluoro-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one 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 pad of Celite and purified by prep HPLC.

[4060] LC-MS (Method 1): R.sub.t=0.88 min; MS (ESIneg): m/z=350 [M−H].sup.−

[4061] .sup.1H-NMR (400 MHz, DMSO-d6) 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-Hydroxypiperidin-1-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[4062] ##STR00332##

[4063] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4064] LC-MS (Method 1): R.sub.t=0.90 min; MS (ESIpos): m/z=344 [M+H].sup.+

Example 228

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

[4065] ##STR00333##

[4066] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4067] LC-MS (Method 1): R.sub.t=0.95 min; MS (ESIpos): m/z=332 [M+H].sup.+

Example 229

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

[4068] ##STR00334##

[4069] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4070] LC-MS (Method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=344 [M+H].sup.+

Example 230

(rac)-1-[4-(2-Oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]piperidine-3-carboxamide

[4071] ##STR00335##

[4072] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4073] LC-MS (Method 1): R.sub.t=0.87 min; MS (ESIpos): m/z=371 [M+H].sup.+

Example 231

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

[4074] ##STR00336##

[4075] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4076] LC-MS (Method 1): R.sub.t=1.02 min; MS (ESIpos): m/z=346 [M+H].sup.+

Example 232

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

[4077] ##STR00337##

[4078] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4079] LC-MS (Method 1): R.sub.t=1.21 min; MS (ESIpos): m/z=364 [M+H].sup.+

Example 233

5-[4-{[(1R,2R,4R)-Bicyclo[2.2.1]heptan-2-yl]amino}-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[4080] ##STR00338##

[4081] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4082] LC-MS (Method 1): R.sub.t=1.38 min; MS (ESIpos): m/z=354 [M+H].sup.+

Example 234

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

[4083] ##STR00339##

[4084] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4085] LC-MS (Method 1): R.sub.t=0.87 min; MS (ESIpos): m/z=330 [M+H].sup.+

Example 235

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

[4086] ##STR00340##

[4087] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4088] LC-MS (Method 1): R.sub.t=0.84 min; MS (ESIpos): m/z=348 [M+H].sup.+

Example 236

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

[4089] ##STR00341##

[4090] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4091] LC-MS (Method 1): R.sub.t=0.88 min; MS (ESIpos): m/z=354 [M+H].sup.+

Example 237

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

[4092] ##STR00342##

[4093] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4094] LC-MS (Method 1): R.sub.t=0.84 min; MS (ESIpos): m/z=340 [M+H].sup.+

Example 238

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

[4095] ##STR00343##

[4096] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4097] LC-MS (Method 1): R.sub.t=0.93 min; MS (ESIpos): m/z=354 [M+H].sup.+

Example 239

1-[4-(2-Oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]piperidine-4-carbonitrile

[4098] ##STR00344##

[4099] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4100] LC-MS (Method 1): R.sub.t=1.07 min; MS (ESIpos): m/z=353 [M+H].sup.+

Example 240

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

[4101] ##STR00345##

[4102] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4103] LC-MS (Method 1): R.sub.t=1.24 min; MS (ESIpos): m/z=328 [M+H].sup.+

Example 241

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

[4104] ##STR00346##

[4105] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4106] LC-MS (Method 1): R.sub.t=1.16 min; MS (ESIpos): m/z=346 [M+H].sup.+

Example 242

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

[4107] ##STR00347##

[4108] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4109] LC-MS (Method 1): R.sub.t=1.07 min; MS (ESIpos): m/z=332 [M+H].sup.+

Example 243

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

[4110] ##STR00348##

[4111] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4112] LC-MS (Method 1): R.sub.t=1.13 min; MS (ESIpos): m/z=344 [M+H].sup.+

Example 244

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

[4113] ##STR00349##

[4114] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4115] LC-MS (Method 1): R.sub.t=0.92 min; MS (ESIpos): m/z=352 [M+H].sup.+

Example 245

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

[4116] ##STR00350##

[4117] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4118] LC-MS (Method 1): R.sub.t=0.97 min; MS (ESIpos): m/z=344 [M+H].sup.+

Example 246

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

[4119] ##STR00351##

[4120] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4121] LC-MS (Method 1): R.sub.t=0.92 min; MS (ESIpos): m/z=332 [M+H].sup.+

Example 247

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

[4122] ##STR00352##

[4123] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4124] LC-MS (Method 1): R.sub.t=0.78 min; MS (ESIpos): m/z=371 [M+H].sup.+

Example 248

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

[4125] ##STR00353##

[4126] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4127] LC-MS (Method 1): R.sub.t=1.33 min; MS (ESIpos): m/z=342 [M+H].sup.+

Example 249

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

[4128] ##STR00354##

[4129] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4130] LC-MS (Method 1): R.sub.t=1.06 min; MS (ESIpos): m/z=358 [M+H].sup.+

Example 250

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

[4131] ##STR00355##

[4132] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4133] LC-MS (Method 1): R.sub.t=0.91 min; MS (ESIpos): m/z=330 [M+H].sup.+

Example 251

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

[4134] ##STR00356##

[4135] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4136] LC-MS (Method 1): R.sub.t=1.03 min; MS (ESIpos): m/z=339 [M+H].sup.+

Example 252

5-[4-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[4137] ##STR00357##

[4138] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4139] LC-MS (Method 1): R.sub.t=1.24 min; MS (ESIpos): m/z=326 [M+H].sup.+

Example 253

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

[4140] ##STR00358##

[4141] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4142] LC-MS (Method 1): R.sub.t=1.12 min; MS (ESIpos): m/z=372 [M+H].sup.+

Example 254

4-[4-(2-Oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)anilino]butanenitrile

[4143] ##STR00359##

[4144] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4145] LC-MS (Method 1): R.sub.t=0.92 min; MS (ESIpos): m/z=327 [M+H].sup.+

Example 255

6-[4-(2-Oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]-2λ.SUP.6.-thia-6-azaspiro[3.3]heptane-2,2-dione

[4146] ##STR00360##

[4147] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4148] LC-MS (Method 1): R.sub.t=0.88 min; MS (ESIpos): m/z=390 [M+H].sup.+

Example 256

N.SUP.2.-[4-(2-Oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]glycinamide

[4149] ##STR00361##

[4150] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4151] LC-MS (Method 1): R.sub.t=0.71 min; MS (ESIpos): m/z=317 [M+H].sup.+

[4152] .sup.1H-NMR (400 MHz, DMSO-d6) 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

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

[4153] ##STR00362##

[4154] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4155] LC-MS (Method 2): R.sub.t=0.88 min; MS (ESIpos): m/z=330 [M+H].sup.+

[4156] .sup.1H-NMR (400 MHz, DMSO-d6) 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-1,3,4-oxadiazin-2-one

[4157] ##STR00363##

[4158] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4159] LC-MS (Method 1): R.sub.t=1.19 min; MS (ESIpos): m/z=346 [M+H].sup.+

[4160] .sup.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-1,3,4-oxadiazin-2-one

[4161] ##STR00364##

[4162] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4163] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=344 [M+H].sup.+

[4164] .sup.1H-NMR (400 MHz, DMSO-d6) 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), 3.225 (0.61), 3.245 (0.91), 3.261 (1.08), 3.275 (0.78), 3.352 (0.91), 3.359 (0.58), 3.372 (0.65), 3.386 (0.46), 3.609 (0.73), 3.630 (1.51), 3.647 (1.96), 3.664 (1.07), 3.732 (1.01), 3.748 (1.75), 3.752 (1.11), 3.765 (1.44), 3.768 (1.32), 3.785 (0.83), 4.026 (1.13), 4.038 (1.31), 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

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

[4165] ##STR00365##

[4166] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4167] LC-MS (Method 1): R.sub.t=1.11 min; MS (ESIpos): m/z=332 [M+H].sup.+

[4168] .sup.1H-NMR (400 MHz, DMSO-d6) 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), 6.936 (3.28), 6.958 (3.43), 7.739 (8.49), 7.764 (2.77), 10.894 (6.48).

Example 261

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

[4169] ##STR00366##

[4170] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4171] LC-MS (Method 1): R.sub.t=1.01 min; MS (ESIpos): m/z=344 [M+H].sup.+

[4172] .sup.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), 1.730 (0.85), 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), 1.810 (0.85), 1.818 (0.77), 1.827 (0.88), 1.831 (0.81), 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

[4173] ##STR00367##

[4174] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4175] LC-MS (Method 1): R.sub.t=0.87 min; MS (ESIpos): m/z=316 [M+H].sup.+

[4176] .sup.1H-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

5-{3-(Difluoromethyl)-4-[1-(propan-2-yl)-1H-pyrazol-4-yl]phenyl}-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[4177] ##STR00368##

[4178] To a solution of 5-(3-(difluoromethyl)-4-(1 H-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)ferrocenepalladium(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 atmosphere. 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 with Prep-HPLC [Column:XBridge C18 19*150; Mobile Phase A: Water/10 mmol/L NH.sub.4HCO.sub.3, Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient:20% B to 60% B in 8 min], to give 9.9 mg (8% yield) of the title compound as a white solid.

[4179] MS(ESIpos): m/z=335 (M+H).sup.+.

Example 264

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

[4180] ##STR00369##

[4181] To a solution of methyl 2-(2-acetoxy-1-(3-fluoro-4-morpholino-5-(trifluoromethyl)phenyl) ethylidene)hydrazinecarboxylate (300 mg, 0.7 mmol, Intermediate 60) in 20 mL of ethanol was added sodium hydride (28 mg, 0.7 mmol, 60% purity), 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 were then dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by Prep-HPLC (Column: Xbridge Prep C18, 5 um, 19*150 mm; Mobile Phase A:Water (0.1% TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 64% B in 8 min; 254 nm & 220 nm; t: 7.18 min), to give 61.4 mg (25%) of the title compound as a white solid.

[4182] MS(ESIpos): m/z=348 (M+H).sup.+.

Example 265

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

[4183] ##STR00370##

[4184] 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 75) and 7.3 g of 3-trifluoromethyl pyrazole (54 mmol), dissolved in 20 mL of DMF, was added 7.0 g of powdered Cs.sub.2CO.sub.3 (22 mmol), and the mixture was heated at 60° C. for 5 h and then stirred at room temperature overnight. Water was added and the mixture was washed several times with EtOAc, the combined EtOAc layers were washed with water and brine, dried (MgSO.sub.4), concentrated and chromatographed on silica with 10-40% EtOAc in hexanes to isolate 3.7 g of product as an off-white solid (87%). The material was recrystallized from hot CH.sub.2Cl.sub.2/hexane to yield white crystals. Chiral SFC analysis (Chiral Pak AD-H column, 3-50% MeOH over 8 min, flow 4 mL/min) showed a 0.06:99.94 enantiomer ratio, retention times 4.18 and 4.74 min.

[4185] .sup.1H NMR (400 MHz, CDCl.sub.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).

[4186] .sup.19F NMR (376 MHz, CDCl.sub.3) δ −59.33, −62.28. 13C NMR (101 MHz, CDCl.sub.3) 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.

[4187] 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-2H-1,3,4-oxadiazin-2-one

[4188] ##STR00371##

[4189] To 100 mg (0.36 mmol) of (S)-5-(4-fluoro-3-(trifluoromethyl)phenyl)-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (Intermediate 75) and 73 mg of 4-trifluoromethyl imidazole (0.54 mmol) dissolved in 2 mL of DMF was added 235 mg of powdered Cs.sub.2CO3 (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 rinsed several times with EtOAc, the combined EtOAc was rinsed with water and brine, dried (MgSO4), and concentrated. Dichloromethane was added and the starting 4-trifluoromethyl imidazole was not soluble and was filtered off. Chromatography with 0-70% EtOAc isolated impure product which was dissolved in EtOAc and extracted with 1 N HCl before drying and concentrating to yield 53 mg of the title product as a white solid (38%). 1H NMR (400 MHz, CDCl.sub.3) 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). 19F NMR (376 MHz, CDCl.sub.3) 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

[4190] ##STR00372##

[4191] 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 an atmosphere of argon, then Pd/C (8.59 mg, 14.3 μmol) was added and the mixture was stirred for 4 hours under a hydrogen atmosphere. The catalyst was removed over celite, washed with dichloromethane and the organic phase was evaporated in vacuo to yield 37.3 mg (95% purity, 78% yield) of the title compound.

[4192] LC-MS (Method 1): Rt=1.11 min; MS (ESIpos): m/z=317 [M+H].sup.+

[4193] .sup.1H-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

[4194] ##STR00373##

[4195] The title compound was synthesized analogously to Example 267 from Example 63.

[4196] LC-MS (Method 1): R.sub.t=1.33 min; MS (ESIpos): m/z=301 [M+H].sup.+

[4197] .sup.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), 7.917 (1.08), 7.922 (1.30), 7.958 (2.77), 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

[4198] ##STR00374##

[4199] The title compound was synthesized analogously to Example 267 from Example 144.

[4200] LC-MS (Method 1): R.sub.t=1.47 min; MS (ESIpos): m/z=329 [M+H].sup.+

[4201] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[4202] ##STR00375##

[4203] 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 an atmosphere of argon, then Pd/C (19.0 mg, 31.7 μmol) was added and the mixture was stirred for 2 hours under an atmosphere of hydrogen. The catalyst was removed over celite, washed with dichloromethane and the organic phase was evaporated in vacuo to yield 72.0 mg (95% purity, 75% yield) of the title compound.

[4204] LC-MS (Method 1): R.sub.t=1.25 min; MS (ESIpos): m/z=287 [M+H].sup.+

[4205] .sup.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

[4206] ##STR00376##

[4207] In an autoclave vessel, 5-[4-(5,6-dihydro-2H-pyran-3-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (40.0 mg, 123 μmol, Example 142) was dissolved in ethanol (2.0 ml) and THF (0.4 mL) under an atmosphere of 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 using mass-triggered prep-HPLC to yield 16.0 mg (95% purity, 38% yield) of the title compound.

[4208] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=329 [M+H].sup.+

[4209] .sup.1H-NMR (400 MHz, DMSO-d6) 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), 3.729 (0.89), 3.738 (0.77), 3.887 (0.97), 3.913 (0.77), 5.408 (16.00), 7.756 (1.93), 7.777 (2.40), 7.929 (1.78), 7.950 (1.49), 7.969 (3.43), 11.172 (4.69).

Example 272

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

[4210] ##STR00377##

[4211] The title compound was synthesized analogously to Example 271 from Example 141.

[4212] LC-MS (Method 1): R.sub.t=0.93 min; MS (ESIpos): m/z=343 [M+H].sup.+

[4213] .sup.1H-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), 2.760 (0.66), 3.504 (0.50), 3.520 (0.81), 3.531 (0.81), 3.542 (0.43), 4.622 (4.07), 4.634 (3.95), 5.399 (16.00), 5.412 (1.18), 7.701 (1.88), 7.721 (2.23), 7.897 (1.57), 7.902 (1.86), 7.925 (4.57), 11.146 (5.52).

Example 273

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

[4214] ##STR00378##

[4215] The title compound was isolated during the synthesis of Example 272 as a side product.

[4216] LC-MS (Method 1): R.sub.t=1.04 min; MS (ESIpos): m/z=343 [M+H].sup.+

[4217] .sup.1H-NMR (400 MHz, DMSO-d6) 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), 2.678 (0.46), 2.801 (0.44), 2.829 (0.77), 3.914 (1.37), 3.921 (1.37), 4.485 (3.52), 4.495 (3.48), 5.402 (16.00), 7.677 (1.97), 7.698 (2.27), 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—salt with hydrochloric acid

[4218] ##STR00379##

[4219] tert-Butyl {2-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)anilino]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 for 3 d. Afterwards, further portions 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 yield 72.0 mg (95% purity, 94% yield).

[4220] LC-MS (Method 1): R.sub.t=0.56 min; MS (ESIpos): m/z=303 [M+H].sup.+

[4221] .sup.1H-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-1,3,4-oxadiazin-2-one—salt with hydrochloric acid

[4222] ##STR00380##

[4223] STEP 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.

[4224] STEP 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 yield the title compound.

[4225] LC-MS (Method 2): R.sub.t=0.92 min; MS (ESIpos): m/z=341 [M+H].sup.+

[4226] .sup.1H-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

[4227] ##STR00381##

[4228] 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 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 water-resistant 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% purity, 3% yield) of the title compound.

[4229] LC-MS (Method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=274 [M+H].sup.+

[4230] .sup.1H-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-1,3,4-oxadiazin-2-one

[4231] ##STR00382##

[4232] 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 74) and 1-methylpiperazine (1.52 mL, 13.67 mmol) in N,N-dimethylacetamide (0.6 mL) was heated at 140° C. for 16 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium chloride solution, with the organic layer isolated and washed with saturated aqueous sodium chloride solution (x4), dried (MgSO.sub.4), filtered and concentrated in vacuo. The residual material was purified by Biotage Isolera™ chromatography (silica gel, eluting with MeOH/DCM, 0:1 to 1:9), with the desired fractions combined and concentrated in vacuo to afford impure desired material (66 mg @ 83% purity). This material was further purified by reverse phase Biotage Isolera™ chromatography (C18, eluting with MeCN-Water, 1:9 to 1:0), with the desired fractions combined and lyopholised to afford the title compound (9.8 mg, 4%) as a pale pink solid.

[4233] LCMS (Method 3, 2 min) 92%@Rt=0.83 min, MS (ESIpos): m/z=357.10 (M+H).sup.+.

[4234] LCMS (MS18, 7 min) 92%@Rt=2.60 min, MS (ESIpos): m/z=357.45 (M+H).sup.+.

[4235] .sup.1H 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=6.9 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.95 (dd, J=8.5, 2.0 Hz, 1H), 8.00 (d, J=2.1 Hz, 1H), 11.17 (s, 1H)—2 missing piperazine ring proton signals covered by solvent peak.

Example 278

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

[4236] ##STR00383##

[4237] 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 of 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 hours under nitrogen atmosphere. 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 Prep-HPLC [Column: XBridge, RP18 OBD 19*150 mm; Mobile Phase A: Water (0.1% NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 40% B in 8 min, hold 1.5 min; 254 & 220 nm Rt: 6.28 min] to give 35.4 mg (33%) of the title compound as a white solid.

[4238] MS (ESIpos):m/z=303 (M+H).sup.+.

[4239] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 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-1,3,4-oxadiazin-2-one

[4240] ##STR00384##

[4241] A 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-i-propyl-1,1′-biphenyl/XPhos (29.6 mg, 0.06 mmol) in 1,4-dioxane (1.5 mL) was degassed via nitrogen-filled balloon and heated at 100° C. for 20 hours. After this time, the reaction mixture was allowed to cool to RT and partitioned between IPA/DCM (1:4 v:v) and water, with the organic layer isolated via phase separation cartridge, and concentrated in vacuo. The residual material was purified by Biotage Isolera™ chromatography (silica gel, eluting with EtOAc/heptane (0:1 to 1:1 to 1:0), with the desired fractions combined and concentrated in vacuo to afford 70 mg (54% yield) of the title compound as a pale yellow solid.

[4242] LCMS (Method 3, 2 min) 99%@Rt=1.17 min, MS (ESIpos): m/z=390.95 (M+MeCN+H).sup.+.

[4243] LCMS (Method 3, 7 min) 92%@Rt=4.02 min, MS (ESIpos): m/z=390.95 (M+MeCN+H).sup.+.

[4244] .sup.1H 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-2H-1,3,4-oxadiazin-2-one

[4245] ##STR00385##

[4246] The title compound was synthesized analogously to Example 280 from Intermediate 74 and 3-hydroxy-3-methylazetidine.

[4247] LCMS (Method 3, 2 min) 97%@Rt=1.04 min, MS (ESIpos): m/z=334.00 (M+H).sup.+.

[4248] LCMS (Method 3, 7 min) 100%@Rt=3.52 min, MS (ESIpos): m/z=334.00 (M+H).sup.+.

[4249] .sup.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

[4250] ##STR00386##

[4251] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4252] LC-MS (Method1): R.sub.t=1.17 min; MS (ESIpos): m/z=346 [M+H].sup.+

Example 282

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

[4253] ##STR00387##

[4254] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4255] LC-MS (Method1): R.sub.t=0.51 min; MS (ESIpos): m/z=368 [M+H].sup.+

Example 283

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

[4256] ##STR00388##

[4257] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4258] LC-MS (Method1): R.sub.t=1.00 min; MS (ESIpos): m/z=346 [M+H].sup.+

Example 284

5-[4-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-3-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,3,4-oxadiazin-2-one

[4259] ##STR00389##

[4260] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4261] LC-MS (Method1): R.sub.t=1.08 min; MS (ESIpos): m/z=370 [M+H].sup.+

Example 285

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

[4262] ##STR00390##

[4263] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4264] LC-MS (Method1): R.sub.t=1.04 min; MS (ESIpos): m/z=346 [M+H].sup.+

Example 286

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

[4265] ##STR00391##

[4266] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4267] LC-MS (Method1): R.sub.t=0.93 min; MS (ESIpos): m/z=354 [M+H].sup.+

Example 287

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

[4268] ##STR00392##

[4269] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4270] LC-MS (Method1): R.sub.t=0.74 min; MS (ESIpos): m/z=343 [M+H].sup.+

Example 288

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

[4271] ##STR00393##

[4272] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4273] LC-MS (Method1): R.sub.t=0.61 min; MS (ESIpos): m/z=351 [M+H].sup.+

Example 289

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

[4274] ##STR00394##

[4275] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4276] LC-MS (Method1): R.sub.t=1.00 min; MS (ESIpos): m/z=372 [M+H].sup.+

Example 290

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

[4277] ##STR00395##

[4278] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4279] LC-MS (Method1): R.sub.t=0.76 min; MS (ESIpos): m/z=357 [M+H].sup.+

Example 291

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

[4280] ##STR00396##

[4281] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4282] LC-MS (Method1): R.sub.t=0.49 min; MS (ESIpos): m/z=354 [M+H].sup.+

Example 292

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

[4283] ##STR00397##

[4284] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4285] LC-MS (Method1): R.sub.t=0.76 min; MS (ESIpos): m/z=348 [M+H].sup.+

Example 293

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

[4286] ##STR00398##

[4287] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4288] LC-MS (Method1): R.sub.t=1.11 min; MS (ESIpos): m/z=360 [M+H].sup.+

Example 294

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

[4289] ##STR00399##

[4290] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4291] LC-MS (Method1): R.sub.t=1.02 min; MS (ESIpos): m/z=358 [M+H].sup.+

Example 295

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

[4292] ##STR00400##

[4293] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4294] LC-MS (Method1): R.sub.t=0.45 min; MS (ESIpos): m/z=354 [M+H].sup.+

Example 296

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

[4295] ##STR00401##

[4296] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4297] LC-MS (Method1): R.sub.t=1.32 min; MS (ESIpos): m/z=354 [M+H].sup.+

Example 297

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

[4298] ##STR00402##

[4299] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4300] LC-MS (Method1): R.sub.t=0.78 min; MS (ESIpos): m/z=355 [M+H].sup.+

Example 298

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

[4301] ##STR00403##

[4302] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4303] LC-MS (Method1): R.sub.t=1.11 min; MS (ESIpos): m/z=372 [M+H].sup.+

Example 299

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

[4304] ##STR00404##

[4305] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4306] LC-MS (Method1): R.sub.t=0.80 min; MS (ESIpos): m/z=352 [M+H].sup.+

Example 300

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

[4307] ##STR00405##

[4308] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4309] LC-MS (Method1): R.sub.t=0.89 min; MS (ESIpos): m/z=354 [M+H].sup.+

Example 301

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

[4310] ##STR00406##

[4311] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4312] LC-MS (Method1): R.sub.t=0.53 min; MS (ESIpos): m/z=371 [M+H].sup.+

Example 302

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

[4313] ##STR00407##

[4314] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4315] LC-MS (Method1): R.sub.t=0.55 min; MS (ESIpos): m/z=371 [M+H].sup.+

Example 303 N-methyl-N.SUP.3.-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]-beta-alaninamide

[4316] ##STR00408##

[4317] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4318] LC-MS (Method1): R.sub.t=0.76 min; MS (ESIpos): m/z=345 [M+H].sup.+

Example 304

N-methyl-1-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]prolinamide

[4319] ##STR00409##

[4320] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4321] LC-MS (Method1): R.sub.t=0.90 min; MS (ESIpos): m/z=371 [M+H].sup.+

Example 305

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

[4322] ##STR00410##

[4323] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4324] LC-MS (Method1): R.sub.t=0.81 min; MS (ESIpos): m/z=371 [M+H].sup.+

Example 306

[4325] -ethyl-N.sup.2-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]glycinamide

##STR00411##

[4326] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4327] LC-MS (Method1): R.sub.t=0.81 min; MS (ESIpos): m/z=345 [M+H].sup.+

Example 307

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

[4328] ##STR00412##

[4329] LC-MS (Method1): R.sub.t=0.88 min; MS (ESIpos): m/z=345 [M+H].sup.+

Example 308

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

[4330] ##STR00413##

[4331] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4332] LC-MS (Method1): R.sub.t=0.79 min; MS (ESIpos): m/z=352 [M+H].sup.+

Example 309

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

[4333] ##STR00414##

[4334] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4335] LC-MS (Method1): R.sub.t=0.48 min; MS (ESIpos): m/z=357 [M+H].sup.+

Example 310

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

[4336] ##STR00415##

[4337] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4338] LC-MS (Method1): R.sub.t=0.50 min; MS (ESIpos): m/z=357 [M+H].sup.+

Example 311

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

[4339] ##STR00416##

[4340] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4341] LC-MS (Method1): R.sub.t=0.52 min; MS (ESIpos): m/z=357 [M+H].sup.+

Example 312

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

[4342] ##STR00417##

[4343] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4344] LC-MS (Method1): R.sub.t=0.71 min; MS (ESIpos): m/z=369 [M+H].sup.+

Example 313

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

[4345] ##STR00418##

[4346] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4347] LC-MS (Method1): R.sub.t=0.77 min; MS (ESIpos): m/z=372 [M+H].sup.+

Example 314

3-{ethyl[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)phenyl]amino}propanenitrile

[4348] ##STR00419##

[4349] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4350] LC-MS (Method1): R.sub.t=1.15 min; MS (ESIpos): m/z=341 [M+H].sup.+

Example 315

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

[4351] ##STR00420##

[4352] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4353] LC-MS (Method1): R.sub.t=0.50 min; MS (ESIpos): m/z=371 [M+H].sup.+

Example 316

N-{2-[4-(2-oxo-3,6-dihydro-2H-1,3,4-oxadiazin-5-yl)-2-(trifluoromethyl)anilino]ethyl}acetamide

[4354] ##STR00421##

[4355] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4356] LC-MS (Method1): R.sub.t=0.75 min; MS (ESIpos): m/z=345 [M+H].sup.+

Example 317

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

[4357] ##STR00422##

[4358] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4359] LC-MS (Method1): R.sub.t=0.51 min; MS (ESIpos): m/z=371 [M+H].sup.+

Example 318

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

[4360] ##STR00423##

[4361] The title compound was prepared analogously to Example 226 from Intermediate 66.

[4362] LC-MS (Method1): R.sub.t=0.52 min; MS (ESIpos): m/z=371 [M+H].sup.+

Example 319

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

[4363] ##STR00424##

[4364] The title compound was prepared analogously to Example 132 from Intermediate 66.

[4365] LC-MS (Method 1): R.sub.t=0.99 min; MS (ESIpos): m/z=346 [M+H].sup.+

[4366] .sup.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)

[4367] ##STR00425##

[4368] The title compound was prepared analogously to Example 132 from Intermediate 66.

[4369] LC-MS (Method2): R.sub.t=0.96 min; MS (ESIpos): m/z=357 [M+H].sup.+

[4370] .sup.1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.311 (0.95), 1.338 (1.33), 1.566 (1.33), 1.575 (1.72), 1.587 (2.17), 1.597 (2.32), 1.611 (1.90), 1.621 (1.94), 1.630 (1.54), 1.748 (1.66), 1.759 (1.27), 1.768 (1.26), 1.777 (1.14), 1.880 (0.48), 1.907 (0.51), 2.518 (2.24), 2.523 (1.56), 2.539 (0.82), 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-oxadiazin-2-one

[4371] ##STR00426##

[4372] The title compound was prepared analogously to Example 132 from Intermediate 66.

[4373] LC-MS (Method2): R.sub.t=0.96 min; MS (ESIpos): m/z=331 [M+H].sup.+

[4374] .sup.1H-NMR (400 MHz, DMSO-d6) 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)

[4375] ##STR00427##

[4376] The title compound was prepared analogously to Example 132 from Intermediate 66.

[4377] LC-MS (Method1): R.sub.t=0.72 min; MS (ESIpos): m/z=357 [M+H].sup.+

[4378] .sup.1H-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), 1.543 (0.46), 1.570 (0.51), 1.650 (1.16), 1.659 (1.16), 1.682 (1.98), 1.698 (2.56), 1.722 (2.08), 1.895 (1.24), 1.926 (1.16), 2.518 (2.84), 2.522 (1.75), 2.888 (0.85), 2.994 (0.41), 3.642 (0.72), 4.852 (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-2-one

[4379] ##STR00428##

[4380] The title compound was prepared analogously to Example 132 from Intermediate 66.

[4381] LC-MS (Method1): R.sub.t=0.58 min; MS (ESIpos): m/z=331 [M+H].sup.+

[4382] .sup.1H-NMR (400 MHz, DMSO-d6) 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-1,3,4-oxadiazin-2-one

[4383] ##STR00429##

[4384] The title compound was prepared analogously to Example 132 from Intermediate 66.

[4385] LC-MS (Method2): R.sub.t=1.06 min; MS (ESIpos): m/z=345 [M+H].sup.+

[4386] .sup.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

[4387] ##STR00430##

[4388] The title compound was prepared analogously to Example 3 from Intermediate 64.

[4389] LC-MS (Method2): R.sub.t=1.19 min; MS (ESIpos): m/z=392 [M+H].sup.+

[4390] .sup.1H-NMR (400 MHz, DMSO-d6) 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-2-one

[4391] ##STR00431##

[4392] The title compound was prepared analogously to Example 3 from Intermediate 64.

[4393] LC-MS (Method2): R.sub.t=0.87 min; MS (ESIpos): m/z=375 [M+H].sup.+

[4394] .sup.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), 8.101 (4.18), 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

[4395] ##STR00432##

[4396] The title compound was prepared analogously to Example 3 from Intermediate 64.

[4397] LC-MS (Method2): R.sub.t=1.04 min; MS (ESIpos): m/z=375 [M+H].sup.+

[4398] .sup.1H-NMR (400 MHz, DMSO-d6) 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-2-one

[4399] ##STR00433##

[4400] The title compound was prepared analogously to Example 3 from Intermediate 64.

[4401] LC-MS (Method2): R.sub.t=0.89 min; MS (ESIpos): m/z=326 [M+H].sup.+

[4402] .sup.1H-NMR (400 MHz, DMSO-d6) 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

[4403] ##STR00434##

[4404] The title compound was prepared in analogy to Example 198 from Intermediate 77.

[4405] 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

[4406] ##STR00435##

[4407] The title compound was synthesized analogously to Example 3 from Intermediate 65.

[4408] LC-MS (Method1): R.sub.t=0.75 min; MS (ESIpos): m/z=288 [M+H].sup.+

Experimental Section—Biological Assays

[4409] Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein [4410] the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and [4411] the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.

[4412] Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.

[4413] The in vitro activity of the compounds of the present invention can be demonstrated in the following assays:

Assay 1

Cell Proliferation Measurement

[4414] The antiproliferative activity of the compounds of the general formula (I) was examined in vitro in human cancer cells. For this purpose, the appropriate number of cells (Hela: 800; SK-MEL-3: 1000; A549: 800) were plated in 384-well plates with appropriate growth medium ((A549: DMEM/Ham's F12 (Biochrom; #FG 4815 with stabile Glutamine), FCS 10% final (Biochrom; #S 0415); Hela: DMEM/Ham's F12 (Biochrom; #FG 4815 with stabile Glutamine), FCS 10% final (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. After 24 h, cells on one plate (0 h plate) were treated with 30 μl/cavity of CTG solution (Promega Cell Titer Glo (catalogue #G755B and G756B)) and incubated at room temperature for 10 min, and luminescence was measured by means of a VICTOR V (Perkin Elmer), in order to determine cell viability on commencement of treatment. The cells on the test plate were treated with the compounds of the general formula (I) as and incubated at 37° C. for 72 h. The compounds were added to the cells by means of an HP D300 digital dispenser in a 10-step 2,5-fold dilution series generally starting at a maximum final drug concentration of 100 nM. As control, the cells were treated with vehicle (DMSO at 0.3% final concentration). After 72 h, the cells were treated with 30 μl/cavity of CTG solution (Promega Cell Titer Glo (catalogue #G755B and G756B)) and incubated at room temperature for 10 min, and luminescence was measured by means of a VICTOR V (Perkin Elmer), in order to determine cell viability at the end of treatment. The percentage effect on cell growth and the IC50 derived therefrom were determined for each test substance using the values from the 0 h plate (=maximum inhibition) and the DMSO control (=minimum inhibition). The IC50 values were calculated using a 4-parameter fit.

TABLE-US-00002 TABLE 2 Anti-proliferation IC.sub.50 values of several examples in vitro in different cell lines Example HeLa (Intermediate, IC.sub.50 [nM] SK-MEL-3 IGR37 where (Cervical IC.sub.50 [nM] IC.sub.50 [nM] indicated) 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  11 19 49  13 27 82  15 8 16  17 7 17  18 18 74  20 15 41  21 15 >67  23 45 >100  24 55 >100  25-1 2 3  25-2 3 5  26 9 29 Example (Intermediate, where indicated) HeLa SK-MEL-3 IGR37  27 2 6  29 46 >100  30 1 4  31 4 11 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  51 30 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 11 23  76 6 13 13  77 8 16  78 10 21  79 12 25  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 30  91 14 17  92 2 4 4  93 7 13  94 16 36  96 18 40  97 5 8  98 5 8  99 5 11 100 5 9 101 2 4 102 23 40 103 3 6 105 8 15 106 9 16 107 6 12 108 6 13 109 4 9 110 8 14 111 2 4 112 6 10 113 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 40 140 1 1 141 2 3 142 3 4 143 15 30 144 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 11 22 160 27 47 161 6 10 12 162 4 7 163 8 14 164 6 8 165 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 0.4 191 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 7 217 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 6 242 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 65 267 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 11 Intermediate 75 22 45 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 12 282 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 >100 307 >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

[4415] Thus one aspect of the invention is the use of the compounds of formula (I) for the treatment of cervical cancer.

[4416] Another aspect of the invention is the use of the compounds of formula (I) for the treatment of skin cancer, especially melanoma.

[4417] Yet another aspect of the invention is the use of compounds of formula (I), for the treatment of skin cancer, especially melanoma, and cervical cancer.

[4418] Another aspect are compounds of formula (I) which effectively inhibit tumor cell proliferation (e.g. in HeLa cells) with IC.sub.50 values of <100 nM.

TABLE-US-00003 TABLE 3-1 Anti-proliferation IC.sub.50 values of several examples in vitro in different cell lines Example 31 92 139 146 267 269 277 Cell line IC.sub.50 [nM] Breast Hs 578T >100 31 >100 28 34 66 >100 Erythroleukemia HEL 47 9 >100 13 26 44 >100 92.1.7 Glioblastoma DK-MG 39 17 61 12 18 49 >100 Glioblastoma DBTRG- 56 18 >100 14 35 50 >100 05-MG Melanoma CHL-1 28 11 58 8 16 47 >100 Melanoma A-2058 51 18 >100 16 40 61 >100 Ovarian PA-1 39 17 >100 12 44 49 >100 teratocarcinoma

TABLE-US-00004 TABLE 3-2 Anti-proliferation IC.sub.50 values of several examples in vitro in different cell lines Example 1 3 4 7 8 135 Cell line IC.sub.50 [nM] Astrocytoma H4 30 25 47 44 50 Breast Hs 578T 29 Erythroleukemia HEL 20 25 92.1.7 Glioblastoma DK-MG 21 Lung NCl- 19 13 40 26 42 H1734 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 PA-1 22 teratocarcinoma

Assay 2

Cell Proliferation Measurement

[4419] The antiproliferative activity of the compounds of the general formula (I) was examined in vitro in human cancer cells. For this purpose, 500 cells, including HeLa cells, A2058 cells, DU145 cells, HMCB cells, IGR37 cells, NCIH1734 cells, OSRC2 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, L17 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 appropriate growth medium and incubated at 37° C. overnight. After 24 h, the cells on the test plate were treated with the compounds of the general formula (I) as and incubated at 37° C. for 72 h. The compounds were added to the cells by means of an HP D300 digital dispenser in a 10 (or more)-step dilution series. As control, the cells were treated with vehicle (DMSO at 0.3% final concentration). After 72 h, the cells were treated with 20 μl/well of 50% CTG solution in PBS (Promega Cell Titer G (catalogue #G755B and G756B)) and incubated at room temperature for 10 m, and luminescence was measured by means of a VICTOR V (Perkin Elmer), in order to determine cell viability at the end of treatment. The percentage effect on cell growth and the IC.sub.50 derived therefrom were determined for each test substance using the values from untreated wells (=percent viability). The IC.sub.50 values were calculated using a 4-parameter fit.

TABLE-US-00005 TABLE 4 Anti-proliferation IC.sub.50 values of several examples in vitro in different cell lines Example Number Example 135 146 265 Cell line IC.sub.50 [nM] Breast, ductal carcinoma HS578T 33 20 116 Breast NS CAL51 37 Cervical HeLa 2 2 5 Glioma_astrocytoma DKMG 22 13 59 Lung adenocarcinoma NCIH1563 18 46 Lung adenocarcinoma NCIH2122 3 Lung non small cell carcinoma H2172 38 37 101 Lung small cell carcinoma H196 150 32 355 Melanoma A2058 38 25 96 Melanoma C32 58 52 132 Melanoma RVH421 140 47 262 Melanoma SKMEL3 5 3 10 Oesophagus squamous cell TE4 15 41 carcinoma Ovary adenocarcinoma JHOM1 8 Pancreas NS L3.3 82 15 312 Prostate NS DU145 14

[4420] Thus one aspect of the invention is the use of the 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 erythroleucemia), lung cancer (especially NSCLC adenocarcinoma and SCLC), skin cancer (especially melanoma), oesophagus cancer (especially squamous cell carcinoma), ovarian cancer, (especially teratocarcinoma, adenocarcinoma), pancreas cancer and prostatic cancer.

Assay 3

In Vivo Xenotransplantation Models

[4421] The anti-tumor activities of Compounds of examples 135 and 146 were examined in murine xenotransplantation models of human cancer. For this purpose, mice were implanted subcutaneously with tumor cells. At a mean tumor size of 20-40 mm.sup.2 animals were randomized into treatment and control groups (at least n=10 animals/group) and treatment started with vehicle only or respective Compound (formulation: 90% PEG400/10% Ethanol; application route: per os (“p.o.”), orally). The oral application volume was 10 ml/kg. In the case of twice daily treatments, the time interval between two applications per day was 6-7 h. The tumor size and the body weight were determined at least weekly. The tumor area was detected by means of an electronic caliper [length (mm)×width (mm)]. The experiment was ended when the study reached the pre-determined ethical endpoint based on German and European animal welfare regulations. In vivo anti-tumor efficacy is presented as T/C ratio at study end (Treatment/Control; mean tumor weight of treatment group/mean tumor weight of control group) in Table 8. A compound having a T/C below 0.5 is defined as active (i.e., effective). Statistical analysis was assessed using SigmaStat software. A one-way analysis of variance was performed and differences to the control were compared by a pair-wise comparison procedure (Dunn's method).

[4422] Compounds of examples 135 and 146 showed potent anti-tumor efficacy in different xenograft models of human tumors upon monotherapy treatment. Specifically, Compound example 135 and/or example 146 were effective in reduction of tumor area in cervical cancer, ovarian teratocarcinoma, AML and melanoma.

TABLE-US-00006 TABLE 5 Anti-tumor activity of Compound of example 135, compound of example 146 and compound of example 265 in different human cancer xenoqraft models in mice Cell line Xenograft isolated from Dose and Model patient with Example schedule T/C IGR-37 Melanoma 146 10 mg/kg 2QD 0.05* p.o. IGR-37 Melanoma 135 10 mg/kg 2QD 0.06* p.o. HEL92.1.7 AML 146 40 mg/kg 2QD 0.08* p.o. HeLa Cervical 146  5 mg/kg 2QD 0.08* cancer p.o. A2058 Melanoma 146 10 mg/kg 2QD 0.23* p.o. PA-1 Ovarian 146 20 mg/kg 2QD 0.49* teratocarcioma p.o. PA-1 Ovarian 135  5 mg/kg 2QD 0.63  teratocarcioma p.o. IGR-37 Melanoma 265 10 mg/kg 2QD 0.27* p.o. * P < 0.05 treatment vs control at study end T/C = ratio of mean final tumor weight of treatment group versus mean final tumor weight of control group The abbreviation 2QD means twice per day, p.o. means per os or-oral.

Assay 4

Method for PDE3A Enzyme Inhibition

[4423] The commercially available 3H-cAMP Scintillation Proximity Assay (SPA, Perkin Elmer) system was used for enzyme inhibition studies. For the determination of the in vitro effect of example compounds on the PDE3A reactions 2 μl of the respective example compound solution in DMSO (serial dilutions) were placed in wells of microtiter plates (Isoplate-96/200W; Perkin Elmer). 50 μl of a dilution of PDE3A cell extract from Sf9 cells overexpressing human full length PDE3A (SB Drug Discovery, UK) in buffer A (50 mM Tris/HCl pH 7.5, 8.3 mM MgCl.sub.2, 1.7 mM EDTA, 0.2% BSA) was added. The dilution of the PDE3A cell extract was chosen such that the reaction kinetics was linear and less than 70% of the substrate was consumed (typical dilution 1:5000). The reaction was started by addition of 50 μl (0.025 ρCi) of 1:2000 in buffer A w/o BSA diluted substrate [8-3H]adenosine 3′,5′-cyclic phosphate (1 ρCi/μl; Perkin Elmer). After incubation at room temperature for 60 min, the reaction was stopped by addition of 25 μl of a suspension containing 18 mg/ml yttrium scintillation proximity beads (Perkin Elmer) in water. The microtiter plates were sealed and measured in a Microbeta scintillation counter (PerkinElmer Wallac). IC.sub.50 values were determined from sigmoidal curves by plotting percentage PDE3A activity vs log compound concentration.

Assay 5

PDE3B Enzyme Inhibition

[4424] The commercially available 3H-cAMP Scintillation Proximity Assay (SPA, Perkin Elmer) system was used for enzyme inhibition studies. For the determination of the in vitro effect of example compounds on the PDE3B reactions 2 μl of the respective example compound solution in DMSO (serial dilutions) were placed in wells of microtiter plates (Isoplate-96/200W; Perkin Elmer). 50 μl of a dilution of PDE3B cell extract from Sf9 cells overexpressing human full length PDE3B (SB Drug Discovery, UK) in buffer A (50 mM Tris/HCl pH 7.5, 8.3 mM MgCl.sub.2, 1.7 mM EDTA, 0.2% BSA) was added. The dilution of the PDE3B cell extract was chosen such that the reaction kinetics was linear and less than 70% of the substrate was consumed (typical dilution 1:6000). The reaction was started by addition of 50 μl (0.025 ρCi) of 1:2000 in buffer A w/o BSA diluted substrate [8-3H]adenosine 3′,5′-cyclic phosphate (1 ρCi/μl; Perkin Elmer). After incubation at room temperature for 60 min, the reaction was stopped by addition of 25 μl of a suspension containing 18 mg/ml yttrium scintillation proximity beads (Perkin Elmer) in water. The microtiter plates were sealed and measured in a Microbeta scintillation counter (PerkinElmer Wallac). IC.sub.50 values were determined from sigmoidal curves by plotting percentage PDE3B activity vs log compound concentration.

[4425] One aspect of the invention are compounds of formula (I) which effectively inhibit tumor cell proliferation with IC.sub.50 values of <100 nM in e.g. HeLa cells while IC.sub.50 values for enzymatic PDE3A or PDE3B inhibition are often >2.5 times higher than IC.sub.50 values for tumor cell proliferation.

[4426] Another aspect of the invention are compounds of formula (I) which effectively inhibit tumor cell proliferation with IC.sub.50 values of <100 nM in e.g. HeLa cells while IC.sub.50 values for enzymatic PDE3A or PDE3B inhibition are often >10 times higher than IC.sub.50 values for tumor cell proliferation.

[4427] One aspect of the invention are compounds of formula (I) which effectively inhibit tumor cell proliferation with IC.sub.50 values of <100 nM in e.g. HeLa cells while IC.sub.50 values for enzymatic PDE3A or PDE3B inhibition are often >30 times higher than IC.sub.50 values for tumor cell proliferation.

TABLE-US-00007 TABLE 6 Inhibition of PDE3A and PDE3B Example/ PDE3A IC.sub.50 PDE3B IC.sub.50 Intermediate [nM] [nM]  1 275 173  3 285 197  4 203 154  5 139 97  6 100 110  7 220 170  8 210 243  9 440 240  10 220 230  11 84 65  13 110 44  15 110 110  17 25 17  18 450 220  20 200 100  21 175 185  23 380 270  24 180 110  25-1 44 22  25-2 17 15  26 700 270  27 75 110  29 300 160  30 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  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 30  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  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 81 112 170 230 113 210 215 114 92 100 115 92 100 116 79 76 117 77 95 118 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 70 120 155 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 77 182 220 260 183 200 170 184 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 74 180 208 110 140 209 275 533 210 140 363 211 29 54 212 26 24 213 68 71 214 59 73 215 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 48 100 244 120 150 245 75 100 246 95 210 247 65 180 248 61 140 249 100 110 250 120 120 251 61 97 252 110 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 10 273 44 53 274 300 400 275 29 64 276 79 240 277 100 87 278 >1000 >1000 279 20 23 280 11 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 30  14 63 71  22 52 33  28 31 40  35 79 75  46 27 17  52 65 30  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 30 327 11 16 328 74 91 329 100 93

Assay 6

Method for Human Cryo Hepatocytes:

[4428] Investigation of in vitro metabolic stability in cryopreserved human hepatocytes (including calculation of hepatic in vivo blood clearance (CL) and maximal oral bioavailability (Fmax))

[4429] Cryopreserved Hepatocytes (e.g. purchased from Celsis InVitroTechnologies) were briefly thawed, washed with 45 mL pre-warmed in in vitro GRO HT medium and centrifuged for 5 min at 50×g. The cell pellet was resuspended in 5 ml of Krebs-Henseleit Butter (KHB). Cell viability was determined by trypan blue exclusion.

[4430] For the metabolic stability assay liver cells were distributed in WME containing 5% FCS to glass vials at a density of 1.0×106 vital cells/ml. The test compound was added to a final concentration of 1 μM. During incubation, the hepatocyte suspensions were continuously shaken at 580 rpm and aliquots were taken at 2, 8, 16, 30, 45 and 90 min, to which equal volumes of cold methanol were immediately added. Samples were frozen at −20° C. over night, after subsequently centrifuged for 15 minutes at 3000 rpm and the supernatant was analyzed with an Agilent 1290 HPLC-system with LCMS/MS detection.

[4431] The half-life of a test compound was determined from the concentration-time plot. From the half-life the intrinsic clearances were calculated. Together with the additional parameters liver blood flow, amount of liver cells in vivo and in vitro. The hepatic in vivo blood clearance (CL) and the maximal oral bioavailability (Fmax) was calculated. The hepatic in vivo blood clearance (CLblood) and the maximal oral bioavailability (Fmax) was calculated using the following formulae: CL'intrinsic [ml/(min*kg)]=kel[1/min]/((cellno/volume of incubation [ml])*fu,inc)*(cellno/liver weight [g])*(specific liver weight [g liver/kg body weight]); CLblood well-stirred [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=1-CLblood/QH and using the following parameter values: Liver blood flow—1.32 L/h/kg human; specific liver weight—21 g/kg body weight; liver cells in vivo—1.1×10.sup.8 cells/g liver, liver cells in vitro—1.0×10.sup.6/ml.; fu,inc and fu,blood is taken as 1.

TABLE-US-00008 TABLE 7 Results of human cryo hepatocytes test Example Fmax [%] Clblood [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 0.62 165 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

Assay 7

[4432] In Vivo Pharmacokinetics in Non-Rodents (e.g. Dogs)

[4433] For in vivo pharmacokinetic experiments test compounds were administered to non-rodents (e.g. female Beagle dogs) intravenously (i.v.) at doses of 0.1 to 1 mg/kg and intragastrally (i.g.) at doses of 0.3 to 3 mg/kg formulated as solutions using solubilizers such as e.g. PEG400 in well-tolerated amounts and are usually given as short term infusion (15 min).

[4434] Blood samples were taken e.g. at 2 min, 8 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after dosing from the vena saphena. Depending on the expected half-life additional samples were taken at later time points (e.g. 48 h, 72 h).

[4435] For pharmacokinetics after intragastral administration test compounds were given intragastrally to fasted non-rodents (e.g. dogs). Blood samples were taken e.g. at 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after dosing. Depending on the expected half-life additional samples were taken at later time points (e.g. 48 h, 72 h). Blood was collected into Lithium-Heparin tubes (Monovetten@, Sarstedt) and centrifuged for 15 min at 3000 rpm. A small aliquot (e.g. 100 μL) from the supernatant (plasma) was taken and precipitated by addition of an aliquot ice cold acetonitrile (e.g. of 400 μL) and frozen at −20° C. over night. Samples were subsequently thawed and centrifuged at 3000 rpm, 4° C. for 20 minutes. 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 a PK calculation software.

[4436] PK parameters derived from concentration-time profiles after i.v.: CLplasma: Total plasma clearance of test compound (in L/kg/h); CLblood: Total blood clearance of test compound: CLplasma*Cp/Cb (abbreviation: CLp;) in L/kg/h) with Cp/Cb being the ratio of concentrations in plasma and blood.

[4437] PK parameters calculated from concentration time profiles after i.q.: Cmax: Maximal plasma concentration (in mg/L); Cmaxnorm: Cmax divided by the administered dose (in kg/L); Tmax: Time point at which Cmax was observed (in h). Parameters calculated from both, i.v. and i.g. 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(0-tlast)norm: Area under the concentration-time curve from t=0 h to the last time point for which plasma concentrations could be measured divided by the administered dose (in kg*h/L); t1/2: terminal half-life (in h); F: oral bioavailability: AUCnorm after intragastral administration divided by AUCnorm after intravenous administration (in %).

TABLE-US-00009 TABLE 8 Results of in vivo pharmacokinetic test Example CLblood dog [L/h/kg]  3 2.39  31 0.49 135 0.49 146 2.84

Assay 8

[4438] In Vivo Pharmacokinetics in Rodents (e.g. Mice) The housing and handling of animals was performed in strict compliance with the European and German Guidelines for Laboratory Animal Welfare. Animals received food and water ad libitum. For the quantification of circulating compounds in plasma, a certain dose (1-100 mg/kg) was orally administered to female NMRInu/nu mice at the age of 6-8 weeks in a solubilized form (n=3 mice per time point).

[4439] Blood was collected into Lithium-Heparin tubes (Monovetten@, Sarstedt) and centrifuged for 15 min at 3000 rpm. A small aliquot (e.g. 100 μL) from the supernatant (plasma) was taken and precipitated by addition of an aliquot ice cold acetonitrile (e.g. of 400 μL) and frozen at −20° C. over night. Samples were subsequently thawed and centrifuged at 3000 rpm, 4° C. for 20 minutes. 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 a PK calculation software.

Assay 9

Validation of PDE3A Modulator-Induced PDE3A Protein Interactions Using Immunoprecipitation and Immunoblotting

[4440] HeLa cells were transfected with ORF overexpression constructs expressing V5-tagged SLFN12, or V5-tagged GFP. ORF expression constructs were obtained from the TRC (clone IDs: TRCN0000468231, TRCN0000476272, ccsbBroad304_99997). At 72 hours post transfection, cells were treated with 10 μM DNMDP or trequinsin for 4 hours followed by lysis using the ModRipa lysis buffer and immunoprecipitation of PDE3A. For each condition, 2 mg total protein lysate was incubated with 1 μg of anti-PDE3A antibody at 4° C. overnight, after which 7.5 μl each of Protein A- and Protein G-Dynabeads (Life Technologies 10001D and 10003D) were added and incubated for another 1 hour. Beads were washed and bound proteins were eluted with 30 μl of LDS PAGE gel loading buffer. Input (˜60 μg total protein lysate) and IP products were resolved on 4-12% Tris-Glycine PAGE gels and immunoblotted with an anti-V5 antibody (Life Technologies R96205, 1:5000), the Bethyl anti-PDE3A antibody (1:1000), and secondary antibodies from LiCOR Biosciences (Cat. #926-32210 and 926068021, each at 1:10,000). Blots were washed and imaged using a LiCOR Odyssey infrared imager.

Other Embodiments

[4441] From the foregoing description, it will be apparent that variations and modifications may be made to the invention described herein to adopt it to various usages and conditions. Such embodiments are also within the scope of the following claims.

[4442] The recitation of a listing of elements in any definition of a variable herein includes definitions of that variable as any single element or combination (or subcombination) of listed elements. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.