AMINE SUBSTITUTED TRIAZOLE DERIVATIVES AND USES THEREOF

Abstract

The present invention relates to novel amine substituted 1,2,4-triazole derivatives, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds, and to the use of such compounds or compositions for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of renal and cardiovascular diseases.

Claims

1. A compound of formula (I) ##STR00177## in which R.sup.1 represents hydrogen or methyl, R.sup.2 represents C.sub.1-C.sub.5-alkyl or a 5- or 6-membered heterocyclyl, where alkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy, amino, aminocarbonyl, aminosulfonyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, C.sub.3-C.sub.6-cycloalkyl, 4- to 7-membered heterocyclyl, methylsulfonyl, methylcarbonylamino, 2,2,2-trifluoroethylaminocarbonyl, methylsulfonylamino and C.sub.1-C.sub.4-alkoxycarbonyl, wherein heterocyclyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, chlorine, fluorine, hydroxy, formyl, aminocarbonyl, methyl, methoxy, trifluoromethyl, methylcarbonyl, methylsulfonyl and C.sub.1-C.sub.4-alkoxycarbonyl, and wherein cycloalkyl may be substituted by one substituent hydroxyl, and where heterocyclyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, chlorine, fluorine, hydroxy, aminocarbonyl, methyl, methoxy, trifluoromethyl, methylcarbonyl, methylsulfonyl and C.sub.1-C.sub.4-alkoxycarbonyl, or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl, 6-oxo-2,5,7-triazaspiro[3.4]octan-2-yl, hexahydro-4H-furo[3,2-b]pyrrol-4-yl, 2,2-dioxido-2-thia-6-azaspiro[3.3]hept-6-yl or 2-oxa-6-azaspiro[3.3]hept-6-yl, where heterocyclyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, chlorine, fluorine, hydroxy, aminocarbonyl, methyl, methoxy, trifluoromethyl, methylcarbonyl, methylsulfonyl and C.sub.1-C.sub.4-alkoxycarbonyl, R.sup.3 represents phenyl, pyridinyl or 3,3,3-trifluoroprop-1-yl, where phenyl may be substituted by one substituent selected from the group consisting of chlorine, fluorine and trifluoromethyl, and where pyridinyl may be substituted by one substituent selected from the group consisting of chlorine, fluorine, trifluoromethyl and trifluoromethoxy, and/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof.

2. A compound of formula (I) according to claim 1, wherein R.sup.1 represents hydrogen or methyl, R.sup.2 represents C.sub.1-C.sub.5-alkyl, pyrrolidin-3-yl or piperidin-5-yl, where alkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy, amino, aminocarbonyl, aminosulfonyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, C.sub.3-C.sub.6-cycloalkyl, oxetan-3-yl, thietan-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, 1,3-oxazolidin-5-yl, imidazolidin-1-yl, piperidin-4-yl, 1,2-thiazinan-2-yl, azepan-4-yl, methylsulfonyl, methylcarbonylamino, 2,2,2-trifluoroethylaminocarbonyl, methylsulfonylamino and C.sub.1-C.sub.4-alkoxycarbonyl, wherein oxetan-3-yl, thietan-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, 1,3-oxazolidin-5-yl, imidazolidin-1-yl, piperidin-4-yl, 1,2-thiazinan-2-yl and azepan-4-yl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, chlorine, fluorine, hydroxy, formyl, aminocarbonyl, methyl, methoxy, trifluoromethyl, methylcarbonyl, methylsulfonyl and C.sub.1-C.sub.4-alkoxycarbonyl, and wherein cycloalkyl may be substituted by one substituent hydroxyl, and where pyrrolidin-3-yl and piperidin-5-yl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, chlorine, fluorine, hydroxy, aminocarbonyl, methyl, methoxy, trifluoromethyl, methylcarbonyl, methylsulfonyl and C.sub.1-C.sub.4-alkoxycarbonyl, or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 6-oxo-2,5,7-triazaspiro[3.4]octan-2-yl, hexahydro-4H-furo[3,2-b]pyrrol-4-yl, 2,2-dioxido-2-thia-6-azaspiro[3.3]hept-6-yl or 2-oxa-6-azaspiro[3.3]hept-6-yl, where azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, chlorine, fluorine, hydroxy, aminocarbonyl, methyl, methoxy, trifluoromethyl, methylcarbonyl, methylsulfonyl and C.sub.1-C.sub.4-alkoxycarbonyl, R.sup.3 represents phenyl, pyridinyl or 3,3,3-trifluoroprop-1-yl, where phenyl may be substituted by one substituent selected from the group consisting of chlorine, fluorine and trifluoromethyl, and where pyridinyl may be substituted by one substituent selected from the group consisting of chlorine, fluorine, trifluoromethyl and trifluoromethoxy, and/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof.

3. A compound of formula (I) according to claim 1, wherein R.sup.1 represents hydrogen or methyl, R.sup.2 represents C.sub.1-C.sub.5-alkyl, pyrrolidin-3-yl or piperidin-5-yl, where alkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy, amino, aminocarbonyl, aminosulfonyl, trifluoromethyl, methoxy, C.sub.3-C.sub.6-cycloalkyl, oxetan-3-yl, thietan-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, 1,3-oxazolidin-5-yl, imidazolidin-1-yl, piperidin-4-yl, 1,2-thiazinan-2-yl, azepan-4-yl, methylsulfonyl, methylcarbonylamino, 2,2,2-trifluoroethylaminocarbonyl, methylsulfonylamino and C.sub.1-C.sub.4-alkoxycarbonyl, wherein oxetan-3-yl, thietan-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, 1,3-oxazolidin-5-yl, imidazolidin-1-yl, piperidin-4-yl, 1,2-thiazinan-2-yl and azepan-4-yl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, hydroxy, formyl, methyl and C.sub.1-C.sub.4-alkoxycarbonyl, and wherein cycloalkyl may be substituted by one substituent hydroxyl, and where pyrrolidin-3-yl and piperidin-5-yl may be substituted by 1 or 2 substituents of oxo, or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 6-oxo-2,5,7-triazaspiro[3.4]octan-2-yl, hexahydro-4H-furo[3,2-b]pyrrol-4-yl, 2,2-dioxido-2-thia-6-azaspiro[3.3]hept-6-yl or 2-oxa-6-azaspiro[3.3]hept-6-yl, where azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, fluorine, hydroxy, aminocarbonyl, methyl, methoxy, trifluoromethyl, methylcarbonyl and methylsulfonyl, R.sup.3 represents phenyl, pyridinyl or 3,3,3-trifluoroprop-1-yl, where phenyl may be substituted by one substituent selected from the group consisting of chlorine, fluorine and trifluoromethyl, and where pyridinyl may be substituted by one substituent selected from the group consisting of chlorine, fluorine and trifluoromethyl, and/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof.

4. A compound of formula (I) according to claim 1, wherein R.sup.1 represents hydrogen, R.sup.2 represents 2-hydroxy-2-methyl-prop-1-yl or 2-amino-2-methyl-prop-1-yl, or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached form piperazinyl or 1,1-dioxidothiomorpholinyl, where piperazinyl is substituted by 1 or 2 substituents independently of one another selected from the group consisting of oxo, methyl and trifluoromethyl, R.sup.3 represents phenyl or pyridin-2-yl, where phenyl is substituted by one substituent trifluoromethyl in ortho-position to the point of attachment of the phenyl to the 1,2,4-triazolyl-ring, and where pyridin-2-yl may be substituted by one substituent selected from the group consisting of chlorine, fluorine and trifluoromethyl in ortho-position to the point of attachment of the pyridin-2-yl to the 1,2,4-triazolyl-ring, and/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof.

5. The compound of formula (I) according to claim 1, wherein R.sup.1 represents hydrogen, R.sup.2 represents methyl, where methyl is substituted by one substituent selected from the group consisting of cyclopropyl, cyclobutyl and thietan-3-yl, wherein thietan-3-yl is substituted by 2 substituents oxo, and wherein cyclopropyl and cyclobutyl are substituted by one substituent hydroxyl, or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or 2,2-dioxido-2-thia-6-azaspiro[3.3]hept-6-yl, where azetidinyl, pyrrolidinyl, piperidinyl and piperazinyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy, methyl, trifluoromethyl, methylcarbonyl and methylsulfonyl, R.sup.3 represents phenyl, where phenyl may be substituted by one substituent selected from the group consisting of chlorine and fluorine in ortho-position or meta-position to the point of attachment of the phenyl to the 1,2,4-triazolyl-ring, and/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof.

6. Process for preparing a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof according to claim 1, comprising reacting [A] a compound of formula ##STR00178## wherein the hydroxy group in formula (II) may be protected with a tert-butyl(dimethyl)silyl group at the beginning of the reaction and which is cleaved under the reaction conditions, with a compound of formula ##STR00179## to give a compound of formula (I) or [B] reacting a compound of formula ##STR00180## with a compound of formula ##STR00181## in which X.sup.1 represents bromine or chlorine, to give a compound of formula (I) or [C] reacting a compound of formula ##STR00182## R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl, where heterocyclyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, chlorine, fluorine, hydroxy, aminocarbonyl, methyl, methoxy, trifluoromethyl, methylcarbonyl, methylsulfonyl and C.sub.1-C.sub.4-alkoxycarbonyl, with a compound of formula ##STR00183## under Chan-Lam coupling conditions to give a compound of formula ##STR00184## in which R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl, where heterocyclyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, chlorine, fluorine, hydroxy, aminocarbonyl, methyl, methoxy, trifluoromethyl, methylcarbonyl, methylsulfonyl and C.sub.1-C.sub.4-alkoxycarbonyl, each [A], [B] and [C] optionally followed, where appropriate, by (i) separating the compound of formula (I) thus obtained into respective diastereomer, and/or (ii) converting the compound of formula (I) into a respective pharmaceutically acceptable salt thereof, solvate thereof or solvate of a salt thereof by treatment with a corresponding solvent and/or acid or base.

7. Compound as defined in claim 1 for treatment and/or prevention of one or more diseases.

8. Compound as defined in claim 1 for treatment and/or prevention of one or more acute and chronic kidney diseases including diabetic nephropathy, acute and chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud's syndrome, dysmenorrhea, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema and the syndrome of inadequate ADH secretion (SIADH).

9. A product comprising a compound as defined in claim 1 for treatment and/or prevention of one or more acute and chronic kidney diseases including diabetic nephropathy, acute and chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud's syndrome dysmenorrhea, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema and the syndrome of inadequate ADH secretion (SIADH).

10. Pharmaceutical composition comprising a compound as defined in claim 1 and one or more pharmaceutically acceptable excipients.

11. Pharmaceutical composition of claim 10 comprising one or more first active ingredients, optionally one or more compounds according to claim 1, and one or more further active ingredients, optionally one or more additional therapeutic agents selected from the group consisting of diuretics, angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers, mineralocorticoid receptor antagonists, organic nitrates, NO donors, activators and stimulators of the soluble guanylate cyclase, and positive-inotropic agents, antiinflammatory agents, immunosuppressive agents, phosphate binders and/or compounds which modulate vitamin D metabolism.

12. The pharmaceutical composition as defined in claim 10 for treatment and/or prevention of acute and chronic kidney diseases including diabetic nephropathy, acute and chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud's syndrome, dysmenorrhea, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema and the syndrome of inadequate ADH secretion (SIADH).

13. Method for treatment and/or prevention of one or more acute and chronic kidney diseases including diabetic nephropathy, acute and chronic heart failure, preeclampsia, peripheral arterial disease (PAD) and coronary microvascular dysfunction (CMD), Raynaud's syndrome dysmenorrhea, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema and the syndrome of inadequate ADH secretion (SIADH) in a human or other mammal, comprising administering to a human or other mammal in need thereof a therapeutically effective amount of one or more compounds as defined in claim 1, or a pharmaceutical composition thereof.

Description

EXPERIMENTAL SECTION

Experimental SectionGeneral Part

[0372] NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.

[0373] Chemical names were generated using the ACD/Name software from ACD/Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names.

[0374] 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 The following table lists the abbreviations used herein. Abbrevia- tion Meaning abs absolut br broad (.sup.1H-NMR signal) conc. concentrated CI chemical ionisation d doublet (.sup.1H-NMR signal) d day(s) DAD diode array detector DCM dichloromethane dd double-doublet DMSO dimethylsulfoxide ESI electrospray (ES) ionisation h hour(s) HPLC high performance liquid chromatography LC-MS liquid chromatography mass spectrometry m multiplet (.sup.1H-NMR signal) min minute(s) MS mass spectrometry MTBE methyl-tert-butylether NMR nuclear magnetic resonance spectroscopy: chemical shifts () are given in ppm. The chemical shifts were corrected by setting the DMSO signal to 2.50 ppm unless otherwise stated. of th. of theory PDA Photo Diode Array R.sub.t retention time (as measured either with HPLC or UPLC) in minutes s singlet (.sup.1H-NMR signal) SQD Single-Quadrupole-Detector t triplet (.sup.1H-NMR signal) td triple-doublet (.sup.1H-NMR signal) THF tetrahydrofuran UPLC ultra performance liquid chromatography

[0375] 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.

[0376] The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

[0377] 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.

[0378] 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 cartidges KP-Sil or KP-NH in combination with a Biotage autopurifier system (SP4 or Isolera Four) and eluents such as 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 gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

[0379] 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, 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.

[0380] In the case of the synthesis intermediates and working examples of the invention described hereinafter, any compound specified in the form of a salt of the corresponding base or acid is generally a salt of unknown exact stoichiometric composition, as obtained by the respective preparation and/or purification process. Unless specified in more detail, additions to names and structural formulae, such as hydrochloride, trifluoroacetate, sodium salt or x HCl, x CF.sub.3COOH, x Na.sup.+ should not therefore be understood in a stoichiometric sense in the case of such salts, but have merely descriptive character with regard to the salt-forming components present therein.

[0381] This applies correspondingly if synthesis intermediates or working examples or salts thereof were obtained in the form of solvates, for example hydrates, of unknown stoichiometric composition (if they are of a defined type) by the preparation and/or purification processes described.

HPLC and LC-MS Methods:

Method 1 (LC-MS)

[0382] MS instrument type: Agilent Technologies 6130 Quadrupole LC-MS; HPLC instrument type: Agilent Technologies 1260 Infinity; column: Waters XSelect (C18, 302.1 mm, 3.5 g); flow: 1 ml/min; column temp: 35 C.; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; lin. gradient: t=0 min 5% A, t=1.6 min 98% A, t=3 min 98% A; detection: DAD (220-320 nm); detection: MSD (ESI pos/neg) mass range: 100-800; detection: ELSD (PL-ELS 2100): gas flow 1.2 ml/min, gas temp: 70 C., nebulizer: 50 C.

Method 2 (LC-MS)

[0383] Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 501 mm; eluent A: 1 l water+0.25 ml 99% formic acid, eluent B: 1 l acetonitrile+0.25 ml 99% formic acid; gradient: 0.0 min 90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5% A; oven: 50 C.; flow rate: 0.40 ml/min; UV detection: 208-400 nm.

Method 3 (LC-MS)

[0384] Instrument MS: Thermo Scientific FT-MS; Instrument type UHPLC+: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.175 mm, C18 1.8 m; eluent A: 1 l water+0.01% formic acid; eluent B: 1 l acetonitrile+0.01% formic acid; gradient: 0.0 min 10% B.fwdarw.2.5 min 95% B.fwdarw.3.5 min 95% B; oven: 50 C.; flow rate: 0.90 ml/min; UV detection: 210 nm/optimum integration path 210-300 nm.

Method 4 (LC-MS)

[0385] Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 501 mm; eluent A: 1 l water+0.25 ml 99% formic acid, Eluent B: 1 l acetonitrile+0.25 ml 99% formic acid; gradient: 0.0 min 95% A.fwdarw.6.0 min 5% A.fwdarw.7.5 min 5% A; oven: 50 C.; flow rate: 0.35 ml/min; UV detection: 210-400 nm.

Method 5 (Preparative HPLC)

[0386] Column: Chromatorex or Reprosil C18 10 m; 12530 mm, Flow: 75 ml/min, Run time: 20 min, Detection at 210 nm, Eluent A: water+0.1% formic acid, Eluent B: acetonitrile+0.1% formic acid or trifluoroacetic acid; Gradient: 3 min 10% B; 17.5 min 95% B; 19.5 min 100% B, 20 min 10% B.

Method 6 (LC-MS)

[0387] instrument type: Reveleris Flash Chromatography System; columns: GraceResolv Silica Cartridge; 4 g, flow 5 ml/min; 12 g, flow 16 ml/min; 40 g, flow 50 ml/min; 80 g, flow 100 ml/min; 120 g, flow 160 ml/min and Davisil Chromatographic Silica Media (LC60A 20-45 micron); 300 g, flow 70 ml/min; 500 g, flow 70 ml/min; eluents: see experiment; detection: UV (200-360 nm), ELSD.

Method 7 (LC-MS)

[0388] MS instrument type: Agilent Technologies 6130 Quadrupole LC-MS; HPLC instrument type: Agilent Technologies 1260 Infinity; column: Waters XSelect (C18, 502.1 mm, 3.5); flow: 0.8 ml/min; column temperature: 35 C.; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; linear gradient: t=0 min 5% A, t=3.5 min 98% A, t=6 min 98% A; detection: DAD (220-320 nm); detection: MSD (ESI pos/neg) mass range: 100-800; detection: ELSD (PL-ELS 2100): gas flow: 1.2 ml/min, gas temperature: 70 C., nebulizer: 50 C.

Method 8 (LC-MS)

[0389] instrument type: Reveleris Flash Chromatography System; columns: Reveleris C18 Flash Cartridge; 4 g, flow 18 ml/min; 12 g, flow 30 ml/min; 40 g, flow 40 ml/min; 80 g, flow 60 ml/min; 120 g, flow 80 ml/min; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; gradient: t=0 min 5% A, t=1 min 5% A, t=13 min 100% A, t=16 min 100% A; detection: UV (200-360 nm), ELSD.

Method 9 (LC-MS)

[0390] MS instrument type: Agilent Technologies LC/MSD SL; HPLC instrument type: Agilent Technologies 1100 Series; column: Waters XSelect (C18, 502.1 mm, 3.5; flow: 0.8 ml/min; column temp: 25 C.; eluent A: 95% acetonitrile+5% ammoniumbicarbonate in water; eluent B: 10 mmM ammoniumbicarbonate in water pH=9.0; linear gradient: t=0 min 5% A, t=3.5 min 98% A, t=6 min 98% A; detection: DAD (220-320 nm); detection: MSD (ESI pos/neg) mass range: 100-800.

Method 10 (LC-MS)

[0391] Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8 502.1 mm; eluent A: 1 l water+0.25 ml 99% ige formic acid, eluent B: 1 l acetonitrile+0.25 ml 99% ige formic acid; gradient: 0.0 min 90% A.fwdarw.0.3 min 90% A.fwdarw.1.7 min 5% A.fwdarw.3.0 min 5% A oven: 50 C.; flow rate: 1.20 ml/min; UV-detection: 205-305 nm.

Method 11 (LC-MS)

[0392] Instrument: Waters Prep LC-MS System, Column: Phenomenex Kinetex C18 5 m 10030 mm; eluent A: water, eluent B: acetonitrile, flow: 65 ml/min plus 5 ml 2% formic acid in water, room temperature, UV detection: 200-400 nm, gradient: 0.0 min 10% B, 2 min 20% B, 2.2 min 60% B, 7 min 92% B, 7.5 min 92% B.

Method 12 (LC-MS)

[0393] Instrument MS: Waters (Micromass) Quattro Micro; Instrument Waters UPLC Acquity; Column: Waters BEH C18 1.7 502.1 mm; eluent A: 1 l water+0.01 mol ammonium format, eluent B: 1 l acetonitrile; gradient: 0.0 min 95% A, 0.1 min 95% A, 2.0 min 15% A, 2.5 min 15% A, 2.51 min 10% A, 3.0 min 10% A; oven: 40 C.; flow rate: 0.5 ml/min; UV-detection: 210 nm

Method 13 (Preparative HPLC)

[0394] Column: Chromatorex C18 10 m 12530 mm, water-acetonitrile-gradient with 0.05% trifluoroacetic acid: 0-3 min. 25% acetonitrile, 3-7 min. gradient to 50% acetonitrile, 7-13 min. gradient to 60% acetonitrile, 12-13 min. 75% acetonitrile, 13-17 min. isocratic 75% acetonitrile; flow: 50 ml/min

Microwave:

[0395] The microwave reactor used was an Initiator.sup.+ microwave system with robot sixty from Biotage.

Experimental SectionStarting Materials and Intermediates

Example 1A

Ethyl 1-(2-chlorophenyl)-1H-1,2,4-triazole-3-carboxylate

[0396] ##STR00015##

[0397] A suspension of 2-chloroaniline (6.1 g, 47.5 mmol, 5.0 ml) in a mixture of water (25 ml) and concentrated hydrochloric acid (14.1 g, 143 mmol, 13.9 ml) was cooled to 0 C. A solution of sodium nitrite (3.3 g, 47.5 mmol) in water (5 ml) was added maintaining the temperature between 0 C. and 5 C. Stirring was continued for 5 min at 0 C. This solution was added drop wise to a mixture of acetic acid sodium salt (25.4 g, 309 mmol) and ethyl 2-isocyanoacetate (4.8 g, 42.8 mmol, 4.7 ml) in a mixture of water (50 ml) and methanol (5 ml). The reaction mixture was stirred at 0 C. for 30 min and was allowed to warm to room temperature. Stirring was continued for 18 h. Ethyl acetate (50 ml) was added and layers were separated. Aqueous layer was extracted with ethyl acetate (350 ml). Combined organic extracts were dried with sodium sulfate and solvents were removed in vacuo. Flash column chromatography (Method 6; 500 g; heptane, 30%-40% ethyl acetate) afforded 6.5 g (25.8 mmol; 60% of th.) of the title compound.

[0398] LC-MS (Method 1): R.sub.t=1.81 min; m/z=252 (M+H).sup.+

[0399] .sup.1H-NMR (300 MHz, DMSO-d6) =9.15 (s, 1H), 7.84-7.71 (m, 2H), 7.70-7.56 (m, 2H), 4.37 (q, 2H), 1.33 (t, 3H).

Example 2A

Ethyl 5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazole-3-carboxylate

[0400] ##STR00016##

[0401] Under argon atmosphere sodium hydride (4.1 g, 101 mmol; 60% in mineral oil) was added to ethyl 1-(2-chlorophenyl)-1H-1,2,4-triazole-3-carboxylate (Example 1A, 8.5 g, 33.8 mmol) and N-bromosuccinimide (30.1 g, 169 mmol) in tetrahydrofuran (dry) (175 ml). Reaction mixture was stirred at room temperature for 16 h and at 50 C. for 16 h. Reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (100 ml) and ethanol (10 ml). The reaction mixture was poured out in saturated aqueous ammonium chloride (100 ml). Layers were separated and aqueous layer was extracted with ethyl acetate (3100 ml). Combined organic layers were dried with sodium sulfate. Solvents were removed in vacuo. Purification by flash column chromatography (Method 6; 500 g; heptane, 25%-35% ethyl acetate) afforded 11.3 g (32.9 mmol; 97% of th.) of the title compound.

[0402] LC-MS (Method 1): R.sub.t=1.99 min; m/z=330/332 (M+H).sup.+

[0403] .sup.1H-NMR (300 MHz, DMSO-d6) =7.88-7.79 (m, 2H), 7.73 (td, 1H), 7.64 (td, 1H), 4.38 (q, 2H), 1.32 (t, 3H).

Example 3A

[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methanol

[0404] ##STR00017##

[0405] Under nitrogen atmosphere at 0 C. to a solution of ethyl 5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazole-3-carboxylate (Example 2A, 1.5 g, 4.54 mmol) in tetrahydrofuran (dry) (15 ml) and ethanol (abs) (15 ml) were added lithium chloride (0.769 g, 18.15 mmol) and sodium borohydride (0.687 g, 18.15 mmol). Reaction mixture was allowed to warm to room temperature and stirring was continued for 18 h. Reaction mixture was slowly added to saturated aqueous ammonium chloride (50 ml). Ethyl acetate (50 ml) was added and layers were separated. Aqueous layer was extracted with ethyl acetate (250 ml). Combined organic layers were dried with sodium sulfate and solvents were removed in vacuo. Flash column chromatography (Method 6; 80 g; heptane, 30%-60% ethyl acetate) afforded 0.93 g (3.22 mmol; 71% of th.) of the title compound.

[0406] LC-MS (Method 1): R.sub.t=1.67 min; m/z=288/290 (M+H).sup.+

[0407] .sup.1H-NMR (300 MHz, DMSO-d6) =7.80-7.73 (m, 1H), 7.70-7.53 (m, 3H), 5.49 (t, 1H), 4.48 (d, 2H).

Example 4A

5-Bromo-3-(chloromethyl)-1-(2-chlorophenyl)-1H-1,2,4-triazole

[0408] ##STR00018##

[0409] Under argon and at 0 C., a solution of [5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methanol (Example 3A, 7.00 g, 24.3 mmol) in dichloromethane (140 ml) was treated portionwise with phosphorous pentachloride (10.1 g, 48.5 mmol). The resulting mixture was stirred 2 h at room temperature and diluted with a ice-water mixture. The aqueous phase was extracted twice with dichloromethane. The combined organice layers were extracted twice with a saturated solution of sodium carbonate, dried over magnesium sulfate and evaporated affording 7.81 g (quant.) of the title compound which was used as such without further purification

[0410] LC-MS (Method 3): R.sub.t=1.82 min; MS (ESIpos): m/z=305.9 [M+H].sup.+

[0411] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.91-7.48 (m, 4H), 4.83 (s, 2H).

Example 5A

2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0412] ##STR00019##

[0413] A solution of 5-bromo-3-(chloromethyl)-1-(2-chlorophenyl)-1H-1,2,4-triazole (Example 4A, 7.81 g, 25.5 mmol) in acetonitrile (83 ml) was treated with 5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (synthesis described as Example 5A in WO 2011/104322-A1, 7.46 g, 24.2 mmol), potassium carbonate (6.70 g, 48.5 mmol) and potassium iodide (402 mg, 2.42 mmol). The resulting mixture was heated at reflux for 6 h and diluted with water. The aqueous phase was extracted with ethyl acetate. The combined organice layers were washed with a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated.

[0414] The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate gradient) affording 6.86 g (48% of th.) of the title compound.

[0415] LC-MS (Method 3): R.sub.t=2.04 min; MS (ESIpos): m/z=577.0 [M+H].sup.+

[0416] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.85-7.52 (m, 8H), 6.90 (d, 1H), 5.17-5.05 (m, 2H), 4.30 (br ddd, 1H), 4.10-3.77 (m, 2H).

Example 6A

{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetonitrile

[0417] ##STR00020##

[0418] In a 2 l reaction vessel, 100 g (273 mmol) of {3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetic acid (synthesis described as Example 8A in WO 2010/105770-A1, 43.3 g, 547 mmol) of pyridine and 33 mg (0.3 mmol) of 4-dimethylaminopyridine were dissolved in 300 ml THF. The resulting solution was treated at 5 C. with 52.8 g (438 mmol) of 2,2-dimethylpropanoylchloride over 15 minutes and the resulting mixture was stirred at room temperature for 2.5 hours. After cooling to 0 C., 183 ml of 28% aqueous ammonia solution was added over 1 h while the solution temperature was kept between 10 C. and 20 C. and at the resulting mixture then stirred at 5 C. for an additional time period of 1 h. 500 ml methyl tert-butylether and 300 ml 20% aqueous citric acid were then added while keeping the internal temperature between 10 C. and 20 C. The phases were the separated and the organic phase was washed with 300 ml of 20% aqueous citric acid followed by 300 ml saturated aqueous sodium hydrogencarbonate solution and finally with 300 ml of 10% aqueous sodium chloride solution. The organic phase was evaporated at 60 C. under reduced pressure until an oily residue was obtained. 300 ml THF was then added and the solution was evaporated again until an oily solution was obtained. This operation was repeated a second time. The oil residue was retaken in 360 ml THF and treated with 172 g (820 mmol) trifluoroacetic acid anhydride over 20 min at a temperature between 10 C. and 20 C. The resulting solution was then stirred at room temperature for 1 h. 720 ml 4-methyl-2-pentanone and 650 ml 7.5% aqueous sodium hydroxide solution were added at a temperature between 10 C. and 20 C. Finally the pH-value was adjusted to pH=9.5 using 7.5% aqueous sodium hydroxide solution. After phase separation, the organic phase was washed twice with 450 ml 10% aqueous sodium chloride solution. The organic phase was evaporated at a temperature of 80 C. under reduced pressure while 1200 ml n-heptane was added. The formed suspension was cooled to 20 C. and a solid formed which was filtered off and washed with 200 ml n-heptane and then dried under reduced pressure (50 C., 30 mbar) affording 88 g (93% of th.) of {3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetonitrile as a solid.

[0419] .sup.1H-NMR (400 MHz, DMSO-d6): [ppm]=7.78 (d, 2H), 7.55 (d, 2H), 6.91 (d, 1H), 5.17 (s, 2H), 4.34-4.23 (m, 1H), 3.98 (dd, 1H), 3.81 (dd, 1H).

Example 7A

Methyl-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluor-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate

[0420] ##STR00021##

[0421] In a 4 l reaction vessel, 200 g (576.9 mmol) of {3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetonitrile (Example 6A) in 1600 ml methanol was treated with 5.2 g (28 mmol) sodium methanolate (30% in methanol) and the resulting mixture was stirred at 50 C. for 2.5 hours. The solution was then evaporated at 50 C. under reduced pressure until an oily solution was obtained. 2000 ml methyl tert-butylether was added and the solution was concentrated until a volume of 800 ml was achieved. 3000 ml n-heptane was then added and a suspension was formed. After cooling at 20 C., the solid was filtered and washed with 500 ml n-heptane and then dried under reduced pressure (50 C., 30 mbar) affording 175 g (80% of th.) of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate as a solid.

[0422] .sup.1H-NMR (400 MHz, DMSO-d6): [ppm]=8.01 (s, 1H), 7.78 (d, 2H), 7.62 (d, 2H), 6.93 (br. s, 1H), 4.50 (s, 2H), 4.35-4.23 (m, 1H), 3.96 (dd, 1H), 3.81 (dd, 1H), 3.67 (s, 3H).

Example 8A

2-{[5-Bromo-1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0423] ##STR00022##

[0424] 5-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (synthesis described as Example 5A in WO 2011/104622-A1, 709 mg, 2.30 mmol), potassium carbonate (637 mg, 4.61 mmol) and catalytic amounts of potassium iodide were dissolved in 17 ml of acetonitrile. To this mixture, 5-bromo-3-(chloromethyl)-1-(3-fluorophenyl)-1H-1,2,4-triazole (Example 52A, 703 mg, 2.42 mmol) was added at room temperature. The mixture was stirred at 70 C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with 20 ml of water and extracted twice with 20 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, cyclohexane/ethyl acetate gradient) to afford 293 mg (23% of th.) of the title compound.

[0425] LC-MS (Method 2): R.sub.t=1.09 min; MS (ESIpos): m/z=560 [M+H].sup.+

[0426] .sup.1H-NMR (500 MHz, DMSO-d6) [ppm]: 0.121 (0.41), 0.008 (3.95), 0.006 (3.45), 0.116 (0.40), 1.160 (3.60), 1.174 (7.22), 1.188 (3.64), 1.235 (0.37), 1.987 (13.68), 2.361 (0.36), 2.635 (0.36), 3.829 (1.81), 3.848 (2.04), 3.858 (2.46), 3.877 (2.63), 3.992 (2.49), 3.998 (2.73), 4.007 (1.30), 4.022 (5.03), 4.027 (1.91), 4.036 (3.35), 4.050 (1.10), 4.292 (1.40), 4.305 (1.35), 4.622 (0.53), 5.099 (16.00), 6.899 (5.05), 6.912 (5.03), 7.431 (1.19), 7.436 (1.45), 7.448 (2.42), 7.453 (2.92), 7.465 (1.54), 7.471 (1.76), 7.494 (1.06), 7.520 (2.75), 7.536 (3.34), 7.601 (1.08), 7.607 (2.14), 7.612 (3.85), 7.618 (10.48), 7.626 (2.84), 7.631 (6.75), 7.635 (14.52), 7.648 (2.55), 7.652 (2.90), 7.665 (2.99), 7.681 (1.28), 7.754 (11.66), 7.772 (9.18).

Example 9A

5-(4-Chlorophenyl)-2-{[5-(pyrrolidin-1-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0427] ##STR00023##

[0428] To a solution of 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetohydrazide (Example 2A in WO 2016/071212 A1, 600 mg, 1.58 mmol) and pyrrolidine-1-carbonitrile (0.955 ml, 9.48 mmol) in 1-butanol (18 ml) was added potassium carbonate (109.2 mg, 0.79 mmol) at room temperature. The reaction mixture was stirred at 150 C. for 2.5 h under microwave irradiation. After cooling, the reaction mixture was concentrated in vacuo, diluted with dichloromethane and water. After phase separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by preparative HPLC (Method 5) affording 285 mg (0.62 mmol, 39% of th.) of the title compound.

[0429] LC-MS (Method 2): R.sub.t=0.84 min; MS [ESIpos]: m/z=458 (M+H).sup.+

[0430] .sup.1H-NMR (500 MHz, DMSO-d6) [ppm]: 7.72-7.77 (m, 2H), 7.60-7.64 (m, 2H), 6.89 (br. s., 1H), 4.80-4.89 (m, 2H), 4.25-4.33 (m, 1H), 3.98 (dd, 1H), 3.84 (dd, 1H), 3.26-3.34 (m, 4H), 1.88-1.93 (m, 4H)

Example 10A

Methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(2-fluorophenyl)-1H-1,2,4-triazole-5-carboxylate

[0431] ##STR00024##

[0432] A solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate (Example 7A, 1.00 g, 2.64 mmol) in tetrahydrofuran (20 ml) was cooled to 0 C. and treated with methyl chloro(oxo)acetate (270 l, 2.9 mmol) followed by N,N-diisopropylethylamine (0.5 ml, 2.9 mmol). The resulting mixture was stirred for 30 min. (2-Fluorophenyl)hydrazine hydrochloride (1:1) (472 mg, 2.90 mmol) and N,N-diisopropylethylamine (0.5 ml, 2.9 mmol) were added, the reaction mixture was warmed up to room temperature and stirred for 30 min, followed by 2 h at 80 C. in a sealed vial under microwave irradiation. The reaction mixture was evaporated and the crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 983 mg (67% of th.) of the title compound.

[0433] LC-MS (Method 3): R.sub.t=1.94 min; MS (ESIpos): m/z=541 [M+H].sup.+

[0434] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 3.776 (1.07), 3.793 (16.00), 3.823 (0.85), 3.847 (0.93), 3.859 (1.17), 3.883 (1.27), 3.991 (1.20), 3.999 (1.35), 4.028 (0.85), 4.036 (0.81), 5.182 (8.11), 6.902 (2.22), 6.918 (2.23), 7.379 (0.90), 7.398 (2.00), 7.417 (1.18), 7.473 (0.83), 7.495 (1.40), 7.520 (1.09), 7.615 (4.48), 7.620 (2.00), 7.631 (2.65), 7.636 (6.14), 7.643 (1.67), 7.649 (1.19), 7.658 (1.19), 7.663 (1.16), 7.677 (1.69), 7.681 (1.57), 7.696 (0.82), 7.701 (0.77), 7.751 (5.34), 7.756 (1.88), 7.767 (1.57), 7.772 (3.95).

Example 11A

5-(4-Chlorophenyl)-2-{[1-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0435] ##STR00025##

[0436] A solution of methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(2-fluorophenyl)-1H-1,2,4-triazole-5-carboxylate (Example 10A, 900 mg, 1.66 mmol) in tetrahydrofuran (42 ml) was treated with an aqueous sodium hydroxid solution (21 ml, 1.0 M, 21 mmol) and stirred for 10 min. The pH of the reaction mixture was adjusted to pH=1 with aqueous hydrochlorid acid (1 M) and stirred for 10 min. Ethyl acetate (20 ml) was added. Layers were separated and the aqueous layer was extracted with ethyl acetate. Combined organic extracts were washed with brine, dried over sodium sulfate and solvents were removed in vacuo. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 800 mg (quant.) of the title compound

[0437] LC-MS (Method 10): R.sub.t=1.32 min; MS (ESIpos): m/z=483 [M+H].sup.+

[0438] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.08), 0.008 (0.91), 1.157 (1.43), 1.175 (2.88), 1.193 (1.46), 1.988 (5.29), 3.288 (1.65), 3.819 (1.58), 3.843 (1.78), 3.855 (2.27), 3.879 (2.50), 3.985 (2.27), 3.994 (2.52), 4.003 (0.67), 4.021 (2.76), 4.030 (1.56), 4.039 (1.43), 4.299 (1.25), 4.316 (1.15), 5.139 (16.00), 6.907 (4.44), 6.923 (4.48), 7.386 (1.26), 7.392 (1.00), 7.396 (1.28), 7.399 (1.81), 7.407 (2.45), 7.415 (1.67), 7.420 (1.77), 7.428 (1.88), 7.521 (4.05), 7.524 (4.60), 7.532 (2.84), 7.538 (3.20), 7.542 (2.51), 7.546 (2.95), 7.553 (3.64), 7.555 (3.87), 7.601 (1.11), 7.607 (7.65), 7.612 (2.88), 7.624 (3.60), 7.629 (10.71), 7.635 (1.53), 7.737 (2.04), 7.743 (10.79), 7.748 (3.51), 7.759 (4.61), 7.764 (8.13), 7.775 (3.37), 7.778 (3.25), 7.796 (1.87), 8.971 (5.16), 8.977 (5.17).

Example 12A

4-[(2S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

[0439] ##STR00026##

[0440] 5-(4-Chlorophenyl)-2-{[1-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 11A, 750 mg, 1.55 mmol), 1H-imidazole (529 mg, 7.77 mmol) and tert-butyl(dimethyl)silyl trifluoromethanesulfonate (780 l, 3.4 mmol) were dissolved in N,N-dimethylformamide (8.0 ml, 100 mmol) and stirred at room temperature for 16 h. The reaction mixture was heated to 60 C. for additional 16 h. After addition of tert-butyl(dimethyl)silyl trifluoromethanesulfonate (780 l, 3.4 mmol), the reaction mixture was heated to 60 C. for additional 16 h. The reaction mixture was evaporated and the crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 772 mg (83% of th.) of the title compound.

[0441] LC-MS (Method 10): R.sub.t=1.77 min; MS (ESIpos): m/z=443.2

Example 13A

2-{[5-Bromo-1-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0442] ##STR00027##

[0443] A solution of 4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 12A, 772 mg, 1.29 mmol) in tetrahydrofuran (20 ml) was treated with sodium hydride (310 mg, 60% purity, 7.76 mmol) and stirred for 5 min. 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (1.48 g, 5.17 mmol) was added and stirred for 2 h under reflux. Water was then added and the resulting mixture was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 860 mg (98% of th.) of the title compound which was directly submitted to the next step.

Example 14A

2-{[5-Bromo-1-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0444] ##STR00028##

[0445] A solution of 2-{[5-bromo-1-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-2-{[tertbutyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 13A, 860 mg, 1.27 mmol) in tetrahydrofuran (5.0 ml) was treated with a solution of tetra-n-butylammoniumfluoride in tetrahydrofuran (1.5 ml, 1.0 M, 1.5 mmol). The resulting mixture was stirred for 30 min at roomtemperature. Purification by preparative HPLC (Method 5) and lyophilisation of the product containing fractions afforded 510 mg (71% of th.) of the title compound.

[0446] LC-MS (Method 10): R.sub.t=1.30 min; MS (ESIpos): m/z=561 [M+H].sup.+, 563 [M+H].sup.+

[0447] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.041 (0.58), 0.008 (2.30), 0.842 (0.83), 3.287 (1.07), 3.819 (1.56), 3.843 (1.79), 3.855 (2.27), 3.879 (2.46), 3.986 (2.28), 3.995 (2.65), 4.023 (1.62), 4.031 (1.60), 4.291 (1.31), 4.307 (1.23), 5.119 (16.00), 6.895 (4.53), 6.910 (4.62), 7.430 (1.72), 7.447 (3.82), 7.468 (2.29), 7.548 (1.32), 7.552 (1.50), 7.571 (2.36), 7.574 (3.01), 7.577 (1.93), 7.596 (2.09), 7.599 (1.91), 7.611 (1.07), 7.617 (7.85), 7.622 (3.32), 7.634 (3.41), 7.639 (10.70), 7.645 (2.13), 7.674 (0.88), 7.678 (1.50), 7.686 (2.68), 7.691 (3.51), 7.696 (2.68), 7.706 (4.07), 7.709 (5.68), 7.714 (2.15), 7.719 (1.04), 7.725 (1.57), 7.728 (3.19), 7.748 (1.69), 7.754 (10.77), 7.759 (4.01), 7.771 (3.07), 7.776 (7.94), 7.782 (1.55).

Example 15A

Methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3-chloropyridin-2-yl)-1H-1,2,4-triazole-5-carboxylate

[0448] ##STR00029##

[0449] A solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate (Example 7A, 150 mg, 396 mol) in tetrahydrofuran (3 ml) was cooled to 0 C. and treated with methyl chloro(oxo)acetate (44 l, 480 mol). The resulting mixture was stirred for 30 min. 3-Chloro-2-hydrazinylpyridine (62.5 mg, 436 mol) and N,N-diisopropylethylamine (280 l, 1.6 mmol) were added, the reaction mixture was warmed up to room temperature and stirred for 1 h, followed by 1 h at 120 C. in a sealed vial under microwave irradiation. The reaction mixture was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 25.3 mg (11% of th.) of the title compound.

[0450] LC-MS (Method 3): R.sub.t=1.82 min; MS (ESIpos): m/z=558 [M+H].sup.+

[0451] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 1.141 (0.80), 1.237 (1.11), 2.085 (1.99), 3.288 (0.69), 3.311 (16.00), 3.822 (0.98), 3.846 (1.08), 3.859 (1.38), 3.883 (1.47), 3.991 (1.44), 3.999 (1.56), 4.028 (1.00), 4.036 (0.95), 4.297 (0.83), 4.315 (0.79), 5.218 (8.81), 6.907 (2.55), 6.923 (2.56), 7.614 (3.93), 7.636 (5.41), 7.749 (7.03), 7.760 (2.42), 7.771 (5.68), 7.780 (2.16), 8.324 (1.73), 8.327 (2.19), 8.344 (1.63), 8.347 (2.04), 8.599 (1.77), 8.603 (2.22), 8.611 (1.85), 8.614 (2.14).

Example 16A

5-(4-Chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0452] ##STR00030##

[0453] A solution of methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3-chloropyridin-2-yl)-1H-1,2,4-triazole-5-carboxylate (Example 15A, 180 mg, 322 mol) in tetrahydrofuran (12 ml) was treated with an aqueous sodium hydroxid solution (7.3 ml, 5.0 M, 37 mmol) and stirred for 10 min. The pH of the reaction mixture was adjusted to pH=1 with aqueous hydrochlorid acid (1 M) and stirred for 20 min. Ethyl acetate (20 ml) was added. Layers were separated and aqueous layer was extracted with ethyl acetate. Combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 130 mg (81% of th.) of the title compound.

[0454] LC-MS (Method 10): R.sub.t=1.21 min; MS (ESIpos): m/z=500 [M+H].sup.+

[0455] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.20), 0.008 (1.24), 1.157 (0.88), 1.175 (1.77), 1.193 (0.90), 1.988 (3.25), 3.289 (1.71), 3.817 (1.56), 3.841 (1.77), 3.854 (2.25), 3.878 (2.45), 3.983 (2.24), 3.991 (2.51), 4.021 (2.17), 4.027 (1.55), 4.039 (0.87), 4.297 (1.25), 4.314 (1.19), 5.150 (16.00), 6.909 (4.56), 6.924 (4.58), 7.602 (1.17), 7.608 (8.03), 7.613 (3.03), 7.625 (3.53), 7.630 (11.04), 7.636 (1.68), 7.657 (3.81), 7.669 (3.90), 7.677 (3.98), 7.689 (4.10), 7.735 (1.85), 7.742 (11.09), 7.747 (3.46), 7.758 (3.07), 7.763 (7.91), 7.769 (1.08), 8.285 (3.90), 8.289 (4.12), 8.306 (3.75), 8.309 (3.73), 8.579 (3.99), 8.582 (4.05), 8.590 (3.99), 8.594 (3.78), 9.068 (10.80).

Example 17A

4-[(2S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

[0456] ##STR00031##

[0457] 5-(4-Chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 16A, 120 mg, 240 mol), 1H-imidazole (131 mg, 1.92 mmol) and tert-butyl(chloro)dimethylsilane (79.5 mg, 528 mol) were dissolved in N,N-dimethylformamide (4.0 ml) and stirred at room temperature for 16 h. The reaction mixture was heated to 60 C. for additional 16 h. After addition of tert-butyl(dimethyl)silyl trifluoromethanesulfonate (170 l, 720 mol), the reaction mixture was heated to 60 C. for additional 16 h. The reaction mixture was purified by preparative HPLC (Method 5).

[0458] Lyophilisation of the product containing fractions afforded 144 mg (97% of th.) of the title compound.

[0459] LC-MS (Method 3): R.sub.t=2.60 min; MS (ESIpos): m/z=614.1 [M+H].sup.+

Example 18A

2-{[5-Bromo-1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0460] ##STR00032##

[0461] A solution of 4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 17A, 140 mg, 228 mol) in tetrahydrofuran (17 ml) was treated with sodium hydride (54.7 mg, 60% purity, 1.37 mmol) and stirred for 5 min. 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (261 mg, 911 mol) was added and stirred for 5 h under reflux. 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (261 mg, 911 mol) was added and the reaction mixture was stirred for 5 h under reflux and 72 h at room temperature. Water was added and the resulting mixture was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 148 mg (94% of th.) of the title compound.

[0462] LC-MS (Method 3): R.sub.t=2.75 min; MS (ESIpos): m/z=703 [M+H].sup.+, 705 [M+H].sup.+

[0463] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.227 (5.46), 0.013 (4.25), 0.706 (1.40), 0.714 (16.00), 5.142 (1.32), 5.163 (1.32), 7.633 (1.24), 7.655 (1.89), 7.735 (1.94), 7.756 (1.25), 7.790 (0.61), 7.801 (0.62), 7.810 (0.64), 7.822 (0.66), 8.376 (0.64), 8.380 (0.67), 8.397 (0.61), 8.401 (0.61), 8.666 (0.64), 8.670 (0.65), 8.678 (0.64), 8.682 (0.62).

Example 19A

Methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3-fluoropyridin-2-yl)-1H-1,2,4-triazole-5-carboxylate

[0464] ##STR00033##

[0465] A solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate (Example 7A, 1.00 g, 2.64 mmol) in tetrahydrofuran (20 ml) was cooled to 0 C. and treated with methyl chloro(oxo)acetate (270 l, 2.9 mmol). The resulting mixture was stirred for 30 min. 3-Fluoro-2-hydrazinylpyridine (369 mg, 2.90 mmol) and N,N-diisopropylethylamine (510 l, 2.9 mmol) were added, the reaction mixture was warmed up to room temperature and stirred for 1 h, followed by 1 h at 120 C. in a sealed vial under microwave irradiation. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 680 mg (48% of th.) of the title compound.

[0466] LC-MS (Method 3): R.sub.t=1.78 min; MS (ESIpos): m/z=542 [M+H].sup.+

[0467] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 3.808 (16.00), 3.821 (1.05), 3.844 (0.95), 3.857 (1.15), 3.881 (1.24), 3.990 (1.20), 3.998 (1.28), 4.027 (0.81), 4.035 (0.78), 5.217 (8.13), 6.907 (2.33), 6.923 (2.34), 7.614 (3.78), 7.618 (1.47), 7.630 (1.62), 7.635 (5.20), 7.751 (5.36), 7.756 (1.78), 7.768 (1.53), 7.773 (3.96), 7.794 (0.74), 7.806 (1.20), 7.816 (1.57), 7.827 (1.42), 7.837 (0.87), 8.135 (0.90), 8.138 (0.95), 8.156 (1.02), 8.159 (1.71), 8.162 (1.23), 8.180 (0.81), 8.184 (0.82), 8.485 (1.74), 8.496 (1.69).

Example 20A

5-(4-Chlorophenyl)-2-{([1-(3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0468] ##STR00034##

[0469] A solution of methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3-fluoropyridin-2-yl)-1H-1,2,4-triazole-5-carboxylate (Example 19A, 700 mg, 80% purity, 1.03 mmol) in tetrahydrofuran (10 ml) was treated with an aqueous sodium hydroxid solution (1.6 ml, 1.0 M, 1.6 mmol) and stirred for 10 min. The pH of the reaction mixture was adjusted to pH=1 with aqueous hydrochlorid acid (1 M) and stirred for 10 min. Ethyl acetate (20 ml) was added. Layers were separated and aqueous layer was extracted with ethyl acetate. Combined organic extracts were washed with brine, dried with sodium sulfate and solvents were removed in vacuo. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 490 mg (88% of th.) of the title compound

[0470] LC-MS (Method 3): R.sub.t=1.68 min; MS (ESIpos): m/z=484 [M+H].sup.+

[0471] .sup.1H-NMR (500 MHz, DMSO-d6) [ppm]: 0.007 (1.02), 0.007 (0.97), 3.289 (0.87), 3.825 (1.64), 3.844 (1.82), 3.854 (2.20), 3.874 (2.32), 3.989 (2.30), 3.996 (2.50), 4.018 (1.65), 4.025 (1.60), 4.290 (0.79), 4.303 (1.25), 4.309 (1.10), 4.316 (1.16), 5.157 (16.00), 5.640 (0.95), 6.916 (4.36), 6.929 (4.41), 7.599 (0.78), 7.603 (1.35), 7.608 (8.01), 7.612 (3.52), 7.616 (1.62), 7.621 (3.48), 7.625 (10.23), 7.630 (1.75), 7.648 (1.59), 7.656 (2.01), 7.657 (2.13), 7.665 (3.28), 7.672 (2.21), 7.674 (2.40), 7.682 (1.79), 7.696 (0.74), 7.738 (1.68), 7.743 (9.92), 7.747 (3.63), 7.756 (3.08), 7.760 (7.70), 7.765 (1.29), 8.088 (1.84), 8.091 (2.00), 8.105 (1.90), 8.107 (2.39), 8.109 (2.49), 8.112 (2.16), 8.126 (1.76), 8.129 (1.84), 8.439 (3.75), 8.441 (2.79), 8.448 (3.68), 8.451 (2.59), 9.160 (8.72).

Example 21A

4-[(2S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

[0472] ##STR00035##

[0473] 5-(4-Chlorophenyl)-2-{[1-(3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 20A, 482 mg, 995 mol), 1H-imidazole (203 mg, 2.99 mmol) and tert-butyl(dimethyl)silyl trifluoromethanesulfonate (340 l, 1.5 mmol) were dissolved in N,N-dimethylformamide (8.0 ml) and stirred at room temperature for 16 h. The reaction mixture was heated to 60 C. for additional 16 h. After addition of tertbutyl(dimethyl)silyl trifluoromethanesulfonate (340 l, 1.5 mmol) the reaction mixture was heated to 60 C. for additional 16 h. The reaction mixture was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 468 mg (78% of th.) of the title compound.

[0474] LC-MS (Method 3): R.sub.t=2.57 min; MS (ESIpos): m/z=598.2 [M+H].sup.+

Example 22A

2-{[5-Bromo-1-(3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0475] ##STR00036##

[0476] A solution of 4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 21A, 465 mg, 777 mol) in tetrahydrofuran (17 ml) was treated with sodium hydride (111 mg, 60%, 4.7 mmol) and stirred for 5 min. 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (889 mg, 3.11 mmol) was added and stirred for 5 h under reflux. 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (889 mg, 3.11 mmol) was added and the reaction mixture was stirred for 5 h under reflux and 72 h at room temperature. Water was added and the resulting mixture was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 303 mg (57% of th.) of the title compound which was directly submitted to the next step.

[0477] LC-MS (Method 3): R.sub.t=2.67 min; MS (ESIpos): m/z=676 [M+H].sup.+

Example 23A

2-{[5-Bromo-1-(3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0478] ##STR00037##

[0479] A solution of 2-{[5-bromo-1-(3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-2-{[tertbutyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 22A, 302 mg, 446 mol) in tetrahydrofuran (6.0 ml) was treated with a solution of tetra-N-butylammoniumfluoride in tetrahydrofuran (540 l, 1.0 M, 540 mol) and stirred for 30 min at room temperature. The reaction mixture was evaporated and the residue was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 218 mg (87% of th.) of the title compound.

[0480] LC-MS (Method 3): R.sub.t=1.84 min; MS (ESIpos): m/z=562 [M+H].sup.+

[0481] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.041 (1.95), 0.008 (1.44), 0.008 (1.18), 0.842 (2.83), 3.815 (1.56), 3.839 (1.75), 3.852 (2.21), 3.876 (2.41), 3.984 (2.34), 3.992 (2.64), 4.020 (1.70), 4.029 (1.61), 4.299 (1.07), 5.148 (16.00), 6.898 (1.77), 6.913 (1.78), 7.609 (1.02), 7.615 (8.12), 7.620 (2.87), 7.631 (3.34), 7.636 (11.08), 7.643 (1.51), 7.746 (1.68), 7.752 (11.13), 7.757 (3.47), 7.769 (2.91), 7.774 (7.98), 7.780 (1.08), 7.838 (1.56), 7.848 (2.43), 7.859 (3.42), 7.870 (2.83), 7.880 (1.91), 8.190 (1.94), 8.194 (2.02), 8.212 (2.27), 8.215 (3.69), 8.218 (2.45), 8.236 (1.78), 8.239 (1.79), 8.558 (3.72), 8.570 (3.63).

Example 24A

Methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-phenyl-1H-1,2,4-triazole-5-carboxylate

[0482] ##STR00038##

[0483] A solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate (Example 7A, 300 mg, 792 mol) in tetrahydrofuran (6 ml) was cooled to 0 C. and treated with methyl chloro(oxo)acetate (80 l, 870 mol). The resulting mixture was stirred for 30 min. Phenylhydrazine (86 l, 870 mol) and N,N-diisopropylethylamine (150 l, 870 mol) were added, the reaction mixture was warmed up to room temperature and stirred for 1 h, followed by 1 h at 120 C. in a sealed vial under microwave irradiation. The reaction mixture was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 347 mg (84% of th.) of the title compound.

[0484] LC-MS (Method 3): R.sub.t=1.31 min; MS (ESIpos): m/z=523 [M+H].sup.+

[0485] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.05), 1.157 (1.22), 1.175 (2.47), 1.192 (1.26), 1.988 (4.57), 3.288 (0.82), 3.777 (16.00), 3.820 (0.81), 3.844 (0.90), 3.857 (1.15), 3.881 (1.24), 3.988 (1.12), 3.996 (1.28), 4.021 (1.42), 4.033 (0.83), 4.038 (1.30), 5.153 (7.84), 6.904 (2.25), 6.920 (2.27), 7.522 (1.30), 7.526 (1.70), 7.534 (3.96), 7.540 (7.60), 7.547 (3.74), 7.552 (4.57), 7.560 (2.14), 7.572 (1.28), 7.577 (0.94), 7.612 (3.85), 7.617 (1.46), 7.628 (1.60), 7.633 (5.25), 7.749 (5.32), 7.754 (1.71), 7.765 (1.44), 7.770 (3.89).

Example 25A

5-(4-Chlorophenyl)-2-[(1-phenyl-1H-1,2,4-triazol-3-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0486] ##STR00039##

[0487] A solution of methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-phenyl-1H-1,2,4-triazole-5-carboxylate (Example 24A, 300 mg, 574 mol) in tetrahydrofuran (14 ml) was treated with an aqueous sodium hydroxid solution (1.4 ml, 5.0 M, 7.2 mmol) and stirred for 10 min. The pH of the reaction mixture was adjusted to pH=1 with aqueous hydrochlorid acid (1 M) and stirred for 20 min. Ethyl acetate (20 ml) was added. Layers were separated and aqueous layer was extracted with ethyl acetate. Combined organic extracts were washed with brine, dried over sodium sulfate and solvents were removed in vacuo. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 254 mg (95% of th.) of the title compound.

[0488] LC-MS (Method 10): R.sub.t=1.28 min; MS (ESIpos): m/z=509 [M+H].sup.+

[0489] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.99), 0.008 (2.07), 1.175 (0.78), 1.356 (2.57), 1.909 (2.75), 1.988 (1.12), 3.820 (1.56), 3.844 (1.77), 3.857 (2.29), 3.881 (2.50), 3.987 (2.30), 3.995 (2.59), 4.023 (1.72), 4.032 (1.60), 4.301 (1.18), 4.317 (1.12), 5.122 (16.00), 6.909 (3.55), 6.924 (3.56), 7.402 (1.55), 7.421 (4.09), 7.437 (1.54), 7.440 (2.64), 7.539 (4.72), 7.543 (2.24), 7.559 (7.46), 7.573 (1.57), 7.578 (4.21), 7.596 (0.98), 7.603 (7.86), 7.607 (2.98), 7.619 (3.26), 7.624 (10.98), 7.630 (1.65), 7.733 (1.57), 7.739 (10.90), 7.744 (3.49), 7.756 (2.93), 7.761 (8.08), 7.767 (1.11), 7.820 (7.57), 7.834 (1.94), 7.839 (6.75), 7.842 (5.29), 9.242 (11.46).

Example 26A

4-[(2S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-[(1-phenyl-1H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0490] ##STR00040##

[0491] 5-(4-Chlorophenyl)-2-[(1-phenyl-1H-1,2,4-triazol-3-yl)methyl]-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 25A, 240 mg, 516 mol), 1H-imidazole (105 mg, 1.55 mmol) and tert-butyl(chloro)dimethylsilane (117 mg, 774 mol) were dissolved in N,N-dimethylformamide (4.0 ml, 52 mmol) and stirred at room temperature for 16 h. The reaction mixture was heated to 60 C. for additional 16 h. After addition of tertbutyl(dimethyl)silyl trifluoromethanesulfonate (140 l, 620 mol) the reaction mixture was heated to 60 C. for additional 16 h. The reaction mixture was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 236 mg (79% of th.) of the title compound which was directly submitted to the next step.

Example 27A

2-[(5-Bromo-1-phenyl-1H-1,2,4-triazol-3-yl)methyl]-4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0492] ##STR00041##

[0493] A solution of [4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-[(1-phenyl-1H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 26A, 236 mg, 408 mol) in tetrahydrofuran (17 ml) was treated with sodium hydride (350 l, 7.0 M, 2.4 mmol) and stirred for 5 min. 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (466 mg, 1.63 mmol) was added and stirred for 5 h under reflux. 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (466 mg, 1.63 mmol) was added and the reaction mixture was stirred for 5 h under reflux and 72 h at room temperature. Water was added and the reaction mixture was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 217 mg (80% of th.) of the title compound which was directly submitted to the next step.

Example 28A

Methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(pyridin-2-yl)-1H-1,2,4-triazole-5-carboxylate

[0494] ##STR00042##

[0495] A solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate (Example 7A; 1.00 g, 2.64 mmol) in tetrahydrofuran (20 ml) was cooled to 0 C. and treated with methyl chloro(oxo)acetate (270 l, 2.9 mmol). The resulting mixture was stirred for 30 min. 2-Hydrazinylpyridine hydrochloride (1:1) (423 mg, 2.90 mmol) and N,N-diisopropylethylamine (1.0 ml, 5.8 mmol) were added, the reaction mixture was warmed up to room temperature and stirred for 30 min, followed by 1 h at 120 C. in a sealed vial under microwave irradiation. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 483 mg (33% of th.) of the title compound.

[0496] LC-MS (Method 3): R.sub.t=1.79 min; MS (ESIpos): m/z=524 [M+H].sup.+

[0497] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 3.820 (0.78), 3.844 (1.02), 3.858 (16.00), 3.880 (1.25), 3.990 (1.15), 3.998 (1.28), 4.026 (0.81), 4.035 (0.78), 5.187 (7.66), 6.905 (2.15), 6.921 (2.27), 7.564 (1.07), 7.577 (1.17), 7.583 (1.19), 7.595 (1.26), 7.608 (3.70), 7.613 (1.40), 7.625 (1.82), 7.629 (4.90), 7.743 (0.97), 7.750 (5.02), 7.755 (1.55), 7.766 (1.45), 7.771 (3.70), 7.815 (1.92), 7.835 (2.21), 8.099 (0.94), 8.103 (0.94), 8.118 (1.49), 8.122 (1.54), 8.138 (0.77), 8.142 (0.75), 8.527 (1.25), 8.532 (1.40), 8.539 (1.33), 8.544 (1.33).

Example 29A

5-(4-Chlorophenyl)-2-{[1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0498] ##STR00043##

[0499] A solution of methyl 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(pyridin-2-yl)-1H-1,2,4-triazole-5-carboxylate (Example 28A, 435 mg, 830 mol) in tetrahydrofuran (5.0 ml) was treated with an aqueous sodium hydroxid solution (1.2 ml, 1.0 M, 1.2 mmol) and stirred for 5 min. The pH of the reaction mixture was adjusted to pH=1 with aqueous hydrochlorid acid (1 M) and stirred for 5 min. The reaction mixture was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 423 mg (98% of th.) of the title compound.

[0500] LC-MS (Method 3): R.sub.t=1.76 min; MS (ESIpos): m/z=466 [M+H].sup.+

[0501] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 3.291 (0.87), 3.824 (1.59), 3.847 (1.85), 3.859 (4.49), 3.884 (2.54), 3.990 (2.45), 3.999 (2.76), 4.027 (1.72), 4.035 (1.68), 4.289 (0.79), 4.305 (1.35), 4.313 (1.16), 4.322 (1.28), 5.153 (16.00), 5.187 (1.38), 6.920 (4.82), 6.936 (4.52), 7.474 (2.22), 7.486 (2.41), 7.493 (2.47), 7.505 (2.42), 7.596 (1.14), 7.603 (7.03), 7.607 (3.64), 7.619 (3.03), 7.624 (9.72), 7.630 (2.48), 7.736 (1.56), 7.742 (9.98), 7.759 (2.91), 7.763 (7.51), 7.771 (1.51), 7.822 (3.73), 7.843 (4.40), 8.056 (1.77), 8.061 (1.87), 8.076 (2.84), 8.080 (3.09), 8.096 (1.49), 8.099 (1.64), 8.532 (2.64), 8.534 (2.82), 8.537 (2.83), 8.544 (2.69), 8.546 (2.80), 8.549 (2.63), 9.337 (7.69).

Example 30A

4-[(2S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

[0502] ##STR00044##

[0503] 5-(4-Chlorophenyl)-2-{[1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 29A, 414 mg, 888 mol), 1H-imidazole (181 mg, 2.66 mmol) and tert-butyl(dimethyl)silyl trifluoromethanesulfonate (310 l, 1.3 mmol) were dissolved in N,N-dimethylformamide (7.0 ml, 91 mmol) and stirred at room temperature for 16 h. The reaction mixture was heated to 60 C. for additional 16 h. After addition of tert-butyl(dimethyl)silyl trifluoromethanesulfonate (310 l, 1.3 mmol) the reaction mixture was heated to 60 C. for additional 16 h. The reaction mixture was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 400 mg (78% of th.) of the title compound which was directly submitted to the next step.

[0504] LC-MS (Method 2): R.sub.t=1.38 min; MS (ESIpos): m/z=580 [M+H].sup.+

Example 31A

2-{[5-Bromo-1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0505] ##STR00045##

[0506] A solution of 4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 30A, 399 mg, 688 mol) in tetrahydrofuran (17 ml) was treated with sodium hydride (99 mg, 60%, 4.1 mmol) and stirred for 5 min. 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (787 mg, 2.75 mmol) was added and stirred for 5 h under reflux. 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (787 mg, 2.75 mmol) was added and the reaction mixture was stirred for 5 h under reflux and 72 h at room temperature. Water was added and the reaction mixture was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 288 mg (58% of th.) of the title compound which was directly submitted to the next step.

[0507] LC-MS (Method 3): R.sub.t=2.72 min; MS (ESIpos): m/z=658 [M+H].sup.+, 661 [M+H].sup.+

Example 32A

2-{[5-Bromo-1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0508] ##STR00046##

[0509] A solution of 2-{[5-bromo-1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-2-{[tertbutyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 31A, 288 mg, 402 mol) in tetrahydrofruan (5.0 ml) was treated with tetra-N-butylammoniumfluoride (480 l, 1.0 M, 480 mol). The resulting mixture was stirred for 30 min at room temperature. The reaction mixture was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 125 mg (53% of th.) of the title compound.

[0510] LC-MS (Method 3): R.sub.t=1.81 min; MS (ESIpos): m/z=544 [M+H].sup.+, 546 [M+H].sup.+

[0511] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.041 (1.78), 0.843 (2.61), 3.291 (1.16), 3.819 (1.64), 3.843 (1.89), 3.858 (3.76), 3.879 (2.55), 3.988 (2.34), 3.996 (2.65), 4.024 (1.67), 4.033 (1.60), 4.297 (1.29), 4.315 (1.22), 5.124 (16.00), 5.153 (0.78), 5.187 (1.12), 6.903 (4.64), 6.919 (4.87), 7.608 (3.83), 7.612 (9.77), 7.617 (3.38), 7.620 (3.14), 7.623 (3.39), 7.629 (6.34), 7.633 (11.66), 7.639 (3.80), 7.641 (3.23), 7.742 (0.80), 7.748 (2.04), 7.754 (11.52), 7.760 (6.94), 7.771 (3.60), 7.776 (8.87), 7.780 (5.92), 8.103 (2.27), 8.108 (2.24), 8.123 (3.41), 8.128 (3.32), 8.142 (1.88), 8.147 (1.83), 8.630 (2.81), 8.633 (2.83), 8.635 (2.66), 8.641 (2.44), 8.643 (2.84), 8.645 (2.67), 8.647 (2.44).

Example 33A

Methyl 1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazole-3-carboxylate

[0512] ##STR00047##

[0513] Methyl 1H-1,2,4-triazole-3-carboxylate (8.11 g, 63.8 mmol) was dissolved in N,N-dimethylformamide (41 ml) and cooled to 0 C. Sodium hydride (3.32 g, 60% purity, 82.9 mmol) was added and the reaction mixture was stirred for 30 min at 0 C. After 1,1,1-trifluoro-3-iodopropane (15.0 g, 67.0 mmol) was added and the resulting mixture was stirred for 16 h at room temperature. Saturated ammonium chloride solution and ethyl acetate were added. Layers were separated and aqueous layer was extracted with ethyl acetate. Combined organic extracts were washed with brine, dried over sodium sulfate and solvents were removed in vacuo. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 2.56 g (18% of th.) of the title compound

[0514] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 2.904 (0.96), 2.921 (2.07), 2.932 (2.97), 2.938 (1.52), 2.948 (5.97), 2.959 (3.22), 2.966 (3.45), 2.976 (5.83), 2.987 (1.41), 2.993 (3.06), 3.004 (1.93), 3.021 (0.94), 3.331 (1.18), 4.556 (8.10), 4.573 (16.00), 4.590 (7.72), 8.776 (11.85).

Example 34A

Methyl 5-bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazole-3-carboxylate

[0515] ##STR00048##

[0516] Methyl 1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazole-3-carboxylate (Example 33A, 1.30 g, 5.83 mmol), 1-bromopyrrolidine-2,5-dione (5.18 g, 29.1 mmol) and sodium hydride (699 mg, 60%, 17.5 mmol) were dissolved in tetrahydrofuran (33 ml, 400 mmol) and stirred at 60 C. for 16 h. Aqueous ammonium chloride solution and ethyl acetate were added. Layers were separated and aqueous layer was extracted with ethyl acetate. Combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 2.56 g (18% of th.) of the title compound

Example 35A

[5-Bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methanol

[0517] ##STR00049##

[0518] Methyl 5-bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazole-3-carboxylate (Example 34A, 2.00 g, 5.30 mmol) was dissolved in ethanol (20 ml, 340 mmol) and tetrahydrofuran (20 ml). Lithium chloride (1.12 g, 26.5 mmol) and sodium borohydride (1.00 g, 26.5 mmol) were added to the reaction mixture and stirred for 17 h at room temperature. The reaction mixture was diluted with ethyl acetate and saturated ammonium chloride solution and stirred for 30 min. Layers were separated and aqueous layer was extracted with ethyl acetate. Combined organic extracts were washed with brine, dried over magnesium sulfate and solvents were removed in vacuo. The crude product was triturated with ethyl acetate/diethyl ether (1/1) and a few drops of methanol. The organic layer was decanted of and dried in vacuo to afford the title product. The crude product was directly used in the next step.

Example 36A

4-[(2S)-2-{[Ttert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0519] ##STR00050##

[0520] To a solution of 5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (synthesis described as Example 5A in WO 2011/104622-A1, 5.00 g, 16.3 mmol) in 20 ml N,N-dimethylformamide was added tert-butyl(chloro)dimethylsilane (4.90 g, 32.5 mmol) and 1H-imidazole (4.43 g, 65.0 mmol). The mixture was stirred for 18 h at room temperature. To this mixture 80 ml of a saturated sodiumcarbonat solution were added and stirring was continued for 30 min. To this solution 1 N hydrochloric acid was added until pH 7 was reached. The mixture was extracted twice with 50 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, cyclohexane/ethyl acetate gradient) to afford 1.35 g (20% of th.) of the title compound.

[0521] LC-MS (Method 2): R.sub.t=1.33 min; MS (ESIpos): m/z=422 [M+H].sup.+

Example 37A

2-{[5-Bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0522] ##STR00051##

[0523] 4-[(2S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 36A, 924 mg, 2.19 mmol), [5-bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methanol (Example 35A, 400 mg, 1.46 mmol) and triphenylphosphine (459 mg, 1.75 mmol) were dissolved in tetrahydrofuran (12 ml, 150 mmol) and cooled down to 0 C. Dipropan-2-yl (E)-diazene-1,2-dicarboxylate (354 mg, 1.75 mmol) was added and the reaction mixture was stirred for 1 h at room temperature. Dipropan-2-yl (E)-diazene-1,2-dicarboxylate (174 mg, 0.88 mmol) was added and the reaction mixture was stirred for 20 min at 60 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 992 mg (66% of th.) of the title compound.

Example 38A

2-{[5-Bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0524] ##STR00052##

[0525] A solution of 2-{[5-bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-2-{[tertbutyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 37A, 941 mg, 1.39 mmol) in tetrahydrofuran (2.0 ml) was treated with a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1.7 ml, 1.0 M, 1.7 mmol). The reaction mixture was stirred for 1 h at room temperature and purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 358 mg (46% of th.) of the title compound

Example 39A

Methyl {4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetate

[0526] ##STR00053##

[0527] To a solution of 4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (synthesis described as Example 7A in WO 2011/104622-A1, 6.60 g, 15.6 mmol) in 50 ml acetonitrile was added caesium carbonate (6.12 g, 18.8 mmol) and dropwise methyl chloroacetate (1.5 ml, 17 mmol). The mixture was heated under reflux for 1 h and an additional 3 h at room temperature. To this mixture 80 ml water were added. The mixture was extracted twice with 50 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification. 8.32 g (quant.) of the title compound were obtained.

[0528] LC-MS (Method 2): R.sub.t=1.39 min; MS (ESIpos): m/z=494 [M+H].sup.+

Example 40A

2-[(5-Amino-4H-1,2,4-triazol-3-yl)methyl]-4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0529] ##STR00054##

[0530] To a solution of sodium methanolate (5.7 ml, 30% purity, 31 mmol) in 20 ml methanol was added hydrazinecarboximidamide hydrochloride (1:1) (3.40 g, 30.8 mmol) at room temperature. To this mixture, methyl {4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetate (Example 39A, 3.80 g, 7.69 mmol) dissolved in 10 ml methanol was. The mixture was heated to reflux for 45 min. After cooling to room temperature the solution was diluted with water, 10 ml of a saturated sodium carbonat solution were added and the mixture was extracted twice with 20 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, cyclohexane/ethyl acetate gradient) to afford 1.50 g (38% of th.) of the title compound.

[0531] LC-MS (Method 2): R.sub.t=1.14 min; MS (ESIpos): m/z=518 [M+H].sup.+

Example 41A

2-{[5-Amino-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0532] ##STR00055##

[0533] 2-[(5-Amino-4H-1,2,4-triazol-3-yl)methyl]-4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 40A, 500 mg, 965 mol), copper(II)acetate (263 mg, 1.45 mmol), 20 mg of molsieves 3A and (3-chlorophenyl)boronic acid (302 mg, 1.93 mmol) were stirred at 60 C. in 5 ml of pyridine for 10 h. After cooling to room temperature the mixture was filtered through a pad of celite. After elution with ethyl acetate, the organic phase was washed twice with water, dried over sodium sulfate, filtered and reduced in vacuo. The crude product was purified by chromatography (silica gel, cyclohexane/ethyl acetate gradient) to afford 464 mg (76% of th.) of the title compound.

[0534] LC-MS (Method 2): R.sub.t=1.39 min; MS (ESIpos): m/z=628 [M+H].sup.+

Example 42A

Ethyl N-[3-({4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3-chlorophenyl)-1H-1,2,4-triazol-5-yl]glycinate

[0535] ##STR00056##

[0536] A solution of 2-{[5-amino-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-2-{[tertbutyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 41A, 50.0 mg, 79.5 mol) in 1 ml of tetrahydrofuran was added slowly to a suspension of sodium hydride (6.36 mg, 60% purity, 159 mol) in 1 ml of tetrahydrofuran at 0 C. After stirring for 10 min, ethyl bromoacetate (11 l, 95 mol) was added and the reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with water and extracted twice with 20 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, cyclohexane/ethyl acetate gradient) to afford 25 mg (39% of th.) of the title compound.

[0537] LC-MS (Method 2): R.sub.t=1.48 min; MS (ESIpos): m/z=714 [M+H].sup.+

[0538] 1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.209 (5.30), 0.009 (5.92), 0.008 (1.78), 0.714 (1.45), 0.725 (16.00), 1.073 (1.77), 1.090 (3.63), 1.108 (1.92), 1.144 (1.71), 1.162 (3.54), 1.180 (1.76), 3.357 (0.64), 3.375 (1.86), 3.392 (1.83), 3.410 (0.59), 3.976 (0.54), 3.984 (1.13), 3.999 (1.15), 4.031 (0.52), 4.041 (0.47), 4.050 (0.55), 4.061 (0.54), 4.078 (1.80), 4.096 (1.54), 4.113 (0.50), 4.805 (0.43), 4.845 (1.12), 4.879 (1.17), 4.918 (0.45), 7.250 (0.59), 7.489 (0.86), 7.494 (0.68), 7.500 (0.55), 7.505 (0.74), 7.543 (0.88), 7.548 (1.97), 7.569 (0.92), 7.620 (1.35), 7.642 (2.07), 7.720 (1.98), 7.741 (1.26).

Example 43A

2-[(5-Amino-1H-1,2,4-triazol-3-yl)methyl]-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0539] ##STR00057##

[0540] At 0 C., to a solution of sodium methoxide (5.06 ml, 27.25 mmol, 30% in methanol, 5.4 M solution), in methanol (17 ml), was added portionwise aminoguanidine hydrochloride (3.012 g, 27.25 mmol). To this suspension was added dropwise a solution of methyl {3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetate (example 1A in WO 2016/071212 A1, 4.139 g, 10.90 mmol). The reaction mixture was stirred at room temperature for 10 min, then at reflux for 4 hours. After cooling, the reaction mixture was concentrated in vacuo, diluted with ethyl acetate and the resulting mixture was washed with saturated aqueous sodium carbonate solution. After phase separation, the organic phase was concentrated in vacuo and diluted with dichloromethane and aqueous hydrochloric acid (100 ml, 1 M). After additional phase separation, the organic phase was discarded. The remaining aqueous phase was slightly basified with aqueous sodium hydroxide and extracted twice with ethyl acetate. After phase separation, the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was dried under high vacuum, affording 3.25 g (8.05 mmol, 73.8% of Th.) of the title compound.

[0541] LC-MS (Method 2): R.sub.t=0.76 min; MS [ESIpos]: m/z=404 (M+H).sup.+

[0542] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 11.85 (br. s., 1H), 7.77-7.71 (m, 2H), 7.58-7.64 (m, 2H), 6.93 (d, 1H), 5.95 (br. s., 2H), 4.74 (br. s., 2H), 4.24-4.34 (m, 1H), 3.97 (dd, 1H), 3.82 (dd, 1H)

Example 44A

Ethyl 5-(dimethylamino)-1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate

[0543] ##STR00058##

[0544] In a sealed reaction vessel (stainless steel; 25 ml) a suspension of dimethylamine (6.02 mmol, 3.01 ml; 2 M in trahydrofuran), ethyl 5-bromo-1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (Example 52A, 0.86 g, 2.74 mmol) and potassium carbonate (1.25 g, 9.04 mmol) in acetonitrile (dry) (15 ml) was stirred at 50 C. overnight. Reaction mixture was allowed to cool to room temperature. Ethyl acetate (50 ml) and a mixture of water (10 ml) and brine (10 ml) were added. Layers were separated and aqueous layer was extracted with ethyl acetate (350 ml). Combined organic extracts were dried with sodium sulfate and solvents were removed in vacuo. 0.75 g (2.70 mmol; 98% of th.) of the title compound were obtained.

[0545] LC-MS (Method 1): R.sub.t=1.88 min; m/z=279 (M+H).sup.+

[0546] .sup.1H-NMR (300 MHz, DMSO-d6) [ppm]: 7.58-7.33 (m, 3H), 7.20-7.07 (m, 1H), 4.48 (q, 2H), 2.87 (s, 6H), 1.42 (t, 3H).

Example 45A

[5-(Dimethylamino)-1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl]methanol

[0547] ##STR00059##

[0548] Under nitrogen atmosphere at 0 C. lithium aluminum hydride (5.13 mmol, 2.14 ml; 2.4 M in tetrahydrofuran) was added to a solution of ethyl 5-(dimethylamino)-1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (Example 53A, 1.36 g, 4.89 mmol) in tetrahydrofuran (dry) (25 ml). Reaction mixture was stirred at 0 C. for 5 min. Reaction mixture was poured out in an ice cold mixture of saturated aqueous ammonium chloride (25 ml) and ethyl acetate (50 ml). Layers were separated. Organic layer was extracted with ethyl acetate (350 ml). Combined organic layers were dried with sodium sulfate and solvents were removed in vacuo. Flash column chromatography (Method 6; 80 g; dichloromethane, 3%-5% methanol) afforded 0.60 g (2.54 mmol; 52% of th.) of the title compound.

[0549] LC-MS (Method 1): R.sub.t=1.56 min; m/z=237 (M+H).sup.+

[0550] .sup.1H-NMR (300 MHz, DMSO-d6) [ppm]: 7.49-7.32 (m, 3H), 7.11-7.02 (m, 1H), 4.67 (s, 2H), 2.84 (s, 6H), 2.62-2.53 (m, 1H).

Example 46A

3-(Chloromethyl)-1-(3-fluorophenyl)-N,N-dimethyl-1H-1,2,4-triazol-5-amine

[0551] ##STR00060##

[0552] Under nitrogen atmosphere at 0 C. to a solution of [5-(dimethylamino)-1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl]methanol (Example 54A, 0.60 g, 2.54 mmol) in dichloromethane (25 ml) was added phosphorus pentachloride (1.06 g, 5.08 mmol). The reaction mixture was stirred at 0 C. for 5 min and was allowed to warm to room temperature. Stirring was continued overnight. Reaction mixture was poured out in a mixture of water (10 ml) and saturated aqueous sodium hydrogencarbonate (10 ml). Layers were separated and the aqueous layer was extracted with dichloromethane (330 ml). Combined organic layers were washed with water (210 ml) and dried with sodium sulfate. Solvents were removed in vacuo. Flash column chromatography (Method 6; 80 g; heptane, 20%-30% ethyl acetate) afforded 0.50 g (1.98 mmol; 78% of th.) of the title compound.

[0553] LC-MS (Method 7): R.sub.t=2.75 min; m/z=255 (M+H).sup.+

[0554] .sup.1H-NMR (300 MHz, DMSO-d6) [ppm]: 7.49-7.30 (m, 3H), 7.15-7.01 (m, 1H), 4.53 (s, 2H), 2.85 (s, 6H).

Example 47A

2-{[5-Amino-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0555] ##STR00061##

[0556] To a solution of 2-[(5-amino-1H-1,2,4-triazol-3-yl)methyl]-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 43A, 1.7 g, 4.21 mmol) in pyridine (13 ml) were added (3-chlorophenyl)boronic acid (1.317 g, 8.42 mmol) and copper(II) acetate (1.53 g, 8.42 mmol). The reaction mixture was stirred at room temperature for 5 days, then diluted with ethyl acetate and quenched with aqueous hydrochloric acid (1 M). After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was first purified by preparative HPLC [Chromatorex C18, 10 m, 12530 mm, water-acetonitrile-gradient 0.05% trifluoroacetic acid]. A second purification by preparative chiral SFC [sample preparation: 1.46 g (purity 90%) dissolved in 60 ml of a mixture of methanol/ethanol/acetonitrile; injection volume: 2 ml; column: Daicel Chiralcel OX-H 5 m, 25020 mm; eluent: carbon dioxide/methanol 70:30; flow rate: 80 ml/min; temperature: 40 C.; UV detection: 210 nm] afforded 1.10 g (2.04 mmol, 48.6% of th.) of the title compound.

[0557] LC-MS (Method 4): R.sub.t=3.06 min; MS [ESIpos]: m/z=514 (M+H).sup.+

[0558] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.72-7.78 (m, 2H), 7.60-7.64 (m, 2H), 7.58 (t, 1H), 7.49-7.56 (m, 2H), 7.41-7.45 (m, 1H), 6.90 (d, 1H), 6.64 (s, 2H), 4.79-4.89 (m, 2H), 4.24-4.35 (m, 1H), 3.99 (dd, 1H), 3.84 (dd, 1H)

Example 48A

Ethyl 5-(azetidin-1-yl)-1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate

[0559] ##STR00062##

[0560] Azetidine (0.46 g, 8.05 mmol, 0.54 ml) was added to a mixture ethyl 5-bromo-1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (Example 52A, 1.15 g, 3.66 mmol) and potassium carbonate (1.67 g, 12.08 mmol) in acetonitrile (dry) (40 ml). The reaction mixture was stirred at 50 C. overnight. Reaction mixture was allowed to cool to room temperature. Ethyl acetate (100 ml) and a mixture of water (25 ml) and brine (25 ml) were added. Layers were separated and aqueous layer was extracted with ethyl acetate (350 ml). Combined organic extracts were dried with sodium sulfate and solvents were removed in vacuo. 1.10 g (3.33 mmol; 91% of th.) of the title compound with a purity of 88% according to LC-MS were obtained.

[0561] LC-MS (Method 1): R.sub.t=1.89 min; m/z=291 (M+H).sup.+

Example 49A

[5-(Azetidin-1-yl)-1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl]methanol

[0562] ##STR00063##

[0563] Under nitrogen atmosphere at 0 C. lithium aluminum hydride (3.98 mmol, 1.66 ml; 2.4 M in tetrahydrofuran) was added drop wise to a solution of ethyl 5-(azetidin-1-yl)-1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (Example 48A, 1.10 g, 3.79 mmol) in tetrahydrofuran (20 ml). Reaction mixture was stirred at 0 C. for 5 min and was poured out in an ice cold mixture of saturated aqueous ammonium chloride (25 ml) and ethyl acetate (50 ml). Layers were separated. Organic layer was extracted with ethyl acetate (2100 ml). Combined organic layers were dried with sodium sulfate and solvents were removed in vacuo. Flash column chromatography (Method 6; 80 g; dichloromethane, 2%-4% methanol) afforded 0.69 g (2.79 mmol; 74% of th.) of the title compound.

[0564] LC-MS (Method 1): R.sub.t=1.60 min; m/z=249 (M+H).sup.+

Example 50A

5-(Azetidin-1-yl)-3-(chloromethyl)-1-(3-fluorophenyl)-1H-1,2,4-triazole

[0565] ##STR00064##

[0566] Under nitrogen atmosphere at 0 C. to a solution of [5-(azetidin-1-yl)-1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl]methanol (Example 49A, 0.69 g, 2.79 mmol) in dichloromethane (25 ml) was added phosphorus pentachloride (1.16 g, 5.58 mmol). The reaction mixture was stirred at 0 C. for 5 min and was allowed to warm to room temperature. Stirring was continued overnight. Reaction mixture was poured out in a mixture of water (10 ml) and saturated aqueous sodium hydrogencarbonate (10 ml). Layers were separated and the aqueous layer was extracted with dichloromethane (330 ml). Combined organic layers were washed with water (210 ml) and dried with sodium sulfate. Solvents were removed in vacuo. Flash column chromatography (Method 6; 80 g; heptane, 20%30% ethyl acetate) afforded 0.42 g (1.57 mmol; 56% of th.) of the title compound.

[0567] LC-MS (Method 7): R.sub.t=2.78 min; m/z=267 (M+H).sup.+

[0568] .sup.1H-NMR (300 MHz, DMSO-d6) [ppm]: 7.42 (td, 1H), 7.36-7.25 (m, 2H), 7.06 (tdd, 1H), 4.53 (s, 2H), 4.02-3.92 (m, 4H), 2.41-2.28 (m, 2H).

Example 51A

Ethyl 1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate

[0569] ##STR00065##

[0570] A solution of 3-fluoroaniline (5.80 g, 52.2 mmol, 5.0 ml) in a mixture of water (25 ml) and concentrated hydrochloric acid (15.43 g, 157 mmol, 15.28 ml) was cooled to 0 C. A solution of sodium nitrite (3.60 g, 52.2 mmol) in water (5 ml) was added maintaining the temperature between 0 C. and 5 C. Stirring was continued for 5 min at 0 C. This solution was added drop wise to a mixture of acetic acid sodium salt (27.8 g, 339 mmol) and ethyl 2-isocyanoacetate (5.31 g, 47.0 mmol, 5.13 ml) in a mixture of water (50 ml) and methanol (5 ml). The reaction mixture was stirred at 0 C. for 30 min and was allowed to warm to room temperature. Stirring was continued for 18 h. Ethyl acetate (100 ml) was added. Layers were separated. Aqueous layer was extracted with ethyl acetate (3100 ml). Combined organic extracts were dried with sodium sulfate and solvents were removed in vacuo. For purification the material was combined with a second batch of crude ethyl 1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate obtained from the conversion of 3-fluoroaniline (2.90 g, 26.1 mmol, 2.5 ml). Flash column chromatography (Method 6; 500 g; heptane, 10%-50% ethyl acetate) and subsequent trituration in diisopropyl ether afforded 6.91 g (29.4 mmol; 38% of th. based on 78.3 mmol) of the title compound.

[0571] LC-MS (Method 1): R.sub.t=1.81 min; m/z=252 (M+H).sup.+

[0572] .sup.1H-NMR (300 MHz, DMSO-d6) [ppm]: 9.50 (s, 1H), 7.90-7.76 (m, 2H), 7.66 (td, 1H), 7.42-7.29 (m, 1H), 4.40 (q, 2H), 1.36 (t, 3H).

Example 52A

Ethyl 5-bromo-1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate

[0573] ##STR00066##

[0574] In a 250 ml-round bottom flask under argon atmosphere sodium hydride (2.42 g, 60.6 mmol; 60% in mineral oil) was added to a suspension of ethyl 1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (Example 51A, 4.75 g, 20.2 mmol) and N-bromosuccinimide (18.0 g, 101 mmol) in tetrahydrofuran (dry) (100 ml). Reaction mixture was stirred at room temperature for 10 min and at reflux for 5 h. The mixture was allowed to cool to room temperature, diluted with ethyl acetate (100 ml) and was poured out in saturated aqueous ammonium chloride (100 ml). Layers were separated and aqueous layer was extracted with ethyl acetate (3100 ml). Combined organic layers were dried with sodium sulfate. Solvents were removed in vacuo. The residue was absorbed on isolute. Purification by flash column chromatography (Method 6; 500 g; heptane, 25%-35% ethyl acetate and Method 6; 500 g; heptane, 20%-35% ethyl acetate) afforded 4.49 g (24.3 mmol; 71% of th.) of the title compound.

[0575] LC-MS (Method 1): R.sub.t=1.94 min; m/z=314/316 (M+H).sup.+

[0576] 1H-NMR (300 MHz, DMSO-d6) [ppm]: 7.76-7.61 (m, 2H), 7.59-7.42 (m, 2H), 4.35 (q, 2H), 1.30 (t, 3H).

Example 53A

[5-Bromo-1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl]methanol

[0577] ##STR00067##

[0578] At 0 C. under nitrogen atmosphere to a solution of ethyl 5-bromo-1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (Example 52A, 4.38 g, 13.9 mmol) in a mixture of tetrahydrofuran (dry) (50 ml) and ethanol (abs) (50 ml) were added lithium chloride (2.36 g, 55.8 mmol) and sodium borohydride (2.11 g, 55.8 mmol). Reaction mixture was allowed to warm to room temperature and stirring was continued for 18 h. The reaction mixture was diluted with ethyl acetate (50 ml) and was poured out in aqueous saturated ammonium chloride. Layers were separated and aqueous layer was extracted with ethyl acetate (350 ml). Combined organic layers were dried with sodium sulfate and solvents were removed in vacuo. Reversed phase flash column chromatography (Method 8; 120 g) afforded 0.9 g (3.3 mmol; 24% of th.) of the title compound.

[0579] LC-MS (Method 1): R.sub.t=1.64 min; m/z=272/274 (M+H).sup.+

Example 54A

5-Bromo-3-(chloromethyl)-1-(3-fluorophenyl)-1H-1,2,4-triazole

[0580] ##STR00068##

[0581] Phosphorus pentachloride (1.4 g, 6.7 mmol) was added to a solution of 5-bromo-1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl]methanol (Example 53A, 0.9 g, 3.3 mmol) in dichloromethane (50 ml). The solution was stirred at room temperature for 1 h. The reaction mixture was washed with saturated aqueous ammonium chloride. The organic layer was dried with sodium sulfate and solvents were removed in vacuo. The crude product was absorbed on isolute. Purification by flash column chromatography (Method 6; 80 g; heptane, 0%-20% ethyl acetate) afforded 0.76 g (2.6 mmol; 79% of th.) of title compound.

[0582] LC-MS (Method 9): R.sub.t=3.38 min; m/z=290/292 (M+H).sup.+

[0583] .sup.1H-NMR (300 MHz, DMSO-d6) [ppm]: 7.71-7.43 (m, 4H), 4.81 (s, 2H).

Example 55A

Ethyl 1-(3-fluorophenyl)-5-(morpholin-4-yl)-1H-1,2,4-triazole-3-carboxylate

[0584] ##STR00069##

[0585] Under nitrogen atmosphere morpholine (0.50 g, 5.76 mmol, 0.50 ml) was added to a mixture of ethyl 5-bromo-1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (Example 52A, 1.72 g, 5.49 mmol) and potassium carbonate (0.76 g, 5.49 mmol) in dimethyl sulfoxide (dry) (20 ml). The reaction mixture was stirred at 50 C. overnight. Reaction mixture was allowed to cool to room temperature and was partitioned between water (10 ml) and a mixture of diethyl ether (100 ml) and ethyl acetate (20 ml). Layers were separated and aqueous layer was extracted with ethyl acetate (350 ml). Combined organic layers were dried with sodium sulfate. Solvents were removed in vacuo Purification by reversed phase flash column chromatography (Method 8; 120 g) afforded 1.05 g (3.28 mmol; 60% of th.) of the title compound.

[0586] LC-MS (Method 1): R.sub.t=1.86 min; m/z=321 (M+H).sup.+

[0587] .sup.1H-NMR (300 MHz, DMSO-d6) [ppm]: 7.56-7.43 (m, 3H), 7.13 (tdd, 1H), 4.49 (q, 2H), 3.78-3.71 (m, 4H), 3.28-3.19 (m, 4H), 1.43 (t, 3H).

Example 56A

[1-(3-Fluorophenyl)-5-(morpholin-4-yl)-1H-1,2,4-triazol-3-yl]methanol

[0588] ##STR00070##

[0589] At 0 C. under nitrogen atmosphere to a solution of ethyl 1-(3-fluorophenyl)-5-(morpholin-4-yl)-1H-1,2,4-triazole-3-carboxylate (Example 55A, 1.05 g, 3.28 mmol) in a mixture of tetrahydrofuran (dry) (10 ml) and ethanol (abs) (10 ml) were added lithium chloride (0.556 g, 13.11 mmol) and sodium borohydride (0.496 g, 13.11 mmol). Reaction mixture was allowed to warm to room temperature and stirring was continued overnight. Reaction mixture was diluted with tetrahydrofuran (dry) (10 ml) and ethanol (abs) (10 ml). Lithium chloride (1.668 g, 39.31 mmol) and sodium borohydride (1.488 g, 39.31 mmol) were added. Stirring at room temperature was continued for 48 h. Reaction mixture was diluted with ethyl acetate (20 ml) and was poured out in saturated aqueous ammonium chloride (20 ml). Layers were separated and aqueous layer was extracted with ethyl acetate (320 ml). Combined organic layers were dried with sodium sulfate and solvents were removed in vacuo. Residue was absorbed on isolute. Flash column chromatography (Method 6; 80 g; dichloromethane, 2%-4% methanol) afforded 0.56 g (2.00 mmol; 61% of th.) of the title compound.

[0590] LC-MS (Method 1): R.sub.t=1.61 min; m/z=279 (M+H).sup.+

[0591] .sup.1H-NMR (300 MHz, DMSO-d6) [ppm]: 7.54-7.39 (m, 3H), 7.07 (tdd, 1H), 4.69 (d, 2H), 3.80-3.72 (m, 4H), 3.19 (dd, 4H), 2.57 (t, 1H).

Example 57A

4-[3-(Chloromethyl)-1-(3-fluorophenyl)-1H-1,2,4-triazol-5-yl]morpholine

[0592] ##STR00071##

[0593] Under nitrogen atmosphere at 0 C. to a solution of [1-(3-fluorophenyl)-5-(morpholin-4-yl)-1H-1,2,4-triazol-3-yl]methanol (Example 56A, 0.55 g, 1.98 mmol) in dichloromethane (dry) (15 ml) was added phosphorus pentachloride (0.82 g, 3.95 mmol). The reaction mixture was stirred at 0 C. for 5 min and was allowed to warm to room temperature. Stirring was continued overnight. Reaction mixture was poured out in a mixture of ice-water (20 ml) and saturated aqueous sodium hydrogencarbonate (20 ml). Layers were separated and aqueous layer was extracted with dichloromethane (320 ml). Combined organic layers were washed with water (210 ml) and dried with sodium sulfate. Solvents were removed in vacuo. 0.57 g (1.92 mmol; 97% of th.) of the title compound were obtained.

[0594] LC-MS (Method 7): R.sub.t=2.73 min; m/z=297 (M+H).sup.+

[0595] .sup.1H-NMR (300 MHz, DMSO-d6) [ppm]: 7.57-7.40 (m, 3H), 7.16-7.04 (m, 1H), 4.56 (s, 2H), 3.80-3.71 (m, 4H), 3.27-3.18 (m, 4H).

EXPERIMENTAL SECTIONEXAMPLES

Example 1

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(2,2-dimethylpropyl)amino]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0596] ##STR00072##

[0597] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 100 mg, 173 mol) in acetonitrile (330 l) was treated with N,N-diisopropylethylamine (450 l, 2.6 mmol) and 2,2-dimethylpropan-1-amine (151 mg, 1.73 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation and evaporated. The residue was purified by preparative HPLC (Method 5) affording 65.5 mg (65% of th.) of the title compound.

[0598] LC-MS (Method 3): R.sub.t=2.14 min; MS (ESIpos): m/z=584.1 [M+H].sup.+

[0599] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.42-7.81 (m, 8H), 6.88 (d, 1H), 6.38 (t, 1H), 4.76-4.92 (m, 2H), 4.20-4.40 (m, 1H), 3.77-4.08 (m, 2H), 3.04 (br d, 2H), 0.83 (s, 9H).

Example 2

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[3-(methylsulfonyl)azetidin-1-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0600] ##STR00073##

[0601] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 100 mg, 173 mol) in acetonitrile (330 l) was treated with N,N-diisopropylethylamine (450 l, 2.6 mmol) and 3-(methylsulfonyl)azetidine (234 mg, 1.73 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation and evaporated. The residue was purified by preparative HPLC (Method 5) affording 21.2 mg (19% of th.) of the title compound.

[0602] LC-MS (Method 3): R.sub.t=1.74 min; MS (ESIpos): m/z=632.1 [M+H].sup.+

[0603] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.45-7.85 (m, 8H), 6.89 (d, 1H), 4.84-5.01 (m, 2H), 4.16-4.45 (m, 2H), 3.75-4.11 (m, 6H), 2.96 (s, 3H).

Example 3

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(3-fluoro-2,2-dimethylpropyl)amino]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0604] ##STR00074##

[0605] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 100 mg, 173 mol) in acetonitrile (330l) was treated with N,N-diisopropylethylamine (450 l, 2.6 mmol) and 3-fluoro-2,2-dimethylpropan-1-amine (182 mg, 1.73 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation. The reaction mixture was evaporated and purified by preparative HPLC (Method 5) affording 36.5 mg (35% of th.) of the title compound.

[0606] LC-MS (Method 3): R.sub.t=2.05 min; MS (ESIpos): m/z=602.1 [M+H].sup.+

[0607] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.43-7.80 (m, 8H), 6.87 (d, 1H), 6.49 (t, 1H), 4.76-4.93 (m, 2H), 4.44-4.22 (m, 1H), 4.12 (d, 2H), 3.73-4.03 (m, 2H), 3.17 (br d, 2H), 0.85 (2 s, 6H).

Example 4

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(2-methoxy-2-methylpropyl)amino]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0608] ##STR00075##

[0609] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 100 mg, 173 mol) in acetonitrile (330 l) was treated with N,N-diisopropylethylamine (450 l, 2.6 mmol) and 2-methoxy-2-methylpropan-1-amine (178 mg, 1.73 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation and evaporated. The residue was purified by preparative HPLC (Method 5) affording 82.5 mg (79% of th.) of the title compound.

[0610] LC-MS (Method 2): R.sub.t=1.05 min; MS (ESIpos): m/z=600.2 [M+H].sup.+

[0611] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.44-7.81 (m, 8H), 6.87 (d, 1H), 6.12 (t, 1H), 4.77-4.93 (m, 2H), 4.29 (br ddd, 1H), 3.78-4.08 (m, 2H), 3.30-3.19 (m, 2H, overlapping with HDO peak), 3.06 (s, 3H), 1.05 (s, 6H).

Example 5

3-{[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]amino}-2,2-dimethylpropanamide

[0612] ##STR00076##

[0613] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 100 mg, 173 mol) in acetonitrile (330 l) was treated with N,N-diisopropylethylamine (450 l, 2.6 mmol) and 3-amino-2,2-dimethylpropanamide (201 mg, 1.73 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation and evaporated. The residue was purified by preparative HPLC (Method 5), followed by a second preparative HPLC (Daicel Chiralcel OZ-H 5 m, 25020 mm, iso-hexane/ethanol: 55/45) and finally by preparative HPLC (Method 5) affording 30.4 mg (29% of th.) of the title compound.

[0614] LC-MS (Method 3): R.sub.t=1.67 min; MS (ESIpos): m/z=613.1 [M+H].sup.+

[0615] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.93-6.75 (m, 11H), 6.38-5.87 (m, 1H), 5.00-4.86 (m, 2H), 4.29 (br m, 1H), 4.07-3.69 (m, 2H), 3.49-3.16 (m, 2H, overlapping with HDO peak), 1.34-0.83 (m, 6H).

Example 6

2-{[5-{[2-Amino-3,3,3-trifluoropropyl]amino}-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomeric Mixture)

[0616] ##STR00077##

[0617] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 100 mg, 173 mol) in acetonitrile (330 l) was treated with N,N-diisopropylethylamine (450 l, 2.6 mmol) and 3,3,3-trifluoropropane-1,2-diamine dihydrochloride (174 mg, 865 mol). The resulting mixture was heated for 8 h at 180 C. under microwave irradiation and evaporated. The residue was purified by preparative HPLC (Method 5) affording 40.0 mg (37% of th.) of the title compound as a mixture of diastereomers.

[0618] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 31.2 mg dissolved in 2 ml 2-propanol; injection volume: 400 l; column: Daicel Chiralcel OZ-H 5 m, 25020 mm; eluent: iso-hexane/2-propanol 60:40; flow rate: 15 ml/min; temperature: 40 C.; UV detection: 220 nm]. After separation, 12 mg of diastereomer 1 (Example 7), which eluted first, and 13 mg of diastereomer 2 (Example 8), which eluted later, were isolated.

Example 7

2-{[5-{[2-Amino-3,3,3-trifluoropropyl]amino}-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomer 1)

[0619] Analytical chiral HPLC: R.sub.t=5.11 min, e.e.=100% [column: Daicel Chiralcel OZ-H 5 m, 2504.6 mm; eluent: iso-hexane/2-propanol 50:50+0.2% diethylamine; flow rate: 1.0 ml/min; temperature: 45 C.; UV detection: 220 nm].

[0620] LC-MS (Method 3): R.sub.t=1.72 min; MS (ESIpos): m/z=625.1 [M+H].sup.+

[0621] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.81-7.43 (m, 8H), 6.91 (d, 1H), 6.59 (t, 1H), 4.89 (d, 2H), 4.42-4.19 (m, 1H), 4.09-3.75 (m, 2H), 3.63-3.44 (m, 2H), 3.23-3.05 (m, 1H), 1.99 (br d, 2H).

Example 8

2-{[5-{[2-Amino-3,3,3-trifluoropropyl]amino}-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomer 2)

[0622] Analytical chiral HPLC: R.sub.t=6.30 min, e.e.=100% [column: Daicel Chiralcel OZ-H 5 m, 2504.6 mm; eluent: iso-hexane/2-propanol 50:50+0.2% diethylamine; flow rate: 1.0 ml/min; temperature: 45 C.; UV detection: 220 nm].

[0623] LC-MS (Method 3): R.sub.t=1.73 min; MS (ESIpos): m/z=625.1 [M+H].sup.+

[0624] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.82-7.43 (m, 8H), 6.92 (d, 1H), 6.59 (br t, 1H), 4.96-4.80 (m, 2H), 4.29 (br ddd, 1H), 4.07-3.72 (m, 2H), 3.60-3.43 (m, 2H), 3.23-3.04 (m, 1H), 2.00 (br d, 2H).

Example 9

1-[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]-4,4-difluoro-L-prolinamide

[0625] ##STR00078##

[0626] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 100 mg, 173 mol) in acetonitrile (330 l) was treated with N,N-diisopropylethylamine (450 l, 2.6 mmol) and 4,4-difluoro-L-prolinamide hydrochloride (1:1) (323 mg, 1.73 mmol). The resulting mixture was heated for 16 h at 180 C. under microwave irradiation and diluted with DMSO. The solution was purified by preparative HPLC (Method 5) affording 43.5 mg (37% of th.) of the title compound.

[0627] LC-MS (Method 3): R.sub.t=1.79 min; MS (ESIpos): m/z=647.1 [M+H].sup.+

[0628] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.89-6.74 (m, 11H), 5.09-4.67 (m, 2H), 4.63-4.17 (m, 2H), 4.06-3.72 (m, 2H), 3.69-3.34 (m, 2H, overlapping with HDO), 2.96-2.59 (m, 1H), 2.44-2.16 (m, 1H).

Example 10

1-[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]-4,4-difluoro-D-prolinamide

[0629] ##STR00079##

[0630] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 100 mg, 173 mol) in acetonitrile (330 l) was treated with N,N-diisopropylethylamine (450 l, 2.6 mmol) and 4,4-difluoro-D-prolinamide hydrochloride (1:1) (323 mg, 1.73 mmol). The resulting mixture was heated for 16 h at 180 C. under microwave irradiation and evaporated. The residue was purified by preparative HPLC (Method 5) affording 50.9 mg (45% of th.) of the title compound.

[0631] LC-MS (Method 3): R.sub.t=1.78 min; MS (ESIpos): m/z=647.1 [M+H].sup.+

[0632] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.80-6.83 (m, 11H), 5.03-4.81 (m, 2H), 4.66-4.15 (m, 2H), 4.10-3.71 (m, 2H), 3.66-3.34 (m, 2H, overlapping with HDO peak), 2.94-2.62 (m, 1H), 2.45-2.19 (m, 1H).

Example 11

2-{[5-{[3-Amino-2-hydroxypropyl]amino}-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomeric Mixture)

[0633] ##STR00080##

[0634] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 300 mg, 519 mol) in acetonitrile (15 ml) was treated with N,N-diisopropylethylamine (190 l, 1.1 mmol) and 1,3-diaminopropan-2-ol (468 mg, 5.19 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation, combined with a 20 mg test reaction and evaporated. The residue was purified by preparative HPLC (Method 5) affording 246 mg (75% of th.) of the title compound as a mixture of diastereomers.

[0635] LC-MS (Method 3): R.sub.t=1.18 min; MS (ESIpos): m/z=587.1 [M+H].sup.+

[0636] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 8.31 (s, 1H), 7.87-7.38 (m, 8H), 6.70-6.49 (m, 1H), 5.08-4.71 (m, 2H), 4.51-3.54 (m, 4H), 3.40-3.06 (m, 2H), 2.82-2.59 (m, 1H).

Example 12

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-({[2-oxo-1,3-oxazolidin-5-yl]methyl}amino)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomeric Mixture)

[0637] ##STR00081##

[0638] A solution of 2-{[5-{[3-amino-2-hydroxypropyl]amino}-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 11, 233 mg, 0.40 mmol) in (3.1 ml) was treated with 1,1-carbonyldiimidazole (71 mg, 0.44 mmol). The resulting mixture was stirred 2 h at roomtemperature and heated at refluxed overnight. The reaction mixture was combined with a 10 mg test reaction, diluted with DMSO and purified by preparative HPLC (Method 5) affording 57 mg (23% of th.) of the title compound as a mixture of diastereomers.

[0639] LC-MS (Method 3): R.sub.t=1.60 min; MS (ESIpos): m/z=613.1 [M+H].sup.+

[0640] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]=7.79-7.43 (m, 9H), 6.93-6.77 (m, 2H), 4.97-4.79 (m, 2H), 4.74-4.61 (m, 1H), 4.29 (br ddd, 1H), 4.06-3.77 (m, 2H), 3.51-3.22 (m, 4H, overlapping with HDO peak).

Example 13

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomeric Mixture)

[0641] ##STR00082##

[0642] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (500 l) was treated with N,N-diisopropylethylamine (680 l, 3.9 mmol) and 3-(trifluoromethyl)pyrrolidin-3-ol hydrochloride (1:1) (497 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation and evaporated. The residue was purified by preparative HPLC (Method 5) affording 131 mg (77% of th.) of the title compound as a mixture of diastereomers.

[0643] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 111 mg dissolved in 4 ml ethanol; injection volume: 150 l; column: Daicel Chiralpak IA 5 m, 25020 mm; eluent: iso-hexane/ethanol 40:60; flow rate: 15 ml/min; temperature: 25 C.; UV detection: 210 nm]. After separation, 50 mg of diastereomer 1 (Example 14), which eluted first, and 52 mg of diastereomer 2 (Example 15), which eluted later, were isolated.

Example 14

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomer 1)

[0644] Analytical chiral HPLC: R.sub.t=2.29 min, e.e.=100% [column: Daicel Chiraltek IA 3 m, 1004.6 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 1.0 ml/min; temperature: 25 C.; UV detection: 220 nm].

[0645] LC-MS (Method 3): R.sub.t=1.94 min; MS (ESIpos): m/z=652.1 [M+H].sup.+

[0646] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.84-7.42 (m, 8H), 6.88 (d, 1H), 6.49 (s, 1H), 5.02-4.76 (m, 2H), 4.29 (br ddd, 1H), 4.10-3.71 (m, 2H), 3.47-3.13 (m, 4H, overlapping with HDO peak), 2.22-1.81 (m, 2H).

Example 15

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomer 2)

[0647] Analytical chiral HPLC: R.sub.t=4.21 min, e.e.=100% [column: Daicel Chiraltek IA 3 m, 1004.6 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 1.0 ml/min; temperature: 25 C.; UV detection: 220 nm].

[0648] LC-MS (Method 3): R.sub.t=1.94 min; MS (ESIpos): m/z=652.1 [M+H].sup.+

[0649] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.84-7.42 (m, 8H), 6.88 (d, 1H), 6.49 (s, 1H), 4.98-4.77 (m, 2H), 4.29 (br ddd, 1H), 4.06-3.76 (m, 2H), 3.43-3.17 (m, 4H, overlapping with HDO peak), 2.20-1.84 (m, 2H).

Example 16

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-{[2-oxopyrrolidin-3-yl]amino}-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomeric Mixture)

[0650] ##STR00083##

[0651] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 300 mg, 519 mol) in acetonitrile (2.0 ml) was treated with N,N-diisopropylethylamine (190 l, 1.1 mmol) and 3-aminopyrrolidin-2-one (519 mg, 5.19 mmol). The resulting mixture was heated for 5 h at 150 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 110 mg (33% of th.) of the title compound as a mixture of diastereomers.

[0652] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 100 mg dissolved in 4 ml acetonitrile; injection volume: 300 l; column: Daicel Chiralcel OX-H 5 m, 25020 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 20 ml/min; temperature: 25 C.; UV detection: 220 nm]. After separation, 24 mg of diastereomer 1 (Example 17), which eluted first, and 33 mg of diastereomer 2 (Example 18), which eluted later, were isolated.

Example 17

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-{[2-oxopyrrolidin-3-yl]amino}-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomer 1)

[0653] Analytical chiral HPLC: R.sub.t=1.94 min, e.e.=100% [column: Daicel Chiralcel OX 3 m, 504.6 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 1.0 ml/min; temperature: 25 C.; UV detection: 220 nm].

[0654] LC-MS (Method 3): R.sub.t=1.61 min; MS (ESIpos): m/z=597.1 [M+H].sup.+

[0655] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.83-7.44 (m, 9H), 6.89 (d, 1H), 6.70 (d, 1H), 4.95-4.76 (m, 2H), 4.41-4.21 (m, 2H), 4.05-3.77 (m, 2H), 3.14 (br dd, 2H), 2.41-2.26 (m, 1H), 1.98-1.82 (m, 1H).

Example 18

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-{[2-oxopyrrolidin-3-yl]amino}-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomer 2)

[0656] Analytical chiral HPLC: R.sub.t=2.648 min, e.e.=98.7% [column: Daicel Chiralcel OX 3 m, 504.6 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 1.0 ml/min; temperature: 25 C.; UV detection: 220 nm].

[0657] LC-MS (Method 3): R.sub.t=1.60 min; MS (ESIpos): m/z=597.1 [M+H].sup.+

[0658] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.82-7.43 (m, 9H), 6.89 (d, 1H), 6.70 (d, 1H), 4.86 (s, 2H), 4.40-4.21 (m, 2H), 4.06-3.78 (m, 2H), 3.15 (dd, 2H), 2.40-2.27 (m, 1H), 2.01-1.83 (m, 1H)

Example 19

tert-Butyl 4-({[1-(2-chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]amino}methyl)-4-hydroxyazepane-1-carboxylate (Diastereomeric Mixture)

[0659] ##STR00084##

[0660] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 200 mg, 346 mol) in acetonitrile (1.3 ml) was treated with N,N-diisopropylethylamine (130 l, 730 mol) and tert-butyl 4-(aminomethyl)-4-hydroxyazepane-1-carboxylate (532 mg, 2.18 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 81.3 mg (32% of th.) of the title compound as a mixture of diastereomers.

[0661] LC-MS (Method 3): R.sub.t=2.14 min; MS (ESIpos): m/z=741.2 [M+H].sup.+

[0662] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.83-7.44 (m, 8H), 6.88 (d, 1H), 6.28 (br d, 1H), 4.96-4.77 (m, 2H), 4.72-4.60 (m, 1H), 4.30 (br ddd, 1H), 4.04-3.77 (m, 2H), 3.60-2.92 (m, 6H, overlap with HDO peak), 1.97-1.16 (m, 15H).

Example 20

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-({4-hydroxyazepan-4-yl]methyl}amino)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomeric Mixture)

[0663] ##STR00085##

[0664] tert-Butyl 4-({[1-(2-chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]amino}methyl)-4-hydroxyazepane-1-carboxylate (Example 19, 200 mg, 270 mol) in a solution of hydrogen chloride in dioxane (5 ml, 4N, 20 mmol,) was stirred overnight at room temperature. The reaction mixture was evaporated and purified by preparative HPLC (Method 5) affording 52.4 mg (30% of th.) of the title compound as a mixture of diastereomers.

[0665] LC-MS (Method 12): R.sub.t=1.47 min; MS (ESIpos): m/z=641.0 [M+H].sup.+

[0666] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 8.36 (s, 1H), 7.86-7.43 (m, 8H), 6.33 (br t, 1H), 4.95-4.76 (m, 2H), 4.29 (br ddd, 1H), 4.06-3.72 (m, 2H), 3.31-3.11 (m, 2H, overlapping with HDO peak), 3.05-2.71 (m, 4H), 1.84-1.42 (m, 6H).

Example 21

tert-Butyl 4-({[1-(2-chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]amino}methyl)-4-hydroxypiperidine-1-carboxylate

[0667] ##STR00086##

[0668] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (1.0 ml) was treated with N,N-diisopropylethylamine (95 l, 540 mol) and tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (597 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 150 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 29.0 mg (15% of th.) of the title compound.

[0669] LC-MS (Method 3): R.sub.t=2.10 min; MS (ESIneg): m/z=725.1 [MH].sup.

[0670] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.83-7.37 (m, 8H), 6.88 (d, 1H), 6.32 (t, 1H), 5.01-4.63 (m, 3H), 4.30 (br ddd, 1H), 4.11-3.48 (m, 4H), 3.26-2.79 (m, 4H), 1.56-1.18 (m, 13H).

Example 22

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-{[(4-hydroxypiperidin-4-yl)methyl]amino}-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0671] ##STR00087##

[0672] tert-Butyl 4-({[1-(2-chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]amino}methyl)-4-hydroxypiperidine-1-carboxylate (Example 21, 30.0 mg, 41.2 mol) in a solution of hydrogen chloride in dioxane (5 ml, 4N, 20 mmol,) was stirred 72 h at room temperature. The reaction mixture was evaporated and purified by preparative HPLC (Method 5) affording 10.6 mg (41% of th.) of the title compound.

[0673] LC-MS (Method 2): R.sub.t=0.72 min; MS (ESIpos): m/z=627.4 [M+H].sup.+

[0674] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 8.35 (br s, 1H), 8.05-7.36 (m, 8H), 6.38 (t, 1H), 4.86 (d, 2H), 4.48-3.69 (m, 3H), 3.35-2.70 (m, 6H, overlapping with HDO), 1.75-1.24 (m, 4H).

Example 23

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(2,2-difluoropropyl)amino]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0675] ##STR00088##

[0676] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (1.0 ml) was treated with N,N-diisopropylethylamine (680 l, 3.9 mmol) and 2,2-difluoropropan-1-amine hydrochloride (1:1) (341 mg, 2.59 mmol). The resulting mixture was heated for 8 h at 180 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 43.6 mg (28% of th.) of the title compound.

[0677] LC-MS (Method 3): R.sub.t=1.93 min; MS (ESIpos): m/z=592.1 [M+H].sup.+

[0678] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.80-7.43 (m, 8H), 6.99 (t, 1H), 6.87 (d, 1H), 4.95-4.80 (m, 2H), 4.36-4.20 (m, 1H), 4.05-3.77 (m, 2H), 3.62 (td, 2H), 1.56 (t, 3H).

Example 24

N-(2-{[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]amino}ethyl)methanesulfonamide

[0679] ##STR00089##

[0680] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (1.0 ml, 19 mmol) was treated with N,N-diisopropylethylamine (680 l, 3.9 mmol) and N-(2-aminoethyl)methanesulfonamide hydrochloride (1:1) (453 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 112 mg (68% of th.) of the title compound.

[0681] LC-MS (Method 2): R.sub.t=0.94 min; MS (ESIpos): m/z=635.2 [M+H].sup.+

[0682] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.83-7.44 (m, 8H), 7.07-6.83 (m, 2H), 6.52 (t, 1H), 4.94-4.78 (m, 2H), 4.28 (br ddd, 1H), 4.09-3.75 (m, 2H), 3.46-2.99 (m, 4H, overlap with HDO peak), 2.86 (s, 3H).

Example 25

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-{[2-(1,1-dioxido-1,2-thiazinan-2-yl)ethyl]amino}-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0683] ##STR00090##

[0684] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (1.0 ml) was treated with N,N-diisopropylethylamine (95 l, 540 mol) and 2-(1,1-dioxido-1,2-thiazinan-2-yl)ethanamine (462 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 150 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 64.1 mg (37% of th.) of the title compound.

[0685] LC-MS (Method 2): R.sub.t=1.03 min; MS (ESIpos): m/z=675.0 [M+H].sup.+

[0686] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.83-7.43 (m, 8H), 6.88 (d, 1H), 6.52 (t, 1H), 4.95-4.78 (m, 2H), 4.30 (br ddd, 1H), 4.05-3.77 (m, 2H), 3.35-3.24 (m, 4H, overlapping with HDO peak), 3.22-3.14 (m, 2H), 3.05-2.97 (m, 2H), 2.05-1.79 (m, 2H), 1.54-1.37 (m, 2H).

Example 26

N-(1-{[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl-1H-1,2,4-triazol-5-yl]amino}-2-methylpropan-2-yl)methanesulfonamide

[0687] ##STR00091##

[0688] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (1.0 ml) was treated with N,N-diisopropylethylamine (680 l, 3.9 mmol) and N-(1-amino-2-methylpropan-2-yl)methanesulfonamide hydrochloride (1:1) (526 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 150 C. under microwave irradiation and diluted with methanol. The resulting solution was purified by preparative HPLC (Method 5) affording 106 mg (62% of th.) of the title compound.

[0689] LC-MS (Method 2): R.sub.t=1.03 min; MS (ESIpos): m/z=663.0 [M+H].sup.+

[0690] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.81-7.44 (m, 8H), 6.98-6.78 (m, 2H), 6.43 (t, 1H), 4.95-4.76 (m, 2H), 4.28 (br ddd, 1H), 4.05-3.75 (m, 2H), 3.41-3.16 (m, 2H, overlap with water peak), 2.88 (s, 3H), 1.23 (s, 6H).

Example 27

2-{[5-{[2-Amino-3,3,3-trifluoro-2-methylpropyl]amino}-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomeric Mixture)

[0691] ##STR00092##

[0692] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (1.0 ml) was treated with N,N-diisopropylethylamine (680 l, 3.9 mmol) and 3,3,3-trifluoro-2-methylpropane-1,2-diamine hydrochloride (1:1) (463 mg, 2.59 mmol). The resulting mixture was heated for 8 h at 180 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 48.9 mg (29% of th.) of the title compound as a diastereomeric mixture.

[0693] LC-MS (Method 3): R.sub.t=1.78 min; MS (ESIpos): m/z=639.1 [M+H].sup.+

[0694] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.79-7.45 (m, 8H), 6.94 (br d, 1H), 6.51-6.39 (m, 1H), 4.97-4.78 (m, 2H), 4.29 (br ddd, 1H), 4.06-3.75 (m, 2H), 3.46-3.36 (m, 2H, overlapping with HDO peak), 2.16 (br. s, 2H), 1.11 (s, 3H).

Example 28

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[4-hydroxy-4-(trifluoromethyl)piperidin-1-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0695] ##STR00093##

[0696] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (1.0 ml) was treated with N,N-diisopropylethylamine (95 l, 540 mol) and 4-(trifluoromethyl)piperidin-4-ol (439 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 119 mg (69% of th.) of the title compound.

[0697] LC-MS (Method 3): R.sub.t=2.10 min; MS (ESIpos): m/z=666.1 [M+H].sup.+

[0698] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.84-7.42 (m, 8H), 6.87 (d, 1H), 6.02 (s, 1H), 5.05-4.72 (m, 2H), 4.29 (br ddd d, 1H), 4.09-3.72 (m, 2H), 3.51-3.19 (m, 2H, overlapping with HDO peak), 3.14-2.75 (m, 2H), 1.95-1.24 (m, 4H).

Example 29

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[3-hydroxy-3-methylpyrrolidin-1-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomeric Mixture)

[0699] ##STR00094##

[0700] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (1.5 ml) was treated with N,N-diisopropylethylamine (95 l, 540 mol) and 3-methylpyrrolidin-3-ol (262 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 150 C. under microwave irradiation. The reaction mixture was purified by preparative HPLC (Method 5) affording 92.1 mg (59% of th.) of the title compound as a mixture of diastereomers.

[0701] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 61 mg dissolved in 5 ml ethanol; injection volume: 500 l; column: Daicel Chiralcel OX-H 5 m, 25020 mm; eluent: iso-hexane/ethanol 40:60; flow rate: 15 ml/min; temperature: 25 C.; UV detection: 210 nm]. After separation, 21 mg of diastereomer 1 (Example 30), which eluted first, and 20 mg of diastereomer 2 (Example 31), which eluted later, were isolated.

Example 30

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[3-hydroxy-3-methylpyrrolidin-1-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomer 1)

[0702] Analytical chiral HPLC: R.sub.t=2.43 min, e.e.=99.0% [column: Daicel Chiralcel OX 3 m, 504.6 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 1.0 ml/min; temperature: 25 C.; UV detection: 220 nm].

[0703] LC-MS (Method 3): R.sub.t=1.75 min; MS (ESIpos): m/z=598.1 [M+H].sup.+

[0704] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.92-7.39 (m, 8H), 6.88 (d, 1H), 4.97-4.61 (m, 3H), 4.29 (br ddd, 1H), 4.10-3.71 (m, 2H), 3.28-2.78 (m, 4H, overlapping with HDO peak), 1.79-1.61 (m, 2H), 1.17 (s, 3H).

Example 31

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[3-hydroxy-3-methylpyrrolidin-1-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomer 2)

[0705] Analytical chiral HPLC: R.sub.t=4.03 min, e.e.=97.6% [column: Daicel Chiralcel OX 3 m, 504.6 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 1.0 ml/min; temperature: 25 C.; UV detection: 220 nm].

[0706] LC-MS (Method 2): R.sub.t=0.97 min; MS (ESIpos): m/z=598.3 [M+H].sup.+

[0707] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.80-7.43 (m, 8H), 6.88 (d, 1H), 4.92-4.69 (m, 3H), 4.29 (br ddd, 1H), 4.06-3.78 (m, 2H), 3.30-2.82 (m, 4H, overlapping with HDO peak), 1.74-1.66 (m, 2H), 1.17 (s, 3H).

Example 32

2-({5-[(2-Amino-2-methylpropyl)amino]-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl}methyl)-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0708] ##STR00095##

[0709] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 1.50 g, 2.59 mmol) in acetonitrile (10 ml) was treated with N,N-diisopropylethylamine (950 l, 5.4 mmol) and 2-methylpropane-1,2-diamine (2.7 ml, 26 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation. The reaction mixture was purified by preparative HPLC (Method 5) affording 1.32 g (82% of th.) of the title compound.

[0710] LC-MS (Method 12): R.sub.t=1.51 min; MS (ESIpos): m/z=585.0 [M+H].sup.+

[0711] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 8.28 (br s, 1H), 7.85-7.38 (m, 8H), 6.67 (br t, 1H), 4.96-4.76 (m, 2H), 4.30 (br ddd, 1H), 4.07-3.74 (m, 2H), 3.70-2.95 (m, 2H, overlapping with HDO peak), 1.08 (s, 6H).

Example 33

4-[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]piperazine-2-carboxamide (Diastereomeric Mixture)

[0712] ##STR00096##

[0713] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (500 l) was treated with N,N-diisopropylethylamine (95 l, 540 mol) and piperazine-2-carboxamide (335 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 54.6 mg (34% of th.) of the title compound as a mixture of diastereomers.

[0714] LC-MS (Method 2): R.sub.t=0.72 min; MS (ESIpos): m/z=626.2 [M+H].sup.+

[0715] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.79-7.42 (m, 9H), 7.24-7.02 (m, 2H), 6.88 (br d, 1H), 4.90 (d, 2H), 4.29 (br ddd, 1H), 4.08-3.93 (m, 1H), 3.84 (dd, 1H), 3.45 (br d, 1H, overlapping with HDO peak), 3.19-2.60 (m, 6H, overlapping with HDO peak).

Example 34

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(4,4-difluoropiperidin-1-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0716] ##STR00097##

[0717] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (500 l, 9.5 mmol) was treated with N,N-diisopropylethylamine (200 l, 1.1 mmol) and 4,4-difluoropiperidine hydrochloride (1:1) (409 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 121 mg (75% of th.) of the title compound.

[0718] LC-MS (Method 2): R.sub.t=1.15 min; MS (ESIpos): m/z=618.2 [M+H].sup.+

[0719] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.80-7.47 (m, 8H), 6.87 (d, 1H), 5.02-4.83 (m, 2H), 4.29 (br ddd, 1H), 4.09-3.75 (m, 2H), 3.27-3.13 (m, 4H), 1.99-1.82 (m, 4H).

Example 35

2-[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]-2,5,7-triazaspiro[3.4]octan-6-one

[0720] ##STR00098##

[0721] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (500 l, 9.5 mmol) was treated with N,N-diisopropylethylamine (200 l, 1.1 mmol) and 2,5,7-triazaspiro[3.4]octan-6-one (330 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 66.2 mg (39% of th.) of the title compound.

[0722] LC-MS (Method 2): R.sub.t=0.88 min; MS (ESIpos): m/z=624.3 [M+H].sup.+

[0723] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.85-7.43 (m, 8H), 7.06-6.78 (m, 2H), 6.30 (br s, 1H), 4.89 (d, 2H), 4.29 (br ddd, 1H), 4.08-3.62 (m, 6H), 3.51-3.42 (m, 2H, overlapping with HDO peak).

Example 36

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0724] ##STR00099##

[0725] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (500 l) was treated with N,N-diisopropylethylamine (200 l, 1.1 mmol) and 3-(trifluoromethyl)azetidin-3-ol (366 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 48.5 mg (29% of th.) of the title compound.

[0726] LC-MS (Method 2): R.sub.t=1.06 min; MS (ESIpos): m/z=638.2 [M+H].sup.+

[0727] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.81-7.47 (m, 8H), 7.35 (br s, 1H), 6.88 (br s, 1H), 4.99-4.84 (m, 2H), 4.29 (br ddd, 1H), 4.05-3.72 (m, 6H).

Example 37

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(3,3-difluoropyrrolidin-1-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0728] ##STR00100##

[0729] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (500 l) was treated with N,N-diisopropylethylamine (95 l, 540 mol) and 3,3-difluoropyrrolidine (278 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 121 mg (77% of th.) of the title compound.

[0730] LC-MS (Method 2): R.sub.t=1.11 min; MS (ESIpos): m/z=604.2 [M+H].sup.+

[0731] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.86-7.44 (m, 8H), 6.88 (br s, 1H), 5.19-4.80 (m, 2H), 4.29 (br ddd, 1H), 4.09-3.76 (m, 2H), 3.62-3.19 (m, 4H, overlapping with HDO peak), 2.49-2.28 (m, 2H).

Example 38

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(hexahydro-4H-furo[3,2-b]pyrrol-4-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0732] ##STR00101##

[0733] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (500 l) was treated with N,N-diisopropylethylamine (95 l, 540 mol) and hexahydro-2H-furo[3,2-b]pyrrole (294 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 118 mg (75% of th.) of the title compound.

[0734] LC-MS (Method 2): R.sub.t=1.04 min; MS (ESIpos): m/z=610.2 [M+H].sup.+

[0735] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): [ppm]: 7.82-7.44 (m, 8H), 6.87 (t, 1H), 4.98-4.79 (m, 2H), 4.47-4.19 (m, 3H), 4.06-3.78 (m, 2H), 3.74-3.56 (m, 2H), 3.20-2.76 (m, 2H), 2.05-1.67 (m, 4H).

Example 39

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(2,2-dimethylmorpholin-4-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0736] ##STR00102##

[0737] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 130 mg, 225 mol) in acetonitrile (200 l) was treated with N,N-diisopropylethylamine (590 l, 3.4 mmol) and 2,2-dimethylmorpholine hydrochloride (1:1) (341 mg, 2.25 mmol). The resulting mixture was heated for 3 h at 180 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 119 mg (86% of th.) of the title compound.

[0738] LC-MS (Method 2): R.sub.t=1.11 min; MS (ESIpos): m/z=612.3 [M+H].sup.+

[0739] .sup.1H-NMR (500 MHz, DMSO-d6) [ppm]: 7.81-7.50 (m, 8H), 6.88 (d, 1H), 4.98-4.85 (m, 2H), 4.36-4.22 (m, 1H), 4.04-3.78 (m, 2H), 3.58-3.48 (m, 2H), 3.01-2.93 (m, 2H), 2.82 (s, 2H), 0.98 (s, 6H).

Example 40

[0740] N.sup.2-[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]-N-(2,2,2-trifluoroethyl)glycinamide

##STR00103##

[0741] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (500 l) was treated with N,N-diisopropylethylamine (95 l, 540 mol) and N-(2,2,2-trifluoroethyl)glycinamide (405 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 75.0 mg (44% of th.) of the title compound.

[0742] LC-MS (Method 2): R.sub.t=1.01 min; MS (ESIpos): m/z=653.3 [M+H].sup.+

[0743] .sup.1H-NMR (500 MHz, DMSO-d6) [ppm]: 8.45 (t, 1H), 7.78-7.47 (m, 8H), 6.88 (d, 1H), 6.73 (t, 1H), 4.92-4.77 (m, 2H), 4.29 (br ddd, 1H), 4.06-3.77 (m, 6H).

Example 41

3-{[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]amino}pyrrolidine-1-carbaldehyde (Diastereomeric Mixture)

[0744] ##STR00104##

[0745] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (1.5 ml) was treated with N,N-diisopropylethylamine (95 l, 540 mol) and 3-aminopyrrolidine-1-carbaldehyde (296 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 150 C. under microwave irradiation and evaporated. The residue was purified by preparative HPLC (Method 5) affording 54.8 mg (32% of th.) of the title compound as a mixture of diastereomers.

[0746] LC-MS (Method 2): R.sub.t=0.91 min; MS (ESIpos): m/z=611.3 [M+H].sup.+

[0747] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 8.28 (br d, 1H), 7.96-7.44 (m, 9H), 6.88 (d, 1H), 4.87 (d, 2H), 4.40-3.72 (m, 4H), 3.28-2.79 (m, 4H, overlapping with HDO peak), 2.11-1.89 (m, 1H), 1.81-1.59 (m, 1H).

Example 42

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[3-methoxypyrrolidin-1-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomeric Mixture)

[0748] ##STR00105##

[0749] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (1.5 ml) was treated with N,N-diisopropylethylamine (95 l, 540 mol) and 3-methoxypyrrolidine hydrochloride (1:1) (357 mg, 2.59 mmol). The resulting mixture was heated for 8 h at 150 C. under microwave irradiation and diluted with water. The resulting solution was purified by preparative HPLC (Method 5) affording 91.0 mg (59% of th.) of the title compound as a mixture of diastereomers.

[0750] LC-MS (Method 2): R.sub.t=1.06 min; MS (ESIpos): m/z=598.3 [MH].sup.+

[0751] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.87-7.35 (m, 8H), 6.88 (d, 1H), 4.97-4.75 (m, 2H), 4.29 (br ddd, 1H), 4.07-3.76 (m, 3H), 3.24-2.94 (m, 7H), 1.98-1.72 (m, 2H).

Example 43

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[3-hydroxypyrrolidin-1-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomeric Mixture)

[0752] ##STR00106##

[0753] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (1.5 ml) was treated with N,N-diisopropylethylamine (95 l, 540 mol) and pyrrolidin-3-ol (210 l, 2.6 mmol). The resulting mixture was heated for 5 h at 150 C. under microwave irradiation and diluted with water. The resulting solution was purified by preparative HPLC (Method 5) affording 45.6 mg (30% of th.) of the title compound as a mixture of diastereomers.

[0754] LC-MS (Method 2): R.sub.t=0.94 min; MS (ESIpos): m/z=584.2 [M+H].sup.+

[0755] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.82-7.42 (m, 8H), 6.88 (d, 1H), 4.95-4.82 (m, 3H), 4.39-4.12 (m, 2H), 4.06-3.76 (m, 2H), 3.27-2.83 (m, 4H, overlapping with HDO peak), 1.92-1.61 (m, 2H).

Example 44

2-{[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]amino}ethanesulfonamide

[0756] ##STR00107##

[0757] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (1.5 ml) was treated with N,N-diisopropylethylamine (95 l, 540 mol) and 2-aminoethanesulfonamide (322 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 150 C. and 14 h at 180 C. under microwave irradiation and evaporated. The reaction volume was concentrated to 1 ml, and 2-aminoethanesulfonamide (322 mg, 2.59 mmol) was added. The resulting mixture was stirred 2 h at 200 C. and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 19.5 mg (12% of th.) of the title compound.

[0758] LC-MS (Method 2): R.sub.t=0.89 min; MS (ESIpos): m/z=621.0 [M+H].sup.+

[0759] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.80-7.43 (m, 8H), 6.92-6.80 (m, 3H), 6.57 (t, 1H), 4.96-4.81 (m, 2H), 4.29 (br ddd, 1H), 4.07-3.77 (m, 2H), 3.65-3.50 (m, 2H), 3.27-3.15 (m, 2H).

Example 45

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-{[2-(2-oxopyrrolidin-1-yl)ethyl]amino}-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0760] ##STR00108##

[0761] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (1.5 ml) was treated with N,N-diisopropylethylamine (95 l, 540 mol) and 1-(2-aminoethyl)pyrrolidin-2-one (333 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 150 C. under microwave irradiation and evaporated. The residue was purified by preparative HPLC (Method 5) affording 85.0 mg (50% of th.) of the title compound.

[0762] LC-MS (Method 2): R.sub.t=0.95 min; MS (ESIpos): m/z=625.3 [M+H].sup.+

[0763] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.82-7.42 (m, 8H), 6.90 (br s, 1H), 6.48 (br t, 1H), 4.86 (d, 2H), 4.31 (br ddd, 1H), 4.06-3.78 (m, 2H), 3.63-3.22 (m, 6H, overlapping with HDO), 2.14-2.03 (m, 2H), 1.79 (quin, 2H).

Example 46

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-{[2-(2-oxoimidazolidin-1-yl)ethyl]amino}-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0764] ##STR00109##

[0765] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (1.5 ml) was treated with N,N-diisopropylethylamine (95 l, 540 mol) and 1-(2-aminoethyl)imidazolidin-2-one (335 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 150 C. under microwave irradiation and evaporated. The residue was purified by preparative HPLC (Method 5) affording 115 mg (64% of th.) of the title compound.

[0766] LC-MS (Method 2): R.sub.t=0.88 min; MS (ESIpos): m/z=626.1 [M+H].sup.+

[0767] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.81-7.41 (m, 8H), 6.89 (d, 1H), 6.47 (t, 1H), 6.22 (s, 1H), 4.86 (d, 2H), 4.30 (br ddd, 1H), 4.06-3.76 (m, 2H), 3.36-3.06 (m, 8H, overlapping with HDO peak).

Example 47

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(2,2-dioxido-2-thia-6-azaspiro[3.3]hept-6-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0768] ##STR00110##

[0769] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 80.0 mg, 138 mol) in acetonitrile (800 l) was treated with N,N-diisopropylethylamine (51 l, 290 mol) and 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide (102 mg, 692 mol). The resulting mixture was heated for 5 h at 180 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 27.8 mg (31% of th.) of the title compound.

[0770] LC-MS (Method 2): R.sub.t=1.00 min; MS (ESIpos): m/z=644.2 [M+H].sup.+

[0771] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.81-7.46 (m, 8H), 6.88 (d, 1H), 4.89 (d, 2H), 4.46-4.21 (m, 5H), 4.06-3.78 (m, 6H).

Example 48

4-[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]piperazin-2-one

[0772] ##STR00111##

[0773] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 100 mg, 173 mol) in acetonitrile (1.0 ml) was treated with N,N-diisopropylethylamine (63 l, 360 mol) and piperazin-2-one (120 l, 1.7 mmol). The resulting mixture was heated for 8 h at 150 C. under microwave irradiation and diluted with DMSO. The resulting solution was purified by preparative HPLC (Method 5) affording 70.8 mg (69% of th.) of the title compound.

[0774] LC-MS (Method 2): R.sub.t=0.91 min; MS (ESIpos): m/z=597.3 [M+H].sup.+

[0775] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 8.01 (br s, 1H), 7.82-7.46 (m, 8H), 6.88 (d, 1H), 4.92 (d, 2H), 4.29 (br ddd, 1H), 4.08-3.77 (m, 2H), 3.59 (s, 2H), 3.29-3.03 (m, 4H, overlapping with HDO peak).

Example 49

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-{[(2R)-2-hydroxypropyl]amino}-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0776] ##STR00112##

[0777] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 60.0 mg, 104 mol) in N-methylpyrrolidone (1.5 ml) was treated with N,N-diisopropylethylamine (54 l, 310 mol) and (2R)-1-aminopropan-2-ol (82 l, 1.0 mmol). The resulting mixture was heated for 5 h at 160 C. and 2 h at 180 C. under microwave irradiation. The reaction mixture was combined with a 20 mg test reaction and evaporated. The residue was retaken in ethyl acetate and washed with a saturated solution of sodium chloride. The organic phase was dried over magnesium sulfate, evaporated and purified by preparative HPLC (Method 5) affording 47.3 mg (78% of th.) of the title compound.

[0778] LC-MS (Method 2): R.sub.t=0.96 min; MS (ESIpos): m/z=572.3 [M+H].sup.+

[0779] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.80-7.43 (m, 8H), 6.88 (d, 1H), 6.31 (t, 1H), 4.94-4.80 (m, 2H), 4.69 (d, 1H), 4.29 (br ddd, 1H), 4.06-3.67 (m, 3H), 3.21-3.02 (m, 2H), 1.01 (d, 3H).

Example 50

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-{[(2S)-2-hydroxypropyl]amino}-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0780] ##STR00113##

[0781] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 80.0 mg, 138 mol) in N-methylpyrrolidone (2.0 ml) was treated with N,N-diisopropylethylamine (72 l, 420 mol) and (2S)-1-aminopropan-2-ol (110 l, 1.4 mmol). The resulting mixture was heated for 5 h at 160 C. under microwave irradiation and evaporated. The residue was retaken in ethyl acetate and washed with a saturated solution of sodium chloride. The organic phase was dried over magnesium sulfate, evaporated and was purified by preparative HPLC (Method 5) affording 31.0 mg (39% of th.) of the title compound.

[0782] LC-MS (Method 2): R.sub.t=0.96 min; MS (ESIpos): m/z=572.3 [M+H].sup.+

[0783] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.80-7.42 (m, 8H), 6.88 (d, 1H), 6.31 (t, 1H), 4.86 (d, 2H), 4.68 (d, 1H), 4.29 (br ddd, 1H), 4.05-3.68 (m, 3H), 3.23-3.02 (m, 2H), 1.01 (d, 3H).

Example 51

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-{[2-(methylsulfonyl)ethyl]amino}-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0784] ##STR00114##

[0785] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (1.5 ml) was treated with N,N-diisopropylethylamine (95 l, 540 mol) and 2-(methylsulfonyl)ethanamine (320 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 150 C., 12 h at 180 C. and 5 h at 200 C. under microwave irradiation. The reaction mixture was purified by preparative HPLC (Method 5) affording 23.4 mg (15% of th.) of the title compound.

[0786] LC-MS (Method 2): R.sub.t=0.94 min; MS (ESIpos): m/z=620.2 [M+H].sup.+

[0787] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.80-7.44 (m, 8H), 6.88 (d, 1H), 6.69 (t, 1H), 4.98-4.84 (m, 2H), 4.29 (br ddd, 1H), 4.06-3.79 (m, 2H), 3.60 (q, 2H), 3.39-3.26 (m, 2H, overlapping with HDO peak), 2.97 (s, 3H).

Example 52

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-{[(1-hydroxycyclobutyl)methyl]amino}-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0788] ##STR00115##

[0789] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 60.0 mg, 104 mol) in N-methylpyrrolidone (900 l) was treated with N,N-diisopropylethylamine (54 l, 310 mol) and 1-(aminomethyl)cyclobutanol (105 mg, 1.04 mmol). The resulting mixture was heated for 5 h at 160 C. under microwave irradiation and evaporated. The residue was retaken in ethyl acetate and washed with a saturated solution of sodium chloride. The organic phase was dried over magnesium sulfate, evaporated and was purified by preparative HPLC (Method 5) affording 50.1 mg (81% of th.) of the title compound.

[0790] LC-MS (Method 2): R.sub.t=1.01 min; MS (ESIpos): m/z=598.2 [M+H].sup.+

[0791] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.82-7.42 (m, 8H), 6.89 (d, 1H), 6.12 (t, 1H), 5.30 (s, 1H), 4.97-4.75 (m, 2H), 4.30 (br ddd, 1H), 4.10-3.71 (m, 2H), 3.44-3.17 (m, 2H, overlapping with HDO peak), 2.12-1.73 (m, 4H), 1.66-1.29 (m, 2H).

Example 53

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-{[3,3,3-trifluoro-2-hydroxypropyl]amino}-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomeric Mixture)

[0792] ##STR00116##

[0793] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 80.0 mg, 138 mol) in acetonitrile (800 l) was treated with N,N-diisopropylethylamine (51 l, 290 mol) and 3-amino-1,1,1-trifluoropropan-2-ol (357 mg, 2.77 mmol). The resulting mixture was heated for 5 h at 150 C. under microwave irradiation. The reaction mixture was purified by preparative HPLC (Method 5) affording 36.0 mg (39% of th.) of the title compound as a mixture of diastereomers.

[0794] LC-MS (Method 4): R.sub.t=3.22 min; MS (ESIpos): m/z=626.0 [M+H].sup.+

[0795] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.81-7.44 (m, 8H), 6.88 (d, 1H), 6.68 (t, 1H), 6.41 (dd, 1H), 4.95-4.83 (m, 2H), 4.36-4.16 (m, 2H), 4.05-3.78 (m, 2H), 3.54-3.19 (m, 2H, overlapping with HDO peak).

Example 54

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-{[(1-hydroxycyclopropyl)methyl]amino}-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0796] ##STR00117##

[0797] A solution of 2-{[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 150 mg, 259 mol) in acetonitrile (1.5 ml) was treated with N,N-diisopropylethylamine (95 l, 540 mol) and 1-(aminomethyl)cyclopropanol (226 mg, 2.59 mmol). The resulting mixture was heated for 5 h at 150 C. under microwave irradiation. The reaction mixture was purified by preparative HPLC (Method 5) affording 47.1 mg (31% of th.) of the title compound.

[0798] LC-MS (Method 2): R.sub.t=0.95 min; MS (ESIpos): m/z=584.1 [M+H].sup.+

[0799] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.83-7.44 (m, 8H), 6.88 (d, 1H), 6.33 (t, 1H), 5.41 (s, 1H), 4.94-4.77 (m, 2H), 4.39-4.19 (m, 1H), 4.06-3.74 (m, 2H), 3.36 (d, 2H), 0.59-0.40 (m, 4H).

Example 55

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(1,1-dioxidothiomorpholin-4-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0800] ##STR00118##

[0801] A solution of 2-{[5-bromo-1 (2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methy}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 200 mg, 346 mol) in acetonitrile (2.0 ml) was treated with N,N-diisopropylethylamine (130 l, 730 mol) and thiomorpholine 1,1-dioxide (935 mg, 6.92 mmol). The resulting mixture was heated for 12 h at 180 C. under microwave irradiation and diluted with water. The resulting solution was purified by preparative HPLC (Method 5) affording 105 mg (48% of th.) of the title compound.

[0802] LC-MS (Method 2): R.sub.t=0.96 min; MS (ESIpos): m/z=632.0 [M+H].sup.+

[0803] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.83-7.46 (m, 8H), 6.87 (d, 1H), 5.02-4.86 (m, 2H), 4.27 (br ddd, 1H), 4.06-3.77 (m, 2H), 3.61-3.45 (m, 4H, overlapping with HDO peak), 3.20-3.06 (m, 4H).

Example 56

(3R)-1-[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]pyrrolidine-3-carboxamide

[0804] ##STR00119##

[0805] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 82.0 mg, 142 mol), (3R)-pyrrolidine-3-carboxamide (162 mg, 1.42 mmol), N,N-diisopropylethylamine (250 l, 1.4 mmol) were dissolved in acetonitrile (1.5 ml) and strirred for 5 h at 180 C. in a sealed vial under microwave irradiation, followed by 5 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 40.4 mg (44% of th.) of the title compound.

[0806] LC-MS (Method 10): R.sub.t=1.17 min; MS (ESIpos): m/z=611 [M+H].sup.+

[0807] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.89), 1.848 (1.44), 1.869 (1.70), 1.879 (2.35), 1.899 (2.25), 1.927 (1.12), 1.945 (2.01), 1.957 (2.48), 1.975 (2.01), 1.989 (1.12), 2.366 (0.59), 2.816 (0.84), 2.835 (2.43), 2.854 (3.41), 2.874 (2.36), 2.892 (0.72), 3.080 (1.73), 3.118 (2.59), 3.143 (3.88), 3.162 (4.13), 3.195 (2.77), 3.288 (3.52), 3.806 (2.08), 3.829 (2.38), 3.842 (2.94), 3.866 (3.08), 3.971 (3.07), 3.979 (3.30), 4.008 (2.12), 4.016 (1.96), 4.284 (1.85), 4.301 (1.71), 4.815 (1.28), 4.855 (7.65), 4.860 (8.00), 4.867 (6.52), 4.907 (0.97), 6.875 (6.99), 6.891 (5.56), 7.375 (4.02), 7.469 (1.86), 7.484 (4.60), 7.503 (3.77), 7.529 (2.79), 7.534 (3.06), 7.549 (4.48), 7.553 (4.69), 7.568 (2.62), 7.611 (12.50), 7.632 (16.00), 7.643 (6.82), 7.664 (4.12), 7.746 (12.52), 7.767 (9.05).

Example 57

(3S)-1-[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]pyrrolidine-3-carboxamide

[0808] ##STR00120##

[0809] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 86.7 mg, 150 mol), (3S)-pyrrolidine-3-carboxamide (245 mg, 70% purity, 1.50 mmol), N,N-diisopropylethylamine (260 l, 1.5 mmol) were dissolved in acetonitrile (1.5 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation, followed by 5 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 44.8 mg (49% of th.) of the title compound.

[0810] LC-MS (Method 3): R.sub.t=1.62 min; MS (ESIpos): m/z=611 [M+H].sup.+

[0811] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.62), 0.008 (1.34), 1.849 (1.01), 1.860 (0.82), 1.869 (1.26), 1.879 (1.92), 1.900 (1.90), 1.928 (0.80), 1.946 (1.57), 1.958 (2.07), 1.975 (1.71), 1.989 (0.93), 2.836 (2.03), 2.855 (2.94), 2.874 (2.11), 3.081 (1.17), 3.119 (1.95), 3.138 (2.34), 3.143 (3.13), 3.162 (3.29), 3.196 (1.83), 3.290 (1.31), 3.806 (1.79), 3.830 (2.05), 3.843 (2.56), 3.867 (2.76), 3.971 (2.42), 3.979 (2.76), 4.008 (1.76), 4.016 (1.65), 4.285 (1.38), 4.301 (1.32), 4.816 (0.73), 4.855 (5.49), 4.861 (8.53), 4.868 (4.81), 4.908 (0.69), 6.882 (6.41), 6.892 (3.67), 6.898 (3.65), 7.374 (3.28), 7.465 (1.54), 7.469 (1.63), 7.484 (4.19), 7.488 (4.28), 7.503 (3.37), 7.507 (3.35), 7.529 (2.40), 7.534 (2.91), 7.549 (3.83), 7.554 (4.46), 7.568 (2.23), 7.573 (2.08), 7.605 (1.62), 7.612 (11.61), 7.616 (6.56), 7.628 (4.88), 7.633 (16.00), 7.639 (4.44), 7.643 (6.17), 7.647 (5.54), 7.663 (3.85), 7.667 (3.57), 7.741 (1.93), 7.747 (11.88), 7.752 (3.60), 7.764 (3.33), 7.768 (8.58), 7.775 (1.14).

Example 58

1-[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]-L-prolinamide

[0812] ##STR00121##

[0813] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 80.0 mg, 85% purity, 118 mol), L-prolinamide (134 mg, 1.18 mmol), N,N-diisopropylethylamine (43 l, 250 mol) were dissolved in acetonitrile (670 l) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation, followed by 5 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 51.2 mg (64% of th.) of the title compound.

[0814] LC-MS (Method 10): R.sub.t=1.20 min; MS (ESIpos): m/z=611 [M+H].sup.+

[0815] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (2.43), 0.008 (2.79), 1.709 (1.75), 1.732 (3.22), 1.748 (3.49), 1.765 (1.94), 1.774 (1.43), 1.783 (1.60), 1.804 (1.46), 1.815 (1.70), 2.019 (1.50), 2.028 (0.94), 2.038 (1.60), 2.050 (1.44), 2.061 (0.87), 2.070 (1.32), 3.018 (0.82), 3.287 (2.55), 3.791 (1.51), 3.815 (1.77), 3.828 (2.25), 3.851 (2.42), 3.956 (2.34), 3.964 (2.65), 3.993 (1.79), 4.000 (1.74), 4.288 (1.69), 4.863 (14.19), 6.898 (5.13), 6.914 (5.31), 6.944 (1.62), 7.458 (1.10), 7.475 (2.30), 7.493 (1.85), 7.526 (2.60), 7.530 (3.04), 7.545 (3.65), 7.550 (3.88), 7.564 (2.24), 7.569 (2.29), 7.610 (8.69), 7.631 (16.00), 7.650 (3.88), 7.721 (1.04), 7.745 (11.06), 7.750 (3.67), 7.762 (3.65), 7.767 (7.76).

Example 59

1-[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]-D-prolinamide

[0816] ##STR00122##

[0817] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 66.0 mg, 85% purity, 97.0 mol), D-prolinamide (111 mg, 970 mol), N,N-diisopropylethylamine (35 l, 200 mol) were dissolved in acetonitrile (550 l) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation, followed by 4 h at 190 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 50.1 mg (82% of th.) of the title compound.

[0818] LC-MS (Method 10): R.sub.t=1.19 min; MS (ESIpos): m/z=611 [M+H].sup.+

[0819] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (0.95), 1.708 (1.89), 1.731 (3.64), 1.748 (3.95), 1.766 (2.06), 1.775 (1.46), 1.785 (1.72), 1.795 (1.27), 1.805 (1.60), 1.816 (1.91), 1.826 (1.45), 1.832 (1.35), 1.843 (0.68), 1.998 (0.78), 2.019 (1.75), 2.028 (1.07), 2.037 (1.80), 2.048 (1.66), 2.060 (0.98), 2.068 (1.39), 3.014 (0.85), 3.288 (2.54), 3.795 (1.80), 3.819 (2.10), 3.831 (2.63), 3.855 (2.82), 3.960 (2.81), 3.968 (3.10), 3.996 (2.02), 4.005 (1.91), 4.279 (1.90), 4.296 (1.80), 4.808 (2.25), 4.848 (7.18), 4.863 (1.98), 4.875 (8.00), 4.915 (2.57), 6.874 (5.41), 6.890 (5.63), 6.900 (1.22), 6.916 (1.50), 6.935 (1.84), 7.455 (1.12), 7.474 (2.56), 7.494 (2.05), 7.526 (2.59), 7.530 (2.76), 7.545 (4.17), 7.550 (4.35), 7.565 (2.54), 7.569 (2.39), 7.600 (1.81), 7.606 (9.34), 7.611 (4.28), 7.623 (5.33), 7.628 (16.00), 7.633 (7.83), 7.650 (4.01), 7.653 (3.77), 7.735 (2.42), 7.741 (12.65), 7.746 (5.07), 7.758 (4.00), 7.763 (9.19), 7.768 (2.26).

Example 60

[0820] 5-{[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]amino}piperidin-2-one (Diastereomeric Mixture)

##STR00123##

[0821] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 120 mg, 85% purity, 176 mol), (5R)-5-aminopiperidin-2-one (190 l, 90% purity, 1.8 mmol), N,N-diisopropylethylamine (92 l, 530 mol) were dissolved in acetonitrile (1.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation, followed by 10 h at 160 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 79.3 mg (66% of th.) of the title compound as a mixture of diastereomers.

[0822] LC-MS (Method 2): R.sub.t=0.87 min; MS (ESIpos): m/z=611 [M+H].sup.+

[0823] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.41), 0.008 (1.26), 1.179 (0.91), 1.695 (1.42), 1.708 (1.31), 1.722 (1.63), 1.732 (1.86), 1.745 (1.18), 1.752 (0.73), 1.990 (1.16), 1.994 (1.18), 2.012 (2.09), 2.023 (2.89), 2.027 (3.77), 2.049 (3.58), 2.060 (5.55), 2.064 (5.01), 2.068 (3.47), 2.086 (3.94), 2.104 (2.35), 2.127 (0.83), 2.191 (1.18), 2.207 (1.65), 2.212 (1.62), 2.226 (1.20), 3.158 (1.37), 3.175 (2.20), 3.191 (2.95), 3.208 (1.76), 3.215 (1.89), 3.230 (3.02), 3.244 (2.09), 3.264 (1.37), 3.278 (0.95), 3.288 (1.37), 3.672 (1.75), 3.687 (2.45), 3.703 (1.70), 3.808 (1.91), 3.832 (2.22), 3.845 (2.92), 3.869 (3.26), 3.970 (3.28), 3.979 (3.67), 4.006 (2.31), 4.015 (2.19), 4.283 (1.84), 4.299 (1.92), 4.819 (1.67), 4.859 (9.47), 4.869 (10.15), 4.883 (1.96), 4.909 (1.48), 5.754 (7.55), 6.531 (2.28), 6.540 (2.64), 6.546 (4.19), 6.559 (2.80), 6.873 (5.31), 6.889 (5.27), 7.349 (1.19), 7.477 (1.36), 7.481 (2.15), 7.485 (1.52), 7.494 (2.83), 7.501 (7.27), 7.514 (4.70), 7.518 (4.79), 7.524 (1.76), 7.531 (1.80), 7.536 (9.35), 7.538 (9.31), 7.540 (6.85), 7.551 (4.10), 7.554 (7.17), 7.559 (5.41), 7.566 (1.88), 7.571 (3.12), 7.576 (3.27), 7.588 (6.48), 7.603 (1.86), 7.610 (10.74), 7.614 (4.87), 7.626 (4.54), 7.631 (15.22), 7.637 (2.69), 7.651 (1.74), 7.653 (1.77), 7.667 (3.69), 7.672 (6.57), 7.683 (1.42), 7.688 (2.53), 7.691 (4.32), 7.734 (2.58), 7.740 (16.00), 7.745 (5.53), 7.757 (4.52), 7.761 (11.69), 7.768 (1.75).

[0824] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 79 mg dissolved in 5 ml iso-propanol; injection volume: 0.35 ml; column: Daicel Chiralcel OD-H 5 m, 25030 mm; eluent: iso-hexane/iso-propanol 50:50; flow rate: 15 ml/min; temperature: 25 C.; UV detection: 210 nm]. 27.3 mg of diastereomer 1 (Example 61), which eluted first, and 12.0 mg of diastereomer 2 (Example 62), which eluted later, were isolated.

Example 61

5-{[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]amino}piperidin-2-one (Diastereomer 2)

[0825] Analytical chiral HPLC: R.sub.t=2.56 min, d.e.=99% [column: Chiraltek OD-3 504.6 mm; eluent: iso-hexane/iso-propanol 50/50, flow rate: 1 ml/min; UV detection: 210 nm].

[0826] LC-MS (Method 2): R.sub.t=0.88 min; MS (ESIpos): m/z=611 [M+H].sup.+

[0827] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.59), 0.779 (1.19), 0.798 (2.58), 0.817 (2.19), 0.822 (7.38), 0.839 (7.82), 0.847 (2.29), 0.865 (4.10), 0.883 (2.07), 1.009 (2.63), 1.038 (14.81), 1.053 (1.11), 1.087 (16.00), 1.141 (0.89), 1.146 (1.04), 1.159 (0.83), 1.236 (1.64), 1.242 (1.46), 1.261 (1.04), 1.289 (1.30), 1.308 (0.90), 1.396 (1.51), 1.406 (0.96), 1.426 (1.28), 1.444 (0.81), 1.694 (0.95), 1.707 (0.93), 1.721 (1.17), 1.731 (1.33), 1.744 (0.79), 1.874 (0.66), 1.990 (0.91), 2.011 (1.45), 2.026 (2.57), 2.049 (2.51), 2.060 (3.88), 2.063 (3.45), 2.086 (2.72), 2.104 (1.57), 3.158 (0.92), 3.175 (1.50), 3.191 (2.07), 3.208 (1.33), 3.214 (1.35), 3.228 (2.08), 3.243 (1.48), 3.262 (0.95), 3.289 (1.18), 3.670 (1.25), 3.685 (1.75), 3.701 (1.24), 3.807 (1.27), 3.831 (1.46), 3.844 (1.84), 3.868 (1.98), 3.971 (1.97), 3.979 (2.15), 4.007 (1.42), 4.016 (1.30), 4.281 (1.10), 4.298 (1.12), 4.819 (1.06), 4.858 (6.12), 4.869 (6.16), 4.909 (1.08), 6.531 (1.41), 6.546 (2.65), 6.561 (1.40), 6.873 (3.63), 6.889 (3.69), 7.477 (0.76), 7.481 (0.87), 7.493 (0.97), 7.501 (2.67), 7.514 (2.95), 7.518 (3.00), 7.536 (6.55), 7.554 (4.64), 7.559 (3.38), 7.571 (1.87), 7.576 (1.85), 7.589 (4.50), 7.603 (1.44), 7.610 (6.38), 7.614 (2.71), 7.626 (3.29), 7.631 (8.60), 7.637 (1.61), 7.667 (2.28), 7.672 (3.70), 7.684 (1.09), 7.691 (2.75), 7.733 (1.70), 7.739 (8.68), 7.744 (3.21), 7.756 (2.83), 7.761 (6.31), 7.767 (1.26), 10.496 (0.75), 10.552 (2.11), 10.616 (2.38).

Example 62

5-{[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]amino}piperidin-2-one (Diastereomer 1)

[0828] Analytical chiral HPLC: R.sub.t=5.34 min, d.e.=99% [column: Chiraltek OD-3 504.6 mm; eluent: iso-hexane/iso-propanol 50/50, flow rate: 1 ml/min; UV detection: 210 nm].

[0829] LC-MS (Method 4): R.sub.t=2.67 min; MS (ESIpos): m/z=611 [M+H].sup.+

[0830] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.66), 0.008 (1.41), 0.779 (0.97), 0.798 (2.07), 0.817 (1.60), 0.822 (5.32), 0.840 (5.68), 0.847 (2.10), 0.865 (4.06), 0.883 (2.10), 0.988 (0.69), 1.010 (2.16), 1.038 (10.86), 1.053 (1.05), 1.087 (16.00), 1.141 (0.76), 1.290 (1.13), 1.308 (0.86), 1.396 (1.49), 1.407 (0.89), 1.426 (1.13), 1.731 (0.94), 1.874 (0.77), 2.012 (1.02), 2.027 (1.80), 2.049 (1.78), 2.060 (2.77), 2.086 (2.13), 2.104 (1.13), 2.206 (0.84), 3.174 (1.10), 3.191 (1.44), 3.206 (0.84), 3.215 (0.91), 3.230 (1.50), 3.245 (1.05), 3.673 (0.87), 3.687 (1.22), 3.703 (0.88), 3.811 (1.02), 3.834 (1.20), 3.847 (1.54), 3.871 (1.70), 3.969 (1.74), 3.977 (1.96), 4.005 (1.24), 4.013 (1.18), 4.282 (0.98), 4.299 (0.96), 4.819 (0.74), 4.858 (4.57), 4.868 (5.01), 4.908 (0.75), 6.531 (1.03), 6.546 (2.01), 6.559 (1.43), 6.873 (2.98), 6.889 (3.01), 7.481 (1.00), 7.494 (1.52), 7.501 (3.51), 7.514 (2.26), 7.518 (2.27), 7.536 (4.83), 7.554 (3.43), 7.559 (2.55), 7.571 (1.36), 7.576 (1.35), 7.588 (3.23), 7.610 (5.52), 7.626 (2.69), 7.631 (7.53), 7.653 (0.96), 7.667 (1.85), 7.672 (3.28), 7.691 (2.09), 7.734 (1.43), 7.740 (8.14), 7.746 (2.88), 7.757 (2.41), 7.762 (5.92), 7.768 (1.12), 10.553 (1.18), 10.616 (1.79).

Example 63

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-({[5-oxopyrrolidin-2-yl]methyl}amino)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomeric Mixture)

[0831] ##STR00124##

[0832] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 120 mg, 85% purity, 176 mol), 5-(aminomethyl)pyrrolidin-2-one (224 mg, 90% purity, 1.76 mmol), N,N-diisopropylethylamine (92 l, 530 mol) were dissolved in acetonitrile (1.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation, followed by 10 h at 160 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 78.6 mg (73% of th.) of the title compound as a mixture of diastereomers.

[0833] LC-MS (Method 2): R.sub.t=0.87 min; MS (ESIpos): m/z=611 [M+H].sup.+

[0834] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 1.141 (1.96), 1.179 (1.06), 1.679 (0.74), 1.695 (1.76), 1.709 (1.70), 1.723 (2.07), 1.732 (2.41), 1.745 (1.37), 1.752 (0.87), 1.991 (1.46), 2.012 (2.57), 2.027 (4.70), 2.050 (4.64), 2.060 (7.04), 2.086 (6.60), 2.104 (2.86), 2.117 (0.88), 2.127 (0.91), 3.143 (0.85), 3.158 (1.67), 3.175 (2.76), 3.192 (3.70), 3.208 (2.24), 3.215 (2.41), 3.230 (3.81), 3.245 (2.60), 3.263 (1.66), 3.278 (1.03), 3.289 (1.22), 3.672 (2.31), 3.688 (3.19), 3.703 (2.21), 3.810 (1.93), 3.834 (2.30), 3.847 (2.97), 3.870 (3.22), 3.970 (3.29), 3.979 (3.77), 4.007 (2.32), 4.016 (2.21), 4.282 (1.89), 4.300 (1.98), 4.819 (1.85), 4.859 (11.34), 4.869 (11.01), 4.909 (1.71), 5.754 (10.86), 6.532 (2.67), 6.547 (4.96), 6.561 (2.60), 6.874 (6.26), 6.890 (6.30), 7.478 (1.31), 7.481 (1.66), 7.494 (1.68), 7.501 (4.87), 7.514 (5.12), 7.518 (5.51), 7.537 (12.14), 7.555 (8.57), 7.560 (6.22), 7.571 (3.48), 7.576 (3.75), 7.589 (8.26), 7.603 (2.25), 7.610 (11.74), 7.614 (5.36), 7.626 (5.36), 7.631 (16.00), 7.667 (4.31), 7.672 (6.92), 7.684 (1.73), 7.691 (5.28), 7.734 (2.76), 7.740 (15.48), 7.761 (11.22).

[0835] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 79 mg dissolved in 5 ml iso-propanol; injection volume: 0.40 ml; column: Daicel Chiralcel OD-H 5 m, 25030 mm; eluent: iso-hexane/iso-propanol 50:50; flow rate: 15 ml/min; temperature: 25 C.; UV detection: 210 nm]. 26.5 mg of diastereomer 1 (Example 64), which eluted first, and 32.1 mg of diastereomer 2 (Example 65), which eluted later, were isolated.

Example 64

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-({[5-oxopyrrolidin-2-yl]methyl}amino)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomer 1)

[0836] Analytical chiral HPLC: R.sub.t=2.61 min, d.e.=99% [column: Chiraltek OD-3 504.6 mm; eluent: iso-hexane/iso-propanol 50/50, flow rate: 1 ml/min; UV detection: 210 nm].

[0837] LC-MS (Method 2): R.sub.t=0.87 min; MS (ESIpos): m/z=611 [M+H].sup.+

[0838] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (3.29), 0.008 (3.00), 0.798 (0.98), 0.822 (1.86), 0.840 (2.00), 0.847 (0.85), 0.865 (1.33), 0.883 (0.71), 0.988 (1.32), 1.003 (1.37), 1.010 (0.87), 1.030 (1.59), 1.038 (3.67), 1.045 (1.56), 1.087 (4.61), 1.135 (1.09), 1.147 (1.67), 1.157 (1.54), 1.175 (2.07), 1.236 (2.16), 1.679 (0.82), 1.695 (1.74), 1.708 (1.66), 1.723 (2.10), 1.732 (2.36), 1.745 (1.40), 1.752 (0.92), 1.989 (1.63), 2.012 (2.58), 2.027 (4.56), 2.049 (4.47), 2.060 (6.92), 2.064 (6.23), 2.086 (4.94), 2.104 (2.83), 2.127 (0.99), 3.141 (0.92), 3.157 (1.76), 3.174 (2.79), 3.190 (3.72), 3.206 (2.20), 3.215 (2.31), 3.230 (3.87), 3.244 (2.77), 3.263 (1.74), 3.278 (1.24), 3.288 (1.73), 3.673 (2.20), 3.687 (3.15), 3.703 (2.23), 3.811 (2.25), 3.834 (2.59), 3.847 (3.28), 3.871 (3.51), 3.969 (3.40), 3.977 (3.80), 4.006 (2.41), 4.014 (2.28), 4.282 (1.90), 4.299 (1.87), 4.323 (0.87), 4.819 (1.86), 4.858 (11.38), 4.868 (11.39), 4.908 (1.81), 5.754 (6.08), 6.531 (2.61), 6.546 (4.83), 6.560 (2.55), 6.872 (6.62), 6.888 (6.67), 7.478 (1.45), 7.481 (1.64), 7.494 (1.78), 7.499 (4.14), 7.501 (4.69), 7.514 (5.32), 7.518 (5.38), 7.536 (11.48), 7.541 (7.76), 7.554 (8.15), 7.560 (5.70), 7.571 (3.35), 7.577 (3.54), 7.587 (8.15), 7.603 (2.16), 7.610 (11.46), 7.615 (4.58), 7.626 (5.32), 7.631 (15.56), 7.637 (2.67), 7.667 (4.06), 7.672 (6.40), 7.684 (1.70), 7.691 (4.87), 7.734 (2.86), 7.740 (16.00), 7.746 (5.32), 7.757 (4.68), 7.762 (11.48), 7.768 (1.76), 10.616 (0.61).

Example 65

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-({[5-oxopyrrolidin-2-yl]methyl}amino)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomer 2)

[0839] Analytical chiral HPLC: R.sub.t=4.83 min, d.e.=99% [column: Chiraltek OD-3 504.6 mm; eluent: iso-hexane/iso-propanol 50/50, flow rate: 1 ml/min; UV detection: 210 nm].

[0840] LC-MS (Method 2): R.sub.t=0.87 min; MS (ESIpos): m/z=611 [M+H].sup.+

[0841] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.18), 0.779 (1.20), 0.798 (2.33), 0.817 (1.78), 0.822 (5.87), 0.840 (6.21), 0.847 (2.15), 0.865 (4.07), 0.883 (2.11), 1.010 (2.19), 1.038 (11.81), 1.088 (16.00), 1.141 (0.88), 1.147 (0.89), 1.173 (1.00), 1.236 (1.01), 1.290 (1.06), 1.308 (0.80), 1.397 (1.50), 1.407 (0.90), 1.416 (0.78), 1.426 (1.15), 1.731 (0.88), 2.012 (0.95), 2.027 (1.71), 2.049 (1.67), 2.060 (2.60), 2.064 (2.30), 2.086 (1.86), 2.104 (1.05), 3.175 (1.01), 3.192 (1.37), 3.208 (0.87), 3.215 (0.91), 3.229 (1.38), 3.244 (0.96), 3.686 (1.16), 3.702 (0.82), 3.808 (0.83), 3.832 (0.95), 3.845 (1.19), 3.868 (1.28), 3.971 (1.25), 3.980 (1.39), 4.008 (0.91), 4.016 (0.84), 4.819 (0.72), 4.859 (4.11), 4.870 (4.09), 4.909 (0.73), 5.754 (0.79), 6.532 (0.93), 6.546 (1.74), 6.561 (0.90), 6.873 (2.36), 6.889 (2.38), 7.499 (1.52), 7.501 (1.73), 7.514 (1.97), 7.518 (2.00), 7.536 (4.33), 7.540 (2.87), 7.554 (3.10), 7.559 (2.23), 7.571 (1.24), 7.577 (1.22), 7.590 (2.98), 7.610 (4.27), 7.614 (1.77), 7.626 (2.10), 7.631 (5.78), 7.637 (1.02), 7.668 (1.53), 7.672 (2.44), 7.688 (1.25), 7.691 (1.84), 7.733 (1.09), 7.739 (5.87), 7.745 (1.99), 7.756 (1.79), 7.761 (4.21), 10.552 (1.42), 10.616 (2.03).

Example 66

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(3-(trifluoromethyl)piperazin-1-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomeric Mixture)

[0842] ##STR00125##

[0843] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 120 mg, 85% purity, 176 mol), 2-(trifluoromethyl)piperazine (163 mg, 1.06 mmol), N,N-diisopropylethylamine (92 l, 530 mol) were dissolved in acetonitrile (1.0 ml) and stirred for 15 h at 180 C. in a sealed vial under microwave irradiation. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 68.5 mg (58% of th.) of the title compound as a mixture of diastereomers.

[0844] LC-MS (Method 10): R.sub.t=1.37 min; MS (ESIpos): m/z=651 [M+H].sup.+

[0845] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (5.07), 0.008 (4.57), 1.147 (1.03), 1.157 (1.17), 1.175 (2.24), 1.192 (1.27), 1.235 (1.62), 1.259 (0.68), 1.552 (1.31), 1.581 (4.76), 1.611 (1.54), 1.907 (1.23), 1.923 (1.76), 1.941 (2.93), 1.958 (3.34), 1.975 (2.75), 1.988 (3.47), 1.993 (1.81), 2.009 (0.96), 2.366 (0.86), 2.710 (0.88), 3.101 (4.66), 3.114 (6.22), 3.128 (4.49), 3.286 (3.43), 3.335 (4.55), 3.364 (8.35), 3.393 (4.02), 3.812 (2.15), 3.835 (2.46), 3.848 (3.47), 3.859 (0.90), 3.872 (3.47), 3.884 (0.78), 3.974 (3.16), 3.982 (3.67), 4.010 (2.26), 4.020 (2.61), 4.038 (0.72), 4.280 (1.95), 4.874 (1.54), 4.914 (12.08), 4.922 (12.08), 4.962 (1.50), 5.115 (2.83), 6.868 (6.52), 6.884 (6.61), 6.896 (1.29), 6.912 (1.15), 7.520 (1.27), 7.524 (1.44), 7.538 (4.21), 7.542 (4.25), 7.557 (4.94), 7.561 (4.86), 7.566 (3.02), 7.572 (4.62), 7.585 (3.73), 7.591 (6.73), 7.600 (8.04), 7.605 (7.79), 7.613 (12.39), 7.618 (8.76), 7.624 (4.86), 7.629 (5.27), 7.634 (15.90), 7.641 (4.68), 7.683 (0.86), 7.707 (5.46), 7.711 (5.39), 7.727 (4.70), 7.731 (4.92), 7.740 (16.00), 7.745 (5.33), 7.756 (5.58), 7.761 (11.49), 7.768 (1.99), 7.775 (3.04).

[0846] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 52.3 mg dissolved in 1.5 ml ethanol; injection volume: 1.0 ml; column: Daicel Chiralpak IA 5 m, 25020 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 15 ml/min; temperature: 25 C.; UV detection: 220 nm]. 12.0 mg of diastereomer 1 (Example 67), which eluted first, and 13.0 mg of diastereomer 2 (Example 68), which eluted later, were isolated.

Example 67

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[3-(trifluoromethyl)piperazin-1-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomer 1)

[0847] Analytical chiral HPLC: R.sub.t=6.00 min, d.e.=99% [column: Chiralpak IA 2504.6 mm; eluent: iso-hexane/ethanol 50/50+0.2% diethylamine, flow rate: 1 ml/min; UV detection: 210 nm].

[0848] LC-MS (Method 2): R.sub.t=1.01 min; MS (ESIpos): m/z=651 [M+H].sup.+

[0849] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (2.09), 0.008 (2.01), 0.822 (0.69), 0.840 (0.72), 1.038 (1.33), 1.087 (2.06), 2.563 (1.94), 2.580 (1.32), 2.593 (1.26), 2.601 (0.85), 2.757 (1.97), 2.765 (2.19), 2.789 (1.57), 2.796 (1.61), 2.833 (1.49), 2.841 (1.50), 2.864 (2.92), 2.871 (2.40), 2.877 (3.26), 2.889 (2.12), 2.900 (4.49), 2.907 (4.56), 2.917 (3.06), 2.930 (5.68), 3.090 (2.69), 3.121 (2.14), 3.288 (2.90), 3.398 (2.69), 3.429 (2.42), 3.436 (2.14), 3.812 (1.97), 3.835 (2.23), 3.848 (2.86), 3.872 (3.10), 3.973 (2.95), 3.982 (3.37), 4.009 (2.13), 4.018 (2.01), 4.278 (1.59), 4.295 (1.53), 4.877 (1.64), 4.917 (10.38), 4.927 (10.34), 4.967 (1.65), 6.867 (5.00), 6.883 (5.01), 7.505 (1.38), 7.508 (1.59), 7.523 (4.16), 7.527 (4.45), 7.542 (3.99), 7.546 (4.02), 7.555 (2.82), 7.560 (3.48), 7.574 (3.96), 7.579 (4.72), 7.593 (2.20), 7.598 (2.00), 7.606 (1.63), 7.612 (10.11), 7.617 (4.22), 7.627 (8.19), 7.634 (16.00), 7.640 (2.78), 7.646 (4.02), 7.650 (3.61), 7.699 (5.16), 7.703 (5.11), 7.719 (4.22), 7.723 (4.13), 7.731 (2.54), 7.737 (14.28), 7.742 (4.67), 7.754 (3.91), 7.759 (10.05), 7.765 (1.49).

Example 68

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[3-(trifluoromethyl)piperazin-1-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomer 2)

[0850] Analytical chiral HPLC: R.sub.t=7.54 min, d.e.=99% [column: Chiralpak IA 2504.6 mm; eluent: iso-hexane/ethanol 50/50+0.2% diethylamine, flow rate: 1 ml/min; UV detection: 210 nm].

[0851] LC-MS (Method 2): R.sub.t=1.01 min; MS (ESIpos): m/z=651 [M+H].sup.+

[0852] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (2.66), 0.008 (2.32), 0.798 (0.84), 0.817 (0.81), 0.822 (1.67), 0.840 (1.83), 0.847 (0.99), 0.865 (1.36), 0.883 (0.71), 1.010 (0.68), 1.038 (2.74), 1.087 (4.07), 1.147 (1.00), 1.172 (0.92), 1.235 (2.61), 2.563 (2.17), 2.593 (1.38), 2.765 (2.31), 2.790 (1.67), 2.796 (1.71), 2.834 (1.58), 2.841 (1.58), 2.865 (3.06), 2.872 (2.51), 2.878 (3.36), 2.890 (2.26), 2.900 (4.68), 2.908 (4.79), 2.918 (3.27), 2.931 (5.74), 3.092 (2.82), 3.123 (2.25), 3.288 (3.30), 3.398 (2.85), 3.428 (2.56), 3.812 (2.02), 3.836 (2.34), 3.849 (2.96), 3.872 (3.21), 3.972 (3.09), 3.981 (3.50), 4.009 (2.23), 4.018 (2.10), 4.276 (1.69), 4.879 (1.13), 4.919 (11.99), 4.925 (11.90), 4.965 (1.14), 6.869 (5.00), 6.884 (5.00), 7.505 (1.38), 7.508 (1.62), 7.523 (4.32), 7.527 (4.56), 7.542 (4.12), 7.546 (4.17), 7.555 (2.92), 7.560 (3.59), 7.574 (4.15), 7.579 (4.88), 7.593 (2.31), 7.598 (2.11), 7.606 (1.73), 7.612 (10.34), 7.617 (4.55), 7.626 (7.56), 7.634 (16.00), 7.640 (3.13), 7.645 (4.37), 7.650 (3.76), 7.699 (5.30), 7.703 (5.26), 7.719 (4.39), 7.723 (4.34), 7.731 (2.81), 7.738 (14.53), 7.742 (5.15), 7.754 (4.23), 7.759 (10.34), 7.765 (1.65), 10.616 (0.57).

Example 69

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-{[5-oxopyrrolidin-3-yl]amino}-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomeric Mixture)

[0853] ##STR00126##

[0854] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 120 mg, 85% purity, 176 mol), 4-aminopyrrolidin-2-one hydrochloride (1:1) (241 mg, 1.76 mmol), N,N-diisopropylethylamine (400 l, 2.3 mmol) were dissolved in acetonitrile (1.0 ml) and N-methyl-2-pyrrolidone (1.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation, followed by 5 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 12.7 mg (11% of th.) of the title compound.

[0855] LC-MS (Method 2): R.sub.t=0.87 min; MS (ESIpos): m/z=597 [M+H].sup.+

[0856] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.796 (0.97), 1.178 (3.06), 1.235 (2.97), 2.128 (2.46), 2.138 (2.40), 2.170 (3.23), 2.180 (3.34), 2.422 (3.58), 2.443 (4.02), 2.463 (3.29), 2.695 (1.66), 3.085 (3.19), 3.096 (3.34), 3.110 (3.63), 3.121 (3.62), 3.287 (2.46), 3.503 (3.29), 3.521 (4.07), 3.528 (3.72), 3.546 (3.11), 3.806 (2.32), 3.830 (2.81), 3.843 (3.57), 3.867 (3.77), 3.969 (3.90), 3.977 (4.33), 4.005 (2.70), 4.013 (2.65), 4.284 (2.55), 4.363 (2.85), 4.381 (2.69), 4.829 (1.12), 4.872 (11.26), 4.878 (11.94), 4.920 (1.19), 5.754 (4.63), 6.856 (6.21), 6.875 (10.64), 6.892 (6.85), 7.466 (1.15), 7.485 (4.51), 7.498 (11.99), 7.503 (13.38), 7.516 (3.84), 7.529 (4.11), 7.535 (4.01), 7.555 (11.28), 7.564 (4.68), 7.571 (3.17), 7.611 (11.30), 7.632 (15.61), 7.656 (7.13), 7.675 (5.43), 7.741 (16.00), 7.762 (11.85).

Example 70

2-({5-[(2-Aminoethyl)amino]-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl}methyl)-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0857] ##STR00127##

[0858] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 120 mg, 85% purity, 176 mol), N-(2-aminoethyl)acetamide (190 l, 90% purity, 1.8 mmol), N,N-diisopropylethylamine (92 l, 530 mol) were dissolved in acetonitrile (1.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 56.6 mg (51% of th.) of the title compound.

[0859] LC-MS (Method 2): R.sub.t=0.71 min; MS (ESIpos): m/z=557 [M+H].sup.+

[0860] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 1.177 (0.75), 1.235 (0.72), 2.328 (0.43), 2.670 (0.58), 2.710 (0.47), 2.813 (3.87), 2.828 (7.64), 2.843 (4.27), 3.243 (1.09), 3.302 (2.99), 3.315 (6.56), 3.330 (6.41), 3.663 (0.80), 3.801 (2.77), 3.825 (3.10), 3.837 (3.83), 3.861 (3.97), 3.963 (4.09), 3.970 (4.67), 3.999 (3.04), 4.007 (2.96), 4.300 (2.05), 4.316 (2.54), 4.333 (1.77), 4.831 (0.85), 4.873 (15.50), 4.914 (0.90), 6.681 (3.00), 7.474 (1.51), 7.491 (4.24), 7.508 (5.44), 7.511 (5.30), 7.532 (6.15), 7.536 (7.68), 7.540 (7.83), 7.549 (6.33), 7.554 (5.66), 7.560 (3.80), 7.566 (2.94), 7.570 (2.21), 7.612 (11.66), 7.634 (15.14), 7.661 (5.04), 7.665 (5.45), 7.685 (4.83), 7.761 (16.00), 7.782 (11.93), 7.975 (0.47), 8.291 (2.05).

Example 71

N-(2-{[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl]amino}ethyl)acetamide

[0861] ##STR00128##

[0862] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 120 mg, 85% purity, 176 mol), N-(2-aminoethyl)acetamide (190 l, 90% purity, 1.8 mmol), N,N-diisopropylethylamine (92 l, 530 mol) were dissolved in acetonitrile (1.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 56.6 mg (51% of th.) of the title compound.

[0863] LC-MS (Method 2): R.sub.t=0.88 min; MS (ESIpos): m/z=599 [M+H].sup.+

[0864] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 1.744 (1.43), 1.752 (16.00), 3.157 (1.61), 3.172 (2.31), 3.186 (1.44), 3.206 (1.38), 3.220 (2.11), 3.235 (1.53), 3.809 (0.70), 3.833 (0.81), 3.845 (1.02), 3.869 (1.10), 3.970 (1.08), 3.979 (1.19), 4.007 (0.77), 4.859 (4.04), 4.865 (4.06), 5.754 (2.35), 6.478 (0.87), 6.493 (1.76), 6.506 (0.80), 6.892 (1.83), 6.908 (1.83), 7.487 (1.10), 7.491 (1.22), 7.502 (3.42), 7.507 (4.19), 7.521 (0.98), 7.525 (1.50), 7.532 (0.78), 7.544 (1.44), 7.551 (1.05), 7.560 (1.02), 7.567 (0.79), 7.610 (3.82), 7.615 (1.39), 7.626 (1.58), 7.632 (5.22), 7.660 (1.89), 7.663 (1.95), 7.682 (1.56), 7.746 (5.30), 7.752 (1.60), 7.763 (1.53), 7.768 (3.82), 7.846 (1.24).

Example 72

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(piperazin-1-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0865] ##STR00129##

[0866] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 120 mg, 85% purity, 176 mol), piperazine (152 mg, 1.76 mmol), N,N-diisopropylethylamine (92 l, 530 mol) were dissolved in acetonitrile (1.0 ml) and stirred for 1 h at 100 C. in a sealed vial under microwave irradiation, followed by 5 h at 120 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 87.9 mg (83% of th.) of the title compound.

[0867] LC-MS (Method 10): R.sub.t=0.93 min; MS (ESIpos): m/z=583 [M+H].sup.+

[0868] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 1.148 (0.80), 2.327 (0.70), 2.365 (0.80), 2.611 (11.55), 2.623 (15.15), 2.636 (12.52), 2.710 (0.74), 2.988 (14.02), 2.995 (12.86), 3.000 (15.89), 3.012 (12.02), 3.313 (1.58), 3.810 (2.53), 3.834 (2.85), 3.846 (3.61), 3.870 (3.86), 3.971 (3.86), 3.980 (4.41), 4.008 (2.82), 4.016 (2.61), 4.288 (2.23), 4.853 (1.41), 4.894 (13.47), 4.900 (13.38), 4.940 (1.38), 5.754 (4.92), 6.885 (0.76), 7.497 (1.64), 7.511 (4.41), 7.515 (4.83), 7.530 (4.88), 7.536 (6.14), 7.542 (4.39), 7.556 (4.67), 7.561 (5.39), 7.575 (2.29), 7.580 (2.05), 7.599 (6.80), 7.603 (6.74), 7.613 (11.97), 7.622 (5.41), 7.634 (15.35), 7.685 (5.82), 7.704 (4.77), 7.708 (4.58), 7.741 (16.00), 7.762 (11.53), 8.182 (11.02).

Example 73

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-{[(1,1-dioxidothietan-3-yl)methyl]amino}-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0869] ##STR00130##

[0870] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 120 mg, 85% purity, 176 mol), 1-(1,1-dioxidothietan-3-yl)methanamine (238 mg, 1.76 mmol), N,N-diisopropylethylamine (92 l, 530 mol) were dissolved in acetonitrile (3.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation, followed by 1 h a 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 38.2 mg (34% of th.) of the title compound.

[0871] LC-MS (Method 10): R.sub.t=1.22 min; MS (ESIpos): m/z=632 [M+H].sup.+

[0872] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.149 (0.60), 0.008 (5.59), 0.008 (4.89), 0.146 (0.58), 2.753 (1.19), 2.763 (1.44), 2.777 (2.12), 2.792 (1.48), 2.801 (1.28), 3.420 (4.63), 3.436 (7.33), 3.453 (4.30), 3.808 (2.25), 3.832 (2.61), 3.845 (3.35), 3.869 (3.66), 3.887 (4.22), 3.901 (4.27), 3.915 (2.25), 3.923 (5.67), 3.930 (2.74), 3.937 (5.36), 3.969 (3.42), 3.977 (3.83), 4.006 (2.45), 4.014 (2.31), 4.136 (5.14), 4.160 (5.72), 4.172 (4.67), 4.196 (3.84), 4.283 (1.90), 4.300 (1.83), 4.825 (2.40), 4.865 (10.95), 4.879 (10.95), 4.919 (2.38), 5.753 (10.74), 6.823 (2.58), 6.838 (5.37), 6.853 (2.64), 6.867 (6.79), 6.883 (6.84), 7.477 (0.80), 7.480 (0.87), 7.496 (3.43), 7.499 (4.09), 7.507 (6.72), 7.514 (15.04), 7.526 (2.54), 7.538 (3.79), 7.546 (2.64), 7.553 (2.24), 7.558 (4.35), 7.566 (3.06), 7.573 (2.76), 7.580 (2.20), 7.600 (1.63), 7.607 (11.32), 7.611 (4.88), 7.623 (5.00), 7.628 (15.95), 7.634 (3.09), 7.674 (5.52), 7.677 (5.84), 7.695 (4.83), 7.732 (2.61), 7.738 (16.00), 7.743 (5.85), 7.755 (4.53), 7.760 (11.82), 7.766 (2.23).

Example 74

1-[1-(2-Chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl] azetidine-3-carboxamide

[0873] ##STR00131##

[0874] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 120 mg, 85% purity, 176 mol), azetidine-3-carboxamide (177 mg, 1.76 mmol), N,N-diisopropylethylamine (92 l, 530 mol) were dissolved in acetonitrile (3.0 ml) and stirred for 7 h at 180 C. in a sealed vial under microwave irradiation. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 66.4 mg (60% of th.) of the title compound.

[0875] LC-MS (Method 10): R.sub.t=1.14 min; MS (ESIpos): m/z=597 [M+H].sup.+

[0876] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (3.24), 0.008 (3.11), 3.264 (0.74), 3.287 (3.19), 3.302 (5.34), 3.340 (1.08), 3.707 (1.89), 3.726 (10.63), 3.732 (12.70), 3.749 (16.00), 3.768 (1.41), 3.807 (2.07), 3.831 (2.38), 3.844 (2.95), 3.867 (3.19), 3.973 (3.13), 3.982 (3.46), 4.010 (2.17), 4.018 (2.04), 4.287 (1.71), 4.304 (1.62), 4.844 (1.17), 4.883 (11.80), 4.889 (11.97), 4.928 (1.05), 5.754 (10.08), 6.881 (6.12), 6.897 (6.17), 6.965 (3.77), 7.322 (3.79), 7.481 (1.61), 7.484 (1.82), 7.499 (4.35), 7.503 (4.75), 7.518 (3.72), 7.522 (3.91), 7.547 (2.61), 7.551 (3.54), 7.566 (4.19), 7.571 (5.30), 7.585 (2.33), 7.590 (2.36), 7.606 (7.01), 7.612 (12.96), 7.617 (4.76), 7.625 (5.38), 7.629 (8.42), 7.634 (14.88), 7.640 (2.49), 7.672 (5.45), 7.676 (5.79), 7.692 (4.03), 7.695 (4.15), 7.742 (2.67), 7.749 (14.15), 7.754 (4.99), 7.765 (3.98), 7.770 (10.40), 7.776 (1.55).

Example 75

2-{[5-(4-Acetylpiperazin-1-yl)-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0877] ##STR00132##

[0878] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 120 mg, 85% purity, 176 mol), 1-(piperazin-1-yl)ethanone (220 l, 1.8 mmol), N,N-diisopropylethylamine (65 l, 370 mol) were dissolved in acetonitrile (1.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 80.4 mg (71% of th.) of the title compound.

[0879] LC-MS (Method 10): R.sub.t=1.22 min; MS (ESIpos): m/z=625 [M+H].sup.+

[0880] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.60), 0.008 (1.50), 1.157 (1.17), 1.175 (2.34), 1.192 (1.20), 1.940 (16.00), 1.988 (4.30), 3.065 (3.78), 3.072 (3.15), 3.286 (1.39), 3.344 (1.73), 3.362 (3.14), 3.370 (2.95), 3.389 (1.36), 3.812 (0.69), 3.836 (0.78), 3.849 (1.00), 3.872 (1.08), 3.974 (0.99), 3.982 (1.14), 4.020 (1.65), 4.038 (1.03), 4.910 (3.95), 4.917 (3.91), 6.869 (2.04), 6.885 (2.05), 7.528 (1.51), 7.532 (1.63), 7.547 (1.44), 7.551 (1.49), 7.558 (1.15), 7.563 (1.33), 7.578 (1.49), 7.583 (1.76), 7.597 (0.83), 7.602 (0.78), 7.613 (3.72), 7.618 (1.41), 7.629 (1.85), 7.634 (6.89), 7.638 (2.83), 7.652 (1.40), 7.657 (1.30), 7.700 (1.85), 7.705 (1.79), 7.720 (1.58), 7.724 (1.46), 7.741 (5.19), 7.746 (1.58), 7.757 (1.39), 7.762 (3.67).

Example 76

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(3,3-dimethylpiperazin-1-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0881] ##STR00133##

[0882] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 120 mg, 85% purity, 176 mol), 2,2-dimethylpiperazine (201 mg, 1.76 mmol), N,N-diisopropylethylamine (65 l, 370 mol) were dissolved in acetonitrile (1.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 80.3 mg (74% of th.) of the title compound.

[0883] LC-MS (Method 10): R.sub.t=0.96 min; MS (ESIpos): m/z=613 [M+H].sup.+

[0884] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.874 (16.00), 1.157 (0.62), 1.175 (1.23), 1.193 (0.64), 1.988 (2.18), 2.687 (0.99), 2.699 (1.39), 2.712 (1.25), 2.751 (4.49), 2.956 (1.17), 2.965 (1.17), 2.970 (1.40), 2.982 (0.97), 3.850 (0.68), 3.873 (0.73), 3.973 (0.74), 3.982 (0.84), 4.020 (0.93), 4.038 (0.57), 4.903 (2.40), 4.911 (2.35), 7.525 (0.86), 7.529 (0.92), 7.544 (0.91), 7.548 (0.98), 7.557 (0.77), 7.571 (0.84), 7.576 (0.99), 7.614 (3.01), 7.620 (1.58), 7.635 (3.49), 7.692 (1.03), 7.696 (1.01), 7.712 (0.82), 7.716 (0.78), 7.739 (2.96), 7.744 (0.92), 7.756 (0.82), 7.761 (2.09), 8.187 (3.06).

Example 77

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[2-(trifluoromethyl)morpholin-4-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0885] ##STR00134##

[0886] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 120 mg, 208 mol), 2-(trifluoromethyl)morpholine hydrochloride (1:1) (199 mg, 1.04 mmol), N,N-diisopropylethylamine (290 l, 1.7 mmol) were dissolved in acetonitrile (3.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 56.0 mg (41% of th.) of the title compound as a mixture of diastereomers.

[0887] LC-MS (Method 10): R.sub.t=1.44 min; MS (ESIpos): m/z=652 [M+H].sup.+

[0888] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.149 (0.66), 0.008 (6.02), 0.008 (5.39), 0.146 (0.64), 2.085 (8.52), 2.977 (3.54), 2.988 (1.46), 3.003 (3.88), 3.008 (5.21), 3.015 (2.39), 3.020 (2.13), 3.034 (3.86), 3.040 (2.39), 3.048 (1.81), 3.130 (2.91), 3.160 (1.78), 3.287 (2.61), 3.444 (2.70), 3.474 (2.36), 3.512 (1.35), 3.519 (1.64), 3.541 (2.93), 3.548 (2.82), 3.569 (1.66), 3.576 (1.33), 3.815 (1.90), 3.839 (2.39), 3.852 (5.24), 3.876 (4.49), 3.975 (2.74), 3.984 (3.05), 4.012 (1.93), 4.021 (1.85), 4.164 (1.04), 4.171 (1.39), 4.180 (1.38), 4.189 (1.84), 4.197 (1.43), 4.206 (1.27), 4.213 (1.00), 4.275 (1.49), 4.894 (1.18), 4.934 (10.22), 4.942 (9.53), 4.983 (1.07), 5.754 (4.21), 6.863 (5.82), 6.879 (5.87), 7.517 (1.55), 7.520 (1.78), 7.535 (4.52), 7.539 (4.70), 7.554 (4.03), 7.558 (4.02), 7.569 (2.93), 7.574 (3.63), 7.589 (4.20), 7.594 (5.00), 7.608 (3.57), 7.613 (12.28), 7.618 (3.97), 7.630 (4.40), 7.635 (15.02), 7.641 (2.25), 7.655 (5.50), 7.660 (5.21), 7.675 (4.03), 7.679 (3.77), 7.711 (5.46), 7.715 (5.27), 7.731 (6.41), 7.737 (16.00), 7.742 (4.55), 7.754 (3.95), 7.759 (10.38), 7.765 (1.35).

Example 78

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-{[(3-methyloxetan-3-yl)methyl]amino}-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0889] ##STR00135##

[0890] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 120 mg, 85% purity, 176 mol), 1-(3-methyloxetan-3-yl)methanamine (178 mg, 1.76 mmol), N,N-diisopropylethylamine (65 l, 370 mol) were dissolved in acetonitrile (1.0 ml) and stirred for 6 h at 160 C. in a sealed vial under microwave irradiation. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 40.0 mg (38% of th.) of the title compound.

[0891] LC-MS (Method 10): R.sub.t=1.25 min; MS (ESIpos): m/z=598 [M+H].sup.+

[0892] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (3.07), 0.008 (2.43), 1.091 (16.00), 1.157 (1.62), 1.175 (3.22), 1.192 (1.64), 1.988 (5.53), 3.232 (3.68), 3.250 (5.62), 3.254 (6.25), 3.268 (4.58), 3.287 (1.73), 3.524 (4.79), 3.543 (4.21), 3.808 (0.88), 3.832 (1.04), 3.844 (1.28), 3.868 (1.39), 3.971 (1.34), 3.979 (1.48), 4.003 (0.79), 4.007 (0.99), 4.016 (0.98), 4.021 (1.61), 4.038 (1.32), 4.825 (1.64), 4.838 (3.28), 4.851 (1.61), 4.866 (5.45), 4.871 (5.39), 6.877 (2.63), 6.892 (2.64), 7.469 (0.73), 7.472 (0.79), 7.487 (2.06), 7.491 (2.15), 7.506 (1.81), 7.510 (1.76), 7.529 (1.21), 7.534 (1.57), 7.549 (1.84), 7.554 (2.30), 7.568 (1.12), 7.573 (1.07), 7.585 (2.69), 7.589 (2.29), 7.604 (2.10), 7.608 (2.34), 7.613 (5.05), 7.618 (1.84), 7.629 (2.19), 7.634 (6.68), 7.641 (0.99), 7.656 (2.53), 7.660 (2.52), 7.676 (1.93), 7.680 (1.77), 7.739 (1.13), 7.745 (6.69), 7.750 (2.12), 7.761 (1.86), 7.766 (4.72).

Example 79

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(2-methoxyethyl)amino]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0893] ##STR00136##

[0894] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 78.0 mg, 135 mol) was dissolved in 2 ml of acetonitrile. 2-methoxyethanamine (113 l, 1.30 mmol) and N,N-diisopropylethylamine (49 l, 280 mol) were added and the mixture was stirred under microwave radiation at 150 C. for 1 h. Additional 2-methoxyethanamine (200 l, 2.3 mmol) was added and the mixture was stirred under microwave radiation at 150 C. for 4 h. After cooling to room temperature, the mixture was diluted with 2 ml of water and extracted twice with 10 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (Method 5) to afford 38.5 mg (50% of th.) of the title compound.

[0895] LC-MS (Method 2): R.sub.t=1.00 min; MS (ESIpos): m/z=572 [M+H].sup.+

[0896] .sup.1H-NMR (500 MHz, DMSO-d6) [ppm]: 0.120 (0.54), 0.007 (5.78), 0.006 (4.40), 0.117 (0.53), 1.077 (1.33), 1.091 (2.69), 1.105 (1.33), 1.236 (0.47), 2.361 (0.51), 2.635 (0.49), 3.207 (16.00), 3.323 (2.17), 3.335 (2.29), 3.346 (1.05), 3.363 (0.47), 3.377 (1.40), 3.390 (3.52), 3.402 (3.06), 3.415 (1.03), 3.814 (0.61), 3.833 (0.67), 3.843 (0.82), 3.862 (0.86), 3.972 (0.84), 3.979 (0.96), 4.002 (0.66), 4.009 (0.61), 4.292 (0.43), 4.824 (0.51), 4.856 (2.91), 4.865 (2.84), 4.897 (0.50), 6.442 (0.70), 6.454 (1.41), 6.465 (0.67), 6.875 (1.07), 6.886 (1.08), 7.482 (3.06), 7.488 (2.36), 7.509 (0.30), 7.527 (0.82), 7.534 (0.72), 7.543 (0.99), 7.549 (0.80), 7.555 (0.62), 7.561 (0.55), 7.613 (2.99), 7.630 (3.87), 7.658 (1.92), 7.675 (1.29), 7.744 (3.83), 7.761 (2.95).

Example 80

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(2-hydroxyethyl)amino]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0897] ##STR00137##

[0898] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 100 mg, 173 mol) was dissolved in 2 ml of acetonitrile. 2-Aminoethanol (261 l, 4.30 mmol) and N,N-diisopropylethylamine (63 l, 360 mol) were added and the mixture was stirred under microwave radiation at 150 C. for 3 h. After cooling to room temperature, the mixture was diluted with 2 ml of water and extracted twice with 10 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (Method 5) to afford 52 mg (54% of th.) of the title compound.

[0899] LC-MS (Method 2): R.sub.t=0.91 min; MS (ESIpos): m/z=558 [M+H].sup.+

[0900] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.01), 0.008 (0.97), 3.162 (2.52), 3.175 (2.60), 3.221 (2.36), 3.237 (7.13), 3.252 (7.83), 3.267 (3.29), 3.440 (3.29), 3.455 (7.94), 3.470 (7.24), 3.486 (2.48), 3.807 (2.09), 3.830 (2.36), 3.843 (2.94), 3.867 (3.18), 3.969 (3.14), 3.978 (3.68), 4.006 (2.36), 4.015 (2.21), 4.077 (0.74), 4.090 (0.74), 4.295 (1.51), 4.643 (3.25), 4.657 (6.97), 4.671 (3.14), 4.814 (1.36), 4.854 (11.78), 4.861 (11.78), 4.900 (1.36), 6.326 (2.52), 6.341 (5.35), 6.355 (2.48), 6.887 (4.96), 7.466 (0.66), 7.469 (0.66), 7.485 (3.10), 7.489 (3.87), 7.496 (5.93), 7.501 (8.68), 7.503 (14.76), 7.510 (1.51), 7.514 (2.05), 7.524 (3.91), 7.532 (2.44), 7.539 (1.98), 7.544 (4.15), 7.547 (1.90), 7.552 (2.83), 7.558 (2.71), 7.566 (2.09), 7.605 (1.28), 7.611 (11.23), 7.616 (3.84), 7.627 (4.30), 7.632 (15.65), 7.639 (2.01), 7.658 (5.00), 7.660 (5.50), 7.677 (3.10), 7.679 (4.73), 7.740 (2.17), 7.746 (16.00), 7.752 (4.61), 7.763 (3.95), 7.768 (11.58), 7.775 (1.39).

Example 81

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(3,3-difluoroazetidin-1-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0901] ##STR00138##

[0902] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 80.0 mg, 138 mol) was dissolved in 2 ml of acetonitrile. 3,3-difluoroazetidine hydrochloride (1:1) (180 mg, 1.38 mmol) and N,N-diisopropylethylamine (240 l, 1.38 mmol) were added and the mixture was stirred under microwave radiation at 120 C. for 2 h. Additional 3,3-difluoroazetidine hydrochloride (1:1) (180 mg, 1.38 mmol) and N,N-diisopropylethylamine (240 l, 1.38 mmol) were added and the mixture was stirred at 85 C. for 48 h in a closed vial. After cooling to room temperature, the mixture was diluted with 5 ml of water and extracted twice with 10 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (SiO2, cyclohexane/ethyl acetate gradient) to afford 34 mg (42% of th.) of the title compound.

[0903] LC-MS (Method 2): R.sub.t=1.09 min; MS (ESIpos): m/z=590 [M+H].sup.+

[0904] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.149 (1.13), 0.008 (14.17), 0.008 (8.32), 1.744 (2.31), 1.821 (0.78), 1.853 (4.83), 1.866 (3.95), 1.872 (3.36), 3.814 (2.15), 3.838 (2.47), 3.851 (3.30), 3.875 (3.36), 3.976 (3.14), 3.985 (3.33), 4.013 (2.42), 4.021 (2.12), 4.044 (1.64), 4.137 (4.97), 4.168 (8.99), 4.198 (4.72), 4.282 (1.80), 4.886 (1.10), 4.926 (13.29), 4.930 (12.72), 4.970 (0.91), 6.875 (6.07), 6.891 (6.01), 7.501 (2.17), 7.505 (2.23), 7.520 (5.21), 7.523 (5.05), 7.539 (4.13), 7.542 (4.05), 7.573 (3.19), 7.577 (3.60), 7.592 (4.81), 7.597 (5.29), 7.615 (13.15), 7.636 (15.30), 7.661 (6.23), 7.665 (5.66), 7.680 (5.61), 7.686 (7.46), 7.690 (6.04), 7.706 (4.46), 7.710 (3.97), 7.744 (16.00), 7.749 (4.81), 7.761 (4.48), 7.765 (10.98).

Example 82

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(2-hydroxy-2-methylpropyl)amino]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0905] ##STR00139##

[0906] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 80.0 mg, 138 mol) was dissolved in 2 ml of acetonitrile. 1-Amino-2-methylpropan-2-ol (123 mg, 1.38 mmol) and N,N-diisopropylethylamine (51 l, 290 mol) were added and the mixture was stirred under microwave radiation at 150 C. for 1 h. Additional 1-amino-2-methylpropan-2-ol (123 mg, 1.38 mmol) and N,N-diisopropylethylamine (51 l, 290 mol) were added and the mixture was stirred under microwave radiation at 150 C. for further 2 h. After cooling to room temperature, the mixture was diluted with 5 ml of water and extracted twice with 10 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (Method 5) to afford 48.5 mg (60% of th.) of the title compound.

[0907] LC-MS (Method 2): R.sub.t=1.01 min; MS (ESIpos): m/z=586 [M+H].sup.+

[0908] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (0.68), 0.008 (0.63), 1.049 (16.00), 1.073 (2.08), 1.091 (4.06), 1.108 (2.06), 1.125 (0.17), 1.158 (3.43), 1.908 (0.12), 2.709 (1.03), 3.168 (1.72), 3.183 (1.73), 3.357 (0.69), 3.375 (1.99), 3.392 (1.95), 3.410 (0.64), 3.803 (0.43), 3.827 (0.50), 3.840 (0.62), 3.864 (0.68), 3.965 (0.62), 3.973 (0.69), 4.002 (0.43), 4.010 (0.42), 4.287 (0.33), 4.640 (3.77), 4.813 (0.29), 4.853 (2.41), 4.860 (2.41), 4.900 (0.29), 4.980 (0.40), 6.112 (0.49), 6.127 (1.03), 6.142 (0.48), 6.880 (1.32), 6.896 (1.33), 7.486 (0.17), 7.502 (0.66), 7.506 (0.79), 7.521 (3.14), 7.537 (1.00), 7.544 (0.57), 7.556 (0.97), 7.564 (0.67), 7.571 (0.60), 7.579 (0.46), 7.611 (2.33), 7.633 (3.27), 7.680 (1.13), 7.699 (0.94), 7.739 (3.29), 7.743 (1.03), 7.755 (0.86), 7.760 (2.32).

Example 83

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(morpholin-4-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0909] ##STR00140##

[0910] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 82.0 mg, 142 mol) was dissolved in 2 ml of acetonitrile. Morpholine (120 l, 1.4 mmol) and N,N-diisopropylethylamine (52 l, 300 mol) were added and the mixture was stirred under microwave radiation at 140 C. for 1 h. Additional morpholine (120 l, 1.4 mmol) and N,N-diisopropylethylamine (52 l, 300 mol) were added and the mixture was stirred under microwave radiation at 140 C. for 1 h. After cooling to room temperature, the mixture was diluted with 5 ml of water and extracted twice with 10 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (Method 5) to afford 51 mg (62% of th.) of the title compound.

[0911] LC-MS (Method 2): R.sub.t=1.03 min; MS (ESIpos): m/z=584 [M+H].sup.+

[0912] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (2.75), 0.008 (2.48), 1.073 (7.78), 1.091 (16.00), 1.108 (8.08), 3.024 (8.34), 3.036 (10.57), 3.048 (9.21), 3.357 (2.71), 3.375 (7.92), 3.392 (7.72), 3.410 (2.55), 3.494 (9.33), 3.507 (10.42), 3.518 (8.40), 3.811 (1.50), 3.834 (1.70), 3.847 (2.16), 3.871 (2.34), 3.972 (2.28), 3.981 (2.65), 4.009 (1.66), 4.018 (1.60), 4.290 (1.03), 4.869 (1.01), 4.908 (8.69), 4.915 (8.69), 4.955 (0.99), 6.880 (2.73), 7.500 (1.09), 7.504 (1.25), 7.518 (3.43), 7.522 (3.56), 7.537 (3.43), 7.541 (3.35), 7.546 (2.51), 7.551 (3.15), 7.566 (3.21), 7.571 (3.96), 7.585 (1.78), 7.589 (1.50), 7.607 (1.07), 7.613 (8.28), 7.619 (6.81), 7.624 (4.61), 7.630 (3.56), 7.635 (12.08), 7.643 (3.54), 7.692 (4.02), 7.696 (3.58), 7.711 (3.37), 7.715 (2.99), 7.735 (1.62), 7.741 (11.66), 7.746 (3.52), 7.758 (2.95), 7.763 (8.24), 7.769 (1.09).

Example 84

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(2-hydroxyethyl)(methyl)amino]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0913] ##STR00141##

[0914] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 82.0 mg, 142 mol) was dissolved in 2 ml of acetonitrile. 2-(Methylamino)ethanol (57 l, 710 mol) and N,N-diisopropylethylamine (52 l, 300 mol) were added and the mixture was stirred under microwave radiation at 150 C. for 2 h. Additional 2-(methylamino)ethanol (57 l, 710 mol) and N,N-diisopropylethylamine (52 l, 300 mol) were added and the mixture was stirred under microwave radiation at 150 C. for further 1.5 h. After cooling to room temperature, the mixture was diluted with 5 ml of water and extracted twice with 10 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (Method 5) to afford 50 mg (62% of th.) of the title compound.

[0915] LC-MS (Method 2): R.sub.t=0.97 min; MS (ESIpos): m/z=572 [M+H].sup.+

[0916] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.50), 0.008 (1.19), 1.073 (6.89), 1.091 (14.03), 1.108 (7.00), 2.366 (0.21), 2.695 (16.00), 3.162 (0.31), 3.175 (0.34), 3.199 (1.33), 3.215 (3.34), 3.230 (1.89), 3.357 (2.30), 3.375 (6.88), 3.392 (7.03), 3.410 (4.45), 3.424 (2.42), 3.440 (0.80), 3.805 (0.68), 3.828 (0.77), 3.841 (0.96), 3.865 (1.04), 3.967 (0.93), 3.976 (1.06), 4.004 (0.68), 4.012 (0.63), 4.278 (0.48), 4.638 (1.31), 4.651 (2.89), 4.664 (1.25), 4.818 (0.53), 4.858 (3.79), 4.866 (3.74), 4.906 (0.51), 6.871 (1.79), 6.886 (1.81), 7.472 (0.52), 7.476 (0.60), 7.490 (1.59), 7.495 (1.62), 7.509 (1.49), 7.513 (1.45), 7.520 (1.06), 7.525 (1.31), 7.540 (1.43), 7.545 (1.75), 7.559 (0.81), 7.563 (0.69), 7.603 (2.16), 7.608 (2.40), 7.611 (3.94), 7.616 (1.39), 7.622 (1.56), 7.627 (2.55), 7.633 (5.27), 7.650 (1.91), 7.653 (1.71), 7.669 (1.51), 7.673 (1.30), 7.741 (5.41), 7.746 (1.52), 7.758 (1.36), 7.763 (3.77).

Example 85

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(2-methoxyethyl)(methyl)amino]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0917] ##STR00142##

[0918] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, 82.0 mg, 142 mol) was dissolved in 2 ml of acetonitrile. 2-Methoxy-N-methylethanamine (126 mg, 1.42 mmol) and N,N-diisopropylethylamine (52 l, 300 mol) were added and the mixture was stirred under microwave radiation at 150 C. for 2 h. Additional 2-methoxy-N-methylethanamine (126 mg, 1.42 mmol) and N,N-diisopropylethylamine (52 l, 300 mol) were added and the mixture was stirred under microwave radiation at 150 C. for further 2 h. After cooling to room temperature, the mixture was diluted with 5 ml of water and extracted twice with 10 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (Method 5) to afford 60 mg (72% of th.) of the title compound.

[0919] LC-MS (Method 2): R.sub.t=1.07 min; MS (ESIpos): m/z=586 [M+H].sup.+

[0920] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (0.59), 1.073 (3.51), 1.091 (7.17), 1.108 (3.63), 2.366 (0.16), 2.681 (13.35), 2.710 (0.20), 3.148 (16.00), 3.162 (1.82), 3.175 (1.82), 3.331 (4.20), 3.340 (3.00), 3.357 (1.51), 3.375 (3.55), 3.392 (3.51), 3.410 (1.16), 3.807 (0.61), 3.830 (0.70), 3.843 (0.92), 3.867 (0.96), 3.968 (0.87), 3.976 (0.98), 4.004 (0.62), 4.013 (0.60), 4.063 (0.12), 4.076 (0.33), 4.089 (0.33), 4.278 (0.51), 4.825 (0.49), 4.864 (3.33), 4.874 (3.29), 4.913 (0.48), 5.119 (0.73), 6.868 (1.86), 6.884 (1.86), 6.897 (0.26), 6.913 (0.23), 7.482 (0.44), 7.498 (1.25), 7.501 (1.27), 7.516 (1.17), 7.520 (1.16), 7.527 (0.83), 7.532 (1.00), 7.546 (1.18), 7.551 (1.37), 7.565 (0.62), 7.570 (0.59), 7.612 (4.31), 7.628 (2.21), 7.633 (4.73), 7.639 (1.03), 7.656 (1.55), 7.660 (1.45), 7.676 (1.23), 7.680 (1.15), 7.738 (4.57), 7.754 (1.62), 7.759 (3.30), 7.774 (0.64), 7.794 (0.13).

Example 86

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0921] ##STR00143##

[0922] 2-{[5-Bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 5A, intermediate 17, 82.0 mg, 142 mol) was dissolved in 2 ml of acetonitrile. 2-Oxa-6-azaspiro[3.3]heptane ethanedioate (1:1) (131 mg, 692 mol) and N,N-diisopropylethylamine (240 l, 1.4 mmol) were added and the mixture was stirred at 80 C. for 5 d in a closed vial. Additional 2-oxa-6-azaspiro[3.3]heptane ethanedioate (1:1) (131 mg, 692 mol) and N,N-diisopropylethylamine (240 l, 1.4 mmol) were added and the mixture was stirred at 80 C. for further 2 d. After cooling to room temperature, the mixture was diluted with 5 ml of water and extracted twice with 10 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (Method 5) to afford 11 mg (13% of th.) of the title compound.

[0923] LC-MS (Method 2): R.sub.t=0.99 min; MS (ESIpos): m/z=596 [M+H].sup.+

[0924] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.01), 0.008 (0.91), 1.073 (1.92), 1.091 (3.85), 1.109 (1.82), 2.328 (0.61), 2.366 (0.81), 2.665 (0.51), 2.670 (0.61), 2.675 (0.51), 2.710 (0.81), 3.357 (1.11), 3.375 (2.03), 3.392 (1.92), 3.410 (0.71), 3.811 (0.81), 3.834 (0.91), 3.847 (1.32), 3.871 (10.43), 3.973 (1.11), 3.981 (1.11), 4.010 (0.71), 4.280 (0.61), 4.558 (16.00), 4.869 (4.56), 4.874 (4.56), 6.876 (2.23), 6.892 (2.23), 7.486 (0.61), 7.490 (0.61), 7.505 (1.92), 7.510 (1.01), 7.523 (1.62), 7.527 (1.62), 7.555 (0.71), 7.560 (1.72), 7.570 (2.13), 7.574 (3.75), 7.577 (3.04), 7.590 (1.32), 7.594 (2.73), 7.599 (0.81), 7.607 (0.61), 7.614 (4.15), 7.618 (1.42), 7.630 (1.82), 7.635 (5.87), 7.641 (0.81), 7.669 (1.72), 7.673 (2.23), 7.683 (0.51), 7.693 (1.62), 7.734 (0.81), 7.739 (5.87), 7.745 (1.62), 7.756 (1.42), 7.761 (4.05), 7.768 (0.51).

Example 87

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0925] ##STR00144##

[0926] To a solution of 5-(4-chlorophenyl)-2-{[5-(pyrrolidin-1-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (example 9A, 100 mg, 0.22 mmol) in pyridine (2.8 ml) were added (2-chlorophenyl)boronic acid (68.3 mg, 0.44 mmol) and copper(II) acetate (79.3 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 3 days, after which extra boronic acid (34.2 mg, 0.22 mmol) was added due to incomplete conversion. After stirring for five additional days, the reaction mixture was diluted with MTBE and then quenched with aqueous hydrochloric acid (0.5 M). After phase separation, the aqueous phase was extracted twice with MTBE. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (Method 13), affording 3.05 mg (4.8 mol, 90% purity, 2.2% of th.) of the title compound.

[0927] LC-MS (Method 3): R.sub.t=1.38 min; MS [ESIpos]: m/z=568 (M+H).sup.+

[0928] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) [ppm]: 7.73-7.78 (m, 2H), 7.60-7.66 (m, 4H), 7.55 (td, 1H), 7.48 (m, 1H), 6.85-6.91 (m, 1H), 4.82-4.90 (m, 2H), 4.25-4.33 (m, 1H), 3.99 (dd, 1H), 3.84 (dd, 1H), 3.00-3.12 (m, 4H), 1.71-1.78 (m, 4H)

Example 88

5-(4-Chlorophenyl)-2-{[1-(3-fluorophenyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0929] ##STR00145##

[0930] To a solution of 5-(4-chlorophenyl)-2-{[5-(pyrrolidin-1-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 9A, 100 mg, 0.22 mmol) in pyridine (2.8 ml) were added (3-fluorophenyl)boronic acid (61.1 mg, 0.44 mmol) and copper(II) acetate (79.3 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 4 days. The reaction mixture was then diluted with MTBE and quenched with aqueous hydrochloric acid (0.5 M). After phase separation, the aqueous phase was extracted twice with MTBE. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (Method 13), affording 3.9 mg (0.01 mmol, 3.0% of th.) of the title compound.

[0931] LC-MS (Method 4): R.sub.t=3.49 min; MS [ESIpos]: m/z=552 (M+H).sup.+

[0932] .sup.1H-NMR (500 MHz, DMSO-d6) [ppm]: 7.73-7.77 (m, 2H), 7.60-7.64 (m, 2H), 7.54 (td, 1H), 7.36 (dt, 1H), 7.26-7.33 (m, 2H), 6.87 (br. s., 1H), 4.83-4.91 (m, 2H), 4.29 (br. s., 1H), 3.99 (dd, 1H), 3.84 (dd, 1H), 3.11-3.17 (m, 4H), 1.75-1.81 (m, 4H)

Example 89

4-[3-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(2-fluorophenyl)-1H-1,2,4-triazol-5-yl]piperazin-2-one

[0933] ##STR00146##

[0934] 2-{[5-bromo-1-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 14A, 80.0 mg, 85% purity, 121 mol), piperazin-2-one (121 mg, 1.21 mmol), N,N-diisopropylethylamine (44 l, 250 mol) were dissolved in acetonitrile (1.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation, followed by 5 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 60.5 mg (86% of th.) of the title compound.

[0935] LC-MS (Method 12): R.sub.t=1.59 min; MS (ESIpos): m/z=581 [M+H].sup.+

[0936] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.80), 3.109 (1.98), 3.121 (3.47), 3.127 (4.06), 3.135 (3.03), 3.142 (2.28), 3.263 (4.34), 3.277 (5.26), 3.289 (4.25), 3.622 (16.00), 3.807 (1.39), 3.830 (1.60), 3.843 (1.94), 3.867 (2.05), 3.973 (2.02), 3.982 (2.16), 4.010 (1.41), 4.018 (1.28), 4.283 (1.13), 4.300 (1.03), 4.927 (11.53), 6.877 (3.84), 6.893 (3.77), 7.370 (1.40), 7.373 (1.38), 7.389 (3.00), 7.392 (2.91), 7.408 (1.80), 7.411 (1.73), 7.470 (1.27), 7.473 (1.25), 7.491 (2.04), 7.495 (2.33), 7.499 (1.39), 7.517 (1.79), 7.520 (1.56), 7.579 (1.08), 7.583 (1.29), 7.592 (1.42), 7.596 (2.04), 7.604 (2.51), 7.611 (8.08), 7.616 (3.94), 7.623 (3.31), 7.628 (4.77), 7.632 (9.80), 7.639 (2.08), 7.643 (3.16), 7.647 (2.35), 7.662 (1.38), 7.667 (1.05), 7.738 (1.99), 7.744 (9.65), 7.750 (2.80), 7.761 (2.82), 7.766 (6.78), 8.017 (2.75).

Example 90

5-(4-Chlorophenyl)-2-{[5-(1,1-dioxidothiomorpholin-4-yl)-1-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0937] ##STR00147##

[0938] 2-{[5-Bromo-1-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 14A, 80.0 mg, 85% purity, 121 mol), thiomorpholine 1,1-dioxide (164 mg, 1.21 mmol), N,N-diisopropylethylamine (44 l, 250 mol) were dissolved in acetonitrile (1.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation, followed by 2 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 69.5 mg (93% of th.) of the title compound.

[0939] LC-MS (Method 12): R.sub.t=1.74 min; MS (ESIpos): m/z=616 [M+H].sup.+

[0940] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (2.11), 0.008 (1.90), 3.133 (7.24), 3.145 (9.33), 3.159 (8.05), 3.289 (1.61), 3.535 (8.10), 3.549 (8.79), 3.562 (7.11), 3.810 (1.94), 3.833 (2.16), 3.846 (2.78), 3.870 (2.95), 3.973 (2.75), 3.982 (3.09), 4.009 (1.94), 4.019 (1.81), 4.276 (1.49), 4.294 (1.40), 4.905 (0.92), 4.945 (11.78), 4.949 (11.90), 4.989 (0.85), 6.866 (5.75), 6.881 (5.81), 7.375 (1.88), 7.378 (2.05), 7.397 (4.26), 7.413 (2.42), 7.417 (2.52), 7.479 (1.68), 7.482 (1.86), 7.500 (2.84), 7.504 (3.53), 7.508 (2.12), 7.525 (2.71), 7.529 (2.54), 7.575 (1.37), 7.580 (1.58), 7.588 (1.65), 7.593 (2.40), 7.610 (12.41), 7.614 (5.56), 7.619 (1.85), 7.626 (5.01), 7.631 (15.14), 7.637 (2.14), 7.698 (2.16), 7.702 (2.19), 7.717 (4.10), 7.721 (4.08), 7.732 (2.73), 7.738 (16.00), 7.743 (5.14), 7.755 (3.69), 7.760 (10.18), 7.766 (1.35).

Example 91

2-({5-[(2-Amino-2-methylpropyl)amino]-1-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl}methyl)-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0941] ##STR00148##

[0942] 2-{[5-Bromo-1-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 14A, 80.0 mg, 85% purity, 121 mol), 2-methylpropane-1,2-diamine (107 mg, 1.21 mmol), N,N-diisopropylethylamine (44 l, 250 mol) were dissolved in acetonitrile (690 l) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation, followed by 5 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 56.9 mg (78% of th.) of the title compound.

[0943] LC-MS (Method 10): R.sub.t=0.93 min; MS (ESIneg): m/z=567 [MH].sup.+

[0944] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.19), 0.008 (0.68), 1.089 (16.00), 3.260 (2.29), 3.274 (2.22), 3.799 (0.73), 3.823 (0.84), 3.836 (0.98), 3.860 (1.06), 3.963 (1.09), 3.972 (1.24), 3.999 (0.82), 4.008 (0.75), 4.867 (5.30), 6.795 (0.76), 7.332 (0.63), 7.336 (0.71), 7.351 (1.37), 7.355 (1.41), 7.370 (0.91), 7.374 (0.97), 7.427 (0.67), 7.449 (1.19), 7.454 (0.72), 7.472 (0.87), 7.475 (0.88), 7.523 (1.69), 7.537 (1.02), 7.542 (2.61), 7.546 (1.74), 7.556 (1.03), 7.561 (1.24), 7.566 (0.91), 7.609 (3.76), 7.614 (1.39), 7.625 (1.54), 7.631 (5.13), 7.637 (0.78), 7.740 (0.67), 7.746 (4.92), 7.751 (1.59), 7.763 (1.34), 7.768 (3.66).

Example 92

2-({5-[(2-Amino-2-methylpropyl)amino]-1-(3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl}methyl)-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0945] ##STR00149##

[0946] 2-{[5-Bromo-1-(3-fluoropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 23A, 60.0 mg, 107 mol), 2-methylpropane-1,2-diamine (110 l, 1.1 mmol), N,N-diisopropylethylamine (39 l, 220 mol) were dissolved in acetonitrile (1.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation, followed by 1 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 26.4 mg (43% of th.) of the title compound.

[0947] LC-MS (Method 3): R.sub.t=1.16 min; MS (ESIpos): m/z=570 [M+H].sup.+

[0948] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 1.109 (16.00), 3.357 (2.14), 3.372 (2.08), 3.805 (0.59), 3.829 (0.66), 3.842 (0.83), 3.866 (0.88), 3.969 (0.91), 3.977 (1.03), 4.005 (0.66), 4.014 (0.63), 4.891 (5.31), 7.523 (0.65), 7.525 (0.71), 7.535 (1.14), 7.544 (0.75), 7.546 (0.85), 7.555 (0.65), 7.605 (2.81), 7.610 (1.36), 7.621 (1.57), 7.627 (4.42), 7.739 (4.12), 7.745 (1.44), 7.756 (1.18), 7.761 (3.12), 7.982 (0.70), 8.006 (0.81), 8.009 (0.77), 8.030 (0.66), 8.366 (1.44), 8.378 (1.45).

Example 93

2-({5-[(2-Amino-2-methylpropyl)amino]-1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl}methyl)-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0949] ##STR00150##

[0950] 2-{[5-Bromo-1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 32A, 60.0 mg, 93% purity, 102 mol), 2-methylpropane-1,2-diamine (110 l, 1.0 mmol), N,N-diisopropylethylamine (37 l, 210 mol) were dissolved in acetonitrile (1.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation, followed by 1 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 57.0 mg (99% of th.) of the title compound.

[0951] LC-MS (Method 3): R.sub.t=1.25 min; MS (ESIpos): m/z=552 [M+H].sup.+

[0952] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 1.260 (1.01), 1.276 (16.00), 1.477 (1.07), 3.626 (2.77), 3.642 (2.72), 3.836 (0.70), 3.859 (0.89), 3.872 (1.11), 3.895 (1.10), 3.995 (1.14), 4.004 (1.33), 4.032 (0.83), 4.041 (0.80), 4.310 (0.70), 4.883 (0.93), 4.923 (4.05), 4.931 (3.96), 4.970 (0.63), 7.324 (1.00), 7.326 (1.00), 7.336 (1.10), 7.338 (1.23), 7.342 (1.23), 7.344 (1.08), 7.355 (1.11), 7.357 (1.04), 7.612 (3.55), 7.617 (1.46), 7.628 (1.85), 7.633 (4.85), 7.639 (0.90), 7.705 (1.89), 7.726 (2.18), 7.739 (0.99), 7.745 (5.00), 7.750 (1.71), 7.762 (1.74), 7.767 (3.60), 7.997 (0.92), 8.001 (0.92), 8.015 (1.26), 8.017 (1.41), 8.019 (1.41), 8.036 (0.81), 8.041 (0.79), 8.133 (2.19), 8.473 (1.32), 8.475 (1.46), 8.478 (1.47), 8.486 (1.39), 8.487 (1.49), 8.490 (1.38), 8.530 (0.76), 8.546 (1.60), 8.563 (0.79).

Example 94

2-({5-[(2-Amino-2-methylpropyl)amino]-1-phenyl-1H-1,2,4-triazol-3-yl}methyl)-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0953] ##STR00151##

[0954] 2-[(5-Bromo-1-phenyl-1H-1,2,4-triazol-3-yl)methyl]-4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 27A; 80.0 mg, 103 mol), 2-methylpropane-1,2-diamine (91.1 mg, 1.03 mmol) and N,N-diisopropylethylamine (38 l, 220 mol) were dissolved in acetonitrile (590 l) and stirred for 5 h at 160 C. in a sealed vial under microwave irradiation, followed by 4 h at 190 C. The reaction mixture was evaporated and the residue was purified by preparative HPLC (Method 5).

[0955] The residue was retaken in tetrahydrofuran (1.0 ml), treated with a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (110 l, 1.0 M, 110 mol) and stirred for 1 h at room temperature. The reaction mixture was purified by preparative HPLC (Method 5) followed by flash chromatography (silica gel, dichloromethane/methanol, 8/2) affording 55.6 mg (89% of th.) of the title compound.

[0956] LC-MS (Method 3): R.sub.t=0.92 min; MS (ESIpos): m/z=551 [M+H].sup.+

[0957] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.918 (1.34), 0.936 (3.26), 0.955 (1.62), 1.088 (16.00), 1.225 (0.74), 1.301 (0.80), 1.319 (0.78), 1.337 (0.91), 3.141 (0.68), 3.163 (0.65), 3.184 (0.74), 3.329 (0.73), 3.800 (0.70), 3.823 (0.79), 3.836 (0.99), 3.860 (1.07), 3.966 (1.08), 3.975 (1.26), 4.002 (0.81), 4.011 (0.75), 4.309 (0.64), 4.873 (5.53), 7.390 (0.67), 7.396 (1.10), 7.406 (0.60), 7.412 (0.94), 7.509 (0.91), 7.525 (0.99), 7.530 (3.44), 7.543 (5.52), 7.547 (8.74), 7.564 (0.99), 7.606 (3.56), 7.610 (1.22), 7.622 (1.57), 7.627 (4.69), 7.741 (0.83), 7.747 (5.39), 7.752 (1.60), 7.764 (1.44), 7.768 (3.90).

Example 95

2-({5-[(2-Amino-2-methylpropyl)amino]-1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl}methyl)-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0958] ##STR00152##

[0959] 2-{[5-Bromo-1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-2-{[tertbutyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 18A, 73.0 mg, 105 mol), 2-methylpropane-1,2-diamine (110 l, 1.1 mmol) and N,N-diisopropylethylamine (55 l, 320 mol) were dissolved in acetonitrile (1.5 ml) and stirred for 8 h at 180 C. in a sealed vial under microwave irradiation, followed by 10 h at 160 C.

[0960] The reaction mixture was cooled to room temperature, a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (160 l, 1.0 M, 160 mol) was added and stirred for 1 h at room temperature. The reaction mixture was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded the crude product, which was dissolved in ethyl acetate and washed with sat. aqueous sodium bicarbonate solution. The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo to afford 20.8 mg (34% of th.) of the title compound.

[0961] LC-MS (Method 3): R.sub.t=1.17 min; MS (ESIpos): m/z=586 [M+H].sup.+

[0962] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.09), 0.008 (0.73), 1.015 (16.00), 1.157 (1.46), 1.175 (2.80), 1.193 (1.54), 1.236 (2.18), 1.988 (4.60), 3.189 (2.24), 3.203 (2.18), 3.800 (0.69), 3.824 (0.79), 3.837 (0.98), 3.861 (1.03), 3.966 (1.10), 3.975 (1.27), 4.003 (1.23), 4.011 (0.82), 4.021 (1.25), 4.039 (1.18), 4.876 (5.85), 6.870 (0.87), 7.565 (1.54), 7.577 (1.59), 7.585 (1.65), 7.597 (1.84), 7.607 (3.45), 7.612 (1.37), 7.624 (1.64), 7.628 (4.64), 7.635 (0.79), 7.734 (0.92), 7.741 (4.54), 7.746 (1.56), 7.757 (1.40), 7.762 (3.27), 8.198 (1.62), 8.202 (1.66), 8.218 (1.59), 8.222 (1.52), 8.532 (1.67), 8.536 (1.66), 8.544 (1.66), 8.548 (1.53).

Example 96

5-(4-Chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-5-(1,1-dioxidothiomorpholin-4-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0963] ##STR00153##

[0964] 2-{[5-Bromo-1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-2-{[tertbutyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 18A, 75.0 mg, 108 mol), thiomorpholine 1,1-dioxide (146 mg, 1.08 mmol) and N,N-diisopropylethylamine (57 l, 320 mol) were dissolved in acetonitrile (1.5 ml) and stirred for 8 h at 180 C. in a sealed vial under microwave irradiation. The reaction mixture was cooled to room temperature, treated with a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (130 l, 1.0 M, 130 mol) and stirred for 1 h at room temperature. The reaction mixture was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 61.0 mg (88% of th.) of the title compound.

[0965] LC-MS (Method 10): R.sub.t=1.18 min; MS (ESIpos): m/z=633 [M+H].sup.+

[0966] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.91), 3.114 (9.54), 3.126 (12.43), 3.140 (10.56), 3.288 (2.34), 3.540 (10.67), 3.553 (11.82), 3.566 (9.45), 3.808 (2.25), 3.832 (2.58), 3.844 (3.26), 3.868 (3.55), 3.970 (3.35), 3.978 (3.75), 4.006 (2.35), 4.015 (2.25), 4.277 (1.89), 4.294 (1.80), 4.906 (1.54), 4.946 (12.54), 4.954 (12.42), 4.994 (1.54), 6.869 (6.92), 6.885 (6.96), 7.602 (1.72), 7.608 (11.39), 7.613 (4.30), 7.625 (5.36), 7.630 (15.64), 7.636 (2.39), 7.686 (4.93), 7.698 (5.10), 7.707 (5.23), 7.718 (5.52), 7.730 (2.87), 7.736 (16.00), 7.742 (5.09), 7.753 (4.78), 7.758 (11.36), 7.764 (1.65), 8.292 (5.57), 8.296 (5.71), 8.312 (5.30), 8.316 (5.14), 8.600 (5.77), 8.604 (5.72), 8.612 (5.77), 8.616 (5.26).

Example 97

4-[3-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]piperazin-2-one

[0967] ##STR00154##

[0968] 2-{[5-Bromo-1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-2-{[tertbutyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 18A, 75.0 mg, 108 mol), piperazin-2-one (108 mg, 1.08 mmol) and N,N-diisopropylethylamine (57 l, 320 mol) were dissolved in acetonitrile (1.5 ml) and stirred for 8 h at 180 C. in a sealed vial under microwave irradiation. The reaction mixture was cooled to room temperature, treated with a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (130 l, 1.0 M, 130 mol) and stirred for 1 h at room temperature. The reaction mixture was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 52.3 mg (80% of th.) of the title compound.

[0969] LC-MS (Method 10): R.sub.t=1.09 min; MS (ESIpos): m/z=598 [M+H].sup.+

[0970] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.74), 0.008 (1.04), 3.122 (1.87), 3.134 (3.30), 3.140 (3.95), 3.148 (3.05), 3.155 (2.23), 3.263 (4.53), 3.278 (5.43), 3.290 (4.99), 3.586 (16.00), 3.806 (1.31), 3.829 (1.54), 3.842 (1.84), 3.866 (1.95), 3.971 (1.90), 3.979 (2.07), 4.008 (1.33), 4.017 (1.18), 4.283 (1.10), 4.300 (0.99), 4.886 (0.73), 4.926 (8.04), 4.931 (7.69), 4.970 (0.57), 6.880 (3.89), 6.896 (3.83), 7.603 (1.28), 7.609 (6.84), 7.614 (2.43), 7.625 (3.11), 7.631 (9.10), 7.637 (1.21), 7.682 (3.05), 7.694 (3.14), 7.702 (3.19), 7.714 (3.32), 7.735 (1.88), 7.742 (9.40), 7.747 (2.80), 7.758 (2.65), 7.763 (6.55), 8.055 (2.64), 8.284 (3.27), 8.288 (3.33), 8.304 (3.07), 8.308 (2.87), 8.593 (3.41), 8.597 (3.36), 8.604 (3.27), 8.608 (2.96).

Example 98

5-(4-Chlorophenyl)-2-({1-(3-chloropyridin-2-yl)-5-[(2-hydroxy-2-methylpropyl)amino]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0971] ##STR00155##

[0972] 2-{[5-Bromo-1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-2-{[tertbutyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 18A, 73.0 mg, 105 mol), 1-amino-2-methylpropan-2-ol and N,N-diisopropylethylamine (55 l, 320 mol) were dissolved in acetonitrile (1.5 ml) and stirred for 8 h at 180 C. in a sealed vial under microwave irradiation. The reaction mixture was cooled to room temperature, treated with a solution of in tetra-n-butylammonium fluoride in tetrahydrofuran (160 l, 1.0 M, 160 mol) and stirred for 1 h at room temperature. The reaction mixture was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 51.2 mg (83% of th.) of the title compound.

[0973] LC-MS (Method 3): R.sub.t=1.75 min; MS (ESIpos): m/z=597 [M+H].sup.+

[0974] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 1.074 (16.00), 3.225 (2.19), 3.239 (2.16), 3.843 (0.64), 3.866 (0.69), 3.975 (0.74), 4.620 (3.08), 4.867 (2.35), 4.876 (2.32), 6.737 (1.06), 6.883 (1.29), 6.899 (1.30), 7.550 (0.91), 7.562 (0.93), 7.570 (0.95), 7.582 (0.99), 7.608 (2.10), 7.613 (0.80), 7.625 (0.96), 7.629 (2.96), 7.734 (2.98), 7.739 (1.06), 7.750 (0.83), 7.755 (2.16), 8.194 (0.90), 8.198 (0.94), 8.214 (0.87), 8.218 (0.87), 8.523 (0.94), 8.527 (0.98), 8.535 (0.97), 8.538 (0.93).

Example 99

5-{[3-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-5-yl]amino}piperidin-2-one (Diastereomeric Mixture)

[0975] ##STR00156##

[0976] 2-{[5-Bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 38A, 100 mg, 177 mol), (5R)-5-aminopiperidin-2-one (203 mg, 1.77 mmol), N,N-diisopropylethylamine (93 l, 530 mol) were dissolved in acetonitrile (3.0 ml) and stirred for 8 h at 170 C. in a sealed vial under microwave irradiation, followed by 5 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 66.4 mg (56% of th.) of the title compound as a mixture of diastereomers.

[0977] LC-MS (Method 10): R.sub.t=1.11 min; MS (ESIpos): m/z=597 [M+H].sup.+

[0978] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.47), 1.665 (0.69), 1.680 (1.46), 1.695 (1.47), 1.709 (2.26), 1.718 (1.72), 1.731 (0.94), 2.035 (1.28), 2.057 (3.09), 2.065 (3.27), 2.086 (3.62), 2.097 (3.36), 2.105 (4.39), 2.119 (1.80), 2.137 (1.86), 2.154 (2.45), 2.178 (1.14), 2.192 (0.69), 2.220 (0.79), 2.240 (1.03), 2.265 (1.37), 2.280 (0.73), 2.654 (1.13), 2.671 (1.98), 2.682 (3.12), 2.700 (3.92), 2.710 (3.50), 2.719 (2.76), 2.728 (3.58), 2.746 (1.95), 2.756 (1.20), 3.057 (0.69), 3.189 (4.29), 3.204 (7.46), 3.219 (4.10), 3.681 (1.91), 3.696 (2.41), 3.711 (1.64), 3.801 (2.31), 3.824 (3.04), 3.837 (3.69), 3.861 (3.58), 3.960 (3.47), 3.969 (3.66), 3.996 (2.32), 4.005 (2.22), 4.082 (4.46), 4.100 (6.99), 4.119 (5.34), 4.137 (2.85), 4.155 (1.61), 4.275 (2.13), 4.713 (1.57), 4.752 (7.73), 4.764 (7.53), 4.778 (2.48), 4.787 (1.72), 4.806 (1.18), 6.608 (1.50), 6.625 (1.42), 6.703 (2.05), 6.718 (3.85), 6.732 (1.81), 6.864 (5.76), 6.880 (5.56), 7.388 (1.50), 7.605 (9.91), 7.626 (14.18), 7.696 (6.32), 7.717 (16.00), 7.734 (5.12), 7.739 (10.69).

Example 100

5-(4-Chlorophenyl)-2-{[5-(1,1-dioxidothiomorpholin-4-yl)-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0979] ##STR00157##

[0980] 2-{[5-Bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 38A, 70.0 mg, 124 mol), thiomorpholine 1,1-dioxide (168 mg, 1.24 mmol), N,N-diisopropylethylamine (65 l, 370 mol) were dissolved in acetonitrile (3.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation, followed by 15 h at 180 C. The crude product was purified by preparative HPLC (Method 5 followed by Method 11). Lyophilisation of the product containing fractions afforded 33.0 mg (41% of th.) of the title compound.

[0981] LC-MS (Method 10): R.sub.t=1.22 min; MS (ESIpos): m/z=618 [M+H].sup.+

[0982] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 2.847 (0.97), 2.875 (0.93), 3.275 (1.74), 3.287 (2.81), 3.301 (2.33), 3.311 (16.00), 3.514 (2.16), 3.522 (2.10), 3.528 (2.20), 3.541 (1.73), 3.870 (0.76), 4.212 (1.36), 4.229 (2.45), 4.247 (1.41), 4.891 (2.53), 4.905 (2.53), 6.861 (1.41), 6.877 (1.43), 7.607 (2.62), 7.612 (0.87), 7.624 (1.26), 7.629 (3.81), 7.718 (3.94), 7.723 (1.08), 7.734 (0.97), 7.739 (2.55).

Example 101

5-(4-Chlorophenyl)-2-{[5-({[(2R)-5-oxopyrrolidin-2-yl]methyl}amino)-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0983] ##STR00158##

[0984] 2-{[5-Bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (60.0 mg, 106 mol), (5R)-5-(aminomethyl)pyrrolidin-2-one (Example 38A, 122 mg, 1.06 mmol), N,N-diisopropylethylamine (56 l, 320 mol) were dissolved in acetonitrile (3.0 ml) and stirred for 10 h at 170 C. in a sealed vial under microwave irradiation, followed by 5 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 39.0 mg (58% of th.) of the title compound.

[0985] LC-MS (Method 10): R.sub.t=1.13 min; MS (ESIpos): m/z=597 [M+H].sup.+

[0986] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 1.665 (0.69), 1.681 (1.74), 1.695 (1.59), 1.709 (2.70), 1.718 (2.08), 1.732 (1.15), 2.034 (1.31), 2.052 (2.40), 2.057 (3.41), 2.062 (3.78), 2.064 (3.75), 2.076 (1.41), 2.083 (4.04), 2.086 (3.92), 2.097 (3.96), 2.106 (5.15), 2.119 (2.09), 2.131 (1.66), 2.137 (2.13), 2.143 (1.55), 2.154 (3.06), 2.178 (1.24), 2.671 (1.43), 2.681 (2.17), 2.690 (1.40), 2.700 (3.61), 2.710 (2.68), 2.718 (2.70), 2.727 (3.49), 2.738 (1.26), 2.746 (2.25), 2.756 (1.23), 3.189 (4.84), 3.204 (8.91), 3.219 (4.98), 3.682 (2.06), 3.697 (2.69), 3.711 (1.93), 3.802 (2.13), 3.825 (2.46), 3.838 (3.13), 3.862 (3.37), 3.959 (3.12), 3.968 (3.48), 3.995 (2.17), 4.004 (2.08), 4.082 (4.67), 4.101 (7.52), 4.119 (4.32), 4.258 (1.06), 4.274 (1.78), 4.290 (1.65), 4.714 (1.87), 4.753 (10.74), 4.764 (10.84), 4.802 (1.86), 6.703 (2.30), 6.718 (4.75), 6.732 (2.22), 6.865 (6.16), 6.880 (6.15), 7.599 (1.49), 7.605 (10.30), 7.610 (4.03), 7.621 (4.85), 7.626 (15.15), 7.632 (2.35), 7.695 (6.92), 7.711 (3.02), 7.717 (16.00), 7.723 (4.98), 7.734 (4.54), 7.739 (10.79), 7.745 (1.47).

Example 102

N-(1-{[3-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-5-yl]amino}-2-methylpropan-2-yl)methanesulfonamide

[0987] ##STR00159##

[0988] 2-{[5-Bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 38A, 60.0 mg, 106 mol), N-(1-amino-2-methylpropan-2-yl)methanesulfonamide hydrochloride (1:1) (216 mg, 1.06 mmol), N,N-diisopropylethylamine (280 l, 1.6 mmol) were dissolved in acetonitrile (3.0 ml) and stirred for 10 h at 180 C. in a sealed vial under microwave irradiation, followed by 5 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 36.5 mg (48% of th.) of the title compound.

[0989] LC-MS (Method 10): R.sub.t=1.25 min; MS (ESIpos): m/z=649 [M+H].sup.+

[0990] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 1.238 (16.00), 2.692 (0.73), 2.709 (1.41), 2.720 (0.86), 2.727 (0.95), 2.738 (1.32), 2.755 (0.75), 2.903 (14.75), 3.790 (0.67), 3.814 (0.78), 3.827 (1.07), 3.850 (1.08), 3.948 (1.04), 3.957 (1.18), 3.984 (0.74), 3.994 (0.70), 4.131 (1.72), 4.148 (3.18), 4.165 (1.61), 4.435 (0.69), 4.698 (1.04), 4.737 (3.03), 4.765 (3.00), 4.804 (1.03), 4.994 (1.03), 6.628 (0.75), 6.644 (1.55), 6.659 (0.74), 6.845 (1.84), 6.861 (1.85), 6.965 (3.64), 7.603 (3.43), 7.620 (1.65), 7.625 (5.40), 7.631 (1.06), 7.695 (0.84), 7.702 (4.80), 7.706 (1.78), 7.718 (1.96), 7.723 (3.46), 8.522 (0.63).

Example 103

5-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({5-[2-(trifluoromethyl)morpholin-4-yl]-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomeric Mixture)

[0991] ##STR00160##

[0992] 2-{[5-Bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 38A, 90.0 mg, 160 mol), (2S)-2-(trifluoromethyl)morpholine (248 mg, 1.60 mmol), N,N-diisopropylethylamine (83 l, 480 mol) were dissolved in acetonitrile (3.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation, followed by 5 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 97.0 mg (95% of th.) of the title compound as a mixture of diastereomers.

[0993] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 95 mg dissolved in 3 ml methyl-tert-butylether; injection volume: 0.40 ml; column: Daicel Chiralpak IA 5 m, 25020 mm; eluent: methyl-tert-butylether/methanol 90:10; flow rate: 15 ml/min; temperature: 30 C.; UV detection: 220 nm]. 38 mg of diastereomer 1 (Example 104), which eluted first, and 40 mg of diastereomer 2 (Example 105), which eluted later, were isolated.

[0994] LC-MS (Method 10): R.sub.t=1.41 min; MS (ESIpos): m/z=638 [M+H].sup.+

[0995] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (2.49), 0.008 (2.34), 2.823 (0.99), 2.834 (1.40), 2.851 (2.71), 2.862 (1.65), 2.869 (1.84), 2.879 (2.66), 2.897 (1.51), 2.907 (0.93), 2.944 (1.99), 2.969 (3.28), 2.974 (3.59), 2.999 (3.97), 3.027 (1.15), 3.033 (1.01), 3.201 (2.27), 3.232 (1.70), 3.285 (2.28), 3.337 (2.32), 3.367 (1.93), 3.754 (0.95), 3.760 (1.15), 3.782 (2.24), 3.789 (2.17), 3.814 (2.38), 3.837 (1.56), 3.851 (2.07), 3.874 (2.23), 3.969 (2.13), 3.978 (2.40), 4.005 (3.10), 4.014 (1.66), 4.028 (1.73), 4.222 (4.02), 4.239 (7.97), 4.256 (4.42), 4.396 (0.84), 4.403 (1.14), 4.412 (1.10), 4.421 (1.52), 4.428 (1.15), 4.438 (1.00), 4.845 (1.23), 4.884 (7.50), 4.895 (7.42), 4.935 (1.22), 5.754 (16.00), 6.860 (4.12), 6.876 (4.11), 7.609 (6.75), 7.614 (2.70), 7.625 (3.40), 7.630 (9.88), 7.636 (1.54), 7.712 (1.82), 7.718 (9.94), 7.723 (3.25), 7.735 (2.79), 7.739 (6.65).

Example 104

5-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({5-[2-(trifluoromethyl)morpholin-4-yl]-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomer 1)

[0996] Analytical chiral HPLC: R.sub.t=4.85 min, d.e.=100% [column: Daicel Chiralpak IA 5 m 2504.6 mm; eluent: methyl-tert-butylether/methanol 90/10+0.2% diethylamine, flow rate: 1 ml/min; UV detection: 270 nm].

[0997] LC-MS (Method 10): R.sub.t=1.42 min; MS (ESIpos): m/z=638 [M+H].sup.+

[0998] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (4.84), 0.008 (2.17), 1.181 (1.52), 1.187 (16.00), 2.825 (1.74), 2.835 (2.33), 2.852 (4.22), 2.863 (2.70), 2.870 (2.94), 2.881 (4.02), 2.898 (2.34), 2.909 (1.45), 2.944 (3.29), 2.970 (5.40), 2.974 (4.94), 3.000 (6.16), 3.008 (2.51), 3.028 (2.16), 3.037 (1.67), 3.202 (3.29), 3.228 (2.44), 3.287 (2.99), 3.339 (3.43), 3.367 (2.76), 3.754 (1.62), 3.760 (1.86), 3.782 (3.57), 3.789 (3.32), 3.815 (3.53), 3.838 (2.51), 3.852 (3.08), 3.875 (3.25), 3.969 (3.47), 3.979 (3.73), 4.006 (4.57), 4.015 (2.55), 4.028 (2.51), 4.222 (6.36), 4.240 (11.89), 4.257 (6.51), 4.275 (1.94), 4.397 (1.54), 4.403 (1.89), 4.413 (1.83), 4.421 (2.34), 4.429 (1.75), 4.439 (1.56), 4.445 (1.21), 4.846 (2.08), 4.885 (11.35), 4.896 (10.80), 4.936 (2.00), 4.947 (3.09), 6.862 (6.21), 6.878 (6.03), 7.603 (2.20), 7.609 (10.63), 7.614 (4.23), 7.625 (5.24), 7.631 (15.39), 7.637 (2.17), 7.712 (3.47), 7.718 (15.35), 7.724 (4.89), 7.735 (4.28), 7.740 (10.13), 7.746 (1.33), 11.670 (1.11).

Example 105

5-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({5-[2-(trifluoromethyl)morpholin-4-yl]-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-H-1,2,4-triazol-3-one (Diastereomer 2)

[0999] Analytical chiral HPLC: R.sub.t=6.11 min, d.e.=100% [column: Daicel Chiralpak IA 5 m 2504.6 mm; eluent: methyl-tert-butylether/methanol 90/10+0.2% diethylamine, flow rate: 1 ml/min; UV detection: 270 nm].

[1000] LC-MS (Method 10): R.sub.t=1.42 min; MS (ESIpos): m/z=638 [M+H].sup.+

[1001] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (2.43), 0.008 (1.74), 1.187 (16.00), 2.825 (1.34), 2.835 (1.88), 2.852 (3.64), 2.863 (2.23), 2.869 (2.46), 2.880 (3.54), 2.897 (2.04), 2.908 (1.28), 2.945 (2.67), 2.974 (5.03), 3.001 (5.22), 3.025 (1.85), 3.033 (1.51), 3.202 (3.03), 3.232 (2.30), 3.287 (1.78), 3.338 (3.09), 3.367 (2.57), 3.755 (1.28), 3.761 (1.55), 3.783 (2.98), 3.790 (2.91), 3.815 (3.16), 3.838 (2.08), 3.852 (2.69), 3.875 (2.90), 3.970 (2.86), 3.979 (3.21), 4.006 (4.11), 4.016 (2.19), 4.030 (2.29), 4.223 (5.26), 4.240 (10.34), 4.257 (5.81), 4.396 (1.16), 4.403 (1.54), 4.413 (1.50), 4.421 (2.06), 4.428 (1.55), 4.438 (1.37), 4.445 (1.09), 4.846 (1.54), 4.885 (9.66), 4.896 (9.54), 4.936 (1.59), 4.947 (3.35), 6.861 (5.63), 6.877 (5.64), 7.610 (8.78), 7.631 (12.84), 7.713 (2.24), 7.719 (12.87), 7.740 (8.79), 11.670 (1.30).

Example 106

5-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({5-[3-(trifluoromethyl)piperazin-1-yl]-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomeric Mixture)

[1002] ##STR00161##

[1003] 2-{[5-Bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 38A, 60.0 mg, 106 mol), (2S)-2-(trifluoromethyl)piperazine (164 mg, 1.06 mmol), N,N-diisopropylethylamine (56 l, 320 mol) were dissolved in acetonitrile (3.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation, followed by 10 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 49.7 mg (72% of th.) of the title compound as a mixture of diastereomers.

[1004] LC-MS (Method 10): R.sub.t=1.30 min; MS (ESIpos): m/z=637 [M+H].sup.+

[1005] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.24), 2.786 (1.67), 2.803 (3.28), 2.813 (3.51), 2.820 (2.82), 2.831 (5.89), 2.841 (3.71), 2.848 (5.01), 2.859 (5.28), 2.876 (5.36), 2.889 (4.41), 2.904 (2.56), 2.912 (4.12), 2.919 (3.86), 2.942 (6.04), 2.955 (5.07), 2.975 (2.48), 3.088 (2.87), 3.116 (2.06), 3.235 (2.67), 3.242 (2.96), 3.264 (2.41), 3.271 (2.38), 3.288 (1.38), 3.554 (1.60), 3.563 (1.57), 3.573 (1.51), 3.811 (2.12), 3.835 (2.43), 3.848 (3.13), 3.871 (3.39), 3.968 (3.20), 3.977 (3.56), 4.005 (2.22), 4.013 (2.16), 4.177 (5.87), 4.194 (11.44), 4.212 (5.54), 4.276 (1.72), 4.291 (1.62), 4.833 (2.03), 4.873 (11.36), 4.884 (11.26), 4.924 (2.02), 6.864 (6.54), 6.880 (6.58), 7.602 (1.56), 7.608 (10.18), 7.613 (3.95), 7.625 (4.99), 7.630 (15.11), 7.636 (2.29), 7.713 (2.51), 7.719 (16.00), 7.724 (4.98), 7.736 (4.09), 7.741 (10.83), 7.747 (1.53).

[1006] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 45.4 mg dissolved in 3 ml methyl-tert-butylether; injection volume: 0.4 ml; column: Daicel Chiralpak IA 5 m, 25020 mm; eluent: methyl-tert-butylether/methanol 90:10; flow rate: 15 ml/min; temperature: 30 C.; UV detection: 220 nm]. 20 mg of diastereomer 1 (Example 107), which eluted first, and 20.0 mg of diastereomer 2 (Example 108), which eluted later, were isolated.

Example 107

5-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({5-[3-(trifluoromethyl)piperazin-1-yl]-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomer 1)

[1007] Analytical chiral HPLC: R.sub.t=10.15 min, d.e.=99% [column: Chiralpak IA 25020 mm; eluent: iso-hexane/iso-propanol 50/50, methyl-tert-butylether/methanol 90:10; flow rate: 15 ml/min; temperature: 30 C.; UV detection: 220 nm].

[1008] LC-MS (Method 10): R.sub.t=1.29 min; MS (ESIpos): m/z=637 [M+H].sup.+

[1009] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 1.182 (2.05), 1.186 (16.00), 1.427 (2.89), 2.786 (1.30), 2.803 (2.23), 2.813 (2.40), 2.831 (3.65), 2.841 (2.49), 2.849 (3.13), 2.858 (3.54), 2.878 (3.42), 2.888 (3.13), 2.911 (2.87), 2.918 (2.50), 2.941 (3.79), 2.955 (3.41), 3.087 (1.85), 3.115 (1.30), 3.235 (1.82), 3.242 (1.98), 3.264 (1.85), 3.271 (1.86), 3.288 (1.75), 3.554 (1.12), 3.574 (1.02), 3.811 (1.28), 3.834 (1.48), 3.847 (1.85), 3.871 (1.94), 3.967 (2.01), 3.976 (2.16), 4.004 (1.37), 4.013 (1.28), 4.176 (3.60), 4.194 (6.61), 4.211 (3.19), 4.277 (1.12), 4.833 (1.22), 4.872 (6.58), 4.884 (6.31), 4.923 (1.12), 4.947 (3.33), 6.866 (3.27), 6.881 (3.16), 7.603 (1.27), 7.608 (5.64), 7.625 (2.87), 7.630 (8.05), 7.713 (1.89), 7.719 (8.50), 7.724 (3.35), 7.735 (2.42), 7.740 (5.78), 11.671 (1.38).

Example 108

5-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({5-[(3-(trifluoromethyl)piperazin-1-yl]-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Diastereomer 2)

[1010] Analytical chiral HPLC: R.sub.t=12.03 min, d.e.=99% [column: Chiralpak IA 25020 mm; eluent: iso-hexane/iso-propanol 50/50, methyl-tert-butylether/methanol 90:10; flow rate: 15 ml/min; temperature: 30 C.; UV detection: 220 nm].

[1011] LC-MS (Method 10): R.sub.t=1.29 min; MS (ESIpos): m/z=637 [M+H].sup.+

[1012] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (2.55), 0.008 (1.11), 1.181 (1.70), 1.187 (16.00), 1.427 (0.91), 2.786 (1.13), 2.802 (2.00), 2.813 (2.19), 2.820 (1.87), 2.830 (3.32), 2.841 (2.37), 2.848 (3.11), 2.852 (2.49), 2.858 (2.80), 2.876 (3.27), 2.882 (2.10), 2.889 (2.28), 2.905 (1.66), 2.912 (2.27), 2.919 (2.22), 2.942 (3.50), 2.954 (2.96), 2.975 (1.33), 3.088 (1.59), 3.116 (1.09), 3.233 (1.55), 3.241 (1.62), 3.263 (1.55), 3.271 (1.51), 3.287 (1.61), 3.811 (1.18), 3.834 (1.37), 3.848 (1.67), 3.871 (1.74), 3.968 (1.78), 3.977 (1.87), 4.005 (1.20), 4.014 (1.09), 4.177 (3.38), 4.194 (6.04), 4.212 (2.88), 4.833 (1.19), 4.872 (6.15), 4.884 (5.81), 4.923 (1.14), 4.947 (2.99), 6.863 (3.41), 6.879 (3.27), 7.602 (1.28), 7.608 (5.84), 7.613 (2.29), 7.625 (2.95), 7.630 (8.26), 7.636 (1.11), 7.713 (1.97), 7.719 (8.47), 7.724 (2.64), 7.736 (2.44), 7.741 (5.57), 11.670 (1.06).

Example 109

5-(4-Chlorophenyl)-2-{[5-({[(2S)-5-oxopyrrolidin-2-yl]methyl}amino)-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[1013] ##STR00162##

[1014] 2-{[5-Bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 38A, 60.0 mg, 106 mol), (5S)-5-(aminomethyl)pyrrolidin-2-one (122 mg, 1.06 mmol), N,N-diisopropylethylamine (56 l, 320 mol) were dissolved in acetonitrile (3.0 ml) and stirred for 8 h at 170 C. in a sealed vial under microwave irradiation, followed by 5 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 44.1 mg (69% of th.) of the title compound.

[1015] LC-MS (Method 10): R.sub.t=1.13 min; MS (ESIpos): m/z=597 [M+H].sup.+

[1016] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (1.22), 1.664 (0.74), 1.680 (1.82), 1.694 (1.72), 1.708 (2.97), 1.717 (2.29), 1.730 (1.24), 2.034 (1.44), 2.056 (3.80), 2.064 (4.04), 2.085 (4.54), 2.096 (4.25), 2.105 (5.86), 2.119 (2.23), 2.137 (2.34), 2.153 (3.17), 2.177 (1.24), 2.653 (0.74), 2.670 (1.57), 2.682 (2.32), 2.699 (3.64), 2.710 (2.98), 2.718 (2.97), 2.727 (3.54), 2.746 (2.42), 2.754 (1.30), 2.774 (0.71), 3.188 (5.32), 3.203 (9.85), 3.218 (5.46), 3.289 (2.70), 3.665 (0.78), 3.681 (2.30), 3.695 (3.08), 3.710 (2.14), 3.799 (2.21), 3.822 (2.58), 3.835 (3.23), 3.859 (3.48), 3.960 (3.40), 3.969 (3.73), 3.997 (2.38), 4.006 (2.20), 4.081 (5.76), 4.100 (9.36), 4.117 (5.26), 4.274 (1.95), 4.291 (1.81), 4.711 (2.56), 4.750 (10.68), 4.767 (10.55), 4.806 (2.52), 6.702 (2.64), 6.716 (5.31), 6.731 (2.49), 6.863 (6.50), 6.879 (6.44), 7.599 (1.98), 7.604 (10.44), 7.609 (4.34), 7.621 (5.47), 7.626 (15.19), 7.632 (2.32), 7.695 (7.82), 7.710 (3.75), 7.716 (16.00), 7.721 (5.31), 7.733 (4.79), 7.738 (10.63), 7.744 (1.52).

Example 110

5-(4-Chlorophenyl)-2-({5-[(2-hydroxy-2-methylpropyl)amino]-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[1017] ##STR00163##

[1018] 2-{[5-Bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 38A, 60.0 mg, 106 mol), 1-amino-2-methylpropan-2-ol (94.9 mg, 1.06 mmol), N,N-diisopropylethylamine (56 l, 320 mol) were dissolved in acetonitrile (3.0 ml) and stirred for 5 h at 160 C. and 3 h at 170 C. in a sealed vial under microwave irradiation, followed by 5 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 49.3 mg (81% of th.) of the title compound.

[1019] LC-MS (Method 10): R.sub.t=1.25 min; MS (ESIpos): m/z=572 [M+H].sup.+

[1020] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 1.072 (16.00), 2.695 (0.83), 2.723 (0.81), 3.163 (1.92), 3.177 (1.82), 3.831 (0.69), 3.854 (0.74), 3.954 (0.72), 3.962 (0.83), 4.144 (1.16), 4.161 (1.98), 4.179 (1.10), 4.758 (2.22), 4.767 (2.19), 7.606 (2.02), 7.610 (0.81), 7.622 (0.94), 7.627 (3.00), 7.715 (3.10), 7.720 (1.04), 7.731 (0.83), 7.736 (2.12).

Example 111

2-({5-[(2-Amino-2-methylpropyl)amino]-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl}methyl)-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[1021] ##STR00164##

[1022] 2-{[5-Bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 38A, 50.0 mg, 88.7 mol), 2-methylpropane-1,2-diamine (78.2 mg, 887 mol), N,N-diisopropylethylamine (46 l, 270 mol) were dissolved in acetonitrile (3.0 ml) and stirred for 5 h at 160 C. and 3 h at 170 C. in a sealed vial under microwave irradiation, followed by 5 h at 180 C. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 37.1 mg (73% of th.) of the title compound.

[1023] LC-MS (Method 10): R.sub.t=0.93 min; MS (ESIpos): m/z=571 [M+H].sup.+

[1024] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 1.132 (16.00), 2.695 (0.65), 2.711 (1.15), 2.723 (0.76), 2.730 (0.82), 2.740 (1.07), 2.758 (0.68), 3.288 (2.28), 3.302 (2.18), 3.793 (0.67), 3.816 (0.75), 3.829 (0.96), 3.853 (1.00), 3.951 (1.02), 3.960 (1.17), 3.987 (0.75), 3.996 (0.70), 4.144 (1.55), 4.162 (2.54), 4.179 (1.46), 4.763 (5.74), 7.603 (2.96), 7.608 (1.32), 7.620 (1.43), 7.625 (4.26), 7.714 (0.82), 7.720 (4.68), 7.725 (1.55), 7.737 (1.30), 7.742 (3.27).

Example 112

4-[3-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-5-yl]piperazin-2-one

[1025] ##STR00165##

[1026] 2-{[5-Bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 38A, 80.0 mg, 142 mol), piperazin-2-one (142 mg, 1.42 mmol), acetonitrile (3.0 ml) were dissolved in N,N-diisopropylethylamine (74 l, 430 mol) and stirred for 8 h at 180 C. in a sealed vial under microwave irradiation. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 50.1 mg (59% of th.) of the title compound.

[1027] LC-MS (Method 10): R.sub.t=1.15 min; MS (ESIpos): m/z=583 [M+H].sup.+

[1028] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 2.838 (1.08), 2.866 (1.04), 3.259 (1.50), 3.267 (1.53), 3.298 (2.23), 3.312 (16.00), 3.841 (0.76), 3.865 (0.81), 3.966 (0.77), 3.974 (0.86), 4.191 (1.44), 4.208 (2.69), 4.226 (1.36), 4.871 (2.95), 4.878 (2.94), 6.877 (1.48), 6.893 (1.48), 7.608 (2.62), 7.613 (1.05), 7.625 (1.19), 7.630 (3.78), 7.724 (3.82), 7.728 (1.25), 7.740 (1.03), 7.745 (2.62), 8.002 (1.17).

Example 113

1-[3-({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-5-yl]azetidine-3-carboxamide

[1029] ##STR00166##

[1030] 2-{[5-Bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 38A, 60.0 mg, 106 mol), azetidine-3-carboxamide (107 mg, 1.06 mmol), N,N-diisopropylethylamine (56 l, 320 mol) were dissolved in acetonitrile (3.0 ml) and stirred for 12 h at 160 C. in a sealed vial under microwave irradiation. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 33.0 mg (52% of th.) of the title compound.

[1031] LC-MS (Method 10): R.sub.t=1.12 min; MS (ESIpos): m/z=583 [M+H].sup.+

[1032] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 2.366 (1.23), 2.710 (1.41), 2.722 (0.97), 2.739 (1.94), 2.750 (2.76), 2.767 (4.98), 2.778 (3.17), 2.784 (3.45), 2.795 (4.70), 2.812 (2.66), 2.823 (1.58), 2.840 (0.77), 3.289 (5.09), 3.400 (0.92), 3.421 (2.53), 3.438 (3.81), 3.455 (2.20), 3.460 (2.48), 3.476 (0.95), 3.798 (2.43), 3.821 (2.86), 3.834 (3.53), 3.858 (3.71), 3.962 (3.86), 3.971 (4.22), 3.999 (3.02), 4.008 (3.12), 4.026 (6.72), 4.043 (11.71), 4.061 (6.29), 4.076 (5.24), 4.094 (14.19), 4.112 (11.68), 4.117 (11.55), 4.139 (11.73), 4.158 (4.24), 4.278 (2.35), 4.294 (2.17), 4.751 (1.69), 4.790 (13.32), 4.797 (12.93), 4.836 (1.38), 6.876 (6.88), 6.891 (6.80), 7.044 (4.40), 7.455 (4.37), 7.607 (11.09), 7.623 (5.50), 7.628 (15.64), 7.729 (16.00), 7.733 (6.98), 7.745 (4.93), 7.750 (11.45).

Example 114

5-(4-Chlorophenyl)-2-{[5-(3,3-dimethylpiperazin-1-yl)-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[1033] ##STR00167##

[1034] 2-{[5-Bromo-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 38A, 50.0 mg, 88.7 mol), 2,2-dimethylpiperazine (101 mg, 887 mol), N,N-diisopropylethylamine (31 l, 180 mol) were dissolved in acetonitrile (3.0 ml) and stirred for 5 h at 180 C. in a sealed vial under microwave irradiation. The crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 41.3 mg (78% of th.) of the title compound.

[1035] LC-MS (Method 10): R.sub.t=0.94 min; MS (ESIpos): m/z=587 [M+H].sup.+

[1036] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (0.86), 1.019 (0.58), 1.153 (15.69), 1.157 (16.00), 2.781 (4.58), 2.797 (0.86), 2.808 (0.99), 2.825 (1.75), 2.836 (1.10), 2.842 (1.19), 2.852 (1.67), 2.870 (1.02), 2.880 (0.69), 2.947 (7.67), 3.810 (0.90), 3.833 (1.04), 3.846 (1.28), 3.870 (1.34), 3.967 (1.40), 3.976 (1.56), 4.003 (1.03), 4.013 (0.96), 4.171 (2.25), 4.189 (4.10), 4.206 (1.97), 4.270 (0.70), 4.287 (0.84), 4.815 (0.66), 4.854 (4.25), 4.864 (4.11), 4.903 (0.63), 7.609 (3.75), 7.614 (1.86), 7.625 (1.82), 7.630 (5.45), 7.716 (1.13), 7.722 (5.66), 7.727 (2.28), 7.739 (1.60), 7.743 (3.97), 8.224 (1.54).

Example 115

Ethyl N-[1-(3-chlorophenyl)-3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-5-yl] glycinate

[1037] ##STR00168##

[1038] Ethyl N-[3-({4-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3-chlorophenyl)-1H-1,2,4-triazol-5-yl]glycinate (Example 42A, 25.0 mg, 35.0 mol) was dissolved in 0.5 ml of tetrahydrofuran and cooled to 0 C. A tetra-n-butylammoniumfluoride solution (1M in THF; 42 l, 42 mol) was added and stirring was continued at room temperature for 15 min. For purification, the mixture was purified by preparative HPLC (Method 5) to afford 16.0 mg (76% of th.) of the title compound.

[1039] LC-MS (Method 2): R.sub.t=1.11 min; MS (ESIpos): m/z=600 [M+H].sup.+

[1040] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.149 (0.90), 0.009 (10.28), 0.008 (7.56), 0.146 (0.92), 1.073 (5.34), 1.090 (11.00), 1.108 (5.50), 1.131 (7.27), 1.149 (16.00), 1.157 (1.08), 1.166 (7.36), 1.174 (1.35), 1.192 (0.63), 1.236 (3.61), 1.988 (2.02), 2.327 (1.12), 2.669 (1.10), 2.674 (0.74), 3.357 (1.91), 3.375 (5.32), 3.392 (5.16), 3.410 (1.66), 3.804 (1.03), 3.828 (1.26), 3.841 (1.53), 3.865 (1.66), 3.963 (1.91), 3.976 (5.16), 3.992 (4.58), 4.020 (0.70), 4.052 (2.09), 4.070 (6.73), 4.088 (6.53), 4.106 (2.09), 4.283 (0.83), 4.813 (0.81), 4.853 (5.92), 4.860 (5.68), 4.900 (0.74), 6.866 (2.02), 6.880 (1.91), 7.242 (1.14), 7.257 (2.40), 7.273 (1.03), 7.472 (1.35), 7.475 (1.64), 7.480 (1.44), 7.491 (3.03), 7.495 (3.84), 7.500 (2.63), 7.508 (2.54), 7.513 (2.96), 7.516 (1.57), 7.552 (3.77), 7.574 (6.31), 7.579 (2.38), 7.591 (1.55), 7.604 (6.04), 7.609 (1.97), 7.620 (2.54), 7.625 (8.06), 7.632 (0.88), 7.725 (1.39), 7.731 (8.21), 7.736 (2.47), 7.748 (2.13), 7.753 (5.63).

Example 116

5-(4-Chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(2-methoxyethyl)amino]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[1041] ##STR00169##

[1042] 2-{[5-Bromo-1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 8A, 87.0 mg, 155 mol) was dissolved in 2 ml of acetonitrile. 2-Methoxyethanamine (130 l, 1.5 mmol) and N,N-diisopropylethylamine (57 l, 330 mol) were added and the mixture was stirred under microwave radiation at 150 C. for 1.5 h. After cooling to room temperature, the mixture was diluted with 2 ml of water and extracted twice with 10 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (Method 5) to afford 58 mg (67% of th.) of the title compound.

[1043] LC-MS (Method 2): R.sub.t=1.01 min; MS (ESIpos): m/z=556 [M+H].sup.+

[1044] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.149 (0.27), 0.008 (2.35), 0.008 (2.16), 0.146 (0.28), 1.073 (0.93), 1.091 (1.88), 1.108 (0.94), 2.366 (0.29), 2.670 (0.20), 2.709 (0.29), 3.230 (16.00), 3.357 (0.36), 3.375 (1.26), 3.388 (1.37), 3.392 (1.44), 3.402 (1.81), 3.414 (0.85), 3.450 (1.90), 3.463 (2.62), 3.477 (0.66), 3.811 (0.48), 3.834 (0.54), 3.847 (0.69), 3.871 (0.74), 3.974 (0.68), 3.983 (0.78), 4.010 (0.49), 4.019 (0.47), 4.286 (0.33), 4.827 (0.29), 4.866 (2.89), 4.872 (2.84), 4.911 (0.29), 6.743 (0.55), 6.757 (1.15), 6.771 (0.53), 6.870 (1.16), 6.886 (1.17), 7.219 (0.35), 7.234 (0.62), 7.239 (0.73), 7.259 (0.39), 7.322 (0.85), 7.333 (0.93), 7.342 (0.65), 7.347 (1.01), 7.353 (1.75), 7.531 (0.57), 7.546 (0.65), 7.551 (0.92), 7.568 (0.90), 7.589 (0.40), 7.607 (2.58), 7.612 (0.87), 7.624 (1.08), 7.628 (3.65), 7.738 (3.74), 7.743 (1.07), 7.755 (0.95), 7.760 (2.65).

Example 117

5-(4-Chlorophenyl)-2-{[1-(3-chlorophenyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[1045] ##STR00170##

[1046] To a solution of 5-(4-chlorophenyl)-2-{[5-(pyrrolidin-1-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 9A, 100 mg, 0.22 mmol) in pyridine (2.8 ml) were added (3-chlorophenyl)boronic acid (68.3 mg, 0.44 mmol) and copper(II) acetate (79.3 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 4 days. The reaction mixture was then diluted with MTBE and quenched with aqueous hydrochloric acid (0.5 M). After phase separation, the aqueous phase was extracted twice with MTBE. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (Method 13), affording 5.2 mg (0.01 mmol, 4.1% of th.) of the title compound.

[1047] LC-MS (Method 4): R.sub.t=3.71 min; MS [ESIpos]: m/z=568 (M+H).sup.+

[1048] .sup.1H-NMR (500 MHz, DMSO-d6) [ppm]: 7.75 (br. d, 2H), 7.62 (br. d, 2H), 7.48-7.58 (m, 3H), 7.43 (dt, 1H), 6.87 (br. s., 1H), 4.82-4.91 (m, 2H), 4.25-4.34 (m, 1H), 3.99 (dd, 1H), 3.84 (dd, 1H), 3.10-3.16 (m, 4H), 1.74-1.82 (m, 4H)

Example 118

5-(4-Chlorophenyl)-2-{[1-(3-chlorophenyl)-5-(methylamino)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[1049] ##STR00171##

[1050] To a solution of 2-{[5-amino-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 47A, 30 mg, 58 mol) in N,N-dimethylformamide (1 ml) was added caesium carbonate (20.9 mg, 64 mol). After 20 minutes of stirring at room temperature, iodomethane (4 l, 64 mol) was added and the reaction mixture was stirred for 15 min at 100 C. under microwave irradiation. After cooling, the reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (Chromatorex C18, 10 m, 12530 mm, water-acetonitrile-gradient 0.05% trifluoroacetic acid), affording the title compound (1.9 mg, 3.6 mol, 6.1% of Th.).

[1051] LC-MS (Method 2): R.sub.t=1.08 min; MS [ESIpos]: m/z=528 (M+H).sup.+

[1052] .sup.1H-NMR (500 MHz, DMSO-d6) [ppm]: 7.75 (br. d, 2H), 7.62 (br. d, 2H), 7.55 (t, 1H), 7.53 (d, 1H), 7.48 (br. s, 1H), 7.45 (td, 1H), 6.88 (br. s., 1H), 6.68-6.75 (m, 1H), 4.83-4.91 (m, 2H), 4.25-4.34 (m, 1H), 4.00 (dd, 1H), 3.84 (dd, 1H), 2.81 (d, 3H)

Example 119

5-(4-Chlorophenyl)-2-{[1-(3-fluorophenyl)-5-(morpholin-4-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[1053] ##STR00172##

[1054] 5-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (synthesis described as Example 5A in WO 2011/104622-A198.7 mg, 321 mol), potassium carbonate (88.7 mg, 642 mol) and catalytic amounts of potassium iodide were dissolved in 4 ml of acetonitrile. To this mixture, 4-[3-(chloromethyl)-1-(3-fluorophenyl)-1H-1,2,4-triazol-5-yl]morpholine (Example 57A, 100 mg, 337 mol) was added at room temperature. The mixture was stirred under reflux for 2.5 h. After cooling to room temperature, the suspension was filtered and the obtained solution was concentrated in vacuo. The crude product was purified by preparative HPLC (Method 5) to afford 103 mg (57% of th.) of the title compound.

[1055] LC-MS (Method 2): R.sub.t=1.03 min; MS (ESIpos): m/z=568 [M+H].sup.+

[1056] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.149 (1.20), 0.008 (16.00), 0.008 (14.08), 0.146 (1.05), 1.073 (3.31), 1.091 (6.71), 1.108 (3.40), 1.147 (0.72), 2.085 (1.20), 2.327 (1.68), 2.366 (1.77), 2.523 (6.04), 2.669 (1.53), 2.709 (1.72), 3.036 (7.62), 3.048 (10.16), 3.059 (8.10), 3.357 (1.25), 3.375 (3.31), 3.392 (3.31), 3.410 (1.10), 3.620 (8.48), 3.632 (10.11), 3.643 (7.52), 3.813 (1.44), 3.837 (1.63), 3.850 (2.11), 3.874 (2.25), 3.976 (2.30), 3.986 (2.63), 4.013 (1.63), 4.022 (1.49), 4.291 (1.34), 4.936 (9.92), 4.939 (10.16), 4.979 (0.53), 6.878 (4.60), 7.257 (1.10), 7.284 (2.11), 7.302 (1.29), 7.502 (2.44), 7.514 (2.63), 7.522 (2.11), 7.534 (5.89), 7.558 (1.96), 7.573 (2.25), 7.579 (2.78), 7.594 (2.59), 7.609 (7.62), 7.614 (3.78), 7.625 (3.40), 7.631 (10.01), 7.733 (1.82), 7.739 (10.49), 7.745 (3.88), 7.756 (3.07), 7.761 (7.52).

Example 120

5-(4-Chlorophenyl)-2-{[5-(dimethylamino)-1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[1057] ##STR00173##

[1058] 5-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (synthesis described as Example 5A in WO 2011/104622-A1, 97.9 mg, 318 mol), potassium carbonate (88.0 mg, 637 mol) and catalytic amounts of potassium iodide were dissolved in 4 ml of acetonitrile. To this mixture, 3-(bromomethyl)-1-(3-fluorophenyl)-N,N-dimethyl-1H-1,2,4-triazol-5-amine (Example 46A, 100 mg, 334 mol) was added at room temperature. The mixture was stirred under reflux for 3 h. After cooling to room temperature, the suspension was filtered and the obtained solution was concentrated in vacuo. The crude product was purified by preparative HPLC (Method 5) to afford 129 mg (76% of th.) of the title compound.

[1059] LC-MS (Method 2): R.sub.t=1.04 min; MS (ESIpos): m/z=526 [M+H].sup.+

[1060] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.149 (0.45), 0.008 (5.68), 0.008 (4.84), 0.146 (0.45), 2.710 (0.58), 2.732 (16.00), 3.872 (0.54), 3.975 (0.52), 3.984 (0.61), 4.894 (2.55), 6.879 (0.86), 7.393 (0.60), 7.410 (1.24), 7.414 (1.27), 7.436 (0.57), 7.555 (0.55), 7.572 (0.64), 7.609 (1.62), 7.626 (0.77), 7.631 (2.22), 7.742 (2.28), 7.747 (0.84), 7.758 (0.66), 7.763 (1.64).

Example 121

2-{[5-(Azetidin-1-yl)-1-(3-fluorophenyl)-1H-1, 2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[1061] ##STR00174##

[1062] 5-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (synthesis described as Example 5A in WO 2011/104622-A1, 94.2 mg, 306 mol), potassium carbonate (84.6 mg, 612 mol) and catalytic amounts of potassium iodide were dissolved in 3 ml of acetonitrile. To this mixture, 5-(azetidin-1-yl)-3-(bromomethyl)-1-(3-fluorophenyl)-1H-1,2,4-triazole (Example 50A, 100 mg, 321 mol) was added at room temperature. The mixture was stirred under reflux for 3 h. After cooling to room temperature, the suspension was filtered and the obtained solution was concentrated in vacuo. The crude product was purified by preparative HPLC (Method 5) to afford 121 mg (73% of th.) of the title compound.

[1063] LC-MS (Method 2): R.sub.t=1.08 min; MS (ESIpos): m/z=538 [M+H].sup.+

[1064] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.171 (0.02), 0.031 (0.29), 0.016 (0.10), 0.014 (0.17), 0.124 (0.02), 2.180 (0.07), 2.198 (0.22), 2.217 (0.31), 2.236 (0.23), 2.255 (0.07), 2.305 (0.04), 2.344 (0.05), 2.495 (0.22), 2.498 (0.22), 2.500 (0.24), 2.502 (0.27), 2.505 (0.31), 2.508 (0.39), 2.510 (0.55), 2.518 (16.00), 2.523 (0.37), 2.525 (0.17), 2.647 (0.04), 2.687 (0.05), 3.787 (0.72), 3.806 (1.02), 3.825 (0.74), 3.848 (0.17), 3.953 (0.16), 3.961 (0.19), 3.989 (0.13), 3.998 (0.11), 4.270 (0.08), 4.830 (0.03), 4.870 (0.92), 4.910 (0.02), 6.861 (0.29), 7.218 (0.08), 7.221 (0.08), 7.236 (0.14), 7.240 (0.16), 7.258 (0.08), 7.264 (0.09), 7.295 (0.38), 7.298 (0.32), 7.305 (0.13), 7.315 (0.26), 7.317 (0.29), 7.324 (0.17), 7.329 (0.08), 7.505 (0.10), 7.523 (0.16), 7.526 (0.19), 7.543 (0.19), 7.548 (0.11), 7.563 (0.09), 7.586 (0.56), 7.591 (0.20), 7.603 (0.25), 7.608 (0.78), 7.614 (0.10), 7.713 (0.14), 7.719 (0.80), 7.724 (0.24), 7.735 (0.22), 7.741 (0.57).

Example 122

5-(4-Chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-5-(3,3-dimethylpiperazin-1-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[1065] ##STR00175##

[1066] A solution of 2-{[5-bromo-1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-2-{[tertbutyl(dimethyl)silyl]oxy}-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 18A, 75.0 mg, 108 mol) in acetonitrile (1.5 ml) was treated with 2,2-dimethylpiperazine (124 mg, 1.08 mmol) and N,N-diisopropylethylamine (57 l, 320 mol). The resulting mixture was stirred 8 h at 180 C. under microwave irradiation. The reaction mixture was cooled to room temperature, treated with a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (110 l, 1.0 M, 110 mol) and stirred for 30 min at room temperature. Purification by preparative HPLC (Method 4) and further purification by flash chromatography (silica gel, eluent dichloromethane/methanol gradient) afforded 39.0 mg (67% of th.) of the title compound.

[1067] LC-MS (Method 12): R.sub.t=1.49 min; MS (ESIpos): m/z=611.9 [M+H].sup.+

[1068] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 8.60 (dd, 1H), 8.28 (dd, 1H), 7.79-7.56 (m, 5H), 6.89 (br s, 1H), 5.01-4.83 (m, 2H), 4.39-4.21 (m, 1H), 4.06-3.93 (m, 1H), 3.84 (dd, 1H), 3.50 (br s, 1H), 3.04-2.90 (m, 2H), 2.77 (s, 2H), 2.74-2.65 (m, 2H), 0.88 (s, 6H).

Example 123

5-(4-Chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(2-hydroxyethyl)amino]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[1069] ##STR00176##

[1070] 2-{[5-Bromo-1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (Example 14A, 100 mg, 178 mol) was dissolved in 2 ml of acetonitrile. 2-aminoethanol (110 l, 1.8 mmol) and N,N-diisopropylethylamine (65 l, 370 mol) were added and the mixture was stirred under microwave radiation at 150 C. for 1.5 h. After cooling to room temperature, the mixture was diluted with 2 ml of water and extracted twice with 10 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (Method 5) to afford 64 mg (66% of th.) of the title compound.

[1071] LC-MS (Method 2): R.sub.t=0.94 min; MS (ESIpos): m/z=542 [M+H].sup.+

[1072] .sup.1H-NMR (400 MHz, DMSO-d6) [ppm]: 0.008 (6.53), 0.008 (6.10), 1.073 (7.20), 1.091 (14.92), 1.108 (7.43), 3.280 (2.59), 3.295 (8.46), 3.357 (2.57), 3.375 (7.22), 3.392 (7.17), 3.410 (2.29), 3.500 (3.67), 3.514 (9.60), 3.529 (8.76), 3.544 (2.75), 3.809 (2.11), 3.832 (2.36), 3.845 (2.96), 3.869 (3.23), 3.974 (2.87), 3.982 (3.26), 4.010 (2.06), 4.019 (1.90), 4.286 (1.49), 4.705 (4.22), 4.719 (9.38), 4.733 (3.99), 4.823 (1.08), 4.862 (12.72), 4.867 (12.72), 4.906 (1.10), 6.659 (2.38), 6.673 (5.02), 6.688 (2.38), 6.874 (6.37), 6.890 (6.42), 7.212 (1.54), 7.230 (3.00), 7.236 (3.28), 7.256 (1.74), 7.362 (6.81), 7.368 (4.33), 7.381 (4.97), 7.393 (3.78), 7.527 (2.29), 7.544 (2.98), 7.548 (4.01), 7.565 (3.92), 7.585 (1.86), 7.607 (11.39), 7.629 (15.66), 7.742 (16.00), 7.747 (4.65), 7.763 (11.42).

Experimental SectionBiological Assays

Abbreviations and Acronyms

[1073] Acc. No. accession number [1074] AVP arginine vasopressin [1075] B.sub.max maximal ligand binding capacity [1076] BSA bovine serum albumin [1077] cAMP cyclic adenosine monophosphate [1078] Cat. No. catalogue number [1079] cDNA complementary deoxyribonucleic acid [1080] CHO chinese hamster ovary [1081] CRE cAMP response element [1082] Ct cycle threshold [1083] DMEM/F12 Dulbecco's modified Eagle's medium/Ham's F12 medium (1:1) [1084] DNA deoxyribonucleic acid [1085] DMSO dimethylsulfoxide [1086] DTT dithiothreitol [1087] EC.sub.50 half-maximal effective concentration [1088] EDTA ethylenediamine-tetraacetic acid [1089] FAM carboxyfluorescein succinimidyl ester [1090] f.c. final concentration [1091] FCS fetal calf serum [1092] HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid [1093] IC.sub.50 half-maximal inhibitory concentration [1094] K.sub.d dissociation constant [1095] K.sub.i dissociation constant of an inhibitor [1096] mRNA messenger ribonucleic acid [1097] PBS phosphate buffered saline [1098] PEG polyethylene glycol [1099] p.o. per os, peroral [1100] RNA ribonucleic acid [1101] RTPCR real-time polymerase chain reaction [1102] SPA scintillation proximity assay [1103] TAMRA carboxytetramethylrhodamine [1104] TRIS; Tris 2-amino-2-hydroxymethylpropane-1,3-diol

[1105] Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to demonstrate the activity of the compounds of the present invention, the following assays may be used.

B-1. Cellular In Vitro Assay for Determining Vasopressin Receptor Activity

[1106] The identification of agonists and antagonists of the V1a and V2 vasopressin receptors from humans, rats and dogs as well as the quantification of the activity of the compounds of the invention is carried out using recombinant cell lines. These cell lines originally derive from a hamster's ovary epithelial cell (Chinese Hamster Ovary, CHO K1, ATCC: American Type Culture Collection, Manassas, Va. 20108, USA). The test cell lines constitutively express the human, rat or dog V1a or V2 receptors. In case of the G.sub.q-coupled V1a receptors, cells are also stably transfected with a modified form of the calcium-sensitive photoproteins aequorin (human and rat V1a) or obelin (dog V1a), which, after reconstitution with the cofactor coelenterazine, emit light when there are increases in free calcium concentrations [Rizzuto R, Simpson A W, Brini M, Pozzan T, Nature 358, 325-327 (1992); Illarionov B A, Bondar V S, Illarionova V A, Vysotski E S, Gene 153 (2), 273-274 (1995)]. The resulting vasopressin receptor cells react to stimulation of the recombinantly expressed V1a receptors by intracellular release of calcium ions, which can be quantified by the resulting photoprotein luminescence. The G.sub.s-coupled V2 receptors are stably transfected into cell lines expressing the gene for firefly luciferase under control of a CRE-responsible promoter. Activation of V2 receptors induces the activation of the CRE-responsive promoter via cAMP increase, thereby inducing the expression of firefly luciferase. The light emitted by photoproteins of V1a cell lines as well as the light emitted by firefly luciferase of V2 cell lines corresponds to the activation or inhibition of the respective vasopressin receptor. The bioluminescence of the cell lines is detected using a suitable luminometer [Milligan G, Marshall F, Rees S, Trends in Pharmacological Sciences 17, 235-237 (1996)].

Test Procedure:

Vasopressin V1a Receptor Cell Lines:

[1107] On the day before the assay, the cells are plated out in culture medium (DMEM/F12, 2% FCS, 2 mM glutamine, 10 mM HEPES, 5 g/ml coelenterazine) in 384-well microtiter plates and kept in a cell incubator (96% humidity, 5% v/v CO.sub.2, 37 C.). On the day of the assay, test compounds in various concentrations are placed for 10 minutes in the wells of the microtiter plate before the agonist [Arg.sup.8]-vasopressin at EC.sub.50 concentration is added. The resulting light signal is measured immediately in a luminometer.

Vasopressin V2 Receptor Cell Lines:

[1108] On the day before the assay, the cells are plated out in culture medium (DMEM/F12, 2% FCS, 2 mM glutamine, 10 mM HEPES) in 384-well microtiter plates and kept in a cell incubator (96% humidity, 5% v/v CO.sub.2, 37 C.). On the day of the assay, test compounds in various concentrations and the agonist [Arg.sup.s]-vasopressin at EC.sub.50 concentration are added together to the wells, and plates are incubated for 3 hours in a cell incubator. Upon addition of the cell lysis reagent Triton and the substrate luciferin, luminescence of firefly luciferase is measured in a luminometer.

[1109] Table 1A below lists individual IC.sub.50 values for the compounds of the invention (including racemic mixtures as well as separated enantiomers) that were obtained from cell lines transfected with the human V1a or V2 receptor:

TABLE-US-00002 TABLE 1A Example IC.sub.50 hV1a IC.sub.50 hV2 ratio IC.sub.50 No. [M] [M] hV2/hV1a 1 0.00075 0.00185 2.5 2 0.00043 0.00084 1.9 3 0.00062 0.00215 3.5 4 0.00230 0.00477 2.1 5 0.00064 0.00380 6.0 6 0.00039 0.00345 8.9 7 0.00022 0.00112 5.2 8 0.00031 0.00169 5.5 9 0.00089 0.01675 18.8 10 0.00063 0.01823 29.2 11 0.00093 0.00465 5.0 12 0.00120 0.00245 2.0 13 0.00035 0.00225 6.5 14 0.00096 0.00585 6.1 15 0.00340 0.01140 3.4 16 0.00033 0.00082 2.5 17 0.00050 0.00190 3.8 18 0.00081 0.00135 1.7 19 0.00255 0.03800 14.9 20 0.00042 0.01200 28.6 21 0.00200 0.03550 17.8 22 0.00046 0.01200 26.1 23 0.00125 0.00120 1.0 24 0.00040 0.00102 2.6 25 0.00043 0.00086 2.0 26 0.00040 0.00220 5.6 27 0.00035 0.00128 3.7 28 0.00066 0.01000 15.3 29 0.00105 0.00490 4.7 30 0.00038 0.00270 7.2 31 0.00108 0.00835 7.7 32 0.00035 0.02475 71.2 33 0.00037 0.00925 25.2 34 0.00046 0.00875 19.0 35 0.00048 0.00605 12.6 36 0.00082 0.00175 2.1 37 0.00044 0.00133 3.1 38 0.00040 0.00355 8.9 39 0.00058 0.01800 31.0 40 0.00072 0.00720 10.1 41 0.00093 0.00740 8.0 42 0.00048 0.00190 4.0 43 0.00042 0.00440 10.5 44 0.00034 0.00116 3.5 45 0.00245 0.01300 5.3 46 0.00065 0.00547 8.5 47 0.00096 0.00563 5.8 48 0.00064 0.01042 16.3 49 0.00063 0.00194 3.1 50 0.00047 0.00208 4.5 51 0.00071 0.00175 2.5 52 0.00065 0.00083 1.3 53 0.00052 0.00185 3.6 54 0.00054 0.00156 2.9 55 0.00039 0.02600 67.1 56 0.00073 0.00565 7.7 57 0.00074 0.00490 6.6 58 0.00165 0.02200 13.3 59 0.00230 0.03950 17.2 60 0.00044 0.00540 12.3 61 0.00135 0.01005 7.4 62 0.00130 0.00945 7.3 63 0.00042 0.00580 14.0 64 0.00080 0.00435 5.5 65 0.00063 0.00645 10.2 66 0.00037 0.00690 18.9 67 0.00116 0.02200 19.0 68 0.00045 0.01350 30.3 69 0.00105 0.00435 4.2 70 0.00090 0.02200 24.4 71 0.00044 0.00240 5.5 72 0.00058 0.01750 30.2 73 0.00113 0.00950 8.4 74 0.00048 0.00360 7.5 75 0.00081 0.00890 11.0 76 0.00042 0.04500 108.4 77 0.00150 0.03900 26.0 78 0.00079 0.00163 2.1 79 0.00032 0.00219 6.8 80 0.00036 0.00279 7.8 81 0.00160 0.01767 11.0 82 0.00086 0.00647 7.5 83 0.00056 0.01430 25.7 84 0.00083 0.01200 14.4 85 0.00058 0.00976 16.9 86 0.00098 0.00666 6.8 87 0.00241 0.02680 11.1 88 0.00559 0.01185 2.1 89 0.00545 0.08050 14.8 90 0.00880 0.24750 28.1 91 0.00115 0.10550 91.7 92 0.04150 3.05000 73.5 93 0.02800 3.15000 112.5 94 0.00430 0.09550 22.2 95 0.00086 0.72750 845.9 96 0.00100 0.40750 407.5 97 0.00056 0.09950 176.9 98 0.00190 0.14500 76.3 99 0.01015 0.35000 34.5 100 0.33000 3.80000 11.5 101 0.02950 0.51000 17.3 102 0.00390 0.12300 31.5 103 0.03000 0.24500 8.2 104 0.03050 0.36500 12.0 105 0.02200 0.18000 8.2 106 0.02650 0.31000 11.7 107 0.04350 0.78500 18.1 108 0.01070 0.08400 7.9 109 0.00940 0.38500 41.0 110 0.00140 0.17000 121.4 111 0.01850 2.75000 148.7 112 0.11450 0.81000 7.1 113 0.03700 0.36000 9.7 114 0.01025 1.80000 175.6 115 0.00586 0.00207 0.4 116 0.00135 0.00198 1.5 117 0.06650 0.01920 0.3 118 0.01645 0.00104 0.1 119 0.00779 0.01713 2.2 120 0.00466 0.00819 1.8 121 0.00640 0.00612 1.0 122 0.00097 1.55000 1606.2 123 0.00215 0.00459 2.1

B-2. Radioactive Binding Assay

[1110] IC.sub.50 and K.sub.i values can be determined in radioactive binding assays using membrane fractions of recombinant human embryonic kidney cell line 293 (HEK293) or CHO-K1 cell lines expressing the respective human vasopressin V1a and V2 receptors.

[1111] Human recombinant vasopressin V1a receptors expressed in HEK293 cells are used in 50 mM Tris-HCl buffer, pH 7.4, 5 mM MgCl.sub.2, 0.1% BSA using standard techniques. Aliquots of prepared membranes are incubated with test compounds in various concentrations in duplicates and 0.03 nM [.sup.125I]Phenylacetyl-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH.sub.2 for 120 minutes at 25 C. Nonspecific binding is estimated in the presence of 1 M [Arg.sup.8]Vasopressin. Receptors are filtered and washed, the filters are then counted to determine [.sup.125I]Phenylacetyl-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH.sub.2 specifically bound.

[1112] CHO-K1 cells stably transfected with a plasmid encoding human vasopressin V2 receptor are used to prepare membranes in 50 mM Tris-HCl buffer, pH 7.4, 10 mM MgCl.sub.2, 0.1% BSA using standard techniques. Aliquots of prepared membrane are incubated with test compounds in various concentrations in duplicates and 4 nM [.sup.3H](Arg.sup.8)-Vasopressin for 120 minutes at 25 C. Nonspecific binding is estimated in the presence of 1 mM (Arg.sup.8)-vasopressin. Membranes are filtered and washed 3 times and the filters are counted to determine [.sup.3H](Arg.sub.8)-Vasopressin specifically bound.

[1113] IC.sub.50 values are determined by a non-linear, least squares regression analysis using MathIQ (ID Business Solutions Ltd., UK). The inhibition constant K.sub.i is calculated using the equation of Cheng and Prusoff (Cheng, Y., Prusoff, W. H., Biochem. Pharmacol. 22:3099-3108, 1973).

B-3. Cellular In Vitro Assay for Detecting the Action of Vasopressin V1a Receptor Antagonists on the Regulation of Pro-Fibrotic Genes

[1114] The cell line H9C2 (American Type Culture Collection ATCC No. CRL-1446), described as a cardiomyocyte type isolated from rat cardiac tissue, endogenously expresses the vasopressin Via receptor AVPR1A in high copy number, whereas AVPR2 expression cannot be detected. Likewise, the cell line NRK49F (ATCC No. CRL1570) isolated from rat kidney tissue, shows similar expression pattern of high AVPR1A mRNA expression and diminishing AVPR2 expression. For cell assays detecting the inhibition of AVPR1A receptor-dependent regulation of gene expression by receptor antagonists, the procedure is as follows:

[1115] H9C2 cells or NRK49F cells are seeded in 6-well microtiter plates for cell culture at a cell density of 50 000 cells/well in 2.0 ml of Opti-MEM medium (Invitrogen Corp., Carlsbad, Calif., USA, Cat. No. 11058-021) and held in a cell incubator (96% humidity, 8% v/v CO.sub.2, 37 C.). After 24 hours, sets of three wells (triplicate) are charged with vehicle solution (negative control) and vasopressin solution ([Arg8]-vasopressin acetate, Sigma, Cat. No. V9879), or test compound (dissolved in vehicle: water with 20% v/v ethanol) and vasopressin solution. In the cell culture, the final vasopressin concentration is 1 nM. The test compound solution is added to the cell culture in small volumes, so that a final concentration of 0.03% of ethanol in the cell assay is not exceeded. After an incubation time of 5 hours, the culture supernatant is drawn off under suction, the adherent cells are lysed in 350 l of RLT buffer (Qiagen, Cat. No. 79216), and the RNA is isolated from the lysate using the RNeasy kit (Qiagen, Cat. No. 74104). This is followed by DNAse digestion (Invitrogen, Cat. No. 18068-015), cDNA synthesis (Promaga, ImProm-II Reverse Transcription System, Cat. No. A3800) and Reverse Transcription Polymerase Chain Reaction (RTPCR) (pPCR MasterMix RT-QP2X-03-075, Eurogentec, Seraing, Belgium). All procedures take place in accordance with the working protocols of the test reagents' manufacturers. The primer sets for the RTPCR are selected on the basis of the mRNA gene sequences (NCBI GenBank Entrez Nucleotide Data Base) using the Primer3Plus program with 6-FAM TAMRA-labelled probes. The RTPCR for determining the relative mRNA expression in the cells of the various assay batches is carried out using the Applied Biosystems ABI Prism 7700 Sequence Detector in 384-well microtiter plate format in accordance with the instrument operating instructions. The relative gene expression is represented by the delta-delta Ct value [Applied Biosystems, User Bulletin No. 2 ABI Prism 7700 SDS, Dec. 11, 1997 (updated 10/2001)] with reference to the level of expression of the ribosomal protein L-32 gene (GenBank Acc. No. NM_013226) and the threshold Ct value of Ct=35.

B-4. Inhibition of Vasopressin Induced Aggregation of Human Platelets

[1116] Human platelets endogenously express the V1a receptor. It was found that relatively high vasopressin concentrations (ca. 50-100 nM) stimulate platelet aggregation ex vivo. Therefore, platelets enriched from human blood may serve as a V1a expressing tissue for pharmacological studies with corresponding high concentrations of vasopressin antagonists.

[1117] Human blood is collected in a 10 mM trisodium citrate solution by venous puncture from nonsmoking healthy volunteers (n=4-8) who were drug free for at least 1 week. Platelet-rich plasma (PRP) is obtained by centrifuging the blood sample at 140 g for 20 min at 4 C. The resulting pellet is further centrifuged (15.000 rpm, 2 min) to produce platelet-poor plasma (PPP). Platelet aggregation is measured turbidimetrically using an aggregometer (APACT 4). The reaction is followed by monitoring changes in light transmission on 178 L PRP aliquots, under continuous stirring at 37 C., against PPP control. Various concentrations of vasopressin antagonists (in 2 L) are added to PRP 5 min before the addition of 20 L Arg-vasopressin (final concentration 100 nM. The inhibitory effects of the compounds are determined by measuring the height of the aggregation wave from the bottom of the shape change compared with the control response. IC50 values are calculated a dose-response inhibition curve by an iterative nonlinear regression program

B-5. Effects on the Contraction of Isolated Rat Vessel Rings

Isolated Aorta

[1118] Test compounds can be investigated on isolated aortic rings from male Wistar rats endogenously expressing the V1a receptor. Male Wistar rats are euthanized using carbon dioxide. The aorta is removed and placed in ice-cold Krebs-Henseleit buffer of following composition (in mmol/l): NaCl 112, KCl 5.9, CaCl.sub.2 2.0, MgCl.sub.2 1.2, NaH.sub.2PO.sub.4 1.2, NaHCO.sub.3 25, glucose 11.5. The aorta is cut into 3 mm rings and transferred to 20 ml organ baths containing Krebs-Henseleit solution equilibrated with 95% O.sub.2, 5% CO.sub.2 at 37 C. For recording of isometric tension the rings are mounted between two hooks. The resting tension is adjusted to 3 g. After an equilibration period, each experiment is started by exposing the preparation to K+(50 mM) Krebs-Henseleit solution. The aortic rings are than pre-contracted using 1 nmol/l Arg-vasopressin. After a stable contraction is established, a cumulative dose response curve of the test compound is constructed. The stabilized contraction induced by Arg-vasopressin is defined as 100% tension. The relaxation is expressed as percentage tension.

Isolated A. renalis

[1119] Male Wistar rats (200-250 g) are euthanized using carbon dioxide. The A. renalis is removed and placed in ice-cold Krebs-Henseleit buffer of following composition (in mmol/1): NaCl 112, KCl 5.9, CaCl.sub.2 2.0, MgCl.sub.2 1.2, NaH.sub.2PO.sub.4 1.2, NaHCO.sub.3 25, glucose 11.5. For measurement of isometric tension, ring segments, 2 mm in length, are mounted in a small vessel chamber myograph (Danish Myo Technology A/S, Denmark) using two tungsten wires fixed to mounting jaws. One mounting jaw is attached to a micrometer, allowing control of vessel circumference. The other mounting jaw is attached to a force transducer for measurement of tension development. The whole preparation is kept in a chamber with physiological salt solution at 37 C., bubbled with oxygen. After a 30 min equilibration period, the vessels are stretched to their optimal lumen diameter for active tension development which is determined based on the internal circumference-wall tension ratio. The internal circumference is set to 90% of what the vessels would have if they are exposed to a passive tension equivalent to that produced by a transmural pressure of 100 mmHg.

[1120] Afterwards, the vessels are washed three times with Krebs-Henseleit buffer and left to equilibrate for 30 min. The contractility is then tested by a twofold exposure to a high K.sup.+ solution (50 mmol/l KCl). After washing with Krebs-Henseleit buffer the vessels are then pre-contracted using 1 nmol/l Arg-vasopressin. After a stable contraction is established, a cumulative dose response curve of the test compound is constructed. The stabilized contraction induced by Arg-vasopressin is defined as 100% tension. The relaxation is expressed as percentage tension.

B-6. In Vivo Assay for Detecting Cardiovascular Effects: Blood Pressure Measurement in Anaesthetized Rats (Vasopressin Challenge Model)

[1121] Male Sprague-Dawley rats (250-350 g body weight) are used under ketamine/xylazine/pentobarbital injection anaesthesia. Polyethylene tubes (PE-50, Intramedic), prefilled with heparin-containing (500 IU/ml) isotonic sodium chloride solution, are introduced into the jugular vein and the femoral vein and then tied in. Arg-vasopressin (SIGMA) is injected via one venous access, with the aid of a syringe; the test substance is administered via the second venous access. For determination of the systolic blood pressure, a pressure catheter (Millar SPR-320 2F) is tied into the carotid artery. The arterial catheter is connected to a pressure transducer which feeds its signals to a recording computer equipped with suitable recording software. In a typical experiment, the experimental animal is administered 3-4 successive bolus injections at intervals of 10-15 min with a defined amount of Arg-vasopressin (30 ng/kg) in isotonic sodium chloride solution. When the blood pressure has reached initial levels again, the test substance is administered as a bolus, with subsequent continuous infusion, in a suitable solvent. After this, at defined intervals (10-15 min), the same amount of Arg-vasopressin as at the start is administered again. On the basis of the blood pressure values, a determination is made of the extent to which the test substance counteracts the hypertensive effect of Arg-vasopressin. Control animals only receive solvent instead of the test substance.

[1122] Following intravenous administration, the compounds of the invention, in comparison to the solvent controls, bring about an inhibition of the blood pressure increase caused by Arg-vasopressin.

B-7. In Vivo Assay for Detecting Cardiovascular Effects: Diuresis Investigations in Conscious Rats Kept in Metabolism Cages

[1123] Wistar rats (220-450 g body weight) are kept with free access to feed (Altromin) and drinking water. During the experiment, the animals are kept with free access to drinking water for 4 to 8 or up to 24 hours individually in metabolism cages suitable for rats of this weight class (Tecniplast Deutschland GmbH, D-82383 Hohenpeienberg). At the beginning of the experiment, the animals are administered the test substance in a volume of 1 to 3 ml/kg body weight of a suitable solvent by means of gavage into the stomach. Control animals only receive solvent. Controls and substance tests are carried out in parallel on the same day. Control groups and substance-dose groups each consist of 4 to 8 animals. During the experiment, the urine excreted by the animals is collected continuously in a receiver at the base of the cage. The volume of urine per time unit is determined separately for each animal, and the concentration of urinary electrolytes is measured by standard methods of flame photometry. Before the beginning of the experiment, the body weight of the individual animals is determined.

B-8. In Vivo Assay for Detecting Protective Renal Effects: Acute Ischemia/Reperfusion Injury Model in Rodents

[1124] Laboratory bred male C57Bl/6J mice 6-8 weeks old are obtained from Taconic Biosciences, male 6-8 weeks old Sprague Dawley rat are obtained from Charles River. Both rats and mice are maintained under standard laboratory conditions, 12 hour light-dark cycles with access to normal chow and drinking water at libitum. For the ischemia reperfusion injury model a total of 10-12 rats or mice is used in each control and experimental group.

[1125] Animals are anesthetized with continuous inhaled isoflurane. A right nephrectomy is performed through a right flank incision 7 days before the ischemic procedures in the contralateral kidneys. For renal ischemia a left flank incision is made. Renal vessels are exposed by dissection of the left renal pedicle. Non-traumatic vascular clamps are used to stop blood flow (artery and vein) during 45 min (rats) or 25 min (mice) of ischemia. Reperfusion is established by removing the clamps. The abdominal wall (muscular layer and skin) is closed with 5.0 polypropylene sutures. Temgesic (Buprenorphin, 0.025 mg/kg s.c.) is applied as an analgesic.

[1126] Urine of each animal is collected in metabolic cages over night before sacrifice at 24 h post ischemia. Upon sacrifice, blood samples are obtained under terminal anesthesia. After centrifugation of the blood samples, serum is isolated. Both serum creatinine and serum urea are measured via clinical biochemistry analyzer (Pentra 400). For the assessment of serum and urinary kidney injury biomarkers (Neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule-1 [KIM-1] and Osteopontin) ELISA's are performed according to the manufacturers protocol. Both urinary creatinine and albumin are measured to determine the albumin/creatinine ratio.

[1127] Total RNA is isolated from kidneys. Left kidneys are snap-frozen in liquid nitrogen at sacrifice. Kidney tissue is then homogenized and RNA is obtained. Total RNA is transcribed to cDNA. Using TaqMan real-time PCR renal NGAL, Osteopontin, KIM-1, Nephrin and Podocin mRNA expression is analyzed in whole kidney tissue.

[1128] Differences between groups are analyzed by one-way ANOVA with Dunnett's corrections for multiple comparisons. Statistical significance is defined as p<0.05. All statistical analyses are done using GraphPad Prism 6.

B-9. In Vivo Assay for Detecting Cardiovascular Effects: Hemodynamic Investigations in Anaesthetized Dogs

[1129] Male beagle dogs (Beagle, Marshall BioResources, USA) with a weight of between 10 and 15 kg are anesthetized with pentobarbital (30 mg/kg iv, Narcoren, Merial, Germany) for the surgical interventions and the hemodynamic and functional investigation termini. Pancuroniumbromide (Pancuronium Inresa, Inresa, Germany, 2-4 mg/animal i.v.) serves additionally as a muscle relaxant. The dogs are intubated and ventilated with an oxygen/ambient air mixture (30/70%), about 2,5-4 L/min. Ventilation takes place using a ventilator from GE Healthcare (Avance, Germany) and is monitored using a carbon dioxide analyzer (-Datex Ohmeda). The anesthesia is maintained by continual infusion of pentobarbital (50 g/kg/min); fentanyl is used as an analgesic (10 g/kg/h).

[1130] In preparatory interventions, the dogs are fitted with a cardiac pacemaker. At start of experiment, a cardiac pacemaker from Biotronik (Logos, Germany) is implanted into a subcutaneous skin pocket and is contacted with the heart via a pacemaker electrode (Siello S60, Biotronik, Germany) which is advanced through the external jugular vein, with illumination, into the right ventricle.

[1131] Thereafter accesses are removed and the dog wakes spontaneously from the anesthesia. After a further 7 days, the above-described pacemaker is activated and the heart is stimulated at a frequency of 220 beats per minute.

[1132] The actual drug testing experiments take place 28 days after the beginning of pacemaker stimulation, using the following instrumentation: [1133] Introduction of a bladder catheter for bladder relief and for measuring the flow of urine [1134] Attachment of electrocardiography (ECG) leads to the extremities for ECG measurement [1135] Introduction of a sheath introducer filled with sodium chloride solution into the femoral artery. This tube is connected to a pressure sensor (Braun Melsungen, Melsungen, Germany) for measuring the systemic blood pressure [1136] Introduction of a Millar Tip catheter (type 350 PC, Millar Instruments, Houston, USA) through a port secured in the carotid artery, for measuring cardiac hemodynamics. [1137] Introduction of a Swan-Ganz catheter (CCOmbo 7.5F, Edwards, Irvine, USA) via the jugular vein into the pulmonary artery, for measuring the cardiac output, oxygen saturation, pulmonary arterial pressures and central venous pressure [1138] Siting of a venous catheter in the cephalic vein, for infusing pentobarbital, for liquid replacement and for blood sampling (determination of the plasma levels of substance or other clinical blood values) [1139] Siting of a venous catheter in the saphenous vein, for infusing fentanyl and for administration of substance [1140] Infusion of vasopressin (Sigma) in increasing dosage, up to a dose of 4 mU/kg/min. The pharmacological substances are then tested with this dosage.

[1141] The primary signals are amplified if necessary (ACQ7700, Data Sciences International, USA or Edwards-Vigilance-Monitor, Edwards, Irvine, USA) and subsequently fed into the Ponemah system (Data Sciences International, USA) for evaluation. The signals are recorded continuously throughout the experimental period, and are further processed digitally by said software, and averaged over 30 seconds.

[1142] Although the invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of the invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The claims are intended to be construed to include all such embodiments and equivalent variations.

C) Working Examples of Pharmaceutical Compositions

[1143] The substances according to the invention can be converted to pharmaceutical preparations as follows:

Tablet:

Composition:

[1144] 100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of maize starch, 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Germany) and 2 mg of magnesium stearate.

[1145] Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

Production:

[1146] The mixture of the compound of Example 1, lactose and starch is granulated with a 5% strength solution (m/m) of the PVP in water. After drying, the granules are mixed with the magnesium stearate for 5 min. This mixture is compressed in a conventional tabletting press (see above for format of the tablet).

Oral Suspension:

Composition:

[1147] 1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum) (from FMC, USA) and 99 g of water.

[1148] 10 ml of oral suspension correspond to a single dose of 100 mg of the compound of the invention.

Production:

[1149] The Rhodigel is suspended in ethanol, and the compound of Example 1 is added to the suspension. The water is added while stirring. The mixture is stirred for about 6 h until swelling of the Rhodigel is complete.

Sterile i.v. Solution:

[1150] The compound according to the invention is dissolved at a concentration below saturation solubility in a physiologically acceptable solvent (for example isotonic sodium chloride solution, glucose solution 5% and/or PEG 400 solution 30%). The solution is sterilized by filtration and filled into sterile and pyrogen-free injection containers.