SUBSTITUTED TRIAZOLE DERIVATIVES AND USES THEREOF

Abstract

The present invention relates to novel 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) ##STR00188## in which R.sup.1 represents 5-oxopyrrolidin-2-yl, 1-methyl-5-oxopyrrolidin-2-yl, 2-oxo-1,3-oxazolidin-4-yl or a group of the formula ##STR00189## in which # represents the point of attachment to the 1,2,4-triazolyl-ring, R.sup.4 represents methyl, where methyl may be substituted by one substituent selected from the group consisting of hydroxy and C1-C4-alkoxy, R.sup.5 represents hydrogen, or R.sup.4 and R.sup.5 together with the carbon atom to which they are attached form a cyclopropyl ring, R.sup.6 represents hydrogen, C1-C4-alkoxycarbonyl, methylcarbonyl, methylsulfonyl or trifluoromethylcarbonyl, R.sup.7 represents hydrogen or methyl, R.sup.8 represents hydrogen or methyl, R.sup.9 represents aminocarbonyl, methylaminocarbonyl or ethylaminocarbonyl, where methylaminocarbonyl and ethylaminocarbonyl may be substituted independently of one another by one substituent selected from the group consisting of trifluoromethyl and methoxy, R.sup.2 represents phenyl, pyridinyl, pyrimidin-2-yl or 3,3,3-trifluoroprop-1-yl, where phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of chlorine, fluorine, methyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy and aminosulfonyl, and where pyridinyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of chlorine, fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy and methylamino, R.sup.3 represents hydrogen, aminocarbonyl or ethylaminocarbonyl, or one of the pharmaceutically acceptable salts thereof, solvates thereof or solvates of the salts thereof.

2. A compound of formula (I) according to claim 1, wherein R.sup.1 represents 2-oxo-1,3-oxazolidin-4-yl or a group of the formula ##STR00190## in which # represents the point of attachment to the 1,2,4-triazolyl-ring, R.sup.4 represents methyl, R.sup.5 represents hydrogen, R.sup.6 represents methylcarbonyl, methylsulfonyl or trifluoromethylcarbonyl, R.sup.7 represents hydrogen, R.sup.8 represents hydrogen or methyl, R.sup.9 represents aminocarbonyl, R.sup.2 represents phenyl or pyridin-2-yl, where phenyl is substituted by one substituent selected from the group consisting of chlorine, trifluoromethyl and trifluoromethoxy in ortho-position to the point of attachment of the phenyl to the 1,2,4-triazolyl-ring, and where pyridin-2-yl is substituted by one substituent selected from the group consisting of chlorine and trifluoromethoxy in ortho-position to the point of attachment of the pyridin-2-yl to the 1,2,4-triazolyl-ring, R.sup.3 represents hydrogen, aminocarbonyl or ethylaminocarbonyl, or one of the pharmaceutically acceptable salts thereof, solvates thereof or solvates of the salts thereof.

3. A compound of formula (I) according to claim 1, wherein R.sup.1 represents a group of the formula ##STR00191## in which # represents the point of attachment to the 1,2,4-triazolyl-ring, R.sup.4 represents methyl, R.sup.5 represents hydrogen, R.sup.6 represents methylcarbonyl, methylsulfonyl or trifluoromethylcarbonyl, R.sup.7 represents hydrogen, R.sup.8 represents hydrogen or methyl, R.sup.9 represents aminocarbonyl, R.sup.2 represents phenyl or pyridin-2-yl, where phenyl is substituted by one substituent selected from the group consisting of chlorine, trifluoromethyl and trifluoromethoxy in ortho-position to the point of attachment of the phenyl to the 1,2,4-triazolyl-ring, and where pyridin-2-yl is substituted by one substituent selected from the group consisting of chlorine and trifluoromethoxy in ortho-position to the point of attachment of the pyridin-2-yl to the 1,2,4-triazolyl-ring, R.sup.3 represents hydrogen, or one of the pharmaceutically acceptable salts thereof, solvates thereof or solvates of the salts thereof.

4. Process for preparing a compound of the formula (I) or one of the pharmaceutically acceptable salts thereof, solvates thereof or solvates of the salts thereof according to claim 1, wherein [A] a compound of the formula ##STR00192## in which R.sup.3 represents hydrogen, and R.sup.10 represents methyl or ethyl, is reacted in a first step in the presence of an at least stoichiometric amount of a base with a compound of the formula ##STR00193## in which R.sup.1 has the meaning as defined for the compound of formula (I) given in claim 1, to give an intermediate compound, which is then allowed to react in a second step with the compound of the formula (IV) or a respective salt thereof ##STR00194## in which R.sup.2 has the meaning as defined for the compound of formula (I) given in claim 1, to give a compound of the formula ##STR00195## in which R.sup.1 and R.sup.2 have the meaning as defined for the compound of formula (I) given in claim 1, and R.sup.3 represents hydrogen, or [B] a compound of the formula ##STR00196## in which R.sup.1 and R.sup.2 have the meaning as defined for the compound of formula (I) given in claim 1, and R.sup.3 represents hydrogen, is reacted with ethyl isocyanate or chlorosulfonyl isocyanate to give a compound of the formula ##STR00197## in which R.sup.1 and R.sup.2 have the meaning as defined for the compound of formula (I) given in claim 1, and R.sup.3 represents aminocarbonyl or ethylaminocarbonyl, each [A] and [B] optionally followed, where appropriate, by (i) separating the compound of formula (I) thus obtained into their respective diastereomers, and/or (ii) converting the compound of formula (I) into their respective pharmaceutically acceptable salts thereof, solvates thereof or the solvates of the salts thereof by treatment with the corresponding solvents and/or acids or bases.

5. Compound for use as defined in claim 1 for the treatment and/or prevention of diseases.

6. Compound as defined in claim 1 for use in a method for the 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).

7. A product comprising a compound as defined in claim 1 for the manufacture of a pharmaceutical composition for the 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).

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

9. Pharmaceutical composition of claim 8 comprising one or more first active ingredients, optionally compound of formula (I), 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.

10. The pharmaceutical composition as defined in claim 8 for the 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).

11. Method for the treatment and/or prevention of 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

[0286] NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.

[0287] 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.

[0288] 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. Abbreviation 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 DCC N,N′-dicyclohexylcarbodiimide DCM dichloromethane dd double-doublet Dess-Martin 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)- periodinane one DMSO dimethylsulfoxide ESI electrospray (ES) ionisation h hour(s) HPLC high performance liquid chromatography HOBt Hydroxybenzotriazole 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 (δ) 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) SFC Supercritical Fluid Chromatography SQD Single-Quadrupole-Detector t triplet (.sup.1H-NMR signal) td triple-doublet (.sup.1H-NMR signal) TFA trifluoroacetic acid THF tetrahydrofuran UPLC ultra performance liquid chromatography

Experimental Section—General Part

[0289] 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.

[0290] The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

[0291] 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.

[0292] 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.

[0293] 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.

[0294] 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.

[0295] 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)

[0296] Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8μ 50×1 mm; eluent A: 1 1 water+0.25 ml 99% formic acid, eluent B: 1 1 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.

[0297] Method 2 (LC-MS)

[0298] Instrument MS: Thermo Scientific FT-MS; Instrument type UHPLC+: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1×75 mm, C18 1.8 μm; eluent A: 1 1 water+0.01% formic acid; eluent B: 1 1 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 3 (LC-MS)

[0299] Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8μ 50×1 mm; eluent A: 1 1 water+0.25 ml 99% formic acid, eluent B: 1 1 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 4 (preparative HPLC)

[0300] Column: Chromatorex or Reprosil C18 10 μm; 125×30 mm, eluent A: water+0.1% formic acid, eluent B: acetonitrile+0.1% formic acid; gradient: 3 min 10% B, 17.5 min 95% B, 19.5 min 100% B, 20 min 10% B; run time: 20 min; flow rate: 75 ml/min; UV detection at 210 nm.

Method 5 (LC-MS)

[0301] Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8μ 50×2.1 mm; eluent A: 1 1 water+0.25 ml 99% formic acid, eluent B: 1 1 acetonitrile+0.25 ml 99% 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 6 (preparative HPLC)

[0302] Column: Chromatorex C18 10 μm, 125 mm×30 mm; eluent A: water+0.05% TFA, eluent B: acetonitrile+0.05% TFA; gradient: 0-2 min 20% B; 9 min 45% B, 14 min 45% B, 16 min 80% B; 21 min 80% B column temperature: room temperature; flow rate: 50 ml/min; UV detection: 210 nm.

Method 7 (LC-MS)

[0303] Instrument MS: Waters (Micromass) Quattro Micro; Instrument Waters UPLC Acquity; Column: Waters BEH C18 1.7 μm 50×2.1 mm; eluent A: 1 1 Water+0.01 mol ammonium formate, eluent B: 1 1 acetonitrile; gradient: 0.0 min 95% A.fwdarw.0.1 min 95% A.fwdarw.2.0 min 15% A.fwdarw.2.5 min 15% A.fwdarw.2.51 min 10% A.fwdarw.3.0 min 10% A; oven: 40° C.; flow rate: 0.5 ml/min; UV detection: 210 nm.

Method 8 (LC-MS):

[0304] Instrument MS: Waters Synapt G2S; UPLC: Waters Acquity I-CLASS; column: Waters, HSST3, 2.1×50 mm, C18 1.8 μm; eluent A: 1 1 water+0.01% formic acid; eluent B: 1 1 acetonitrile+0.01% formic acid; gradient: 0.0 min 2% B.fwdarw.2.0 min 2% B.fwdarw.13.0 min 90% B.fwdarw.15.0 min 90% B; oven: 50° C.; flow rate: 1.20 ml/min; UV detection: 210 nm.

[0305] Microwave:

[0306] The microwave reactor used was an Initiator.sup.+ microwave system with robot sixty from Biotage®.

Experimental Section—Starting Materials and Intermediates

Example 1A

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

[0307] ##STR00015##

[0308] 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 then 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.

[0309] .sup.1H-NMR (400 MHz, DMSO-d6) δ[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 2A

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

[0310] ##STR00016##

[0311] In a 41 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 1A) 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.

[0312] .sup.1H-NMR (400 MHz, DMSO-d6) δ[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 3A

(1S)-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-(2,6-dichlorophenyl)-1H-1,2,4-triazol-5-yl]ethyl Acetate

[0313] ##STR00017##

[0314] Under argon, 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 2A, 200 mg, 528 μmol) in tetrahydrofuran (2.0 ml) was treated at 0° C. with N,N-diisopropylethylamine (260 μl, 1.5 mmol) and (2S)-1-chloro-1-oxopropan-2-yl acetate (73 μl, 580 μmol) and stirred at 0° C. for 1 h. (2,6-Dichlorophenyl)hydrazine hydrochloride (1:1) (124 mg, 581 μmol) was added in portion and the resulting mixture was stirred at 0° C. for 1.5 h, overnight at RT, 2 h at refluxed temperature and 4 h at 100° C. under microwave irradiation. The reaction mixture was evaporated and the residue was purified by preparative HPLC (Method 4) affording 123 mg (38% of th.) of the title compound.

[0315] LC-MS (Method 1): R.sub.t=1.08 min; MS (ESIpos): m/z=619.0 [M+H].sup.+

[0316] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.86-7.55 (m, 7H), 6.95-6.84 (m, 1H), 5.87-5.71 (m, 1H), 5.22-5.04 (m, 2H), 4.37-4.22 (m, 1H), 4.10-3.77 (m, 2H), 1.84-1.69 (m, 3H), 1.55 (d, 3H).

Example 4A

(1R)-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-(2,6-dichlorophenyl)-1H-1,2,4-triazol-5-yl]ethyl Acetate

[0317] ##STR00018##

[0318] Under argon, 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 2A, 200 mg, 528 μmol) in tetrahydrofuran (2.0 ml) was treated at 0° C. with N,N-diisopropylethylamine (280 μl, 1.6 mmol) and (2R)-1-chloro-1-oxopropan-2-yl acetate (73 μl, 580 μmol) and stirred at 0° C. for 30 min. (2,6-Dichlorophenyl)hydrazine hydrochloride (1:1) (124 mg, 581 μmol) was added and the resulting mixture was stirred overnight at RT and 3 h at 150° C. under microwave irradiation. Purification by preparative HPLC (Method 4) afforded 152 mg (46% of th.) of the title compound.

[0319] LC-MS (Method 1): R.sub.t=1.12 min; MS (ESIpos): m/z=619.2 [M+H].sup.+

[0320] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.87-7.54 (m, 7H), 6.90 (d, 1H), 5.78 (q, 1H), 5.27-5.02 (m, 2H), 4.37-4.20 (m, 1H), 4.13-3.72 (m, 2H), 1.78 (s, 3H), 1.55 (d, 3H).

Example 5A

(1R)-1-[1-(2-Chloro-6-fluorophenyl)-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]ethyl Acetate

[0321] ##STR00019##

[0322] Under argon, 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 2A, 150 mg, 396 μmol) in tetrahydrofuran (1.5 ml, 18 mmol) was treated at 0° C. with N,N-diisopropylethylamine (210 μl, 1.2 mmol) and (2R)-1-chloro-1-oxopropan-2-yl acetate (55 μl, 440 μmol) and stirred at 0° C. for 30 min. (2-Chloro-6-fluorophenyl)hydrazine (70.0 mg, 436 μmol) was added and the resulting mixture was stirred overnight at room temperature and 1 h at 150° C. under microwave irradiation. Purification by preparative HPLC (Method 4) afforded 163 mg (68% of th.) of the title compound.

[0323] LC-MS (Method 1): R.sub.t=1.10 min; MS (ESIpos): m/z=603.3 [M+H].sup.+

[0324] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.85-7.39 (m, 7H), 6.89 (d, 1H), 5.85-5.63 (m, 1H), 5.24-5.01 (m, 2H), 4.37-4.22 (m, 1H), 4.09-3.75 (m, 2H), 1.79 (d, 3H), 1.54 (dd, 3H).

Example 6A

(1R)-1-[1-(2-Chloro-4-fluorophenyl)-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]ethyl Acetate

[0325] ##STR00020##

[0326] Under argon, 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 2A, 250 mg, 660 μmol) in tetrahydrofuran (5.0 ml) was treated at 0° C. with N,N-diisopropylethylamine (340 μl, 2.0 mmol) and (2R)-1-chloro-1-oxopropan-2-yl acetate (55 μl, 730 μmol) and stirred at 0° C. for 30 min. (2-Chloro-4-fluorophenyl)hydrazine hydrochloride (1:1) (143 mg, 726 μmol) was added and the resulting mixture was stirred overnight at room temperature and 3 h at 120° C. under microwave irradiation. Purification by preparative HPLC (Method 4) afforded 178 mg (45% of th.) of the title compound as mixture of rotamers.

[0327] LC-MS (Method 1): R.sub.t=1.10 min; MS (ESIpos): m/z=603.2 [M+H].sup.+

[0328] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.99-7.28 (m, 7H), 6.89 (d, 1H), 5.95-5.50 (m, 1H), 5.10 (d, 2H), 4.40-4.219 (m, 1H), 4.09-3.72 (m, 2H), 1.92-1.70 (m, 3H), 1.53 (d, 3H).

Example 7A

(1S)-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-[2-(difluoromethoxy)phenyl]-1H-1,2,4-triazol-5-yl}ethyl Acetate

[0329] ##STR00021##

[0330] Under argon, 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 2A, 150 mg, 396 μmol) in tetrahydrofuran (1.5 ml) was treated at 0° C. with N,N-diisopropylethylamine (210 μl, 1.2 mmol) and (2S)-1-chloro-1-oxopropan-2-yl acetate (55 μl, 440 μmol) and stirred at 0° C. for 30 min. [2-(Difluoromethoxy)phenyl]hydrazine (75.9 mg, 436 μmol) was added and the resulting mixture was stirred overnight at room temperature and 3 h at 100° C. under microwave irradiation. Purification by preparative HPLC (Method 4) afforded 143 mg (58% of th.) of the title compound.

[0331] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=617.1 [M+H].sup.+

[0332] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.84-6.77 (m, 10H), 5.79-5.57 (m, 1H), 5.21-4.95 (m, 2H), 4.38-4.20 (m, 1H), 4.10-3.74 (m, 2H), 1.88-1.67 (m, 3H), 1.53 (d, 3H).

Example 8A

(1R)-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-[2-(difluoromethoxy)phenyl]-1H-1,2,4-triazol-5-yl}ethyl Acetate

[0333] ##STR00022##

[0334] Under argon, 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 2A, 200 mg, 528 μmol) in tetrahydrofuran THF (2.0 ml) was treated at 0° C. with N,N-diisopropylethylamine (280 μl, 1.6 mmol) and (2R)-1-chloro-1-oxopropan-2-yl acetate (55 μl, 580 μmol) and stirred at 0° C. for 30 min. [2-(Difluoromethoxy)phenyl]hydrazine (101 mg, 581 μmol) was added and the resulting mixture was stirred overnight at room temperature and 3 h at 150° C. under microwave irradiation. Purification by preparative HPLC (Method 4) afforded 202 mg (62% of th.) of the title compound.

[0335] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=617.3 [M+H].sup.+

[0336] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.84-6.78 (m, 10H), 5.69 (br q, 1H), 5.09 (d, 2H), 4.44-4.18 (m, 1H), 4.11-3.73 (m, 2H), 1.76 (s, 3H), 1.53 (d, 3H).

Example 9A

(1S)-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-[2-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-5-yl}ethyl Acetate

[0337] ##STR00023##

[0338] Under argon, 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 2A, 150 mg, 396 μmol) in tetrahydrofuran (3.0 ml) was treated at 0° C. with N,N-diisopropylethylamine (210 μl, 1.2 mmol) and (2S)-1-chloro-1-oxopropan-2-yl acetate (55 μl, 440 μmol) and stirred at 0° C. for 30 min. [2-(Trifluoromethoxy)phenyl]hydrazine hydrochloride (1:1) (99.6 mg, 436 μmol) was added and the resulting mixture was stirred overnight at room temperature and 3 h at 120° C. under microwave irradiation. Purification by preparative HPLC (Method 4) afforded 141 mg (56% of th.) of the title compound.

[0339] LC-MS (Method 1): R.sub.t=1.14 min; MS (ESIpos): m/z=635.3 [M+H].sup.+

Example 10A

(1R)-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-[2-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-5-yl}ethyl Acetate

[0340] ##STR00024##

[0341] Under argon, 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 2A, 250 mg, 660 μmol) in tetrahydrofuran (5.0 ml) was treated at 0° C. with N,N-diisopropylethylamine (340 μl, 2.0 mmol) and (2R)-1-chloro-1-oxopropan-2-yl acetate (55 μl, 730 μmol) and stirred at 0° C. for 30 min. [2-(Trifluoromethoxy)phenyl]hydrazine hydrochloride (1:1) (166 mg, 726 μmol) was added and the resulting mixture was stirred overnight at room temperature and 3 h at 120° C. under microwave irradiation. Purification by preparative HPLC (Method 4) afforded 168 mg (40% of th.) of the title compound.

[0342] LC-MS (Method 1): R.sub.t=1.13 min; MS (ESIpos): m/z=635.3 [M+H].sup.+

[0343] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.81-7.51 (m, 8H), 6.89 (d, 1H), 5.75 (q, 1H), 5.21-4.97 (m, 2H), 4.42-4.17 (m, 1H), 4.11-3.73 (m, 2H), 1.80-1.66 (m, 3H), 1.53 (d, 3H).

Example 11A

(1S)-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-(2-sulfamoylphenyl)-1H-1,2,4-triazol-5-yl]ethyl Acetate

[0344] ##STR00025##

[0345] Under argon, 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 2A, 150 mg, 396 μmol) in tetrahydrofuran (3.0 ml) was treated at 0° C. with N,N-diisopropylethylamine (280 μl, 1.6 mmol) and (2S)-1-chloro-1-oxopropan-2-yl acetate (55 μl, 440 μmol) and stirred at 0° C. for 30 min. 2-Hydrazinylbenzenesulfonamide (81.6 mg, 436 μmol) was added and the resulting mixture was stirred overnight at room temperature and 3 h at 120° C. under microwave irradiation. Purification by preparative HPLC (Method 4) afforded 193 mg (76% of th.) of the title compound rotamers.

[0346] LC-MS (Method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=630.3 [M+H].sup.+

[0347] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.24-6.72 (m, 11H), 6.13-5.41 (m, 1H), 5.29-4.99 (m, 2H), 4.38-4.20 (m, 1H), 4.09-3.70 (m, 2H), 1.87 (br s, 3H), 1.48 (d, 3H).

Example 12A

(1S)-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-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Acetate

[0348] ##STR00026##

[0349] Under argon, 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 2A, 200 mg, 528 μmol) in THF (2.0 ml) was treated at 0° C. with N,N-diisopropylethylamine (280 μl, 1.6 mmol) and (2S)-1-chloro-1-oxopropan-2-yl acetate (79 μl, 580 μmol) and stirred at 0° C. for 30 min. 2-Hydrazinylpyridine (63.4 mg, 581 μmol) was then added and the resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 199 mg (68% of th.) of the title compound.

[0350] LC-MS (Method 1): R.sub.t=1.05 min; MS (ESIpos): m/z=552 [M+H].sup.+

[0351] .sup.1H-NMR (500 MHz, DMSO-d6) δ[ppm]: 8.55-8.47 (m, 1H), 8.19-8.02 (m, 1H), 7.83-7.44 (m, 6H), 6.90 (d, 1H), 6.51 (q, 1H), 5.17-5.05 (m, 2H), 4.31 (m, 1H), 4.06-3.81 (m, 2H), 1.89 (s, 3H), 1.62 (d, 3H).

Example 13A

(1R)-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-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Acetate

[0352] ##STR00027##

[0353] Under argon, 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 2A, 200 mg, 528 μmol) in THF (2.0 ml) was treated at 0° C. with N,N-diisopropylethylamine (280 μl, 1.6 mmol) and (2R)-1-chloro-1-oxopropan-2-yl acetate (55 μl, 580 μmol) and stirred at 0° C. for 30 min. 2-Hydrazinylpyridine (63.4 mg, 581 μmol) was then added and the resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 214 mg (73% of th.) of the title compound.

[0354] LC-MS (Method 1): R.sub.t=1.05 min; MS (ESIpos): m/z=552 [M+H].sup.+

[0355] 1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.51 (dd, 1H), 8.08 (m, 1H), 7.84-7.45 (m, 6H), 6.90 (d, 1H), 6.51 (q, 1H), 5.11 (m, 2H), 4.31 (m, 1H), 4.08-3.80 (m, 2H), 1.89 (s, 3H), 1.62 (d, 3H).

Example 14A

(1S)-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-fluoropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Acetate

[0356] ##STR00028##

[0357] Under argon, 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 2A, 150 mg, 396 μmol) in THF (1.5 ml) was treated at 0° C. with N,N-diisopropylethylamine (210 μl, 1.2 mmol) and (2S)-1-chloro-1-oxopropan-2-yl acetate (55 μl, 440 μmol) and stirred at 0° C. for 30 min. 3-Fluoro-2-hydrazinylpyridine (55.4 mg, 436 μmol) was then added and the resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 152 mg (67% of th.) of the title compound.

[0358] LC-MS (Method 1): R.sub.t=1.01 min; MS (ESIpos): m/z=570 [M+H].sup.+

[0359] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.46 (br. d, 1H), 8.23-8.05 (m, 1H), 7.88-7.53 (m, 5H), 6.89 (d, 1H), 5.93 (q, 1H), 5.12 (m, 2H), 4.30 (m, 1H), 4.08-3.71 (m, 2H), 1.79 (s, 3H), 1.59 (d, 3H).

Example 15A

(1R)-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-fluoropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Acetate

[0360] ##STR00029##

[0361] Under argon, 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 2A, 200 mg, 528 μmol) in THF (2.0 ml) was treated at 0° C. with N,N-diisopropylethylamine (280 μl, 1.6 mmol) and (2R)-1-chloro-1-oxopropan-2-yl acetate (73 μl, 580 μmol) and stirred at 0° C. for 30 min. 3-Fluoro-2-hydrazinylpyridine (73.8 mg, 581 μmol) was then added and the resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 195 mg (65% of th.) of the title compound.

[0362] LC-MS (Method 1): R.sub.t=1.01 min; MS (ESIpos): m/z=570 [M+H].sup.+

[0363] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.46 (br. d, 1H), 8.14 (m, 1H), 7.86-7.53 (m, 5H), 6.89 (d, 1H), 5.93 (q, 1H), 5.12 (m, 2H), 4.30 (m, 1H), 4.11-3.74 (m, 2H), 1.79 (s, 3H), 1.59 (d, 3H).

Example 16A

(1S)-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-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Acetate

[0364] ##STR00030##

[0365] Under argon, 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 2A, 150 mg, 396 μmol) in THF (1.5 ml) was treated at 0° C. with N,N-diisopropylethylamine (210 μl, 1.2 mmol) and (2S)-1-chloro-1-oxopropan-2-yl acetate (55 μl, 440 μmol) and stirred at 0° C. for 30 min. 3-Chloro-2-hydrazinylpyridine (62.5 mg, 436 μmol) was then added and the resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 78.1 mg (34% of th.) of the title compound.

[0366] LC-MS (Method 1): R.sub.t=1.03 min; MS (ESIpos): m/z=586 [M+H].sup.+

[0367] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.59 (dd, 1H), 8.32 (dd, 1H), 7.83-7.48 (m, 6H), 6.89 (d, 1H), 5.87 (q, 1H), 5.12 (m, 2H), 4.42-4.21 (m, 1H), 3.98 (d, 1H), 3.85 (dd, 1H), 1.75 (s, 3H), 1.56 (d, 3H).

Example 17A

(1R)-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-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Acetate

[0368] ##STR00031##

[0369] Under argon, 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 2A, 500 mg, 1.32 mmol) in (5.0 ml) THF was treated at 0° C. with N,N-diisopropylethylamine (690 μl, 4.0 mmol) and (2R)-1-chloro-1-oxopropan-2-yl acetate (55 μl, 1.5 mmol) and stirred at 0° C. for 30 min. A solution of 3-chloro-2-hydrazinylpyridine (208 mg, 1.45 mmol) in (2.0 μl) THF and (1.0 μl) dioxane was then added and the resulting mixture was stirred overnight at room temperature, followed by 2 h at 150° C. in the microwave and evaporated. The residue was purified by preparative HPLC (Method 4) affording 85.2 mg (11% of th.) of the title compound.

[0370] LC-MS (Method 1): R.sub.t=1.02 min; MS (ESIpos): m/z=586 [M+H].sup.+

[0371] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.59 (dd, 1H), 8.32 (dd, 1H), 7.86-7.49 (m, 5H), 6.89 (d, 1H), 5.87 (q, 1H), 5.12 (m, 2H), 4.42-4.18 (m, 1H), 4.07-3.75 (m, 2H), 1.75 (s, 3H), 1.56 (d, 3H).

Example 18A

(1S)-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-(5-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Acetate

[0372] ##STR00032##

[0373] Under argon, 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 2A, 150 mg, 396 μmol) in THF (1.5 ml) was treated at 0° C. with N,N-diisopropylethylamine (210 μl, 1.2 mmol) and (2S)-1-chloro-1-oxopropan-2-yl acetate (55 μl, 440 μmol) and stirred at 0° C. for 30 min. 5-Chloro-2-hydrazinylpyridine (62.5 mg, 436 μmol) was then added and the resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 165 mg (71% of th.) of the title compound.

[0374] LC-MS (Method 1): R.sub.t=1.14 min; MS (ESIpos): m/z=586 [M+H].sup.+

[0375] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.58 (d, 1H), 8.21 (dd, 1H), 7.89-7.54 (m, 5H), 6.90 (d, 1H), 6.46 (q, 1H), 5.23-5.00 (m, 2H), 4.31 (m, 1H), 4.12-3.76 (m, 2H), 1.92 (s, 3H), 1.61 (d, 3H).

Example 19A

(1R)-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-(5-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Acetate

[0376] ##STR00033##

[0377] Under argon, 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 2A, 250 mg, 660 μmol) in tetrahydrofuran (5.0 ml) was treated at 0° C. with N,N-diisopropylethylamine (340 μl, 2.0 mmol) and (2R)-1-chloro-1-oxopropan-2-yl acetate (55 μl, 730 μmol) and stirred at 0° C. for 30 min. 5-Chloro-2-hydrazinylpyridine (104 mg, 726 μmol) was added and the resulting mixture was stirred overnight at room temperature. Purification by preparative HPLC (Method 4) afforded 187 mg (47% of th.) of the title compound.

[0378] LC-MS (Method 1): R.sub.t=1.13 min; MS (ESIpos): m/z=586.2 [M+H].sup.+

[0379] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.58 (d, 1H), 8.21 (dd, 1H), 7.95-7.48 (m, 5H), 6.90 (d, 1H), 6.46 (q, 1H), 5.12 (d, 2H), 4.46-4.19 (m, 1H), 4.11-3.71 (m, 2H), 1.92 (s, 3H), 1.61 (d, 3H).

Example 20A

(1S)-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-chloropyridin-4-yl)-1H-1,2,4-triazol-5-yl]ethyl Acetate

[0380] ##STR00034##

[0381] Under argon, 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 2A, 150 mg, 396 μmol) in THF (1.5 ml) was treated at 0° C. with N,N-diisopropylethylamine (210 μl, 1.2 mmol) and (2S)-1-chloro-1-oxopropan-2-yl acetate (55 μl, 440 μmol) and stirred at 0° C. for 30 min. 3-Chloro-4-hydrazinylpyridine (62.5 mg, 436 μmol) was then added and the resulting mixture was stirred 3 h at room temperature, followed by 3 h at 150° C. in the microwave and evaporated. The residue was purified by preparative HPLC (Method 4) affording 133 mg (57% of th.) of the title compound.

[0382] LC-MS (Method 1): R.sub.t=0.99 min; MS (ESIpos): m/z=586 [M+H].sup.+

[0383] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.97 (s, 1H), 8.78 (d, 1H), 7.84-7.58 (m, 5H), 6.89 (d, 1H), 5.88-5.72 (m, 1H), 5.13 (m, 2H), 4.40-4.20 (m, 1H), 4.09-3.79 (m, 2H), 1.76 (s, 3H), 1.56 (d, 3H).

Example 21A

(1S)-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-(3,5-dichloropyridin-4-yl)-1H-1,2,4-triazol-5-yl]ethyl Acetate

[0384] ##STR00035##

[0385] Under argon, 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 2A, 150 mg, 396 μmol) in THF (1.5 ml) was treated at 0° C. with N,N-diisopropylethylamine (210 μl, 1.2 mmol) and (2S)-1-chloro-1-oxopropan-2-yl acetate (55 μl, 440 μmol) and stirred at 0° C. for 30 min. 3,5-Dichloro-4-hydrazinylpyridine (77.6 mg, 436 μmol) was then added and the resulting mixture was stirred 3 h at room temperature, followed by 3 h at 150° C. in the microwave and evaporated. The residue was purified by preparative HPLC (Method 4) affording 89.6 mg (33% of th.) of the title compound as a mixture of rotamers.

[0386] LC-MS (Method 1): R.sub.t=1.07 min; MS (ESIpos): m/z=620 [M+H].sup.+

[0387] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.99 (d, 1H), 7.80-7.51 (m, 5H), 6.88 (m, 1H), 5.81 (q, 1H), 5.15 (m, 2H), 4.43-4.21 (m, 1H), 4.11-3.74 (m, 2H), 1.77 (s, 3H), 1.57 (d, 3H).

Example 22A

(1R)-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-(3,5-dichloropyridin-4-yl)-1H-1,2,4-triazol-5-yl]ethyl Acetate

[0388] ##STR00036##

[0389] Under argon, 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 2A, 200 mg, 528 μmol) in THF (2.0 ml) was treated at 0° C. with N,N-diisopropylethylamine (280 μl, 1.6 mmol) and (2R)-1-chloro-1-oxopropan-2-yl acetate (79 μl, 580 μmol) and stirred at 0° C. for 30 min. 3,5-Dichloro-4-hydrazinylpyridine (103 mg, 581 μmol) was then added and the resulting mixture was stirred 2 h at room temperature, followed by 3 h at 150° C. in the microwave and evaporated. The residue was purified by preparative HPLC (Method 4) affording 108 mg (31% of th.) of the title compound as a mixture of rotamers.

[0390] LC-MS (Method 1): R.sub.t=1.06 min; MS (ESIpos): m/z=620 [M+H].sup.+

[0391] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.99 (d, 1H), 7.84-7.51 (m, 5H), 6.89 (m, 1H), 5.81 (m, 1H), 5.16 (m, 2H), 4.37-4.14 (m, 1H), 4.09-3.69 (m, 2H), 1.77 (s, 3H), 1.57 (d, 3H).

Example 23A

(1S)-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-(4-chloropyridin-3-yl)-1H-1,2,4-triazol-5-yl]ethyl Acetate

[0392] ##STR00037##

[0393] Under argon, 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 2A, 150 mg, 396 μmol) in THF (1.5 ml) was treated at 0° C. with N,N-diisopropylethylamine (210 μl, 1.2 mmol) and (2S)-1-chloro-1-oxopropan-2-yl acetate (55 μl, 440 μmol) and stirred at 0° C. for 30 min. 4-Chloro-3-hydrazinylpyridine hydrochloride (78.4 mg, 436 μmol) was then added and the resulting mixture was stirred 3 h at room temperature, followed by 3 h at 150° C. in the microwave and evaporated. The residue was purified by preparative HPLC (Method 4) affording 118 mg (51% of th.) of the title compound.

[0394] LC-MS (Method 1): R.sub.t=0.98 min; MS (ESIpos): m/z=586 [M+H].sup.+

[0395] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.97-8.65 (m, 2H), 8.01-7.46 (m, 5H), 6.89 (d, 1H), 5.75 (m, 1H), 5.12 (m, 2H), 4.36-4.20 (m, 1H), 4.14-3.76 (m, 2H), 1.79 (s, 3H), 1.55 (d, 3H).

Example 24A

(1S)-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-(trifluoromethoxy)pyridin-2-yl]-1H-1,2,4-triazol-5-yl}ethyl Acetate

[0396] ##STR00038##

[0397] Under argon, 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 2A, 250 mg, 660 μmol) in THF (5.0 ml) was treated at 0° C. with N,N-diisopropylethylamine (460 μl, 2.6 mmol) and (2S)-1-chloro-1-oxopropan-2-yl acetate (92 μl, 730 μmol) and stirred at 0° C. for 30 min. 2-Hydrazinyl-3-(trifluoromethoxy)pyridine 4-methylbenzenesulfonate (1:1) (265 mg, 726 μmol) was then added and the resulting mixture was stirred overnight at room temperature, followed by 2 h at 150° C. in the microwave and evaporated. The residue was purified by preparative HPLC (Method 4) affording 188 mg (45% of th.) of the title compound.

[0398] LC-MS (Method 1): R.sub.t=1.08 min; MS (ESIpos): m/z=636 [M+H].sup.+

[0399] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.62 (dd, 1H), 8.27 (dt, 1H), 7.94-7.50 (m, 5H), 6.89 (d, 1H), 5.99 (q, 1H), 5.13 (m, 2H), 4.43-3.72 (m, 3H), 1.74 (s, 3H), 1.58 (d, 3H).

Example 25A

(1R)-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-(trifluoromethoxy)pyridin-2-yl]-1H-1,2,4-triazol-5-yl}ethyl Acetate

[0400] ##STR00039##

[0401] Under argon, 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 2A, 250 mg, 660 μmol) in THF (5.0 ml) was treated at 0° C. with N,N-diisopropylethylamine (460 μl, 2.6 mmol) and (2R)-1-chloro-1-oxopropan-2-yl acetate (92 μl, 730 μmol) and stirred at 0° C. for 30 min. 2-Hydrazinyl-3-(trifluoromethoxy)pyridine 4-methylbenzenesulfonate (1:1) (265 mg, 726 μmol) was then added and the resulting mixture was stirred 5 h at room temperature, followed by 3 h at 120° C. in the microwave and evaporated. The residue was purified by preparative HPLC (Method 4) affording 199 mg (47% of th.) of the title compound.

[0402] LC-MS (Method 1): R.sub.t=1.08 min; MS (ESIpos): m/z=636 [M+H].sup.+

[0403] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.62 (dd, 1H), 8.27 (d, 1H), 7.99-7.55 (m, 5H), 6.89 (d, 1H), 5.99 (q, 1H), 5.25-5.01 (m, 2H), 4.41-4.18 (m, 1H), 4.05-3.78 (m, 2H), 1.74 (s, 3H), 1.58 (d, 3H).

Example 26A

5-(4-Chlorophenyl)-2-({1-(2,6-dichlorophenyl)-5-[(1S)-1-hydroxyethyl]-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

[0404] ##STR00040##

[0405] At 0° C., a solution of (1S)-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-(2,6-dichlorophenyl)-1H-1,2,4-triazol-5-yl]ethyl acetate (Example 3A, 119 mg, 192 μmol) in methanol (2.0 ml) was treated with an aqueous sodium hydroxide solution (350 μl, 1.0 M, 350 μmol) and stirred for 30 min at room temperature. 0.5 g of activated ion exchange resin (Dowex 50WX8, 200-400 mesh) were added and the resulting mixture was stirred at room temperature for 15 min. The resin was filtered off and washed with methanol. The filtrate was evaporated affording 115 mg (quant.) of the title compound.

[0406] LC-MS (Method 1): R.sub.t=1.00 min; MS (ESIpos): m/z=576.9 [M+H].sup.+

[0407] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.87-7.52 (m, 7H), 6.90 (d, 1H), 5.55 (d, 1H), 5.19-4.94 (m, 2H), 4.63 (quin, 1H), 4.39-4.22 (br m, 1H), 4.10-3.74 (m, 2H), 1.41 (d, 3H).

Example 27A

5-(4-Chlorophenyl)-2-({1-(2,6-dichlorophenyl)-5-[(1R)-1-hydroxyethyl]-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

[0408] ##STR00041##

[0409] At 0° C., a solution of (1R)-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-(2,6-dichlorophenyl)-1H-1,2,4-triazol-5-yl]ethyl acetate (Example 4A, 141 mg, 227 μmol) in methanol (2.4 ml) was treated with an aqueous sodium hydroxide solution (350 μl, 1.0 M, 350 μmol) and stirred for 30 min at room temperature. 0.5 g of activated ion exchange resin (Dowex 50WX8, 200-400 mesh) were added and the resulting mixture was stirred at room temperature for 15 min. The resin was filtered off and washed with methanol. The filtrate was evaporated affording 128 mg (97% of th.) of the title compound.

[0410] LC-MS (Method 1): R.sub.t=1.01 min; MS (ESIpos): m/z=577.2 [M+H].sup.+

[0411] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.83-7.51 (m, 7H), 6.90 (d, 1H), 5.55 (d, 1H), 5.19-4.94 (m, 2H), 4.63 (quin, 1H), 4.39-4.20 (m, 1H), 4.10-3.73 (m, 2H), 1.51-1.34 (m, 3H).

Example 28A

2-({1-(2-Chloro-6-fluorophenyl)-5-[(1R)-1-hydroxyethyl]-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] ##STR00042##

[0413] At 0° C., a solution of (1R)-1-[1-(2-chloro-6-fluorophenyl)-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]ethyl acetate (Example 5A, 152 mg, 252 μmol) in methanol (1.5 ml) was treated with an aqueous sodium hydroxide solution (250 μl, 1.0 M, 250 μmol) and stirred for 30 min at room temperature. 0.5 g of activated ion exchange resin (Dowex 50WX8, 200-400 mesh) were added and the resulting mixture was stirred at room temperature for 15 min. The resin was filtered off and washed with methanol. The filtrate was evaporated affording 137 mg (95% of th.) of the title compound as a mixture of atropisomers.

[0414] LC-MS (Method 1): R.sub.t=0.99 min; MS (ESIpos): m/z=561.2 [M+H].sup.+

[0415] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.82-7.41 (m, 7H), 6.90 (d, 1H), 5.67-5.51 (m, 1H), 5.23-4.94 (m, 2H), 4.85-4.55 (m, 1H), 4.39-4.20 (m, 1H), 4.09-3.72 (m, 2H), 1.52-1.30 (m, 3H).

Example 29A

2-({1-(2-Chloro-4-fluorophenyl)-5-[(1R)-1-hydroxyethyl]-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

[0416] ##STR00043##

[0417] At 0° C., a solution of (1R)-1-[1-(2-chloro-4-fluorophenyl)-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]ethyl acetate (Example 6A, 166 mg, 274 μmol) in methanol (3.3 ml) was treated with an aqueous sodium hydroxide solution (270 μl, 1.0 M, 270 μmol) and stirred for 30 min at room temperature. Formic acid (21 μl, 50% purity, 270 μmol) was added and the resulting mixture was purified by preparative HPLC (Method 4) affording 144 mg (94% of th.) of the title compound.

[0418] LC-MS (Method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=561.0 [M+H].sup.+

[0419] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.94-7.29 (m, 7H), 6.90 (d, 1H), 5.51 (d, 1H), 5.06 (s, 2H), 4.72-4.52 (m, 1H), 4.43-4.19 (m, 1H), 4.11-3.71 (m, 2H), 1.38 (d, 3H).

Example 30A

5-(4-Chlorophenyl)-2-({1-[2-(difluoromethoxy)phenyl]-5-[(1S)-1-hydroxyethyl]-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

[0420] ##STR00044##

[0421] At 0° C., a solution of (1S)-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-[2-(difluoromethoxy)phenyl]-1H-1,2,4-triazol-5-yl}ethyl acetate (Example 7A, 132 mg, 214 μmol) in methanol (1.3 ml) was treated with an aqueous sodium hydroxide solution (210 μl, 1.0 M, 210 μmol) and stirred for 30 min at room temperature. 0.5 g of activated ion exchange resin (Dowex 50WX8, 200-400 mesh) were added and the resulting mixture was stirred at room temperature for 15 min. The resin was filtered off and washed with methanol. The filtrate was evaporated affording 117 mg (95% of th.) of the title compound.

[0422] LC-MS (Method 1): R.sub.t=0.99 min; MS (ESIpos): m/z=575.3 [M+H].sup.+

[0423] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.87-6.81 (m, 10H), 5.48 (d, 1H), 5.20-4.96 (m, 2H), 4.71-4.51 (m, 1H), 4.38-4.24 (br m, 1H), 4.08-3.76 (m, 2H), 1.39 (d, 3H).

Example 31A

5-(4-Chlorophenyl)-2-({1-[2-(difluoromethoxy)phenyl]-5-[(1R)-1-hydroxyethyl]-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

[0424] ##STR00045##

[0425] At 0° C., a solution of (1R)-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-[2-(difluoromethoxy)phenyl]-1H-1,2,4-triazol-5-yl}ethyl acetate (Example 8A, 192 mg, 311 μmol) in methanol (1.9 ml) was treated with an aqueous sodium hydroxide solution (310 μl, 1.0 M, 310 μmol) and stirred for 30 min at room temperature. 0.5 g of activated ion exchange resin (Dowex 50WX8, 200-400 mesh) were added and the resulting mixture was stirred at room temperature for 15 min. The resin was filtered off and washed with methanol. The filtrate was evaporated affording 172 mg (96% of th.) of the title compound.

[0426] LC-MS (Method 1): R.sub.t=0.99 min; MS (ESIpos): m/z=575.3 [M+H].sup.+

[0427] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.88-6.75 (m, 10H), 5.48 (d, 1H), 5.06 (s, 2H), 4.73-4.52 (m, 1H), 4.38-4.23 (br m, 1H), 4.10-3.76 (m, 2H), 1.54-1.31 (m, 3H).

Example 32A

5-(4-Chlorophenyl)-2-({5-[(1S)-1-hydroxyethyl]-1-[2-(trifluoromethoxy)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

[0428] ##STR00046##

[0429] At 0° C., a solution of (1S)-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-[2-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-5-yl}ethyl acetate (Example 9A, 140 mg, 220 μmol) in methanol (2.0 ml) was treated with an aqueous sodium hydroxide solution (220 μl, 1.0 M, 220 μmol) and stirred for 1 h at room temperature. Formic acid (17 μl, 50% purity, 220 μmol) was added and the resulting mixture was purified by preparative HPLC (Method 4) affording 123 mg (94% of th.) of the title compound.

[0430] LC-MS (Method 1): R.sub.t=1.04 min; MS (ESIpos): m/z=593.3 [M+H].sup.+

[0431] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.85-7.44 (m, 8H), 6.89 (d, 1H), 5.54 (d, 1H), 5.19-4.95 (m, 2H), 4.63 (quin, 1H), 4.41-4.20 (m, 1H), 4.10-3.75 (m, 2H), 1.40 (d, 3H).

Example 33A

5-(4-Chlorophenyl)-2-({5-[(1R)-1-hydroxyethyl]-1-[2-(trifluoromethoxy)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

[0432] ##STR00047##

[0433] At 0° C., a solution of (1R)-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-[2-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-5-yl}ethyl acetate (Example 10A, 159 mg, 250 μmol) in methanol (3.0 ml) was treated with an aqueous sodium hydroxide solution (250 μl, 1.0 M, 250 μmol) and stirred for 30 min at room temperature. Formic acid (19 μl, 50% purity, 250 μmol) was added and the resulting mixture was purified by preparative HPLC (Method 4) affording 140 mg (94% of th.) of the title compound.

[0434] LC-MS (Method 1): R.sub.t=1.00 min; MS (ESIpos): m/z=593.0 [M+H].sup.+

[0435] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.88-7.44 (m, 8H), 6.90 (d, 1H), 5.54 (d, 1H), 5.14-4.98 (m, 2H), 4.63 (quin, 1H), 4.40-4.21 (m, 1H), 4.08-3.73 (m, 2H), 1.40 (d, 3H).

Example 34A

2-{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)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-1-yl}benzenesulfonamide

[0436] ##STR00048##

[0437] At 0° C., a solution of (1S)-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-(2-sulfamoylphenyl)-1H-1,2,4-triazol-5-yl]ethyl acetate (Example 11A, 180 mg, 285 μmol) in methanol (3.0 ml) was treated with an aqueous sodium hydroxide solution (280 μl, 1.0 M, 280 μmol) and stirred for 1 h at room temperature. Aqueous formic acid (21 μl, 50% purity, 280 μmol) was added and the resulting mixture was purified by preparative HPLC (Method 4) affording 145 mg (87% of th.) of the title compound.

[0438] LC-MS (Method 1): R.sub.t=0.86 min; MS (ESIpos): m/z=588.3 [M+H].sup.+

[0439] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.16-7.49 (m, 8H), 7.21-6.73 (m, 3H), 5.51 (d, 1H), 5.21-4.96 (m, 2H), 4.54 (br s, 1H), 4.38-4.15 (m, 1H), 4.06-3.71 (m, 2H), 1.35 (d, 3H).

Example 35A

5-(4-Chlorophenyl)-2-({5-[(1S)-1-hydroxyethyl]-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

[0440] ##STR00049##

[0441] At 0° C., a solution of (1S)-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-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl acetate (Example 12A, 194 mg, 352 μmol) in methanol (2.1 ml) was treated with an aqueous sodium hydroxide solution (350 μl, 1.0 M, 350 μmol) and stirred for 1.5 h at room temperature. 0.5 g of activated ion exchange resin (Dowex 50WX8, 200-400 mesh) were added and the resulting mixture was stirred at room temperature for 15 min. The resin was filtered off and washed with methanol. The filtrate was evaporated affording 157 mg (88% of th.) of the title compound.

[0442] LC-MS (Method 1): R.sub.t=0.94 min; MS (ESIpos): m/z=510 [M+H].sup.+

[0443] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.61-8.54 (m, 1H), 8.14-8.03 (m, 1H), 7.85-7.48 (m, 6H), 6.90 (d, 1H), 5.6 (br. s, 1H), 5.41 (q, 1H), 5.17-4.99 (m, 2H), 4.31 (m, 1H), 4.10-3.78 (m, 2H), 1.49 (d, 3H).

Example 36A

5-(4-Chlorophenyl)-2-({5-[(1R)-1-hydroxyethyl]-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

[0444] ##STR00050##

[0445] A solution of (1R)-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-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl}ethyl acetate (Example 13A, 203 mg, 368 μmol) in methanol (2.2 ml) was treated with an aqueous sodium hydroxide solution (370 μl, 1.0 M, 370 μmol) and stirred 30 min at room temperature. 0.5 g of activated ion exchange resin (Dowex 50WX8, 200-400 mesh) were added and the resulting mixture was stirred at room temperature for 15 min. The resin was filtered off and washed with methanol. The filtrate was evaporated affording 180 mg (96% of th.) of the title compound.

[0446] LC-MS (Method 1): R.sub.t=0.95 min; MS (ESIpos): m/z=510 [M+H].sup.+

[0447] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.58 (dd, 1H), 8.08 (td, 1H), 7.82-7.47 (m, 6H), 6.91 (d, 1H), 5.61 (br s, 1H), 5.41 (q, 1H), 5.09 (s, 2H), 4.31 (m, 1H), 4.08-3.79 (m, 2H), 1.49 (d, 3H).

Example 37A

5-(4-Chlorophenyl)-2-({1-(3-fluoropyridin-2-yl)-5-[(1S)-1-hydroxyethyl]-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

[0448] ##STR00051##

[0449] A solution of (1S)-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-fluoropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Acetate (Example 14A, 135 mg, 237 μmol) in methanol (1.4 ml) was treated with an aqueous sodium hydroxide solution (240 μl, 1.0 M, 240 μmol) and stirred 30 min at room temperature. 0.5 g of activated ion exchange resin (Dowex 50WX8, 200-400 mesh) were added and the resulting mixture was stirred at room temperature for 15 min. The resin was filtered off and washed with methanol. The filtrate was evaporated affording 94.8 mg (76% of th.) of the title compound.

[0450] LC-MS (Method 1): R.sub.t=0.90 min; MS (ESIpos): m/z=528 [M+H].sup.+

[0451] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.45 (d, 1H), 8.08 (m, 1H), 7.84-7.51 (m, 5H), 6.90 (d, 1H), 5.53 (br d, 1H), 5.18-5.02 (m, 2H), 4.98-4.85 (m, 1H), 4.30 (m, 1H), 4.08-3.74 (m, 2H), 1.45 (d, 3H).

Example 38A

5-(4-Chlorophenyl)-2-({1-(3-fluoropyridin-2-yl)-5-[(1R)-1-hydroxyethyl]-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] ##STR00052##

[0453] At 0° C., a solution of (1R)-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-fluoropyridin-2-yl)-1H-1,2,4-triazol-5-yl}ethyl acetate (Example 15A, 184 mg, 323 μmol) in methanol (1.9 ml) was treated with an aqueous sodium hydroxide solution (320 μl, 1.0 M, 320 μmol) and stirred 30 min at room temperature. 0.5 g of activated ion exchange resin (Dowex 50WX8, 200-400 mesh) were added and the resulting mixture was stirred at room temperature for 15 min. The resin was filtered off and washed with methanol. The filtrate was evaporated affording 167 mg (98% of th.) of the title compound.

[0454] LC-MS (Method 1): R.sub.t=0.90 min; MS (ESIpos): m/z=528 [M+H].sup.+

[0455] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.45 (d, 1H), 8.08 (ddd, 1H), 7.81-7.54 (m, 5H), 6.90 (d, 1H), 5.52 (br d, 1H), 5.08 (s, 2H), 4.98-4.87 (m, 1H), 4.30 (m, 1H), 4.09-3.76 (m, 2H), 1.45 (d, 3H).

Example 39A

5-(4-Chlorophenyl)-2-({1-(3-chloropyridin-2-yl)-5-[(1S)-1-hydroxyethyl]-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

[0456] ##STR00053##

[0457] A solution of (1S)-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-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl acetate (Example 16A, 72.0 mg, 123 μmol) in methanol (730 μl) was treated with an aqueous sodium hydroxide solution (120 μl, 1.0 M, 120 μmol) and stirred 30 min at room temperature. 0.5 g of activated ion exchange resin (Dowex 50WX8, 200-400 mesh) were added and the resulting mixture was stirred at room temperature for 15 min. The resin was filtered off and washed with methanol. The filtrate was evaporated affording 63.3 mg (89% of th.) of the title compound.

[0458] LC-MS (Method 1): R.sub.t=0.88 min; MS (ESIpos): m/z=544 [M+H].sup.+

[0459] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.57 (dd, 1H), 8.25 (dd, 1H), 7.78-7.58 (m, 5H), 6.90 (d, 1H), 5.50 (d, 1H), 5.07 (m, 2H), 4.83 (quin, 1H), 4.30 (m, 1H), 4.10-3.78 (m, 2H), 1.43 (d, 3H).

Example 40A

5-(4-Chlorophenyl)-2-({1-(3-chloropyridin-2-yl)-5-[(1R)-1-hydroxyethyl]-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

[0460] ##STR00054##

[0461] At 0° C., a solution of (1R)-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-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl acetate (Example 17A, 253 mg, 431 μmol) in methanol (2.6 ml) was treated with an aqueous sodium hydroxide solution (430 μl, 1.0 M, 430 μmol) and stirred 30 min at room temperature. 0.5 g of activated ion exchange resin (Dowex 50WX8, 200-400 mesh) were added and the resulting mixture was stirred at room temperature for 15 min. The resin was filtered off and washed with methanol. The filtrate was evaporated affording 234 mg (84% of th.) of the title compound.

[0462] LC-MS (Method 1): R.sub.t=0.90 min; MS (ESIpos): m/z=544 [M+H].sup.+

[0463] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.57 (dd, 1H), 8.25 (dd, 1H), 7.80-7.57 (m, 5H), 6.90 (d, 1H), 5.50 (d, 1H), 5.07 (m, 2H), 4.83 (quin, 1H), 4.30 (m, 1H), 4.09-3.78 (m, 2H), 1.43 (d, 3H).

Example 41A

5-(4-Chlorophenyl)-2-({1-(5-chloropyridin-2-yl)-5-[(1S)-1-hydroxyethyl]-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

[0464] ##STR00055##

[0465] At 0° C., a solution of (1S)-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-(5-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl acetate (Example 18A, 154 mg, 263 μmol) in methanol (1.6 ml) was treated with an aqueous sodium hydroxide solution (260 μl, 1.0 M, 260 μmol) and stirred 2.5 h at room temparture. 0.5 g of activated ion exchange resine (Dowex 50WX8, 200-400 mesh) were added and the resulting mixture was stirred at room temperature for 15 min. The resine was filtered off and washed with methanol. The filtrate was evaporated affording 141 mg (99% of th.) of the title compound.

[0466] LC-MS (Method 1): R.sub.t=1.04 min; MS (ESIpos): m/z=544 [M+H].sup.+

[0467] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.65 (d, 1H), 8.19 (dd, 1H), 7.84-7.55 (m, 5H), 6.90 (d, 1H), 5.54-5.35 (m, 2H), 5.20-5.02 (m, 2H), 4.31 (m, 1H), 4.07-3.79 (m, 2H), 1.48 (d, 3H).

Example 42A

5-(4-Chlorophenyl)-2-({1-(5-chloropyridin-2-yl)-5-[(1R)-1-hydroxyethyl]-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] ##STR00056##

[0469] At 0° C., a solution of (1R)-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-(5-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl acetate (Example 19A, 175 mg, 298 μmol) in methanol (3.5 ml) was treated with an aqueous sodium hydroxide solution (300 μl, 1.0 M, 300 μmol) and stirred for 30 min at room temperature. Aqueous formic acid (23 μl, 50% purity, 300 μmol) was added and the resulting mixture was purified by preparative HPLC (Method 4) affording 144 mg (89% of th.) of the title compound.

[0470] LC-MS (Method 1): R.sub.t=1.03 min; MS (ESIpos): m/z=544.2 [M+H].sup.+

[0471] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.65 (d, 1H), 8.19 (dd, 1H), 7.94-7.54 (m, 5H), 6.91 (d, 1H), 5.65-5.29 (m, 2H), 5.09 (s, 2H), 4.41-4.20 (m, 1H), 4.09-3.76 (m, 2H), 1.48 (d, 3H).

Example 43A

5-(4-Chlorophenyl)-2-({1-(3-chloropyridin-4-yl)-5-[(1S)-1-hydroxyethyl]-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

[0472] ##STR00057##

[0473] At 0° C., a solution of (1S)-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-chloropyridin-4-yl)-1H-1,2,4-triazol-5-yl]ethyl acetate (Example 20A, 122 mg, 208 μmol) in methanol (1.2 ml) was treated with an aqueous sodium hydroxide solution (210 μl, 1.0 M, 210 μmol) and stirred 2.5 h at room temperature. 0.5 g of activated ion exchange resin (Dowex 50WX8, 200-400 mesh) were added and the resulting mixture was stirred at room temperature for 15 min. The resin was filtered off and washed with methanol. The filtrate was evaporated affording 98.9 mg (87% of th.) of the title compound.

[0474] LC-MS (Method 1): R.sub.t=0.89 min; MS (ESIpos): m/z=544 [M+H].sup.+

[0475] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.91 (s, 1H), 8.73 (d, 1H), 7.79-7.56 (m, 5H), 6.89 (d, 1H), 5.59 (d, 1H), 5.08 (m, 2H), 4.77 (quin, 1H), 4.36-4.22 (m, 1H), 4.08-3.78 (m, 2H), 1.42 (d, 3H).

Example 44A

5-(4-Chlorophenyl)-2-({1-(3,5-dichloropyridin-4-yl)-5-[(1S)-1-hydroxyethyl]-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

[0476] ##STR00058##

[0477] A solution of (1S)-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-(3,5-dichloropyridin-4-yl)-1H-1,2,4-triazol-5-yl]ethyl acetate (Example 21A, 90.0 mg, 145 μmol) in (4.1 ml, 7.0 M, 29 mmol) was treated with an aqueous sodium hydroxide solution and stirred 30 min at room temperature. Formic acid (3 ml) was added, the resulting mixture concentrated and purified via preparative HPLC (Chromatorex; C18; 10 μm; 125×30 mm; water/acetonitrile-gradient 0.1% formic acid) affording 22.3 mg (27% of th.) of the title compound.

[0478] LC-MS (Method 1): R.sub.t=0.92 min; MS (ESIpos): m/z=578 [M+H].sup.+

[0479] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.90 (s, 2H), 7.82-7.55 (m, 4H), 6.89 (d, 1H), 5.69 (d, 1H), 5.09 (m, 2H), 4.80 (quin, 1H), 4.28 (m, 1H), 4.07-3.78 (m, 2H), 1.44 (d, 3H).

Example 45A

5-(4-Chlorophenyl)-2-({1-(3,5-dichloropyridin-4-yl)-5-[(1R)-1-hydroxyethyl]-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

[0480] ##STR00059##

[0481] At 0° C., a solution of (1R)-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-(3,5-dichloropyridin-4-yl)-1H-1,2,4-triazol-5-yl]ethyl acetate (Example 22A, 100 mg, 161 μmol) in methanol (960 μl) was treated with an aqueous sodium hydroxide solution (160 μl, 1.0 M, 160 μmol) and stirred for 1.5 h at room temperature. 0.5 g of activated ion exchange resin (Dowex 50WX8, 200-400 mesh) were added and the resulting mixture was stirred at room temperature for 15 min. The resin was filtered off and washed with methanol and the filtrate was evaporated. The residue was purified via preparative HPLC (Chromatorex C18, 10 μm, 125×30 mm. water/acetonitrile-gradient 0.1% formic acid). affording 21.0 mg (23% of th.) of the title compound.

[0482] LC-MS (Method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=578 [M+H].sup.+

[0483] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.90 (s, 2H), 7.82-7.52 (m, 4H), 6.89 (d, 1H), 5.69 (d, 1H), 5.18-4.97 (m, 2H), 4.79 (quin, 1H), 4.28 (m, 1H), 4.11-3.74 (m, 2H), 1.44 (d, 3H).

Example 46A

5-(4-Chlorophenyl)-2-({1-(4-chloropyridin-3-yl)-5-[(1S)-1-hydroxyethyl]-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

[0484] ##STR00060##

[0485] At 0° C., a solution of (1S)-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-(4-chloropyridin-3-yl)-1H-1,2,4-triazol-5-yl]ethyl acetate (Example 23A, 182 mg, 310 μmol) in methanol (1.8 ml) was treated with an aqueous sodium hydroxide solution (310 μl, 1.0 M, 310 μmol) and stirred for 1.5 h at room temperature. 0.5 g of activated ion exchange resin (Dowex 50WX8, 200-400 mesh) were added and the resulting mixture was stirred at room temperature for 15 min. The resin was filtered off and washed with methanol. The filtrate was evaporated affording 103 mg (59% of th.) of the title compound.

[0486] LC-MS (Method 1): R.sub.t=0.87 min; MS (ESIpos): m/z=544 [M+H].sup.+

[0487] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.82-8.61 (m, 2H), 7.89-7.57 (m, 5H), 6.96-6.83 (m, 1H), 5.50 (br. s, 1H), 5.08 (m, 2H), 4.72 (q, 1H), 4.29 (m, 1H), 4.08-3.74 (m, 2H), 1.41 (d, 3H).

Example 47A

5-(4-Chlorophenyl)-2-({5-[(1S)-1-hydroxyethyl]-1-[3-(trifluoromethoxy)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

[0488] ##STR00061##

[0489] A solution of (1S)-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-(trifluoromethoxy)pyridin-2-yl]-1H-1,2,4-triazol-5-yl}ethyl acetate (Example 24A, 80.5 mg, 127 μmol) in methanol (2.0 ml) was treated with an aqueous sodium hydroxide solution (250 μl, 1.0 M, 250 μmol) and stirred 2 h at room temperature. 50% aqueous formic acid (29 μl) was added and the resulting mixture was purified via preparative HPLC (Reprosil; C18; 10 μm; 125×30 mm; water/acetonitrile-gradient 0.1% formic acid) affording 68.5 mg (87% of th.) of the title compound.

[0490] LC-MS (Method 5): R.sub.t=2.94 min; MS (ESIpos): m/z=594 [M+H].sup.+

[0491] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.61 (dd, 1H), 8.19 (dt, 1H), 7.83-7.57 (m, 5H), 6.90 (d, 1H), 5.49 (d, 1H), 5.08 (m, 2H), 4.92 (quin, 1H), 4.36-4.24 (m, 1H), 4.11-3.75 (m, 2H), 1.44 (d, 3H).

Example 48A

5-(4-Chlorophenyl)-2-({5-[(1R)-1-hydroxyethyl]-1-[3-(trifluoromethoxy)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

[0492] ##STR00062##

[0493] A solution of (1R)-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-(trifluoromethoxy)pyridin-2-yl]-1H-1,2,4-triazol-5-yl}ethyl acetate (Example 25A, 190 mg, 299 μmol) in (600 μl, 1.0 M, 600 μmol) was treated with an aqueous sodium hydroxide solution methanol (4.6 ml) and stirred 1 h at room temperature. 50% aqueous formic acid (68 μl) was added and the resulting mixture was purified via preparative HPLC (Reprosil; C18; 10 μm; 125×30 mm; water/acetonitrile-gradient 0.1% formic acid) affording 162 mg (87% of th.) of the title compound.

[0494] LC-MS (Method 5): R.sub.t=1.23 min; MS (ESIpos): m/z=594 [M+H].sup.+

[0495] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.61 (dd, 1H), 8.19 (dt, 1H), 7.83-7.56 (m, 5H), 6.90 (d, 1H), 5.49 (d, 1H), 5.14-5.01 (m, 2H), 4.92 (quin, 1H), 4.30 (br d, 1H), 4.04-3.78 (m, 2H), 1.44 (d, 3H).

Example 49A

[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-fluorophenyl)-1H-1,2,4-triazol-5-yl]methyl phenyl carbonate

[0496] ##STR00063##

[0497] At 0° C., to a solution of 5-(4-chlorophenyl)-2-{[1-(3-fluorophenyl)-5-(hydroxymethyl)-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 2 in WO 2016/071212 A1; 25 mg, 0.049 mmol) and pyridine (39 μl, 0.49 mmol) in dichloromethane (2 ml) was added phenyl chloroformate (7.4 μl, 58.8 μmol). The reaction mixture was stirred at 0° C. for 2 h and then overnight at room temperature. Additional phenyl chloroformate (3.1 μl, 24 μmol) was then added, due to incomplete conversion and the reaction mixture was stirred for 5 h. The reaction mixture was diluted with dichloromethane and water. After phase separation, the combined organic phases were dried over sodium sulfate, filtered, and concentrate in vacuo. The crude product was purified by preparative HPLC (Method 6) affording 10.7 mg (34.7% of th.) of the title compound.

[0498] LC-MS (Method 3): Rt=3.80 min; MS [ESIpos]: m/z=633 (M+H).sup.+

[0499] .sup.1H-NMR (500 MHz, DMSO-d6) δ[ppm]: 7.73-7.78 (m, 2H), 7.59-7.69 (m, 3H), 7.56 (dt, 1H), 7.36-7.49 (m, 4H), 7.28 (dt, 1H), 7.11-7.16 (m, 2H), 6.91 (d, 1H), 5.48 (s, 2H), 5.13 (s, 2H), 4.26-4.35 (m, 1H), 4.01 (dd, 1H), 3.86 (dd, 1H).

Example 50A

2-{[5-Acetyl-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

[0500] ##STR00064##

[0501] To a solution of 5-(4-chlorophenyl)-2-{[1-(3-fluorophenyl)-5-[(1R)-hydroxyethyl]-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 77 in WO2016/071212-A1; 150 mg, 0.285 mmol) in dichloroethane (9 ml) was added manganese (IV) oxide (74.2 mg, 0.854 mmol) at room temperature. The reaction mixture was stirred for four days at 60° C. Over this time, four additional portions of manganese (IV) oxide (123.75 mg in total, 1.42 mmol) were added. The reaction mixture was then filtered through celite. After washing the celite with a mixture of dicloromethane and methanol, the combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was first purified by preparative HPLC (Method 6). A second purification by preparative chiral HPLC (SFC) [sample preparation: 133 mg dissolved in a mixture (10 ml) of ethanol, methanol and acetonitrile; injection volume: 0.5 ml; column: Daicel Chiralcel® OX-H 5 μm, 250×20 mm; eluent: carbon dioxide/methanol 90:10; flow rate: 100 ml/min; temperature: 40° C.; UV detection: 210 nm] gave 48 mg (0.09 mmol, 32% of th.) of the desired compound.

[0502] LC-MS (Method 8): R.sub.t=7.77 min; MS [ESIpos]: m/z=525 (M+H).sup.+

[0503] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.72-7.79 (m, 2H), 7.60-7.65 (m, 2H), 7.49-7.60 (m, 2H), 7.35-7.43 (m, 2H), 6.89 (d, 1H), 5.12-5.22 (m, 2H), 4.24-4.33 (m, 1H), 4.01 (dd, 1H), 3.86 (dd, 1H), 2.62 (s, 3H)

Example 51A

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

[0504] ##STR00065##

[0505] At reflux temperature, a suspension 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, 12.4 g, 33.9 mmol) in ethanol (470 ml) was treated with a solution of concentrated sulfuric acid (150 μl) in ethanol (2 ml). The resulting solution was heated at reflux temperature over night and evaporated. Co-evaporation of the residue with toluene afforded 14 g (quant.) of the title compound.

[0506] LC-MS (Method 1): R.sub.t=0.97 min; MS (ESIpos): m/z=394.1 [M+H].sup.+

Example 52A

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

[0507] ##STR00066##

[0508] Under argon and at 0° C., a solution of trimethylaluminium in toluene (6.3 ml, 2.0 M, 13 mmol) was added dropwise to a suspension of ammonium chloride (679 mg, 12.7 mmol) in toluene (25 ml). The resulting mixture was stirred 1 h at room temperature (until no more evolution of gas). Ethyl {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 51A, 1.00 g, 2.54 mmol) was then added. The resulting mixture was stirred 30 min at room temperature, followed by overnight at 80° C. and then cooled to 0° C. Methanol (2.5 ml) was added dropwise and the resulting mixture was stirred 1 h at room temperature. The solid was filtered off and washed with methanol (2×6 ml). The filtrate was evaporated. The residue was triturated in a dichloromethane/methanol mixture. The solid was filtered off and the filtrated evaporated affording 544 mg (50% of th.) of the title compound.

[0509] LC-MS (Method 1): R.sub.t=0.64 min; MS (ESIpos): m/z=364.2 [M+H].sup.+

[0510] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.90 (br s, 2H), 7.92-7.53 (m, 5H), 7.31 (br s, 1H), 6.93 (br d, 1H), 4.99-4.72 (m, 2H), 4.43-4.21 (br m, 1H), 4.00-3.68 (m, 2H).

Example 53A

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

[0511] ##STR00067##

[0512] A solution of {3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidamide (Example 52A; 450 mg, 1.12 mmol) in (9.0 ml) was treated with tert-butyl [(2S)-1-hydrazinyl-1-oxopropan-2-yl]carbamate (see Chemical Biology & Drug Design, 79(2), 216-222; 2012, 229 mg, 1.12 mmol) and sodium methoxide (191 mg, 2.81 mmol). The resulting mixture was stirred 1 h at 140° C. under microwave irradiation and quenched with water. Purification by preparative HPLC (Method 4) afforded 277 mg (46% of th., 88% purity) of the title compound.

[0513] LC-MS (Method 1): R.sub.t=1.00 min; MS (ESIpos): m/z=532.2 [M+H].sup.+

Example 54A

2-{[5-Acetyl-1-(2-methylphenyl)-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

[0514] ##STR00068##

[0515] To a solution of 5-(4-chlorophenyl)-2-{[5-(1-hydroxyethyl)-1-(2-methylphenyl)-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 (see Example 71 in WO2016/071212-A1; 118.2 mg, 0.226 mmol, diastereomer 2) in dichloromethane (7 ml) was added Dess-Martin periodinane (143.8 mg, 0.339 mmol) at 0° C. After stirring overnight at 0° C., the reaction mixture was quenched with aqueous sodium bicarbonate (1M) and aqueous sodium thiosulfate (10%). After phase separation, the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was first purified by preparative HPLC (Method 6). A second purification by preparative chiral HPLC [sample preparation: 75 mg dissolved in a mixture of isopropanol and ethanol (1.5 ml); injection volume: 0.1 ml; column: Daicel AZ-H; eluent: isohexane/isopropanol 60:40; flow rate: 20 ml/min; temperature: 23° C.; UV detection: 220 nm] gave 27.1 mg (0.05 mmol, 23% of th.) of the desired compound.

[0516] LC-MS (Method 8): R.sub.t=7.85 min; MS [ESIpos]: m/z=521 (M+H).sup.+

[0517] .sup.1H-NMR (500 MHz, DMSO-d6) δ[ppm]: 7.72-7.77 (m, 2H), 7.60-7.65 (m, 2H), 7.37-7.47 (m, 2H), 7.29-7.33 (m, 2H), 6.89 (d, 1H), 5.13-5.23 (m, 2H), 4.24-4.35 (m, 1H), 4.01 (dd, 1H), 3.85 (dd, 1H), 2.57-2.62 (m, 3H), 1.89-1.95 (m, 3H)

Example 55A

2-{[5-Acetyl-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

[0518] ##STR00069##

[0519] To a solution of 5-(4-chlorophenyl)-2-{[1-(2-chlorophenyl)-5-[(1R)-hydroxyethyl)]-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 (see Example 83 in WO2016/071212-A1; 560 mg, 1.031 mmol) in dichloroethane (34 ml) was added manganese (IV) oxide (358.4 mg, 4.123 mmol) at room temperature. The reaction mixture was stirred for 5 h at 60° C. After an overnight stirring at room temperature, additional portion of manganese (IV) oxide (358.4 mg, 4.12 mmol) was added, due to incomplete conversion. The reaction mixture was stirred for 9 h at 60° C. and then filtered through celite. After washing the celite with a mixture of dicloromethane and methanol, the combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was first purified by preparative HPLC (Method 6). A second purification by preparative chiral HPLC (SFC) [sample preparation: 450 mg dissolved in a mixture (20 ml) of ethanol, methanol and acetonitrile; injection volume: 0.3 ml; column: Daicel Chiralcel® OX-H 5 μm, 250×20 mm; eluent: carbon dioxide/methanol 85:15; flow rate: 90 ml/min; temperature: 40° C.; UV detection: 210 nm] gave 320 mg (0.59 mmol, 56.7% of th.) of the desired compound.

[0520] LC-MS (Method 8): R.sub.t=7.89 min; MS [ESIpos]: m/z=541 (M+H).sup.+

[0521] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm] 7.72-7.78 (m, 2H), 7.67-7.71 (m, 1H), 7.56-7.65 (m, 4H), 7.48-7.54 (m, 1H), 6.89 (d, 1H), 5.15-5.24 (m, 2H), 4.24-4.36 (m, 1H), 4.01 (dd, 1H), 3.86 (dd, 1H), 2.61 (s, 3H)

Example 56A

1-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclopropanecarboxylic Acid

[0522] ##STR00070##

[0523] A solution of 1-aminocyclopropanecarboxylic acid (500 mg, 4.95 mmol) in toluene (15 ml) was treated with phtalic acid (732 mg, 4.95 mmol) and triethylamine (45 μl, 320 μmol). The resulting solution was stirred 48 h at reflux temperature and evaporated. The residue was retaken in a water (20 ml) and aqueous hydrogen chloride solution (2 ml, 1M) mixture and stirred 20 min. The solid was filtered off, washed with water and dried at the high vaccum pump affording 993 mg (87% of th.) of the title compound.

[0524] LC-MS (Method 1): R.sub.t=0.61 min; MS (ESIpos): m/z=232 [M+H].sup.+

[0525] .sup.1H-NMR (500 MHz, DMSO-d6) δ[ppm]: 13.01 (br s, 1H), 8.30-7.47 (m, 4H), 1.70-1.35 (m, 4H)

Example 57A

1-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclopropanecarbonyl Chloride

[0526] ##STR00071##

[0527] A solution of 1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclopropanecarboxylic acid (Example 56A, 993 mg, 4.29 mmol) in dichloromethane (29 ml) was treated with 1-chloro-N,N,2-trimethylprop-1-en-1-amine (680 μl, 5.2 mmol). The resulting mixture was stirred 20 min at room temperature and evaporated affording the title compound which was used as such in the next step without further purification.

Example 58A

(2R)-3-tert-Butoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoic Acid

[0528] ##STR00072##

[0529] A solution of O-tert-butyl-D-serine (500 mg, 3.10 mmol) in toluene (20 ml) was treated with phtalic acid (459 mg, 3.10 mmol) and triethylamine (28 μl, 200 μmol). The resulting solution was stirred overnight at reflux temperature and evaporated. The residue was retaken in ethyl acetate and extracted twice with an aqueous hydrogen chloride solution (2 ml, 1M) followed by a saturated sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated affording 830 mg (90% of th.) of the title compound.

[0530] LC-MS (Method 2): R.sub.t=1.52 min; MS (ESIneg): m/z=290 [M+H].sup.−

[0531] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 13.37 (br s, 1H), 8.06-7.61 (m, 4H), 4.90 (dd, 1H), 4.02-3.82 (m, 2H), 1.01 (s, 9H).

Example 59A

3-tert-Butoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl Chloride

[0532] ##STR00073##

[0533] A solution of (2R)-3-tert-butoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoic acid (Example 58A, 1.72 g, 5.92 mmol) in dichloromethane (39 ml) was treated with 1-chloro-N,N,2-trimethylprop-1-en-1-amine (940 μl, 7.1 mmol). The resulting mixture was stirred 20 min at room temperature and evaporated affording the title compound which was used as such in the next step without further purification.

Example 60A

(2S)-3-tert-Butoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoic Acid

[0534] ##STR00074##

[0535] A solution of O-tert-butyl-L-serine (500 mg, 3.10 mmol) in toluene (20 ml) was treated with phtalic acid (459 mg, 3.10 mmol) and triethylamine (28 μl, 200 μmol). The resulting solution was stirred 4 h at reflux temperature and evaporated. The residue was retaken in N,N-dimethylformamide (10 ml), water (150 ml) and aqueous hydrogen chloride solution (5 ml, 1M). The solution was extracted twice with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated affording 987 mg (89% of th.) of the title compound.

[0536] LC-MS (Method 1): R.sub.t=0.84 min; MS (ESIpos): m/z=292 [M+H].sup.+

[0537] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 13.37 (br s, 1H), 8.16-7.56 (m, 4H), 4.90 (dd, 1H), 4.01-3.83 (m, 2H), 1.01 (s, 9H).

Example 61A

3-tert-Butoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl Chloride

[0538] ##STR00075##

[0539] A solution of (2S)-3-tert-butoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoic acid (Example 60A; 987 mg, 2.78 mmol) in dichloromethane (18 ml) was treated with 1-chloro-N,N,2-trimethylprop-1-en-1-amine (440 μl, 3.3 mmol). The resulting mixture was stirred 20 min at room temperature and evaporated affording the title compound which was used as such in the next step without further purification.

Example 62A

2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl Chloride

[0540] ##STR00076##

[0541] A solution of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoic acid (350 mg, 1.60 mmol) in dichloromethane (11 ml) was treated with 1-chloro-N,N,2-trimethylprop-1-en-1-amine (250 μl, 1.9 mmol). The resulting mixture was stirred 20 min at room temperature and evaporated affording the title compound which was used as such in the next step without further purification.

Example 63A

1-Methyl-5-oxo-prolyl Chloride

[0542] ##STR00077##

[0543] A solution of 1-methyl-5-oxo-proline (88.7 mg, 620 μmol) in dichloromethane (4.2 ml) was treated with 1-chloro-N,N,2-trimethylprop-1-en-1-amine (98 μl, 740 μmol). The resulting mixture was stirred 20 min at room temperature and evaporated affording the title compound which was used as such in the next step without further purification.

Example 64A

5-Oxo-D-prolyl Chloride

[0544] ##STR00078##

[0545] A solution of 5-oxo-D-proline (200 mg, 1.55 mmol) in dichloromethane (10 ml) was treated with 1-chloro-N,N,2-trimethylprop-1-en-1-amine (250 μl, 1.9 mmol). The resulting mixture was stirred 20 min at room temperature and evaporated affording the title compound which was used as such in the next step without further purification.

Example 65A

5-Oxo-L-prolyl Chloride

[0546] ##STR00079##

[0547] A solution of 5-oxo-L-proline (200 mg, 1.55 mmol) in dichloromethane (10 ml) was treated with 1-chloro-N,N,2-trimethylprop-1-en-1-amine (250 μl, 1.9 mmol). The resulting mixture was stirred 20 min at room temperature and evaporated affording the title compound which was used as such in the next step without further purification.

Example 66A

2-{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]cyclopropyl}-1H-isoindole-1,3(2H)-dione

[0548] ##STR00080##

[0549] 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 2A, 1.48 g, 3.90 mmol) in dioxane (30 ml) was treated with N,N-diisopropylethylamine (2.7 ml, 16 mmol) and with a solution of 1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclopropanecarbonyl chloride (Example 57A 1.07 g, 4.29 mmol) in dioxane (8 ml) and stirred 30 min at room temperature. (2-Chlorophenyl)hydrazine hydrochloride (1:1) (769 mg, 4.29 mmol) was added. The resulting mixture was stirred 1.5 h at room temperature followed by overnight at reflux temperature and evaporated. The residue was retaken in xylol (60 ml), the resulting mixture was stirred 48 h at reflux temperature and evaporated. The residue was purified by flash chromatography (silica gel, eluent ethyl acetate/hexane) affording 1.69 g (52% of th., 83% purity) of the title compound.

[0550] LC-MS (Method 1): R.sub.t=1.14 min; MS (ESIpos): m/z=683 [M+H].sup.+

Example 67A

2-{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-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-1H-isoindole-1,3(2H)-dione (Diastereomeric Mixture)

[0551] ##STR00081##

[0552] 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 2A, 479 mg, 1.27 mmol) in 1,4-dioxane (8 ml) was treated with N,N-diisopropylethylamine (880 μl, 5.1 mmol) and with a solution of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl chloride (Example 62A, 331 mg, 1.39 mmol) in dioxane (4 ml) and stirred 30 min at room temperature. 3-Chloro-2-hydrazinylpyridine (200 mg, 1.39 mmol) was added. The resulting mixture was stirred 1.5 h at room temperature followed by overnight at reflux temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 212 mg (23% of th.) of the title compound.

[0553] LC-MS (Method 2): R.sub.t=1.95 min; MS (ESIpos): m/z=673 [M+H].sup.+

[0554] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.22-8.08 (m, 1H), 8.08-7.97 (m, 1H), 7.84-7.57 (m, 8H), 7.47-7.41 (m, 1H), 6.96-6.79 (m, 1H), 5.59-5.45 (m, 1H), 5.23-5.02 (m, 2H), 4.39-4.22 (m, 1H), 4.06-3.76 (m, 2H), 1.78 (d, 3H).

Example 68A

2-{2-tert-Butoxy-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-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-1H-isoindole-1,3(2H)-dione (Diastereomeric Mixture)

[0555] ##STR00082##

[0556] 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 2A, 667 mg, 1.76 mmol) in 1,4-dioxane (24 ml) was treated with N,N-diisopropylethylamine (280 μl, 1.6 mmol) and with a solution of 3-tert-butoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl chloride (Example 59A, 600 mg, 1.94 mmol) in dioxane (1 ml) and stirred 30 min at room temperature. 3-Chloro-2-hydrazinylpyridine (278 mg, 1.94 mmol) was added. The resulting mixture was stirred 2 h at room temperature followed by overnight at reflux temperature and evaporated. The residue was purified by flash chromatography (silica gel, eluent ethyl acetate/hexane) followed by preparative HPLC (Method 4) affording 159 mg (12% of th.) of the title compound which has racemized under the reaction conditions.

[0557] LC-MS (Method 1): R.sub.t=1.16 min; MS (ESIpos): m/z=745 [M+H].sup.+

[0558] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.28-8.21 (m, 1H), 8.12-8.03 (m, 1H), 7.87-7.46 (m, 9H), 6.89 (d, 1H), 5.51-5.40 (m, 1H), 5.26-5.06 (m, 2H), 4.39-4.13 (m, 3H), 4.06-3.77 (m, 2H), 0.99 (s, 9H).

Example 69A

2-{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-(4-chloropyridin-3-yl)-1H-1,2,4-triazol-5-yl]ethyl}-1H-isoindole-1,3(2H)-dione (Diastereomeric Mixture)

[0559] ##STR00083##

[0560] 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 2A, 479 mg, 1.27 mmol) in 1,4-dioxane (8 ml) was treated with N,N-diisopropylethylamine (880 μl, 5.1 mmol) and with a solution of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl chloride (Example 62A, 331 mg, 1.39 mmol) in dioxane (4 ml) and stirred 30 min at room temperature. 4-Chloro-3-hydrazinylpyridine hydrochloride (1:1) (251 mg, 1.39 mmol) was added. The resulting mixture was stirred 5 min at room temperature followed by overnight at reflux temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 650 mg (73% of th.) of the title compound.

[0561] LC-MS (Method 2): R.sub.t=1.89 min; MS (ESIpos): m/z=673 [M+H].sup.+

[0562] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 9.23-8.27 (m, 2H), 8.02-7.21 (m, 9H), 6.98-6.78 (m, 1H), 5.82-5.40 (m, 1H), 5.23-5.02 (m, 2H), 4.44-4.20 (m, 1H), 4.12-3.75 (m, 2H), 1.79 (d, 3H).

Example 70A

2-{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-(pyrimidin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-1H-isoindole-1,3(2H)-dione (Diastereomeric Mixture)

[0563] ##STR00084##

[0564] 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 2A, 549 mg, 1.45 mmol) in dioxane (8 ml) was treated with N,N-diisopropylethylamine (1.0 ml, 5.8 mmol) and with a solution of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl chloride (Example 62A, 379 mg, 1.59 mmol) in dioxane (4 ml) and stirred 30 min at room temperature. 2-Hydrazinylpyrimidine (176 mg, 1.59 mmol) was added. The resulting mixture was stirred 5 min at room temperature followed by overnight at reflux temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 740 mg (75% of th.) of the title compound.

[0565] LC-MS (Method 2): R.sub.t=1.87 min; MS (ESIpos): m/z=640 [M+H].sup.+

[0566] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.85-8.66 (m, 2H), 7.89-7.39 (m, 9H), 6.99-6.84 (m, 1H), 6.16-5.93 (m, 1H), 5.18-5.06 (m, 2H), 4.39-4.19 (m, 1H), 4.07-3.77 (m, 2H), 1.79 (d, 3H).

Example 71A

2-[2-tert-Butoxy-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-(trifluoromethoxy)pyridin-2-yl]-1H-1,2,4-triazol-5-yl}ethyl]-1H-isoindole-1,3(2H)-dione (Diastereomeric Mixture)

[0567] ##STR00085##

[0568] 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 2A, 667 mg, 1.76 mmol) in dioxane (24 ml) was treated with N,N-diisopropylethylamine (280 μl, 1.6 mmol) and with a solution of 3-tert-butoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl chloride (Example 59A, 600 mg, 1.94 mmol) in dioxane (1 ml) and stirred 30 min at room temperature. 2-Hydrazino-3-(trifluoromethoxy)pyridine toluenesulfonic acid (1:1) (708 mg, 1.94 mmol) was added. The resulting mixture was stirred 2 h at room temperature followed by overnight at reflux temperature and evaporated. The residue was purified by flash chromatography (silica gel, eluent ethyl acetate/hexane) followed by preparative HPLC (Method 4) affording 480 mg (34% of th.) of the title compound which has racemized under the reaction conditions.

[0569] LC-MS (Method 1): R.sub.t=1.20 min; MS (ESIpos): m/z=794 [M+H].sup.+

[0570] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.40-8.24 (m, 1H), 8.10-7.98 (m, 1H), 7.90-7.55 (m, 9H), 6.89 (d, 1H), 5.66-5.51 (m, 1H), 5.31-5.01 (m, 2H), 4.39-3.71 (m, 5H), 0.99 (s, 9H).

Example 72A

2-{2-tert-Butoxy-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]ethyl}-1H-isoindole-1,3(2H)-dione (Diastereomeric Mixture)

[0571] ##STR00086##

[0572] 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 2A, 956 mg, 2.53 mmol) in 1,4-dioxane (30 ml) was treated with N,N-diisopropylethylamine and with a solution of 3-tert-butoxy-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl chloride (Example 61A, 860 mg, 2.78 mmol) in dioxane (8 ml) and stirred 30 min at room temperature. (2-Chlorophenyl)hydrazine hydrochloride (1:1) (497 mg, 2.78 mmol) was added. The resulting mixture was stirred 1.5 h at room temperature followed by overnight at reflux temperature and evaporated. The residue was purified by preparative HPLC (Method 4) followed by flash chromatography (silica gel, eluent cyclohexane/ethyl acetate) affording 840 mg (44% of th.) of the title compound which has racemized under the reaction conditions.

[0573] LC-MS (Method 1): R.sub.t=1.25 min; MS (ESIpos): m/z=744 [M+H].sup.+

Example 73A

2-{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]ethyl}-1H-isoindole-1,3(2H)-dione (Diastereomeric Mixture)

[0574] ##STR00087##

[0575] 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 2A, 313 mg, 826 μmol) in tetrahydrofurane (7.9 ml) was treated with N,N-diisopropylethylamine (580 μl, 3.3 mmol) and with a solution of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl chloride (Example 62A, 216 mg, 909 μmol) in tetrahydrofurane (4 ml) and stirred 45 min at room temperature. (2-Chlorophenyl)hydrazine hydrochloride (1:1) (163 mg, 909 μmol) was added. The resulting mixture was stirred 2 h at room temperature followed by 2 h at 130° C. under microwave irradiation and evaporated. The residue was purified by preparative HPLC (Method 4) affording 315 mg (56% of th.) of the title compound.

[0576] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=672 [M+H].sup.+

[0577] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.92-6.72 (m, 13H), 5.67-5.41 (m, 1H), 5.28-4.94 (m, 2H), 4.44-4.18 (m, 1H), 4.09-3.67 (m, 2H), 1.89-1.60 (m, 3H).

Experimental Section—Examples

Example 1

(1S)-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-(2,6-dichlorophenyl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate

[0578] ##STR00088##

[0579] At 0° C., a solution of 5-(4-chlorophenyl)-2-({1-(2,6-dichlorophenyl)-5-[(1S)-1-hydroxyethyl]-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 26A, 56.0 mg, 96.9 μmol) in dichloromethane (4.6 ml) was treated with trichloroacetyl isocyanate (12 μl, 97 μmol), stirred 10 min. Methanol (460 μl) was then added followed by triethylamine (140 μl, 970 μmol). The resulting mixture was stirred 1 h at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 15.3 mg (25% of th.) of the title compound.

[0580] LC-MS (Method 3): R.sub.t=3.06 min; MS (ESIpos): m/z=620.2 [M−H].sup.+

[0581] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.82-7.51 (m, 7H), 7.03-6.81 (m, 1H), 6.50 (br s, 2H), 5.66-5.43 (m, 1H), 5.29-4.91 (m, 2H), 4.37-4.21 (m, 1H), 4.12-3.73 (m, 2H), 1.61-1.31 (m, 3H).

Example 2

(1R)-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-(2,6-dichlorophenyl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate

[0582] ##STR00089##

[0583] At −78° C., a solution of 5-(4-chlorophenyl)-2-({1-(2,6-dichlorophenyl)-5-[(1R)-1-hydroxyethyl]-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 27A, 97.8 mg, 169 μmol) in dichloromethane (6.2 ml) was treated with sulfurisocyanatidoyl chloride (19 μl, 220 μmol) and stirred 48 h at −20° C. The reaction mixture was quenched with hydrochloric acid (2N, 1 ml) and evaporated. The residue was purified by preparative HPLC (Method 4) affording 28 mg (27% of th.) of the title compound.

[0584] LC-MS (Method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=620.0 [M+H].sup.+

[0585] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.88-7.50 (m, 7H), 6.90 (br s, 1H), 6.50 (br s, 2H), 5.66-5.46 (m, 1H), 5.22-5.01 (m, 2H), 4.37-4.19 (m, 1H), 4.11-3.71 (m, 2H), 1.63-1.32 (m, 3H).

Example 3

(1R)-1-[1-(2-Chloro-6-fluorophenyl)-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]ethyl Carbamate

[0586] ##STR00090##

[0587] At −78° C., a solution of 2-({1-(2-chloro-6-fluorophenyl)-5-[(1R)-1-hydroxyethyl]-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 28A, 105 mg, 187 μmol) in dichloromethane (6.9 ml) was treated with sulfurisocyanatidoyl chloride (21 μl, 240 μmol) and stirred 48 h at −20° C. The reaction mixture was quenched with hydrochloric acid (2N, 1 ml) and evaporated. The residue was purified by preparative HPLC (Method 4) affording 64.0 mg (57% of th.) of the title compound.

[0588] LC-MS (Method 3): R.sub.t=2.93 min; MS (ESIpos): m/z=604.1 [M+H].sup.+

[0589] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.88-7.38 (m, 7H), 6.90 (d, 1H), 6.48 (br s, 2H), 5.82-5.38 (m, 1H), 5.25-4.96 (m, 2H), 4.37-4.18 (m, 1H), 4.13-3.70 (m, 2H), 1.67-1.37 (m, 3H).

Example 4

(1R)-1-[1-(2-Chloro-4-fluorophenyl)-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]ethyl Carbamate

[0590] ##STR00091##

[0591] At −20° C., a solution of 2-({1-(2-chloro-4-fluorophenyl)-5-[(1R)-1-hydroxyethyl]-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 29A, 99.5 mg, 177 μmol) dichloromethane (7.0 ml) was treated with sulfurisocyanatidoyl chloride (20 μl, 230 μmol) and stirred 24 h at −20° C. The reaction mixture was quenched with hydrochloric acid (1N, 7 ml), heated 1 h at 60° C. and evaporated. The residue was purified by preparative HPLC (Method 4) affording 61.5 mg (57% of th.) of the title compound.

[0592] LC-MS (Method 2): R.sub.t=1.79 min; MS (ESIpos): m/z=604.1 [M+H].sup.+

[0593] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.89-7.32 (m, 7H), 6.90 (d, 1H), 6.47 (br s, 2H), 5.49 (br s, 1H), 5.29-4.93 (m, 2H), 4.38-4.23 (m, 1H), 4.11-3.76 (m, 2H), 1.49 (d, 3H).

Example 5

(1S)-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-[2-(difluoromethoxy)phenyl]-1H-1,2,4-triazol-5-yl}ethyl Carbamate

[0594] ##STR00092##

[0595] At 0° C., a solution of 5-(4-chlorophenyl)-2-({1-[2-(difluoromethoxy)phenyl]-5-[(1S)-1-hydroxyethyl]-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 30A, 81.0 mg, 141 μmol) in dichloromethane (6.7 ml) was treated with trichloroacetyl isocyanate (17 μl, 140 μmol) and stirred 10 min at 0° C. Methanol (670 μl) was added, followed by triethylamine (200 μl, 1.4 mmol). The resulting mixture was stirred 24 h at room temperature and 18 h at 60° C. The reaction mixture was evaporated and the residue purified by preparative HPLC (Method 4) and evaporated. The residue was purified by a preparative HPLC [sample preparation: 68 mg dissolved in 1 ml ethanol+1 ml iso-hexane; injection volume: 250 μl; column: Daicel Chiralpak AZ-H 5 μm, 250×20 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 15 ml/min; temperature: 30° C.; UV detection: 220 nm] affording 25.0 mg (29% of th.) of the title compound.

[0596] LC-MS (Method 1): R.sub.t=0.94 min; MS (ESIpos): m/z=618.0 [M+H].sup.+

[0597] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.87-6.83 (m, 10H), 6.79-6.26 (m, 2H), 5.58-5.39 (m, 1H), 5.18-4.97 (m, 2H), 4.37-4.20 (m, 1H), 4.11-3.75 (m, 2H), 1.49 (d, 3H).

Example 6

(1R)-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-[2-(difluoromethoxy)phenyl]-1H-1,2,4-triazol-5-yl}ethyl Carbamate

[0598] ##STR00093##

[0599] At −78° C., a solution of 5-(4-chlorophenyl)-2-({1-[2-(difluoromethoxy)phenyl]-5-[(1R)-1-hydroxyethyl]-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 31A, 140 mg, 243 μmol) in dichloromethane (9.0 ml) was treated with sulfurisocyanatidoyl chloride (27 μl, 320 μmol) and stirred 48 h at −20° C. The reaction mixture was quenched with hydrochloric acid (2N, 1 ml) and evaporated. The residue was purified by preparative HPLC (Method 4) affording 113 mg (75% of th.) of the title compound.

[0600] LC-MS (Method 1): R.sub.t=0.94 min; MS (ESIpos): m/z=618.0 [M+H].sup.+

[0601] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.88-6.82 (m, 10H), 6.75-6.25 (m, 2H), 5.47 (q, 1H), 5.20-4.96 (m, 2H), 4.39-4.22 (m, 1H), 4.13-3.77 (m, 2H), 1.49 (d, 3H).

Example 7

(1S)-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-[2-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-5-yl}ethyl Carbamate

[0602] ##STR00094##

[0603] At −20° C., a solution of 5-(4-chlorophenyl)-2-({5-[(1S)-1-hydroxyethyl]-1-[2-(trifluoromethoxy)-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 32A, 15.0 mg, 25.3 μmol) in dichloromethane (1.0 ml) was treated with sulfurisocyanatidoyl chloride (2.9 μl, 33 μmol) and stirred 24 h at −20° C. The reaction mixture was quenched with hydrochloric acid (1N, 7 ml), heated 1 h at 60° C. and evaporated. The residue was purified by preparative HPLC (Method 4) affording 16.0 mg (99% of th.) of the title compound.

[0604] LC-MS (Method 1): R.sub.t=0.99 min; MS (ESIpos): m/z=636 [M+H].sup.+

[0605] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.87-7.46 (m, 8H), 6.89 (d, 1H), 6.75-6.28 (m, 2H), 5.59-5.42 (m, 1H), 5.22-4.93 (m, 2H), 4.37-4.21 (m, 1H), 4.10-3.71 (m, 2H), 1.49 (d, 3H).

Example 8

(1R)-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-[2-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-5-yl}ethyl Carbamate

[0606] ##STR00095##

[0607] At −20° C., a solution of 5-(4-chlorophenyl)-2-({5-[(1R)-1-hydroxyethyl]-1-[2-(trifluoromethoxy)-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 33A, 98.0 mg, 165 μmol) in dichloromethane (6.3 ml) was treated with sulfurisocyanatidoyl chloride (19 μl, 210 μmol) and stirred 24 h at −20° C. The reaction mixture was quenched with hydrochloric acid (1N, 6 ml), heated 1 h at 60° C. and evaporated. The residue was purified by preparative HPLC (Method 4) affording 39.0 mg (37% of th.) of the title compound.

[0608] LC-MS (Method 2): R.sub.t=1.85 min; MS (ESIpos): m/z=636.1 [M+H].sup.+

[0609] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.80-7.46 (m, 8H), 6.90 (d, 1H), 6.75-6.14 (m, 2H), 5.64-5.38 (m, 1H), 5.09 (d, 2H), 4.40-4.21 (m, 1H), 4.10-3.75 (m, 2H), 1.49 (d, 3H).

Example 9

(1S)-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-(2-sulfamoylphenyl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate

[0610] ##STR00096##

[0611] At −20° C., a solution of 2-{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)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-1-yl}benzenesulfonamide (Example 34A, 30.0 mg, 51.0 μmol) in dichloromethane (2.0 ml) was treated with sulfurisocyanatidoyl chloride (5.8 μl, 66 μmol) and stirred 24 h at −20° C. The reaction mixture was quenched with hydrochloric acid (1N, 2 ml), heated 1 h at 60° C. and evaporated. The residue was purified by preparative HPLC (Method 4) affording 23.8 mg (73% of th.) of the title compound.

[0612] LC-MS (Method 1): R.sub.t=0.85 min; MS (ESIpos): m/z=631.2 [M+H].sup.+

[0613] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.16-7.52 (m, 8H), 7.14 (br s, 2H), 6.97-6.33 (m, 3H), 5.42 (br s, 1H), 5.23-4.99 (m, 2H), 4.41-4.19 (m, 1H), 4.09-3.74 (m, 2H), 1.42 (d, 3H).

Example 10

(1S)-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-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate

[0614] ##STR00097##

[0615] At −78° C., a solution of 5-(4-chlorophenyl)-2-({5-[(1S)-1-hydroxyethyl]-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 35A, 131 mg, 256 μmol) in dichloromethane (12 ml) was treated with sulfurisocyanatidoyl chloride (29 μl, 330 μmol) and stirred overnight at −20° C. The reaction mixture was quenched with hydrochloric acid (2N, 1 ml) and evaporated. The residue was purified by preparative HPLC (Method 4) affording 28.8 mg (20% of th.) of the title compound.

[0616] LC-MS (Method 1): R.sub.t=0.92 min; MS (ESIpos): m/z=553.2 [M+H].sup.+

[0617] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.64-8.37 (m, 1H), 8.07 (td, 1H), 7.88-7.41 (m, 6H), 6.91 (d, 1H), 6.77-6.14 (m, 3H), 5.10 (d, 2H), 4.40-4.22 (m, 1H), 4.11-3.76 (m, 2H), 1.58 (d, 3H).

Example 11

(1R)-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-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate

[0618] ##STR00098##

[0619] At −78° C., a solution of 5-(4-chlorophenyl)-2-({5-[(1R)-1-hydroxyethyl]-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 36A, 148 mg, 289 μmol) in dichloromethane (11 ml) was treated with sulfurisocyanatidoyl chloride (33 μl, 380 μmol) and stirred 48 h at −20° C. The reaction mixture was quenched with hydrochloric acid (2N, 1 ml) and evaporated. The residue was purified by preparative HPLC (Method 4) affording 97.3 mg (55% of th.) of the title compound.

[0620] LC-MS (Method 3): R.sub.t=2.71 min; MS (ESIpos): m/z=553.1 [M+H].sup.+

[0621] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.53 (dd, 1H), 8.20-7.94 (m, 1H), 7.88-7.41 (m, 6H), 7.05-6.28 (m, 4H), 5.19-4.96 (m, 2H), 4.41-4.22 (m, 1H), 4.08-3.76 (m, 2H), 1.58 (d, 3H).

Example 12

(1S)-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-fluoropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate

[0622] ##STR00099##

[0623] At 0° C., a solution of 5-(4-chlorophenyl)-2-({1-(3-fluoropyridin-2-yl)-5-[(1S)-1-hydroxyethyl]-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 37A, 94.8 mg, 180 μmol) in dichloromethane (8.6 ml) was treated with trichloroacetyl isocyanate (21 μl, 180 μmol) and stirred 10 min. Methanol (860 μl) was then added followed by triethylamine (250 μl, 1.8 mmol). The resulting mixture was stirred 24 h at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 102 mg (quant.) of the title compound.

[0624] LC-MS (Method 1): R.sub.t=0.90 min; MS (ESIpos): m/z=571.3 [M+H].sup.+

[0625] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.52-8.32 (m, 1H), 8.18-7.95 (m, 1H), 7.82-7.52 (m, 5H), 6.90 (d, 1H), 6.73-6.23 (m, 2H), 5.82-5.73 (m, 1H), 5.20-4.99 (m, 2H), 4.38-4.20 (m, 1H), 4.12-3.73 (m, 2H), 1.63-1.36 (m, 3H).

Example 13

(1R)-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-fluoropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate

[0626] ##STR00100##

[0627] At −78° C., a solution of 5-(4-chlorophenyl)-2-({1-(3-fluoropyridin-2-yl)-5-[(1R)-1-hydroxyethyl]-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 38A, 134 mg, 253 μmol) in dichloromethane (9.3 ml) was treated with sulfurisocyanatidoyl chloride (29 μl, 330 μmol) and stirred 48 h at −20° C. The reaction mixture was quenched with hydrochloric acid (2N, 1 ml) and evaporated. The residue was purified by preparative HPLC (Method 4) affording 92.7 mg (64% of th.) of the title compound.

[0628] LC-MS (Method 1): R.sub.t=0.87 min; MS (ESIpos): m/z=571.1 [M+H].sup.+

[0629] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.44 (d, 1H), 8.09 (ddd, 1H), 7.85-7.48 (m, 5H), 6.90 (d, 1H), 6.76-6.22 (m, 2H), 5.78 (q, 1H), 5.23-4.96 (m, 2H), 4.38-4.22 (m, 1H), 4.07-3.76 (m, 2H), 1.56 (d, 3H).

Example 14

(1S)-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-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate

[0630] ##STR00101##

[0631] At −78° C., a solution of 5-(4-chlorophenyl)-2-({1-(3-chloropyridin-2-yl)-5-[(1S)-1-hydroxyethyl]-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 39A, 77.7 mg, 143 μmol) in dichloromethane (6.8 ml) was treated with sulfurisocyanatidoyl chloride (15 μl, 170 μmol) and stirred overnight at −20° C. The reaction mixture was quenched with hydrochloric acid (2N, 1 ml) and evaporated. The residue was purified by preparative HPLC (Method 4) affording 61.8 mg (74% of th.) of the title compound.

[0632] LC-MS (Method 1): R.sub.t=0.90 min; MS (ESIpos): m/z=587.2 [M+H].sup.+

[0633] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.57 (dd, 1H), 8.28 (dd, 1H), 7.92-7.43 (m, 5H), 6.89 (d, 1H), 6.69-6.24 (m, 2H), 5.77-5.60 (m, 1H), 5.11 (s, 2H), 4.39-4.21 (m, 1H), 4.11-3.73 (m, 2H), 1.53 (d, 3H).

Example 15

(1R)-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-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate

[0634] ##STR00102##

[0635] At −78° C., a solution of 5-(4-chlorophenyl)-2-({1-(3-chloropyridin-2-yl)-5-[(1R)-1-hydroxyethyl]-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 40A, 232 mg, 426 μmol) in dichloromethane (16 ml) was treated with sulfurisocyanatidoyl chloride (48 μl, 550 μmol) and stirred overnight at −20° C. The reaction mixture was quenched with hydrochloric acid (2N, 1 ml) and evaporated. The residue was purified by preparative HPLC (Method 4) affording 134 mg (54% of th.) of the title compound.

[0636] LC-MS (Method 2): R.sub.t=1.62 min; MS (ESIpos): m/z=587.1 [M+H].sup.+

[0637] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.57 (dd, 1H), 8.28 (dd, 1H), 7.86-7.52 (m, 5H), 6.90 (d, 1H), 6.43 (br s, 2H), 5.70 (q, 1H), 5.22-5.01 (m, 2H), 4.41-4.23 (m, 1H), 4.10-3.76 (m, 2H), 1.53 (d, 3H)

Example 16

(1S)-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-(5-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate

[0638] ##STR00103##

[0639] At −20° C., a solution of 5-(4-chlorophenyl)-2-({1-(5-chloropyridin-2-yl)-5-[(1S)-1-hydroxyethyl]-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 41A, 90.0 mg, 165 μmol) in dichloromethane (6.0 ml) was treated with sulfurisocyanatidoyl chloride (19 μl, 210 μmol) and stirred 24 h at −20° C. The reaction mixture was quenched with hydrochloric acid (1N, 6 ml), heated 1 h at 60° C. and evaporated. The residue was purified by preparative HPLC (Method 4) affording 71.0 mg (69% of th.) of the title compound.

[0640] LC-MS (Method 1): R.sub.t=1.01 min; MS (ESIpos): m/z=587.2 [M+H].sup.+

[0641] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.60 (d, 1H), 8.20 (dd, 1H), 7.92-7.49 (m, 5H), 7.01-6.19 (m, 4H), 5.20-4.97 (m, 2H), 4.43-4.18 (m, 1H), 4.12-3.76 (m, 2H), 1.58 (d, 3H).

Example 17

(1R)-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-(5-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate

[0642] ##STR00104##

[0643] At −20° C., a solution of 5-(4-chlorophenyl)-2-({1-(5-chloropyridin-2-yl)-5-[(1R)-1-hydroxyethyl]-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 42A, 100 mg, 184 μmol) in dichloromethane (7.0 ml) was treated with sulfurisocyanatidoyl chloride (21 μl, 240 μmol) and stirred 24 h at −20° C. The reaction mixture was quenched with hydrochloric acid (1N, 7 ml), heated 1 h at 60° C. and evaporated. The residue was purified by preparative HPLC (Method 4) affording 82.0 mg (74% of th.) of the title compound.

[0644] LC-MS (Method 5): R.sub.t=1.27 min; MS (ESIneg): m/z=585.0 [M−H].sup.+

[0645] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.60 (d, 1H), 8.20 (dd, 1H), 7.90-7.56 (m, 5H), 7.03-6.26 (m, 4H), 5.22-4.97 (m, 2H), 4.42-4.22 (m, 1H), 4.13-3.76 (m, 2H), 1.58 (d, 3H).

Example 18

(1S)-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-chloropyridin-4-yl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate

[0646] ##STR00105##

[0647] At 0° C., a solution of 5-(4-chlorophenyl)-2-({1-(3-chloropyridin-4-yl)-5-[(1S)-1-hydroxyethyl]-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 43A, 62.2 mg, 114 μmol) in dichloromethane (5.4 ml) was treated with trichloroacetyl isocyanate (14 μl, 110 μmol) and stirred 10 min. Methanol (540 al) was then added followed by triethylamine (160 μl, 1.1 mmol). The resulting mixture was stirred 24 h at room temperature. Trichloroacetyl isocyanate (9.9 μl, 110 μmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloroethane (2 ml), heated 5 h at 80° C. and evaporated. The residue was purified by preparative HPLC (Method 4) and evaporated. The residue was purified by chiral preparative HPLC (sample preparation: 49 mg dissolved in 1 ml ethanol; injection volume: 500 al; column: Daicel Chiralpak OZ-H 5 μm, 250×20 mm; eluent: iso-hexane/ethanol 70:30; flow rate: 15 ml/min; temperature: 35° C.; UV detection: 220 nm) affording 15 mg (25% of th.) of the title compound.

[0648] LC-MS (Method 1): R.sub.t=0.91 min; MS (ESIpos): m/z=587.0 [M+H].sup.+

[0649] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 9.04-8.62 (m, 2H), 7.91-7.50 (m, 5H), 6.89 (d, 1H), 6.71-6.26 (m, 2H), 5.58 (q, 1H), 5.28-4.98 (m, 2H), 4.40-4.16 (m, 1H), 4.09-3.74 (m, 2H), 1.52 (d, 3H).

Example 19

(1S)-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-(3,5-dichloropyridin-4-yl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate

[0650] ##STR00106##

[0651] At −78° C., a solution of 5-(4-chlorophenyl)-2-({1-(3,5-dichloropyridin-4-yl)-5-[(1S)-1-hydroxyethyl]-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 44A, 25.3 mg, 43.7 μmol) in dichloromethane (2.1 ml) was treated with sulfurisocyanatidoyl chloride (4.6 μl, 52 μmol) and stirred overnight at −20° C. The reaction mixture was quenched with hydrochloric acid (2N, 1 ml) and evaporated. The residue was purified by preparative HPLC (Method 4) affording 19.5 mg (70% of th.) of the title compound.

[0652] LC-MS (Method 1): R.sub.t=0.94 min; MS (ESIpos): m/z=621.2 [M+H].sup.+

[0653] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 9.00-8.83 (m, 2H), 7.81-7.46 (m, 4H), 6.89 (d, 1H), 6.65-6.38 (m, 2H), 5.76-5.58 (m, 1H), 5.31-4.98 (m, 2H), 4.38-4.20 (m, 1H), 4.11-3.71 (m, 2H), 1.55 (d, 3H).

Example 20

(1R)-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-(3,5-dichloropyridin-4-yl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate

[0654] ##STR00107##

[0655] At −78° C., a solution of 5-(4-chlorophenyl)-2-({1-(3,5-dichloropyridin-4-yl)-5-[(1R)-1-hydroxyethyl]-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 45A, 13.9 mg, 24.0 μmol) in dichloromethane (1.2 ml) was treated with sulfurisocyanatidoyl chloride (2.5 μl, 29 μmol) and stirred overnight at −20° C. The reaction mixture was quenched with hydrochloric acid (2N, 1 ml) and evaporated. The residue was purified by preparative HPLC (Method 4) affording 4.30 mg (29% of th.) of the title compound.

[0656] LC-MS (Method 1): R.sub.t=0.94 min; MS (ESIpos): m/z=621.2 [M+H].sup.+

[0657] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 9.00-8.81 (m, 2H), 7.90-7.53 (m, 4H), 7.01-6.79 (m, 1H), 6.51 (br s, 2H), 5.78-5.55 (m, 1H), 5.23-5.09 (m, 2H), 4.38-4.21 (m, 1H), 4.11-3.73 (m, 2H), 1.55 (d, 3H).

Example 21

(1S)-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-(4-chloropyridin-3-yl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate

[0658] ##STR00108##

[0659] At −78° C., a solution of 5-(4-chlorophenyl)-2-({1-(4-chloropyridin-3-yl)-5-[(1S)-1-hydroxyethyl]-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 46A, 100 mg, 184 μmol) in dichloromethane (8.8 ml) was treated with sulfurisocyanatidoyl chloride (21 μl, 240 μmol) and stirred overnight at −20° C. The reaction mixture was quenched with hydrochloric acid (2N, 1 ml) and evaporated. The residue was purified by preparative HPLC (Method 4) affording 32 mg (30% of th.) of the title compound.

[0660] LC-MS (Method 1): R.sub.t=0.87 min; MS (ESIpos): m/z=587.2 [M+H].sup.+

[0661] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.85-8.64 (m, 2H), 7.95-7.53 (m, 5H), 6.89 (d, 1H), 6.73-6.34 (m, 2H), 5.63-5.41 (m, 1H), 5.21-5.00 (m, 2H), 4.39-4.19 (m, 1H), 4.13-3.74 (m, 2H), 1.52 (d, 3H).

Example 22

(1S)-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-(trifluoromethoxy)pyridin-2-yl]-1H-1,2,4-triazol-5-yl}ethyl Carbamate

[0662] ##STR00109##

[0663] At −20° C., a solution of 5-(4-chlorophenyl)-2-({5-[(1S)-1-hydroxyethyl]-1-[3-(trifluoromethoxy)-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 47A, 100 mg, 168 μmol) in dichloromethane (5.0 ml) was treated with sulfurisocyanatidoyl chloride (19 μl, 220 μmol) and stirred 24 h at −20° C. The reaction mixture was quenched with hydrochloric acid (1N, 7 ml), heated 1 h at 60° C. and evaporated. The residue was purified by preparative HPLC (Method 4) and evaporated. The residue was purified by preparative SFC (sample preparation: 63 mg dissolved in 13 ml methanol/acetonitrile/ethanol mixture; injection volume: 800 μl; column: Daicel Chiralpak IC 5 μm, 250×20 mm; eluent: carbon dioxide/ethanol 80:20; flow rate: 80 ml/min; temperature: 40° C.; UV detection: 210 nm) affording 30.0 mg (28% of th.) of the title compound.

[0664] LC-MS (Method 1): R.sub.t=0.94 min; MS (ESIpos): m/z=637.0 [M+H].sup.+

[0665] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.61 (dd, 1H), 8.22 (dt, 1H), 7.87-7.56 (m, 5H), 6.89 (d, 1H), 6.74-6.23 (m, 2H), 5.87-5.76 (m, 1H), 5.11 (d, 2H), 4.40-4.20 (m, 1H), 4.09-3.75 (m, 2H), 1.55 (d, 3H).

Example 23

(1R)-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-(trifluoromethoxy)pyridin-2-yl]-1H-1,2,4-triazol-5-yl}ethyl Carbamate

[0666] ##STR00110##

[0667] At −20° C., a solution of 5-(4-chlorophenyl)-2-({5-[(1R)-1-hydroxyethyl]-1-[3-(trifluoromethoxy)-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 48A, 118 mg, 199 μmol) in dichloromethane (7 ml) was treated with sulfurisocyanatidoyl chloride (23 μl, 260 μmol) and stirred 24 h at −20° C. The reaction mixture was quenched with hydrochloric acid (1N, 7 ml), heated 1 h at 60° C. and evaporated. The residue was purified by preparative HPLC (Method 4) and evaporated. The residue was purified by a chiral HPLC (sample preparation: 27 mg dissolved in 1 ml ethanol+1 ml iso-hexane; injection volume: 700 μl; column: Daicel Chiralpak IE 5 μm, 250×20 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 15 ml/min; temperature: 40° C.; UV detection: 220 nm) affording 16.0 mg (13% of th.) of the title compound.

[0668] LC-MS (Method 5): R.sub.t=1.23 min; MS (ESIneg): m/z=635.0

[0669] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.61 (dd, 1H), 8.29-8.14 (m, 1H), 7.90-7.52 (m, 5H), 6.90 (br s, 1H), 6.69-6.24 (m, 2H), 5.80 (q, 1H), 5.20-5.01 (m, 2H), 4.38-4.20 (m, 1H), 4.07-3.75 (m, 2H), 1.55 (d, 3H).

Example 24

[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]methyl Carbamate

[0670] ##STR00111##

[0671] Under argon at −15° C., chlorosulfonyl isocyanate (8.7 μl, 99 μmol) was added dropwise to a solution of 5-(4-chlorophenyl)-2-{[1-(3-chlorophenyl)-5-(hydroxymethyl)-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 1 in WO 2016/071212 A1; 35 mg, 66 μmol) in acetonitrile (2.45 ml). After stirring overnight at room temperature, the reaction mixture was cooled to −15° C., after which chlorosulfonyl isocyanate (3.5 μl, 40 μmol) was added due to incomplete conversion. After stirring for 1 h at 15° C., the reaction mixture was quenched with aqueous hydrochloric acid (2 M). The resulting mixture was stirred at 60° C. for 2 h and then concentrated in vacuo. The crude product was purified by preparative HPLC (Method 6), affording the title compound (11 mg, 0.02 mmol, 28.8% of th.) and (2S)-3-[1-({5-[(carbamoyloxy)methyl]-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl}methyl)-3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl carbamate (16 mg, 0.03 mmol, 40.6% of th., see Example 25).

[0672] LC-MS (Method 3): R.sub.t=3.02 min; MS [ESIpos]: m/z=572 (M+H).sup.+

[0673] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.72-7.79 (m, 2H), 7.67-7.72 (m, 1H), 7.54-7.65 (m, 5H), 6.50-6.96 (m, 3H), 5.06-5.12 (m, 4H), 4.30 (br. s., 1H), 4.01 (dd, 1H), 3.85 (dd, 1H).

Example 25

(2S)-3-[1-({5-[(Carbamoyloxy)methyl]-1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl}methyl)-3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl Carbamate

[0674] ##STR00112##

[0675] For reaction conditions see Example 24.

[0676] LC-MS (Method 3): R.sub.t=2.84 min; MS [ESIpos]: m/z=615 (M+H).sup.+

[0677] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.65-7.71 (m, 3H), 7.59-7.64 (m, 4H), 7.53-7.59 (m, 1H), 7.05 (br. s., 1H), 6.90 (br. s., 1H), 6.55-6.86 (m, 2H), 5.32-5.44 (m, 1H), 4.99-5.14 (m, 4H), 4.24 (dd, 1H), 4.07 (dd, 1H).

Example 26

[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-fluorophenyl)-1H-1,2,4-triazol-5-yl]methyl Carbamate

[0678] ##STR00113##

[0679] Under argon at −30° C., chlorosulfonyl isocyanate (20.1 μl, 0.23 mmol) was added dropwise to a solution of 5-(4-chlorophenyl)-2-{[1-(3-fluorophenyl)-5-(hydroxymethyl)-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 2 in WO 2016/071212 A1; 79 mg, 0.154 mmol) in acetonitrile (5.7 ml). The reaction mixture was stirred at 7° C. for 2 days, after which chlorosulfonyl isocyanate (13 0.154 mmol) was added due to incomplete conversion. After stirring for 2 additional days at 7° C., the reaction mixture was quenched with aqueous hydrochloric acid (2 M). The resulting mixture was stirred at 60° C. for 2 h and then concentrated in vacuo. The crude product was purified by preparative HPLC (Method 6), affording the title compound (5 mg, 0.01 mmol, 5.8% of th.).

[0680] LC-MS (Method 3): R.sub.t=2.88 min; MS [ESIpos]: m/z=556 (M+H).sup.+

[0681] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.73-7.78 (m, 2H), 7.59-7.66 (m, 3H), 7.50 (dt, 1H), 7.38-7.46 (m, 2H), 6.90 (d, 1H), 6.53-6.86 (m, 2H), 5.11 (s, 2H), 5.09 (s, 2H), 4.30 (br. s., 1H), 4.01 (dd, 1H), 3.85 (dd, 1H).

Example 27

[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-methoxyphenyl)-1H-1,2,4-triazol-5-yl]methyl Carbamate

[0682] ##STR00114##

[0683] Under argon at −30° C., chlorosulfonyl isocyanate (9.1 μl, 0.104 mmol) was added dropwise to a solution of 5-(4-chlorophenyl)-2-{[5-(hydroxymethyl)-1-(2-methoxyphenyl)-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 3 in WO 2016/071212 A1; 42 mg, 0.08 mmol) in acetonitrile (3 ml). The reaction mixture was stirred at 7° C. overnight and then quenched with aqueous hydrochloric acid (2 M). The resulting mixture was stirred at 60° C. for 2 h and then concentrated in vacuo. The crude product was purified by preparative HPLC (Method 6), affording the title compound (3.9 mg, 0.01 mmol, 8.4% of th.).

[0684] LC-MS (Method 3): R.sub.t=2.77 min; MS [ESIpos]: m/z=568 (M+H).sup.+

[0685] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.74-7.79 (m, 2H), 7.60-7.66 (m, 2H), 7.55 (td, 1H), 7.38 (dd, 1H), 7.26 (d, 1H), 7.10 (td, 1H), 6.91 (br. d, 1H), 6.41-6.80 (m, 2H), 5.06 (s, 2H), 4.85 (s, 2H), 4.25-4.35 (m, 1H), 4.00 (dd, 1H), 3.85 (dd, 1H), 3.78 (s, 3H).

Example 28

[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]methyl Carbamate

[0686] ##STR00115##

[0687] Under argon at −15° C., chlorosulfonyl isocyanate (10.6 μl, 122 μmol) was added dropwise to a solution of 5-(4-chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(hydroxymethyl)-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 4 in WO 2016/071212 A1; 43 mg, 81 μmol) in acetonitrile (3 ml). After stirring overnight at room temperature, the reaction mixture was cooled to −15° C., after which chlorosulfonyl isocyanate (3.5 μl, 40 μmol) was added due to incomplete conversion. After stirring at −15° C. for 1 h, the reaction mixture was quenched with aqueous hydrochloric acid (2 M). The resulting mixture was stirred at 60° C. for 2 h and then concentrated in vacuo. The crude product was first purified by preparative HPLC (Method 6). A second purification by preparative HPLC (column: Kinetix 5 μm C18, 100×21.2 mm; eluent: water/acetonitrile/formic acid 40/50/10; flow rate: 25 ml/min; temperature: 40° C.; UV detection: 210 nm] afforded the title compound (4 mg, 0.01 mmol, 7.7% of th.) and (2S)-3-[1-({5-[(carbamoyloxy)methyl]-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl}methyl)-3-(4 chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl carbamate (24 mg, 0.04 mmol, 48% of th.; see Example 29).

[0688] LC-MS (Method 3): R.sub.t=2.85 min; MS [ESIpos]: m/z=572 (M+H).sup.+

[0689] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.71-7.78 (m, 3H), 7.59-7.65 (m, 4H), 7.52-7.58 (m, 1H), 6.91 (d, 1H), 6.46-6.75 (m, 2H), 5.09 (s, 2H), 4.91 (s, 2H), 4.25-4.35 (m, 1H), 4.01 (dd, 1H), 3.85 (dd, 1H).

Example 29

(2S)-3-[1-({5-[(Carbamoyloxy)methyl]-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl}methyl)-3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl Carbamate

[0690] ##STR00116##

[0691] For reaction conditions see Example 28.

[0692] LC-MS (Method 3): R.sub.t=2.67 min; MS [ESIpos]: m/z=615 (M+H).sup.+

[0693] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.66-7.76 (m, 3H), 7.50-7.66 (m, 5H), 7.05 (br. s., 1H), 6.91 (br. s., 1H), 6.44-6.76 (m, 2H), 5.38 (br. s., 1H), 5.00-5.15 (m, 2H), 4.90 (s, 2H), 4.20-4.28 (m, 1H), 4.08 (dd, 1H).

Example 30

(1S)-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-fluorophenyl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate

[0694] ##STR00117##

[0695] Under argon at −20° C., chlorosulfonyl isocyanate (5.2 μl, 60 μmol) was added dropwise to a solution of 5-(4-chlorophenyl)-2({1-(3-fluorophenyl)-5-[(1S)-1-hydroxyethyl]-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 76 in WO 2016/071212 A1; 30 mg, 57 μmol) in dichloromethane (2.1 ml). After stirring at −20° C. for 3 days, chlorosulfonyl isocyanate (1 μl, 11 μmol) was added due to incomplete conversion. After stirring at −20° C. for 4 h, the reaction mixture was quenched with aqueous hydrochloric acid (2 M, 4 ml). The resulting mixture was stirred at 60° C. for 2 h and then concentrated in vacuo. The crude product was purified by preparative HPLC (Method 6), affording the title compound (17 mg, 0.03 mmol, 52.4% of th.).

[0696] LC-MS (Method 3): R.sub.t=2.92 min; MS [ESIpos]: m/z=570 (M+H).sup.+

[0697] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.73-7.78 (m, 2H), 7.57-7.65 (m, 3H), 7.35-7.47 (m, 3H), 6.89 (d, 1H), 6.40-6.79 (m, 2H), 5.72 (q, 1H), 5.03-5.13 (m, 2H), 4.24-4.35 (m, 1H), 4.01 (dd, 1H), 3.85 (dd, 1H), 1.52 (d, 3H).

Example 31

(1R)-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]ethyl Carbamate

[0698] ##STR00118##

[0699] Under argon at −20° C., chlorosulfonyl isocyanate (6.2 μl, 72 μmol) was added dropwise to a solution of 5-(4-chlorophenyl)-2({1-(2-chlorophenyl)-5-[(1R)-1-hydroxyethyl]-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 83 in WO 2016/071212 A1; 30 mg, 55 μmol) in dichloromethane (2 ml). After stirring at −20° C. for 3 days, the reaction mixture was quenched with aqueous hydrochloric acid (2 M, 4 ml). The resulting mixture was stirred at 60° C. for 2 h and then concentrated in vacuo. The crude product was purified by preparative HPLC (Method 6), affording the title compound (26 mg, 0.04 mmol, 80.3% of th.) and (2S)-3-[1-({5-[(1R)-1-(carbamoyloxy)ethyl]-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl}methyl)-3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl carbamate (3.2 mg, 0.005 mmol, 9.2% of th.; see Example 32).

[0700] LC-MS (Method 3) R.sub.t=2.93 min; MS [ESIpos]: m/z=586 (M+1-1).sup.+

[0701] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.69-7.79 (m, 3H), 7.50-7.66 (m, 5H), 6.92 (br. s., 1H), 6.35-6.71 (m, 2H), 5.46 (br. s., 1H), 5.05-5.14 (m, 2H), 4.30 (br. s., 1H), 4.01 (dd, 1H), 3.85 (dd, 1H), 1.48 (d, 3H).

Example 32

(2S)-3-[1-({5-[(1R)-1-(Carbamoyloxy)ethyl]-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl}methyl)-3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl Carbamate

[0702] ##STR00119##

[0703] For reaction conditions see Example 31.

[0704] LC-MS (Method 3): R.sub.t=2.75 min; MS [ESIpos]: m/z=629 (M+H).sup.+

[0705] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.66-7.74 (m, 3H), 7.50-7.65 (m, 5H), 7.07 (br. s., 1H), 6.92 (br. s., 1H), 6.35-6.70 (m, 2H), 5.33-5.51 (m, 2H), 5.01-5.14 (m, 2H), 4.24 (dd, 1H), 4.07 (dd, 1H), 1.47 (d, 3H).

Example 33

(1S)-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]ethyl Carbamate

[0706] ##STR00120##

[0707] Under argon at −20° C., chlorosulfonyl isocyanate (6.2 μl, 72 μmol) was added dropwise to a solution of 5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-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 82 in WO 2016/071212 A1; 30 mg, 55 μmol) in dichloromethane (2 ml). After stirring at −20° C. for 3 days, the reaction mixture was quenched with aqueous hydrochloric acid (2 M, 4 ml). The resulting mixture was stirred at 60° C. for 2 h and then concentrated in vacuo. The crude product was purified by preparative HPLC (Method 6), affording the title compound (25 mg, 0.04 mmol, 77.2% of th.) and (2S)-3-[1-({5-[(1S)-1-(carbamoyloxy)ethyl]-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl}methyl)-3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl carbamate (2.1 mg, 0.003 mmol, 6% of th.; see Example 34).

[0708] LC-MS (Method 3): R.sub.t=2.94 min; MS [ESIpos]: m/z=586 (M+H).sup.+

[0709] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.69-7.78 (m, 3H), 7.56-7.66 (m, 4H), 7.53 (td, 1H), 6.91 (br. s., 1H), 6.37-6.72 (m, 2H), 5.45 (br. s., 1H), 5.04-5.15 (m, 2H), 4.30 (br. s., 1H), 4.01 (dd, 1H), 3.85 (dd, 1H), 1.48 (d, 3H).

Example 34

(2S)-3-[1-({5-[(1S)-1-(Carbamoyloxy)ethyl]-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl}methyl)-3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl Carbamate

[0710] ##STR00121##

[0711] For reaction conditions see Example 33.

[0712] LC-MS (Method 3): R.sub.t=2.75 min; MS [ESIpos]: m/z=629 (M+H).sup.+

[0713] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.66-7.74 (m, 3H), 7.55-7.65 (m, 4H), 7.53 (td, 1H), 7.06 (br. s., 1H), 6.92 (br. s., 1H), 6.35-6.72 (m, 2H), 5.32-5.53 (m, 2H), 5.00-5.16 (m, 2H), 4.24 (dd, 1H), 4.07 (dd, 1H), 1.47 (d, 3H).

Example 35

(1S)-1-[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]ethyl Carbamate

[0714] ##STR00122##

[0715] Under argon, a diastereomeric mixture (51 mg, 0.094 mmol, diastereomeric ratio 9/1) of 5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-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 79 in WO 2016/071212 A1) and 5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1R)-1-hydroxyethyl]-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 80 in WO 2016/071212 A1) was dissolved in dichloromethane (3.5 ml). The solution was cooled to −20° C. and chlorosulfonyl isocyanate (12.2 μl, 141 μmol) was added dropwise. After stirring at −20° C. for 3 days, the reaction mixture was quenched with aqueous hydrochloric acid (2 M, 3 ml). The resulting mixture was stirred at 60° C. for 2 h and then concentrated in vacuo. The crude product was first purified by preparative HPLC (Method 6). The 2 diastereomers were separated by preparative chiral HPLC [sample preparation: 21 mg dissolved in 1 ml ethanol/isohexane (1:1); injection volume: 1 ml; column: Daicel Chiralpak IA 5 μm, 250×20 mm; eluent: isohexane/ethanol 60:40; flow rate: 15 ml/min; temperature: 25° C.; UV detection: 220 nm]. After separation, 17 mg of the title compound (1S)-diastereomer, which eluted first, and 2 mg of (1R)-diastereomer (see Example 36) which eluted later, were isolated.

[0716] Analytical chiral HPLC: R.sub.t=5.38 min, d.e.=100% [column: Daicel Chiralpak IA 5 μm, 250×4.6 mm; eluent: isohexane/ethanol 60:40; flow rate: 1 ml/min; temperature: 30° C.; UV detection: 220 nm].

[0717] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.72-7.78 (m, 2H), 7.55-7.66 (m, 5H), 7.50 (dt, 1H), 6.89 (d, 1H), 6.43-6.78 (m, 2H), 5.70 (q, 1H), 5.02-5.14 (m, 2H), 4.29 (br. s., 1H), 4.01 (dd, 1H), 3.85 (dd, 1H), 1.49-1.56 (m, 3H).

Example 36

(1R)-1-[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]ethyl Carbamate

[0718] ##STR00123##

[0719] For reaction conditions see Example 35.

[0720] Analytical chiral HPLC: R.sub.t=8.64 min, d.e.=100% [column: Daicel Chiralpak IA 5 μm, 250×4.6 mm; eluent: isohexane/ethanol 60:40; flow rate: 1 ml/min; temperature: 30° C.; UV detection: 220 nm].

[0721] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.72-7.79 (m, 2H), 7.55-7.67 (m, 5H), 7.50 (dt, 1H), 6.89 (d, 1H), 6.40-6.80 (m, 2H), 5.71 (q, 1H), 5.08 (s, 2H), 4.30 (br. s., 1H), 4.01 (dd, 1H), 3.85 (dd, 1H), 1.52 (d, 3H).

Example 37

[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-methylphenyl)-1H-1,2,4-triazol-5-yl]methyl Carbamate

[0722] ##STR00124##

[0723] Under argon at −20° C., chlorosulfonyl isocyanate (10.6 μl, 122 μmol) was added dropwise to a solution of 5-(4-chlorophenyl)-2-{[5-(hydroxymethyl)-1-(2-methylphenyl)-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 5 in WO 2016/071212 A1; 47.7 mg, 94 μmol) in dichloromethane (3.5 ml). After stirring at −20° C. for 4 days, chlorosulfonyl isocyanate (8.2 μl, 94 μmol) was added due to incomplete conversion. The reaction mixture was stirred at −20° C. overnight and then quenched with aqueous hydrochloric acid (2 M). The resulting mixture was stirred at 60° C. for 2 h and then concentrated in vacuo. The crude product was first purified by preparative HPLC (Method 6). This purification afforded 12.3 mg (19% of th.) (2S)-3-[1-({5-[(carbamoyloxy)methyl]-1-(2-methylphenyl)-1H-1,2,4-triazol-3-yl}methyl)-3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1 trifluoropropan-2-yl carbamate (see Example 38) and the title compound. The title compound was further purified by preparative chiral HPLC [sample preparation: 22.8 mg dissolved in 4 ml ethanol/isohexane (1:1); injection volume: 2 ml; column: Daicel Chiralcel® OXH 5 μm, 250×20 mm; eluent: isohexane/ethanol 50:50; flow rate: 20 ml/min; temperature: 40° C.; UV detection: 220 nm]. After separation, 14 mg (0.03 mmol, 27% of th.) of the title compound were isolated.

[0724] LC-MS (Method 3): R.sub.t=2.83 min; MS [ESIpos]: m/z=552 (M+H).sup.+

[0725] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.72-7.78 (m, 2H), 7.59-7.65 (m, 2H), 7.32-7.51 (m, 4H), 6.90 (d, 1H), 6.43-6.83 (m, 2H), 5.08 (s, 2H), 4.85 (s, 2H), 4.30 (br. s., 1H), 4.00 (dd, 1H), 3.85 (dd, 1H), 2.01 (s, 3H).

Example 38

(2S)-3-[1-({5-[(Carbamoyloxy)methyl]-1-(2-methylphenyl)-1H-1,2,4-triazol-3-yl}methyl)-3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl Carbamate

[0726] ##STR00125##

[0727] For reaction conditions see Example 37.

[0728] LC-MS (Method 3): R.sub.t=2.66 min; MS [ESIpos]: m/z=595 (M+H).sup.+

[0729] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.65-7.71 (m, 2H), 7.59-7.64 (m, 2H), 7.40-7.50 (m, 2H), 7.32-7.40 (m, 2H), 7.04 (br. s., 1H), 6.89 (br. s., 1H), 6.45-6.79 (m, 2H), 5.32-5.44 (m, 1H), 5.07 (q, 2H), 4.84 (s, 2H), 4.24 (dd, 1H), 4.07 (dd, 1H), 2.00 (s, 3H).

Example 39

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-(2-methoxyphenyl)-1H-1,2,4-triazol-5-yl]ethyl Carbamate (Diastereomeric Mixture)

[0730] ##STR00126##

[0731] Under argon at −20° C., chlorosulfonyl isocyanate (4.0 μl, 46 μmol) was added dropwise to a solution of 5-(4-Chlorophenyl)-2-{[5-(1-hydroxyethyl)-1-(2-methoxyphenyl)-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) (Example 11 in WO 2016/071212 A1; 19 mg, 35 μmol) in dichloromethane (1.3 ml). After stirring at −20° C. for 3 days, extra portion chlorosulfonyl isocyanate (5 μl, 57 μmol) was added over 2 days at −20° C., due to incomplete conversion. The reaction mixture was then quenched with aqueous hydrochloric acid (2 M, 4 ml), stirred at 60° C. for 2 h and concentrated in vacuo. The crude product was purified by preparative HPLC (Method 6) affording 12 mg (55.6% of th.) of the title compound and 7 mg (31% of th.) of (2S)-3-[1-({5-[1-(carbamoyloxy)ethyl]-1-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl}methyl)-3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl carbamate (see Example 40).

[0732] LC-MS (Method 3): R.sub.t=2.83 min; MS [ESIpos]: m/z=582 (M+H).sup.+

[0733] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.76 (br. d, 2H), 7.63 (br. d, 2H), 7.53 (td, 1H), 7.33 (d, 1H), 7.24 (d, 1H), 7.08 (t, 1H), 6.89 (d, 1H), 6.30-6.68 (m, 2H), 5.37-5.45 (m, 1H), 5.02-5.11 (m, 2H), 4.25-4.35 (m, 1H), 4.01 (dd, 1H), 3.85 (dd, 1H), 3.76 (s, 3H), 1.45 (d, 3H).

Example 40

(2S)-3-[1-({5-[1-(Carbamoyloxy)ethyl]-1-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl}methyl)-3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl Carbamate (Diastereomeric Mixture)

[0734] ##STR00127##

[0735] For reaction conditions see Example 39.

[0736] LC-MS (Method 1): R.sub.t=0.88 min; MS [ESIpos]: m/z=625 (M+H).sup.+

Example 41

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-(2-methoxyphenyl)-1H-1,2,4-triazol-5-yl]ethyl carbamate (Diastereomeric Mixture)

[0737] ##STR00128##

[0738] Under argon at −20° C., chlorosulfonyl isocyanate (10.3 μl, 118 μmol) was added dropwise to a solution of 5-(4-Chlorophenyl)-2-{[5-(1-hydroxyethyl)-1-(2-methoxyphenyl)-1H-1,2,4-triazol-5 3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (diastereomer 2) (Example 12 in WO 2016/071212 A1; 49 mg, 91 μmol) in dichloromethane (3.4 ml). After stirring at −20° C. for 3 days, chlorosulfonyl isocyanate (2 μl, 30 μmol) was added due to incomplete conversion. After stirring at −20° C. for 24 h, the reaction mixture was quenched, with aqueous hydrochloric acid (2 M, 4 ml), then stirred at 60° C. for 2 h and concentrated in vacuo. The crude product was purified by preparative HPLC (Method 6), affording 14 mg (52% of th.) of the title compound and 15 mg (56% of th.) of (2S)-3-[1-({5-[1-(carbamoyloxy)ethyl]-1-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl}methyl)-3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl carbamate (see Example 42).

[0739] LC-MS (Method 3): R.sub.t=2.83 min; MS [ESIpos]: m/z=582 (M+H).sup.+

[0740] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.74-7.78 (m, 2H), 7.61-7.65 (m, 2H), 7.53 (td, 1H), 7.32 (dd, 1H), 7.24 (dd, 1H), 7.08 (td, 1H), 6.90 (d, 1H), 6.27-6.70 (m, 2H), 5.42 (q, 1H), 5.06 (s, 2H), 4.25-4.35 (m, 1H), 4.00 (dd, 1H), 3.85 (dd, 1H), 3.76 (s, 3H), 1.45 (d, 3H).

Example 42

(2S)-3-[1-({5-[1-(Carbamoyloxy)ethyl]-1-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl}methyl)-3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl Carbamate (Diastereomeric Mixture)

[0741] ##STR00129##

[0742] For reaction conditions see Example 41.

[0743] LC-MS (Method 1): R.sub.t=0.91 min; MS [ESIpos]: m/z=625 (M+H).sup.+

[0744] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.66-7.72 (m, 2H), 7.59-7.64 (m, 2H), 7.53 (ddd, 1H), 7.31 (dd, 1H), 7.23 (dd, 1H), 7.07 (td, 1H), 7.05 (br. s., 1H), 6.90 (br. s., 1H), 6.27-6.69 (m, 2H), 5.33-5.46 (m, 2H), 5.04 (q, 2H), 4.23 (dd, 1H), 4.07 (dd, 1H), 3.75 (s, 3H), 1.45 (d, 3H).

Example 43

[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-fluorophenyl)-1H-1,2,4-triazol-5-yl]methyl Ethylcarbamate

[0745] ##STR00130##

[0746] Under argon at −20° C., ethyl isocyanate (6 μl, 76 μmol) was added dropwise to a solution of 5-(4-chlorophenyl)-2-{[1-(3-fluorophenyl)-5-(hydroxymethyl)-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 2 in WO 2016/071212 A1; 30 mg, 0.058 mmol) in dichloromethane (2.2 ml). The reaction mixture was, first, stirred at room temperature for 24 h, and then under reflux for 4 h. The resulting mixture was concentrated in vacuo and the crude product was purified by preparative HPLC (Method 6), affording 21.4 mg (59% of th.) of the title compound.

[0747] LC-MS (Method 5): R.sub.t=0.91 min; MS [ESIpos]: m/z=584 (M+H).sup.+

[0748] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.73-7.78 (m, 2H), 7.59-7.66 (m, 3H), 7.36-7.54 (m, 3H), 7.31 (t, 1H), 6.90 (d, 1H), 5.15 (s, 2H), 5.08 (s, 2H), 4.24-4.36 (m, 1H), 4.00 (dd, 1H), 3.85 (dd, 1H), 2.94 (quin, 2H), 0.95 (t, 3H).

Example 44

[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-fluorophenyl)-1H-1,2,4-triazol-5-yl]methyl (2-methoxyethyl)carbamate

[0749] ##STR00131##

[0750] Under argon at −20° C., 1-isocyanato-2-methoxyethane (12.8 mg, 127 μmol) was added dropwise to a solution of 5-(4-chlorophenyl)-2-{[1-(3-fluorophenyl)-5-(hydroxymethyl)-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 2 in WO 2016/071212 A1; 50 mg, 0.097 mmol) in dichloromethane (3.6 ml). The reaction mixture was, first, stirred at room temperature for 24 h, and then under reflux for 2 h. The resulting mixture was concentrated in vacuo and the crude product was purified by preparative HPLC (Method 6), affording 44.6 mg (70% of th.) of the title compound.

[0751] LC-MS (Method 3): R.sub.t=3.05 min; MS [ESIpos]: m/z=614 (M+H).sup.+

[0752] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.72-7.78 (m, 2H), 7.59-7.66 (m, 3H), 7.37-7.54 (m, 4H), 6.91 (d, 1H), 5.15 (s, 2H), 5.09 (s, 2H), 4.24-4.36 (m, 1H), 4.01 (dd, 1H), 3.85 (dd, 1H), 3.27 (t, 2H), 3.20 (s, 3H), 3.08 (q, 2H).

Example 45

[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-fluorophenyl)-1H-1,2,4-triazol-5-yl]methyl (2,2,2-trifluoroethyl)-carbamate

[0753] ##STR00132##

[0754] Under argon at room temperature, 2,2,2-trifluoroethylisocyanate (15.8 mg, 127 μmol) was added dropwise to a solution of 5-(4-chlorophenyl)-2-{[1-(3-fluorophenyl)-5-(hydroxymethyl)-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 2 in WO 2016/071212 A1; 50 mg, 0.097 mmol) in dichloroethane (2 ml). After stirring at room temperature, extra portion of 2,2,2-trifluoroethylisocyanate (12.1 mg, 97 μmol) was added portionwise and the reaction mixture was stirred at 150° C. under microwave irradiation for 3 h. The resulting mixture was concentrated in vacuo and the crude product was purified by preparative HPLC (Method 6) affording 38 mg (61% of th.) of the title compound.

[0755] LC-MS (Method 3): R.sub.t=3.37 min; MS [ESIpos]: m/z=638 (M+H).sup.+

[0756] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.17 (t, 1H), 7.75 (d, 2H), 7.58-7.66 (m, 3H), 7.38-7.53 (m, 3H), 6.90 (br. s., 1H), 5.23 (s, 2H), 5.09 (s, 2H), 4.24-4.37 (m, 1H), 4.01 (dd, 1H), 3.85 (dd, 1H), 3.75 (m, 2H).

Example 46

[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-fluorophenyl)-1H-1,2,4-triazol-5-yl]methyl Methylcarbamate

[0757] ##STR00133##

[0758] To a solution of [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-fluorophenyl)-1H-1,2,4-triazol-5-yl]methyl phenyl carbonate (Example 49A, 8.5 mg, 13.4 μmol) in THF (1 ml) was added a solution of methylamine in THF (6.7 μl, 13.4 μmol, 2M solution). The reaction mixture was stirred at 50° C. for 24 h and then concentrated in vacuo. The crude product was purified by preparative HPLC (Method 6) affording 2.1 mg (27.4% of th.) of the title compound.

[0759] LC-MS (Method 5): R.sub.t=1.26 min; MS [ESIpos]: m/z=570 (M+H).sup.+

[0760] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.75 (br. d, 2H), 7.58-7.67 (m, 3H), 7.36-7.55 (m, 3H), 7.18-7.23 (m, 1H), 6.90 (d, 1H), 5.15 (s, 2H), 5.09 (s, 2H), 4.23-4.38 (m, 1H), 4.01 (dd, 1H), 3.85 (dd, 1H).

Example 47

[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]methyl Ethylcarbamate

[0761] ##STR00134##

[0762] Under argon at −20° C., ethyl isocyanate (3.6 μl, 45 μmol) was added dropwise to a solution of 5-(4-chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(hydroxymethyl)-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 4 in WO 2016/071212 A1; 20 mg, 38 μmol) in dichloroethane (1.5 ml). The reaction mixture was stirred at 60° C. for 24 h. The resulting mixture was concentrated in vacuo and the crude product was purified by preparative HPLC (Method 6), affording 15 mg (66% of th.) of the title compound.

[0763] LC-MS (Method 3): R.sub.t=3.19 min; MS [ESIpos]: m/z=600 (M+H).sup.+

[0764] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.70-7.78 (m, 3H), 7.59-7.65 (m, 4H), 7.54 (td, 1H), 7.18 (t, 1H), 6.91 (d, 1H), 5.09 (s, 2H), 4.96 (s, 2H), 4.29 (br. s., 1H), 4.01 (dd, 1H), 3.85 (dd, 1H), 2.89 (quin, 2H), 0.92 (t, 3H).

Example 48

[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]methyl (2-methoxyethyl)carbamate

[0765] ##STR00135##

[0766] Under argon at −20° C., 1-isocyanato-2-methoxyethane (5 mg, 49 μmol) was added dropwise to a solution of 5-(4-chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(hydroxymethyl)-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 4 in WO 2016/071212 A1; 20 mg, 38 μmol) in dichloroethane (1.5 ml). The reaction mixture was stirred at 60° C. for 24 h. The resulting mixture was concentrated in vacuo and the crude product was purified by preparative HPLC (Method 6), affording 19 mg (78% of th.) of the title compound.

[0767] LC-MS (Method 3): R.sub.t=3.08 min; MS [ESIpos]: m/z=630 (M+H).sup.+

[0768] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.70-7.80 (m, 3H), 7.59-7.66 (m, 4H), 7.54 (td, 1H), 7.26 (t, 1H), 6.91 (d, 1H), 5.09 (s, 2H), 4.96 (s, 2H), 4.30 (br. s., 1H), 4.01 (dd, 1H), 3.85 (dd, 1H), 3.24 (t, 2H), 3.19 (s, 3H), 3.02 (q, 2H).

Example 49

{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-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-5-yl}methyl ethylcarbamate

[0769] ##STR00136##

[0770] Under argon at −20° C., ethyl isocyanate (3.4 μl, 43 μmol) was added dropwise to a solution of 5-(4-chlorophenyl)-2-({5-(hydroxymethyl)-1-[2-(trifluoromethyl)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 8 in WO 2016/071212 A1; 20 mg, 35.5 μmol) in dichloroethane (1.5 ml). The reaction mixture was stirred at 60° C. for 24 h. The resulting mixture was concentrated in vacuo and the crude product was purified by preparative HPLC (Method 6), affording 14 mg (60% of th.) of the title compound and 8 mg (30.4% of th.) of (2S)-3-{3-(4-chlorophenyl)-1-[(5-{[ethylcarbamoyl)oxy]methyl}-1-[2-(trifluoro-methyl)phenyl]-1H-1,2,4-triazol-3-yl)methyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl}-1,1,1-trifluoropropan-2-yl ethylcarbamate (see Example 50).

[0771] LC-MS (Method 3): R.sub.t=3.35 min; MS [ESIpos]: m/z=634 (M+H).sup.+

[0772] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.98 (d, 1H), 7.80-7.91 (m, 2H), 7.73-7.78 (m, 2H), 7.70 (d, 1H), 7.60-7.66 (m, 2H), 7.17 (t, 1H), 6.90 (d, 1H), 5.02-5.13 (m, 2H), 4.96 (s, 2H), 4.24-4.35 (m, 1H), 4.00 (dd, 1H), 3.85 (dd, 1H), 2.88 (quin, 2H), 0.92 (t, 3H).

Example 50

(2S)-3-{3-(4-Chlorophenyl)-1-[(5-{[(ethylcarbamoyl)oxy]methyl}-1-[2-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl)methyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl}-1,1,1-trifluoropropan-2-yl ethylcarbamate

[0773] ##STR00137##

[0774] For reaction conditions see Example 49.

[0775] LC-MS (Method 3): R.sub.t=3.52 min; MS [ESIpos]: m/z=705 (M+H).sup.+

[0776] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.95-8.00 (m, 1H), 7.79-7.91 (m, 2H), 7.58-7.72 (m, 5H), 7.48 (t, 1H), 7.17 (t, 1H), 5.30-5.42 (m, 1H), 5.06 (q, 2H), 4.94 (s, 2H), 4.25 (dd, 1H), 4.11 (dd, 1H), 2.81-2.94 (m, 4H), 0.87-0.98 (m, 6H).

Example 51

{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-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-5-yl}methyl (2-methoxyethyl)-carbamate

[0777] ##STR00138##

[0778] Under argon at −20° C., 1-isocyanato-2-methoxyethane (2.3 mg, 23 μmol) was added dropwise to a solution of 5-(4-chlorophenyl)-2-({5-(hydroxymethyl)-1-[2-(trifluoromethyl)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 8 in WO 2016/071212 A1; 10 mg, 18 μmol) in dichloroethane (0.65 ml). The reaction mixture was stirred at 7° C. for 3 days. The resulting mixture was concentrated in vacuo and the crude product was purified by preparative HPLC (Method 6) affording 4.8 mg (39% of th.) of the title compound.

[0779] LC-MS (Method 3): R.sub.t=3.19 min; MS [ESIpos]: m/z=664 (M+H).sup.+

[0780] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.98 (br. d, 1H), 7.80-7.92 (m, 2H), 7.73-7.78 (m, 2H), 7.70 (d, 1H), 7.60-7.67 (m, 2H), 7.25 (t, 1H), 6.90 (d, 1H), 5.03-5.13 (m, 2H), 4.96 (s, 2H), 4.24-4.35 (m, 1H), 4.00 (dd, 1H), 3.85 (dd, 1H), 3.23 (t, 2H), 3.19 (s, 3H), 3.02 (q, 2H).

Example 52

{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-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-5-yl}methyl Carbamate

[0781] ##STR00139##

[0782] Under argon at −20° C., chlorosulfonyl isocyanate (6.5 μl, 75 μmol) was added dropwise to a solution of 5-(4-chlorophenyl)-2-({5-(hydroxymethyl)-1-[2-(trifluoromethyl)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 8 in WO 2016/071212 A1; 30 mg, 53 μmol) in acetonitrile (2 ml). The reaction mixture was stirred at −20° C. overnight, then at 7° C. for 3 days. The reaction mixture was quenched with aqueous hydrochloric acid (2 M, 1.5 ml). The resulting mixture was stirred at 60° C. for 1 h and then concentrated in vacuo. The crude product was first purified by preparative HPLC (Chromatorex C18, 10 μm, 125×30 mm, water-acetonitrile-gradient 0.05% trifluoroacetic acid). A second purification by preparative chiral HPLC [sample preparation: 12 mg dissolved in 2 ml isopropanol; injection volume: 1 ml; column: Daicel Chiralcel® OX-H 5 μm, 250×20 mm; eluent: isohexane/isopropanol 50:50; flow rate: 15 ml/min; temperature: 25° C.; UV detection: 220 nm] afforded 3 mg (9.2% of th.) of the title compound.

[0783] LC-MS (Method 5): R.sub.t=1.23 min; MS [ESIpos]: m/z=606 (M+H).sup.+

[0784] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.99 (d, 1H), 7.80-7.92 (m, 2H), 7.67-7.79 (m, 3H), 7.63 (br. d, 2H), 6.92 (br. s., 1H), 6.60 (br. s., 2H), 5.02-5.14 (m, 2H), 4.90 (s, 2H), 4.30 (br. s., 1H), 4.00 (dd, 1H), 3.85 (dd, 1H).

Example 53

2-({5-[1-Aminoethyl]-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 trifluoroacetate (Diastereomeric Mixture)

[0785] ##STR00140##

[0786] To a solution of 2-{[5-acetyl-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 (30 mg, 0.057 mmol, Example 50A) in ethanol absolute (1 ml) were added ammonium acetate (66.1 mg, 0.857 mmol) and sodium cyanoborohydride (14.37 mg, 0.229 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature followed by 10 min at 100° C. under microwave irradiation. After cooling, the reaction mixture was concentrated in vacuo, then diluted with ethyl acetate and quenched with aqueous sodium carbonate. 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 purified by preparative HPLC (Method 6) affording 10 mg (0.02 mmol, 27.3% of th.) of the title compound.

[0787] LC-MS (Method 1): R.sub.t=0.75 min; MS (ESIpos): m/z=526 [M+H-TFA].sup.+

[0788] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.54 (br s, 3H), 7.59-7.79 (m, 5H), 7.41-7.57 (m, 3H), 6.89 (br d, 1H), 5.08-5.21 (m, 2H), 4.58-4.71 (m, 1H), 4.21-4.35 (m, 1H), 4.01 (br dd, 1H), 3.88 (br dd, 1H), 1.45 (d, 3H).

Example 54

2-({5-[1-Aminoethyl]-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 (Diastereomer 1)

[0789] ##STR00141##

[0790] The diastereomeric mixture of 2-({5-[1-aminoethyl]-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 trifluoroacetate (21.50 mg, 0.04 mmol, Example 53) was separated by preparative chiral HPLC [sample preparation: 21.5 mg dissolved in 1 ml ethanol+1 drop of diethylamine; injection volume: 1 ml; column: Daicel Chiralcel® OX-H 5 μm, 250×20 mm; eluent: isohexane/ethanol 50:50+0.2% diethylamine; flow rate: 15 ml/min; temperature: 35° C.; UV detection: 220 nm]. After phase separation, 8 mg of diastereomer 1, which eluted first, were isolated and 8 mg of diastereomer 2 (see Example 55).

[0791] Analytical chiral HPLC: R.sub.t=6.44 min, d.e.=100% [column: 250×4.6 mm filled with Daicel Chiralcel® OX-H 5 μm; eluent: isohexane/ethanol 50%:50%+0.2% diethylamine; flow rate: 1 ml/min; temperature: 40° C.; UV detection: 220 nm

[0792] .sup.1H-NMR (500 MHz, DMSO-d6) δ[ppm]: 7.73-7.78 (m, 2H), 7.58-7.65 (m, 4H), 7.47-7.51 (m, 1H), 7.39 (td, 1H), 6.92 (d, 1H), 5.01-5.09 (m, 2H), 4.25-4.35 (m, 1H), 4.05 (q, 1H), 4.00 (dd, 1H), 3.85 (dd, 1H), 1.33 (d, 3H).

Example 55

2-({5-[1-Aminoethyl]-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 (Diastereomer 2)

[0793] ##STR00142##

[0794] For separation conditions see Example 54.

[0795] Analytical chiral HPLC: R.sub.t=9.76 min, d.e.=99% [column: 250×4.6 mm filled with Daicel Chiralcel® OX-H 5 am; eluent: isohexane/ethanol 50%:50%+0.2% diethylamine; flow rate: 1 ml/min; temperature: 40° C.; UV detection: 220 nm

[0796] .sup.1H-NMR (500 MHz, DMSO-d6) δ[ppm]: 7.72-7.78 (m, 2H), 7.58-7.65 (m, 4H), 7.49 (dd, 1H), 7.39 (td, 1H), 6.92 (d, 1H), 5.05 (s, 2H), 4.26-4.35 (m, 1H), 3.97-4.07 (m, 2H), 3.85 (dd, 1H), 1.33 (d, 3H).

Example 56

tert-Butyl {(1S)-1-[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]ethyl}Carbamate

[0797] ##STR00143##

[0798] A suspension of tert-butyl {(1S)-1-[5-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-4H-1,2,4-triazol-3-yl]ethyl}carbamate (Example 53A, 277 mg, 88% purity, 458 μmol) in pyridine (5.8 ml) was treated with (3-chlorophenyl)boronic acid (158 mg, 1.01 mmol) and copper acetate (183 mg, 1.01 mmol). The resulting mixture was stirred 3 days at room temperature. A suspension of (3-chlorophenyl)boronic acid (158 mg, 1.01 mmol) in pyridine (5.8 ml) was added and the resulting mixture was stirred 24 h at room temperature. The reaction was quenched with methyl tert-butylether and a hydrochloric acid solution (0.5 M). The organic phase was washed with a saturated solution of sodium hydrogenocarbonate, dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC (Method 4). The residue was purified by preparative chiral HPLC [sample preparation: 145 mg dissolved in 2 ml ethanol+2 ml iso-hexane; injection volume: 400 al; column: Daicel Chiralcel® OX-H 5 μm, 250×20 mm; eluent: isohexane/ethanol 60:40; flow rate: 15 ml/min; temperature: 25° C.; UV detection: 220 nm] affording 60.0 mg (20% of th.) of the title compound.

[0799] LC-MS (Method 1): R.sub.t=1.23 min; MS (ESIpos): m/z=642.2 [M+H].sup.+

[0800] .sup.1H-NMR (500 MHz, DMSO-d6) δ[ppm]: 7.77-7.72 (m, 2H), 7.67-7.34 (m, 7H), 6.88 (d, 1H), 5.16-4.99 (m, 2H), 4.91-4.78 (br m, 1H), 4.38-4.20 (br m, 1H), 4.06-3.75 (m, 2H), 1.36 (br d, 3H), 1.25 (s, 9H).

Example 57

2-({5-[(1S)-1-Aminoethyl]-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 hydrochloride

[0801] ##STR00144##

[0802] A solution of tert-butyl (1S)-1-[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]ethyl carbamate (Example 56, 54.0 mg, 84.1 μmol) in dichloromethane was treated with a hydrochloric acid solution in dioxane (100 μl, 4M). The resulting mixture was stirred 3 days at room temperature and evaporated affording 47.0 mg (94% of th.) of the title compound.

[0803] LC-MS (Method 1): R.sub.t=0.80 min; MS (ESIpos): m/z=542.0 [M+H].sup.+

[0804] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.71-8.43 (m, 3H), 7.83-7.48 (m, 7H), 6.90 (d, 1H), 5.23-5.04 (m, 2H), 4.59 (q, 1H), 4.43-4.16 (br m, 1H), 4.10-3.74 (m, 2H), 1.46 (d, 3H).

Example 58

Methyl {(1S)-1-[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]ethyl}Carbamate

[0805] ##STR00145##

[0806] A solution of 2-({5-[(1S)-1-aminoethyl]-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 hydrochloride (Example 57, 45.0 mg, 77.7 μmol) in a methanol (800 μl)/water (0.40 μl) mixture was treated with N,N-diisopropylethylamine (14 μl, 78 μmol) and stirred 5 min at room temperature. 1-[(Methoxycarbonyl)oxy]pyrrolidine-2,5-dione (13.7 mg, 79.3 μmol) was added and the resulting suspension was stirred 10 min at room temperature. Methanol (0.4 al) was added and the resulting solution was stirred 45 min at room temperature. Purification by preparative HPLC (Method 4) afforded 32.0 mg (69% of th.) of the title compound.

[0807] LC-MS (Method 1): R.sub.t=1.06 min; MS (ESIpos): m/z=600.1 [M+H].sup.+

[0808] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.89-7.46 (m, 9H), 6.89 (br d, 1H), 5.15-4.99 (m, 2H), 4.83 (quin, 1H), 4.29 (br s, 1H), 4.07-3.78 (m, 2H, overlap with HDO peak), 3.41 (s, 3H), 1.39 (br d, 3H).

Example 59

2-({5-[1-Aminoethyl]-1-(2-methylphenyl)-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 trifluoroacetate (Diastereomeric Mixture)

[0809] ##STR00146##

[0810] A solution of 2-{[5-acetyl-1-(2-methylphenyl)-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 (20 mg, 0.038 mmol, Example 54A) and ammonium acetate (44.4 mg, 0.576 mmol) in ethanol absolute (0.7 ml) were stirred for 2 h at 70° C. After cooling the reaction mixture to 0° C., sodium cyanoborohydride (9.7 mg, 0.154 mmol) was added. The reaction mixture was stirred for 4 h at 0° C., after which extra portion of sodium cyanoborohydride was added due to incomplete conversion. After stirring overnight at 7° C., the reaction mixture was quenched with aqueous sodium hydroxide (1M), and then concentrated in vacuo. The crude product was purified by preparative HPLC (Method 6) affording 4.4 mg (0.01 mmol, 90% purity, 24.4% of th.) of the title compound.

[0811] LC-MS (Method 3): R.sub.t=2.15 min; MS (ESIpos): m/z=522 [M+H-TFA].sup.+

[0812] .sup.1H-NMR (500 MHz, DMSO-d6) δ[ppm]: 8.57 (br s, 3H), 7.70-7.78 (m, 2H), 7.59-7.67 (m, 2H), 7.38-7.57 (m, 4H), 6.88 (d, 1H), 5.08-5.21 (m, 2H), 4.23-4.36 (m, 2H), 4.00 (dd, 1H), 3.87 (dd, 1H), 2.02 (s, 3H), 1.34 (br d, 3H)

Example 60

2-({5-[1-Aminoethyl]-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 trifluoroacetate (Diastereomeric Mixture)

[0813] ##STR00147##

[0814] A solution of 2-{[5-acetyl-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 (60 mg, 0.111 mmol, Example 55A) and ammonium acetate (128.2 mg, 1.66 mmol) in ethanol absolute (2 ml) were stirred overnight at room temperature. After cooling the reaction mixture to 0° C., sodium cyanoborohydride (27.9 mg, 0.44 mmol) was added. The reaction mixture was stirred for 4 h at 0° C., after which extra portion of sodium cyanoborohydride was added due to incomplete conversion. The reaction mixture was further stirred at 7° C. for 3 days. Over this time, an additional portion of sodium cyanoborohydride was added. After this the reaction mixture was concentrated in vacuo, then diluted with ethyl acetate and quenched with aqueous sodium carbonate. 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 purified by preparative HPLC (Method 6) affording 21 mg (0.03 mmol, 28.6% of th.) of the title compound.

[0815] LC-MS (Method 3): R.sub.t=2.20 min; MS (ESIpos): m/z=542 [M+H-TFA].sup.+

[0816] .sup.1H-NMR (500 MHz, DMSO-d6) δ[ppm]: 8.59 (br s, 3H), 7.80 (dd, 1H), 7.72-7.77 (m, 2H), 7.67-7.72 (m, 2H), 7.59-7.66 (m, 3H), 6.88 (d, 1H), 5.10-5.21 (m, 2H), 4.22-4.39 (m, 2H), 4.01 (dd, 1H), 3.88 (dd, 1H), 1.36 (d, 3H)

[0817] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 19 mg dissolved in 1 ml ethanol; injection volume: 1 ml; column: Daicel Chiralcel® OX-H 5 μm, 250×20 mm; eluent: isohexane/ethanol 50:50+0.2% diethylamine; flow rate: 15 ml/min; temperature: 35° C.; UV detection: 220 nm]. After phase separation, 12 mg of diastereomer 1 (Example 61), which eluted first, and 7 mg of diastereomer 2 (Example 62), which eluted later, were isolated.

Example 61

2-({5-[1-Aminoethyl]-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)

[0818] ##STR00148##

[0819] For separation conditions see Example 60.

[0820] Analytical chiral HPLC: R.sub.t=7.53 min, d.e.=100% [column: 250×4.6 mm filled with Daicel Chiralcel® OX-H 5 μm; eluent: isohexane/ethanol 50:50+0.2% diethylamine; flow rate: 1 ml/min; temperature: 40° C.; UV detection: 220 nm]

[0821] .sup.1H-NMR (500 MHz, DMSO-d6) δ[ppm]: 8.51 (br s, 3H), 7.80 (d, 1H), 7.74 (d, 2H), 7.67-7.72 (m, 2H), 7.59-7.66 (m, 3H), 6.89 (d, 1H), 5.11-5.20 (m, 2H), 4.23-4.36 (m, 2H), 4.01 (dd, 1H), 3.87 (dd, 1H), 1.36 (d, 3H)

Example 62

2-({5-[1-Aminoethyl]-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)

[0822] ##STR00149##

[0823] For separation conditions see Example 60.

[0824] Analytical chiral HPLC: R.sub.t=12.14 min, d.e.=99% [column: 250×4.6 mm filled with Daicel Chiralcel® OX-H 5 μm; eluent: isohexane/ethanol 50:50+0.2% diethylamine; flow rate: 1 ml/min; temperature: 40° C.; UV detection: 220 nm]

[0825] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.66-7.78 (m, 4H), 7.59-7.65 (m, 3H), 7.55 (td, 1H), 6.92 (d, 1H), 5.06 (s, 2H), 4.24-4.36 (m, 1H), 4.00 (dd, 1H), 3.85 (dd, 1H), 3.68-3.78 (m, 1H), 1.25 (br d, 3H)

Example 63

2-{[5-(1-Aminoethyl)-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)

[0826] ##STR00150##

[0827] A solution of 2-{(1R)-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]ethyl}-1H-isoindole-1,3(2H)-dione (Example 73A, 315 mg, 468 μmol) in ethanol (9.7 ml) was treated with a methylamine solution in ethanol (820 μl, 33% purity, 9.4 mmol). The resulting mixture was stirred 3 h at 70° C. under microwave irradiation. The reaction mixture was evaporated and the residue purified by preparative HPLC (Method 4) affording 216.8 mg (85% of th.) of the title compound.

[0828] LC-MS (Method 1): R.sub.t=0.73 min; MS (ESIpos): m/z=542 [M+H].sup.+

[0829] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.86-7.43 (m, 8H), 6.93 (br d, 1H), 5.06 (s, 2H), 4.45-4.18 (m, 1H), 4.12-3.62 (m, 3H), 2.02-1.75 (m, 2H), 1.24 (d, 3H).

Example 64

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]ethyl}acetamide (Diastereomeric Mixture)

[0830] ##STR00151##

[0831] Under Argon and at 0° C., a solution of 2-({5-[(1R)-1-aminoethyl]-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 63, 42.0 mg, 77.4 μmol) in dichloromethane (3.0 ml) was treated with pyridine (63 μl, 770 μmol) and acetyl chloride (6.1 μl, 85 μmol). The resulting mixture was stirred 30 min at 0° C. and evaporated. The residue was purified by preparative HPLC (Method 4) affording 30 mg (66 of th.) of the title compound.

[0832] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 30 mg dissolved in 3 ml ethanol; injection volume: 250 μl; column: Daicel Chiralpak IA 5 μm, 250×20 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 20 ml/min; temperature: 25° C.; UV detection: 220 nm]. After separation, 11.5 mg of diastereomer 1 (Example 65), which eluted first, and 10.3 mg of diastereomer 2 (Example 66), which eluted later, were isolated.

[0833] LC-MS (Method 1): R.sub.t=0.91 min; MS (ESIpos): m/z=584 [M+H].sup.+

[0834] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.38 (br d, 1H), 7.85-7.42 (m, 8H), 6.89 (d, 1H), 5.22-4.61 (m, 3H), 4.44-4.19 (m, 1H), 4.07-3.74 (m, 2H), 1.61 (s, 3H), 1.36 (d, 3H).

Example 65

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]ethyl}acetamide (diastereomer 1)

[0835] For separation conditions see Example 64.

[0836] Analytical chiral HPLC: R.sub.t=1.23 min, e.e.=100% [column: Daicel Chiralpak IA-3 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 1.0 ml/min; temperature: 23° C.; UV detection: 220 nm].

[0837] LC-MS (Method 2): R.sub.t=1.69 min; MS (ESIpos): m/z=584 [M+H].sup.+

[0838] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.47-8.28 (m, 1H), 7.80-7.46 (m, 8H), 6.91-6.84 (m, 1H), 5.17-4.98 (m, 2H), 4.92-4.67 (m, 1H), 4.39-4.17 (m, 1H), 4.10-3.77 (m, 2H), 1.61 (s, 3H), 1.36 (d, 3H).

Example 66

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]ethyl}acetamide (diastereomer 2)

[0839] For separation conditions see Example 64.

[0840] Analytical chiral HPLC: R.sub.t=1.58 min, e.e.=99.2% [column: Daicel Chiralpak IA-3 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 1.0 ml/min; temperature: 23° C.; UV detection: 220 nm].

[0841] LC-MS (Method 2): R.sub.t=1.69 min; MS (ESIpos): m/z=584 [M+H].sup.+

[0842] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.48-8.26 (m, 1H), 7.84-7.43 (m, 8H), 6.89 (d, 1H), 5.19-4.95 (m, 2H), 4.93-4.67 (m, 1H), 4.41-4.20 (m, 1H), 4.09-3.71 (m, 2H), 1.61 (s, 3H), 1.36 (d, 3H).

Example 67

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]ethyl}methanesulfonamide (Diastereomeric Mixture)

[0843] ##STR00152##

[0844] Under Argon and at 0° C., a solution of 2-({5-[(1R)-1-aminoethyl]-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 63, 42.0 mg, 77.4 μmol) in dichloromethane (3.0 ml) was treated with pyridine (63 μl, 770 μmol) and methanesulfonyl chloride (6.6 μl, 85 μmol). The resulting mixture was stirred 30 min at 0° C. and overnight at room temperature. The reaction mixture was evaporated and the residue was purified by preparative HPLC (Method 4) affording 23 mg (47 of th.) of the title compound.

[0845] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 20 mg dissolved in 2 ml ethanol+1 ml isopropanol; injection volume: 100 μl; column: Daicel Chiralpak IE 5 μm, 250×20 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 20 ml/min; temperature: 23° C.; UV detection: 220 nm]. After separation, 8.2 mg of diastereomer 1 (Example 68), which eluted first, and 5.7 mg of diastereomer 2 (Example 69), which eluted later, were isolated.

[0846] LC-MS (Method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=620 [M+H].sup.+

[0847] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.93-7.47 (m, 9H), 6.89 (d, 1H), 5.20-4.99 (m, 2H), 4.53-4.18 (m, 2H), 4.08-3.71 (m, 2H), 2.61 (s, 3H), 1.43 (d, 3H).

Example 68

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]ethyl}methanesulfonamide (diastereomer 1)

[0848] For separation conditions see Example 67.

[0849] Analytical chiral HPLC: R.sub.t=1.59 min, e.e.=100% [column: Daicel Chiralpak ID-3 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 1.0 ml/min; temperature: 30° C.; UV detection: 220 nm].

[0850] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.95-7.46 (m, 9H), 6.89 (d, 1H), 5.09 (s, 2H), 4.52-4.15 (m, 2H), 4.09-3.74 (m, 2H), 2.61 (s, 3H), 1.43 (d, 3H).

Example 69

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]ethyl}methanesulfonamide (Diastereomer 2)

[0851] For separation conditions see Example 67.

[0852] Analytical chiral HPLC: R.sub.t=1.91 min, e.e.=95.6% [column: Daicel Chiralpak ID-3 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 1.0 ml/min; temperature: 30° C.; UV detection: 220 nm].

[0853] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.93-7.45 (m, 9H), 6.89 (d, 1H), 5.09 (q, 2H), 4.52-4.18 (m, 2H), 4.09-3.76 (m, 2H), 2.61 (s, 3H), 1.43 (d, 3H).

Example 70

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(1-methyl-5-oxopyrrolidin-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 (Diastereomeric Mixture)

[0854] ##STR00153##

[0855] Under Argon, 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 2A, 390 mg, 1.03 mmol) in tetrahydrofuran (9.8 ml) was treated with N,N-diisopropylethylamine (720 μl, 4.1 mmol) and 1-methyl-5-oxo-prolyl chloride (183 mg, 1.13 mmol). The resulting mixture was stirred 30 min at room temperature. (2-Chlorophenyl)hydrazine hydrochloride (1:1) (203 mg, 1.13 mmol) was added and stirred 2 h at room temperature followed by 1 h at 130° C. under microwave irradiation. The reaction mixture was evaporated and the residue purified by preparative HPLC (Method 4) affording 186 mg (28% of th.) of the title compound.

[0856] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 180 mg dissolved in 25 ml ethanol/acetonitrile; injection volume: 1.5 ml; column: Daicel Chiralcel OX-H 5 μm SFC, 250×30 mm; eluent: carbon dioxide/methanol 70:30; flow rate: 100 ml/min; temperature: 40° C.; UV detection: 210 nm]. After separation, 69.9 mg of diastereomer 1 (Example 71), which eluted first, and 68.7 mg of diastereomer 2 (Example 72), which eluted later, were isolated.

[0857] LC-MS (Method 1): R.sub.t=0.93 min; MS (ESIpos): m/z=596 [M+H].sup.+

[0858] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.84-7.55 (m, 8H), 6.88 (dd, 1H), 5.26-4.98 (m, 2H), 4.60-4.45 (m, 1H), 4.39-4.19 (m, 1H), 4.04-3.74 (m, 2H), 2.53 (s, 3H, overlap with DMSO peak), 2.41-1.88 (m, 4H).

Example 71

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(1-methyl-5-oxopyrrolidin-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 (Diastereomer 1)

[0859] For separation conditions see Example 70.

[0860] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 54 mg of the title compound.

[0861] Analytical chiral HPLC: R.sub.t=3.71 min, e.e.=100% [column: Daicel Chiralcel OX SFC 3.5 μm, 100×4.6 mm; eluent: carbon dioxide/ethanol 70:30; flow rate: 3.0 ml/min; temperature: 40° C.; UV detection: 210 nm].

[0862] LC-MS (Method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=596 [M+H].sup.+

[0863] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.83-7.50 (m, 8H), 6.88 (d, 1H), 5.20-4.99 (m, 2H), 4.58-4.48 (m, 1H), 4.37-4.22 (m, 1H), 4.05-3.77 (m, 2H), 2.53 (s, 3H, overlap with DMSO peak), 2.36-1.89 (m, 4H).

Example 72

5-(4-Chlorophenyl)-2-{[1-(2-chlorophenyl)-5-(1-methyl-5-oxopyrrolidin-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 (diastereomer 2)

[0864] For separation conditions see Example 70.

[0865] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 55 mg of the title compound.

[0866] Analytical chiral HPLC: R.sub.t=4.52 min, e.e.=100% [column: Daicel Chiralcel OX SFC 3.5 μm, 100×4.6 mm; eluent: carbon dioxide/ethanol 70:30; flow rate: 3.0 ml/min; temperature: 40° C.; UV detection: 210 nm].

[0867] LC-MS (Method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=596 [M+H].sup.+

[0868] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.86-7.51 (m, 8H), 6.87 (d, 1H), 5.11 (s, 2H), 4.58-4.48 (m, 1H), 4.37-4.21 (m, 1H), 4.05-3.75 (m, 2H), 2.53 (s, 3H, overlap with DMSO peak), 2.37-1.88 (m, 4H).

Example 73

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]ethyl}-2,2,2-trifluoroacetamide (Diastereomeric Mixture)

[0869] ##STR00154##

[0870] Under argon, a solution of 2-({5-[(1R)-1-aminoethyl]-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 63, 42.0 mg, 77.4 μmol) in dichloromethane (3.0 ml) was treated with triethylamine (13 μl, 93 μmol) and trifluoroacetic anhydride (12 μl, 85 μmol) and stirred 1 h at room temperature. Trifluoroacetic anhydride (5 μl, 38 μmol) and triethylamine (6 μl, 38 μmol) were added and the resulting mixture was stirred 30 min at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 34 mg (68% of th.) of the title compound.

[0871] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 31 mg dissolved in 4 ml ethanol; injection volume: 250 μl; column: Daicel Chiralpak IA 5 μm, 250×20 mm; eluent: iso-hexane/ethanol 90:10; flow rate: 20 ml/min; temperature: 23° C.; UV detection: 220 nm]. After separation, diastereomer 1 (Example 74), which eluted first, and diastereomer 2 (Example 75), which eluted later, were isolated.

[0872] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=638 [M+H].sup.+

[0873] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 10.04-9.92 (m, 1H), 7.83-7.46 (m, 8H), 6.89 (d, 1H), 5.25-4.82 (m, 3H), 4.41-4.15 (m, 1H), 4.11-3.70 (m, 2H), 1.50 (d, 3H).

Example 74

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]ethyl}-2,2,2-trifluoroacetamide (diastereomer 1)

[0874] For separation conditions see Example 73.

[0875] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 13 mg of the title compound.

[0876] Analytical chiral HPLC: R.sub.t=1.50 min, e.e.=100% [column: Daicel Chiralpak IA-3 3 μm, 50×4.6 mm; eluent: isohexane/ethanol 90:10; flow rate: 1.0 ml/min; temperature: 23° C.; UV detection: 220 nm].

[0877] LC-MS (Method 2): R.sub.t=1.98 min; MS (ESIpos): m/z=638 [M+H].sup.+

[0878] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 10.05-9.96 (m, 1H), 7.84-7.38 (m, 8H), 6.89 (d, 1H), 5.10 (d, 3H), 4.40-4.18 (m, 1H), 4.08-3.74 (m, 2H), 1.50 (d, 3H).

Example 75

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]ethyl}-2,2,2-trifluoroacetamide (diastereomer 2)

[0879] For separation conditions see Example 73.

[0880] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 13 mg of the title compound.

[0881] Analytical chiral HPLC: R.sub.t=1.77 min, e.e.=100% [column: Daicel Chiralpak IA-3 3 μm, 50×4.6 mm; eluent: isohexane/ethanol 90:10; flow rate: 1.0 ml/min; temperature: 23° C.; UV detection: 220 nm].

[0882] LC-MS (Method 2): R.sub.t=1.98 min; MS (ESIpos): m/z=638 [M+H].sup.+

[0883] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 10.07-9.89 (m, 1H), 7.87-7.38 (m, 8H), 6.89 (d, 1H), 5.24-4.78 (m, 3H), 4.45-4.16 (m, 1H), 4.08-3.71 (m, 2H), 1.50 (d, 3H).

Example 76

2-{[5-(1-Aminocyclopropyl)-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 hydrochloride

[0884] ##STR00155##

[0885] A solution of 2-{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]cyclopropyl}-1H-isoindole-1,3(2H)-dione (Example 66A, 1.69 g, 83% purity, 2.05 mmol) in ethanol (42 ml) was treated with a solution of methylamine in ethanol (3.6 ml, 33% purity, 41 mmol). The resulting mixture was stirred 72 h at 70° C. and evaporated. The crude material was purified by preparative HPLC (Method 4). The residue was retaken in an aqueous hydrogen chloride solution (10 ml, 10 M) and evaporated affording 1.19 g (88% of th.) of the title compound.

[0886] LC-MS (Method 1): R.sub.t=0.80 min; MS (ESIpos): m/z=554 [M+H].sup.+

[0887] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 9.04 (br s, 3H), 7.89-7.52 (m, 8H), 6.91 (br d, 1H), 5.29-4.97 (m, 2H), 4.36-4.17 (m, 1H), 4.08-3.79 (m, 2H), 1.40-1.25 (m, 2H), 1.02-0.81 (m, 2H).

Example 77

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]cyclopropyl}acetamide

[0888] ##STR00156##

[0889] Under argon, a solution of 2-{[5-(1-aminocyclopropyl)-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 hydrochloride (Example 76, 200 mg, 339 μmol) in dichloromethane (13 ml) was treated with pyridine (270 μl, 3.4 mmol) and acetyl chloride (26 μl, 370 μmol). The resulting mixture was stirred 3 h at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 141 mg (66% of th.) of the title compound.

[0890] LC-MS (Method 1): R.sub.t=0.90 min; MS (ESIpos): m/z=596 [M+H].sup.+

[0891] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.06 (s, 1H), 7.81-7.45 (m, 7H), 7.36 (dd, 1H), 6.90 (d, 1H), 4.98 (s, 2H), 4.38-4.20 (m, 1H), 4.09-3.75 (m, 2H), 1.86-0.55 (m, 7H).

Example 78

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]cyclopropyl}methane sulfonamide

[0892] ##STR00157##

[0893] Under argon, a solution of 2-{[5-(1-aminocyclopropyl)-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 hydrochloride (Example 76, 200 mg, 339 μmol) in dichloromethane (13 ml) was treated with pyridine (270 μl, 3.4 mmol) and methanesulfonyl chloride (29 μl, 370 μmol). The resulting mixture was stirred 24 h at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 117 mg (54% of th.) of the title compound.

[0894] LC-MS (Method 1): R.sub.t=0.94 min; MS (ESIpos): m/z=632 [M+H].sup.+

[0895] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.82-7.42 (m, 9H), 6.89 (d, 1H), 5.13-4.90 (m, 2H), 4.40-4.19 (m, 1H), 4.06-3.72 (m, 2H), 2.72 (s, 3H), 1.60-1.15 (m, 4H).

Example 79

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[1-(dimethylamino)cyclopropyl]-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

[0896] ##STR00158##

[0897] A solution of 1-(dimethylamino)cyclopropanecarboxylic acid (150 mg, 1.16 mmol) in tetrahydrofuran (3.0 ml, 37 mmol) was treated with DCC (240 mg, 1.16 mmol) and HOBt (178 mg, 1.16 mmol) and stirred 30 min at room temperature. The solid was filtered off, rinsed with dichloromethane (5 ml) and the filtrate evaporated. The residue was retaken in 1,4-dioxane (4 ml), 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 2A; 400 mg, 1.06 mmol) and N,N-diisopropylethylamine (370 μl, 2.1 mmol) were added and the resulting mixture was stirred overnight at room temperature. (2-Chlorophenyl)hydrazine hydrochloride (1:1) (208 mg, 1.16 mmol) was added and the resulting mixture was stirred 2 h at room temperature and overnight at reflux temperature. The reaction mixture was evaporated and the residue purified by preparative HPLC (Method 4) followed by a preparative TLC affording 4.3 mg (0.7% of th.) of the title compound.

[0898] LC-MS (Method 2): R.sub.t=1.92 min; MS (ESIpos): m/z=582 [M+H].sup.+

[0899] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.90-7.39 (m, 8H), 6.87 (d, 1H), 5.16-4.93 (m, 2H), 4.38-4.19 (m, 1H), 4.11-3.69 (m, 2H), 2.06-1.84 (m, 6H), 1.06-0.82 (m, 4H).

Example 80

2-({5-[1-Amino-2-tert-butoxyethyl]-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)

[0900] ##STR00159##

[0901] A solution of 2-{(1R)-2-tert-butoxy-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]ethyl}-1H-isoindole-1,3(2H)-dione (Example 72A, 238 mg, 320 μmol) in ethanol was treated with a solution of methylamine in ethanol (560 μl, 33% purity, 6.4 mmol), stirred 4 h at 70° C. and evaporated. The residue was purified by preparative HPLC (Method 4) affording 500 mg (55% of th.) of the title compound.

[0902] LC-MS (Method 2): R.sub.t=1.47 min; MS (ESIpos): m/z=614 [M+H].sup.+

Example 81

2-({5-[1-Amino-2-hydroxyethyl]-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 hydrochloride (Diastereomeric Mixture)

[0903] ##STR00160##

[0904] 2-({5-[(1R)-1-Amino-2-tert-butoxyethyl]-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 80, 60.0 mg, 97.6 μmol) was treated with a solution of hydrogen chloride in dioxane (1.0 ml, 4.0 M, 4.0 mmol) and the resulting solution was stirred overnight at room temperature. A solution of hydrogen chloride in dioxane (1.0 ml) was added, the resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4). Addition of an aqueous solution of hydrogen chloride (3 ml) to the fractions containing products followed by evaporation afforded 49 mg (84% of th.) of the title compound.

[0905] LC-MS (Method 2): R.sub.t=1.15 min; MS (ESIpos): m/z=558 [M+H].sup.+

[0906] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.85-8.57 (m, 3H), 7.86-7.51 (m, 8H), 6.90 (d, 1H), 5.50 (t, 1H), 5.26-5.01 (m, 2H), 4.44-3.46 (m, 6H).

Example 82

N-{2-tert-Butoxy-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]ethyl}methanesulfonamide (Diastereomeric Mixture)

[0907] ##STR00161##

[0908] A solution of 2-({5-[(1R)-1-amino-2-tert-butoxyethyl]-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 80, 200 mg, 325 μmol) in dichloromethane (13 ml) was treated with pyridine (260 μl, 3.3 mmol) and methanesulfonyl chloride (28 μl, 360 μmol). The resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 163 mg (72% of th.) of the title compound.

[0909] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 54 mg dissolved in 4 ml warm ethanol; injection volume: 250 μl; column: Daicel Chiralpak ID 5 μm, 250×20 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 15 ml/min; temperature: 25° C.; UV detection: 210 nm]. After separation, 23.6 mg of diastereomer 1 (Example 83), which eluted first, and 24.5 mg of diastereomer 2 (Example 84), which eluted later, were isolated.

[0910] LC-MS (Method 1): R.sub.t=1.10 min; MS (ESIpos): m/z=692 [M+H].sup.+

[0911] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.05-7.95 (m, 1H), 7.79-7.49 (m, 8H), 6.89 (d, 1H), 5.19-5.00 (m, 2H), 4.37-4.21 (m, 2H), 4.06-3.79 (m, 2H), 3.68-3.50 (m, 2H), 2.73 (br s, 3H), 1.01 (s, 9H).

Example 83

N-{2-tert-Butoxy-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]ethyl}methanesulfonamide (Diastereomer 1)

[0912] For separation conditions see Example 82.

[0913] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 20 mg of the title compound.

[0914] Analytical chiral HPLC: R.sub.t=1.34 min, e.e.=98.5% [column: Daicel Chiralpak ID-3 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 1.0 ml/min; temperature: 30° C.; UV detection: 220 nm].

[0915] LC-MS (Method 2): R.sub.t=2.07 min; MS (ESIpos): m/z=692 [M+H].sup.+

[0916] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.00 (d, 1H), 7.79-7.50 (m, 8H), 6.88 (d, 1H), 5.17-5.01 (m, 2H), 4.36-4.23 (m, 2H), 4.06-3.78 (m, 2H), 3.67-3.53 (m, 2H), 2.73 (br s, 3H), 1.01 (s, 9H).

Example 84

N-{2-tert-Butoxy-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]ethyl}methanesulfonamide (diastereomer 2)

[0917] For separation conditions see Example 82.

[0918] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 21 mg of the title compound.

[0919] Analytical chiral HPLC: R.sub.t=1.69 min, e.e.=98.6% [column: Daicel Chiralpak ID-3 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 1.0 ml/min; temperature: 30° C.; UV detection: 220 nm].

[0920] LC-MS (Method 2): R.sub.t=2.08 min; MS (ESIpos): m/z=692 [M+H].sup.+

[0921] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.01 (d, 1H), 7.78-7.50 (m, 8H), 6.89 (d, 1H), 5.16-5.03 (m, 2H), 4.35-4.20 (m, 2H), 4.04-3.79 (m, 2H), 3.66-3.51 (m, 2H), 2.73 (br s, 3H), 1.01 (s, 10H).

Example 85

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]-2-hydroxyethyl}-methanesulfonamide (Diastereomeric Mixture)

[0922] ##STR00162##

[0923] N-{(1R)-2-tert-Butoxy-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]ethyl}methanesulfonamide (Example 82, 100 mg, 144 μmol) was treated with a solution of hydrogen chloride in dioxane (5.0 ml, 4.0 M, 20 mmol). The resulting solution was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 50 mg (53% of th.) of the title compound.

[0924] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 41 mg dissolved in 3 ml warm ethanol; injection volume: 150 μl; column: Daicel Chiralcel OZ-H 5 μm, 250×20 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 15 ml/min; temperature: 25° C.; UV detection: 210 nm]. After separation, 18.2 mg of diastereomer 1 (Example 86), which eluted first, and 23.1 mg of diastereomer 2 (Example 87), which eluted later, were isolated.

[0925] LC-MS (Method 1): R.sub.t=0.94 min; MS (ESIpos): m/z=636 [M+H].sup.+

[0926] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.03-7.42 (m, 9H), 6.90 (d, 1H), 5.29-4.93 (m, 3H), 4.41-4.20 (m, 2H), 4.13-3.53 (m, 4H), 2.70 (s, 3H).

Example 86

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]-2-hydroxyethyl}-methanesulfonamide (diastereomer 1)

[0927] For separation conditions see Example 85.

[0928] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 15 mg of the title compound.

[0929] Analytical chiral HPLC: R.sub.t=1.12 min, e.e.=98.3% [column: Daicel Chiralpak OZ-3 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 1.0 ml/min; temperature: 23° C.; UV detection: 220 nm].

[0930] LC-MS (Method 2): R.sub.t=1.66 min; MS (ESIpos): m/z=636 [M+H].sup.+

[0931] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.96-7.42 (m, 9H), 6.89 (d, 1H), 5.27-4.99 (m, 3H), 4.37-4.21 (m, 2H), 4.07-3.53 (m, 4H), 2.69 (s, 3H).

Example 87

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]-2-hydroxyethyl}-methanesulfonamide (Diastereomer 2)

[0932] For separation conditions see Example 85.

[0933] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 15 mg of the title compound.

[0934] Analytical chiral HPLC: R.sub.t=1.62 min, e.e.=99.0% [column: Daicel Chiralpak OZ-3 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 1.0 ml/min; temperature: 23° C.; UV detection: 220 nm].

[0935] LC-MS (Method 2): R.sub.t=1.65 min; MS (ESIpos): m/z=636 [M+H].sup.+

[0936] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.01-7.43 (m, 9H), 6.90 (d, 1H), 5.29-4.98 (m, 3H), 4.35-4.22 (m, 2H), 4.05-3.78 (m, 2H), 3.72-3.60 (m, 2H), 2.70 (s, 3H).

Example 88

N-{2-tert-Butoxy-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]ethyl}acetamide (Diastereomeric Mixture)

[0937] ##STR00163##

[0938] A solution of 2-({5-[(1R)-1-amino-2-tert-butoxyethyl]-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 80, 200 mg, 325 μmol) in dichloromethane (13 ml) was treated with pyridine (260 μl, 3.3 mmol) and acetyl chloride (25 μl, 360 μmol). The resulting mixture was stirred 3 h at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 190 mg (88% of th.) of the title compound.

[0939] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 84 mg dissolved in 2 ml ethanol+2 ml iso-hexane; injection volume: 450 μl; column: Daicel Chiralpak AS-H 5 μm, 250×20 mm; eluent: iso-hexane/ethanol 90:10; flow rate: 15 ml/min; temperature: 40° C.; UV detection: 220 nm]. After separation, 41 mg of diastereomer 1 (Example 89), which eluted first, and 31 mg of diastereomer 2 (Example 90), which eluted later, were isolated.

[0940] LC-MS (Method 1): R.sub.t=1.05 min; MS (ESIpos): m/z=656 [M+H].sup.+

[0941] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.44 (br d, 1H), 7.79-7.46 (m, 8H), 6.88 (d, 1H), 5.26-4.94 (m, 2H), 4.87-4.63 (m, 1H), 4.40-4.19 (m, 1H), 4.07-3.71 (m, 2H), 3.67-3.36 (m, 2H), 1.73 (s, 3H), 0.96 (s, 9H).

Example 89

N-{2-tert-Butoxy-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]ethyl}acetamide (Diastereomer 1)

[0942] For separation conditions see Example 88.

[0943] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 37 mg of the title compound.

[0944] Analytical chiral HPLC: R.sub.t=4.26 min, e.e.=100% [column: Daicel Chiralpak AS-H 5 μm, 250×4.6 mm; eluent: iso-hexane/ethanol 85:15+0.2% trifluoroacetic acid; flow rate: 1.0 ml/min; temperature: 30° C.; UV detection: 220 nm].

[0945] LC-MS (Method 2): R.sub.t=1.98 min; MS (ESIpos): m/z=656 [M+H].sup.+

[0946] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.44 (br d, 1H), 7.79-7.49 (m, 8H), 6.88 (d, 1H), 5.08 (s, 2H), 4.83-4.67 (m, 1H), 4.34-4.20 (m, 1H), 4.08-3.80 (m, 2H), 3.62-3.39 (m, 2H), 1.73 (s, 3H), 0.96 (s, 9H).

Example 90

N-{2-tert-Butoxy-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]ethyl}acetamide (Diastereomer 2)

[0947] For separation conditions see Example 88.

[0948] After diastereomeric separation, the obtained compound was purified by preparative HPLC (Method 4) affording 30 mg of the title compound.

[0949] Analytical chiral HPLC: R.sub.t=5.86 min, e.e.=100% [column: Daicel Chiralpak AS-H 5 μm, 250×4.6 mm; eluent: iso-hexane/ethanol 85:15+0.2% trifluoroacetic acid; flow rate: 1.0 ml/min; temperature: 30° C.; UV detection: 220 nm].

[0950] LC-MS (Method 2): R.sub.t=1.97 min; MS (ESIpos): m/z=656 [M+H].sup.+

[0951] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.44 (br d, 1H), 7.82-7.41 (m, 8H), 6.88 (d, 1H), 5.24-4.96 (m, 2H), 4.86-4.67 (m, 1H), 4.40-4.19 (m, 1H), 4.06-3.78 (m, 2H), 3.67-3.36 (m, 2H), 1.73 (s, 3H), 0.96 (s, 9H).

Example 91

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]-2-hydroxyethyl}acetamide (Diastereomeric Mixture)

[0952] ##STR00164##

[0953] N-{(1R)-2-tert-Butoxy-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]ethyl}acetamide (Example 88, 100 mg, 152 μmol) was treated with a solution of hydrogen chloride in dioxane (5.0 ml, 4.0 M, 20 mmol). The resulting solution was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 42 mg (45% of th.) of the title compound.

[0954] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 37 mg dissolved in 3 ml warm isopropanol; injection volume: 150 al; column: Daicel Chiralpak AY-H 5 μm, 250×20 mm; eluent: iso-hexane/iso-propanol 60:40; flow rate: 15 ml/min; temperature: 25° C.; UV detection: 210 nm]. After separation, 18.6 mg of diastereomer 1 (Example 92), which eluted first, and 15.8 mg of diastereomer 2 (Example 93), which eluted later, were isolated.

[0955] LC-MS (Method 1): R.sub.t=0.84 min; MS (ESIpos): m/z=600 [M+H].sup.+

[0956] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.32 (br d, 1H), 7.80-7.46 (m, 8H), 6.89 (d, 1H), 5.21-4.90 (m, 3H), 4.86-4.67 (m, 1H), 4.38-4.21 (m, 1H), 4.07-3.79 (m, 2H), 3.74-3.49 (m, 2H), 1.70 (s, 3H).

Example 92

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]-2-hydroxyethyl}acetamide (Diastereomer 1)

[0957] For separation conditions see Example 91.

[0958] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 15 mg of the title compound.

[0959] Analytical chiral HPLC: R.sub.t=0.696 min, e.e.=99.4% [column: Daicel Chiralpak AY-3 5 μm, 50×4.6 mm; eluent: iso-hexane/iso-propanol 50:50; flow rate: 1.0 ml/min; temperature: 23° C.; UV detection: 220 nm].

[0960] LC-MS (Method 2): R.sub.t=1.56 min; MS (ESIpos): m/z=600 [M+H].sup.+

[0961] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.32 (br d, 1H), 7.81-7.48 (m, 8H), 6.89 (d, 1H), 5.18-4.92 (m, 3H), 4.87-4.68 (m, 1H), 4.39-4.19 (m, 1H), 4.07-3.78 (m, 2H), 3.74-3.51 (m, 2H), 1.70 (s, 3H).

Example 93

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]-2-hydroxyethyl}acetamide (Diastereomer 2)

[0962] For separation conditions see Example 91.

[0963] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 13 mg of the title compound.

[0964] Analytical chiral HPLC: R.sub.t=0.949 min, e.e.=92.6% [column: Daicel Chiralpak AY-3 5 μm, 50×4.6 mm; eluent: iso-hexane/iso-propanol 50:50; flow rate: 1.0 ml/min; temperature: 23° C.; UV detection: 220 nm].

[0965] LC-MS (Method 1): R.sub.t=0.84 min; MS (ESIpos): m/z=600 [M+H].sup.+

[0966] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.32 (br d, 1H), 7.87-7.39 (m, 8H), 6.93-6.83 (m, 1H), 5.18-4.96 (m, 2H), 4.90-4.69 (m, 1H), 4.42-4.19 (m, 1H), 4.10-3.77 (m, 2H), 3.74-3.52 (m, 3H), 1.70 (s, 3H), OH not visible.

Example 94

N-{2-tert-Butoxy-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]ethyl}-2,2,2-trifluoroacetamide (Diastereomeric Mixture)

[0967] ##STR00165##

[0968] A soution of 2-({5-[(1R)-1-amino-2-tert-butoxyethyl]-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 80, 100 mg, 163 μmol) in dichloromethane (2.0 ml) was treated wtih pyridine (130 μl, 1.6 mmol) and trifluoroacetic anhydride (11 81 μmol). The resulting mixture was stirred overnight at room temperature. Trifluoroacetic anhydride (11 μl, 81 μmol) was added, the resulting mixture was stirred 2 h at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 91.8 mg (79% of th.) of the title compound.

[0969] LC-MS (Method 2): R.sub.t=2.24 min; MS (ESIpos): m/z=710 [M+H].sup.+

[0970] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 9.98 (d, 1H), 7.82-7.42 (m, 8H), 6.87 (br s, 1H), 5.23-4.83 (m, 3H), 4.51-3.53 (m, 5H), 1.02 (s, 9H).

Example 95

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]-2-hydroxyethyl}-2,2,2-trifluoroacetamide (Diastereomeric Mixture)

[0971] ##STR00166##

[0972] N-{(1R)-2-tert-Butoxy-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]ethyl}-2,2,2-trifluoroacetamide (Example 94, 86.0 mg, 121 μmol) was treated with a solution of hydrogen chloride in dioxane (3.5 ml, 4.0 M, 14 mmol). The resulting solution was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 41.8 mg (52% of th.) of the title compound.

[0973] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 35 mg dissolved in 2 ml ethanol; injection volume: 500 μl; column: Daicel Chiralcel OZ-H 5 μm, 250×20 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 1.0 ml/min; temperature: 40° C.; UV detection: 220 nm]. After separation, 15 mg of diastereomer 1 (Example 96), which eluted first, and 17 mg of diastereomer 2 (Example 97), which eluted later, were isolated.

[0974] LC-MS (Method 1): R.sub.t=0.98 min; MS (ESIpos): m/z=654 [M+H].sup.+

[0975] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 9.92 (br d, 1H), 7.83-7.41 (m, 8H), 6.89 (d, 1H), 5.20-4.83 (m, 4H), 4.38-4.19 (m, 1H), 4.07-3.69 (m, 4H).

Example 96

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]-2-hydroxyethyl}-2,2,2-trifluoroacetamide (Diastereomer 1)

[0976] For separation conditions see Example 95.

[0977] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 12.7 mg of the title compound.

[0978] Analytical chiral HPLC: R.sub.t=5.44 min, e.e.=99.1% [column: Daicel Chiralcel OZ-H 5 μm, 250×4.6 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 1.0 ml/min; temperature: 40° C.; UV detection: 220 nm].

[0979] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 10.01-9.81 (m, 1H), 7.85-7.42 (m, 8H), 6.89 (d, 1H), 5.25-4.84 (m, 4H), 4.44-4.18 (m, 1H), 4.13-3.66 (m, 4H).

Example 97

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]-2-hydroxyethyl}-2,2,2-trifluoroacetamide (diastereomer 2)

[0980] For separation conditions see Example 95.

[0981] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 13.8 mg of the title compound.

[0982] Analytical chiral HPLC: R.sub.t=7.70 min, e.e.=99.8% [column: Daicel Chiralcel OZ-H 5 μm, 250×4.6 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 1.0 ml/min; temperature: 40° C.; UV detection: 220 nm].

[0983] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 9.92 (br d, 1H), 7.86-7.40 (m, 8H), 6.89 (d, 1H), 5.19-4.80 (m, 4H), 4.39-4.18 (m, 1H), 4.08-3.67 (m, 4H).

Example 98

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[2-oxo-1,3-oxazolidin-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 (Diastereomeric Mixture)

[0984] ##STR00167##

[0985] A solution of 2-({5-[(1R)-1-amino-2-hydroxyethyl]-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 hydrochloride (Example 81, 38.0 mg, 63.9 μmol) in acetonitrile (1 ml) was treated with triethylamine (9.8 μl, 70 μmol) and 1,1′-carbonyldiimidazole (11.4 mg, 70.3 μmol). The resulting mixture was stirred overnight at room temperature and purified by preparative HPLC (Method 4) affording 366 mg (93% of th.) of the title compound.

[0986] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 366 mg dissolved in 30 ml methanol/acetonitrile; injection volume: 3.0 ml; column: Daicel Chiralcel OX-H 5 μm, 250×30 mm; eluent: carbon dioxide/ethanol 70:30; flow rate: 100 ml/min; temperature: 40° C.; UV detection: 210 nm]. After separation, 144 mg of diastereomer 1 (Example 99), which eluted first, and 194 mg of diastereomer 2 (Example 100), which eluted later, were isolated.

[0987] LC-MS (Method 1): R.sub.t=0.90 min; MS (ESIpos): m/z=584 [M+H].sup.+

[0988] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.24 (s, 1H), 7.82-7.52 (m, 8H), 6.95-6.84 (m, 1H), 5.18-5.03 (m, 2H), 4.89-4.74 (m, 1H), 4.62-4.22 (m, 3H), 4.07-3.77 (m, 2H).

Example 99

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[2-oxo-1,3-oxazolidin-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 (Diastereomer 1)

[0989] For separation conditions see Example 98.

[0990] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 120 mg of the title compound.

[0991] Analytical chiral HPLC: R.sub.t=1.20 min, e.e.=100% [column: Daicel Chiralcel OX SFC 3.5 μm, 100×4.6 mm; eluent: carbon dioxide/ethanol 60:40; flow rate: 3.0 ml/min; temperature: 40° C.; UV detection: 210 nm].

[0992] LC-MS (Method 2): R.sub.t=1.71 min; MS (ESIpos): m/z=584 [M+H].sup.+

[0993] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.24 (s, 1H), 7.82-7.50 (m, 8H), 6.89 (d, 1H), 5.19-5.03 (m, 2H), 4.88-4.74 (m, 1H), 4.62-4.21 (m, 3H), 4.06-3.77 (m, 2H).

Example 100

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[2-oxo-1,3-oxazolidin-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 (Diastereomer 2)

[0994] For separation conditions see Example 98.

[0995] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 163 mg of the title compound.

[0996] Analytical chiral HPLC: R.sub.t=2.04 min, e.e.=100% [column: Daicel Chiralcel OX SFC 3.5 μm, 100×4.6 mm; eluent: carbon dioxide/ethanol 60:40; flow rate: 3.0 ml/min; temperature: 40° C.; UV detection: 210 nm].

[0997] LC-MS (Method 2): R.sub.t=1.71 min; MS (ESIpos): m/z=584 [M+H].sup.+

[0998] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.24 (s, 1H), 7.81-7.51 (m, 8H), 6.90 (d, 1H), 5.11 (s, 2H), 4.86-4.77 (m, 1H), 4.58-4.48 (m, 1H), 4.41-4.23 (m, 2H), 4.06-3.79 (m, 2H).

Example 101

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(2R)-5-oxopyrrolidin-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

[0999] ##STR00168##

[1000] 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 2A, 480 mg, 1.27 mmol) in 1,4-dioxane (13 ml) was treated with N,N-diisopropylethylamine (550 μl, 3.2 mmol) and 5-oxo-D-prolyl chloride (206 mg, 1.39 mmol) and stirred 1 h at room temperature. (2-Chlorophenyl)hydrazine hydrochloride (1:1) (250 mg, 1.39 mmol) was added. The resulting mixture was stirred 1.5 h at room temperature followed by overnight at reflux temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 125 mg (16% of th.) of the title compound.

[1001] LC-MS (Method 1): R.sub.t=0.94 min; MS (ESIpos): m/z=582 [M+H].sup.+

[1002] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.06 (br s, 1H), 7.89-7.47 (m, 8H), 6.90 (d, 1H), 5.09 (s, 2H), 4.62-4.19 (m, 2H), 4.14-3.72 (m, 2H), 2.39-1.96 (m, 4H).

Example 102

5-(4-Chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(2S)-5-oxopyrrolidin-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

[1003] ##STR00169##

[1004] 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 2A, 480 mg, 1.27 mmol) in 1,4-dioxane (13 ml) was treated with N,N-diisopropylethylamine (550 μl, 3.2 mmol) and 5-oxo-L-prolyl chloride (206 mg, 1.39 mmol) and stirred 1 h at room temperature. (2-Chlorophenyl)hydrazine hydrochloride (1:1) (250 mg, 1.39 mmol) was added. The resulting mixture was stirred 1.5 h at room temperature followed by overnight at reflux temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 113 mg (15% of th.) of the title compound.

[1005] LC-MS (Method 1): R.sub.t=0.95 min; MS (ESIpos): m/z=582 [M+H].sup.+

[1006] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.07 (br s, 1H), 7.80-7.53 (m, 8H), 6.88 (d, 1H), 5.15-5.01 (m, 2H), 4.58-4.44 (m, 1H), 4.38-4.18 (m, 1H), 4.07-3.76 (m, 2H), 2.38-1.83 (m, 4H).

Example 103

5-(4-Chlorophenyl)-2-({1-(3-chloropyridin-2-yl)-5-[(2R)-1-methyl-5-oxopyrrolidin-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 (Diastereomeric Mixture)

[1007] ##STR00170##

[1008] 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 2A, 479 mg, 1.27 mmol) in 1,4-dioxane (8 ml) was treated with N,N-diisopropylethylamine (880 μl, 5.1 mmol) and with a solution of 1-methyl-5-oxo-L-prolyl chloride (225 mg, 1.39 mmol) in dioxane (4 ml) and stirred 30 min at room temperature. 3-Chloro-2-hydrazinylpyridine (200 mg, 1.39 mmol) was added. The resulting mixture was stirred 2 h at room temperature followed by overnight at reflux temperature. The reaction mixture was diluted with ethyl acetate. The organic phased was washed twice with an aqueous solution of ammonium chloride (10%) followed by a saturated solution of sodium chloride. The organic phase was dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC (Method 4). The residue was suspended in ethyl acetate. The solid was filtered off and washed with ethyl acetate. The filtrate was evaporated and the residue purified by flash chromatography (silica gel, eluent ethyl acetate/methanol) affording 105 mg (13% of th.) of the title compound.

[1009] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 97 mg dissolved in 4 ml ethanol; injection volume: 400 μl; column: Daicel Chiralcel OX-H 5 μm, 250×20 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 15 ml/min; temperature: 40° C.; UV detection: 220 nm]. After separation, 43 mg of diastereomer 1 (Example 104), which eluted first, and 41 mg of diastereomer 2 (Example 105), which eluted later, were isolated.

[1010] LC-MS (Method 1): R.sub.t=0.87 min; MS (ESIpos): m/z=597 [M+H].sup.+

[1011] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.63 (dd, 1H), 8.35 (dd, 1H), 7.79-7.56 (m, 5H), 6.88 (d, 1H), 5.22-5.05 (m, 2H), 4.82-4.69 (m, 1H), 4.37-4.22 (m, 1H), 4.08-3.72 (m, 2H), 2.52 (s, 3H), 2.42-2.15 (m, 3H), 2.07-1.94 (m, 1H).

Example 104

5-(4-Chlorophenyl)-2-({1-(3-chloropyridin-2-yl)-5-[(2R)-1-methyl-5-oxopyrrolidin-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 (Diastereomer 1)

[1012] For separation conditions see Example 103.

[1013] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 40 mg of the title compound.

[1014] Analytical chiral HPLC: R.sub.t=9.38 min, e.e.=100% [column: Daicel Chiralcel OX-H 5 μm, 250×4.6 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 1.0 ml/min; temperature: 40° C.; UV detection: 220 nm].

[1015] LC-MS (Method 1): R.sub.t=0.87 min; MS (ESIpos): m/z=597 [M+H].sup.+

[1016] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.63 (dd, 1H), 8.35 (dd, 1H), 7.81-7.57 (m, 5H), 6.88 (d, 1H), 5.21-5.04 (m, 2H), 4.82-4.70 (m, 1H), 4.37-4.21 (m, 1H), 4.04-3.79 (m, 2H), 2.52 (s, 3H, overlap with DMSO peak), 2.40-1.92 (m, 4H).

Example 105

5-(4-Chlorophenyl)-2-({1-(3-chloropyridin-2-yl)-5-[(2R)-1-methyl-5-oxopyrrolidin-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 (Diastereomer 2)

[1017] For separation conditions see Example 103.

[1018] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 36 mg of the title compound.

[1019] Analytical chiral HPLC: R.sub.t=10.59 min, e.e.=99.5% [column: Daicel Chiralcel OX-H 5 μm, 250×4.6 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 1.0 ml/min; temperature: 40° C.; UV detection: 220 nm].

[1020] LC-MS (Method 2): R.sub.t=1.62 min; MS (ESIpos): m/z=597 [M+H].sup.+

[1021] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.67-8.58 (m, 1H), 8.35 (d, 1H), 7.81-7.53 (m, 5H), 6.87 (d, 1H), 5.12 (s, 2H), 4.80-4.68 (m, 1H), 4.36-4.20 (m, 1H), 4.07-3.77 (m, 2H), 2.52 (br s, 3H, overlap with DMSO peak), 2.38-1.94 (m, 4H).

Example 106

2-({5-[1-Aminoethyl]-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 (Diastereomeric Mixture)

[1022] ##STR00171##

[1023] A solution of 2-{(1R)-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-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-1H-isoindole-1,3(2H)-dione (Example 67A, 212 mg, 315 μmol) in ethanol (6.5 ml) was treated with a methylamine solution in ethanol (550 μl, 33% purity, 6.3 mmol). The resulting mixture was stirred 3 h at 70° C. and evaporated. The residue was purified by preparative HPLC (Method 4) affording 110 mg (58% of th.) of the title compound.

[1024] LC-MS (Method 1): R.sub.t=0.70 min; MS (ESIpos): m/z=543 [M+H].sup.+

[1025] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.59 (dd, 1H), 8.29 (dd, 1H), 7.80-7.55 (m, 5H), 6.92 (dd, 1H), 5.07 (s, 2H), 4.44-4.17 (m, 1H), 4.05-3.78 (m, 3H), 1.96 (br s, 2H), 1.29 (dd, 3H).

Example 107

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-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}acetamide (Diastereomeric Mixture)

[1026] ##STR00172##

[1027] A solution of 2-({5-[(1R)-1-aminoethyl]-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 (Example 106, 105 mg, 193 μmol) in dichloromethane (7.5 ml) was treated with pyridine (160 μl, 1.9 mmol) and acetyl chloride (15 μl, 210 μmol). The resulting mixture was stirred 3 h at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 72 mg (63% of th.) of the title compound.

[1028] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 72 mg dissolved in 2 ml warm 2-propanol; injection volume: 300 μl; column: Daicel Chiralpak IC 5 μm, 250×20 mm; eluent: iso-hexane/isopropanol 80:20; flow rate: 15 ml/min; temperature: 40° C.; UV detection: 220 nm]. After separation, 30 mg of diastereomer 1 (Example 108), which eluted first, and 32 mg of diastereomer 2 (Example 109), which eluted later, were isolated.

[1029] LC-MS (Method 2): R.sub.t=1.57 min; MS (ESIpos): m/z=585 [M+H].sup.+

[1030] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.57 (dd, 1H), 8.40-8.23 (m, 2H), 7.80-7.56 (m, 5H), 6.89 (dd, 1H), 5.16-4.91 (m, 3H), 4.39-4.21 (m, 1H), 4.08-3.78 (m, 2H), 1.57 (s, 3H), 1.41 (d, 3H).

Example 108

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-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}acetamide (Diastereomer 1)

[1031] For separation conditions see Example 107.

[1032] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 22 mg of the title compound.

[1033] Analytical chiral HPLC: R.sub.t=7.20 min, e.e.=100% [column: Daicel Chiralpak IC 5 μm, 250×4.6 mm; eluent: iso-hexane/iso-propanol 70:30+0.2% of trifluroacetic acid; flow rate: 1.0 ml/min; temperature: 30° C.; UV detection: 220 nm].

[1034] LC-MS (Method 2): R.sub.t=1.59 min; MS (ESIpos): m/z=585 [M+H].sup.+

[1035] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.60-8.54 (m, 1H), 8.40-8.22 (m, 2H), 7.81-7.55 (m, 5H), 6.90 (d, 1H), 5.18-4.95 (m, 3H), 4.39-4.21 (m, 1H), 4.07-3.79 (m, 2H), 1.57 (s, 3H), 1.41 (d, 3H).

Example 109

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-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}acetamide (Diastereomer 2)

[1036] For separation conditions see Example 107.

[1037] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 22 mg of the title compound.

[1038] Analytical chiral HPLC: R.sub.t=8.03 min, e.e.=97.2% [column: Daicel Chiralpak IC 5 μm, 250×4.6 mm; eluent: iso-hexane/iso-propanol 70:30+0.2% of trifluroacetic acid; flow rate: 1.0 ml/min; temperature: 30° C.; UV detection: 220 nm].

[1039] LC-MS (Method 2): R.sub.t=1.58 min; MS (ESIpos): m/z=585 [M+H].sup.+

[1040] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.57 (dd, 1H), 8.39-8.21 (m, 2H), 7.82-7.57 (m, 5H), 6.89 (d, 1H), 5.16-4.96 (m, 3H), 4.37-4.21 (m, 1H), 4.06-3.78 (m, 2H), 1.57 (s, 3H), 1.40 (d, 3H).

Example 110

2-({5-[1-Amino-2-tert-butoxyethyl]-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 (Diastereomeric Mixture)

[1041] ##STR00173##

[1042] A solution of 2-{(1S)-2-tert-butoxy-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-chloropyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-1H-isoindole-1,3(2H)-dione (Example 68A, 159 mg, 214 μmol) in ethanol (10 ml) was treated with a solution of methylamine in methanol (370 μl, 33% purity, 4.3 mmol). The resulting mixture was stirred 4 h at 70° C. and evaporated. The residue was purified by preparative HPCL (Method 4) affording 127 mf (96% of th.) of the title compound.

[1043] LC-MS (Method 2): R.sub.t=1.38 min; MS (ESIpos): m/z=615 [M+H].sup.+

[1044] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.58 (dd, 1H), 8.27 (dd, 1H), 7.80-7.56 (m, 5H), 7.11-6.68 (m, 1H), 5.08 (d, 2H), 4.40-4.22 (m, 1H), 4.11-3.76 (m, 3H), 3.52-3.38 (m, 3H), 0.95 (s, 8H), NH.sub.2 not visible.

Example 111

2-({5-[1-Amino-2-hydroxyethyl]-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 hydrochloride (Diastereomeric Mixture)

[1045] ##STR00174##

[1046] 2-({5-[(1S)-1-Amino-2-tert-butoxyethyl]-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 (Example 110, 127 mg, 206 μmol) was treated with a solution of hydrogen chloride in dioxane (2.1 ml, 4.0 M, 8.5 mmol). The resulting solution was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 115 mg (93% of th.) of the title compound.

[1047] LC-MS (Method 1): R.sub.t=0.69 min; MS (ESIpos): m/z=559 [M+H].sup.+

Example 112

5-(4-Chlorophenyl)-2-({1-(3-chloropyridin-2-yl)-5-[2-oxo-1,3-oxazolidin-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 (Diastereomeric Mixture)

[1048] ##STR00175##

[1049] A solution of 2-({5-[(1S)-1-amino-2-hydroxyethyl]-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 hydrochloride (Example 111, 115 mg, 193 μmol) in acetonitrile (3.0 ml) was treated with triethylamine (30 μl, 210 μmol) and 1,1′-Carbonyldiimidazole (34.4 mg, 212 μmol). The resulting mixture was stirred overnight at room temperature. Purification by preparative HPLC (Method 4) afforded 38.5 mg (33% of th.) of the title compound.

[1050] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 33 mg dissolved in 3 ml warm ethanol; injection volume: 250 μl; column: Daicel Chiralcel OX-H 5 μm, 250×20 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 15 ml/min; temperature: 25° C.; UV detection: 210 nm]. After separation, 9.7 mg of diastereomer 1 (Example 113), which eluted first, and 18.2 mg of diastereomer 2 (Example 114), which eluted later, were isolated.

[1051] LC-MS (Method 2): R.sub.t=1.59 min; MS (ESIpos): m/z=585 [M+H].sup.+

[1052] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.58 (dd, 1H), 8.35-8.20 (m, 2H), 7.81-7.57 (m, 5H), 6.95-6.86 (m, 1H), 5.17-5.05 (m, 3H), 4.66-4.53 (m, 1H), 4.45-4.21 (m, 2H), 4.08-3.77 (m, 2H).

Example 113

5-(4-Chlorophenyl)-2-({1-(3-chloropyridin-2-yl)-5-[2-oxo-1,3-oxazolidin-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 (Diastereomer 1)

[1053] For separation conditions see Example 112.

[1054] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 7 mg of the title compound.

[1055] Analytical chiral HPLC: R.sub.t=3.17 min, e.e.=94.4% [column: Daicel Chiratekl OX-3 3 μm, 100×4.6 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 1.0 ml/min; temperature: 50° C.; UV detection: 220 nm].

[1056] LC-MS (Method 2): R.sub.t=1.62 min; MS (ESIpos): m/z=585 [M+H].sup.+

[1057] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.58 (dd, 1H), 8.35-8.19 (m, 2H), 7.81-7.55 (m, 5H), 6.90 (d, 1H), 5.18-5.03 (m, 3H), 4.66-4.54 (m, 1H), 4.46-4.24 (m, 2H), 4.07-3.75 (m, 2H).

Example 114

5-(4-Chlorophenyl)-2-({1-(3-chloropyridin-2-yl)-5-[2-oxo-1,3-oxazolidin-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 (Diastereomer 2)

[1058] For separation conditions see Example 112.

[1059] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 15 mg of the title compound.

[1060] Analytical chiral HPLC: R.sub.t=4.22 min, e.e.=98.6% [column: Daicel Chiralcel OX-3 3 μm, 100×4.6 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 1.0 ml/min; temperature: 50° C.; UV detection: 220 nm].

[1061] LC-MS (Method 2): R.sub.t=1.62 min; MS (ESIpos): m/z=585 [M+H].sup.+

[1062] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.58 (dd, 1H), 8.35-8.21 (m, 2H), 7.78-7.57 (m, 5H), 6.90 (d, 1H), 5.17-5.06 (m, 3H), 4.65-4.54 (m, 1H), 4.44-4.23 (m, 2H), 4.07-3.75 (m, 2H).

Example 115

2-({5-[1-Amino-2-tert-butoxyethyl]-1-[3-(trifluoromethoxy)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 (Diastereomeric Mixture)

[1063] ##STR00176##

[1064] A solution of 2-[(1S)-2-tert-butoxy-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-(trifluoromethoxy)pyridin-2-yl]-1H-1,2,4-triazol-5-yl}ethyl]-1H-isoindole-1,3(2H)-dione (Example 71A, 480 mg, 604 μmol) in ethanol (28 ml) was treated with a solution of metylamine in ethanol (1.1 ml, 33% purity, 12 mmol). The resulting mixture was stirred 4 h at 70° C. and evaporated. The residue was purified by preparative HPLC (Method 4) affording 381.9 mg (95% of th.) of the title compound.

[1065] LC-MS (Method 2): R.sub.t=1.49 min; MS (ESIpos): m/z=665 [M+H].sup.+

[1066] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.62 (dd, 1H), 8.26-8.17 (m, 1H), 7.83-7.54 (m, 5H), 7.13-6.64 (br s, 1H), 5.16-5.00 (m, 2H), 4.38-4.20 (m, 1H), 4.18-4.07 (m, 1H), 4.05-3.79 (m, 2H), 3.50-3.38 (m, 2H), 0.93 (s, 9H), NH.sub.2 not visible.

Example 116

2-({5-[1-Amino-2-hydroxyethyl]-1-[3-(trifluoromethoxy)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 hydrochloride (Diastereomeric Mixture)

[1067] ##STR00177##

[1068] 2-({5-[(1S)-1-Amino-2-tert-butoxyethyl]-1-[3-(trifluoromethoxy)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 115, 381 mg, 573 μmol) was treated with a solution of hydrogen chloride in dioxane (5.9 ml, 4.0 M, 23 mmol). The resulting solution was stirred overnight at room temperature and evaporated affording 350 mg (94% of th.) of the title compound.

[1069] LC-MS (Method 1): R.sub.t=0.78 min; MS (ESIpos): m/z=609 [M+H].sup.+

Example 117

5-(4-Chlorophenyl)-2-({5-[2-oxo-1,3-oxazolidin-4-yl]-1-[3-(trifluoromethoxy)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 (Diastereomeric Mixture)

[1070] ##STR00178##

[1071] A solution of 2-({5-[(1S)-1-amino-2-hydroxyethyl]-1-[3-(trifluoromethoxy)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 hydrochloride (Example 116, 200 mg, 310 μmol) in acetonitrile (4.9 ml) was treated with triethylamine (48 μl, 340 μmol) and 1,1′-Carbonyldiimidazole (55.3 mg, 341 μmol). The resulting mxitutre was stirred overnight at room temperature. Purification by preparative HPLC (Method 4) afforded 38.5 mg (33% of th.) of the title compound.

[1072] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 58 mg dissolved in 2 ml ethanol; injection volume: 400 μl; column: Daicel Chiralcel OX-H 5 μm, 250×20 mm; eluent: iso-hexane/ethanol 65:35; flow rate: 15 ml/min; temperature: 40° C.; UV detection: 220 nm]. After separation, 20 mg of diastereomer 1 (Example 118), which eluted first, and 29 mg of diastereomer 2 (Example 119), which eluted later, were isolated.

[1073] LC-MS (Method 2): R.sub.t=1.74 min; MS (ESIpos): m/z=635 [M+H].sup.+

[1074] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.61 (dd, 1H), 8.29-8.19 (m, 2H), 7.84-7.58 (m, 5H), 6.90 (d, 1H), 5.28-5.04 (m, 3H), 4.70-4.60 (m, 1H), 4.48-4.22 (m, 2H), 4.06-3.77 (m, 2H).

Example 118

5-(4-Chlorophenyl)-2-({5-[2-oxo-1,3-oxazolidin-4-yl]-1-[3-(trifluoromethoxy)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 (Diastereomer 1)

[1075] For separation conditions see Example 117.

[1076] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 17 mg of the title compound.

[1077] Analytical chiral HPLC: R.sub.t=5.81 min, e.e.=98.6% [column: Daicel Chiralcel OX-H 5 μm, 250×4.6 mm; eluent: iso-hexane/ethanol 60:40; flow rate: 1.0 ml/min; temperature: 30° C.; UV detection: 220 nm].

[1078] LC-MS (Method 2): R.sub.t=1.76 min; MS (ESIpos): m/z=635 [M+H].sup.+

[1079] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.64-8.56 (m, 1H), 8.28-8.18 (m, 2H), 7.83-7.58 (m, 5H), 6.89 (d, 1H), 5.28-5.04 (m, 3H), 4.65 (t, 1H), 4.51-4.21 (m, 2H), 4.06-3.79 (m, 2H).

Example 119

5-(4-Chlorophenyl)-2-({5-[2-oxo-1,3-oxazolidin-4-yl]-1-[3-(trifluoromethoxy)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 (Diastereomer 2)

[1080] For separation conditions see Example 117.

[1081] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 25 mg of the title compound.

[1082] Analytical chiral HPLC: R.sub.t=7.50 min, e.e.=100% [column: Daicel Chiralcel OX-H 5 μm, 250×4.6 mm; eluent: iso-hexane/ethanol 60:40; flow rate: 1.0 ml/min; temperature: 30° C.; UV detection: 220 nm].

[1083] LC-MS (Method 2): R.sub.t=1.76 min; MS (ESIpos): m/z=635 [M+H].sup.+

[1084] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.61 (dd, 1H), 8.28-8.19 (m, 2H), 7.83-7.56 (m, 5H), 6.90 (d, 1H), 5.28-5.05 (m, 3H), 4.65 (t, 1H), 4.49-4.21 (m, 2H), 4.04-3.79 (m, 2H).

Example 120

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-(trifluoromethoxy)pyridin-2-yl]-1H-1,2,4-triazol-5-yl}-2-hydroxyethyl]acetamide (Diastereomeric Mixture)

[1085] ##STR00179##

[1086] A solution of 2-({5-[(1S)-1-amino-2-hydroxyethyl]-1-[3-(trifluoromethoxy)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 hydrochloride (Example 116, 150 mg, 232 μmol) in dichloromethane (9.0 ml) was treated with pyridine (190 μl, 2.3 mmol) and acetyl chloride (18 μl, 260 μmol). The resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 69 mg (44% of th.) of the title compound.

[1087] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 65 mg dissolved in 1 ml ethanol+1 ml acetonitrile; injection volume: 100 μl; column: Daicel Chiralpak AY-H 5 μm, 250×20 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 30 ml/min; temperature: 23° C.; UV detection: 220 nm]. After separation, 11.4 mg of diastereomer 1 (Example 121), which eluted first, and 31.6 mg of diastereomer 2 (Example 122), which eluted later, were isolated.

[1088] LC-MS (Method 2): R.sub.t=1.58 min; MS (ESIpos): m/z=651 [M+H].sup.+

[1089] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.61 (dd, 1H), 8.33-8.14 (m, 2H), 7.85-7.56 (m, 5H), 6.89 (d, 1H), 5.23-4.84 (m, 4H), 4.39-4.21 (m, 1H), 4.06-3.56 (m, 4H), 1.65 (s, 3H).

Example 121

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-(trifluoromethoxy)pyridin-2-yl]-1H-1,2,4-triazol-5-yl}-2-hydroxyethyl]acetamide (diastereomer 1)

[1090] For separation conditions see Example 120.

[1091] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 10 mg of the title compound.

[1092] Analytical chiral HPLC: R.sub.t=0.96 min, e.e.=95.4% [column: Daicel Chiralpak AY-3 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 1.0 ml/min; temperature: 23° C.; UV detection: 220 nm].

[1093] LC-MS (Method 1): R.sub.t=0.86 min; MS (ESIpos): m/z=651 [M+H].sup.+

[1094] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.61 (dd, 1H), 8.34-8.12 (m, 2H), 7.84-7.56 (m, 5H), 6.89 (d, 1H), 5.25-4.86 (m, 4H), 4.37-4.20 (m, 1H), 4.04-3.53 (m, 4H), 1.65 (s, 3H).

Example 122

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-(trifluoromethoxy)pyridin-2-yl]-1H-1,2,4-triazol-5-yl}-2-hydroxyethyl]acetamide (Diastereomer 2)

[1095] For separation conditions see Example 120.

[1096] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 32 mg of the title compound.

[1097] Analytical chiral HPLC: R.sub.t=1.57 min, e.e.=98.2% [column: Daicel Chiralpak AY-3 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 80:20; flow rate: 1.0 ml/min; temperature: 23° C.; UV detection: 220 nm].

[1098] LC-MS (Method 1): R.sub.t=0.86 min; MS (ESIpos): m/z=651 [M+H].sup.+

[1099] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.61 (dd, 1H), 8.33-8.13 (m, 2H), 7.84-7.57 (m, 5H), 6.89 (d, 1H), 5.19-4.91 (m, 4H), 4.38-4.22 (m, 1H), 4.04-3.52 (m, 4H), 1.65 (s, 3H).

Example 123

5-(4-Chlorophenyl)-2-({1-(4-chloropyridin-3-yl)-5-[(2S)-5-oxopyrrolidin-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

[1100] ##STR00180##

[1101] 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 2A, 488 mg, 1.29 mmol) in 1,4-dioxane (25 ml) was treated with N,N-diisopropylethylamine (900 μl, 5.2 mmol) followed by a solution of 5-oxo-L-prolyl chloride (228 mg, 1.55 mmol) in dioxane (1 ml). The reaction mixture was stirred 30 min at room temperature. 4-Chloro-3-hydrazinylpyridine hydrochloride (1:1) (255 mg, 1.42 mmol) was added. The resulting mixture was stirred 2 h at room temperature, overnight at reflux temperature and evaporated. The residue was purified by preparative HPLC (Method 4) followed by a flash chromatography (silica gel, dichloromethane/methanol gradient) affording 22 mg (2% of th.) of the title compound.

[1102] LC-MS (Method 2): R.sub.t=1.48 min; MS (ESIpos): m/z=583 [M+H].sup.+

[1103] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.84 (s, 1H), 8.77 (d, 1H), 8.07 (s, 1H), 7.90 (d, 1H), 7.81-7.59 (m, 4H), 6.88 (d, 1H), 5.19-5.02 (m, 2H), 4.60 (dd, 1H), 4.35-4.21 (m, 1H), 4.06-3.79 (m, 2H), 2.41-2.03 (m, 4H).

Example 124

2-({5-[1-Aminoethyl]-1-[4-(methylamino)pyridin-3-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 hydrochloride (Diastereomeric Mixture)

[1104] ##STR00181##

[1105] A solution of 2-{(1R)-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-(4-chloropyridin-3-yl)-1H-1,2,4-triazol-5-yl]ethyl}-1H-isoindole-1,3(2H)-dione (Example 69A, 650 mg, 965 μmol) in ethanol (20 ml) was treated with a solution of methylamine in ethanol (1.7 ml, 33% purity, 19 mmol). The resulting mixture was stirred 3 h at 70° C. and evaporated. The residue was purified by preparative HPLC (Method 4). Addition of an aqueous solution of hydrogen chloride (3 ml) to the fractions containing products followed by evaporation afforded 177 mg (29% of th.) of the title compound.

[1106] LC-MS (Method 2): R.sub.t=0.79 min; MS (ESIpos): m/z=538 [M+H].sup.+

[1107] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 14.47-13.92 (br s, 1H), 8.99-8.66 (m, 4H), 8.51-8.37 (m, 1H), 8.22-8.05 (m, 1H), 7.85-7.57 (m, 4H), 7.15 (d, 1H), 7.05-6.84 (m, 1H), 5.12 (s, 2H), 4.58-3.79 (m, 4H), 2.97-2.82 (m, 3H), 1.43 (d, 3H).

Example 125

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-[4-(methylamino)pyridin-3-yl]-1H-1,2,4-triazol-5-yl}ethyl]acetamide hydrochloride (Diastereomeric Mixture)

[1108] ##STR00182##

[1109] A solution of 2-({5-[1-aminoethyl]-1-[4-(methylamino)pyridin-3-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 hydrochloride (Example 124, 172 mg, 282 μmol) in dichloromethane (10 ml) was treated with pyridine (5.0 ml, 62 mmol) and acetyl chloride (44 μl, 620 μmol). The resulting mixture was stirred 3 h at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4). Addition of an aqueous solution of hydrogen chloride (2 ml) to the fractions containing products followed by evaporation afforded 134 mg (76% of th.) of the title compound.

[1110] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 133 mg dissolved in 8 ml warm ethanol; injection volume: 500 μl; column: Daicel Chiralcel OX-H 5 μm, 250×20 mm; eluent: iso-hexane/ethanol 30:70; flow rate: 15 ml/min; temperature: 25° C.; UV detection: 210 nm]. After separation, 70.4 mg of diastereomer 1 (Example 126), which eluted first, and 61.5 mg of diastereomer 2 (Example 127), which eluted later, were isolated.

[1111] LC-MS (Method 2): R.sub.t=1.03 min; MS (ESIpos): m/z=580 [M+H].sup.+

[1112] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 14.14-13.72 (m, 1H), 8.57-8.30 (m, 3H), 7.93-7.55 (m, 5H), 7.17-6.75 (m, 2H), 5.18-4.76 (m, 3H), 4.39-3.73 (m, 3H), 2.89 (d, 3H), 1.64 (s, 3H), 1.40 (d, 3H).

Example 126

Formic acid-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-[4-(methylamino)pyridin-3-yl]-1H-1,2,4-triazol-5-yl}ethyl]acetamide (Diastereomer 1)

[1113] ##STR00183##

[1114] For separation conditions see Example 125.

[1115] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4; eluent water+0.1% formic acid/acetonitrile) affording 34 mg of the title compound.

[1116] Analytical chiral HPLC: R.sub.t=2.15 min, e.e.=100% [column: Daicel Chiralcel OX-3 3 μm, 100×4.6 mm; eluent: iso-hexane/ethanol 50:50+0.2% diethylamine; flow rate: 1.0 ml/min; temperature: 50° C.; UV detection: 220 nm].

[1117] LC-MS (Method 2): R.sub.t=1.06 min; MS (ESIpos): m/z=580.2 [M+H].sup.+

[1118] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 13.02-12.47 (m, 1H), 8.37 (d, 1H), 8.26-7.97 (m, 3H), 7.82-7.55 (m, 4H), 6.95-6.60 (m, 2H), 6.11-5.93 (m, 1H), 5.06 (s, 2H), 4.79-4.64 (m, 1H), 4.36-4.18 (m, 1H), 4.08-3.78 (m, 2H), 2.69 (d, 3H), 1.67 (s, 3H), 1.32 (d, 3H).

Example 127

Formic acid-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-[4-(methylamino)pyridin-3-yl]-1H-1,2,4-triazol-5-yl}ethyl]acetamide (Diastereomer 2)

[1119] ##STR00184##

[1120] For separation conditions see Example 125.

[1121] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4; eluent water+0.1% formic acid/acetonitrile) affording 29 mg of the title compound.

[1122] Analytical chiral HPLC: R.sub.t=2.53 min, e.e.=99.2% [column: Daicel Chiralcel OX-3 3 μm, 100×4.6 mm; eluent: iso-hexane/ethanol 50:50+0.2% diethylamine; flow rate: 1.0 ml/min; temperature: 50° C.; UV detection: 220 nm].

[1123] LC-MS (Method 2): R.sub.t=1.02 min; MS (ESIpos): m/z=580.2 [M+H].sup.+

[1124] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 13.17-12.32 (m, 1H), 8.36 (d, 1H), 8.26-7.95 (m, 3H), 7.82-7.54 (m, 4H), 6.95-6.62 (m, 2H), 6.06-5.92 (m, 1H), 5.05 (s, 2H), 4.72 (quin, 1H), 4.39-4.20 (m, 1H), 4.09-3.79 (m, 2H), 2.68 (d, 3H), 1.67 (s, 3H), 1.32 (d, 3H).

Example 128

2-({5-[1-Aminoethyl]-1-(pyrimidin-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 hydrochloride (Diastereomeric Mixture)

[1125] ##STR00185##

[1126] A solution 2-{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-(pyrimidin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-1H-isoindole-1,3(2H)-dione (Example 70A, 740 mg, 1.16 mmol) in ethanol (24 ml) was treated with a solution of methylamine in ethanol (2.0 ml, 33% purity, 23 mmol). The resulting mixture was stirred 6 h at reflux temperature and evaporated. The residue was purified by preparative HPLC (Method 4). Addition of an aqueous solution of hydrogen chloride (3 ml) to the fractions containing products followed by evaporation afforded 415 mg (65% of th.) of the title compound.

[1127] LC-MS (Method 7): R.sub.t=1.40 min; MS (ESIpos): m/z=510 [M+H].sup.+

[1128] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 9.01 (d, 2H), 8.81-8.52 (m, 3H), 7.82-7.56 (m, 5H), 7.08-6.82 (m, 1H), 5.39-5.06 (m, 3H), 4.39-4.22 (m, 1H), 4.09-3.81 (m, 2H), 1.62 (d, 3H).

Example 129

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-(pyrimidin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}acetamide (Diastereomeric Mixture)

[1129] ##STR00186##

[1130] A solution of 2-({5-[1-aminoethyl]-1-(pyrimidin-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 hydrochloride (Example 128, 200 mg, 366 μmol) in dichloromethane (14 ml) was treated with pyridine (300 μl, 3.7 mmol) and acetyl chloride (29 μl, 400 μmol). The resulting mixture was stirred 2 h at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 140 mg (68% of th.) of the title compound.

[1131] LC-MS (Method 2): R.sub.t=1.49 min; MS (ESIpos): m/z=552 [M+H].sup.+

[1132] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.97 (d, 2H), 8.51 (d, 1H), 7.83-7.55 (m, 5H), 6.92 (d, 1H), 5.80-5.66 (m, 1H), 5.17-5.02 (m, 2H), 4.41-4.22 (m, 1H), 4.08-3.80 (m, 2H), 1.73-1.64 (m, 3H), 1.46 (d, 3H).

Example 130

5-(4-Chlorophenyl)-2-({5-[1-methyl-5-oxopyrrolidin-2-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 (Diastereomeric Mixture)

[1133] ##STR00187##

[1134] 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 2A, 672 mg, 1.77 mmol) in 1,4-dioxane (10 ml) was treated with N,N-diisopropylethylamine (1.2 ml, 7.1 mmol) and with a solution of 1-methyl-5-oxo-prolyl chloride (315 mg, 1.95 mmol) in dioxane (7 ml) and stirred 30 min at room temperature. (3,3,3-Trifluoropropyl)hydrazine (305 mg, 82% purity, 1.95 mmol) was added. The resulting mixture was stirred 2 h at room temperature followed by overnight at reflux temperature and evaporated. The residue was purified by preparative HPLC (Method 4) followed by flash chromatography (silica gel, ethyl acetate/methanol gradient) affording 335 mg (31% of th.) of the title compound.

[1135] The two diastereomers were separated by preparative chiral HPLC [sample preparation: 330 mg dissolved in 11 ml ethanol; injection volume: 200 μl; column: Daicel Chiralcel OX-H 5 μm SFC, 250×20 mm; eluent: carbon dioxide/methanol 80:20; flow rate: 100 ml/min; temperature: 30° C.; UV detection: 210 nm]. After separation, 161 mg of diastereomer 1 (Example 131), which eluted first, and 149 mg of diastereomer 2 (Example 132), which eluted later, were isolated.

[1136] LC-MS (Method 1): R.sub.t=0.91 min; MS (ESIpos): m/z=582 [M+H].sup.+

[1137] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.78-7.52 (m, 4H), 6.93-6.80 (m, 1H), 5.15-4.89 (m, 3H), 4.54-4.17 (m, 3H), 4.06-3.75 (m, 2H), 3.01-2.77 (m, 2H), 2.45-2.18 (m, 3H), 1.99-1.81 (m, 1H), CH.sub.3 not visible.

Example 131

5-(4-Chlorophenyl)-2-({5-[1-methyl-5-oxopyrrolidin-2-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 (Diastereomer 1)

[1138] For separation conditions see Example 130.

[1139] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 109 mg of the title compound.

[1140] Analytical chiral HPLC: R.sub.t=1.82 min, e.e.=97.1% [column: Daicel Chiralcel OX SFC 3.5 μm, 100×4.6 mm; eluent: carbon dioxide/ethanol 80:20; flow rate: 3.0 ml/min; temperature: 30° C.; UV detection: 210 nm].

[1141] LC-MS (Method 1): R.sub.t=0.89 min; MS (ESIpos): m/z=582 [M+H].sup.+

[1142] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.76-7.58 (m, 4H), 6.87 (d, 1H), 5.10-4.89 (m, 3H), 4.53-4.18 (m, 3H), 4.04-3.76 (m, 2H), 3.00-2.81 (m, 2H), 2.45-2.19 (m, 3H), 1.97-1.82 (m, 1H), CH.sub.3 not visible.

Example 132

5-(4-Chlorophenyl)-2-({5-[1-methyl-5-oxopyrrolidin-2-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 (Diastereomer 2)

[1143] For separation conditions see Example 130.

[1144] After diastereomeric separation, the compound was purified by preparative HPLC (Method 4) affording 132 mg of the title compound.

[1145] Analytical chiral HPLC: R.sub.t=2.21 min, e.e.=94.8% [column: Daicel Chiralcel OX SFC 3.5 μm, 100×4.6 mm; eluent: carbon dioxide/ethanol 80:20; flow rate: 3.0 ml/min; temperature: 30° C.; UV detection: 210 nm].

[1146] LC-MS (Method 1): R.sub.t 0.89 min; MS (ESIpos): m/z=582 [M+H].sup.+

[1147] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 7.81-7.53 (m, 4H), 6.86 (d, 1H), 5.18-4.84 (m, 3H), 4.58-4.15 (m, 3H), 4.07-3.74 (m, 2H), 3.02-2.76 (m, 2H), 2.46-2.19 (m, 3H), 1.99-1.76 (m, 1H), CH.sub.3 not visible.

Experimental Section—Biological Assays

Abbreviations and Acronyms

[1148] Acc. No. accession number [1149] AVP arginine vasopressin [1150] B.sub.max maximal ligand binding capacity [1151] BSA bovine serum albumin [1152] cAMP cyclic adenosine monophosphate [1153] Cat. No. catalogue number [1154] cDNA complementary deoxyribonucleic acid [1155] CHO chinese hamster ovary [1156] CRE cAMP response element [1157] Ct cycle threshold [1158] DMEM/F12 Dulbecco's modified Eagle's medium/Ham's F12 medium (1:1) [1159] DNA deoxyribonucleic acid [1160] DMSO dimethylsulfoxide [1161] DTT dithiothreitol [1162] EC.sub.50 half-maximal effective concentration [1163] EDTA ethylenediamine-tetraacetic acid [1164] FAM carboxyfluorescein succinimidyl ester [1165] f.c. final concentration [1166] FCS fetal calf serum [1167] HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid [1168] IC.sub.50 half-maximal inhibitory concentration [1169] K.sub.d dissociation constant [1170] K.sub.i dissociation constant of an inhibitor [1171] mRNA messenger ribonucleic acid [1172] PBS phosphate buffered saline [1173] PEG polyethylene glycol [1174] p.o. per os, peroral [1175] RNA ribonucleic acid [1176] RTPCR real-time polymerase chain reaction [1177] SPA scintillation proximity assay [1178] TAMRA carboxytetramethylrhodamine [1179] TRIS; Tris 2-amino-2-hydroxymethylpropane-1,3-diol

[1180] 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

[1181] 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.αq-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:

[1182] Vasopressin V1a receptor cell lines:

[1183] 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 μg/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:

[1184] 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.8]-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.

[1185] 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. [μM] [μM] hV2/hV1a 1 0.00350 0.01633 4.7 2 0.00097 0.00580 6.0 3 0.00135 0.00685 5.1 4 0.00146 0.01340 9.2 5 0.00160 0.00705 4.4 6 0.00081 0.02075 25.6 7 0.00360 0.02667 7.4 8 0.00085 0.16100 190.5 9 0.03150 0.13500 4.3 10 0.05250 0.10500 2.0 11 0.11500 0.22500 2.0 12 0.03550 0.12667 3.6 13 0.01345 0.03500 2.6 14 0.00175 0.05200 29.7 15 0.00102 0.03550 34.8 16 0.16000 0.05250 0.3 17 0.55750 0.15000 0.3 18 0.00770 0.03000 3.9 19 0.00155 0.06300 40.7 20 0.00330 0.05200 15.8 21 0.00190 0.01750 9.2 22 0.00995 0.14350 14.4 23 0.00540 0.28500 52.8 24 0.02594 0.00529 0.2 25 0.02655 0.00226 0.1 26 0.00529 0.00482 0.9 27 0.00178 0.00311 1.8 28 0.00043 0.00257 6.0 29 0.00129 0.00293 2.3 30 0.03660 0.00381 0.1 31 0.00094 0.00742 7.9 32 0.00051 0.01025 20.3 33 0.00099 0.00363 3.7 34 0.00064 0.00275 4.3 35 0.04145 0.00199 0.1 36 0.02855 0.00181 0.1 37 0.00077 0.00662 8.6 38 0.00065 0.00356 5.5 39 0.00110 0.00176 1.6 40 0.00586 0.00635 1.1 41 0.00201 0.00969 4.8 42 0.00108 0.00737 6.8 43 0.00559 0.00593 1.1 44 0.02765 0.00798 0.3 45 0.01123 0.00513 0.5 46 0.00647 0.00936 1.5 47 0.00043 0.00716 16.6 48 0.00112 0.00591 5.3 49 0.00099 0.01670 16.9 50 0.00095 0.02200 23.0 51 0.00390 0.02967 7.6 52 0.00215 0.01400 6.5 53 0.01825 0.00529 0.3 54 0.00309 0.00420 1.4 55 0.01800 0.02600 1.4 56 0.28550 0.03340 0.1 57 0.01314 0.00128 0.1 58 0.02135 0.00195 0.1 59 0.00119 0.00274 2.3 60 0.00074 0.00317 4.3 61 0.00045 0.00283 6.3 62 0.00097 0.01135 11.7 64 0.00180 0.01767 9.8 65 0.00205 0.01080 5.3 66 0.00375 0.05250 14.0 67 0.00083 0.00243 2.9 68 0.00097 0.00450 4.6 69 0.00070 0.00865 12.4 70 0.00081 0.00703 8.7 71 0.00070 0.01380 19.7 72 0.00067 0.00663 9.9 73 0.00156 0.00860 5.5 74 0.00535 0.01800 3.4 75 0.00420 0.05900 14.1 76 0.00048 0.00395 8.3 77 0.00650 0.34000 52.3 78 0.00110 0.00970 8.8 79 0.00100 0.01450 14.5 80 0.00061 0.01900 31.4 81 0.00125 0.00795 6.4 82 0.00064 0.04800 75.6 83 0.00195 0.08050 41.3 84 0.00475 0.04450 9.4 85 0.00035 0.00225 6.4 86 0.00097 0.00200 2.1 87 0.00225 0.03550 15.8 88 0.00150 0.04550 30.3 89 0.00345 0.12900 37.4 90 0.01250 4.90000 392.0 91 0.00071 0.00890 12.5 92 0.00510 0.01750 3.4 93 0.00078 0.01550 20.0 94 0.00110 0.02750 25.0 95 0.00210 0.01800 8.6 96 0.00055 0.00325 6.0 97 0.00445 0.02000 4.5 98 0.00062 0.00600 9.8 99 0.00330 0.02100 6.4 100 0.00433 0.08750 20.2 101 0.00077 0.00380 4.9 102 0.00025 0.00120 4.8 103 0.00145 0.02650 18.3 104 0.00310 0.17475 56.4 105 0.00210 0.05100 24.3 106 0.00165 0.01850 11.2 107 0.01350 0.24000 17.8 108 0.00603 0.06940 11.5 109 0.03900 0.40800 10.5 112 0.00840 0.21000 25.0 113 0.00580 0.13388 23.1 114 0.02267 0.52500 23.2 117 0.02150 0.47000 21.9 118 0.01700 0.38500 22.7 119 0.05700 0.87500 15.4 120 0.01250 0.41000 32.8 121 0.14750 2.77500 18.8 122 0.00635 0.28000 44.1 123 0.00110 0.03450 31.5 124 0.03400 0.07450 2.2 125 0.06400 0.59500 9.3 126 1.38500 1.25500 0.9 127 0.05300 1.55000 29.3 128 0.09450 2.15000 22.8 129 0.19000 1.55000 8.2 130 0.02100 2.68500 127.9 131 0.00955 1.54000 161.3 132 0.01850 1.73000 93.5

B-2. Radioactive Binding Assay

[1186] IC.sub.50 and 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.

[1187] 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.251]Phenylacetyl-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH.sub.2 for 120 minutes at 25° C. Non-specific binding is estimated in the presence of 1 μM [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.

[1188] 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. Non-specific 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.

[1189] 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, 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

[1190] 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 V1a 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:

[1191] 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 ([Arg.sub.8]-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 μl 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 Oct. 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

[1192] 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.

[1193] 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 mM) 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 μL PRP aliquots, under continuous stirring at 37° C., against PPP control. Various concentrations of vasopressin antagonists (in 2 μL) are added to PRP 5 mM before the addition of 20 μL 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. IC.sub.50 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

[1194] 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/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. 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/1 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

[1195] 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

[1196] 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/1 KCl). After washing with Krebs-Henseleit buffer the vessels are then pre-contracted using 1 nmol/1 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)

[1197] 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 ‘Um’) 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.

[1198] 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

[1199] 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 HohenpeiBenberg). 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

[1200] 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.

[1201] 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.

[1202] 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.

[1203] 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.

[1204] 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

[1205] 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 μg/kg/min); fentanyl is used as an analgesic (10 μg/kg/h).

[1206] 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 S600, Biotronik, Germany) which is advanced through the external jugular vein, with illumination, into the right ventricle.

[1207] 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.

[1208] The actual drug testing experiments take place 28 days after the beginning of pacemaker stimulation, using the following instrumentation: [1209] Introduction of a bladder catheter for bladder relief and for measuring the flow of urine [1210] Attachment of electrocardiography (ECG) leads to the extremities for ECG measurement [1211] 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 [1212] 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. [1213] 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 [1214] 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) [1215] Siting of a venous catheter in the saphenous vein, for infusing fentanyl and for administration of substance [1216] 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.

[1217] 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.

[1218] 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

[1219] The substances according to the invention can be converted to pharmaceutical preparations as follows:

Tablet:

Composition:

[1220] 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.

[1221] Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

Production:

[1222] 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:

[1223] 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.

[1224] 10 ml of oral suspension correspond to a single dose of 100 mg of the compound of the invention.

Production:

[1225] 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:

[1226] 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.