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SUBSTITUTED OXOPYRIDINE DERIVATIVES

20170298052 · 2017-10-19

    Inventors

    Cpc classification

    International classification

    Abstract

    The invention relates to substituted oxopyridine derivatives and to processes for preparation thereof, and also to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially of cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and oedemas, and also ophthalmic disorders.

    Claims

    1. Compound of the formula ##STR00226## in which R.sup.1 is a group of the formula ##STR00227## steht, where * is the attachment point to the oxopyridine ring, R.sup.6 is bromine, chlorine, fluorine, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy, R.sup.7 is bromine, chlorine, fluorine, cyano, nitro, hydroxyl, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, ethynyl, 3,3,3-trifluoroprop-1-yn-1-yl or cyclopropyl, R.sup.8 is hydrogen, chlorine or fluorine, R.sup.2 is hydrogen, bromine, chlorine, fluorine, cyano, C.sub.1-C.sub.3-alkyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C.sub.1-C.sub.3-alkoxy, difluoromethoxy, trifluoromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, methylcarbonyl or cyclopropyl, R.sup.3 is hydrogen, C.sub.1-C.sub.5-alkyl, C.sub.1-C.sub.4-alkoxy, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 1,1,2,2,2-pentadeuteroethyl, 3,3,3-trifluoro-2-hydroxyprop-1-yl, 3,3,3-trifluoro-2-methoxyprop-1-yl, 3,3,3-trifluoro-2-ethoxyprop-1-yl, prop-2-yn-1-yl, cyclopropyloxy or cyclobutyloxy, where alkyl may be substituted by a substituent selected from the group consisting of fluorine, cyano, hydroxyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, C.sub.3-C.sub.6-cycloalkyl, 4- to 6-membered oxoheterocyclyl, 1,4-dioxanyl, oxazolyl, oxadiazolyl, pyrazolyl,dihydrooxazolyl, phenyl, pyridyl and C.sub.3-C.sub.6-cycloalkyloxy, in which tert-butoxy and isopropoxy may be substituted by 1 to 3 fluorine substituents, and in which cycloalkyl may be substituted by 1 to 2 substituents selected independently from the group consisting of fluorine, hydroxyl, methyl, ethyl, methoxy, ethoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy, and in which oxoheterocyclyl may be substituted by 1 to 2 substituents selected independently from the group consisting of oxo, fluorine, methyl, ethyl, difluoromethyl and trifluoromethyl, and in which oxazolyl, oxadiazolyl, pyrazolyl and dihydrooxazolyl may be substituted by 1 to 2 substituents selected independently from the group consisting of methyl, ethyl and cyclopropyl, and in which cycloalkyloxy may be substituted by 1 to 2 substituents selected independently from the group consisting of fluorine and methyl, R.sup.4 is hydrogen, R.sup.5 is a group of the formula ##STR00228## where # is the attachment point to the nitrogen atom, R.sup.9 is hydrogen, chlorine, fluorine or methoxy, R.sup.10 is hydrogen or fluorine, R.sup.11 is hydrogen or C.sub.1-C.sub.4-alkyl, or one of the salts thereof, solvates thereof or solvates of the salts thereof.

    2. Compound according to claim 1, wherein R.sup.1 is a group of the formula ##STR00229## where * is the attachment point to the oxopyridine ring, R.sup.6 is chlorine, R.sup.7 is fluorine, cyano, difluoromethyl or difluoromethoxy, R.sup.8 is hydrogen, R.sup.2 is chlorine, cyano, methoxy or difluoromethoxy, R.sup.3 is methyl, ethyl, n-propyl or n-butyl, where methyl may be substituted by a substituent selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, tetrahydro-2H-pyranyl, oxazolyl and pyridyl, in which cyclobutyl and cyclohexyl may be substituted by 1 to 2 substituents selected independently from the group consisting of hydroxyl and methoxy, and in which oxazolyl may be substituted by a methyl substituent, and where ethyl, n-propyl and n-butyl may be substituted by a substituent selected from the group consisting of methoxy and trifluoromethoxy, R.sup.4 is hydrogen, R.sup.5 is a group of the formula ##STR00230## where # is the attachment point to the nitrogen atom, R.sup.9 is hydrogen or fluorine, R.sup.10 is hydrogen or fluorine, R.sup.11 is hydrogen, methyl or ethyl, or one of the salts thereof, solvates thereof or solvates of the salts thereof.

    3. Compound according to claim 1, wherein R.sup.1 is a group of the formula ##STR00231## where * is the attachment point to the oxopyridine ring, R.sup.6 is chlorine, R.sup.7 is cyano, R.sup.8 is hydrogen, R.sup.2 is chlorine or methoxy, R.sup.3 is methyl or ethyl, where methyl is substituted by a substituent selected from the group consisting of tetrahydro-2H-pyranyl, oxazolyl and pyridyl, in which oxazolyl may be substituted by a methyl substituent, and where ethyl may be substituted by a methoxy substituent, R.sup.4 is hydrogen, R.sup.5 is a group of the formula ##STR00232## where # is the attachment point to the nitrogen atom, R.sup.9 is hydrogen, R.sup.10 is fluorine, R.sup.11 is hydrogen or methyl, or one of the salts thereof, solvates thereof or solvates of the salts thereof.

    4. Process for preparing a compound of the formula (I) or one of the salts thereof, solvates thereof or solvates of the salts thereof according to claim 1, wherein either [A] a compound of the formula ##STR00233## in which R.sup.1, R.sup.2 and R.sup.3 have the definition given in claim 1 is reacted in the first stage with a compound of the formula ##STR00234## in which R.sup.4 R.sup.5 have the definition given in claim 1 in the presence of a dehydrating reagent, and optionally converted in a second stage by acidic or basic ester hydrolysis to a compound of the formula (I), or [B] a compound of the formula ##STR00235## in which R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the definition given in claim 1, and X.sup.1 is chlorine, bromine or iodine is reacted with a compound of the formula
    R.sup.1-Q   (V) in which R.sup.1 has the definition given in claim 1, and Q is —B(OH).sub.2, a boronic ester, preferably boronic acid pinacol ester, or —BF.sub.3.sup.−K.sup.+, under Suzuki coupling conditions to give a compound of the formula

    5. Compound according to claim 1 for treatment and/or prophylaxis of diseases.

    6. Use of a compound according to claim 1 for production of a medicament for treatment and/or prophylaxis of diseases.

    7. Use of a compound according to claim 1 for production of a medicament for treatment and/or prophylaxis of thrombotic or thromboembolic disorders.

    8. Use of a compound according to claim 1 for production of a medicament for treatment and/or prophylaxis of ophthalmic disorders.

    9. Use of a compound according to claim 1 for production of a medicament for treatment and/or prophylaxis of hereditary angiooedema or inflammatory disorders of the intestine, such as Crohn's disease or ulcerative colitis.

    10. Medicament comprising a compound according to claim 1 in combination with an inert, nontoxic, pharmaceutically suitable excipient.

    11. Medicament according to claim 10 for treatment and/or prophylaxis of thrombotic or thromboembolic disorders.

    12. Medicament according to claim 10 for treatment and/or prophylaxis of ophthalmic disorders.

    13. Medicament according to claim 10 for treatment and/or prophylaxis of hereditary angiooedema or inflammatory disorders of the intestine, such as Crohn's disease or ulcerative colitis.

    14. Method for combating thrombotic or thromboembolic disorders or ophthalmic disorders or hereditary angiooedema or inflammatory disorders of the intestine, such as Crohn's disease or ulcerative colitis, in man and animals by administration of a therapeutically effective amount of at least one compound according to claim 1; a medicament comprising the compound in combination with an inert, nontoxic, pharmaceutically suitable excipient; or the medicament for treatment and/or prophylaxis of diseases.

    Description

    A) EXAMPLES

    [0407] Abbreviations: [0408] Boc tert-butyloxycarbonyl [0409] Ex. Example [0410] d day(s), doublet (in NMR) [0411] TLC thin-layer chromatography [0412] DCM dichloromethane [0413] DCI direct chemical ionization (in MS) [0414] dd doublet of doublets (in NMR) [0415] DIC N,N′-diisopropylcarbodiimide [0416] DIEA N,N-diisopropylethylamine [0417] DMAP 4-dimethylaminopyridine [0418] DMF N,N-dimethylformamide [0419] DMSO dimethyl sulphoxide [0420] eq. equivalent(s) [0421] ESI electrospray ionization (in MS) [0422] h hour(s) [0423] HATU O-(7-azabenzotriazol-1-yl)-N,N,′,N′-tetramethyluronium hexafluorophosphate [0424] HPLC high-pressure, high-performance liquid chromatography [0425] HV high vacuum [0426] LC-MS liquid chromatography-coupled mass spectroscopy [0427] LDA lithium diisopropylamide [0428] m multiplet (in NMR) [0429] min minute(s) [0430] MS mass spectroscopy [0431] NMR nuclear magnetic resonance spectroscopy [0432] Oxima ethyl hydroxyiminocyanoacetate [0433] q quartet or quadruplet (in NMR) [0434] quant. quantitative [0435] quin quintet (in NMR) [0436] RP reversed phase (in HPLC) [0437] RT room temperature [0438] R.sub.t retention time (in HPLC) [0439] s singlet (in NMR) [0440] sxt sextet (in NMR) [0441] SFC supercritical fluid chromatography (with supercritical carbon dioxide as mobile phase) [0442] t triplet (in NMR) [0443] THF tetrahydrofuran [0444] TFA trifluoroacetic acid [0445] T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide [0446] Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene [0447] XPhos precatalyst [(2′-aminobiphenyl-2-yl)(chloro)palladium dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (1:1)], J. Am. Chem. Soc. 2010, 132, 14073-14075

    [0448] HPLC, LC-MS and GC Methods:

    [0449] Method 1: Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8μ 50 mm×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.

    [0450] Method 2: Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8μ 50 mm×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.

    [0451] Method 3: Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9μ 50 mm×1 mm; eluent A: 1 1 water+0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile+0.5 ml 50% formic acid; gradient: 0.0 min 97% A.fwdarw.0.5 min 97% A.fwdarw.3.2 min 5% A.fwdarw.4.0 min 5% A; oven: 50° C.; flow rate: 0.3 ml/min; UV detection: 210 nm.

    [0452] Method 4: MS instrument: Waters (Micromass) Quattro Micro; HPLC instrument: Agilent 1100 Series; column: YMC-Triart C18 3μ 50 mm×3 mm; eluent A: 1 1 water+0.01 mol ammonium carbonate, eluent B: 1 1 acetonitrile; gradient: 0.0 min 100% A.fwdarw.2.75 min 5% A.fwdarw.4.5 min 5% A; oven: 40° C.; flow rate: 1.25 ml/min; UV detection: 210 nm.

    [0453] Method 5: MS instrument: Waters (Micromass) QM; HPLC instrument: Agilent 1100 series; column: Agilent ZORBAX Extend-C18 3.0 mm×50 mm 3 5 micron; eluent A: 1 1 water+0.01 mol ammonium carbonate, eluent B: 1 1 acetonitrile; gradient: 0.0 min 98% A.fwdarw.0.2 min 98% A.fwdarw.3.0 min 5% A.fwdarw.4.5 min 5% A; oven: 40° C.; flow rate: 1.75 ml/min; UV detection: 210 nm.

    [0454] Method 6: MS instrument: Waters (Micromass) ZQ; HPLC instrument: Agilent 1100 series; column: Agilent ZORBAX Extend-C18 3.0 mm×50 mm 3 5 micron; eluent A: 1 1 water+0.01 mol ammonium carbonate, eluent B: 1 1 acetonitrile; gradient: 0.0 min 98% A.fwdarw.0.2 min 98% A.fwdarw.3.0 min 5% A.fwdarw.4.5 min 5% A; oven: 40° C.; flow rate: 1.75 ml/min; UV detection: 210 nm.

    [0455] Method 7: Instrument: Thermo DFS, Trace GC Ultra; column: Restek RTX-35, 15 m×200 μm×0.33 μm; constant flow rate of helium: 1.20 ml/min; oven: 60° C.; inlet: 220° C.; gradient: 60° C., 30° C./min.fwdarw.300° C. (hold for 3.33 min).

    [0456] Method 8: Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; column: Waters Acquity UPLC HSS T3 1.8μ 50 mm×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.

    [0457] Method 9: Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra; column: Restek RTX-35MS, 15 m×200 μm×0.33 μm; constant flow rate of helium: 1.20 ml/min; oven: 60° C.; inlet: 220° C.; gradient: 60° C., 30° C./min.fwdarw.300° C. (hold for 3.33 min).

    [0458] Method 10: MS instrument type Thermo Scientific FT-MS; UHPLC+instrument type Thermo Scientific UltiMate 3000; column Waters, HSST3, 2.1 mm×75 mm, C18 1.8 μm; eluent A 1 1 of water+0.01% formic acid; eluent B 1 1 of 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.

    [0459] Method 11 : MS instrument: Waters (Micromass) Quattro Micro; instrument: Waters UPLC Acquity; column: Waters BEH C18 1.7μ 50 mm×2.1 mm; eluent A: 1 1 water+0.01 mol ammonium formate, eluent B: 11 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.

    [0460] Microwave: The microwave reactor used was a “single-mode” instrument of the Emrys™ Optimizer type.

    [0461] When compounds according to the invention are purified by preparative HPLC by the above-described methods in which the eluents contain additives, for example trifluoroacetic acid, formic acid or ammonia, the compounds according to the invention may be obtained in salt form, for example as trifluoroacetate, formate or ammonium salt, if the compounds according to the invention contain a sufficiently basic or acidic functionality. Such a salt can be converted to the corresponding free base or acid by various methods known to the person skilled in the art.

    [0462] 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.

    [0463] 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.

    [0464] Starting Compounds

    [0465] General Method 1A: Preparation of a Boronic Acid

    [0466] To a solution of the appropriate pyridine derivative in tetrahydrofuran (about 3 ml/mmol) at −78° C. was added lithium diisopropylamide (2 M in tetrahydrofuran/heptane/ethylbenzene), the mixture was stirred for 2 to 4 h and then triisopropyl borate was then added quickly. The reaction mixture was maintained at −78° C. for a further 2 to 3 h and then slowly thawed to RT overnight. After addition of water, the tetrahydrofuran was removed under reduced pressure and the aqueous phase was extracted twice with ethyl acetate. The aqueous phase was acidified with aqueous hydrochloric acid (2M), generally resulting in formation of a precipitate which was filtered off, washed with water and dried. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried (sodium sulphate or magnesium sulphate), filtered and concentrated under reduced pressure.

    [0467] General Method 2A: Suzuki Coupling

    [0468] A flask which had been dried by heating and flushed with argon was initially charged with 1.0 eq. of the appropriate boronic acids, 1.0 eq. of the aryl bromide or aryl iodide, 3.0 eq. of potassium carbonate and 0.1 eq. of [1,1-bis(diphenylphosphino)ferrocene] palladium(II) chloride/monodichloromethane adduct or tetrakis(triphenylphosphine)palladium(0). The flask was then evacuated three times and in each case vented with argon. Dioxane (about 6 ml/mmol) was added, and the reaction mixture was stirred at 110° C. for a number of hours until substantially complete conversion had been achieved. The reaction mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure. Water was added to the residue. After addition of ethyl acetate and phase separation, the organic phase was washed once with water and once with saturated aqueous sodium chloride solution, dried (sodium sulphate or magnesium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified either by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

    [0469] General Method 3A: Methoxypyridine Cleavage

    [0470] 20 eq. of pyridinium hydrochloride or pyridinium hydrobromide were added to a solution of the appropriate methoxypyridine in dimethylformamide (10-12.5 ml/mmol) and the mixture was stirred at 100° C. for a number of hours to days, with further pyridinium hydrochloride or pyridinium hydrobromide possibly being added, until substantially complete conversion had been achieved. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was stirred with water. The precipitate formed was filtered off, washed with water and dried under reduced pressure.

    [0471] General Method 4A: N-Alkylation of 2-pyridinone Derivatives with the Appropriate 2-bromo- or 2-chloropropanoic Ester Derivatives in the Presence of Potassium Carbonate

    [0472] To a solution of 1.0 eq. of the appropriate 2-pyridinone derivative in dimethylformamide (5-10 ml/mmol) under argon and at RT were added 1.2 eq. of the appropriate 2-bromo- or 2-chloropropanoic ester derivative and 1.5 eq. of potassium carbonate, and the mixture was stirred at 100° C. After removal of the dimethylformamide and addition of water/ethyl acetate and phase separation, the organic phase was washed with water and with saturated aqueous sodium chloride solution, dried (sodium sulphate or magnesium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified either by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

    [0473] General Method 5A: Amide Coupling with HATU/DIEA

    [0474] To a solution of the appropriate carboxylic acid (1.0 eq.) in dimethylformamide (7-15 ml/mmol) under argon and at RT were added the amine (1.1 eq.), N,N-diisopropylethylamine (2.2 eq.) and a solution of HATU (1.2 eq.) in a little dimethylformamide. The reaction mixture was stirred at RT. After addition of water/ethyl acetate and phase separation, the organic phase was washed with water and with saturated aqueous sodium chloride solution, dried (sodium sulphate or magnesium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified either by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

    [0475] General Method 5B: Amide Coupling Using T3P/pyridine

    [0476] A solution of the appropriate carboxylic acid or carboxylic acid hydrochloride (1 eq.) and the appropriate amine or amine hydrochloride (1.1-1.9 eq.) in pyridine (about 0.1 M) was heated to 60° C., and T3P (50% in ethyl acetate, 1.5-15 eq.) was added dropwise. Alternatively, T3P was added at RT and the mixture was then stirred at RT or heated to 50 to 90° C. After 1 to 20 h, the reaction mixture was cooled to RT and either purified directly by means of preparative RP-HPLC (water-acetonitrile gradient or water-methanol gradient) or admixed with water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous buffer solution (pH=5), with saturated aqueous sodium hydrogencarbonate solution and with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was then optionally purified either by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

    [0477] General Method 6A: Hydrolysis of a tert-butyl Ester or a Boc-Protected Amine Using TFA

    [0478] To a solution of 1.0 eq. of the appropriate tert-butyl ester derivative in dichloromethane (about 5-10 ml/mmol) at RT were added 20 eq. of TFA, and the mixture was stirred at RT for 1 to 8 h. The reaction mixture was then concentrated under reduced pressure and the residue was co-evaporated repeatedly with dichloromethane and toluene and dried under reduced pressure. The crude product was then optionally purified either by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

    [0479] General Method 6B: Hydrolysis of a tert-butyl Ester Using Hydrogen Chloride in Dioxane

    [0480] A solution of 1.0 eq. of the appropriate tert-butyl ester derivative in 4M hydrogen chloride in dioxane (concentration of the tert-butyl ester derivative about 0.1M) was either stirred at RT for 2 to 48 h or treated in an ultrasound bath for 2 to 5 h. The reaction mixture was then concentrated under reduced pressure and the residue was co-evaporated repeatedly with tetrahydrofuran and dried under reduced pressure. The crude product was converted without further purification.

    [0481] General Method 6C: Hydrolysis of a tert-butyl Ester Using Lithium Hydroxide

    [0482] To a solution of 1.0 eq. of the appropriate tert-butyl ester in tetrahydrofuran/ethanol (1:2, 15-50 ml/mmol) at RT was added lithium hydroxide (2-5 eq.). The reaction mixture was stirred at RT to 60° C., saturated aqueous ammonium chloride solution was then added and the mixture was adjusted to pH 1 using aqueous hydrochloric acid (1N). After addition of water/ethyl acetate and phase separation, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried (sodium sulphate or magnesium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified either by means of normal phase chromatography (cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

    [0483] General Method 7A: Preparation of Triflates

    [0484] A solution of the appropriate alcohol (1 eq.) was initially charged in dichloromethane (0.1M), and at −20° C. lutidine (1.1-1.5 eq.) or triethylamine (1.1-1.5 eq.) and trifluoromethanesulphonic anhydride (1.05-1.5 eq.) were added in succession. The reaction mixture was stirred at −20° C. for another 1 h and then diluted with three times the amount (based on the reaction volume) of methyl tert-butyl ether. The organic phase was washed three times with a 3:1 mixture of saturated aqueous sodium chloride solution/1N hydrochloric acid and finally with saturated aqueous sodium hydrogencarbonate solution, dried (sodium sulphate or magnesium sulphate) and filtered, and the solvent was removed under reduced pressure. The crude product was used in the next stage without further purification.

    [0485] General Method 8A: Alkylation of Acetic Esters with Triflates

    [0486] To a solution of the appropriate acetic ester (1 eq.) in tetrahydrofuran (0.1-0.2M) under argon and at −78° C. was added dropwise lithium bis(trimethylsilyl)amide (1.0M in THF, 1.1-1.3 eq.), and the mixture was stirred for 15 min. The appropriate alkyl triflate (1.5-2.0 eq.) was then added neat or as a solution in THF. The resulting reaction mixture was stirred at −78° C. for another 15 min and at RT for another 1 h. Saturated aqueous ammonium chloride solution was added to the reaction mixture. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (sodium sulphate or magnesium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified either by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

    [0487] General Method 8B: Alkylation of Acetic Esters with Halides

    [0488] To a solution of the appropriate acetic ester in THF (about 10 ml/mmol) under argon and at −78° C. were added 1.1 eq. of lithium bis(trimethylsilyl)amide (1.0M in THF), and the mixture was stirred at −78° C. for 10 min. A solution of the appropriate iodide/bromide/chloride in THF was then added, and the reaction mixture was stirred at −78° C. for 10 min and further in an ice bath and then quenched with water. After addition of ethyl acetate and phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified either by flash chromatography (silica gel 60, eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative HPLC (Reprosil C18, water/acetonitrile gradient or water/methanol gradient).

    [0489] General Method 9A: Nitro Reduction with Iron

    [0490] The appropriate nitro compound was dissolved in an ethanol/water mixture (5:1) (about 2-3M), and concentrated hydrochloric acid (0.5-1 eq.) and iron powder (3-8 eq.) were added. The reaction mixture was heated at 80 to 100° C. until the reaction had gone to completion (about 1 to 6 h). The hot reaction mixture was filtered through kieselguhr. The filtercake was washed with methanol and the filtrate was concentrated under reduced pressure. The crude product was then purified either by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

    Example 1.1A

    2-Fluoro-4-nitrobenzamide

    [0491] ##STR00037##

    [0492] According to General Method 5B, 5.00 g (27 mmol) of 2-fluoro-4-nitrobenzoic acid and 2.17 g (40.5 mmol, 1.5 eq.) of ammonium chloride were reacted. The crude product was purified by means of normal phase chromatography (eluent: dichloromethane/methanol 2-5%). Yield: 2.65 g (53% of theory)

    [0493] LC/MS [Method 1]: R.sub.t=0.48 min; MS (ESIpos): m/z=185 (M+H).sup.+,

    [0494] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.19 (dd, 1H), 8.12 (dd, 1H), 8.05 (bs, 1H), 7.91 (bs, 1H), 7.86 (dd, 1H).

    Example 1.1B

    4-Amino-2-fluorobenzamide

    [0495] ##STR00038##

    [0496] According to General Method 9A, 2.65 g (14.4 mmol) of 2-fluoro-4-nitrobenzamide were reacted. The crude product was purified by means of normal phase chromatography (eluent: dichloromethane/methanol 5-10%). Yield: 1.64 g (74% of theory)

    [0497] LC/MS [Method 5]: R.sub.t=0.89 min; MS (ESIpos): m/z=155 (M+H).sup.+,

    [0498] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.48 (t, 1H), 7.15 (bs, 1H), 6.97 (bs, 1H), 6.38 (dd, 1H), 6.27 (dd, 1H), 5.93 (s, 2H).

    Example 1.1C

    2-Fluoro-N-methyl-4-nitrobenzamide

    [0499] ##STR00039##

    [0500] According to General Method 5B, 1.00 g (5.40 mmol) of 2-fluoro-4-nitrobenzoic acid and 547 mg (8.10 mmol, 1.5 eq.) of methylamine hydrochloride were reacted. Yield: 1.07 g (94% purity, 94% of theory)

    [0501] LC/MS [Method 1]: R.sub.t=0.56 min; MS (ESIpos): m/z=199 (M+H).sup.+,

    [0502] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.58 (bs, 1H), 8.20 (dd, 1H), 8.13 (dd, 1H), 7.85 (dd, 1H), 2.80 (d, 3H).

    Example 1.1D

    4-Amino-2-fluoro-N-methylbenzamide

    [0503] ##STR00040##

    [0504] According to General Method 9A, 1.07 g (5.07 mmol) of 2-fluoro-N-methyl-4-nitrobenzamide were reacted. The crude product was purified by means of normal phase chromatography (eluent: dichloromethane/methanol 5-10%). Yield: 624 mg (72% of theory)

    [0505] LC/MS [Method 5]: R.sub.t=1.20 min; MS (ESIpos): m/z=169 (M+H).sup.+,

    [0506] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.54 (bs, 1H), 7.43 (t, 1H), 6.38 (dd, 1H), 6.27 (dd, 1H), 5.88 (s, 2H), 2.72 (d, 3H).

    Example 1.2A

    tert-Butyl 2-fluoro-4-nitrobenzoate

    [0507] ##STR00041##

    [0508] To a solution of 500 mg (2.7 mmol) of 2-fluoro-4-nitrobenzoic acid and 1.03 g (5.4 mmol, 2.0 eq.) of para-toluenesulphonyl chloride in 5.4 ml of pyridine were added, at 0° C., 0.258 ml (2 7 mmol, 1.0 eq.) of tert-butanol, the mixture was stirred for 60 min, and a further 0.258 ml (2.7 mmol, 1.0 eq.) of tert-butanol was added. The reaction mixture was stirred for a further 18 h and concentrated under reduced pressure. The residue was admixed with saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate 14-20% mixtures). Yield: 524 mg (75% of theory).

    [0509] LC/MS [Method 1]: R.sub.t=1.16 min; MS (ESIneg): m/z=226 (M−CH.sub.3).sup.−,

    [0510] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.21 (dd, 1H), 8.16-8.12 (m, 1H), 8.06 (dd, 1H), 1.56 (s, 9H).

    Example 1.2B

    tert-Butyl 4-amino-2-fluorobenzoate

    [0511] ##STR00042##

    [0512] A solution of 1.109 g (20.73 mmol, 10 eq.) of ammonium chloride in 6.25 ml of ethanol and 3.125 ml of water was heated to 95° C., and 500 mg (2.07 mmol) of tert-butyl 2-fluoro-4-nitrobenzoate were added. 347 mg (6.22 mmol, 3 eq.) of iron powder were added in small portions over the course of 1 h. The reaction mixture was then stirred at 95° C. for 30 min and hot-filtered through kieselguhr. The filtercake was washed with ethanol and the filtrate was freed of ethanol under reduced pressure. The aqueous phase was extracted three times with 20 ml each time of diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was purified by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate 30-50% mixtures). Yield: 280 mg (51% of theory).

    [0513] LC/MS [Method 8]: R.sub.t=1.18 min; MS (ESIneg): m/z=210 (M−H).sup.−,

    [0514] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.49 (t, 1H), 6.36 (dd, 1H), 6.25 (dd, 1H), 6.15 (s, 2H), 1.48 (s, 9H).

    Example 1.3A

    4-Amino-2-chloro-N-methylbenzamide

    [0515] ##STR00043##

    [0516] 250 mg (1.46 mmol) of 4-amino-2-chlorobenzoic acid and 2.19 ml (4.37 mmol, 3 eq.) of 2N methanamine in THF were initially charged in 5.0 ml of DMF, 685 μl (3.93 mmol, 2.7 eq.) of N,N-diisopropylethylamine and 776 mg (2.04 mmol, 1.4 eq.) of HATU were added and the mixture was stirred at RT for two days. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated. The residue was purified by means of Biotage-Isolera (eluent: dichloromethane/methanol, 5-10%). Yield: 227 mg (84% of theory).

    [0517] LC/MS [Method 1]: R.sub.t=0.32 min; MS (ESIpos): m/z=185 (M+H).sup.+,

    [0518] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.89 (d, 1H), 7.15 (d, 1H), 6.57 (d, 1H), 6.48 (dd, 1H), 5.65 (s, 2H), 2.69 (d, 3H).

    Example 1.4A

    Methyl 4-[tert-butoxycarbonyl)amino]-2,6-difluorobenzoate

    [0519] ##STR00044##

    [0520] A microwave vial was initially charged with 900 mg (3.59 mmol) of methyl 4-bromo-2,6-difluorobenzoate, 1680 mg (14.34 mmol, 4 eq.) of tert-butyl carbamate, 40 mg (0.18 mmol, 0.05 eq.) of palladium(II) acetate, 207 mg (0.36 mmol, 0.10 eq.) of Xantphos and 5841 mg (17.93 mmol, 5 eq.) of caesium carbonate and purged with argon, then 36 ml of dioxane were added. The reaction mixture was stirred in the microwave at 140° C. for 30 min. The cooled suspension was partitioned between ethyl acetate and water, and the aqueous phase was extracted once more with ethyl acetate. The combined organic phases were washed once with water, then with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-50%). Yield: 1.67 g (60% purity, 97% of theory).

    [0521] LC/MS [Method 1]: R.sub.t=1.07 min; MS (ESIpos): m/z=288 (M+H).sup.+,

    [0522] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.09 (s, 1H), 7.25 (d, 2H), 3.82 (s, 3H), 1.48 (s, 9H).

    Example 1.4B

    4-[(tert-Butoxycarbonyl)amino]-2,6-difluorobenzoic acid

    [0523] ##STR00045##

    [0524] 1.67 g (3.49 mmol, 80% purity) of methyl 4-[(tert-butoxycarbonyl)amino]-2,6-difluorobenzoate were dissolved in 36 ml of methanol, 2.27 g (6.98 mmol, 1.5 eq.) of caesium carbonate and 9 ml of water were added and the mixture was stirred at 60° C. for 4 h. The reaction mixture was removed from the methanol, and the aqueous residue was diluted with 15 ml of water and then extracted with 30 ml of ethyl acetate. The aqueous phase was adjusted to pH 3 with 1N aqueous hydrogen chloride solution, stirred for 10 min, filtered with suction and washed with water. The residue was dried under high vacuum. Yield: 380 mg (39% of theory).

    [0525] LC/MS [Method 8]: R.sub.t=1.10 min; MS (ESIneg): m/z=272 (M−H).sup.−,

    [0526] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.43 (bs, 1H), 10.01 (s, 1H), 7.23 (d, 2H), 1.48 (s, 9H).

    Example 1.4C

    tert-Butyl (4-carbamoyl-3,5-difluorophenyl)carbamate

    [0527] ##STR00046##

    [0528] 280 mg (1.03 mmol) of 4-[(tert-Butoxycarbonyl)amino]-2,6-difluorobenzoic acid and 274 mg (5.12 mmol, 5 eq.) of ammonium chloride were dissolved in 8.4 ml DMF, and 482 μl (2.77 mmol, 2.7 eq.) of N,N-diisopropylethylamine were added. Subsequently, 545 mg (1.44 mmol, 1.4 eq.) of HATU were added while cooling with an ice bath, and the mixture was stirred for 10 min and then stirred overnight while coming to RT. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and semi-saturated aqueous sodium hydrogencarbonate solution. The organic phase was washed once with saturated aqueous sodium hydrogencarbonate solution and once with saturated aqueous sodium chloride solution, then dried and concentrated. The residue was dissolved in 3 ml of DMSO and purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.15% formic acid). Yield: 110 mg (39% of theory).

    [0529] LC/MS [Method 1]: R.sub.t=0.75 min; MS (ESIpos): m/z=273 (M+H).sup.+,

    [0530] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=9.86 (s, 1H), 7.93 (s, 1H), 7.68 (s, 1H), 7.18 (d, 2H), 1.48 (s, 9H).

    Example 1.4D

    4-Amino-2,6-difluorobenzamide hydrochloride

    [0531] ##STR00047##

    [0532] To 110 mg (0.404 mmol) of tert-butyl (4-carbamoyl-3,5-difluorophenyl)carbamate were added 5 ml of 4N hydrogen chloride in dioxane, and the mixture was stirred at RT for 5 h. The reaction mixture was concentrated, dissolved in acetonitrile/water 1:1 and lyophilized. Yield: 85 mg (quant.).

    [0533] LC/MS [Method 11]: R.sub.t=0.55 min; MS (ESIpos): m/z=173 (M+H).sup.+,

    [0534] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.58 (s, 1H), 7.38 (s, 1H), 6.17 (d, 2H).

    Example 1.5A

    2-Methoxy-4-nitrobenzamide

    [0535] ##STR00048##

    [0536] 1.50 g (7.61 mmol) of 2-methoxy-4-nitrobenzoic acid and 1.22 g (22.83 mmol, 3 eq.) of ammonium chloride were initially charged in 26 ml of pyridine and heated to 60° C., 7.23 ml (30.43 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 60° C. for 18 h. The reaction mixture was cooled down and admixed with 100 ml of ethyl acetate and 30 ml of saturated aqueous sodium hydrogencarbonate solution. Subsequently, ethyl acetate and pyridine were removed on a rotary evaporator. The aqueous suspension was filtered and the remaining solids were washed with water, isopropanol and then pentane, and dried. Yield: 1.15 g (74% of theory).

    [0537] LC/MS [Method 1]: R.sub.t=0.56 min; MS (ESIpos): m/z=197 (M+H).sup.+,

    [0538] .sup.1H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.90-7.84 (m, 3H), 7.80 (s, 1H), 7.76 (s, 1H), 3.98 (s, H).

    Example 1.5B

    4-Amino-2-methoxybenzamide

    [0539] ##STR00049##

    [0540] To a solution of 1.15 g (5.86 mmol) of 2-methoxy-4-nitrobenzamide in 17 ml of ethanol and 2.5 ml of water was added 0.241 ml (2.93 mmol, 0.5 eq.) of concentrated hydrochloric acid and the mixture was heated to 80° C. Over a period of one hour, 2.13 g (38.11 mmol, 6.5 eq.) of iron powder were added in 4 portions and the mixture was stirred at 80° C. for 2 h. The reaction mixture was hot-filtered through silica gel and washed with ethanol, and the filtrate was concentrated. Subsequently, the residue was purified by means of Biotage-Isolera (eluent: dichloromethane/methanol, 0-5%). Yield: 520 mg (53% of theory).

    [0541] LC/MS [Method 1]: R.sub.t=0.72 min; MS (ESIpos): m/z=167 (M+H).sup.+,

    [0542] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.62 (d, 1H), 7.31 (bs, 1H), 7.00 (bs, 1H), 6.22 (d, 1H), 6.17 (dd, 1H), 5.70 (s, 2H), 3.80 (s, 3H).

    Example 2.1A

    2,5-Dimethoxypyridin-4-ylboronic acid

    [0543] ##STR00050##

    [0544] According to General Method 1A, 11.53 g (82.9 mmol) of 2,5-dimethoxypyridine were reacted. The desired product precipitated out after acidification of the aqueous phase. Yield: 9.53 g (61% of theory)

    [0545] LC/MS [Method 1]: R.sub.t=0.47 min; MS (ESIpos): m/z=184 (M+H).sup.+

    Example 2.1B

    4-Chloro-2-(2,5-dimethoxypyridin-4-yl)benzonitrile

    [0546] ##STR00051##

    [0547] According to General Method 2A, 7.87 g (95% purity, 40.86 mmol) of 2,5-dimethoxypyridin-4-ylboronic acid were reacted with 8.85 g (40.86 mmol) of 2-bromo-4-chlorobenzonitrile in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct. Yield: 6.23 g (92% purity, 51% of theory).

    [0548] LC/MS [Method 1]: R.sub.t=1.08 min; MS (ESIpos): m/z=275 (M+H).sup.+

    Example 2.1C

    4-Chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile

    [0549] ##STR00052##

    [0550] According to General Method 3A, 7.23 g (92% purity, 24.21 mmol) of 4-chloro-2-(2,5-dimethoxypyridin-4-yl)benzonitrile were reacted with pyridinium hydrochloride. Yield: 6.66 g (91% purity, 96% of theory).

    [0551] LC/MS [Method 1]: R.sub.t=0.76 min; MS (ESIpos): m/z=261 (M+H).sup.+

    [0552] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=11.45 (br. s, 1H), 7.98 (d, 1H), 7.75-7.67 (m, 2H), 7.29 (br. s, 1H), 6.43 (s, 1H), 3.64 (s, 3H).

    Example 2.2A

    2-Bromo-4-chloro-1-(difluoromethyl)benzene

    [0553] ##STR00053##

    [0554] 1.50 g (6.84 mmol) of 2-bromo-4-chlorobenzaldehyde were initially charged in 18 ml of dichloromethane, 1.36 ml (10.25 mmol, 1.5 eq.) of N-ethyl-N-(trifluoro-lambda4-sulphanyl)-ethanamine were added at 0° C. and the mixture was stirred at RT for 3 h. Subsequently, 80 ml of saturated aqueous sodium hydrogencarbonate solution were added dropwise and the mixture was extracted twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. Yield: 1.6 g (92% purity, 89% of theory).

    [0555] LC/MS [Method 9]: R.sub.t=3.22 min; MS (ESIpos): m/z=241 (M+H).sup.+,

    [0556] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.95 (s, 1H), 7.72-7.61 (m, 2H), 7.13 (s, 1H)

    Example 2.2B

    4-[5-Chloro-2-(difluoromethyl)phenyl]-2,5-dimethoxypyridine

    [0557] ##STR00054##

    [0558] 1.36 g (5.08 mmol) of diisopropyl (2,5-dimethoxypyridin-4-yl)borate, 2.11 g (15.24 mmol, 3 eq.) of potassium carbonate and 0.415 g (0.508 mmol, 0.1 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct were initially charged in a flask, which was then evacuated and filled with argon three times. 1.60 g (6.10 mmol, 1.2 eq) of 2-bromo-4-chloro-1-(difluoromethyl)benzene and 37 ml of dioxane were added, argon was passed through for 2 min and the mixture was stirred at 100° C. overnight. The reaction mixture was filtered through kieselguhr and washed with acetonitrile, and the filtrate was concentrated. The crude product was purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-17%). Yield: 1.06 g (68% of theory).

    [0559] LC/MS [Method 1]: R.sub.t=1.10 min; MS (ESIpos): m/z=300 (M+H).sup.+,

    [0560] .sup.1H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.99 (s, 1H), 7.75-7.62 (m, 2H), 7.43 (s, 1H), 6.74 (s, 1H), 6.68 (t, 1H), 3.84 (s, 3H), 3.75 (m, 3H).

    Example 2.2C

    4-[5-Chloro-2-(difluoromethyl)phenyl]-5-methoxypyridin-2(1H)-one

    [0561] ##STR00055##

    [0562] To 1.06 g (3.47 mmol) of 4-[5-chloro-2-(difluoromethyl)phenyl]-2,5-dimethoxypyridine and 4.44 g (27.73 mmol, 8 eq.) of pyridine hydrobromide were added 38 ml of DMF and the mixture was stirred at 100° C. for 5 h. The reaction mixture was cooled down and concentrated, and water and ethyl acetate were added. The aqueous phase was extracted once more with ethyl acetate. The combined organic phases were washed with saturated aqueous ammonium chloride solution and with saturated aqueous sodium chloride solution, then dried and concentrated. The residue was admixed with 5 ml of dichloromethane and left to stand overnight. The crystals formed were filtered off with suction and washed with a little dichloromethane and dried. The filtrate was purified by means of Biotage-Isolera (eluent: dichloromethane/methanol, 0-5%). Overall yield: 790 mg (79% of theory).

    [0563] LC/MS [Method 1]: R.sub.t=0.80 min; MS (ESIpos): m/z=286 (M+H).sup.+,

    [0564] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=11.32 (bs, 1H), 7.78-7.60 (m, 2H), 7.43 (s, 1H), 7.20 (s, 1H), 6.73 (t, 1H), 6.28 (s, 1H), 3.58 (s, 3H).

    Example 2.3A

    2-(2,5-Dimethoxypyridin-4-yl)-4-methylbenzonitrile

    [0565] ##STR00056##

    [0566] 2.50 g (9.36 mmol) of diisopropyl (2,5-dimethoxypyridin-4-yl)borate, 3.88 g (28.08 mmol, 3 eq.) of potassium carbonate and 0.764 g (0.936 mmol, 0.1 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct were initially charged in a flask, which was then evacuated and filled with argon three times. 2.27 g (11.23 mmol, 1.2 eq) of 2-bromo-4-methylbenzonitrile and 68 ml of dioxane were added, argon was passed through for 2 min and the mixture was stirred at 100° C. overnight. The reaction mixture was filtered through kieselguhr and washed with dichloromethane/methanol 9:1, and the filtrate was concentrated. The crude product was purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-40%). Yield: 1.72 g (71% of theory).

    [0567] LC/MS [Method 1]: R.sub.t=1.00 min; MS (ESIpos): m/z=255 (M+H).sup.+,

    [0568] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.03 (s, 1H), 7.81 (d, 1H), 7.42 (d, 1H), 7.37 (s, 1H), 6.78 (s, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 2.42 (s, 3H).

    Example 2.3B

    2-(5-Methoxy-2-oxo-1,2-dihydropyridin-4-yl)-4-methylbenzonitrile

    [0569] ##STR00057##

    [0570] To 1.72 g (6.63 mmol) of 2-(2,5-dimethoxypyridin-4-yl)-4-methylbenzonitrile and 8.49 g (53.03 mmol, 8 eq.) of pyridine hydrobromide were added 72 ml of DMF and the mixture was stirred at 100° C. for 4 h. The reaction mixture was cooled down and concentrated. The residue was stirred with 40 ml of water, filtered off with suction and washed with water. Subsequently, the residue was twice slurried in acetonitrile, concentrated and dried under high vacuum. Overall yield: 1.35 g (90% purity, 76% of theory).

    [0571] LC/MS [Method 1]: R.sub.t=0.63 min; MS (ESIpos): m/z=241 (M+H).sup.+,

    [0572] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.80 (d, 1H), 7.42 (d, 1H), 7.35 (s, 1H), 7.28 (bs, 1H), 6.35 (s, 1H), 3.63 (s, 3H), 2.42 (s, 3H).

    Example 3.1A

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoate (Racemate)

    [0573] ##STR00058##

    [0574] To a solution of 5.0 g (13.3 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate under argon and at −78° C. were added dropwise 14.0 ml (1.0M in THF, 14.0 mmol, 1.05 eq.) of lithium bis(trimethylsilyl)amide in 100 ml of tetrahydrofuran, and the mixture was stirred at −78° C. for 15 min. 2.6 g (14.7 mmol, 1.1 eq.) of neat ethyl trifluoromethanesulphonate were then added dropwise. The cooling bath was removed and the reaction mixture was stirred at RT for another 1 h. The reaction mixture was cooled to 0° C., and saturated aqueous ammonium chloride solution was added. After phase separation, the aqueous phase was extracted twice with methyl-tert-butyl ether. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified by means of flash chromatography (340 g of silica gel, eluent: cyclohexane-ethyl acetate mixtures 8:1, 4:1). The product-containing fractions were combined and concentrated under reduced pressure. The residue was dissolved in hot methyl tert-butyl ether and the solution was left to stand on the open bench, and after 10 min the mixture had crystallized almost completely. The crystals were filtered off and washed twice with methyl tert-butyl ether. The combined filtrates were concentrated under reduced pressure and the residue was re-crystallized as described. The two crystal batches were combined and dried under reduced pressure. Yield: 4.2 g (78% of theory)

    [0575] LC/MS [Method 1]: R.sub.t=1.05 min; MS (ESIpos): m/z=403 (M+H).sup.+,

    [0576] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.99 (d, 1H), 7.77-7.70 (m, 2H), 7.36 (s, 1H), 6.50 (s, 1H), 5.03 (dd, 1H), 3.64 (s, 3H), 2.19-2.06 (m, 2H), 1.40 (s, 9H), 0.85 (t, 3H).

    Example 3.1B

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (Racemate)

    [0577] ##STR00059##

    [0578] To a solution of 4.1 g (10.2 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoate (racemate) in 40 ml of dichloromethane under argon and at RT were added 7.8 ml (101.8 mmol, 10 eq.) of trifluoroacetic acid, the mixture was stirred at RT for 1 h, a further 7.8 ml (101.8 mmol, 10 eq.) of trifluoroacetic acid were added, the mixture was stirred at RT for 1 h, a further 7.8 ml (101.8 mmol, 10 eq.) of trifluoroacetic acid were added and the mixture was stirred at RT for 1 h. On completion of conversion, the reaction mixture was concentrated under reduced pressure and the residue was co-evaporated three times with dichloromethane and once with toluene and dried under reduced pressure. The residue was taken up in 100 ml of ethyl acetate and washed repeatedly with a highly dilute aqueous sodium hydrogencarbonate solution (where the pH of the wash water should not exceed pH 3-4 since the product otherwise has good solubility in water). The organic phase was subsequently dried (sodium sulphate), filtered and concentrated under reduced pressure. The residue was stirred in methyl tert-butyl ether, filtered, washed twice with methyl tert-butyl ether and dried under reduced pressure. Yield: 2.9 g (83% of theory)

    [0579] LC/MS [Method 1]: R.sub.t=0.81 min; MS (ESIpos): m/z=347 (M+H).sup.+,

    [0580] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=12.97 (s, 1H), 7.99 (d, 1H), 7.77-7.70 (m, 2H), 7.41 (s, 1H), 6.49 (s, 1H), 5.09 (dd, 1H), 3.64 (s, 3H), 2.21-2.09 (m, 2H), 0.84 (t, 3H).

    Example 3.1C

    tert-Butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2-fluorobenzoate (Racemate)

    [0581] ##STR00060##

    [0582] According to General Method 5B, 150 mg (0.43 mmol, 1.0 eq.) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 152 mg (0.65 mmol, 1.5 eq.) of tert-butyl 2-fluoro-4-aminophenylcarboxylate were reacted. The crude product was purified by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate 20-50% mixtures). Yield: 250 mg (93% purity, 99% of theory)

    [0583] LC/MS [Method 8]: R.sub.t=1.51 min; MS (ESIneg): m/z=538 (M−H).sup.−

    [0584] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.95 (s, 1H), 8.02-7.97 (m, 1H), 7.81 (t, 1H), 7.75-7.66 (m, 3H), 7.47 (s, 1H), 7.42 (dd, 1H), 6.54 (s, 1H), 5.59 (dd, 1H), 3.69 (s, 3H), 2.25-2.13 (m, 2H), 1.53 (s, 9H), 0.90 (t, 3H).

    Example 3.1D

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2-fluorobenzoic acid (Racemate)

    [0585] ##STR00061##

    [0586] According to General Method 2, 249 mg (0.43 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2-fluorobenzoate (racemate) were reacted. The crude product was purified by means of preparative HPLC (water/acetonitrile-0.1% formic acid gradient). Yield: 145 mg (65% of theory)

    [0587] LC/MS [Method 8]: R.sub.t=1.19 min; MS (ESIpos): m/z=484 (M+H).sup.+,

    [0588] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=12.99 (br. s, 1H), 10.94 (s, 1H), 8.02-7.97 (m, 1H), 7.86 (t, 1H), 7.77-7.67 (m, 3H), 6.54 (s, 1H), 5.60 (dd, 1H), 3.69 (s, 3H), 3.26-2.11 (m, 2H), 0.91 (t, 3H),

    [0589] .sup.19F-NMR (376.54 MHz, DMSO-d.sub.6): δ [ppm]=−107.7.

    Example 4.1A

    tert-Butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate

    [0590] ##STR00062##

    [0591] According to General Method 4A, 516 mg (91% purity, 1.8 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile were reacted with 1.2 eq. of tert-butyl bromoacetate at 100° C. Yield: 464 mg (68% of theory)

    [0592] LC/MS [Method 1]: R.sub.t=1.00 min; MS (ESIpos): m/z=375 (M+H).sup.+

    Example 5.1A

    5-(Bromomethyl)-1,3-oxazole

    [0593] ##STR00063##

    [0594] To a solution of 1.83 ml (13.12 mmol, 1.3 eq.) of triethylamine and 1.0 g (10.09 mmol, 1 eq.) of 1,3-oxazol-5-ylmethanol in 14 ml of N,N′-dimethylformamide under argon and at 0° C. were added dropwise 1.02 ml (13.12 mmol, 1.3 eq.) of methanesulphonyl chloride, and the mixture was stirred at 0° C. for 1 h. 2.45 g (28.26 mmol, 2.8 eq.) of lithium bromide were then added, and this reaction mixture was stirred at 0° C. for 1 h. After addition of water, the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was then purified by means of normal phase chromatography (eluent: dichloromethane). Yield 1.23 g (80% purity, 60% of theory)

    [0595] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.42 (s, 1H), 7.26 (s, 1H), 4.93 (s, 2H).

    Example 5.1B

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-5-yl)propanoate (Racemate)

    [0596] ##STR00064##

    [0597] According to General Method 8B, 1.5 g (4.00 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate were reacted with 1.78 g (51% purity, 5.60 mmol, 1.4 eq.) f 5-(bromomethyl)-1,3-oxazole. Yield: 1.89 g (60% purity, 62% of theory).

    [0598] LC/MS [Method 1]: R.sub.t=0.98 min; MS (ESIpos): m/z=456 (M+H).sup.+.

    Example 5.1C

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-5-yl)propanoic acid (Racemate)

    [0599] ##STR00065##

    [0600] According to General Method 6A, 1.89 g (60% purity, 2.48 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-5-yl)propanoate (racemate) in 28 ml of dichloromethane were reacted with 14 ml (435 mmol) of TFA. Yield: 597 mg (80% purity, 48% of theory)

    [0601] LC/MS [Method 1]: R.sub.t=0.70 min; MS (ESIpos): m/z=400 (M+H).sup.+,

    [0602] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.24 (br. s, 1H), 8.17 (s, 1H), 8.02-7.93 (m, 1H), 7.77-7.66 (m, 2H), 7.35 (s, 1H), 6.85 (s, 1H), 6.47 (s, 1H), 5.32 (dd, 1H), 3.63-3.72 (m, 1H), 3.58-3.47 (m, 4H).

    Example 6.1A

    4-(Bromomethyl)-1,3-oxazole

    [0603] ##STR00066##

    [0604] To a solution of 1.91 ml (13.72 mmol, 1.3 eq.) of triethylamine and 1.05 g (10.56 mmol) of 1,3-oxazol-4-ylmethanol in 15 ml of N,N′-dimethylformamide under argon and at 0° C. were added dropwise 1.06 ml (13.72 mmol, 1.3 eq.) of methanesulphonyl chloride, and the mixture was stirred at 0° C. for 1 h. 2.57 g (29.56 mmol, 2.8 eq.) of lithium bromide were then added, and the reaction mixture was stirred at 0° C. for 1 h. After addition of water, the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was converted without further workup. Yield 1.97 g (50% purity, 58% of theory)

    [0605] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.40 (s, 1H), 8.18 (s, 1H), 4.59 (s, 2H).

    Example 6.1B

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-4-yl)propanoate (Racemate)

    [0606] ##STR00067##

    [0607] According to General Method 8B, 813 mg (2.17 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate were reacted with 983.8 mg (50% purity, 3.04 mmol, 1.4 eq.) of 4-(bromomethyl)-1,3-oxazole. Yield: 655 mg (65% of theory)

    [0608] LC/MS [Method 1]: R.sub.t=0.98 min; MS (ESIpos): m/z=456 (M+H).sup.+,

    [0609] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.28 (s, 1H), 7.97 (d, 1H), 7.78 (s, 1H), 7.75-7.61 (m, 2H), 7.31 (s, 1H), 6.45 (s, 1H), 5.34 (dd, 1H), 3.56 (s, 3H), 3.50-3.39 (m, 1H), 3.36-3.26 (m, 1H), 1.41 (s, 9H).

    Example 6.1C

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-4-yl)propanoic acid (Racemate)

    [0610] ##STR00068##

    [0611] According to General Method 6A, 655 mg (1.41 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-4-yl)propanoate (racemate) in 14 ml of dichloromethane were reacted with 7 ml (90.86 mmol) of TFA. Yield: 403 mg (70% of theory)

    [0612] LC/MS [Method 1]: R.sub.t=0.73 min; MS (ESIpos): m/z=400 (M+H).sup.+,

    [0613] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.14 (br. s, 1H), 8.26 (s, 1H), 7.97 (d, 1H), 7.78-7.65 (m, 3H), 7.33 (s, 1H), 6.43 (s, 1H), 5.36 (dd, 1H), 3.55 (s, 3H), 3.53-3.43 (m, 1H), 3.38-3.25 (m, 1H).

    Example 7.1A

    Pyridin-2-ylmethyl methanesulphonate

    [0614] ##STR00069##

    [0615] To a solution of 4.00 g (36.65 mmol) of pyridin-2-ylmethanol and 11.24 ml (80.64 mmol, 2.2 eq.) of triethylamine in 122 ml of tetrahydrofuran under argon and at 0° C. was added a solution of 2.84 ml (36.65 mmol, 1 eq.) of methanesulphonyl chloride in 24 ml of tetrahydrofuran, and the mixture was stirred for 3 h. Tetrahydrofuran was removed under reduced pressure. The crude product was then dissolved in dichloromethane, and the resulting mixture was washed with saturated aqueous sodium chloride solution. The organic phase was dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate (20-50%) mixtures). Yield: 4.72 g (68% of theory)

    [0616] LC/MS [Method 3]: R.sub.t=0.98 min; MS (ESIpos): m/z=188 (M+H).sup.+,

    [0617] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.67-8.48 (m, 1H), 7.89 (td, 1H), 7.54 (d, 1H), 7.42 (ddd, 1H), 5.30 (s, 2H), 3.28 (s, 3H).

    Example 7.1B

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-2-yl)propanoate (Racemate)

    [0618] ##STR00070##

    [0619] To a solution of 1.50 g (4.00 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 30 ml of tetrahydrofuran under argon and at −78° C. were added dropwise 4.60 ml (1.0M in THF, 1.15 eq.) of lithium bis(trimethylsilyl)amide, and the mixture was stirred for 15 min. 1.06 g (5.6 mmol, 1.4 eq.) of neat pyridin-2-ylmethyl methanesulphonate were then added. The resulting reaction mixture was stirred at −78° C. for another 30 min and at RT for another 1.5 h. Saturated aqueous ammonium chloride solution was added to the reaction mixture. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution. The organic phase was dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified by means of normal phase chromatography (eluent: dichloromethane/methanol (2-5%) mixtures). Yield 1.99 g (93% purity, 99% of theory)

    [0620] LC/MS [Method 1]: R.sub.t=0.97 min; MS (ESIpos): m/z=466 (M+H).sup.+.

    Example 7.1C

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-2-yl)propanoic acid (Racemate)

    [0621] ##STR00071##

    [0622] According to General Method 6A, 1.99 g (93% purity, 3.98 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-2-yl)propanoate (racemate) in 40 ml of dichloromethane were reacted with 20 ml (259.6 mmol) of TFA. Yield: 220 mg (93% purity, 13% of theory)

    [0623] LC/MS [Method 1]: R.sub.t=0.64 min; MS (ESIpos): m/z=410 (M+H).sup.+,

    [0624] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.08 (br. s, 1H), 8.48 (d, 1H), 7.95 (d, 1H), 7.73-7.60 (m, 3H), 7.27 (s, 1H), 7.24-7.11 (m, 2H), 6.40 (s, 1H), 5.55 (t, 1H), 3.66-3.57 (m, 2H), 3.49 (s, 3H).

    Example 8.1A

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-3-yl)propanoate (Racemate)

    [0625] ##STR00072##

    [0626] To a solution of 2.40 g (6.40 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 48 ml of tetrahydrofuran under argon and at −78° C. were added dropwise 16.01 ml (1.0M in THF, 2.5 eq.) of lithium bis(trimethylsilyl)amide, and the mixture was stirred for 20 min. Subsequently, 2.27 g (8.96 mmol, 1.4 eq.) of 3-(bromomethyl)pyridine hydrobromide were added. The resulting reaction mixture was stirred at −78° C. for another 30 min and at RT for another 1.5 h. Saturated aqueous ammonium chloride solution was added to the reaction mixture. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution. The organic phase was dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate (0-100%) mixtures). Yield 2.0 g (90% purity, 62% of theory)

    [0627] LC/MS [Method 1]: R.sub.t=0.84 min; MS (ESIpos): m/z=466 (M+H).sup.+,

    [0628] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=ppm 8.43 (d, 1H), 8.39 (dd, 1H), 7.96 (d, 1H), 7.71 (dd, 1H), 7.65 (d, 1H), 7.55-7.48 (m, 1H), 7.25 (dd, 1H), 7.21 (s, 1H), 6.46 (s, 1H), 5.32 (dd, 1H), 3.54-3.38 (m, 5H), 1.40 (s, 9H).

    Example 8.1B

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-3-yl)propanoic acid hydrochloride (Racemate)

    [0629] ##STR00073##

    [0630] According to General Method 6B, 2.0 g (3.86 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-3-yl)propanoate (racemate) and 39 ml of a hydrogen chloride in dioxane (4 M) solution were reacted. Yield: 1.8 g (88% purity, 92% of theory).

    [0631] LC/MS [Method 1]: R.sub.t=0.57 min; MS (ESIpos): m/z=410 (M+H).sup.+,

    [0632] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.89 (s, 1H), 8.77 (d, 1H), 8.29 (d, 1H), 7.97 (d, 1H), 7.91 (dd, 1H), 7.77-7.63 (m, 2H), 7.40 (s, 1H), 6.44 (s, 1H), 5.50 (dd, 1H), 3.76 (dd, 1H), 3.65 (dd, 1H), 3.52 (s, 3H).

    Example 9.1A

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoate (Racemate)

    [0633] ##STR00074##

    [0634] To a solution of 2.25 g (6.00 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 48 ml of tetrahydrofuran under argon and at −78° C. were added dropwise 15.01 ml (1.0M in THF, 2.5 eq.) of lithium bis(trimethylsilyl)amide, and the mixture was stirred for 20 min. Subsequently, 2.13 g (8.40 mmol, 1.4 eq.) of 4-(bromomethyl)pyridine hydrobromide were added. The resulting reaction mixture was stirred at −78° C. for another 30 min and at RT for another 1.5 h. Saturated aqueous ammonium chloride solution was added to the reaction mixture. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution. The organic phase was dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate (0-100%) mixtures). Yield 2.0 g (87% purity, 62% of theory)

    [0635] LC/MS [Method 1]: R.sub.t=0.76 min; MS (ESIpos): m/z=466 (M+H).sup.+,

    [0636] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.46-8.37 (m, 2H), 7.97 (d, 1H), 7.71 (dd, 1H), 7.66 (d, 1H), 7.26-7.13 (m, 3H), 6.45 (s, 1H), 5.36 (t, 1H), 3.53-3.40 (m, 5H), 1.40 (s, 9H).

    Example 9.1B

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoic acid hydrochloride (Racemate)

    [0637] ##STR00075##

    [0638] According to General Method 6B, 2.1 g (3.97 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoate (racemate) and 40 ml of a hydrogen chloride in dioxane (4 M) solution were reacted. Yield: 1.9 g (93% purity, 100% of theory).

    [0639] LC/MS [Method 1]: R.sub.t=0.58 min; MS (ESIpos): m/z=410 (M+H).sup.+,

    [0640] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.78 (d, 2H), 7.97 (d, 1H), 7.92 (d, 2H), 7.75-7.66 (m, 2H), 7.42 (s, 1H), 6.44 (s, 1H), 5.63 (dd, 1H), 3.87-3.73 (m, 2H), 3.54 (s, 3H).

    Example 10.1A

    6-Methoxypyridin-3-ol

    [0641] ##STR00076##

    [0642] To a solution of 46.0 g (392 mmol) of N-methylmorpholine N-oxide in 500 ml of dichloromethane at RT were added 50 g (327 mmol) of 6-methoxypyridin-3-ylboronic acid, and the mixture was stirred at 50° C. for 14 h. Additional N-methylmorpholine N-oxide was added until conversion was complete. The reaction mixture was concentrated under reduced pressure and the crude product was purified by means of flash chromatography (silica gel 60, cyclohexane/ethyl acetate mixtures). Yield: 32.9 g (80% of theory)

    [0643] LC/MS [Method 1]: R.sub.t=0.37 min; MS (ESIpos): m/z=126 (M+H).sup.+,

    [0644] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=9.27 (s, 1H), 7.67 (d, 1H), 7.16 (dd, 1H), 6.66 (d, 1H), 3.74 (s, 3H).

    Example 10.1B

    2-Methoxy-5-(tetrahydro-2H-pyran-2-yloxy)pyridine

    [0645] ##STR00077##

    [0646] 10.1 g (119.9 mmol, 1.5 eq.) of 3,4-dihydro-2H-pyran and 1.4 g (8.0 mmol, 0.1 eq.) of 4-toluenesulphonic acid were added to a solution of 10.0 g (79 9 mmol) of 6-methoxypyridin-3-ol in 150 ml of dichloromethane, and the mixture was stirred at RT for 5 days. After addition of water/dichloromethane and phase separation, the aqueous phase was extracted with dichloromethane. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. Yield: 17.3 g (100% of theory)

    [0647] LC/MS [Method 1]: R.sub.t=0.95 min; MS (ESIpos): m/z=210 (M+H).sup.+.

    Example 10.1C

    4-Iodo-2-methoxy-5-(tetrahydro-2H-pyran-2-yloxy)pyridine

    [0648] ##STR00078##

    [0649] To a solution of 16.2 g (75.1 mmol) of 2-methoxy-5-(tetrahydro-2H-pyran-2-yloxy)pyridine in 250 ml of THF at −78° C. were added 13.6 ml (90.1 mmol, 1.2 eq.) of 1,2-bis(dimethylamino)ethane and 54.0 ml (86.4 mmol, 1.15 eq.) of n-butyllithium, and the mixture was stirred at −78° C. for 1 h. 24.8 g (97.6 mmol, 1.3 eq.) of iodine were then added, and the reaction mixture was stirred at −78° C. for 1 h and then allowed to come to RT overnight. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium thiosulphate solution, dried (sodium sulphate), filtered and concentrated under reduced pressure. Yield: 25.1 g (82% purity, 82% of theory).

    [0650] LC/MS [Method 1]: R.sub.t=1.18 min; MS (ESIpos): m/z=336 (M+H).sup.+.

    Example 10.1D

    4-Iodo-6-methoxypyridin-3-ol

    [0651] ##STR00079##

    [0652] To a solution of 25.1 g (82% purity, 61 3 mmol) of 4-iodo-2-methoxy-5-(tetrahydro-2H-pyran-2-yloxy)pyridine in 50 ml of dioxane and 50 ml of water were added 50 ml (3 molar, 150 mmol) of hydrochloric acid, and the mixture was stirred at RT for 2 h. The reaction mixture was then filtered and the precipitate was rinsed with water and dried under high vacuum. Yield: 13.5 g (93% purity, 81% of theory).

    [0653] LC/MS [Method 1]: R.sub.t=0.76 min; MS (ESIpos): m/z=252 (M+H).sup.+,

    [0654] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.70 (s, 1H), 7.22 (s, 1H), 3.74 (s, 3H).

    Example 10.1E

    5-(Difluoromethoxy)-4-iodo-2-methoxypyridine

    [0655] ##STR00080##

    [0656] To a solution of 600 mg (93% purity, 2.22 mmol) of 4-iodo-6-methoxypyridin-3-ol in 4.8 ml of acetonitrile were added 4.8 ml of aqueous potassium hydroxide solution (6 M), the mixture was cooled in an ice bath, and 863 μl (75% purity, 3.56 mmol, 1.6 eq.) of difluoromethyl trifluormethanesulphonate [Angew. Chem. Int. Ed. 2013, 52, 1-5; Journal of Fluorine Chemistry 2009, 130, 667-670] were added with vigorous stirring. The reaction mixture was stirred for 2 min and diluted with 33 ml of water. The aqueous phase was extracted twice with 40 ml each time of diethyl ether. The combined organic phases were dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. The crude product was purified by flash chromatography (silica gel, petroleum ether/ethyl acetate (12-20%) mixtures). Yield: 407 mg (90% purity, 55% of theory)

    [0657] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.1 (s, 1H), 7.45 (s, 1H), 7.16 (t, 1H), 3.84 (s, 3H).

    Example 10.1F

    4-Chloro-2-[5-(difluoromethoxy)-2-methoxypyridin-4-yl]benzonitrile

    [0658] ##STR00081##

    [0659] According to General Method 2A, 460 mg (90% purity, 1.38 mmol) of 5-(difluoromethoxy)-4-iodo-2-methoxypyridine were reacted with 299 mg (1.65 mmol, 1.2 eq.) of 5-chloro-2-cyanophenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct. The crude product was purified by flash chromatography (silica gel, petroleum ether/ethyl acetate (10-15%) mixtures). Yield: 230 mg (80% purity, 43% of theory)

    [0660] LC/MS [Method 1]: R.sub.t=1.12 min; MS (ESIpos): m/z=311 (M+H).sup.+,

    [0661] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.26 (s, 1H), 8.06 (d, 1H), 7.82-7.74 (m, 2H), 7.09 (s, 1H), 7.06 (t, 1H), 3.91 (s, 3H).

    Example 10.1G

    4-Chloro-2-[5-(difluoromethoxy)-2-oxo-1,2-dihydropyridin-4-yl]benzonitrile

    [0662] ##STR00082##

    [0663] According to General Method 3A, 230 mg (80% purity, 0.59 mmol) of 4-chloro-2-[5-(difluoromethoxy)-2-methoxypyridin-4-yl]benzonitrile were reacted with pyridinium hydrobromide. The crude product was purified by flash chromatography (silica gel, dichloromethane/methanol (3-25%) mixtures). Yield: 167 mg (95% of theory)

    [0664] LC/MS [Method 1]: R.sub.t=0.79 min; MS (ESIpos): m/z=297 (M+H).sup.+,

    [0665] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=11.88 (br. s, 1H), 8.03 (d, 1H), 7.80-7.65 (m, 3H), 6.87 (t, 1H), 6.56 (s, 1H).

    Example 11.1A

    tert-Butyl [4-(5-chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]acetate

    [0666] ##STR00083##

    [0667] According to General Method 4B, 1.19 g (92% purity, 3.69 mmol) of 4-chloro-2-[5-(difluoromethoxy)-2-oxo-1,2-dihydropyridin-4-yl]benzonitrile were reacted with 1.2 eq. of tert-butyl bromoacetate at 100° C. Yield: 1.30 g (95% purity, 81% of theory).

    [0668] LC/MS [Method 1]: R.sub.t=0.97 min; MS (ESIpos): m/z=411 (M+H).sup.+,

    [0669] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.09-7.97 (m, 2H), 7.81-7.70 (m, 2H), 6.81 (t, 1H), 6.63 (s, 1H), 4.66 (s, 2H), 1.44 (s, 9H).

    Example 11.1B

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]-3-(pyridin-2-yl)propanoate (Racemate)

    [0670] ##STR00084##

    [0671] To a solution of 800 mg (1.85 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]acetate in 18 ml of tetrahydrofuran under argon at −78° C. were added dropwise 2.13 ml (1.0 M in THF, 1.15 eq.) of lithium bis(trimethylsilyl)amide, and the mixture was stirred for 15 min. 533 mg (91% purity, 2.59 mmol, 1.4 eq.) of neat pyridin-2-ylmethyl methanesulphonate were then added. The resulting reaction mixture was stirred at −78° C. for another 30 min and at RT for another 1.5 h. Saturated aqueous ammonium chloride solution was added to the reaction mixture. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution. The organic phase was dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate (0-75%) mixtures). Yield 250 mg (95% purity, 26% of theory)

    [0672] LC/MS [Method 1]: R.sub.t=1.00 min; MS (ESIpos): m/z=502 (M+H).sup.+.

    [0673] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.48 (d, 1H), 8.01 (d, 1H), 7.85 (s, 1H), 7.75 (dd, 1H), 7.72-7.63 (m, 2H), 7.26-7.17 (m, 2H), 6.68 (t, 1H), 6.55 (s, 1H), 5.63 (t, 1H), 3.65-3.55 (m, 2H), 1.37 (s, 9H).

    Example 11.1C

    2-[4-(5-Chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]-3-(pyridin-2-yl)propanoic acid-trifluoroacetic acid (Racemate)

    [0674] ##STR00085##

    [0675] According to General Method 6A, 250 mg (0.47 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]-3-(pyridin-2-yl)propanoate (racemate) in 8 ml of dichloromethane were reacted with 4 ml of TFA. Yield: 300 mg (86% purity, 97% of theory)

    [0676] LC/MS [Method 1]: R.sub.t=0.66 min; MS (ESIpos): m/z=446 (M+H).sup.+,

    [0677] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.65 (d, 1H), 8.12-7.98 (m, 2H), 7.87 (s, 1H), 7.82-7.67 (m, 2H), 7.58-7.46 (m, 2H), 6.70 (t, 1H), 6.57 (s, 1H), 5.57 (dd, 1H), 3.80 (dd, 1H), 3.68 (dd, 1H).

    Example 12.1A

    4-(5-Chloro-2-fluorophenyl)-2,5-dimethoxypyridine

    [0678] ##STR00086##

    [0679] According to General Method 2A, 200 mg (1.09 mmol, 1.2 eq.) of (2,5-dimethoxypyridin-4-yl)boric acid were reacted with 274 mg (1.31 mmol) of 2-bromo-4-chloro-1-fluorobenzene in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct. After workup, the crude product was then purified by means of flash chromatography (silica gel 60, cyclohexane/dichloromethane 0-20% mixtures). Yield: 150 mg (50% of theory)

    [0680] LC/MS [Method 1]: R.sub.t=1.11 min; MS (ESIpos): m/z=268 (M+H).sup.+,

    [0681] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.00 (s, 1H), 7.53 (dd, 1H), 7.49 (dd, 1H), 7.40-7.32 (m, 1H), 6.80 (s, 1H), 3.84 (s, 3H), 3.78 (s, 3H)

    Example 12.1B

    4-(5-Chloro-2-fluorophenyl)-5-methoxypyridin-2(1H)-one

    [0682] ##STR00087##

    [0683] According to General Method 3A, 4.45 g (16.46 mmol) of 4-(5-chloro-2-fluorophenyl)-2,5-dimethoxypyridine were reacted with pyridinium hydrochloride. Yield: 4.00 g (80% purity, 77% of theory).

    [0684] LC/MS [Method 1]: R.sub.t=0.75 min; MS (ESIpos): m/z=254 (M+H).sup.+.

    [0685] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=11.32 (bs, 1H), 7.53 (ddd, 1H), 7.49-7.42 (m, 1H), 7.34 (t, 1H), 7.21 (s, 1H), 6.36 (s, 1H), 3.61 (s, 3H).

    Example 12.1C

    tert-Butyl [4-(5-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate

    [0686] ##STR00088##

    [0687] According to General Method 4A, 4.0 g (80% purity, 12.62 mmol) of 4-(5-chloro-2-fluorophenyl)-5-methoxypyridin-2(1H)-one were reacted with 1.2 eq. of tert-butyl bromoacetate at 100° C. Yield: 3.85 g (83% of theory)

    [0688] LC/MS [Method 1]: R.sub.t=0.96 min, MS (ESIpos): m/z=368 (M+H).sup.+,

    [0689] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=87.58-7.51 (m, 1H), 7.51-7.42 (m, 2H), 7.36 (dd, 1H), 6.42 (s, 1H), 4.58 (s, 2H), 3.59 (s, 3H), 1.44 (s, 9 H).

    Example 12.1D

    tert-Butyl 2-[4-(5-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-2-yl)propanoate (Racemate)

    [0690] ##STR00089##

    [0691] To a solution of 1.00 g (2.72 mmol) of tert-butyl [4-(5-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 20 ml of tetrahydrofuran under argon at −78° C. were added dropwise 6.80 ml (1.0 M in THF, 2.5 eq.) of lithium bis(trimethylsilyl)amide, and the mixture was stirred for 15 min. Subsequently, 963 mg (3.81 mmol, 1.4 eq.) of 2-(bromomethyl)pyridine hydrobromide were added. The resulting reaction mixture was stirred at −78° C. for another 30 min and at RT for another 1.5 h. Saturated aqueous ammonium chloride solution was added to the reaction mixture. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution. The organic phase was dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate (0-70%) mixtures). Yield: 1.04 g (82% of theory)

    [0692] LC/MS [Method 1]: R.sub.t=0.97 min; MS (ESIpos): m/z=459 (M+H).sup.+.

    [0693] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.49 (dd, 1H), 7.78-7.62 (m, 1H), 7.53 (ddd, 1H), 7.44 (dd, 1H), 7.33 (t, 1H), 7.29-7.12 (m, 3H), 6.37 (s, 1H), 5.60 (dd, 1H), 3.67-3.51 (m, 2H), 3.50 (s, 3H), 1.36 (s, 9H).

    Example 12.1E

    2-[4-(5-Chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-2-yl)propanoic acid hydrochloride (Racemate)

    [0694] ##STR00090##

    [0695] According to General Method 6B, 1.04 g (2.22 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoate (racemate) and 22.4 ml of a hydrogen chloride in dioxane (4 M) solution were reacted. Yield: 1.15 g (75% purity, 88% of theory).

    [0696] LC/MS [Method 1]: R.sub.t=0.70 min; MS (ESIpos): m/z=403 (M+H).sup.+.

    [0697] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.78 (d, 1H), 8.41-8.32 (m, 1H), 7.92-7.74 (m, 2H), 7.54 (ddd, 1H), 7.50-7.41 (m, 2H), 7.38-7.31 (m, 1H), 6.40 (s, 1H), 5.65-5.57 (m, 1H), 3.98 (dd, 1H), 3.74 (dd, 1H), 3.55 (s, 3H).

    Example 13.1A

    (5-Chloro-2-methoxypyridin-4-yl)boronic acid

    [0698] ##STR00091##

    [0699] According to General Method 1A, 10.0 g (69.65 mmol) of 5-chloro-2-methoxypyridine were reacted. The desired product precipitated on acidification with hydrochloric acid (2N). Yield: 10.44 g (91% purity, 73% of theory).

    [0700] LC/MS [Method 1]: R.sub.t=0.50 min; MS (ESIpos): m/z=188 (M+H).sup.+

    [0701] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.64 (bs, 2H), 8.12 (s, 1H), 6.81 (s, 1H), 3.82 (s, 3H).

    Example 13.1B

    4-Chloro-2-(5-chloro-2-methoxypyridin-4-yl)benzonitrile

    [0702] ##STR00092##

    [0703] According to General Method 2A, 5.36 g (91% purity, 26.03 mmol) of 5-chloro-2-methoxypyridin-4-ylboronic acid were reacted with 5.12 g (23.66 mmol) of 2-bromo-4-chlorobenzonitrile in the presence of [1,1-bis(diphenylphosphino)ferrocene] palladium(II) chloride/dichloromethane monoadduct. After workup, the crude product was then purified by flash chromatography (silica gel 60, cyclohexane/dichloromethane mixtures). Yield: 4.11 g (91% purity, 52% of theory).

    [0704] LC/MS [Method 1]: R.sub.t=1.17 min; MS (ESIpos): m/z=279 (M+H).sup.+.

    Example 13.1C

    4-Chloro-2-(5-chloro-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile

    [0705] ##STR00093##

    [0706] According to General Method 3A, 6.34 g (93% purity, 21.12 mmol) of 4-chloro-2-(5-chloro-2-methoxypyridin-4-yl)benzonitrile were reacted with pyridinium hydrochloride. Yield: 4.23 g (76% of theory)

    [0707] LC/MS [Method 1]: R.sub.t=0.82 min; MS (ESIpos): m/z=265 (M+H).sup.+.

    Example 13.1D

    tert-Butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate

    [0708] ##STR00094##

    [0709] According to General Method 4A, 3.1 g (11.46 mmol) of 4-chloro-2-(5-chloro-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile were reacted with 1.2 eq. of tert-butyl bromoacetate at 100° C. Yield: 3.65 g (84% of theory)

    [0710] LC/MS [Method 8]: R.sub.t=1.34 min, MS (ESIneg): m/z=377 (M−H).sup.−,

    [0711] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.20 (s, 1H), 8.09-8.20 (m, 1H), 7.85-7.72 (m, 2H), 6.67 (s, 1H), 4.65 (s, 2H), 1.44 (s, 9H).

    Example 13.1E

    tert-Butyl 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-2-yl)propanoate (Racemate)

    [0712] ##STR00095##

    [0713] To a solution of 1.00 g (2.34 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate in 20 ml of tetrahydrofuran under argon at −78° C. were added dropwise 3.56 ml (1.0 M in THF, 1.35 eq.) of lithium bis(trimethylsilyl)amide, and the mixture was stirred for 15 min. 568 mg (3.03 mmol, 1.15 eq.) of neat pyridin-2-ylmethyl methanesulphonate were then added. The resulting reaction mixture was stirred at −78° C. for another 15 min and at RT for another 45 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution. The organic phase was dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate (20-50%) mixtures). Yield: 698 mg (56% of theory)

    [0714] LC/MS [Method 1]: R.sub.t=1.09 min; MS (ESIpos): m/z=470 (M+H).sup.+.

    [0715] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.49 (dd, 1H), 8.03 (d, 2H), 7.77 (dd, 1H), 7.73 (d, 1H), 7.69 (td, 1H), 7.26-7.17 (m, 2H), 6.60 (s, 1H), 5.69-5.55 (m, 1H), 3.65-3.55 (m, 2H), 1.40 (s, 9H)

    Example 13.1F

    2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-2-yl)propanoic acid (Racemate)

    [0716] ##STR00096##

    [0717] According to General Method 6A, 698 mg (1.48 mmol) of tert-butyl 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-2-yl)propanoate (racemate) in 24 ml of dichloromethane were reacted with 6 ml (78 mmol) of TFA. The crude product was then purified by means of preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 298 mg (49% of theory).

    [0718] LC/MS [Method 1]: R.sub.t=0.71 min; MS (ESIpos): m/z=414 (M+H).sup.+,

    [0719] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.30 (bs, 1H), 8.52-8.41 (m, 1H), 8.15-7.93 (m, 2H), 7.79-7.71 (m, 2 H), 7.67 (td, 1H), 7.28-7.11 (m, 2H), 6.56 (s, 1H), 5.79-5.50 (m, 1H), 3.63 (d, 2H).

    Example 14.1A

    2-[(Benzyloxy)methyl]tetrahydro-2H-pyran (Racemate)

    [0720] ##STR00097##

    [0721] At 0° C., a solution of 25.0 g (215 mmol) of tetrahydro-2H-pyran-2-ylmethanol (racemate) in 500 ml of THF was slowly added dropwise to a suspension of 9.47 g (237 mmol, 60% in mineral oil) of sodium hydride in 500 ml of THF, and after the addition had ended, the mixture was stirred at 0° C. for another 30 min. 25.7 ml (215 mmol) of benzyl bromide were then added, and the mixture was stirred at 0° C. for another 30 min and at room temperature for another 1 h. The reaction was terminated by addition of 200 ml of saturated aqueous ammonium chloride solution, and the phases were separated. The aqueous phase was extracted twice with 200 ml of methyl tert-butyl ether. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/cyclohexane gradient, 340 g silica cartridge, flow rate: 100 ml/min), giving the title compound. Yield: 41.9 g (94% of theory)

    [0722] LC/MS [Method 3]: R.sub.t=2.18 min; MS (ESIpos): m/z=207 (M+H).sup.+,

    [0723] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.37-7.25 (m, 5H), 4.47 (s, 2H), 3.87-3.81 (m, 1H), 3.47-3.28 (m, 4H), 1.80-1.72 (m, 1H), 1.58-1.37 (m, 4H), 1.25-1.13 (m, 1H).

    Example 14.1B

    (R)-2-[(Benzyloxy)methyl]tetrahydro-2H-pyran

    [0724] ##STR00098##

    [0725] Enantiomer separation of 41.9 g of the racemate from Example 3.12A gave 16.7 g of the title compound Example 3.12B (enantiomer 1): chiral HPLC: R.sub.t=5.28 min; 99% ee, purity 93%.

    [0726] Optical rotation: [α].sub.589.sup.20.0=+14.9° (c 0.43 g/100 cm.sup.3, chloroform)

    [0727] Separation method: column: OD-H 5 μm 250 mm×20 mm; eluent: 95% isohexane, 5% 2-propanol; temperature: 25° C.; flow rate: 25 ml/min; UV detection: 210 nm.

    [0728] Analysis: column: OD-H 5 μm 250 mm×4.6 mm; eluent: 95% isohexane, 5% 2-propanol; flow rate: 1 ml/min; UV detection: 220 nm.

    Example 14.1C

    (S)-2-[(Benzyloxy)methyl]tetrahydro-2H-pyran

    [0729] ##STR00099##

    [0730] Enantiomer separation of 41.9 g of the racemate from Example 3.12A gave 17.0 g of the title compound Example 3.12C (enantiomer 2): chiral HPLC: R.sub.t=7.36 min; 96% ee, 96% purity.

    [0731] Optical rotation: [α].sub.589.sup.20.0=−13.9° (c 0.61 g/100 cm.sup.3, chloroform)

    [0732] Separation method: column: OD-H 5 μm 250 mm×20 mm; eluent: 95% isohexane, 5% 2-propanol; temperature: 25° C.; flow rate: 25 ml/min; UV detection: 210 nm.

    [0733] Analysis: column: OD-H 5 μm 250 mm×4.6 mm; eluent: 95% isohexane, 5% 2-propanol; flow rate: 1 ml/min; UV detection: 220 nm.

    Example 14.1D

    (25)-Tetrahydro-2H-pyran-2-ylmethanol

    [0734] ##STR00100##

    [0735] To a solution of 17.0 g (82.4 mmol) of (S)-2-[(benzyloxy)methyl]tetrahydro-2H-pyran (96% ee, 96% purity) in 120 ml of ethanol were added 3.51 g (3.30 mmol) of palladium on carbon (10%), and hydrogenation was effected at room temperature and under standard pressure overnight. Another 1.75 g (1.65 mmol) of palladium on carbon (10%) were then added, and hydrogenation was effected at room temperature for a further 72 h. Subsequently, the reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by chromatography (silica, dichloromethane/methanol gradient) and the product fractions were freed of the solvent at <25° C. and >50 mbar. Yield: 8.23 g (86% of theory)

    [0736] Optical rotation: [α].sub.589.sup.20.0=+9.1° (c 0.36 g/100 cm.sup.3, chloroform), cf. A. Aponick, B. Biannic, Org. Lett. 2011, 13, 1330-1333.

    [0737] GC/MS [Method 7]: R.sub.t=1.82 min; MS: m/z=116 (M).sup.+,

    [0738] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=4.51 (t, 1H), 3.87-3.81 (m, 1H), 3.37-3.18 (m, 4H), 1.80-1.71 (m, 1H), 1.59-1.50 (m, 1H), 1.49-1.36 (m, 3H), 1.19-1.05 (m, 1H).

    Example 14.1E

    (2S)-Tetrahydro-2H-pyran-2-ylmethyl trifluoromethanesulphonate

    [0739] ##STR00101##

    [0740] According to General Method 7A, 330 mg (2.84 mmol) of (2S)-tetrahydro-2H-pyran-2-ylmethanol were reacted with 0.57 ml (3.41 mmol, 1.2 eq.) of trifluoromethanesulphonic anhydride in the presence of 0.48 ml (3.41 mmol, 1.2 eq.) of triethylamine The crude product was reacted in the next stage without further purification.

    [0741] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=4.32 (dd, 1H), 4.18 (dd, 1H), 4.00-3.92 (m, 1H), 3.60-3.52 (m, 1H), 3.48-3.39 (m, 1H), 1.85-1.74 (m, 1H), 1.56-1.41 (m, 4H), 1.28-1.14 (m, 1H).

    Example 14.1F

    tert-Butyl 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoate (Diastereomer Mixture)

    [0742] ##STR00102##

    [0743] According to General Method 8A, 2.13 g (5.60 mmol) of tert-butyl 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoate, 1.70 g (90% purity, 6.16 mmol) of (25)-tetrahydro-2H-pyran-2-ylmethyl trifluoromethanesulphonate and 5.56 ml (5.56 mmol) of lithium bis(trimethylsilyl)amide (1 M in THF) in 90 ml of THF were reacted. After aqueous workup, the crude product was then purified by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate (15-40%) mixtures). Yield 1.61 g (95% purity, 57% of theory).

    [0744] LC/MS [Method 1]: R.sub.t=1.26 min; MS (ESIpos): m/z=477 (M−15).sup.+.

    Example 14.1G

    2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoic acid (Diastereomer Mixture)

    [0745] ##STR00103##

    [0746] According to General Method 6A, 1.61 g (95% purity, 3.20 mmol) of tert-butyl 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoate (diastereomer mixture) in 64 ml of dichloromethane were reacted with 12.8 ml of TFA. The crude product was then purified by means of preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 1.05 g (78% of theory)

    [0747] LC/MS [Method 1]: R.sub.t=0.97 min; MS (ESIpos): m/z=421 (M+H).sup.+,

    [0748] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.09 (bs, 1H), 8.14-8.01 (m, 2H), 7.86-7.74 (m, 2H), 6.67-6.56 (m, 1H), 5.39-5.13 (m, 1H), 3.90-3.75 (m, 1H), 3.27-2.74 (m, 2H), 2.44-2.22 (m, 1H), 2.16-2.00 (m, 1H), 1.79-1.67 (m, 1H), 1.64-1.09 (m, 5H).

    Example 15.1A

    tert-Butyl 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-4-yl)propanoate (Racemate)

    [0749] ##STR00104##

    [0750] According to General Method 8B, 600 mg (1.58 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate were reacted with 717.6 mg (50% purity, 2.22 mmol, 1.4 eq.) of 4-(bromomethyl)-1,3-oxazole. Yield: 530 mg (73% of theory)

    [0751] LC/MS [Method 1]: R.sub.t=1.07 min; MS (ESIpos): m/z=460 (M+H).sup.+,

    [0752] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.29 (s, 1H), 8.11-7.97 (m, 2H), 7.87-7.69 (m, 3H), 6.62 (s, 1H), 5.45-5.25 (m, 1H), 3.55-3.38 (m, 1H), 3.38-3.25 (m, 1H), 1.41 (s, 9H).

    Example 15.1B

    2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-4-yl)propanoic acid (Racemate)

    [0753] ##STR00105##

    [0754] According to General Method 6A, 530 mg (1.15 mmol) of tert-butyl 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-4-yl)propanoate (racemate) in 12 ml of dichloromethane were reacted with 6 ml (77.9 mmol) of TFA were reacted. Yield: 359 mg (77% of theory)

    [0755] LC/MS [Method 1]: R.sub.t=0.78 min; MS (ESIpos): m/z=404 (M+H).sup.+,

    [0756] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.36 (br. s, 1H), 8.26 (s, 1H), 8.11-7.98 (m, 2H), 7.87-7.67 (m, 3H), 6.59 (s, 1H), 5.42 (dd, 1H), 3.59-3.41 (m, 1H), 3.38-3.28 (m, 1 H).

    Example 16.1A

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-5-yl)propanoate (Racemate)

    [0757] ##STR00106##

    [0758] According to General Method 8B, 600 mg (1.39 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]acetate were reacted with 421 mg (80% purity, 2.08 mmol, 1.5 eq.) of 5-(bromomethyl)-1,3-oxazole. Yield: 320 mg (47% of theory)

    [0759] LC/MS [Method 1]: R.sub.t=0.97 min; MS (ESIpos): m/z=492 (M+H).sup.+,

    [0760] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.18 (s, 1H), 8.03 (d, 1H), 7.86 (s, 1H), 7.82-7.71 (m, 2H), 6.90 (s, 1H), 6.72 (t, 1H), 6.62 (s, 1H), 5.35 (dd, 1H), 3.68-3.48 (m, 2H), 1.40 (s, 9H).

    Example 16.1B

    2-[4-(5-Chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-5-yl)propanoic acid (Racemate)

    [0761] ##STR00107##

    [0762] According to General Method 6A, 320 mg (0.65 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-5-yl)propanoate (racemate) in 10 ml of dichloromethane were reacted with 5 ml (64.9 mmol) of TFA. Yield: 290 mg (quant.)

    [0763] LC/MS [Method 1]: R.sub.t=0.74 min; MS (ESIpos): m/z=436 (M+H).sup.+,

    [0764] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.42 (br. s, 1H), 8.15 (s, 1H), 8.03 (d, 1H), 7.87 (s, 1H), 7.81-7.69 (m, 2H), 6.86 (s, 1H), 6.72 (t, 1H), 6.60 (s, 1H), 5.37 (dd, 1H), 3.64 (dd, 2H), 3.53 (dd, 1H).

    Example 17.1A

    tert-Butyl 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-5-yl)propanoate (Racemate)

    [0765] ##STR00108##

    [0766] According to General Method 8B, 610 mg (1.61 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate were reacted with 1.57 g (23% purity, 2.25 mmol, 1.4 eq.) of 5-(bromomethyl)-1,3-oxazole. Yield: 468 mg (83% purity, 52% of theory)

    [0767] LC/MS [Method 1]: R.sub.t=1.05 min; MS (ESIpos): m/z=460 (M+H).sup.+.

    Example 17.1B

    2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-5-yl)propanoic acid (Racemate)

    [0768] ##STR00109##

    [0769] According to General Method 6A, 468 mg (83% purity, 0.84 mmol) of tert-butyl 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-5-yl)propanoate (racemate) in 9 ml of dichloromethane were reacted with 4.5 ml (58.4 mmol) of TFA. Yield: 290 mg (85% purity, 72% of theory)

    [0770] LC/MS [Method 1]: R.sub.t=0.76 min; MS (ESIpos): m/z=404 (M+H).sup.+,

    [0771] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.48 (br. s, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 8.08-8.01 (m, 1H), 7.81-7.75 (m, 2H), 6.87 (s, 1H), 6.64 (s, 1H), 5.39 (br. s, 1H), 3.65 (dd, 1H), 3.56 (dd, 1H).

    Example 18.1A

    2-Methoxyethyl trifluoromethanesulphonate

    [0772] ##STR00110##

    [0773] At −78° C., 16.3 g (57 8 mmol) of trifluoromethanesulphonic anhydride were initially charged in 20 ml of dichloromethane, and a solution of 4.00 g (52.6 mmol) of 2-methoxyethanol and 5.85 g (57.8 mmol) of triethylamine in 20 ml of dichloromethane was slowly added dropwise such that the internal temperature did not exceed −50° C. The mixture was left to stir at −78° C. for 15 min and then warmed to RT. The mixture was diluted with 100 ml of methyl tert-butyl ether and washed three times with in each case 50 ml of a 3:1 mixture of saturated aqueous sodium chloride solution and 1N hydrochloric acid. The organic phase was dried over sodium sulphate and concentrated under reduced pressure at RT. This gave 13 g of the crude product which was directly reacted further.

    Example 18.1B

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoate (Racemate)

    [0774] ##STR00111##

    [0775] 8.09 g (21.6 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate were initially charged in 180 ml of THF, and the mixture was cooled to −78° C. 23.7 ml of lithium bis(trimethylsilyl)amide (1M in THF) were added dropwise, and the mixture was left to stir for a further 15 min. 8.99 g (43.2 mmol) of 2-methoxyethyl trifluoromethanesulphonate were then added dropwise, and the mixture was left to stir at −78° C. for 15 min and at RT for a further 45 min. Saturated aqueous ammonium chloride solution was then added, and the mixture was extracted repeatedly with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by means of flash chromatography (silica gel 50, cyclohexane-ethyl acetate gradient). Yield: 7.87 g (95% purity, 80% of theory).

    [0776] LC/MS [Method 1]: R.sub.t=1.02 min; MS (ESIpos): m/z=433 (M+H).sup.+,

    [0777] 1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.01-7.96 (m, 1H), 7.76-7.69 (m, 2H), 7.37 (s, 1H), 6.48 (s, 1H), 5.11 (dd, 1H), 3.64 (s, 3H), 3.43-3.35 (m, 1H), 3.20 (s, 3H), 3.19-3.13 (m, 1H), 2.39-2.28 (m, 2H), 1.40 (s, 9H).

    Example 18.1C

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (Racemate)

    [0778] ##STR00112##

    [0779] 7.87 g (95% purity, 17.3 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoate-(racemate) were initially charged in 175 ml of dichloromethane. 42 ml (545 mmol) of trifluoroacetic acid were added, and the mixture was left to stir at RT for 3 h. The reaction mixture was concentrated under reduced pressure and repeatedly the residue was taken up in dichloromethane and concentrated again. Then, twice, toluene was added and the mixture was concentrated again. The residue was stirred with acetonitrile and filtered off with suction. Yield 5.81 g (95% purity, 84% of theory)

    [0780] LC/MS [Method 1]: R.sub.t=0.78 min; MS (ESIpos): m/z=377 (M+H).sup.+,

    [0781] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): δ [ppm]=13.40-12.67 (m, 1H), 7.99 (d, 1H), 7.75 (d, 1H), 7.73 (dd, 1H), 7.43 (s, 1H), 6.48 (s, 1H), 5.14 (t, 1H), 3.64 (s, 3H), 3.41-3.36 (m, 1H), 3.19 (s, 3H), 3.13 (dt, 1H), 2.40-2.31 (m, 2H).

    Example 19.1A

    tert-Butyl 2-[4-(5-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyl-1,2-oxazol-5-yl)propanoate (Racemate)

    [0782] ##STR00113##

    [0783] To a solution of 900 mg (2.45 mmol) of tert-butyl [4-(5-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 18 ml of tetrahydrofuran under argon at −78° C. were added dropwise 3.06 ml (1.0 M in THF, 1.25 eq.) of lithium bis(trimethylsilyl)amide, and the mixture was stirred for 30 min. Subsequently, 635 mg (3.43 mmol, 1.4 eq.) of 5-(bromomethyl)-3-methyl-1,2-oxazole were added. The resulting reaction mixture was stirred at −78° C. for another 30 min and at RT for another 90 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution. The organic phase was dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate (0-38%) mixtures). Yield: 1.00 g (88% of theory)

    [0784] LC/MS [Method 1]: R.sub.t=1.10 min; MS (ESIpos): m/z=463 (M+H).sup.+,

    [0785] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.54 (ddd, 1H), 7.48 (dd, 1H), 7.35 (t, 1H), 7.31 (s, 1H), 6.43 (s, 1H), 6.13 (s, 1H), 5.35 (dd, 1H), 3.68-3.56 (m, 2H), 3.55 (s, 3H), 2.16 (s, 3H), 1.40 (m, 9H).

    Example 19.1B

    2-[4-(5-Chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyl-1,2-oxazol-5-yl)propanoic acid (Racemate)

    [0786] ##STR00114##

    [0787] According to General Method 6B, 1.06 g (3.20 mmol) of tert-butyl 2-[4-(5-chloro-2-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyl-1,2-oxazol-5-yl)propanoate (racemate) and 23 ml of a hydrogen chloride in dioxane (4 M) solution were reacted. Yield: 0.98 g (90% purity, 95% of theory).

    [0788] LC/MS [Method 1]: R.sub.t=0.78 min; MS (ESIpos): m/z=407 (M+H).sup.+,

    [0789] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.26 (bs, 1H), 7.61-7.41 (m, 2H), 7.41-7.24 (m, 2H), 6.41 (s, 1H), 6.11 (s, 1H), 5.39 (dd, 1H), 3.72-3.63 (m, 1H), 3.63-3.56 (m, 1H), 3.54 (s, 3H), 2.15 (s, 3H).

    Example 20.1A

    2-Ethoxyethyl trifluoromethanesulphonate

    [0790] ##STR00115##

    [0791] According to General Method 7A, 1.00 g (11.10 mmol) of 2-ethoxyethanol was reacted at 0-5° C. with 2.80 ml (16.64 mmol, 1.5 eq.) of trifluoromethanesulphonic anhydride in the presence of 2.90 ml (16.64 mmol, 1.5 eq.) of N,N-diisopropylethylamine The crude product was converted without further purification in the next stage.

    [0792] GC/MS [Method 9]: R.sub.t=1.67 min; MS (EI): m/z=177 (M−OEt).sup.−,

    [0793] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm]=4.62 (t, 2H), 3.75 (t, 2H), 3.56 (q, 2H), 1.22 (s, 3H).

    Example 20.1B

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-ethoxybutanoate (Racemate)

    [0794] ##STR00116##

    [0795] According to General Method 8A, 500 mg (1.33 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate were reacted in the presence of 1.60 ml (1.60 mmol, 1.2 eq.) of lithium bis(trimethylsilyl)amide (1M in THF) with 362 mg (1.47 mmol, 1.1 eq.) of 2-ethoxyethyl trifluoromethanesulphonate. Yield: 500 mg (83% of theory)

    [0796] LC/MS [Method 1]: R.sub.t=1.12 min; MS (ESIpos): m/z=447 (M+H).sup.+.

    Example 20.1C

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-ethoxybutanoic acid

    [0797] ##STR00117##

    [0798] According to General Method 6C, 499 mg (1.12 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-ethoxybutanoate (racemate) were hydrolysed with lithium hydroxide in ethanol/tetrahydrofuran. Yield: 436 mg (99% of theory)

    [0799] LC/MS [Method 1]: R.sub.t=0.84 min; MS (ESIpos): m/z=391 (M+H).sup.+.

    Example 21.1A

    2-Isopropoxyethyl trifluoromethanesulphonate

    [0800] ##STR00118##

    [0801] According to General Method 7A, 0.50 g (4 8 mmol) of 2-isopropoxyethanol was reacted at 0° C. with 1.2 ml (7.2 mmol, 1.5 eq.) of trifluoromethanesulphonic anhydride in the presence of 0.84 ml (7.2 mmol, 1.5 eq.) of 2,6-dimethylpyridine. The crude product was converted without further purification in the next stage.

    [0802] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm]=4.60 (t, 2H), 3.73 (t, 2H), 3.69-3.59 (m, 1H), 1.18 (d, 6H).

    Example 21.1B

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-isopropoxybutanoate (Racemate)

    [0803] ##STR00119##

    [0804] According to General Method 8A, 1.00 g (2.67 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 1.13 g (4.80 mmol, 1.8 eq.) of 2-isopropoxyethyl trifluoromethanesulphonate and 3.47 ml (3.47 mmol, 1.3 eq.) of lithium bis(trimethylsilyl) amide (1M in THF) were reacted in 27 ml of THF. After aqueous workup, the crude product was purified by means of flash chromatography (50 g silica cartridge, flow rate: 50 ml/min, cyclohexane/ethyl acetate mixture). Yield: 784 mg (64% of theory).

    [0805] LC/MS [Method 1]: R.sub.t=1.11 min; MS (ESIpos): m/z=461 (M+H).sup.+,

    [0806] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.99 (d, 1H), 7.75-7.69 (m, 2H), 7.36 (s, 1H), 6.48 (s, 1H), 5.13 (dd, 1H), 3.63 (s, 3H), 3.48-3.39 (m, 2H), 3.20-3.11 (m, 1H), 2.41-2.23 (m, 2H), 1.41 (s, 9H), 1.05 (d, 3H), 1.03 (d, 3H).

    Example 21.1C

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-isopropoxybutanoic acid (Racemate)

    [0807] ##STR00120##

    [0808] According to General Method 6C, 784 mg (1.70 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-isopropoxybutanoate (racemate) in 50 ml of ethanol and 25 ml of tetrahydrofuran were reacted in the presence of 204 mg (8.50 mmol, 5.0 eq.) of lithium hydroxide.

    [0809] Yield: 681 mg (99% of theory)

    [0810] LC/MS [Method 1]: R.sub.t=0.85 min; MS (ESIpos): m/z=405 (M+H).sup.+.

    Example 22.1A

    2-(Cyclobutyloxy)ethyl trifluoromethanesulphonate

    [0811] ##STR00121##

    [0812] According to General Method 7A, 0.50 g (4.3 mmol) of 2-(cyclobutyloxy)ethanol was reacted at 0° C. with 1.1 ml (6.5 mmol, 1.5 eq.) of trifluoromethanesulphonic anhydride in the presence of 1.1 ml (6.5 mmol, 1.5 eq.) of N,N-diisopropylethylamine. The crude product was converted without further purification in the next stage.

    [0813] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm]=4.60 (t, 2H), 4.01-3.93 (m, 1H), 3.65 (t, 2H), 2.26-2.16 (m, 2H), 2.00-1.90 (m, 2H), 1.77-1.67 (m, 2H).

    Example 22.1B

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(cyclobutyloxy)-butanoate (Racemate)

    [0814] ##STR00122##

    [0815] According to General Method 8A, 500 mg (1.33 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 405 mg (90% purity, 1.47 mmol, 1.1 eq.) of 2-(cyclobutyloxy)ethyl trifluoromethanesulphonate and 1.60 ml (1.60 mmol, 1.2 eq.) of lithium bis(trimethylsilyl)amide (1M in THF) were reacted in 25 ml of THF. After aqueous workup, the crude product was purified by means of flash chromatography (50 g silica cartridge, flow rate: 50 ml/min, cyclohexane/ethyl acetate mixture). Yield: 493 mg (77% of theory)

    [0816] LC/MS [Method 1]: R.sub.t=1.22 min; MS (ESIpos): m/z=473 (M+H).sup.+,

    [0817] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.99 (d, 1H), 7.75-7.69 (m, 2H), 7.38 (s, 1H), 6.49 (s, 1H), 5.14 (dd, 1H), 3.86-3.77 (m, 1H), 3.64 (s, 3H), 3.36-3.28 (m, 1H, beside DMSO), 3.15-3.08 (m, 1H), 2.39-2.27 (m, 2H), 2.14-2.02 (m, 2H), 1.86-1.70 (m, 2H), 1.63-1.55 (m, 1H), 1.48-1.4 (m, 1H), 1.41 (s, 9H).

    Example 22.1C

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(cyclobutyloxy)butanoic acid (Racemate)

    [0818] ##STR00123##

    [0819] According to General Method 6C, 491 mg (1.04 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(cyclobutyloxy)butanoate (racemate) in 28 ml of ethanol and 14 ml of tetrahydrofuran were converted in the presence of 124 mg (5.19 mmol, 5.0 eq.) of lithium hydroxide. Yield: 510 mg (quant.)

    [0820] LC/MS [Method 1]: R.sub.t=0.99 min; MS (ESIpos): m/z=417 (M+H).sup.+.

    Example 23.1A

    2-tert-Butoxyethyl trifluoromethanesulphonate

    [0821] ##STR00124##

    [0822] According to General Method 7A, 0.50 g (4 2 mmol) of 2-tert-butoxyethanol was reacted at 0° C. with 1.1 ml (6.3 mmol, 1.5 eq.) of trifluoromethanesulphonic anhydride in the presence of 0.74 ml (6.3 mmol, 1.5 eq.) of N,N-diisopropylethylamine. The crude product was converted without further purification in the next stage.

    [0823] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm]=4.58 (t, 2H), 3.67 (t, 2H), 1.21 (s, 9H).

    Example 23.1B

    tert-Butyl 4-tert-butoxy-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoate (Racemate)

    [0824] ##STR00125##

    [0825] According to General Method 8A, 953 mg (2.54 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 1.06 g (4.22 mmol, 1.7 eq.) of 2-tert-butoxyethyl trifluoromethanesulphonate and 3.31 ml (3.31 mmol, 1.3 eq.) of lithium bis(trimethylsilyl)amide (1M in THF) were reacted in 25 ml of THF. After aqueous workup, the crude product was purified by means of flash chromatography (50 g silica cartridge, flow rate: 50 ml/min, cyclohexane/ethyl acetate mixture). Yield: 900 mg (75% of theory)

    [0826] LC/MS [Method 1]: R.sub.t=1.15 min; MS (ESIpos): m/z=475 (M+H).sup.+,

    [0827] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.98 (d, 1H), 7.75-7.68 (m, 2H), 7.37 (s, 1H), 6.48 (s, 1H), 5.15 (dd, 1H), 3.64 (s, 3H), 3.41-3.33 (m, 1H), 3.19-3.10 (m, 1H), 2.42-2.31 (m, 1H), 2.31-2.20 (m, 1H), 1.41 (s, 9H), 1.08 (s, 9H).

    Example 23.1C

    4-tert-Butoxy-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (Racemate)

    [0828] ##STR00126##

    [0829] According to General Method 6C, 900 mg (1.90 mmol) of tert-butyl 4-tert-butoxy-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoate (racemate) in 50 ml of ethanol and 25 ml of tetrahydrofuran were reacted in the presence of 227 mg (9.47 mmol, 5.0 eq.) of lithium hydroxide. Yield: 609 mg (74% of theory)

    [0830] LC/MS [Method 1]: R.sub.t=0.90 min; MS (ESIpos): m/z=419 (M+H).sup.+.

    Example 24.1A

    2-(2,2-difluoroethoxy)ethyl trifluoromethanesulphonate

    [0831] ##STR00127##

    [0832] According to General Method 7A, 0.50 g (4 2 mmol) of 2-(2,2-difluoroethoxy)ethanol was reacted at 0° C. with 1.0 ml (5.9 mmol, 1.5 eq.) of trifluoromethanesulphonic anhydride in the presence of 1.04 ml (5.9 mmol, 1.5 eq.) of 2,6-dimethylpyridine. The crude product was converted without further purification in the next stage.

    [0833] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm]=5.88 (tt, 1H), 4.63 (dd, 2H), 3.90 (dd, 2H), 3.75 (td, 2H).

    Example 24.1B

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(2,2-difluoroethoxy)butanoate (Racemate)

    [0834] ##STR00128##

    [0835] According to General Method 8A, 500 mg (1.33 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 474 mg (1.47 mmol, 1.1 eq.) of 2-(2,2-difluoroethoxy)ethyl trifluoromethanesulphonate and 1.60 ml (1.60 mmol, 1.2 eq.) of lithium bis(trimethylsilyl)amide (1M in THF) were reacted in 25 ml of THF. After aqueous workup, the crude product was purified by means of flash chromatography (50 g silica cartridge, flow rate: 50 ml/min, cyclohexane/ethyl acetate mixture). Yield: 550 mg (84% of theory)

    [0836] LC/MS [Method 1]: R.sub.t=1.08 min; MS (ESIpos): m/z=483 (M+H).sup.+,

    [0837] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.99 (d, 1H), 7.76-7.69 (m, 2H), 7.36 (s, 1H), 6.49 (s, 1H), 6.11 (tt, 1H), 5.11 (t, 1H), 3.69-3.55 (m, 3H), 3.63 (s, 3H), 3.42-3.34 (m, 1H), 2.43-2.31 (m, 2H), 1.40 (s, 9H).

    Example 24.1C

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(2,2-difluoroethoxy)butanoic acid (Racemate)

    [0838] ##STR00129##

    [0839] According to General Method 6C, 547 mg (1.13 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(2,2-difluoroethoxy)butanoate (racemate) were reacted in 31 ml of ethanol and 15 ml of tetrahydrofuran in the presence of 136 mg (5.66 mmol, 5.0 eq.) of lithium hydroxide. Yield: 294 mg (60% of theory)

    [0840] LC/MS [Method 1]: R.sub.t=0.82 min; MS (ESIpos): m/z=427 (M+H).sup.+.

    Example 25.1A

    2-(2,5-Dimethoxypyridin-4-yl)-4-methoxybenzonitrile

    [0841] ##STR00130##

    [0842] According to General Method 2A, 984 mg (5.38 mmol) of 5-chloro-2-methoxypyridin-4-ylboronic acid were reacted with 950 mg (4.48 mmol) of 2-bromo-4-methoxybenzonitrile in the presence of [1,1-bis-(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane monoadduct. On completion of conversion, the reaction mixture was combined with a previous test batch via 50 mg (0.24 mmol) of 2-bromo-4-methoxybenzonitrile, and the solvent was removed under reduced pressure. The residue was taken up in water, and the precipitating solid was filtered, washed with water and dried under reduced pressure. Yield: 1.18 g (86% purity, 80% of theory)

    [0843] The combined mother liquors were than extracted twice with ethyl acetate. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure and dried. The residue was purified by means of flash chromatography (silica gel 60, cyclohexane/dichloromethane mixtures). Yield: 195 mg (15% of theory)

    [0844] LC/MS [Method 1]: R.sub.t=0.93 min; MS (ESIpos): m/z=271 (M+H).sup.+.

    Example 25.1B

    4-Methoxy -2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile

    [0845] ##STR00131##

    [0846] According to General Method 3A, 1.18 g (86% purity, 3.76 mmol) of 2-(2,5-dimethoxypyridin-4-yl)-4-methoxybenzonitrile were reacted with pyridinium hydrochloride. Yield: 1.33 g (78% purity, quant.)

    [0847] LC/MS [Method 1]: R.sub.t=0.59 min; MS (ESIpos): m/z=257 (M+H).sup.+.

    Example 25.1C

    tert-Butyl [4-(2-Cyano-5-methoxyphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate

    [0848] ##STR00132##

    [0849] According to General Method 4A, 1.55 g (78% purity, 4.77 mmol) of 4-methoxy-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile were reacted with 1.2 eq. of tert-butyl bromoacetate in the presence of 1.5 eq. of potassium carbonate. After aqueous workup, the residue was purified by means of flash chromatography (silica gel 60, cyclohexane/ethyl acetate-mixtures). Yield: 849 mg (48% of theory)

    [0850] LC/MS [Method 1]: R.sub.t=0.86 min; MS (ESIpos): m/z=371 (M+H).sup.+.

    Example 25.1D

    tert-Butyl 2-[4-(2-cyano-5-methoxyphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoate (Racemate)

    [0851] ##STR00133##

    [0852] According to General Method 8A, 849 mg (2.29 mmol) of tert-butyl [4-(2-cyano-5-methoxyphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate were reacted in the presence of 2.98 ml (2.98 mmol, 1.3 eq.) of lithium bis(trimethylsilyl)amide (1M in THF) with 716 mg (3.44 mmol, 1.5 eq.) of 2-methoxyethyl trifluoromethanesulphonate. Yield: 709 mg (94% purity, 68% of theory)

    [0853] LC/MS [Method 1]: R.sub.t=0.99 min; MS (ESIpos): m/z=429 (M+H).sup.+.

    Example 25.1E

    2-[4-(2-Cyano-5-methoxyphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (Racemate)

    [0854] ##STR00134##

    [0855] According to General Method 6A, 709 mg (94% purity, 1.56 mmol) of tert-butyl 2-[4-(2-cyano-5-methoxyphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoate (racemate) were hydrolysed with TFA, which were converted further as crude product. Yield: 743 mg.

    [0856] LC/MS [Method 1]: R.sub.t=0.72 min; MS (ESIpos): m/z=373 (M+H).sup.+.

    Example 26.1A

    tert-Butyl (4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)acetate

    [0857] ##STR00135##

    [0858] 2.97 g (14.6 mmol) of 4-bromo-5-methoxypyridin-2(1H)-one and 3.02 g (21.8 mmol, 1.5 eq.) of potassium carbonate were initially charged in 66 ml of DMF, 2.63 ml (17.5 mmol, 1.2 eq.) of tert-butyl bromoacetate were added and the mixture was stirred at 50° C. for 70 min. The reaction mixture was then concentrated. 30 ml of water were added, the mixture was stirred for 5 min and filtered off with suction and the product was washed with water, suspended in acetonitrile and concentrated. The crude product was purified by means of Biotage-Isolera (eluent: dichloromethane/methanol, 0-8%). Yield: 3.70 g (80% of theory).

    [0859] LC/MS [Method 1]: R.sub.t=0.78 min; MS (ESIpos): m/z=320 (M+H).sup.+,

    [0860] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.53 (s, 1H), 6.85 (s, 1H), 4.53 (s, 2H), 3.31 (s, 3H), 1.42 (s, 9H).

    Example 26.1B

    tert-Butyl 2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanoate (Racemate)

    [0861] ##STR00136##

    [0862] To a solution of 4.26 g (13.4 mmol) of tert-butyl (4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)acetate in 170 ml of THF under argon at −70° C. were added 18.1 ml (18.1 mmol, 1.35 eq.) of 1 N lithium bis(trimethylsilyl)amide in THF, and the mixture was stirred for 20 min. Subsequently, 2.37 ml (15.4 mmol, 1.15 eq.) of 2-methoxyethyl trifluoromethanesulphonate were added, the mixture was stirred at −70° C. for 15 min and then stirred while coming to RT for 1 h. The reaction mixture was cooled to −70° C. and another 5.4 ml (5.4 mmol, 0.4 eq.) of 1 N lithium bis(trimethylsilyl)amide in THF were added and, after 15 min, 0.72 ml (4.7 mmol, 0.35 eq.) of 2-methoxyethyl trifluoromethanesulphonate was added, and the mixture was stirred at −70° C. for 15 min and then at RT for 2 h. To the reaction mixture were added 40 ml of saturated aqueous ammonium chloride solution, 40 ml of water and 350 ml of ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was then purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-60%). Yield: 3.65 g (70% of theory).

    [0863] LC/MS [Method 1]: R.sub.t=0.94 min; MS (ESIpos): m/z=376 (M+H).sup.+,

    [0864] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.36 (s, 1H), 6.85 (s, 1H), 5.04 (dd, 1H), 3.71 (s, 3H), 3.39-3.29 (m, 1H), 3.20-3.03 (m, 4H), 2.35-2.20 (m, 2H), 1.38 (s, 9H).

    Example 26.1C

    tert-Butyl 4-methoxy-2-[5-methoxy-2-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl]butanoate (Racemate)

    [0865] ##STR00137##

    [0866] 3.05 g (8.1 mmol) of tert-butyl 2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanoate (racemate), 2.26 g (8.9 mmol, 1.1 eq.) of bis(pinacolato)diboron and 2.39 g (24.3 mmol, 3 eq.) of potassium acetate were initially charged in 84 ml of dioxane under argon, 199 mg (0.24 mmol, 0.03 eq) of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex were added and the mixture was stirred at 80° C. for 6 h. The reaction mixture was cooled down, filtered through kieselguhr and washed through with ethyl acetate/THF. The filtrate was concentrated, and the residue was twice admixed with THF and concentrated. Subsequently, the residue was dissolved in diethyl ether, concentrated again and dried at 40° C. under high vacuum. Yield: 4.60 g (70% purity, 94% of theory).

    [0867] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.09 (s, 1H), 6.49 (s, 1H), 5.00 (dd, 1H), 3.60 (s, 3H), 3.36-3.27 (m, 3H), 3.17 (s, 3H), 3.14-3.05 (m, 1H), 2.30-2.21 (m, 2H), 1.37 (s, 9H), 1.27 (s, 12H).

    Example 27.1A

    2-Bromo-4-chloro-5-fluorobenzonitrile

    [0868] ##STR00138##

    [0869] 1.0 g (2.98 mmol) of 1-bromo-5-chloro-4-fluoro-2-iodobenzene were dissolved in 17.5 ml of DMF, and 185 mg (1.58 mmol, 0.53 eq.) of zinc cyanide were added. Argon was passed through the reaction mixture for 5 min. Subsequently, 286 mg (0.25 mmol, 0.08 eq.) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was stirred at 70° C. overnight. The mixture was heated to 90° C. and stirred at 90° C. overnight. The reaction mixture was concentrated and the residue was purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-10%). The product fractions were combined and concentrated. The residue was admixed with diethyl ether, then filtered, and the filtrate was concentrated. Yield: 0.34 g (89% purity, 43% of theory).

    [0870] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.31 (d, 1H), 8.25 (d, 1H).

    Example 27.1B

    tert-Butyl 2-[4-(5-chloro-2-cyano-4-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoate (Racemate)

    [0871] ##STR00139##

    [0872] To 500 mg (0.65 mmol, 55% purity) of tert-butyl 4-methoxy-2-[5-methoxy-2-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl]butanoate (racemate), 171 mg (0.65 mmol, 89% purity) of 2-bromo-4-chloro-5-fluorobenzonitrile and 269 mg (1.95 mmol, 3 eq.) of potassium carbonate were added 6.6 ml of dioxane. Argon was passed through the reaction mixture for 5 min. Subsequently, 16 mg (0.02 mmol, 0.03 eq) of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex were added and the mixture was stirred at 80° C. for 3 days. The reaction mixture was filtered through kieselguhr, washed with dichloromethane/acetonitrile, and the filtrate was concentrated. The crude product was purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-45%). Yield: 280 mg (60% purity, 57% of theory).

    [0873] LC/MS [Method 1]: R.sub.t=1.05 min; MS (ESIpos): m/z=451 (M+H).sup.+,

    [0874] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.22 (d, 1H), 7.97-7.89 (m, 1H), 7.37 (s, 1H), 6.49 (s, 1H), 5.16-5.04 (m, 1H), 3.64 (s, 3H), 3.43-3.35 (m, 1H), 3.23-3.10 (m, 4H), 2.39-2.25 (m, 2H), 1.40 (s, 9H)

    Example 27.1C

    2-[4-(5-Chloro-2-cyano-4-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (Racemate)

    [0875] ##STR00140##

    [0876] To 280 mg (0.37 mmol, 60% purity) of tert-butyl 2-[4-(5-chloro-2-cyano-4-fluorophenyl)-5-methoxy-5-oxopyridin-1(2H)-yl]-4-methoxybutanoate were added 3.64 ml of 4 N hydrogen chloride in dioxane and the mixture was stirred at RT overnight. The residue was concentrated, admixed with THF and concentrated again. The residue was dried under high vacuum. Yield: 260 mg (56% purity, 99% of theory).

    [0877] LC/MS [Method 10]: R.sub.t=1.44 min; MS (ESIpos): m/z=395 (M+H).sup.+,

    [0878] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=12.98 (bs, 1H), 8.22 (d, 1H), 7.95 (d, 1H), 7.42 (s, 1H), 6.48 (s, 1H), 5.20-5.07 (m, 1H), 3.63 (s, 3H), 3.42-3.33 (m, 1H), 3.19 (s, 3H), 3.16-3.08 (m, 1H), 2.41-2.29 (m, 2H).

    Example 28.1A

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyl-1,2-oxazol-5-yl)propanoate (Racemate)

    [0879] ##STR00141##

    [0880] To a solution of 900 mg (2.4 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 18 ml of THF under argon at −70° C. were added 3.0 ml (3 0 mmol, 1.25 eq.) of 1 N lithium bis(trimethylsilyl)amide in THF, and the mixture was stirred for 30 min. Subsequently, 623 mg (3.4 mmol, 1.4 eq.) of 5-(bromomethyl)-3-methyl-1,2-oxazole were added, the mixture was stirred at −70° C. for 30 min and then stirred while coming to RT for 90 min. To the reaction mixture were added 15 ml of saturated aqueous ammonium chloride solution, 15 ml of water and 150 ml of ethyl acetate. The aqueous phase was extracted once with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution, then dried and concentrated. The crude product was purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-38%). Yield: 1.10 g (95% of theory).

    [0881] LC/MS [Method 1]: R.sub.t=1.04 min; MS (ESIpos): m/z=470 (M+H).sup.+,

    [0882] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.03-7.93 (m, 1H), 7.76-7.67 (m, 2H), 7.37 (s, 1H), 6.50 (s, 1H), 6.05 (s, 1H), 5.36 (dd, 1H), 3.72-3.51 (m, 5H), 2.14 (s, 3H), 1.40 (s, 9H)

    Example 28.1B

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyl-1,2-oxazol-5-yl)propanoic acid (Racemate)

    [0883] ##STR00142##

    [0884] To 1.10 g (2.27 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyl-1,2-oxazol-5-yl)propanoate (racemate) were added 23 ml of 4 N hydrogen chloride in dioxane and the mixture was stirred at RT for 24 h. The reaction mixture was concentrated, and the residue was twice stirred in THF, concentrated again and dried under high vacuum. Yield: 1.05 g (89% purity, 99% of theory).

    [0885] LC/MS [Method 1]: R.sub.t=0.77 min; MS (ESIpos): m/z=414 (M+H).sup.+,

    [0886] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.28 (bs, 1H), 8.05-7.92 (m, 1H), 7.79-7.67 (m, 2H), 7.40 (s, 1H), 6.48 (s, 1H), 5.99 (s, 1H), 5.39 (dd, 1H), 3.77-3.64 (m, 1H), 3.63-3.52 (m, 4H), 2.13 (s, 3H)

    Example 29.1A

    Mixture of: 3-(bromomethyl)-5-methyl-1,2,4-oxadiazole and 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole

    [0887] ##STR00143##

    [0888] Under argon, 0.95 g (7.91 mmol, 95% purity) of (5-methyl-1,2,4-oxadiazol-3-yl)methanol and 1.43 ml (10.28 mmol, 1.3 eq.) of triethylamine were dissolved in 11 ml of DMF and cooled to 0° C. At this temperature, 0.796 ml (10.28 mmol, 1.3 eq.) of methanesulphonyl chloride was added dropwise and the mixture was stirred at 0° C. for 1 h. 1.92 g (22.14 mmol, 2.8 eq.) of lithium bromide were then added, and the mixture was stirred at 0° C. for 1 h. The reaction mixture was admixed with 60 ml of water and 15 g of sodium chloride and extracted four times with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. The residue was purified by means of Biotage-Isolera (eluent: dichloromethane, then dichloromethane/methanol 20:1). Yield: 610 mg (43% of theory)

    [0889] LC/MS [Method 9]: R.sub.t=2.80 min; MS (ESIneg): m/z=175 (M−H).sup.−,

    [0890] LC/MS [Method 9]: R.sub.t=2.31 min; MS (ESIpos): m/z=133 (M+H).sup.+.

    Example 29.1B

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(2-methyl-1,2,4-oxadiazol-3-yl)propanoate (Racemate)

    [0891] ##STR00144##

    [0892] To a solution of 900 mg (2.40 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 18 ml of THF under argon at −70° C. were added 3.0 ml (3 0 mmol, 1.25 eq.) of 1 N lithium bis(trimethylsilyl)amide in THF, and the mixture was stirred for 30 min. Subsequently, 607 mg (3.36 mmol, 1.4 eq.) of a mixture of 3-(bromomethyl)-5-methyl-1,2,4-oxadiazole and 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole were added, the mixture was stirred at −70° C. for 30 min and then stirred while coming to RT for 90 min. To the reaction mixture were added 15 ml of saturated aqueous ammonium chloride solution, 15 ml of water and 150 ml of ethyl acetate. The aqueous phase was extracted once more with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, then dried and concentrated. The crude product was purified twice by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-50%). Yield: 560 mg (49% of theory).

    [0893] LC/MS [Method 1]: R.sub.t=1.04 min; MS (ESIpos): m/z=471 (M+H).sup.+,

    [0894] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.97 (d, 1H), 7.77-7.67 (m, 2H), 7.44 (s, 1H), 6.48 (s, 1H), 5.44 (dd, 1H), 3.67-3.46 (m, 5H), 2.55 (s, 3H), 1.37 (s, 9H).

    Example 29.1C

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)propanoic acid (Racemate)

    [0895] ##STR00145##

    [0896] To 560 mg (1.17 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)propanoate (racemate) were added 11.7 ml of 4 N hydrogen chloride in dioxane and the mixture was stirred at RT for 18 h. The reaction mixture was concentrated, and the residue was twice stirred in THF, concentrated again and dried under high vacuum overnight. The crude product was purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 415 mg (86% of theory).

    [0897] LC/MS [Method 1]: R.sub.t=0.77 min; MS (ESIpos): m/z=415 (M+H).sup.+,

    [0898] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.24 (bs, H), 8.04-7.91 (m, 1H), 7.74-7.68 (m, 2H), 7.45 (s, 1H), 6.46 (s, 1H), 5.44 (dd, 1H), 3.67-3.52 (m, 5H), 2.53 (s, 3H).

    Example 30.1A

    tert-Butyl {4-[5-chloro-2-(difluoromethyl)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetate

    [0899] ##STR00146##

    [0900] To 0.790 g (2.71 mmol) of 4-[5-chloro-2-(difluoromethyl)phenyl]-5-methoxypyridin-2(1H)-one, 0.490 ml (3.25 mmol, 1.2 eq.) of tert-butyl bromoacetate and 0.532 g (4.07 mmol, 1.5 eq.) of potassium carbonate were added 16 ml of DMF and the mixture was stirred at 100° C. for 90 min. The reaction mixture was concentrated. The residue was admixed with ethyl acetate and water, and the aqueous phase was extracted once more with ethyl acetate. The combined organic phases were washed with saturated aqueous ammonium chloride solution and then with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-50%). Yield: 790 mg (73% of theory).

    [0901] LC/MS [Method 1]: R.sub.t=1.00 min; MS (ESIpos): m/z=400 (M+H).sup.+,

    [0902] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.77-7.61 (m, 2H), 7.53-7.42 (m, 2H), 6.76 (t, 1H), 6.35 (s, 1H), 4.70-4.50 (m, 2H), 3.56 (s, 3H), 1.45 (s, 9H).

    Example 30.1B

    tert-Butyl 2-{4-[5-chloro-2-(difluoromethyl)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-(pyridin-2-yl)propanoate (Racemate)

    [0903] ##STR00147##

    [0904] To a solution of 790 mg (1.98 mmol) of tert-butyl {4-[5-chloro-2-(difluoromethyl)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetate in 15 ml of THF under argon at −70° C. were added 4.94 ml (4.94 mmol, 2.50 eq.) of 1 N lithium bis(trimethylsilyl)amide in THF, and the mixture was stirred for 15 min. Subsequently, 700 mg (2.77 mmol, 1.4 eq.) of 2-(bromomethyl)pyridine hydrobromide were added, the mixture was stirred at −70° C. for 30 min and then stirred while coming to RT for 90 min. To the reaction mixture were added 10 ml of saturated aqueous ammonium chloride solution, 10 ml of water and 70 ml of ethyl acetate. The aqueous phase was extracted once with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was then purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-45%). Yield: 760 mg (77% of theory).

    [0905] LC/MS [Method 1]: R.sub.t=1.07 min; MS (ESIpos): m/z=491 (M+H).sup.+,

    [0906] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.49 (d, 1H), 7.80-7.60 (m, 3H), 7.40 (s, 1H), 7.31-7.16 (m, 3H), 6.83-6.34 (m, 1H), 6.30 (s, 1H), 5.68-5.45 (m, 1H), 3.70-3.39 (m, 4H), 1.37 (s, 9H).

    Example 30.1C

    2-{4-[5-Chloro-2-(difluoromethyl)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-(pyridin-2-yl)propanoic acid hydrochloride (Racemate)

    [0907] ##STR00148##

    [0908] To 760 mg (1.52 mmol) of tert-butyl 2-{4-[5-chloro-2-(difluoromethyl)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-(pyridin-2-yl)propanoate (racemate) were added 15.7 ml of 4 N hydrogen chloride in dioxane and the mixture was stirred at RT for 18 h. The reaction mixture was concentrated, and the residue was twice stirred in THF, concentrated again and dried under high vacuum overnight. Yield: 800 mg (85% purity, 95% of theory).

    [0909] LC/MS [Method 1]: R.sub.t=0.74 min; MS (ESIpos): m/z=435 (M+H).sup.+,

    [0910] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.90-8.70 (m, 1H), 8.50-8.35 (m, 1H), 8.00-7.78 (m, 2H), 7.77-7.57 (m, 2H), 7.57-7.34 (m, 2H), 6.90-6.50 (m, 1H), 6.40-6.19 (m, 1H), 5.84-5.40 (m, 1H), 4.09-3.92 (m, 1H), 3.82-3.68 (m, 1H), 3.63-3.53 (m, 3H).

    Example 31.1A

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)propanoate (Racemate)

    [0911] ##STR00149##

    [0912] To a solution of 750 mg (2.00 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 15 ml of THF were added, under argon at −70° C., 2.50 ml (2.50 mmol, 1.25 eq.) of 1N lithium bis(trimethylsilyl)amide in THF and the mixture was stirred for 30 min. Subsequently, 273 μl (2.66 mmol, 1.33 eq.) of 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole were added and the mixture was stirred at −70° C. for 30 min and while coming to RT overnight. The reaction mixture was admixed with 10 ml of saturated aqueous ammonium chloride solution, 10 ml of water and 80 ml of ethyl acetate. The aqueous phase was extracted once with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was then purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 20-75%). Yield: 448 mg (47% of theory).

    [0913] LC/MS [Method 1]: R.sub.t=0.94 min; MS (ESIpos): m/z=471 (M+H).sup.+,

    [0914] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.98 (d, 1H), 7.75-7.69 (m, 2H), 7.51 (s, 1H), 6.52 (s, 1H), 5.43 (dd, 1H), 3.83-3.75 (m, 1H), 3.68-3.58 (m, 4H), 2.44 (s, 3H), 1.37 (s, 9H)

    Example 31.1B

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)propanoic acid (Racemate)

    [0915] ##STR00150##

    [0916] To 448 mg (0.93 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)propanoate (racemate) were added 9.0 ml of 4N hydrogen chloride in dioxane and the mixture was stirred at RT overnight. The reaction mixture was concentrated and the residue was purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 150 mg (85% purity, 33% of theory).

    [0917] LC/MS [Method 2]: R.sub.t=1.76 min; MS (ESIpos): m/z=415 (M+H).sup.+,

    [0918] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.30 (bs, 1H), 8.03-7.95 (m, 1H), 7.76-7.69 (m, 2H), 7.52 (s, 1H), 6.50 (s, 1H), 5.43 (dd, 1H), 3.80-3.63 (m, 2H), 3.59 (s, 3H), 2.42 (s, 3H)

    Example 32.1A

    2-(Bromomethyl)-1,3-oxazole

    [0919] ##STR00151##

    [0920] Under argon, 0.50 g (5.05 mmol) of 1,3-oxazol-2-ylmethanol and 0.91 ml (6.56 mmol, 1.3 eq.) of triethylamine were dissolved in 7.0 ml of DMF and cooled to 0° C. At this temperature, 0.508 ml (6.56 mmol, 1.3 eq.) of methanesulphonyl chloride was added dropwise and the mixture was stirred at 0° C. for 1 h. 1.23 g (14.13 mmol, 2.8 eq.) of lithium bromide were then added, and the mixture was stirred at 0° C. for 1 h. The reaction mixture was admixed with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. The residue was purified by means of Biotage-Isolera (eluent: dichloromethane). Yield: 450 mg (90% purity, 50% of theory)

    [0921] LC/MS [Method 9]: R.sub.t=2.21 min; MS (ESIneg): m/z=162 (M+H).sup.+,

    [0922] .sup.1H-NMR (400 MHz, CDCl.sub.3-d.sub.6): δ [ppm]=7.68 (s, 1H), 7.13 (s, 1H), 4.63 (s, 2H).

    Example 32.1B

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-2-yl)propanoate (Racemate)

    [0923] ##STR00152##

    [0924] To a solution of 642 mg (1.71 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 13 ml of THF under argon at −70° C. were added 2.14 ml (2.14 mmol, 1.25 eq.) of 1 N lithium bis(trimethylsilyl)amide in THF, and the mixture was stirred for 30 min. Subsequently, 410 mg (2.28 mmol, 90% purity, 1.33 eq.) of 2-(bromomethyl)-1,3-oxazole were added, the mixture was stirred at −70° C. for 30 min and then stirred while coming to RT for 2 h. To the reaction mixture were added 10 ml of saturated aqueous ammonium chloride solution, 10 ml of water and 80 ml of ethyl acetate. The aqueous phase was extracted once with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution, then dried and concentrated. The crude product was purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-66%). Yield: 570 mg (71% of theory).

    [0925] LC/MS [Method 1]: R.sub.t=1.01 min; MS (ESIpos): m/z=456 (M+H).sup.+,

    [0926] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.01-7.95 (m, 2H), 7.75-7.67 (m, 2H), 7.43 (s, 1H), 7.14-7.11 (m, 1H), 6.49 (s, 1H), 5.45 (dd, 1H), 3.73-3.64 (m, 1H), 3.61-3.51 (m, 4H), 1.37 (s, 9H)

    Example 32.1C

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-2-yl)propanoic acid (Racemate)

    [0927] ##STR00153##

    [0928] To 570 mg (1.21 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-2-yl)propanoate (racemate) were added 12 ml of 4 N hydrogen chloride in dioxane and the mixture was stirred at RT for 18 h. Another 10 ml of 4 N hydrogen chloride in dioxane were added and the mixture was stirred at RT for 3 days. The reaction mixture was concentrated, and the residue was admixed with THF and concentrated. The crude product was purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 400 mg (81% of theory).

    [0929] LC/MS [Method 1]: R.sub.t=0.72 min; MS (ESIpos): m/z=400 (M+H).sup.+,

    [0930] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.21 (bs, 1H), 8.00-7.93 (m, 2H), 7.74-7.66 (m, 2H), 7.42 (s, 1H), 7.10 (s, 1H), 6.47 (s, 1H), 5.49-5.39 (m, 1H), 3.68-3.60 (m, 2H), 3.56 (s, 3H)

    Example 33.1A

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-methyl-1,2-oxazol-3-yl)propanoate (Racemate)

    [0931] ##STR00154##

    [0932] To a solution of 737 mg (1.97 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 15 ml of THF under argon at −70° C. were added 2.46 ml (2.46 mmol, 1.25 eq.) of 1 N lithium bis(trimethylsilyl)amide in THF, and the mixture was stirred for 30 min. Subsequently, 500 mg (2.76 mmol, 1.40 eq.) of 3-(bromomethyl)-5-methyl-1,2-oxazole were added, the mixture was stirred at −70° C. for 30 min and then stirred while coming to RT for 2 h. To the reaction mixture were added 10 ml of saturated aqueous ammonium chloride solution, 10 ml of water and 80 ml of ethyl acetate. The aqueous phase was extracted once with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution, then dried and concentrated. The crude product was purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-35%). Yield: 800 mg (87% of theory).

    [0933] LC/MS [Method 1]: R.sub.t=1.08 min; MS (ESIpos): m/z=470 (M+H).sup.+,

    [0934] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.01-7.93 (m, 1H), 7.75-7.67 (m, 2H), 7.37 (s, 1H), 6.48 (s, 1H), 6.05-7.98 (m, 1H), 5.33 (dd, 1H), 3.57 (s, 3H), 3.55-3.38 (m, 2H), 2.32 (s, 3H), 1.40 (s, 9H)

    Example 33.1B

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-methyl-1,2-oxazol-3-yl)propanoic acid (Racemate)

    [0935] ##STR00155##

    [0936] To 800 mg (1.70 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-methyl-1,2-oxazol-3-yl)propanoate (racemate) were added 17 ml of 4 N hydrogen chloride in dioxane and the mixture was stirred at RT for 24 h. The reaction mixture was concentrated, and the residue was twice admixed with THF and concentrated. Yield: 780 mg (88% purity, 97% of theory).

    [0937] LC/MS [Method 1]: R.sub.t=0.81 min; MS (ESIpos): m/z=414 (M+H).sup.+,

    [0938] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.22 (bs, 1H), 8.00-7.95 (m, 1H), 7.75-7.69 (m, 2H), 7.41 (s, 1H), 6.47 (s, 1H), 5.99-5.93 (m, 1H), 5.36 (dd, 1H), 3.59-3.40 (m, 5H), 2.31 (s, 3H).

    Example 34.1A

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methyl-1H-pyrazol-3-yl)propanoate (Racemate)

    [0939] ##STR00156##

    [0940] To a solution of 750 mg (2.00 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 15 ml of THF under argon at −70° C. were added 2.50 ml (2.50 mmol, 1.25 eq.) of 1 N lithium bis(trimethylsilyl)amide in THF, and the mixture was stirred for 30 min. Subsequently, 725 mg (1.91 mmol, 0.95 eq., 46% purity) of 3-(bromomethyl)-1-methyl-1H-pyrazole were added, the mixture was stirred at −70° C. for 30 min and then stirred while coming to RT for 2 h. To the reaction mixture were added 10 ml of saturated aqueous ammonium chloride solution, 10 ml of water and 80 ml of ethyl acetate. The aqueous phase was extracted once with ethyl acetate, and the combined organic phases were washed once with saturated aqueous sodium chloride solution, then dried and concentrated. The crude product was purified by means of Biotage Isolera (eluent: dichloromethane/methanol, 0-10%). Yield: 1.01 g (85% purity, 92% of theory).

    [0941] LC/MS [Method 1]: R.sub.t=0.99 min; MS (ESIpos): m/z=469 (M+H).sup.+,

    [0942] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.97 (d, 1H), 7.75-7.66 (m, 2H), 7.50 (d, 1H), 7.30 (s, 1H), 6.44 (s, 1H), 5.96 (d, 1H), 5.29 (dd, 1H), 3.73 (s, 3H), 3.55 (s, 3H), 3.49-3.37 (m, 1H), 3.36-3.27 (m, 1H), 1.41 (s, 9H)

    Example 34.1B

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methyl-1H-pyrazol-3-yl)propanoic acid (Racemate)

    [0943] ##STR00157##

    [0944] To 1.02 g (1.85 mmol, 85% purity) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methyl-1H-pyrazol-3-yl)propanoate (racemate) were added 18 ml of 4 N hydrogen chloride in dioxane and the mixture was stirred at RT overnight. The reaction mixture was concentrated and lyophilized. The residue was purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 620 mg (81% of theory).

    [0945] LC/MS [Method 1]: R.sub.t=0.77 min; MS (ESIpos): m/z=413 (M+H).sup.+,

    [0946] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.05 (bs, 1H), 8.02-7.92 (m, 1H), 7.74-7.66 (m, 2H), 7.48 (d, 1H), 7.32 (s, 1H), 6.42 (s, 1H), 5.91 (d, 1H), 5.30 (dd, 1H), 3.72 (s, 3H), 3.54 (s, 3H), 3.47 (dd, 1H), 3.38-3.26 (m, 1H)

    Example 35.1A

    2-(Bromomethyl)-5-cyclopropyl-1,3,4-oxadiazole

    [0947] ##STR00158##

    [0948] Under argon, 1.0 g (7.14 mmol) of (5-cyclopropyl-1,3,4-oxadiazol-2-yl)methanol and 1.29 ml (9.28 mmol, 1.3 eq.) of triethylamine were dissolved in 9.9 ml of DMF and cooled to 0° C. At this temperature, 0.72 ml (9.28 mmol, 1.3 eq.) of methanesulphonyl chloride was added dropwise and the mixture was stirred at 0° C. for 1 h. Subsequently, 1.74 g (19.98 mmol, 2.8 eq.) of lithium bromide were added and the mixture was stirred at 0° C. for 1 h. The reaction mixture was admixed with 60 ml of water and 15 g of sodium chloride and extracted four times with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. The residue was purified by means of Biotage-Isolera (eluent: dichloromethane). Yield: 470 mg (90% purity, 29% of theory)

    [0949] .sup.1H-NMR (400 MHz, CDCl.sub.3-d.sub.6): δ [ppm]=4.64 (s, 2H), 2.24-2.10 (m, 1H), 1.23-1.12 (m, 4H).

    Example 35.1B

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)propanoate (Racemate)

    [0950] ##STR00159##

    [0951] To a solution of 587 mg (1.57 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 12 ml of THF were added, under argon at −70° C., 1.96 ml (1.96 mmol, 1.25 eq.) of 1N lithium bis(trimethylsilyl)amide in THF and the mixture was stirred for 30 min. Subsequently, 470 mg (2.08 mmol, 1.33 eq., 90% purity) of 2-(bromomethyl)-5-cyclopropyl-1,3,4-oxadiazole were added, the mixture was stirred at −70° C. for 30 min and then while coming to RT for 2 h. The reaction mixture was admixed with 10 ml of saturated aqueous ammonium chloride solution, 10 ml of water and 80 ml of ethyl acetate. The aqueous phase was extracted once with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution, then dried and concentrated. The crude product was purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-66%). Yield: 530 mg (66% of theory).

    [0952] LC/MS [Method 1]: R.sub.t=1.02 min; MS (ESIpos): m/z=497 (M+H).sup.+,

    [0953] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.98 (d, 1H), 7.73 (dd, 1H), 7.69 (d, 1H), 7.49 (s, 1H), 6.53 (s, 1H), 5.41 (dd, 1H), 3.78-3.71 (m, 1H), 3.66-3.58 (m, 4H), 2.22-2.14 (m, 1H), 1.37 (s, 9H), 1.13-1.05 (m, 2H), 0.98-0.87 (m, 2H).

    Example 35.1C

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)propanoic acid (Racemate)

    [0954] ##STR00160##

    [0955] To 530 mg (1.04 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)propanoate (racemate) were added 10 ml of 4N hydrogen chloride in dioxane and the mixture was stirred at RT for 8 h. The reaction mixture was concentrated, dissolved in THF and concentrated again. The residue was purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 310 mg (80% purity, 54% of theory).

    [0956] LC/MS [Method 1]: R.sub.t=0.75 min; MS (ESIpos): m/z=441 (M+H).sup.+,

    [0957] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.33 (bs, 1H), 7.98 (d, 1H), 7.73 (dd, H), 7.69 (d, 1H), 7.51 (s, 1H), 6.51 (s, 1H), 5.45-5.38 (m, 1H), 3.72-3.67 (m, 2H), 3.59 (s, 3H), 2.20-2.13 (m, 1H), 1.11-1.04 (m, 2H), 0.96-0.85 (m, 2H).

    Example 36.1A

    Mixture of: 4-(bromomethyl)-2-methyl-1,3-oxazole and 4-(chloromethyl)-2-methyl-1,3-oxazole

    [0958] ##STR00161##

    [0959] Under argon, 1.00 g (8.84 mmol) of (2-methyl-1,3-oxazol-4-yl)methanol and 1.60 ml (11.49 mmol, 1.3 eq.) of triethylamine were dissolved in 12.5 ml of DMF and cooled to 0° C. At this temperature, 0.890 ml (11.49 mmol, 1.3 eq.) of methanesulphonyl chloride was added dropwise and the mixture was stirred at 0° C. for 1 h. 2.15 g (24.75 mmol, 2.8 eq.) of lithium bromide were then added, and the mixture was stirred at 0° C. for 1 h. The reaction mixture was admixed with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. The residue was purified by means of Biotage-Isolera (eluent: dichloromethane). Yield: 3.00 g (38% purity, 73% of theory).

    [0960] LC/MS [Method 9]: R.sub.t=2.73 min; MS (ESIpos): m/z=177 (M+H).sup.+,

    [0961] LC/MS [Method 9]: R.sub.t=2.19 min; MS (ESIpos): m/z=133 (M+H).sup.+.

    Example 36.1B

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(2-methyl-1,3-oxazol-4-yl)propanoate (Racemate)

    [0962] ##STR00162##

    [0963] To a solution of 1.00 g (2.67 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 26 ml of THF under argon at −70° C. were added 3.34 ml (3.34 mmol, 1.25 eq.) of 1 N lithium bis(trimethylsilyl)amide in THF, and the mixture was stirred for 30 min. Subsequently, 1.09 mg (2.35 mmol, 0.9 eq., 38% purity) of the mixture of 4-(bromomethyl)-2-methyl-1,3-oxazole and 4-(chloromethyl)-2-methyl-1,3-oxazole were added, the mixture was stirred at −70° C. for 30 min and then stirred while coming to RT for 2 h. To the reaction mixture were added 10 ml of saturated aqueous ammonium chloride solution, 10 ml of water and 80 ml of ethyl acetate. The aqueous phase was extracted once with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution, then dried and concentrated. The crude product was purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 50-100%). Yield: 1.11 g (99% of theory).

    [0964] LC/MS [Method 1]: R.sub.t=1.03 min; MS (ESIpos): m/z=470 (M+H).sup.+,

    [0965] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.97 (d, 1H), 7.76-7.67 (m, 2H), 7.60 (s, 1H), 7.33 (s, 1H), 6.45 (s, 1H), 5.31 (dd, 1H), 3.57 (s, 3H), 3.36 (dd, 1H), 3.24 (dd, 1H), 2.33 (s, 3H), 1.40 (s, 9H).

    Example 36.1C

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(2-methyl-1,3-oxazol-4-yl)propanoic acid hydrochloride (Racemate)

    [0966] ##STR00163##

    [0967] To 1.11 g (2.34 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(2-methyl-1,3-oxazol-4-yl)propanoate (racemate) were added 25 ml of 4 N hydrogen chloride in dioxane and the mixture was stirred at RT overnight. The reaction mixture was concentrated and lyophilized. Yield: 893 mg (94% purity, 79% of theory).

    [0968] LC/MS [Method 1]: R.sub.t=0.79 min; MS (ESIpos): m/z=414 (M+H).sup.+,

    [0969] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.02-7.93 (m, 1H), 7.76-7.65 (m, 2H), 7.55 (s, 1H), 7.35 (s, 1H), 6.43 (s, 1H), 5.32 (dd, 1H), 3.56 (s, 3H), 3.41 (dd, 1H), 3.23 (dd, 1H), 2.32 (s, 3H).

    Example 37.1A

    4-{[tert-Butyl(dimethyl)silyl]oxy}but-2-yn-1-ol

    [0970] ##STR00164##

    [0971] 5.00 g (58.08 mmol) of but-2-yne-1,4-diol were initially charged in 62.5 ml of DMF, 2.97 g (43.56 mmol, 0.75 eq.) of 1H-imidazole and 5.25 g (34.85 mmol, 0.6 eq.) of tert-butyl(chloro)dimethylsilane were added and the mixture was stirred at RT for 24 h. The reaction mixture was admixed with 20 ml of methanol and 60 ml of water and then concentrated. The aqueous residue was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. The residue was purified by means of Biotage-Isolera (eluent: dichloromethane/methanol, 1-10%). Yield: 4.30 g (36% of theory).

    [0972] LC/MS [Method 9]: R.sub.t=3.74 min; MS (ESIpos): m/z=143 (M−C.sub.4H.sub.9).sup.+,

    [0973] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=5.14 (t, 1H), 4.32 (t, 2H), 4.08 (dt, 2H), 0.90-0.85 (m, 9H), 0.11-0.06 (m, 6H).

    Example 37.1B

    2-[(4-{[tert-Butyl(dimethyl)silyl]oxy}but-2-yn-1-yl)oxy]-1H-isoindole-1,3(2H)-dione

    [0974] ##STR00165##

    [0975] A solution of 4.30 g (20.82 mmol) of 4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-ol, 4.08 g (24.98 mmol, 1.2 eq.) of 2-hydroxy-1H-isoindole-1,3(2H)-dione and 8.19 g (31.23 mmol, 1.5 eq.) of triphenylphosphine in 40 ml of dichloromethane was cooled to 0° C., 6.13 ml (31.23 mmol, 1.5 eq.) of diisopropyl (E)-diazene-1,2-dicarboxylate were added and the mixture was stirred at 0° C. for 30 min and then for 4 h while coming to RT. The reaction mixture was concentrated and the residue was purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 25%-50%). Yield: 7.67 g (82% purity, 88% of theory).

    [0976] LC/MS [Method 1]: R.sub.t=1.25 min; MS (ESIpos): m/z=346 (M+H).sup.+,

    [0977] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.88 (s, 4H), 4.94 (t, 2H), 4.34 (t, 2H), 0.81-0.78 (m, 9H), 0.00 (s, 6H).

    Example 37.1C

    {[4-(Aminooxy)but-2-yn-1-yl]oxy}(tert-butyl)dimethylsilane

    [0978] ##STR00166##

    [0979] A solution of 7.67 g (18.21 mmol, 82% purity) of 2-[(4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-yl)oxy]-1H-isoindole-1,3(2H)-dione in 90 ml of dichloromethane was cooled to 0° C., 8.05 ml (91.03 mmol, 5 eq., 55% purity) of hydrazine hydrate were added and the mixture was stirred at 0° C. for 10 min. The reaction mixture was stirred at RT overnight and then diluted with 90 ml of a 5% aqueous sodium carbonate solution and extracted three times with in each case 90 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. The crude product was purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-35%). Yield: 3.59 g (81% purity, 74% of theory).

    [0980] LC/MS [Method 9]: R.sub.t=4.24 min; MS (ESIpos): m/z=158 (M−C.sub.4H.sub.9).sup.+,

    [0981] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=6.10 (s, 2H), 4.35 (t, 2H), 4.21 (t, 2H), 0.88-0.86 (m, 9H), 0.10-0.08 (m, 6H).

    Example 37.1D

    3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4,5-dihydro-1,2-oxazole

    [0982] ##STR00167##

    [0983] 2.00 g (7.52 mmol, 81% purity) of {[4-(aminooxy)but-2-yn-1-yl]oxy}(tert-butyl)dimethylsilane were dissolved in 75 ml of dichloromethane, 116 mg (0.15 mmol, 0.02 eq.) of [(2-biphenyl)di-tert-butylphosphine]gold(I) hexafluoroantimonate-acetonitrile monoadduct were added and the mixture was stirred at RT for 30 min. Subsequently, 1.05 ml (7.52 mmol, 1 eq.) of triethylamine were added, and the mixture was filtered through silica gel and washed with dichloromethane. The filtrate was concentrated and the residue was purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-10%). Yield: 1.36 g (89% purity, 75% of theory).

    [0984] LC/MS [Method 9]: R.sub.t=4.19 min; MS (ESIpos): m/z=158 (M−C.sub.4H.sub.9).sup.+,

    [0985] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=4.40 (s, 2H), 4.23 (t, 2H), 3.00 (t, 2H), 0.90-0.85 (m, 9H), 0.09-0.07 (m, 6H).

    Example 37.1E

    4,5-Dihydro-1,2-oxazol-3-ylmethanol

    [0986] ##STR00168##

    [0987] 1.36 g (5.62 mmol, 89% purity) of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4,5-dihydro-1,2-oxazole were initially charged in 125 ml of THF, 8.43 ml (8.43 mmol, 1.5 eq.) of 1 N tetra-n-butylammonium fluoride in THF were added and the mixture was stirred at RT for 1 h. The reaction mixture was admixed with 6.3 g of silica gel and concentrated, and the residue was purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, isocratic run: 50% ethyl acetate, then 30% ethyl acetate; then dichloromethane/methanol 25%). Yield: 598 mg (81% purity, 85% of theory).

    [0988] LC/MS [Method 9]: R.sub.t=3.06 min; MS (ESIpos): m/z=101 (M).sup.+,

    [0989] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=5.24 (t, 1H), 4.22-4.15 (m, 4H), 2.98 (t, 2H).

    Example 37.1F

    Mixture of: 3-(bromomethyl)-4,5-dihydro-1,2-oxazole and 3-(chloromethyl)-4,5-dihydro-1,2-oxazole

    [0990] ##STR00169##

    [0991] Under argon, 598 mg (4.79 mmol, 81% purity) of 4,5-dihydro-1,2-oxazol-3-ylmethanol and 868 (6.23 mmol, 1.3 eq.) of triethylamine were dissolved in 8.5 ml of DMF and cooled to 0° C. At this temperature, 482 μl (6.23 mmol, 1.3 eq.) of methanesulphonyl chloride was added dropwise and the mixture was stirred at 0° C. for 1 h. 1.17 g (13.41 mmol, 2.8 eq.) of lithium bromide were then added, and the mixture was stirred at 0° C. for 1 h. The reaction mixture was admixed with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. The residue was purified by means of Biotage-Isolera (eluent: dichloromethane). Yield: 631 mg (77% of theory)

    [0992] LC/MS [Method 9]: R.sub.t=3.26 min; MS (ESIneg): m/z=162 (M−H).sup.−,

    [0993] LC/MS [Method 9]: R.sub.t=2.74 min; MS (ESIpos): m/z=121 (M+H).sup.+.

    Example 37.1G

    tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4,5-dihydro-1,2-oxazol-3-yl)propanoate (Racemate)

    [0994] ##STR00170##

    [0995] To a solution of 1.00 g (2.67 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 26 ml of THF under argon at −70° C. were added 3.34 ml (3.34 mmol, 1.25 eq.) of 1 N lithium bis(trimethylsilyl)amide in THF, and the mixture was stirred for 30 min. Subsequently, 638 mg (3.74 mmol, 1.4 eq.) of the mixture of 3-(bromomethyl)-4,5-dihydro-1,2-oxazole and 3-(chloromethyl)-4.5-dihydro-1,2-oxazole were added, the mixture was stirred at −70° C. for 30 min and then stirred while coming to RT for 2 h. To the reaction mixture were added 20 ml of saturated aqueous ammonium chloride solution, 20 ml of water and 150 ml of ethyl acetate. The aqueous phase was extracted once with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution, then dried and concentrated. The crude product was purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 50-100%). Yield: 875 mg (70% of theory).

    [0996] LC/MS [Method 1]: R.sub.t=1.00 min; MS (ESIpos): m/z=458 (M+H).sup.+,

    [0997] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.03-7.95 (m, 1H), 7.75-7.70 (m, 2H), 7.46 (s, 1H), 6.51 (s, 1H), 5.38-5.30 (m, 1H), 4.22-4.06 (m, 2H), 3.63 (s, 3H), 3.25-3.18 (m, 2H), 3.08-2.96 (m, 1 H), 2.94-2.82 (m, 1H), 1.40 (s, 9H).

    Example 37.1H

    2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4,5-dihydro-1,2-oxazol-3-yl)propanoic acid hydrochloride (Racemate)

    [0998] ##STR00171##

    [0999] To 875 mg (1.87 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4,5-dihydro-1,2-oxazol-3-yl)propanoate (racemate) were added 20 ml of 4 N hydrogen chloride in dioxane and the mixture was stirred at RT overnight. The reaction mixture was concentrated and lyophilized. Yield: 743 mg (94% purity, 85% of theory).

    [1000] LC/MS [Method 1]: R.sub.t=0.69 min; MS (ESIpos): m/z=402 (M+H).sup.+,

    [1001] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.20 (bs, 1H), 8.03-7.95 (m, 1H), 7.76-7.69 (m, 2H), 7.51 (s, 1H), 6.50 (s, 1H), 5.37 (dd, 1H), 4.20-4.02 (m, 2H), 3.62 (s, 3H), 3.33-3.16 (m, 2H), 3.06-2.93 (m, 1H), 2.91-2.76 (m, 1H).

    Example 38.1A

    tert-Butyl [4-(2-cyano-5-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate

    [1002] ##STR00172##

    [1003] To 1.35 g (5.06 mmol, 90% purity) of 2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)-4-methylbenzonitrile, 0.914 ml (6.07 mmol, 1.2 eq.) of tert-butyl bromoacetate and 1.05 g (7.59 mmol, 1.5 eq.) of potassium carbonate were added 31 ml of DMF and the mixture was stirred at 100° C. for 90 min. The reaction mixture was concentrated. The residue was dissolved in 6 ml of dichloromethane and purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-70%). Yield: 1.29 g (72% of theory).

    [1004] LC/MS [Method 1]: R.sub.t=0.94 min; MS (ESIpos): m/z=355 (M+H).sup.+,

    [1005] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.81 (d, 1H), 7.53 (s, 1H), 7.43 (d, 1H), 7.37 (s, 1H), 6.39 (s, 1H), 4.60 (s, 2H), 3.60 (s, 3H), 2.42 (s, 3H), 1.44 (s, 9H).

    Example 38.1B

    tert-Butyl 2-[4-(2-cyano-2-methylphenyl)-5-methoxy-5-oxopyridin-1(2H)-yl]-3-(1-methyl-1H-pyrazol-3-yl)propanoate (Racemate)

    [1006] ##STR00173##

    [1007] To a solution of 0.90 g (2.54 mmol) of tert-butyl [4-(2-cyano-5-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 19 ml of THF under argon at −70° C. were added 3.17 ml (3.17 mmol, 1.25 eq.) of 1 N lithium bis(trimethylsilyl)amide in THF, and the mixture was stirred for 30 min. Subsequently, 543 mg (3.56 mmol, 1.4 eq.) of the mixture of 3-(bromomethyl)-1-methyl-1H-pyrazole and 3-(chloromethyl)-1-methyl-1H-pyrazole were added, the mixture was stirred at −70° C. for 30 min and then stirred while coming to RT for 2 h. To the reaction mixture were added 15 ml of saturated aqueous ammonium chloride solution, 15 ml of water and 150 ml of ethyl acetate. The aqueous phase was extracted once with ethyl acetate, and the combined organic phases were washed once with saturated aqueous sodium chloride solution, then dried and concentrated. The crude product was purified by means of Biotage-Isolera (eluent: dichloromethane/methanol, 0-5%). The product fractions were combined and purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 640 mg (58% of theory).

    [1008] LC/MS [Method 1]: R.sub.t=0.94 min; MS (ESIpos): m/z=449 (M+H).sup.+,

    [1009] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.79 (d, 1H), 7.51 (d, 1H), 7.42 (d, 1H), 7.35 (s, 1H), 7.27 (s, 1H), 6.33 (s, 1H), 5.95 (d, 1H), 5.29 (dd, 1H), 3.73 (s, 3H), 3.53 (s, 3 H), 3.47-3.38 (m, 1H), 3.36-3.28 (m, 3H), 2.41 (s, 3H), 1.41 (s, 9H).

    Example 38.1C

    2-[4-(2-Cyano-5-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methyl-1H-pyrazol-3-yl)propanoic acid hydrochloride (Racemate)

    [1010] ##STR00174##

    [1011] To 640 mg (1.33 mmol) of tert-butyl 2-[4-(2-cyano-5-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methyl-1H-pyrazol-3-yl)propanoate (racemate) were added 13 ml of 4 N hydrogen chloride in dioxane and the mixture was stirred at RT overnight. The reaction mixture was concentrated and dried under high vacuum. The residue was twice admixed with THF and concentrated again. Yield: 700 mg (80% purity, 98% of theory).

    [1012] LC/MS [Method 1]: R.sub.t=0.71 min; MS (ESIpos): m/z=393 (M+H).sup.+,

    [1013] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.79 (d, 1H), 7.50 (d, 1H), 7.41 (d, 1H), 7.35 (s, 1H), 7.29 (s, 1H), 6.32 (s, 1H), 5.92 (d, 1H), 5.31 (dd, 1H), 3.72 (s, 3H), 3.52 (s, 3H), 3.51-3.43 (m, 1H), 3.39-3.28 (m, 1H), 2.41 (s, 3H).

    Example 39.1A

    tert-Butyl 2-[4-(2-cyano-2-methylphenyl)-5-methoxy-5-oxopyridin-1(2H)-yl]-4-methoxybutanoate (Racemate)

    [1014] ##STR00175##

    [1015] 0.545 g (2.70 mmol) of 2-bromo-4-methylbenzonitrile, 1.87 g (2.70 mmol, 1 eq., 61% purity) of tert-butyl 4-methoxy-2-[5-methoxy-2-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl]butanoate (racemate) and 1.12 g (8.08 mmol, 3 eq.) of potassium carbonate were initially charged in 27 ml of dioxane under argon, 66 mg (0.08 mmol, 0.03 eq) of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex were added, and the mixture was stirred at 80° C. for 16 h. The reaction mixture was cooled and filtered through kieselguhr, and the filtercake was washed with dichloromethane and acetonitrile. The filtrate was concentrated and the residue was then purified by means of Biotage-Isolera (eluent: cyclohexane/ethyl acetate, 0-70%). Yield: 1.04 g (85% purity, 80% of theory).

    [1016] LC/MS [Method 10]: R.sub.t=1.86 min; MS (ESIpos): m/z=413 (M+H).sup.+,

    [1017] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.80 (d, 1H), 7.43 (d, 1H), 7.39 (s, 1H), 7.34 (s, 1H), 6.38 (s, 1H), 5.15-5.05 (m, 1H), 3.62 (s, 3H), 3.43-3.35 (m, 1H), 3.23-3.11 (m, 4H), 2.42 (s, 3H), 2.38-2.29 (m, 2H), 1.40 (s, 9H).

    Example 39.1B

    2-[4-(2-Cyano-5-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (Racemate)

    [1018] ##STR00176##

    [1019] To 1.04 g (2.14 mmol, 85% purity) of tert-butyl 2-[4-(2-cyano-5-methylphenyl)-5-methoxy-5-oxopyridin-1(2H)-yl]-4-methoxybutanoate (racemate) were added 20.4 ml of 4 N hydrogen chloride in dioxane and the mixture was stirred at RT overnight. The reaction mixture was concentrated, and the residue was twice dissolved in THF, concentrated again and dried under high vacuum. Yield: 890 mg (99% of theory).

    [1020] LC/MS [Method 10]: R.sub.t=1.31 min; MS (ESIpos): m/z=357 (M+H).sup.+,

    [1021] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=12.96 (s, 1H), 7.81 (d, 1H), 7.46-7.36 (m, 3H), 6.37 (s, 1H), 5.18-5.09 (m, 1H), 3.62 (s, 3H), 3.42-3.35 (m, 1H), 3.19 (s, 3H), 3.17-3.09 (m, 1H), 2.42 (s, 3H), 2.40-2.31 (m, 2H).

    Working Examples

    [1022] General Method 1: Amide Coupling with HATU/DIEA

    [1023] To a solution of the appropriate carboxylic acid (1.0 eq.) in dimethylformamide (7-15 ml/mmol) under argon and at RT were added the amine (1.1 eq.), N,N-diisopropylethylamine (2.2 eq.) and a solution of HATU (1.2 eq.) in a little dimethylformamide The reaction mixture was stirred at RT. After addition of water/ethyl acetate and phase separation, the organic phase was washed with water and with saturated aqueous sodium chloride solution, dried (sodium sulphate or magnesium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified either by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

    [1024] General Method 2: Amide Coupling Using T3P/Pyridine

    [1025] A solution of the appropriate carboxylic acid or carboxylic acid hydrochloride (1 eq.) and the appropriate amine or amine hydrochloride (1.1-1.9 eq.) in pyridine (about 0.1 M) was heated to 60° C., and T3P (50% in ethyl acetate, 1.5-15 eq.) was added dropwise. Alternatively, T3P was added at RT and the mixture was then stirred at RT or heated to 50 to 90° C. After 1 to 20 h, the reaction mixture was cooled to RT and either purified directly by means of preparative HPLC (water-acetonitrile gradient or water-methanol gradient) or admixed with water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous buffer solution (pH=5), with saturated aqueous sodium hydrogencarbonate solution and with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was then optionally purified either by means of normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

    [1026] The following Examples 1 to 8 were prepared according to General Method 1:

    TABLE-US-00001 Ex. IUPAC name/structure Yield Analysis 1 [00177]embedded image 22 mg 56% of theory MS (ESI): m/z = 572 [M + H].sup.+ LC/MS (Method 8): R.sub.t = 1.08 min. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.96 (s, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 8.04 (d, 1H), 7.80- 7.73 (m, 2H), 7.70 (t, 1H), 7.63 (dd. 1H), 7.59-7.51 (m, 2H), 7.39 (dd, 1H), 6.90 (s, 1H), 6.82 (t, 1H), 6.62 (s, 1H), 5.94 (dd, 1H), 3.73 (dd, 1H), 3.63 (dd, 1H). 2 [00178]embedded image 41 mg 60% of theory MS (ESI): m/z = 540 [M + H].sup.+ LC/MS (Method 1): R.sub.t = 0.84 min. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.98 (bs, 1H), 8.34- 8.23 (m, 2H), 8.05 (d, 1H), 7.85-7.73 (m, 3H), 7.70 (t, 1H), 7.65 (dd, 1H), 7.59- 7.49 (m, 2H), 7.41 (dd, 1H), 6.61 (s, 1H), 5.94 (dd, 1H), 3.57 (dd, 1H), 3.41 (dd, 1H). 3 [00179]embedded image 30 mg, 94% purity 43% of theory MS (ESI): m/z = 536 [M + H].sup.+ LC/MS (Method 1): R.sub.t = 0.78 min. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.90 (s, 1H), 8.29 (s, 1H), 7.98 (d, 1H), 7.81 (s, 1H), 7.76- 7.63 (m, 4H), 7.58- 7.49 (m, 3H), 7.43 (dd, 1H), 6.47 (s, 1H), 5.94 (dd, 1H), 3.67 (s, 3H), 3.55 (dd, 1H), 3.40 (dd, 1H). 4 [00180]embedded image 5 mg, 93% purity 8% of theory MS (ESI): m/z = 540 [M + H].sup.+ LC/MS (Method 1): R.sub.t = 0.81 min. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.94 (bs, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 8.06 (d, 1H), 7.85- 7.74 (m, 2H), 7.70 (t, 1H), 7.63 (dd, 1H), 7.55 (bs, 2H), 7.39 (dd, 1H), 6.90 (s, 1H), 6.65 (s, 1H), 5.92 (dd, 1H), 3.78 (dd, 1H), 3.65 (dd, 1H). 5 [00181]embedded image 9 mg 16% of theory MS (ESIneg): m/z = 534 [M − H].sup.− LC/MS (Method 8): R.sub.t = 1.02 min. .sup.1H-NMR (400 MHz. DMSO-d.sub.6) δ ppm 10.86 (s, 1H), 8.23 (s, 1H), 7.99 (d, 1H), 7.76-7.62 (m, 4H). 7.58-7.49 (m, 3H), 7.41 (dd, 1H), 6.90 (s, 1H), 6.50 (s, 1H), 5.93 (dd, 1H), 3.82- 3.71 (m, 1H), 3.71- 3.57 (m, 4H). 6 [00182]embedded image 18 mg 32% of theory MS (ESI): m/z = 517 [M + H].sup.+ LC/MS (Method 1): R.sub.t = 0.92 min. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.87 (bs, 1H), 8.22 (s, 1H), 8.06 (d, 1H), 7.85-7.76 (m, 2H), 7.73-7.61 (m, 2H), 7.58-7.48 (m, 2H), 7.41 (dd, 1H), 6.67 (s, 1H), 5.79-5.67 (m, 1H), 3.41 (dt, 1H), 3.28-3.22 (m, 1H), 3.19 (s, 3H), 2.42 (q, 2H). 7 [00183]embedded image 28 mg 68% of theory MS (ESI): m/z = 483 [M + H].sup.+ LC/MS (Method 1): R.sub.t = 0.89 min. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.86 (s, 1H), 8.05- 7.95 (m, 1H), 7.78- 7.61 (m, 4H), 7.59- 7.45 (m, 3H), 7.40 (dd, 1H), 6.54 (s, 1H), 5.60 (dd, 1H), 3.69 (s, 3H), 2.25-2.10 (m, 2H), 0.90 (t, 3H). 8 [00184]embedded image 25 mg, 61% of theory MS (ESI): m/z = 497 [M + H].sup.+ LC/MS (Method 8): R.sub.t = 1.19 min. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.85 (s, 1H), 8.12- 8.03 (m, 1H), 8.03- 7.96 (m, 1H), 7.77- 7.71 (m, 2H), 7.71- 7.60 (m, 2H), 7.48 (s, 1H), 7.40 (dd, 1H), 6.54 (s, 1H), 5.60 (dd, 1H), 3.69 (s, 3H), 2.76 (d, 3H), 2.27- 2.08 (m, 2H), 0.90 (t, 3H).

    [1027] The following Examples 9 to 17 were prepared according to General Method 2:

    TABLE-US-00002 Ex. IUPAC name/structure Yield Analysis 9 [00185]embedded image 42 mg 70% of theory MS (ESI): m/z = 546 [M + H].sup.+ LC/MS (Method 1): R.sub.t = 0.72 min. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.86 (s, 1H), 8.52 (d, 1H), 8.40 (dd, 1H), 7.97 (d, 1H), 7.75- 7.50 (m, 8H), 7.39 (dd, 1H), 7.27 (dd, 1 H), 6.43 (s, 1H), 5.99 (dd, 1H), 3.68 (s, 3H), 3.64-3.48 (m, 2H). 10 [00186]embedded image 22 mg 39% of theory MS (ESI): m/z = 546 [M + H].sup.+ LC/MS (Method 1): R.sub.t = 0.68 min. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.88 (s, 1H), 8.44 (d, 2H), 7.97 (d, 1H), 7.75-7.61 (m, 4H), 7.61-7.45 (m, 3H), 7.40 (dd, 1H), 7.26 (d, 2H), 6.43 (s, 1H), 6.02 (dd, 1H), 3.67 (s, 3H), 3.65-3.49 (m, 2H). 11 [00187]embedded image 22 mg 93% purity 25% of theory MS (ESI): m/z = 582 [M + H].sup.+ LC/MS (Method 1): R.sub.t = 0.87 min. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.01 (s, 1H), 8.53- 8.39 (m, 1H), 8.09 (s, 1H), 8.01 (d, 1H), 7.78-7.61 (m, 6H), 7.58-7.47 (m, 2H), 7.42 (dd, 1H), 7.34 (d, 1H), 7.22 (dd, 1H), 6.76 (t, 1H), 6.54 (s, 1H), 6.13 (t, 1H), 3.72-3.63 (m, 2 H). 12 [00188]embedded image 100 mg 53% of theory MS (ESI): m/z = 546 [M + H].sup.+ LC/MS (Method 1): R.sub.t = 0.80 min. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.94 (s, 1H), 8.48 (d, 1H), 7.96 (d, 1H), 7.75-7.62 (m, 5H), 7.59-7.47 (m, 3H), 7.43 (dd, 1H), 7.35 (d, 1H), 7.22 (dd, 1H), 6.42 (s, 1H), 6.10 (dd, 1H), 3.75- 3.65 (m, 2H), 3.63 (s, 3H). 13 [00189]embedded image 24 mg 36% of theory MS (ESI): m/z = 550 [M + H].sup.+ LC/MS (Method 1): R.sub.t = 0.90 min. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.99 (bs, 1H), 8.49 (d, 1H), 8.27 (bs, 1H), 8.03 (d, 1H), 7.80- 7.61 (m, 5H), 7.59- 7.49 (m, 2H), 7.44- 7.33 (m, 2H), 7.29- 7.21 (m, 1H), 6.57 (s, 1H), 6.18-6.07 (m, 1H), 3.64-3.81 (m, 2H). 14 [00190]embedded image 39 mg 56% of theory MS (ESI): m/z = 557 [M + H].sup.+ LC/MS (Method 1): R.sub.t = 1.03 min. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.84 (bs, 1H), 8.27- 8.10 (m, 1H), 8.10- 8.00 (m, 1H), 7.85- 7.74 (m, 2H), 7.72- 7.59 (m, 2H), 7.58- 7.45 (m, 2H), 7.45- 7.37 (m, 1H), 6.66 (s, 1H), 5.85-5.65 (m, 1H), 3.89-3.73 (m, 1H), 3.33-3.10 (m, 1H), 3.10-2.97 (m., 1H), 2.46-2.12 (m, 2H), 1.80-1.67 (m, 1H), 1.64-1.53 (m, 1H), 1.48-1.32 (m, 3 H), 1.32-1.16 (m, 1H). 15 [00191]embedded image 48 mg 70% of theory MS (ESI): m/z = 571 [M + H].sup.+ LC/MS (Method 1): R.sub.t = 1.06 min. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.83 (bs, 1H), 8.20 (d, 1H), 8.13-7.98 (m, 2H), 7.90-7.72 (m, 2H), 7.72-7.53 (m, 2H), 7.49-7.33 (m, 1H), 6.66 (s, 1H), 5.90-5.65 (m, 1H), 3.88-3.74 (m, 1H), 3.27-3.10 (m, 1H), 3.10-3.00 (m, 1H), 2.77 (d, 3H), 2.47- 2.12 (m, 2H), 1.78- 1.70 (m, 1H), 1.64- 1.55 (m, 1H), 1.47- 1.33 (m, 3H), 1.32- 1.16 (m, 1H). 16 [00192]embedded image 50 mg 69% of theory MS (ESI): m/z = 543 [M + H].sup.+ LC/MS (Method 1): R.sub.t = 0.91 min. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) d ppm 10.83 (s, 1H), 7.70 (t, 1H), 7.65 (dd, 1H), 7.58-7.51 (m, 3H), 7.51-7.45 (m, 2H), 7.40 (dd, 1H), 7.36 (t, 1H), 6.45 (s, 1H), 6.12 (s, 1H), 5.95 (dd, 1H), 3.81 (dd, 1H), 3.71-3.59 (m, 4H), 2.16 (s, 3H). 17 [00193]embedded image 12 mg 19% of theory MS (ESI): m/z = 539 [M + H].sup.+ LC/MS (Method 1): R.sub.t = 0.81 min. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.90 (s, 1H), 8.60- 8.39 (m, 1H), 7.77- 7.62 (m, 3H), 7.57- 7.48 (m, 3H), 7.47 (s, 1H), 7.46-7.37 (m, 3H), 7.33 (t, 1H), 7.25 (dd, 1H), 6.36 (s, 1H), 6.10 (t, 1H), 3.69 (d, 2H), 3.59 (s, 3H).

    Example 18

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-ethoxybutanoyl}amino)-2-fluorobenzamide (Racemate)

    [1028] ##STR00194##

    [1029] According to General Method 2, 50 mg (0.13 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-ethoxybutanoic acid (racemate) and 30 mg (0.19 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide in 2 ml of pyridine were reacted at 80° C. with 0.30 ml (0.51 mmol, 4.0 eq.) propylphosphonic anhydride (T3P, 50% in ethyl acetate). The crude product was purified by means of preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, eluent: water/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min of 90% acetonitrile)]. Yield: 40 mg (59% of theory)

    [1030] LC/MS [Method 1]: R.sub.t=0.93 min; MS (ESIpos): m/z=527 (M+H).sup.+,

    [1031] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.79 (s, 1H), 8.00 (d, 1H), 7.76-7.64 (m, 4H), 7.57-7.50 (br. m, 2H), 7.50 (s, 1H), 7.44 (dd, 1H), 6.53 (s, 1H), 5.74 (dd, 1H), 3.69 (s, 3H), 3.49-3.42 (m, 1H), 3.42-3.36 (m, 1H), 3.37-3.27 (m, 2H), 2.45-2.37 (m, 2H), 1.05 (t, 3H).

    Example 19

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-isopropoxybutanoyl}amino)-2-fluorobenzamide (Racemate)

    [1032] ##STR00195##

    [1033] According to General Method 2, 80 mg (0.20 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-isopropoxybutanoic acid (racemate) and 46 mg (0.30 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide in 3 ml of pyridine were reacted at 80° C. with 0.46 ml (0.79 mmol, 4.0 eq.) of propylphosphonic anhydride (T3P, 50% in ethyl acetate). The crude product was purified by means of preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, eluent: water/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min of 90% acetonitrile)]. Yield: 11 mg (11% of theory)

    [1034] LC/MS [Method 1]: R.sub.t=0.94 min; MS (ESIpos): m/z=541 (M+H).sup.+,

    [1035] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.79 (s, 1H), 8.00 (d, 1H), 7.76-7.64 (m, 4H), 7.57-7.50 (br. m, 2H), 7.49 (s, 1H), 7.44 (dd, 1H), 6.53 (s, 1H), 5.75 (dd, 1H), 3.69 (s, 3H), 3.51-3.39 (m, 2H), 3.3-3.25 (m, 1H), 2.44-2.36 (m, 2H), 1.02 (d, 3H), 0.98 (d, 3H).

    Example 20

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(cyclobutyloxy)-butanoyl}amino)-2-fluorobenzamide (Racemate)

    [1036] ##STR00196##

    [1037] According to General Method 2, 60 mg (0.14 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(cyclobutyloxy)butanoic acid (racemate) and 32 mg (0.21 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide in 2 ml of pyridine were reacted at 80° C. with 0.32 ml (0.55 mmol, 4.0 eq.) of propylphosphonic anhydride (T3P, 50% in ethyl acetate). The crude product was purified by means of preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, eluent: water/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min of 90% acetonitrile)]. Yield: 27 mg (36% of theory)

    [1038] LC/MS [Method 1]: R.sub.t=0.97 min; MS (ESIpos): m/z=553 (M+H).sup.+,

    [1039] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.82 (s, 1H), 8.00 (d, 1H), 7.76-7.64 (m, 4H), 7.57-7.50 (br. m, 2H), 7.49 (s, 1H), 7.44 (dd, 1H), 6.54 (s, 1H), 5.75 (t, 1H), 3.87-3.77 (m, 1H), 3.69 (s, 3H), 3.39-3.3 (m, 1H), 3.26-3.17 (m, 1H), 2.45-2.35 (m, 2H), 2.12-1.98 (m, 2H), 1.82-1.63 (m 2H), 1.61-1.50 (m, 1H), 1.46-1.33 (m, 1H).

    Example 21

    4-({4-tert-Butoxy-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2-fluorobenzamide (Racemate)

    [1040] ##STR00197##

    [1041] According to General Method 2, 80 mg (0.19 mmol) of 4-tert-butoxy-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 43 mg (0.28 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide in 3 ml of pyridine were reacted at 80° C. with 0.43 ml (0.74 mmol, 4.0 eq.) of propylphosphonic anhydride (T3P, 50% in ethyl acetate). The crude product was purified by means of preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, eluent: water/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min of 90% acetonitrile)]. Yield: 43 mg (41% of theory)

    [1042] LC/MS [Method 1]: R.sub.t=0.95 min; MS (ESIpos): m/z=555 (M+H).sup.+,

    [1043] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.80 (s, 1H), 7.99 (d, 1H), 7.73 (dd, 1H), 7.71-7.64 (m, 3H), 7.57-7.50 (br. m, 2H), 7.49 (s, 1H), 7.45 (dd, 1H), 6.53 (s, 1H), 5.76 (t, 1H), 3.69 (s, 3H), 3.44-3.37 (m, 1H), 3.3-3.23 (m, 1H), 2.43-2.35 (m, 2H), 1.04 (s, 9H).

    Example 22

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(2,2-difluoroethoxy)-butanoyl}amino)-2-fluorobenzamide (Racemate)

    [1044] ##STR00198##

    [1045] According to General Method 2, 50 mg (0.12 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(2,2-difluoroethoxy)butanoic acid (racemate) and 27 mg (0.18 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide in 1.8 ml of pyridine were reacted at 80° C. with 0.27 ml (0.47 mmol, 4.0 eq.) of propylphosphonic anhydride (T3P, 50% in ethyl acetate). The crude product was purified by means of preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, eluent: water/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min of 90% acetonitrile)]. Yield: 15 mg (22% of theory)

    [1046] LC/MS [Method 1]: R.sub.t=0.92 min; MS (ESIpos): m/z=563 (M+H).sup.+,

    [1047] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.79 (s, 1H), 8.00 (d, 1H), 7.77-7.63 (m, 4H), 7.58-7.50 (br. m, 2H), 7.49 (s, 1H), 7.42 (dd, 1H), 6.54 (s, 1H), 6.06 (tt, 1H), 5.73 (dd, 1H), 3.73-3.55 (m, 3H), 3.69 (s, 3H), 3.52-3.44 (m, 1H), 2.5-2.40 (m, 2H).

    Example 23

    4-({2-[4-(2-Cyano-5-methoxyphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-2-fluorobenzamide (Racemate)

    [1048] ##STR00199##

    [1049] Analogously to General Method 2, 47 mg (purity assumed to be 80% according to theoretical yield, 0.10 mmol) of 2-[4-(2-cyano-5-methoxyphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxy-butanoic acid (racemate), 23 mg (0.15 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide were reacted in the presence of 4.5 eq. T3P (50% in dimethylformamide) at RT in 1.0 ml of pyridine. After aqueous workup, the crude product was purified by means of preparative RP-HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 22 mg (42% of theory)

    [1050] LC/MS [Method 1]: R.sub.t=0.80 min; MS (ESIpos): m/z=509 (M+H).sup.+,

    [1051] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.79 (s, 1H), 7.87 (d, 1H), 7.72-7.63 (m, 2H), 7.52 (br. m, 2H), 7.47 (s, 1H), 7.43 (dd, 1H), 7.15 (dd, 1H), 7.11 (d, 1H), 6.46 (s, 1H), 5.72 (dd, 1H), 3.88 (s, 3H), 3.68 (s, 3H), 3.44-3.37 (m, 1H), 3.3-3.25 (m, 1H), 3.21 (s, 3H), 2.45-2.37 (m, 2H).

    Example 24

    4-({2-[4-(2-Cyano-5-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-2-fluorobenzamide (Enantiomer 1)

    [1052] ##STR00200##

    [1053] Enantiomer separation of 115 mg of 4-({2-[4-(2-cyano-5-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-2-fluorobenzamide (racemate) gave 30 mg of the Example 24 title compound (Enantiomer 1), chiral HPLC: R.sub.t=7.25 min, 100% ee., and 29 mg of enantiomer 2 (chiral HPLC: R.sub.t=11.10 min).

    [1054] Separation method: column: Daicel Chiralpak IC 5 μm, 250 mm×20 mm; eluent: carbon dioxide 65%/isopropanol 35%; temperature: 40° C.; flow rate: 80 ml/min; pressure: 100 bar; UV detection: 210 nm.

    [1055] Analysis: column: Chiralpak IC 250 mm×4.6 mm; eluent: 65% carbon dioxide, 35% isopropanol; flow rate: 3 ml/min; UV detection: 210 nm.

    [1056] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.79 (s, 1H), 7.82 (d, 1H), 7.73-7.63 (m, 2H), 7.59-7.49 (m, 2H), 7.49-7.37 (m, 4H), 6.42 (s, 1H), 5.76-5.67 (m, 1H), 3.67 (s, 3H), 3.44-3.36 (m, 1H), 3.29-3.24 (m, 1H), 3.20 (s, 3H), 2.46-2.34 (m, 5H)

    Example 25

    4-({2-[4-(5-Chloro-2-cyano-4-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxy-butanoyl}amino)-2-fluorobenzamide (Racemate)

    [1057] ##STR00201##

    [1058] 65 mg (0.092 mmol, 56% purity) 2-[4-(5-chloro-2-cyano-4-fluorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 21 mg (0.138 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide were initially charged in 1.0 ml of pyridine at RT, 87 μl (0.368 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 90 min. The reaction mixture was purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 48 mg (97% of theory).

    [1059] LC/MS [Method 1]: R.sub.t=0.86 min; MS (ESIpos): m/z=531 (M+H).sup.+,

    [1060] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.80 (s, 1H), 8.23 (d, 1H), 7.94 (d, 1H), 7.73-7.62 (m, 2H), 7.58-7.46 (m, 3H), 7.43 (dd, 1H), 6.54 (s, 1H), 5.76-5.68 (m, 1H), 3.69 (s, 3H), 3.44-3.36 (m, 1H), 3.29-3.23 (m, 1H), 3.20 (s, 3H), 2.46-2.37 (m, 2H)

    Example 26

    4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-N-methylbenzamide (Racemate)

    [1061] ##STR00202##

    [1062] 50 mg (0.137 mmol, 95% purity) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 31 mg (0.205 mmol, 1.5 eq.) of 4-amino-N-methylbenzamide were initially charged in 1.2 ml of pyridine, the mixture was heated to 60° C., 130 μl (0.548 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 60° C. for 30 min. The reaction mixture was admixed with water and ethyl acetate. The aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed once with aqueous buffer solution (pH=5) and once with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. The residue was purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 65 mg (96% of theory).

    [1063] LC/MS [Method 8]: R.sub.t=1.12 min; MS (ESIneg): m/z=477 (M−H).sup.−,

    [1064] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.69 (s, 1H), 8.37-8.29 (m, 1H), 8.03-7.96 (m, 1H), 7.84-7.78 (m, 2H), 7.77-7.67 (m, 4H), 7.50 (s, 1H), 6.54 (s, 1H), 5.64 (dd, 1H), 3.69 (s, 3H), 2.76 (d, 3H), 2.27-2.08 (m, 2H), 0.91 (t, 3H)

    Example 27

    2-Chloro-4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-N-methylbenzamide (Racemate)

    [1065] ##STR00203##

    [1066] 50 mg (0.137 mmol, 95% purity) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 39 mg (0.205 mmol, 1.5 eq.) of 4-amino-2-chloro-N-methylbenzamide were initially charged in 1.0 ml of pyridine, the mixture was heated to 60° C., 130 μl (0.548 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 60° C. for 30 min. The reaction mixture was admixed with water and ethyl acetate. The aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed once with aqueous buffer solution (pH=5) and once with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. The residue was purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 58 mg (82% of theory).

    [1067] LC/MS [Method 1]: R.sub.t=0.93 min; MS (ESIpos): m/z=513 (M+H).sup.+,

    [1068] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.75 (s, 1H), 8.29-8.21 (m, 1H), 8.03-7.97 (m, 1H), 7.86 (d, 1H), 7.77-7.70 (m, 2H), 7.53 (dd, 1H), 7.48 (s, 1H), 7.41 (d, 1H), 6.54 (s, 1H), 5.59 (dd, 1H), 3.69 (s, 3H), 2.74 (d, 3H), 2.25-2.10 (m, 2H), 0.90 (t, 3H).

    Example 28

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-2-yl)propanoyl}amino)-2-fluorobenzamide (Enantiomer 1)

    [1069] ##STR00204##

    [1070] Enantiomer separation of 1400 mg of 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-2-yl)propanoyl}amino)-2-fluorobenzamide (racemate) gave 556 mg of the Example 28 title compound (Enantiomer 1), chiral HPLC: R.sub.t=6.30 min, 100% ee., and 565 mg of enantiomer 2 (chiral HPLC: R.sub.t=9.25 min).

    [1071] Separation method: column: Daicel Chiralpak IC 5 μm, 250 mm×20 mm; eluent: carbon dioxide 65%/isopropanol 35%; temperature: 40° C.; flow rate: 80 ml/min; pressure: 100 bar; UV detection: 210 nm.

    [1072] Analysis: column: Chiralpak IC-3 3 μm 50 mm×4.6 mm; eluent: 50% isohexane, 50% ethanol; flow rate: 1 ml/min; UV detection: 220 nm.

    [1073] LC/MS [Method 1]: R.sub.t=0.79 min; MS (ESIpos): m/z=546 (M+H).sup.+,

    [1074] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.92 (s, 1H), 8.49 (d, 1H), 7.96 (d, 1H), 7.74-7.63 (m, 5H), 7.58-7.47 (m, 3H), 7.43 (dd, 1H), 7.34 (d, 1H), 7.22 (dd, 1H), 6.42 (s, 1H), 6.10 (dd, 1H), 3.76-3.64 (m, 2H), 3.63 (s, 3H)

    Example 29

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoyl}amino)-2-fluorobenzamide (Enantiomer 2)

    [1075] ##STR00205##

    [1076] Enantiomer separation of 130 mg of 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoyl}amino)-2-fluorobenzamide (racemate) gave 24 mg of enantiomer 1 (chiral HPLC: R.sub.t=17.3 min) and 26 mg of the Example 29 title compound (Enantiomer 2): chiral HPLC: R.sub.t=36.25 min; 100% ee.

    [1077] Separation method: column: Chiralcel OX-H 5 μm, 250 mm×20 mm; eluent: carbon dioxide 75%/ethanol 25%; temperature: 40° C.; flow rate: 100 ml/min; pressure: 100 bar; UV detection: 210 nm.

    [1078] Analysis: column: Daicel OX-3 5 μm 250 mm×4.6 mm; eluent: carbon dioxide/ethanol gradient 5-60%; flow rate: 3 ml/min; UV detection: 210 nm.

    [1079] LC/MS [Method 1]: R.sub.t=0.66 min; MS (ESIpos): m/z=546 (M+H).sup.+,

    [1080] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.87 (s, 1H), 8.47-8.40 (m, 2H), 7.97 (d, 1H), 7.74-7.63 (m, 4H), 7.60-7.50 (m, 3H), 7.40 (dd, 1H), 7.29-7.23 (m, 2H), 6.43 (s, 1H), 6.02 (dd, 1H), 3.67 (s, 3H), 3.65-3.49 (m, 2H)

    Example 30

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-2-yl)propanoyl}amino)-2-fluoro-N-methylbenzamide (Racemate)

    [1081] ##STR00206##

    [1082] 75 mg (0.168 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-2-yl)propanoic acid hydrochloride (racemate) and 43 mg (0.252 mmol, 1.5 eq.) of 4-amino-2-fluoro-N-methylbenzamide were initially charged in 1.5 ml of pyridine, 159 μl (0.672 mmol, 50% in ethyl acetate, 4.0 eq.) T3P were added and the mixture was stirred at 50° C. for 3 h. The reaction mixture was purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). The product fractions were combined, concentrated and filtered by means of a hydrogen carbonate cartridge. Yield: 23 mg (25% of theory).

    [1083] LC/MS [Method 1]: R.sub.t=0.85 min; MS (ESIpos): m/z=560 (M+H).sup.+,

    [1084] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.92 (s, 1H), 8.52-8.45 (m, 1H), 8.12-8.03 (m, 1H), 7.96 (d, 1H), 7.74-7.61 (m, 5H), 7.54 (s, 1H), 7.43 (dd, 1 H), 7.34 (d, 1H), 7.25-7.19 (m, 1H), 6.42 (s, 1H), 6.10 (dd, 1H), 3.76-3.65 (m, 2H), 3.63 (s, 3H), 2.77 (d, 3H).

    Example 31

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-2-fluorobenzamide (Racemate)

    [1085] ##STR00207##

    [1086] 50 mg (0.121 mmol, 91% purity) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 28 mg (0.182 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide were initially charged in 1.0 ml of pyridine, 115 μl (0.485 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 5 h. The reaction mixture was purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 46 mg (74% of theory).

    [1087] LC/MS [Method 1]: R.sub.t=0.83 min; MS (ESIpos): m/z=513 (M+H).sup.+,

    [1088] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.80 (s, 1H), 8.02-7.97 (m, 1H), 7.76-7.64 (m, 4H), 7.57-7.48 (m, 3H), 7.43 (dd, 1H), 6.53 (s, 1H), 5.76-5.69 (m, 1H), 3.69 (s, 3H), 3.44-3.36 (m, 1H), 3.29-3.24 (m, 1H), 3.20 (s, 3H), 2.46-2.36 (m, 2H)

    Example 32

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyl-1,2-oxazol-5-yl)propanoyl}amino)-2-fluorobenzamide (Racemate)

    [1089] ##STR00208##

    [1090] 60 mg (0.129 mmol, 89% purity) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyl-1,2-oxazol-5-yl)propanoic acid (racemate) and 30 mg (0.194 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide were initially charged in 1.0 ml of pyridine, 123 μl (0.516 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 2 h. The reaction mixture was purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 63 mg (88% of theory).

    [1091] LC/MS [Method 1]: R.sub.t=0.87 min; MS (ESIpos): m/z=550 (M+H).sup.+,

    [1092] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.86 (s, 1H), 7.99 (d, 1H), 7.76-7.62 (m, 4H), 7.55 (s, 3H), 7.41 (dd, 1H), 6.51 (s, 1H), 6.02 (s, 1H), 5.97 (dd, 1H), 3.86 (dd, 1H), 3.71-3.60 (m, 4H), 2.14 (s, 3H)

    Example 33

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)propanoyl}amino)-2-fluorobenzamide (Racemate)

    [1093] ##STR00209##

    [1094] 50 mg (0.121 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)propanoic acid (racemate) and 28 mg (0.181 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide were initially charged in 1.0 ml of pyridine, 114 μl (0.482 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 90 min. The reaction mixture was purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 61 mg (91% of theory).

    [1095] LC/MS [Method 1]: R.sub.t=0.84 min; MS (ESIpos): m/z=551 (M+H).sup.+,

    [1096] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.82 (s, 1H), 7.98 (d, 1H), 7.75-7.62 (m, 4H), 7.57-7.49 (m, 3H), 7.41 (dd, 1H), 6.50 (s, 1H), 5.95 (dd, 1H), 3.78-3.61 (m, 5H), 2.53 (s, 3H)

    Example 34

    4-{[2-{4-[5-Chloro-2-(difluoromethyl)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-(pyridin-2-yl)propanoyl}amino]-2-fluorobenzamide (Racemate)

    [1097] ##STR00210##

    [1098] 70 mg (0.126 mmol, 85% purity) of 2-{4-[5-chloro-2-(difluoromethyl)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-(pyridin-2-yl)propanoic acid hydrochloride (racemate) and 29 mg (0.189 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide were initially charged in 1.0 ml of pyridine, 120 μl (0.505 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 2 h. The reaction mixture was purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). The product fractions were combined and concentrated. The residue was dissolved in a little acetonitrile/water 1:1 and purified by means of a hydrogencarbonate cartridge, and the solution was lyophilized. Yield: 19 mg (95% purity, 25% of theory).

    [1099] LC/MS [Method 1]: R.sub.t=0.89 min; MS (ESIpos): m/z=571 (M+H).sup.+,

    [1100] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.85 (bs, 1H), 8.49 (d, 1H), 7.75-7.61 (m, 5H), 7.57-7.31 (m, 5H), 7.34 (d, 1H), 7.23 (dd, 1H), 6.90-6.35 (m, 1H), 6.29 (s, 1H), 6.17-6.00 (m, 1H), 3.75-3.59 (m, 2H), 3.56 (s, 3H).

    Example 35

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)propanoyl}amino)-2-fluorobenzamide (Racemate)

    [1101] ##STR00211##

    [1102] 50 mg (0.102 mmol, 85% purity) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)propanoic acid (racemate) and 24 mg (0.154 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide were initially charged in 1.0 ml of pyridine, 97 μl (0.410 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added, and the mixture was stirred at 50° C. for 60 min and then at RT overnight. The reaction mixture was admixed with 4 ml of water and 4 ml of saturated aqueous sodium hydrogencarbonate solution, stirred for 10 min, then filtered with suction and washed with water and three times with 2 ml of acetonitrile. Yield: 31 mg (53% of theory).

    [1103] LC/MS [Method 1]: R.sub.t=0.80 min; MS (ESIpos): m/z=551 (M+H).sup.+,

    [1104] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.81 (s, 1H), 7.99 (d, 1H), 7.76-7.60 (m, 4H), 7.59-7.49 (m, 3H), 7.40 (dd, 1H), 6.54 (s, 1H), 5.99-5.90 (m, 1H), 3.90-3.80 (m, 2H), 3.66 (s, 3H), 2.42 (s, 3H).

    Example 36

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-2-yl)propanoyl}amino)-2-fluorobenzamide (Racemate)

    [1105] ##STR00212##

    [1106] 40 mg (0.098 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-2-yl)propanoic acid (racemate) and 23 mg (0.147 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide were initially charged in 0.81 ml of pyridine, 93 μl (0.392 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 2 h. The reaction mixture was admixed with 6 ml of saturated aqueous sodium hydrogencarbonate solution, stirred for 10 min and then filtered with suction. The residue was washed with water, 500 μl of isopropanol and then pentane. Yield: 43 mg (82% of theory).

    [1107] LC/MS [Method 1]: R.sub.t=0.83 min; MS (ESIpos): m/z=536 (M+H).sup.+,

    [1108] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.83 (s, 1H), 8.02-7.96 (m, 2H), 7.76-7.60 (m, 4H), 7.58-7.48 (m, 3H), 7.40 (dd, 1H), 7.14-7.09 (m, 1H), 6.51 (s, 1H), 6.02-5.94 (m, 1H), 3.80-3.71 (m, 2H), 3.64 (s, 3H).

    Example 37

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-methyl-1,2-oxazol-3-yl)propanoyl}amino)-2-fluorobenzamide (Racemate)

    [1109] ##STR00213##

    [1110] 50 mg (0.106 mmol, 88% purity) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-methyl-1,2-oxazol-3-yl)propanoic acid (racemate) and 25 mg (0.159 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide were initially charged in 1.0 ml of pyridine, 101 μl (0.425 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 2 h. The reaction mixture was admixed with 4 ml of water and 4 ml of saturated aqueous sodium hydrogencarbonate solution, stirred for 10 min and then filtered with suction. The residue was washed with water and three times with 2 ml of acetonitrile and then lyophilized. Yield: 56 mg (95% of theory).

    [1111] LC/MS [Method 1]: R.sub.t=0.91 min; MS (ESIpos): m/z=550 (M+H).sup.+,

    [1112] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.86 (s, 1H), 7.99 (d, 1H), 7.75-7.63 (m, 4H), 7.58-7.50 (m, 3H), 7.42 (dd, 1H), 6.50 (s, 1H), 5.98 (s, 1H), 5.93 (dd, 1H), 3.69-3.60 (m, 4H), 3.57-3.49 (m, 1H), 2.33 (s, 3H).

    Example 38

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methyl-1H-pyrazol-3-yl)propanoyl}amino)-2-fluorobenzamide (Racemate)

    [1113] ##STR00214##

    [1114] 50 mg (0.121 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methyl-1H-pyrazol-3-yl)propanoic acid (racemate) and 28 mg (0.182 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide were initially charged in 1.0 ml of pyridine, 115 μl (0.484 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 2 h. The reaction mixture was purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 47 mg (71% of theory).

    [1115] LC/MS [Method 1]: R.sub.t=0.83 min; MS (ESIpos): m/z=549 (M+H).sup.+,

    [1116] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.88 (s, 1H), 7.98 (d, 1H), 7.74-7.63 (m, 4H), 7.58 (s, 1H), 7.56-7.49 (m, 3H), 7.42 (dd, 1H), 6.46 (s, 1H), 5.98 (d, 1H), 5.87 (dd, 1H), 3.73 (s, 3H), 3.67 (s, 3H), 3.54-3.40 (m, 2H).

    Example 39

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)propanoyl}amino)-2-fluorobenzamide (Racemate)

    [1117] ##STR00215##

    [1118] 55 mg (0.10 mmol, 80% purity) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)propanoic acid (racemate) and 23 mg (0.15 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide were initially charged in 1.0 ml of pyridine, 95 μl (0.40 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 90 min. The reaction mixture was admixed with 4 ml of water and 4 ml of saturated aqueous sodium hydrogencarbonate solution, stirred for 10 min and then filtered with suction. The residue was washed with water, isopropanol and then pentane. Yield: 41 mg (70% of theory).

    [1119] LC/MS [Method 1]: R.sub.t=0.85 min; MS (ESIpos): m/z=577 (M+H).sup.+,

    [1120] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.81 (s, 1H), 8.00 (d, 1H), 7.74 (dd, 1H), 7.72-7.67 (m, 2H), 7.63 (dd, 1H), 7.59-7.51 (m, 3H), 7.40 (dd, 1H), 6.55 (s, 1H), 5.99-5.92 (m, 1H), 3.84-3.78 (m, 2H), 3.67 (s, 3H), 2.20-2.13 (m, 1H), 1.10-1.02 (m, 2H), 0.93-0.83 (m, 2H).

    Example 40

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-5-yl)propanoyl}amino)-2,6-difluorobenzamide (Racemate)

    [1121] ##STR00216##

    [1122] 30 mg (0.06 mmol, 80% purity) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-5-yl)propanoic acid (racemate) and 19 mg (0.09 mmol, 1.5 eq.) of 4-amino-2,6-difluorobenzamide hydrochloride were initially charged in 0.6 ml of pyridine, 57 μl (0.24 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 2 h. The reaction mixture was cooled and purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 15 mg (45% of theory).

    [1123] LC/MS [Method 1]: R.sub.t=0.78 min; MS (ESIpos): m/z=554 (M+H).sup.+,

    [1124] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.88 (s, 1H), 8.23 (s, 1H), 8.05-7.96 (m, 2H), 7.80-7.68 (m, 3H), 7.53 (s, 1H), 7.38 (d, 2H), 6.90 (s, 1H), 6.50 (s, 1H), 5.87 (dd, 1H), 3.80-3.70 (m, 1H), 3.69-3.58 (m, 4H).

    Example 41

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(2-methyl-1,3-oxazol-4-yl)-propanoyl}amino)-2-fluorobenzamide (Racemate)

    [1125] ##STR00217##

    [1126] 50 mg (0.10 mmol, 94% purity) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(2-methyl-1,3-oxazol-4-yl)propanoic acid hydrochloride (racemate) and 24 mg (0.16 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide were initially charged in 1.0 ml of pyridine, 99 μl (0.42 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 4 h. The reaction mixture was cooled and purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 53 mg (92% of theory).

    [1127] LC/MS [Method 1]: R.sub.t=0.86 min; MS (ESIpos): m/z=550 (M+H).sup.+,

    [1128] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.88 (s, 1H), 7.98 (d, 1H), 7.75-7.61 (m, 5H), 7.58-7.48 (m, 3H), 7.42 (dd, 1H), 6.47 (s, 1H), 5.89 (dd, 1H), 3.67 (s, 3H), 3.47 (dd, 1H), 3.37-3.27 (m, 1H), 2.33 (s, 3H).

    Example 42

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4,5-dihydro-1,2-oxazol-3-yl)propanoyl}amino)-2-fluorobenzamide (Racemate)

    [1129] ##STR00218##

    [1130] 50 mg (0.10 mmol, 94% purity) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4,5-dihydro-1,2-oxazol-3-yl)propanoic acid hydrochloride (racemate) and 25 mg (0.16 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide were initially charged in 1.0 ml of pyridine, 102 μl (0.43 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 1 h. The reaction mixture was cooled and purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 40 mg (68% of theory).

    [1131] LC/MS [Method 1]: R.sub.t=0.79 min; MS (ESIpos): m/z=538 (M+H).sup.+,

    [1132] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.86 (s, 1H), 8.03-7.96 (m, 1H), 7.76-7.62 (m, 4H), 7.58-7.47 (m, 3H), 7.41 (dd, 1H), 6.56 (s, 1H), 5.91 (dd, 1H), 4.21-4.07 (m, 2H), 3.68 (s, 3H), 3.38-3.22 (m, 2H), 2.96 (t, 2H).

    Example 43

    4-({2-[4-(2-Cyano-5-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methyl-1H-pyrazol-3-yl)propanoyl}amino)-2-fluorobenzamide (Racemate)

    [1133] ##STR00219##

    [1134] 50 mg (0.09 mmol, 80% purity) of 2-[4-(2-cyano-5-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methyl-1H-pyrazol-3-yl)propanoic acid hydrochloride (racemate) and 22 mg (0.14 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide were initially charged in 0.8 ml of pyridine, 86 μl (0.37 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 2 h. The reaction mixture was cooled and purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 40 mg (81% of theory).

    [1135] LC/MS [Method 1]: R.sub.t=0.78 min; MS (ESIpos): m/z=529 (M+H).sup.+,

    [1136] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.88 (s, 1H), 7.80 (d, 1H), 7.73-7.63 (m, 2H), 7.57-7.49 (m, 4H), 7.45-7.39 (m, 2H), 7.36 (s, 1H), 6.35 (s, 1H), 5.99 (d, 1H), 5.87 (dd, 1H), 3.74 (s, 3H), 3.65 (s, 3H), 3.55-3.38 (m, 2H), 2.41 (s, 3H).

    Example 44

    4-({2-[4-(2-Cyano-5-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methyl-1H-pyrazol-3-yl)propanoyl}amino)-2-fluoro-N-methylbenzamide (Racemate)

    [1137] ##STR00220##

    [1138] 50 mg (0.09 mmol, 80% purity) of 2-[4-(2-cyano-5-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methyl-1H-pyrazol-3-yl)propanoic acid hydrochloride (racemate) and 24 mg (0.14 mmol, 1.5 eq.) of 4-amino-2-fluoro-N-methylbenzamide were initially charged in 0.8 ml of pyridine, 89 μl (0.37 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 2 h. The reaction mixture was cooled and purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 40 mg (79% of theory).

    [1139] LC/MS [Method 1]: R.sub.t=0.82 min; MS (ESIpos): m/z=543 (M+H).sup.+,

    [1140] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.87 (s, 1H), 8.12-8.03 (m, 1H), 7.80 (d, 1H), 7.71-7.61 (m, 2H), 7.54 (s, 1H), 7.52 (d, 1H), 7.45-7.39 (m, 2H), 7.36 (s, 1H), 6.35 (s, 1H), 5.99 (d, 1H), 5.87 (dd, 1H), 3.74 (s, 3H), 3.65 (s, 3H), 3.54-3.39 (m, 2H), 2.77 (d, 3H), 2.41 (s, 3H).

    Example 45

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-5-yl)propanoyl}amino)-2-fluorobenzamide (Enantiomer 2)

    [1141] ##STR00221##

    [1142] Enantiomer separation of 80 mg 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-5-yl)propanoyl}amino)-2-fluorobenzamide (racemate) gave 35 mg of enantiomer 1 (chiral HPLC: R.sub.t=4.75 min) and 33 mg of the Example 45 title compound (enantiomer 2): chiral HPLC: R.sub.t=7.45 min; 100% ee.

    [1143] Separation method: column: Chiralcel OD-H 5 μm, 250 mm×20 mm; eluent: carbon dioxide 75%/methanol 25%; temperature: 40° C.; flow rate: 80 ml/min; pressure: 100 bar; UV detection: 210 nm.

    [1144] Analysis: column: Daicel Chiralpak OD 5 μm 250 mm×4.6 mm; eluent: 80% carbon dioxide, 20% methanol; flow rate: 3 ml/min; UV detection: 210 nm.

    [1145] LC/MS [Method 1]: R.sub.t=0.80 min; MS (ESIpos): m/z=536 (M+H).sup.+,

    [1146] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.86 (s, 1H), 8.23 (s, 1H), 7.99 (d, 1H), 7.76-7.62 (m, 4H), 7.59-7.49 (m, 3H), 7.41 (dd, 1H), 6.90 (s, 1H), 6.50 (s, 1H), 5.93 (dd, 1H), 3.82-3.71 (m, 1H), 3.67 (s, 3H), 3.66-3.56 (m, 1H).

    Example 46

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methyl-1H-pyrazol-3-yl)propanoyl}amino)-2-methoxybenzamide (Racemate)

    [1147] ##STR00222##

    [1148] 45 mg (0.10 mmol, 94% purity) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methyl-1H-pyrazol-3-yl)propanoic acid (racemate) and 26 mg (0.15 mmol, 1.5 eq.) of 4-amino-2-methoxybenzamide were initially charged in 0.8 ml of pyridine, 97 μl (0.41 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 2 h. The reaction mixture was cooled and purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 45 mg (79% of theory).

    [1149] LC/MS [Method 1]: R.sub.t=0.81 min; MS (ESIpos): m/z=561 (M+H).sup.+,

    [1150] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.77 (s, 1H), 7.98 (d, 1H), 7.84 (d, 1H), 7.75-7.68 (m, 2H), 7.62-7.57 (m, 2H), 7.55 (bs, 1H), 7.52 (d, 1H), 7.43 (bs, 1H), 7.25 (dd, 1H), 6.45 (s, 1H), 5.99 (d, 1H), 5.90 (dd, 1H), 3.88 (s, 3H), 3.74 (s, 3H), 3.67 (s, 3H), 3.56-3.39 (m, 2H).

    Example 47

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(2-methyl-1,3-oxazol-4-yl)propanoyl}amino)-2-fluoro-N-methylbenzamide (Racemate)

    [1151] ##STR00223##

    [1152] 50 mg (0.10 mmol, 94% purity) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(2-methyl-1,3-oxazol-4-yl)propanoic acid hydrochloride (racemate) and 26 mg (0.16 mmol, 1.5 eq.) of 4-amino-2-fluoro-N-methylbenzamide were initially charged in 1.0 ml of pyridine, 99 μl (0.42 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 2 h. The reaction mixture was cooled and purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 40 mg (68% of theory).

    [1153] LC/MS [Method 1]: R.sub.t=0.86 min; MS (ESIpos): m/z=564 (M+H).sup.+,

    [1154] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.87 (s, 1H), 8.13-8.02 (m, 1H), 7.98 (d, 1H), 7.75-7.57 (m, 5H), 7.54 (s, 1H), 7.42 (dd, 1H), 6.47 (s, 1H), 5.89 (dd, 1H), 3.67 (s, 3H), 3.52-3.42 (m, 1H), 3.36-3.25 (m, 1H), 2.76 (d, 3H), 2.33 (s, 3H).

    Example 48

    4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-2-methoxybenzamide (Racemate)

    [1155] ##STR00224##

    [1156] 40 mg (0.097 mmol, 91% purity) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 24 mg (0.145 mmol, 1.5 eq.) of 4-amino-2-methoxybenzamide were initially charged in 1.0 ml of pyridine, 92 μl (0.386 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 1 h. The reaction mixture was cooled and purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 32 mg (60% of theory).

    [1157] LC/MS [Method 1]: R.sub.t=0.85 min; MS (ESIpos): m/z=525 (M+H).sup.+,

    [1158] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.67 (s, 1H), 8.05-7.94 (m, 1H), 7.83 (d, 1H), 7.77-7.69 (m, 2H), 7.61-7.47 (m, 3H), 7.43 (bs, 1H), 7.27 (dd, 1H), 6.53 (s, 1H), 5.80-5.69 (m, 1H), 3.87 (s, 3H), 3.69 (s, 3H), 3.45-3.36 (m, 1H), 3.29-3.24 (m, 1H), 3.21 (s, 3H), 2.47-2.38 (m, 2H).

    Example 49

    4-({2-[4-(2-Cyano-5-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-2-fluorobenzamide (Racemate)

    [1159] ##STR00225##

    [1160] 40 mg (0.11 mmol) of 2-[4-(2-cyano-5-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxy-butanoic acid (racemate) and 25 mg (0.16 mmol, 1.5 eq.) of 4-amino-2-fluorobenzamide were initially charged in 1.0 ml of pyridine, 102 μl (0.43 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 50° C. for 1 h. The reaction mixture was cooled and purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 41 mg (76% of theory).

    [1161] LC/MS [Method 1]: R.sub.t=0.82 min; MS (ESIpos): m/z=493 (M+H).sup.+,

    [1162] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.79 (s, 1H), 7.82 (d, 1H), 7.72-7.62 (m, 2H), 7.57-7.49 (m, 2H), 7.49-7.36 (m, 4H), 6.42 (s, 1H), 5.77-5.66 (m, 1H), 3.67 (s, 3H), 3.45-3.36 (m, 1H), 3.29-3.23 (m, 1H), 3.20 (s, 3H), 2.45-2.35 (m, 5H).

    B) ASSESSMENT OF PHYSIOLOGICAL EFFICACY

    [1163] The suitability of the compounds according to the invention for treating thromboembolic disorders can be demonstrated in the following assay systems:

    [1164] a) Test Descriptions (In Vitro)

    [1165] a.1) Measurement of FXIa Inhibition

    [1166] The factor XIa inhibition of the substances according to the invention is determined using a biochemical test system which utilizes the reaction of a peptidic factor XIa substrate to determine the enzymatic activity of human factor XIa. Here, factor XIa cleaves from the peptic factor XIa substrate the C-terminal aminomethylcoumarin (AMC), the fluorescence of which is measured. The determinations are carried out in microtitre plates.

    [1167] Test substances are dissolved in dimethyl sulphoxide and serially diluted in dimethyl sulphoxide (3000 μM to 0.0078 μM; resulting final concentrations in the test: 50 μM to 0.00013 μM). 1 μl of the diluted substance solutions is placed into each of the wells of white microtitre plates from Greiner (384 wells). 20 μl of assay buffer (50 mM of Tris/HCl pH 7.4; 100 mM of sodium chloride; 5 mM of calcium chloride; 0.1% of bovine serum albumin) and 20 μl of factor XIa from Kordia (0.45 nM in assay buffer) are then added successively. After 15 min of incubation, the enzyme reaction is started by addition of 20 μl of the factor XIa substrate Boc-Glu(OBzl)-Ala-Arg-AMC dissolved in assay buffer (10 μM in assay buffer) from Bachem, the mixture is incubated at room temperature (22° C.) for 30 min and fluorescence is then measured (excitation: 360 nm, emission: 460 nm). The measured emissions of the test batches with test substance are compared to those of control batches without test substance (only dimethyl sulphoxide instead of test substance in dimethyl sulphoxide), and IC.sub.50 values are calculated from the concentration/activity relationships. Activity data from this test are listed in Table A below:

    TABLE-US-00003 TABLE A Example No. IC.sub.50 [nM] Example No. IC.sub.50 [nM] 1 240 2 190 3 43 4 52 5 14 6 47 7 25 8 12 9 11 10 9 11 160 12 11 13 63 14 25 15 28 16 200 17 290 18 14 19 12.5 20 7.4 21 7.4 22 21 23 170 24 27 25 310 26 20 27 50 28 6.6 29 5.1 30 9.7 31 10 32 13 33 15 34 42 35 12 36 13 37 12 38 6.2 39 70 40 34 41 28 42 51 43 12 44 19 45 6.4 46 8.9 47 32 48 15 49 28

    [1168] a.2) Determination of the Selectivity

    [1169] To demonstrate the selectivity of the substances with respect to FXIa inhibition, the test substances are examined for their inhibition of other human serine proteases, such as factor Xa, trypsin and plasmin. To determine the enzymatic activity of factor Xa (1.3 nmol/l from Kordia), trypsin (83 mU/ml from Sigma) and plasmin (0.1 μg/ml from Kordia), these enzymes are dissolved (50 mmol/l of Tris buffer [C,C,C-tris(hydroxymethyl)aminomethane], 100 mmol/l of NaCl, 0.1% BSA [bovine serum albumin], 5 mmol/l of calcium chloride, pH 7.4) and incubated for 15 min with test substance in various concentrations in dimethyl sulphoxide and also with dimethyl sulphoxide without test substance. The enzymatic reaction is then started by addition of the appropriate substrates (5 μmol/l of Boc-Ile-Glu-Gly-Arg-AMC from Bachem for factor Xa and trypsin, 5 50 μmol/l of MeOSuc-Ala-Phe-Lys-AMC from Bachem for plasmin). After an incubation time of 30 min at 22° C., fluorescence is measured (excitation: 360 nm, emission: 460 nm). The measured emissions of the test mixtures with test substance are compared to the control mixtures without test substance (only dimethyl sulphoxide instead of test substance in dimethyl sulphoxide) and IC.sub.50 values are calculated from the concentration/activity relationships.

    [1170] a.3) Thrombin Generation Assay (Thrombogram)

    [1171] The effect of the test substances on the thrombogram (thrombin generation assay according to Hemker) is determined in vitro in human plasma (Octaplas® from Octapharma).

    [1172] In the thrombin generation assay according to Hemker, the activity of thrombin in coagulating plasma is determined by measuring the fluorescent cleavage products of the substrate 1-1140 (Z-Gly-Gly-Arg-AMC, Bachem). The reactions are carried out in the presence of varying concentrations of test substance or the corresponding solvent. To start the reaction, reagents from Thrombinoscope (30 pM or 0.1 pM recombinant tissue factor, 24 μM phospholipids in HEPES) are used. In addition, a thrombin calibrator from Thrombinoscope is used whose amidolytic activity is required for calculating the thrombin activity in a sample containing an unknown amount of thrombin. The test is carried out according to the manufacturer's instructions (Thrombinoscope BV): 4 μl of test substance or of the solvent, 76 μl of plasma and 20 μl of PPP reagent or thrombin calibrator are incubated at 37° C. for 5 min. After addition of 20 μl of 2.5 mM thrombin substrate in 20 mM Hepes, 60 mg/ml of BSA, 102 mM of calcium chloride, the thrombin generation is measured every 20 s over a period of 120 min. Measurement is carried out using a fluorometer (Fluoroskan Ascent) from Thermo Electron fitted with a 390/460 nm filter pair and a dispenser.

    [1173] Using the Thrombinoscope software, the thrombogram is calculated and represented graphically. The following parameters are calculated: lag time, time to peak, peak, ETP (endogenous thrombin potential) and start tail.

    [1174] a.4) Determination of Anticoagulatory Activity

    [1175] The anticoagulatory activity of the test substances is determined in vitro in human plasma and rat plasma. To this end, blood is drawn off in a mixing ratio of sodium citrate/blood of 1:9 using a 0.11 molar sodium citrate solution as receiver Immediately after the blood has been drawn off, it is mixed thoroughly and centrifuged at about 4000 g for 15 minutes. The supernatant is pipetted off.

    [1176] The prothrombin time (PT, synonyms: thromboplastin time, quick test) is determined in the presence of varying concentrations of test substance or the corresponding solvent using a commercial test kit (Neoplastin® from Boehringer Mannheim or Hemoliance® RecombiPlastin from Instrumentation Laboratory). The test compounds are incubated with the plasma at 37° C. for 3 minutes. Coagulation is then started by addition of thromboplastin, and the time when coagulation occurs is determined. The concentration of test substance which effects a doubling of the prothrombin time is determined.

    [1177] The activated partial thromboplastin time (APTT) is determined in the presence of varying concentrations of test substance or the corresponding solvent using a commercial test kit (PTT reagent from Roche). The test compounds are incubated with the plasma and the PTT reagent (cephalin, kaolin) at 37° C. for 3 minutes. Coagulation is then started by addition of 25 mM calcium chloride, and the time when coagulation occurs is determined. The concentration of test substance which effects an extension by 50% or a doubling of the APTT is determined.

    [1178] a.5) Determination of the Plasma Kallikrein Activity

    [1179] To determine the plasma kallikrein inhibition of the substances according to the invention, a biochemical test system is used which utilizes the reaction of a peptidic plasma kallikrein substrate to determine the enzymatic activity of human plasma kallikrein. Here, plasma kallikrein cleaves from the peptic plasma kallikrein substrate the C-terminal aminomethylcoumarin (AMC), the fluorescence of which is measured. The determinations are carried out in microtitre plates.

    [1180] Test substances are dissolved in dimethyl sulphoxide and serially diluted in dimethyl sulphoxide (3000 μM to 0.0078 μM; resulting final concentrations in the test: 50 μM to 0.00013 μM). 1 μl of the diluted substance solutions is placed into each of the wells of white microtitre plates from Greiner (384 wells). 20 μl of assay buffer (50 mM Tris/HCl pH 7.4; 100 mM sodium chloride solution; 5 mM of calcium chloride solution; 0.1% of bovine serum albumin) and 20 μl of plasma kallikrein from Kordia (0.6 nM in assay buffer) are then added successively. After 15 min of incubation, the enzyme reaction is started by addition of 20 μl of the substrate H-Pro-Phe-Arg-AMC dissolved in assay buffer (10 μM in assay buffer) from Bachem, the mixture is incubated at room temperature (22° C.) for 30 min and fluorescence is then measured (excitation: 360 nm, emission: 460 nm). The measured emissions of the test batches with test substance are compared to those of control batches without test substance (only dimethyl sulphoxide instead of test substance in dimethyl sulphoxide), and IC.sub.50 values are calculated from the concentration/activity relationships.

    TABLE-US-00004 TABLE B Example No. IC.sub.50 [nM] Example No. IC.sub.50 [nM] 1 490 2 260 3 33 4 140 5 14 6 110 7 36 8 30 9 6 10 7 11 490 12 10 13 110 14 210 15 260 16 350 17 230 18 11 19 7.4 20 6.1 21 6.8 22 12 23 310 24 25 25 160 26 20 27 71 28 4.8 29 2.7 30 8.2 31 9.7 32 11 33 10 34 53 35 7.3 36 11 37 6.2 38 3.6 39 38 40 27 41 21 42 38 43 8.3 44 12 45 4.0 46 2.4 47 24 48 7.7 49 27

    [1181] a.6) Determination of Endothelium Integrity

    [1182] The activity of the compounds according to the invention is characterized by means of an in vitro permeability assay on “human umbilical venous cells” (HUVEC). Using the EOS apparatus (EC IS: Electric Cell-substrate Impedance Sensing; Applied Biophysics Inc; Troy, N.Y.), it is possible to measure continuously variations in the transendothelial electrical resistance (TEER) across an endothelial cell monolayer plated over gold electrodes. HUVECs are sown on a 96-well sensor electrode plate (96W1 E, Ibidi GmbH, Martinsried, Germany). Hyperpermeability of the confluent cell monolayer formed is induced by stimulation with kininogen, prekallikrein and factor XII (100 nM each). The compounds according to the invention are added prior to the addition of the substances indicated above. The customary concentrations of the compounds are 1×10.sup.−10 to 1×10.sup.−6 M.

    [1183] a.7) Determination of the In Vitro Permeability of Endothelial Cells

    [1184] In a further hyperpermeability model, the activity of the substances on the modulation of macromolecular permeability is determined. HUVECs are sown on a fibronectin-coated Transwell filter membrane (24-well plates, 6.5 mm insert with 0.4 μM polycarbonate membrane; Costar #3413). The filter membrane separates the upper from the lower cell culture space, with the confluent endothelial cell layer on the floor of the upper cell culture space. 250 g/ml of 40 kDa FITC dextan (Invitrogen, D1844) are added to the medium of the upper chamber. Hyperpermeability of the monolayer is induced by stimulation with kininogen, prekallikrein and factor XII (100 nM each). Every 30 min, medium samples are removed from the lower chamber and relative fluorescence as a parameter for changes in macromolecular permeability as a function of time is determined using a fluorimeter. The compounds according to the invention are added prior to the addition of the substances indicated above. The customary concentrations of the compounds are 1×10.sup.−10 to 1×10.sup.−6 M.

    [1185] b) Determination of Antithrombotic Activity (In Vivo)

    [1186] b.1) Arterial Thrombosis Model (iron(II) chloride-Induced Thrombosis) in Combination with Ear Bleeding Time in Rabbits

    [1187] The antithrombotic activity of the FXIa inhibitors is tested in an arterial thrombosis model. Thrombus formation is triggered here by causing chemical injury to a region in the carotid artery in rabbits. Simultaneously, the ear bleeding time is determined.

    [1188] Male rabbits (Crl:KBL (NZW)BR, Charles River) receiving a normal diet and having a body weight of 2.2-2.5 kg are anaesthetized by intramuscular administration of xylazine and ketamine (Rompun, Bayer, 5 mg/kg and Ketavet, Pharmacia & Upjohn GmbH, 40 mg/kg body weight). Anaesthesia is furthermore maintained by intravenous administration of the same preparations (bolus: continuous infusion) via the right auricular vein.

    [1189] The right carotid artery is exposed and the vessel injury is then caused by wrapping a piece of filter paper (10 mm×10 mm) on a Parafilm® strip (25 mm×12 mm) around the carotid artery without disturbing the blood flow. The filter paper contains 100 μL of a 13% strength solution of iron(II) chloride (Sigma) in water. After 5 min, the filter paper is removed and the vessel is rinsed twice with aqueous 0.9% strength sodium chloride solution. 30 min after the injury the injured region of the carotid artery is extracted surgically and any thrombotic material is removed and weighed.

    [1190] The test substances are administered either intravenously to the anaesthetized animals via the femoral vein or orally to the awake animals via gavage, in each case 5 min and 2 h, respectively, before the injury.

    [1191] Ear bleeding time is determined 2 min after injury to the carotid artery. To this end, the left ear is shaved and a defined 3 mm-long incision (blade Art. Number 10-150-10, Martin, Tuttlingen, Germany) is made parallel to the longitudinal axis of the ear. Care is taken here not to damage any visible vessels. Any blood that extravasates is taken up in 15 second intervals using accurately weighed filter paper pieces, without touching the wound directly. Bleeding time is calculated as the time from making the incision to the point in time where no more blood can be detected on the filter paper. The volume of the extravasated blood is calculated after weighing of the filter paper pieces.

    [1192] c) Determination of the Effect on Extravasation/Oedema Formation and/or Neovascularization in the Eve (In Vivo)

    [1193] c.1) Test of the Efficacy of Substances in the Laser-Induced Choroidal Neovascularization Model

    [1194] This study serves to investigate the efficacy of a test substance on reduction of extravasation/oedema formation and/or choroidal neovascularization in the rat model of laser-induced choroidal neovascularization.

    [1195] To this end, pigmented rats of the Brown-Norway strain not showing any signs of ophthalmic disorders are selected and randomized into treatment groups. On day 0, the animals are anaesthetized by intraperitoneal injection (15 mg/kg xylazine and 80 mg/kg ketamine). Following instillation of a drop of a 0.5% strength tropicamide solution to dilate the pupils, choroidal neovascularization is triggered on six defined locations around the optical nerve using a 532 nm argon laser photocoagulator (diameter 50-75 μm, intensity 150 mW, duration 100 ms). The test substance and the appropriate vehicle (e.g. PBS, isotonic saline) are administered either systemically by the oral or intraperitonal route, or topically to the eye by repeated administration as eye drops or intravitreal injection. The body weight of all the animals is determined before the start of the study, and then daily during the study.

    [1196] On day 21, an angiography is carried out using a fluorescence fundus camera (e.g. Kowe, HRA). Under anaesthesia and after another pupil dilation, a 10% strength sodium fluorescein dye is injected subcutaneously (s.c.). 2-10 min later, pictures of the eye background are taken. The degree of extravasation/the oedema, represented by the leakage of fluorescein, is assessed by two to three blinded observers and classified into degrees of severity from 0 (no extravasation) to 3 (strong colouration exceeding the actual lesion).

    [1197] The animals are sacrificed on day 23, after which the eyes are removed and fixated in 4% strength paraformaldehyde solution for one hour at room temperature. After one washing, the retina is carefully peeled off and the sclera-choroidea complex is stained using an FITC isolectin B4 antibody and then applied flat to a microscope slide. The preparations obtained in this manner are evaluated using a fluorescence microscope (Apotom, Zeiss) at an excitation wavelength of 488 nm. The area or volume of the choroidal neovascularization (in μm.sup.2 and μm.sup.3, respectively) is calculated by morphometric analysis using Axiovision 4.6 software.

    [1198] c.2) Test of the Efficacy of Substances in the Oxygen-Induced Retinopathy Model

    [1199] It has been shown that oxygen-induced retinopathy is a useful animal model for the study of pathological retinal angiogenesis. This model is based on the observation that hyperoxia during early postnatal development in the retina causes arrest or delay of the growth of normal retinal blood vessels. When, after a 7-day hyperoxia phase, the animals are returned to normoxic room air, this is equivalent to relative hypoxia since the retina is missing the normal vessels which are required to ensure adequate supply of the neural tissue under normoxic conditions. The ischaemic situation caused in this manner results in an abnormal neovascularization which has some similarities with pathophysiological neovascularization in eye disorders such as wet AMD. In addition, the neovascularization caused is highly reproducible, quantifiable and an important parameter for examining the disease mechanisms and possible treatments for various forms of retinal disorders.

    [1200] The aim of this study is to examine the efficacy of daily systemically administered doses of the test compound on the growth of retinal vessels in the oxygen-induced retinopathy model. Neonates of C57B1/6 mice and their mothers are exposed to hyperoxia (70% oxygen) on postnatal day 7 (PD7) for 5 days. From PD12, the mice are kept under normoxic conditions (room air, 21% oxygen) until PD17. From day 12 to day 17, the mice are treated daily with the test substance or the corresponding vehicle. On day 17, all mice are anaesthetized with isoflurane and then sacrificed by cervical fracture. The eyes are removed and fixated in 4% formalin. After washing in phosphate-buffered saline, the retina is excised, a flat preparation thereof is produced and this is stained with isolectin B4 antibody. Quantification of neovascularization is carried out using a Zeiss ApoTome.

    C) WORKING EXAMPLES FOR PHARMACEUTICAL COMPOSITIONS

    [1201] The substances according to the invention can be converted to pharmaceutical preparations as follows:

    [1202] Tablet:

    [1203] Composition:

    [1204] 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.

    [1205] Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

    [1206] Production:

    [1207] 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 using a conventional tableting press (see above for format of the tablet).

    [1208] Oral Suspension:

    [1209] Composition:

    [1210] 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.

    [1211] 10 ml of oral suspension correspond to a single dose of 100 mg of the compound of the invention.

    [1212] Production:

    [1213] 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.

    [1214] Solution or Suspension for Topical Administration to the Eye (Eye Drops):

    [1215] A sterile pharmaceutical preparation for topical administration to the eye can be prepared by reconstituting a lyophilisate of the inventive compound in sterile saline. Suitable preservatives for such a solution or suspension are, for example, benzalkonium chloride, thiomersal or phenylmercury nitrate in a concentration range of from 0.001 to 1 per cent by weight.

    [1216] Solution or Suspension for Topical Administration to the Eye (Eye Drops):

    [1217] A sterile pharmaceutical preparation for topical administration to the eye can be prepared by reconstituting a lyophilisate of the inventive compound in sterile saline. Suitable preservatives for such a solution or suspension are, for example, benzalkonium chloride, thiomersal or phenylmercury nitrate in a concentration range of from 0.001 to 1 per cent by weight.