Substituted oxopyridine derivatives

Abstract

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

Claims

1. A compound of the formula ##STR00187## in which R.sup.1 represents a group of the formula ##STR00188## where * is the point of attachment to the oxopyridine ring, R.sup.6 represents bromine, chlorine, fluorine, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy, R.sup.7 represents bromine, chlorine, fluorine, cyano, nitro, hydroxy, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, ethynyl, 3,3,3-trifluoroprop-1-yn-1-yl or cyclopropyl, R.sup.8 represents hydrogen, chlorine or fluorine, R.sup.2 represents hydrogen, bromine, chlorine, fluorine, cyano, C.sub.1-C.sub.3-alkyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C1-C3-alkoxy, difluoromethoxy, trifluoromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, hydroxycarbonyl, methylcarbonyl or cyclopropyl, R.sup.3 represents hydrogen, C.sub.1-C.sub.5-alkyl, C.sub.1-C.sub.4-alkoxy, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 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, hydroxy, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C.sub.3-C.sub.6-cycloalkyl, 4- to 6-membered oxoheterocyclyl, 1,4-dioxanyl, oxazolyl, phenyl and pyridyl, where cycloalkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy, methyl, ethyl, methoxy, ethoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy, R.sup.4 represents hydrogen, R.sup.5 represents a group of the formula ##STR00189## where # is the point of attachment to the nitrogen atom, Y.sup.1 represents a nitrogen atom or C—R.sup.11, where R.sup.11 represents hydrogen, chlorine, hydroxy, methoxy or C.sub.1-C.sub.3-alkoxycarbonyl, Y.sup.2 represents a nitrogen atom or C—R.sup.12, where R.sup.12 represents hydrogen, chlorine, hydroxy or methoxy, R.sup.9 represents hydrogen, hydroxycarbonyl, hydroxycarbonylmethyl or phenyl, where phenyl may be substituted by 1 to 2 fluorine substituents, R.sup.10 represents hydrogen, chlorine, fluorine or methyl, Y.sup.3 represents a nitrogen atom or C—R.sup.15, where R.sup.15 represents hydrogen, chlorine, hydroxy or methoxy, y.sup.4 represents a nitrogen atom or C—R.sup.16, where R.sup.16 represents hydrogen, chlorine, hydroxy or methoxy, R.sup.13 represents hydrogen, hydroxycarbonyl, hydroxycarbonylmethyl, C.sub.1-C.sub.3-alkoxycarbonyl or aminocarbonyl, R.sup.14 represents hydrogen, chlorine, fluorine or methyl, R.sup.17 represents hydrogen, chlorine, hydroxy, C.sub.1-C.sub.4-alkyl, methoxy, C.sub.1-C.sub.3-alkylaminomethyl or morpholinylmethyl, R.sup.18 represents hydrogen, chlorine, fluorine or methyl, R.sup.19 represents hydrogen, chlorine, hydroxy or methoxy, R.sup.20 represents hydrogen, chlorine, fluorine or methyl, R.sup.21 represents hydrogen, hydroxycarbonyl or hydroxycarbonylmethyl, R.sup.22 represents hydrogen, chlorine, fluorine or methyl, or one of the salts thereof, solvates thereof or solvates of the salts thereof.

2. The compound of claim 1, wherein R.sup.1 represents a group of the formula ##STR00190## where * is the point of attachment to the oxopyridine ring, R.sup.6 represents chlorine, R.sup.7 represents cyano, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy, R.sup.8 represents hydrogen, R.sup.2 represents chlorine, cyano, methoxy, ethoxy or difluoromethoxy, R.sup.3 represents hydrogen, methyl, ethyl, n-propyl, 2-methylprop-1-yl, n-butyl or ethoxy, where methyl may be substituted by a substituent selected from the group consisting of difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl and 1,4-dioxanyl, where cyclopropyl, cyclobutyl, cyclohexyl and oxetanyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy, methyl, ethyl and methoxy, and where ethyl, n-propyl and n-butyl may be substituted by a substituent selected from the group consisting of fluorine, methoxy and trifluoromethoxy, R.sup.4 represents hydrogen, R.sup.5 represents a group of the formula ##STR00191## where # is the point of attachment to the nitrogen atom, Y.sup.1 represents a nitrogen atom or C—R.sup.11, where R.sup.11 represents hydrogen, chlorine, hydroxy or methoxy, Y.sup.2 represents a nitrogen atom or C—R.sup.12, where R.sup.12 represents hydrogen, chlorine, hydroxy or methoxy, R.sup.9 represents hydrogen or hydroxycarbonyl, R.sup.10 represents hydrogen or fluorine, Y.sup.3 represents a nitrogen atom or C—R.sup.15, where R.sup.15 represents hydrogen, chlorine, hydroxy or methoxy, Y.sup.4 represents a nitrogen atom or C—R.sup.16, where R.sup.16 represents hydrogen, chlorine, hydroxy or methoxy, R.sup.13 represents hydrogen or hydroxycarbonyl, R.sup.14 represents hydrogen or fluorine, R.sup.21 represents hydrogen or hydroxycarbonyl, or one of the salts thereof, solvates thereof or solvates of the salts thereof.

3. The compound of claim 1, wherein R.sup.1 represents a group of the formula ##STR00192## where * is the point of attachment to the oxopyridine ring, R.sup.6 represents chlorine, R.sup.7 represents cyano or difluoromethoxy, R.sup.8 represents hydrogen, R.sup.2 represents methoxy, R.sup.3 represents methyl or ethyl where methyl may be substituted by a substituent selected from the group consisting of cyclobutyl and tetrahydro-2H-pyranyl, and where ethyl may be substituted by a methoxy substituent, R.sup.4 represents hydrogen, R.sup.5 represents a group of the formula ##STR00193## where # is the point of attachment to the nitrogen atom, Y.sup.1 represents C—R.sup.11, where R.sup.11 represents hydrogen or chlorine, Y.sup.2 represents a nitrogen atom, R.sup.9 represents hydrogen or hydroxycarbonyl, R.sup.10 represents hydrogen, Y.sup.3 represents a nitrogen atom, and Y.sup.4 represents C—R.sup.16, where R.sup.16 represents hydrogen, or Y.sup.3 represents C—R.sup.15, where R.sup.15 represents hydrogen or chlorine, and Y.sup.4 represents a nitrogen atom, R.sup.13 represents hydrogen or hydroxycarbonyl, R.sup.14 represents hydrogen, or one of the salts thereof, solvates thereof or solvates of the salts thereof.

4. A method of making the compound of claim 1 of the formula (I), or one of the salts thereof, solvates thereof or solvates of the salts thereof, characterized in that either [A] a compound of the formula ##STR00194## in which R.sup.1, R.sup.2 and R.sup.3 are each as defined in claim 1, is reacted in the first step with a compound of the formula ##STR00195## in which R.sup.4 and R.sup.5 are each as defined in claim 1, in the presence of a dehydrating agent, and optionally in a second step converted by acidic or basic ester hydrolysis into a compound of the formula (I), or [B] a compound of the formula ##STR00196## in which R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the meaning given in claim 1, and X.sup.1 represents chlorine, bromine or iodine, is reacted with a compound of the formula
R.sup.1-Q  (V) in which R.sup.1 has the meaning given in claim 1, and Q represents —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 (I).

5. A medicament comprising the compound of claim 1 in combination with an inert, nontoxic, pharmaceutically suitable excipient.

6. A medicament for the treatment of thrombotic or thromboembolic disorders comprising the compound of claim 1 in combination with an inert, nontoxic, pharmaceutically suitable excipient.

7. A method for the treatment of thrombotic or thromboembolic disorders comprising administering an effective amount of the compound of claim 1.

8. A method for combating thrombotic or thromboembolic disorders comprising administering a therapeutically effective amount of the compound of claim 1.

9. A method for treating thrombotic or thromboembolic disorders comprising administering an effective amount of the medicament of claim 5.

Description

A) EXAMPLES

(1) Abbreviations:

(2) Boc tert.-butyloxycarbonyl ca. circa d day(s), doublet (in NMR) DABCO 1,4-diazabicyclo[2.2.2]octane TLC thin-layer chromatography DCI direct chemical ionization (in MS) dd doublet of doublets (in NMR) DIC N,N′-diisopropylcarbodiimide DIEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulphoxide eq. equivalent(s) ESI electrospray ionization (in MS) h hour(s) HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HPLC high-pressure, high-performance liquid chromatography HV high vacuum LC-MS liquid chromatography-coupled mass spectroscopy LDA lithium diisopropylamide m multiplet (in NMR) min minute(s) MS mass spectroscopy NMR nuclear magnetic resonance spectroscopy Oxima ethyl hydroxyiminocyanoacetate q quartet (in NMR) quant. quantitative quin quintet (in NMR) RP reversed phase (in HPLC) RT room temperature R.sub.t retention time (in HPLC) s singlet (in NMR) sxt sextet (in NMR) SFC supercritical fluid chromatography (with supercritical carbon dioxide as mobile phase) t triplet (in NMR) THF tetrahydrofuran TFA trifluoroacetic acid T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene 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 CATAXCium A precatalyst (2′-aminobiphenyl-2-yl)(methanesulphonate)palladium butyl[di-precatalist (3S,5S,7S)tricyclo[3.3.1.13,7]dec-1-yl]phosphane (1:1)
HPLC, LC-MS and GC Methods:

(3) Method 1: Instrument: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 1.8μ 50 mm×1 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength 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.

(4) Method 2: Instrument: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 1.8μ 50 mm×1 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength 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.

(5) Method 3: Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9μ 50 mm×1 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength 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.

(6) Method 4: MS instrument: Waters (Micromass) Quattro Micro; HPLC instrument: Agilent 1100 series; column: YMC-Triart C18 3μ 50 mm×3 mm; mobile phase A: 1 l of water+0.01 mol of ammonium carbonate, mobile phase B: 1 l of 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.

(7) Method 5: MS instrument: Waters (Micromass) QM; HPLC instrument: Agilent 1100 series; column: Agient ZORBAX Extend-C18 3.0 mm×50 mm 3.5 micron; mobile phase A: 11 of water+0.01 mol of ammonium carbonate, mobile phase B: 1 l of 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.

(8) Method 6: MS instrument: Waters (Micromass) ZQ; HPLC instrument: Agilent 1100 series; column: Agient ZORBAX Extend-C18 3.0 mm×50 mm 3.5 micron; mobile phase A: 11 of water+0.01 mol of ammonium carbonate, mobile phase B: 1 l of 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.

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

(10) Method 8: Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; column: Waters Acquity UPLC HSS T3 1.8μ 50 mm×2.1 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength 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.

(11) 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 with helium: 1.20 ml/min; oven: 60° C.; inlet: 220° C.; gradient: 60° C., 30° C./min.fwdarw.300° C. (maintained for 3.33 min)

(12) Microwave: The microwave reactor used was a “single-mode” instrument of the Emrys™ Optimizer type.

(13) 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.

(14) 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.

(15) 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.

(16) Starting Materials

(17) General Method 1A: Preparation of a Boronic Acid

(18) At −78° C., lithium diisopropylamide (2 M in tetrahydrofuran/heptane/ethylbenzene) was added to a solution of the appropriate pyridine derivative in tetrahydrofuran (3 ml/mmol), the mixture was stirred for 2-4 h and triisopropyl borate was then added quickly. The reaction mixture was maintained at −78° C. for a further 2-3 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.

(19) General Method 2A: Suzuki Coupling

(20) In a flask which had been dried by heating and flushed with argon, 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) were initially charged. 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 normal phase chromatography (mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or by preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

(21) General Method 3A: Methoxypyridine Cleavage

(22) 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 triturated with water. The precipitate formed was filtered off, washed with water and dried under reduced pressure.

(23) General Method 4A: N-Alkylation of 2-pyridinone Derivatives with the Appropriate 2-bromo- or 2-chloropropanoic Acid Derivatives

(24) Under argon, a suspension of 1.0 eq. of the appropriate 2-pyridinone derivative, 2.0 eq. of magnesium di-tert-butoxide and 1.05 eq. of potassium tert-butoxide in tetrahydrofuran (5-10 ml/mmol) was stirred at RT for 10-20 min. The reaction mixture was cooled in an ice bath, and 1.5 eq. of the appropriate 2-bromo- or 2-chloropropanoic acid derivative were added. The reaction mixture was then stirred initially at RT for 2.5 h and then further at 35−90° C. overnight, and aqueous hydrochloric acid (6 N) was added. 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 normal phase chromatography (mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or by preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

(25) General Method 4B: N-Alkylation of 2-pyridinone Derivatives with the Appropriate 2-bromo- or 2-chloropropanoic Ester Derivatives in the Presence of Potassium Carbonate

(26) Under argon and at RT, 1.2 eq. of the appropriate 2-bromo- or 2-chloropropanoic ester derivative and 1.5 eq. of potassium carbonate were added to a solution of 1.0 eq. of the appropriate 2-pyridinone derivative in dimethylformamide (5-10 ml/mmol), 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 normal phase chromatography (mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or by preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

(27) General Method 4C: N-Alkylation of 2-pyridinone Derivatives with the Appropriate Triflates in the Presence of Sodium Hydride

(28) Under argon and at RT, sodium hydride (1.1-1.5 eq.) was added to a solution of the appropriate 2-pyridinone derivative (1 eq.) in tetrahydrofuran (0.05-0.2M), and the mixture was stirred for 30-90 min. The appropriate triflate (1.0-2.0 eq.) was then added neat or as a solution in tetrahydrofuran. The resulting reaction mixture was stirred 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 dried (sodium sulphate or magnesium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified either by normal phase chromatography (mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or by preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

(29) General Method 5A: Amide Coupling with HATU/DIEA

(30) Under argon and at RT, the amine (1.1 eq.), N,N-diisopropylethylamine (2.2 eq.) and a solution of HATU (1.2 eq.) in a little dimethylformamide were added to a solution of the appropriate carboxylic acid (1.0 eq.) in dimethylformamide (7-15 ml/mmol). 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 normal phase chromatography (mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or by preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

(31) General Method 5B: Amide Coupling with OXIMA/DIC

(32) N,N′-Diisopropylcarbodiimide (DIC) (1 eq.) was added dropwise to a degassed solution of the appropriate carboxylic acid (1 eq.), aniline (1 eq.) and ethyl hydroxyiminocyanoacetate (Oxima) (1 eq.) in dimethylformamide (0.1M), and the resulting reaction solution was stirred at RT to 40° C. for 8-24 h. The solvent was removed under reduced pressure. The residue was either admixed with water and the desired product was filtered off or purified by normal phase chromatography (cyclohexane/ethyl acetate gradient) or preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

(33) General Method 5C: Amide Coupling Using T3P/DIEA

(34) Under argon and at 0° C., N,N-diisopropylethylamine (3 eq.) and propylphosphonic anhydride (T3P, 50% in dimethylformamide, 3 eq.) were added dropwise to a solution of the carboxylic acid and the appropriate amine (1.1-1.5 eq.) in dimethylformamide (0.15-0.05 mmol). The reaction mixture was stirred at RT and then concentrated under reduced pressure. After addition of water/ethyl acetate and phase separation, the aqueous phase was extracted twice 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 flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or by preparative HPLC (Reprosil C18, water/acetonitrile gradient or water/methanol gradient).

(35) General Method 5D: Amide Coupling Using T3P/Pyridine

(36) A solution of the appropriate carboxylic acid (1 eq.) and the appropriate amine (1.1-1.5 eq.) in pyridine (about 0.1M) was heated to 60° C., and T3P (50% in ethyl acetate, 15 eq.) was added dropwise. Alternatively, T3P was added at RT and the mixture was then stirred at RT or heated to 60 to 90° C. After 1-20 h, the reaction mixture was cooled to RT, and water and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous buffer solution (pH=5), with saturated aqueous sodium bicarbonate 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 normal phase chromatography (mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or by preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

(37) General Method 6A: Hydrolysis of a Tert-butyl Ester or a Boc-protected Amine Using TFA

(38) At RT, 20 eq. of TFA were added to a solution of 1.0 eq. of the appropriate tert-butyl ester derivative in dichloromethane (about 5-10 ml/mmol), and the mixture was stirred at RT for 1-8 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 normal phase chromatography (mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or by preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

(39) General Method 6B: Hydrolysis of a Methyl/Ethyl or Benzyl Ester with Lithium Hydroxide

(40) At RT, lithium hydroxide (2-4 eq.) was added to a solution of 1.0 eq. of the appropriate methyl or ethyl ester in tetrahydrofuran/water (3:1, ca. 7-15 ml/mmol). The reaction mixture was stirred at RT to 60° C. and then 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 normal phase chromatography (mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or by preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

(41) General Method 7A: Preparation of Triflates

(42) 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 triple 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 bicarbonate 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 step without further purification.

(43) General Method 8A: Alkylation of Acetic Esters with Triflates

(44) Under argon and at −78° C., bis(trimethylsilyl)lithium amide (1.0M in THF, 1.1-1.3 eq.) was added dropwise to a solution of the appropriate acetic ester (1 eq.) in tetrahydrofuran (0.1-0.2M), 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 normal phase chromatography (mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or by preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

(45) General Method 8B: Alkylation of Acetic Esters with Halides

(46) Under argon and at −78° C., 1.1 eq. of bis(trimethylsilyl)lithium amide (1.0M in THF) were added to a solution of the appropriate acetic ester in THF (about 10 ml/mmol), 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, mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or by preparative HPLC (Reprosil C18, water/acetonitrile gradient or water/methanol gradient).

Example 1.1A

Ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate

(47) ##STR00041##

(48) A solution of 250 mg (1.01 mmol) of ethyl 6-nitroimidazo[1,2-a]pyridine-2-carboxylate in 20 ml of ethanol was hydrogenated in the presence of 30 mg of palladium (10% on activated carbon) at RT and standard pressure for 5 h. The reaction mixture was then filtered through Celite and the residue was washed with ethanol. The combined filtrates were concentrated under reduced pressure and dried. Yield: 215 mg (quant.)

(49) LC/MS [Method 5]: R.sub.t=1.40 min; MS (ESIpos): m/z=206 (M+H).sup.+,

(50) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.33 (s, 1H), 7.66 (s, 1H), 7.37 (d, 1H), 6.94 (dd, 1H), 5.11 (s, 2H), 4.26 (q, 2H), 1.29 (t, 3H).

Example 1.2A

Ethyl 7-nitroimidazo[1,2-a]pyridine-2-carboxylate

(51) ##STR00042##

(52) Under argon and at RT, 434 mg (3.14 mmol, 1.1 eq.) of potassium carbonate, 212 μl (2.66 mmol, 1.1 eq.) of iodoethane and 5 ml of tetrahydrofuran (to improve stirrability) were added to a suspension of 500 mg (2.41 mmol) of 7-nitroimidazo[1,2-a]pyridine-2-carboxylic acid in 20 ml of dimethylformamide, and the mixture was stirred at RT overnight. After addition of a further 35 μl (0.48 mmol, 0.2 eq.) of iodoethane and stirring at RT for a further 2 d, the reaction mixture was concentrated under reduced pressure. Water was added to the residue, the mixture was filtered and the product was dried under reduced pressure. Yield: 273 mg (48% of theory)

(53) LC/MS [Method 1]: R.sub.t=0.71 min; MS (ESIpos): m/z=236 (M+H).sup.+.

Example 1.2B

Ethyl 7-aminoimidazo[1,2-a]pyridine-2-carboxylate

(54) ##STR00043##

(55) A solution of 273 mg (1.16 mmol) of ethyl 7-nitroimidazo[1,2-a]pyridine-2-carboxylate in 10 ml of ethanol was hydrogenated in the presence of 30 mg of palladium (10% on activated carbon) at RT and standard pressure overnight. The reaction mixture was then filtered through Celite and the residue was washed with ethanol. The combined filtrates were concentrated under reduced pressure and dried. Yield: 214 mg (90% of theory)

(56) LC/MS [Method 5]: R.sub.t=1.45 min; MS (ESIpos): m/z=206 (M+H).sup.+,

(57) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.16 (d, 1H), 8.14 (s, 1H), 6.46 (dd, 1H), 6.32 (d, 1H), 5.84 (s, 2H), 4.24 (q, 2H), 1.28 (t, 3H).

Example 1.3A

Imidazo[1,2-a]pyridine-6-amine

(58) ##STR00044##

(59) A solution of 600 mg (3.68 mmol) of 6-nitroimidazo[1,2-a]pyridine in 30 ml of ethanol was hydrogenated in the presence of 60 mg of palladium (10% on activated carbon) at RT and standard pressure overnight. The reaction mixture was then filtered through Celite and the residue was washed with ethanol. The combined filtrates were concentrated under reduced pressure and dried. The crude product was used without further purification in the next step. Yield: 512 mg (quant.)

(60) LC/MS [Method 5]: R.sub.t=0.89 min; MS (ESIpos): m/z=134 (M+H).sup.+,

(61) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.72-7.62 (m, 2H), 7.33 (d, 1H), 7.30 (d, 1H), 6.80 (dd, 1H), 4.83 (s, 2H).

Example 1.4A

Ethyl 6-nitroimidazo[1,2-a]pyridine-3-carboxylate

(62) ##STR00045##

(63) 3.00 g (21.6 mmol) of 2-amino-5-nitropyridine and 13.4 g (71.2 mmol, 3.3 eq.) of potassium (1E)-2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (T. Ikemoto et al., Tetrahedron 2000, 56, 7915-7921) were dissolved in 136 ml of ethanol, and 1.91 ml of sulphuric acid were added carefully. The mixture was heated at reflux for 12 h and the precipitate was filtered off and washed with ethanol. The filtrate was concentrated under reduced pressure. The residue was taken up in ethyl acetate and water and acidified slightly with 1M hydrochloric acid. The aqueous phase was then extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and the solvent was removed under reduced pressure. 3 g of the crude product were purified by flash chromatography (silica gel 50, mobile phase: cyclohexane/ethyl acetate mixtures), giving 720 mg of product (93% pure). The remainder was purified by preparative HPLC (XBridge C18, 5 μM, 100 mm×30 mm, mobile phase: acetonitrile/water 2:3), giving a further 690 mg of product. Yield: 720 mg (93% pure, 13% of theory) and 690 mg (14% of theory)

(64) LC/MS [Method 5]: R.sub.t=2.12 min; MS (ESIpos): m/z=236 (M+H).sup.+,

(65) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.14 (dd, 1H), 8.51 (s, 1H), 8.25 (dd, 1H), 7.98 (dd, 1H), 4.43 (q, 2H), 1.38 (t, 3H).

Example 1.4B

Ethyl 6-aminoimidazo[1,2-a]pyridine-3-carboxylate

(66) ##STR00046##

(67) 250 mg (1.06 mmol) of ethyl 6-nitroimidazo[1,2-a]pyridine-3-carboxylate were initially charged in 10 ml of ethanol 68 mg (64 μmol, 0.06 eq.) of 10% palladium on activated carbon was added, and the mixture was hydrogenated under standard pressure overnight. The reaction solution was filtered off through kieselguhr and concentrated under reduced pressure. Yield: 217 mg (99% of theory)

(68) LC/MS [Method 1]: R.sub.t=0.33 min; MS (ESIpos): m/z=206 (M+H).sup.+,

(69) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.62 (d, 1H), 8.04 (s, 1H), 7.53 (d, 1H), 7.11 (dd, 1H), 5.35 (s, 2H), 4.32 (q, 2H), 1.33 (t, 3H).

Example 1.5A

7-Nitroimidazo[1,2-a]pyridine-2-carboxamide

(70) ##STR00047##

(71) 16 ml of a methanolic ammonia solution (7N) and 30 ml of ammonia solution (35% in water) were added to 670 mg (2.85 mmol) of ethyl 7-nitroimidazo[1,2-a]pyridine-2-carboxylate. The reaction was divided into 4 aliquots and these were heated in closed vessels in the microwave at 80° C. for 1.5 h. Subsequently, the reaction solutions were combined and taken up in ethyl acetate/water, and the aqueous phase was neutralized with hydrochloric acid (1N). The mixture was extracted twice with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over magnesium sulphate. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica gel 50, dichloromethane/methanol mixtures). Yield 81 mg (91% pure, 12% of theory)

(72) LC/MS [Method 5]: R.sub.t=1.40 min; MS (ESIpos): m/z=207 (M+H).sup.+,

(73) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=9.92 (dd, 1H), 8.57 (d, 1H), 8.01 (dd, 1H), 7.87 (br. s, 1H), 7.75 (dt, 1H), 7.59 (br. s, 1H).

Example 1.5B

7-Aminoimidazo[1,2-a]pyridine-2-carboxamide

(74) ##STR00048##

(75) 80 mg (91% pure, 0.35 mmol) of 7-nitroimidazo[1,2-a]pyridine-2-carboxamide were initially charged in 15 ml of ethanol 19 mg of palladium (10% on activated carbon) were added and the mixture was hydrogenated at RT and standard pressure for 3 h. The reaction solution was filtered through kieselguhr and the solvent was removed under reduced pressure. Yield 50 mg (90% pure, 73% of theory)

(76) LC/MS [Method 5]: R.sub.t=0.95 min; MS (ESIpos): m/z=177 (M+H).sup.+,

(77) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.10 (d, 1H), 7.68 (dd, 1H), 7.48 (br. s, 1H), 7.33 (d, 1H), 7.18 (br. s, 1H), 6.92 (dd, 1H), 5.02 (s, 2H).

Example 1.6A

2-(4-Fluorophenyl)-6-nitroimidazo[1,2-a]pyridine

(78) ##STR00049##

(79) 80.6 mg (0.72 mmol, 0.1 eq.) of DABCO and 36 ml of water were added to 1.00 g (7.19 mmol) of 2-amino-5-nitropyridine and 1.56 g (7.19 mmol) of 2-bromo-1-(4-fluorophenyl)ethanone. The mixture was stirred at 65° C. for 2 h and, after stirring overnight at RT, for a further 6 h at 65° C. After 48 h at RT, the resulting precipitate was filtered off with suction, stirred with methyl tert.-butyl ether and filtered off with suction. Yield: 576 mg (purity 92%, 29% of theory)

(80) LC/MS [Method 1]: R.sub.t=0.93 min; MS (ESIpos): m/z=258 (M+H).sup.+,

(81) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=9.84 (d, 1H), 8.60 (s, 1H), 8.07-8.01 (m, 2H), 7.96 (dd, 1H), 7.74 (d, 1H), 7.36-7.29 (m, 2H).

Example 1.6B

2-(4-Fluorophenyl)imidazo[1,2-a]pyridine-6-amine

(82) ##STR00050##

(83) 450 mg (92% pure, 1.61 mmol) of 2-(4-fluorophenyl)-6-nitroimidazo[1,2-a]pyridine were initially charged in 20 ml of ethanol. 171 mg (161 μmol, 0.1 eq.) of 10% palladium on activated carbon were added, and the mixture was hydrogenated under standard pressure overnight. The reaction solution was filtered off through kieselguhr and concentrated under reduced pressure. An analogous reaction was carried out using 100 mg of starting material. The products were combined, stirred with methyl tert-butyl ether and filtered off with suction. Yield: 395 mg (purity 80%, 71% of theory)

(84) LC/MS [Method 1]: R.sub.t=0.46 min; MS (ESIpos): m/z=228 (M+H).sup.+,

(85) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.16 (s, 1H), 7.91 (dd, 2H), 7.67 (d, 1H), 7.33 (d, 1H), 7.22 (t, 2H), 6.85 (dd, 1H), 4.95 (br. s, 2H).

Example 1.7A

6-Nitro[1,2,4]triazolo[4,3-a]pyridine

(86) ##STR00051##

(87) 2.00 g (13.0 mmol) of 2-hydrazino-5-nitropyridine were initially charged in 80 ml of dichloromethane, and 5.51 g (51.9 mmol) of trimethyl orthoformate were added. The mixture was left stirring at RT for 15 min 1.00 ml (13.0 mmol) of trifluoroacetic acid was then added, and stirring was continued for 30 min Volatile constituents were then removed under reduced pressure, and the product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures). Yield: 896 mg (42% of theory)

(88) LC/MS [Method 1]: R.sub.t=0.41 min; MS (ESIpos): m/z=165 (M+H).sup.+,

(89) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.2 (dd, 1H), 8.82 (s, 1H), 8.39 (d, 1H), 8.37 (d, 1H), 8.04 (dd, 2H).

Example 1.7B

[1,2,4]Triazolo[4,3-a]pyridine-6-amine

(90) ##STR00052##

(91) A solution of 890 mg (5.42 mmol) of 6-nitro[1,2,4]triazolo[4,3-a]pyridine in 60 ml of ethanol was hydrogenated in the presence of 577 mg of palladium (10% on activated carbon) at RT and standard pressure for 6 h. The reaction mixture was then filtered through Celite, the same amount of palladium catalyst was added again and the mixture was hydrogenated for a further 2 h. After filtration through Celite, the reaction mixture was concentrated, the residue was crystallized with pentane/methyl tert-butyl ether and the solid was filtered off with suction. Yield: 469 mg (65% of theory)

(92) LC/MS [Method 5]: R.sub.t=0.62 min; MS (ESIpos): m/z=135 (M+H).sup.+,

(93) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.17 (s, 1H), 8.02 (dd, 1H), 7.56 (dd, 1H), 7.19 (dd, 1H), 5.24 (br. s, 2H).

Example 1.8A

3-Methyl-6-nitro[1,2,4]triazolo[4,3-a]pyridine

(94) ##STR00053##

(95) 2.00 g (13.0 mmol) of 2-hydrazino-5-nitropyridine were initially charged in 50 ml of ethanol, and 25 ml (195 mmol, 15 eq.) of trimethyl orthoacetate were added. The mixture was heated at reflux for 1 h. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures). Yield: 1.81 g (78% of theory)

(96) LC/MS [Method 5]: R.sub.t=1.30 min; MS (ESIpos): m/z=179 (M+H).sup.+,

(97) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=9.57 (dd, 1H), 7.98 (dd, 1H), 7.87 (d, 1H), 2.81 (s, 3H).

Example 1.8B

3-Methyl[1,2,4]triazolo[4,3-a]pyridine-6-amine

(98) ##STR00054##

(99) 1.27 g (5.61 mmol, 5.0 eq.) of tin(II) chloride dihydrate were added to a suspension of 200 mg (1.12 mmol) of 3-methyl-6-nitro[1,2,4]triazolo[4,3-a]pyridine in 10 ml of ethanol, and the mixture was heated at reflux for 12 h. Saturated aqueous sodium bicarbonate solution was then added and the reaction solution was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. Yield: 83 mg (purity 74%, 37% of theory)

(100) LC/MS [Method 5]: R.sub.t=0.94 min; MS (ESIpos): m/z=149 (M+H).sup.+.

Example 1.9A

3-Ethyl-6-nitro[1,2,4]triazolo[4,3-a]pyridine

(101) ##STR00055##

(102) 2.00 g (13.0 mmol) of 2-hydrazino-5-nitropyridine were initially charged in 50 ml of ethanol, and 27 ml (195 mmol, 15 eq.) of trimethyl orthopropionate were added. The mixture was heated at reflux for 1 h. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures, then ethyl acetate/propanol mixtures). Yield: 2.37 g (95% of theory)

(103) LC/MS [Method 5]: R.sub.t=1.42 min; MS (ESIpos): m/z=193 (M+H).sup.+,

(104) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=9.58 (dd, 1H), 7.98 (dd, 1H), 7.88 (dd, 1H), 3.22 (q, 3H), 1.40 (t, 4H).

Example 1.9B

3-Ethyl[1,2,4]triazolo[4,3-a]pyridine-6-amine

(105) ##STR00056##

(106) 1.00 g (5.20 mmol) of 3-ethyl-6-nitro[1,2,4]triazolo[4,3-a]pyridine was initially charged in 60 ml of ethanol 554 mg (0.52 mmol) of 10% palladium on activated carbon were added, and the mixture was hydrogenated under standard pressure for 4 h. The reaction solution was filtered off through kieselguhr and concentrated under reduced pressure. The crude product was then purified by flash chromatography (silica gel 50, dichloromethane/methanol mixtures). Yield: 600 mg (69% of theory)

(107) LC/MS [Method 5]: R.sub.t=1.07 min; MS (ESIpos): m/z=163 (M+H).sup.+,

(108) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.50 (dd, 1H), 7.35 (dd, 1H), 6.96 (dd, 1H), 5.11 (s, 2H), 2.92 (d, 2H), 1.32 (t, 3H).

Example 1.10A

3-Butyl-6-nitro[1,2,4]triazolo[4,3-a]pyridine

(109) ##STR00057##

(110) 1.00 g (6.49 mmol) of 2-hydrazino-5-nitropyridine were initially charged in 13 ml of ethanol, and 2.2 ml (13 mmol, 2 eq.) of trimethyl orthovalerate were added. The mixture was heated at reflux for 1 h. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures, then ethyl acetate/2-propanol mixtures). Yield: 1.47 g (99% of theory)

(111) LC/MS [Method 5]: R.sub.t=1.86 min; MS (ESIpos): m/z=221 (M+H).sup.+,

(112) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=9.62 (dd, 1H), 7.98 (dd, 1H), 7.87 (dd, 1H), 3.22 (t, 2H), 1.81 (quin, 2H), 1.44 (tq, 2H), 0.95 (t, 3H).

Example 1.10B

3-Butyl[1,2,4]triazolo[4,3-a]pyridine-6-amine

(113) ##STR00058##

(114) 1.20 g (5.45 mmol) of 3-butyl-6-nitro[1,2,4]triazolo[4,3-a]pyridine were initially charged in 65 ml of ethanol. 580 mg (0.55 mmol) of 10% palladium on activated carbon were added, and the mixture was hydrogenated under standard pressure overnight. The reaction solution was filtered off through kieselguhr and concentrated under reduced pressure. The crude product was then purified by flash chromatography (silica gel 50, dichloromethane/methanol mixtures). Yield: 86 mg (purity 85%, 7% of theory)

(115) LC/MS [Method 5]: R.sub.t=1.64 min; MS (ESIpos): m/z=191 (M+H).sup.+,

(116) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.93 (d, 1H), 7.42 (d, 1H), 7.12 (dd, 1H), 5.12 (s, 2H), 2.69 (t, 2H), 1.69 (quin, 2H), 1.34 (tq, 2H), 0.89 (t, 3H).

Example 1.11A

3-(Chloromethyl)-6-nitro[1,2,4]triazolo[4,3-a]pyridine

(117) ##STR00059##

(118) 10.0 g (64.9 mmol) of 2-hydrazino-5-nitropyridine were initially charged in 125 ml of ethanol, and 17.5 ml (130 mmol, 2 eq.) of 2-chloro-1,1,1-trimethoxyethane were added. The mixture was heated at reflux for 1 h. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures, then ethyl acetate/2-propanol mixtures). Yield: 13.1 g (95% of theory)

(119) LC/MS [Method 1]: R.sub.t=0.52 min; MS (ESIpos): m/z=213 (M+H).sup.+,

(120) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=9.84 (dd, 1H), 8.12 (dd, 1H), 8.03 (dd, 1H), 5.57 (s, 2H).

Example 1.11B

N,N-Dimethyl-1-(6-nitro[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanamine

(121) ##STR00060##

(122) 200 mg (0.94 mmol) of 3-(chloromethyl)-6-nitro[1,2,4]triazolo[4,3-a]pyridine were dissolved in 2.9 ml of 33% strength dimethylamine solution in ethanol, and the solution was stirred at RT for 4 h. The precipitated solid was then filtered off and dried under reduced pressure. Yield: 148 mg (61% of theory)

(123) LC/MS [Method 5]: R.sub.t=1.54 min; MS (ESIpos): m/z=222 (M+H).sup.+,

(124) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.10 (dd, 1H), 8.35 (dd, 1H), 7.95 (dd, 1H), 3.74 (s, 3H), 2.27 (s, 6H).

Example 1.11C

3-[(Dimethylamino)methyl][1,2,4]triazolo[4,3-a]pyridine-6-amine

(125) ##STR00061##

(126) 145 mg (0.66 mmol) of N,N-dimethyl-1-(6-nitro[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanamine were initially charged in 10.7 ml of ethanol 15 mg (56 μmol, 0.1 eq., 83% pure) of platinum(IV) dioxide was added, and the mixture was hydrogenated under standard pressure for 4 h. The mixture was then filtered off through kieselguhr and the filtrate was carefully concentrated under reduced pressure. Yield: 115 mg (92% of theory)

(127) LC/MS [Method 5]: R.sub.t=1.19 min; MS (ESIpos): m/z=192 (M+H).sup.+,

(128) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.96 (d, 1H), 7.48 (d, 1H), 7.15 (dd, 1H), 5.18 (s, 2H), 3.55 (s, 2H), 2.22 (s, 6H).

Example 1.12A

3-(Morpholin-4-ylmethyl)-6-nitro[1,2,4]triazolo[4,3-a]pyridine

(129) ##STR00062##

(130) 300 g (1.41 mmol) of 3-(chloromethyl)-6-nitro[1,2,4]triazolo[4,3-a]pyridine were dissolved in 2.0 ml of ethanol, and 0.37 ml (4.23 mmol, 3.0 eq.) of morpholine were added. The mixture was left to stir at RT for 4 h and then heated at 50 C for a further 4 h, and ethyl acetate and saturated aqueous sodium bicarbonate solution were added. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. Yield: 150 mg (40% of theory)

(131) LC/MS [Method 5]: R.sub.t=1.51 min; MS (ESIpos): m/z=264 (M+H).sup.+,

(132) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.11 (dd, 1H), 8.35 (dd, 1H), 7.95 (dd, 1H), 3.80 (s, 2H), 3.60-3.55 (m, 4H).

Example 1.12B

3-(Morpholin-4-ylmethyl)[1,2,4]triazolo[4,3-a]pyridine-6-amine

(133) ##STR00063##

(134) 140 mg (0.53 mmol) of 3-(morpholin-4-ylmethyl)-6-nitro[1,2,4]triazolo[4,3-a]pyridine were initially charged in 9.3 ml of ethanol 12 mg (53 μmol, 0.1 eq., 83% pure) of platinum(IV) dioxide were added, and the mixture was hydrogenated under standard pressure for 4 h. The mixture was then filtered off through kieselguhr and the filtrate was carefully concentrated under reduced pressure. Yield: 93 mg (purity 77%, 58% of theory)

(135) LC/MS [Method 5]: R.sub.t=1.20 min; MS (ESIpos): m/z=234 (M+H).sup.+,

(136) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.97 (d, 1H), 7.47 (d, 1H), 7.16 (dd, 1H), 5.20 (br. s, 2H), 3.60 (s, 2H), 3.59-3.51 (m, 8H).

Example 1.13A

tert.-Butyl imidazo[1,5-a]pyridin-6-ylcarbamate

(137) ##STR00064##

(138) Under argon, a microwave vessel was charged with 200 mg (1.02 mmol) of 6-bromoimidazo[1,5-a]pyridine, 428 mg (3.63 mmol, 3.6 eq.) of tert-butyl carbamate, 16.6 mg (0.07 mmol) of palladium(II) acetate, 58.7 mg (0.10 mmol) of Xantphos, 496 mg (1.52 mmol, 1.5 eq.) of caesium carbonate and 10 ml of 1,4-dioxane. A stream of argon was passed through the suspension for 2 min. The reaction mixture was heated in the microwave at 140° C. for 4 h. After filtration through kieselguhr, the filtrate was concentrated under reduced pressure. The crude product was purified by normal phase chromatography (mobile phase: dichloromethane/methanol (2-5%) mixtures). Yield: 31.5 mg (13% of theory)

(139) LC/MS [Method 1]: R.sub.t=0.52 min; MS (ESIpos): m/z=234 (M+H).sup.+,

(140) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=9.35 (br. s, 1H), 8.71 (br. s, 1H), 8.33 (s, 1H), 7.46 (d, 1H), 7.26 (s, 1H), 6.70 (dd, 1H), 1.49 (s, 9H).

Example 1.13B

Imidazo[1,5-a]pyridine-6-amine

(141) ##STR00065##

(142) At RT, 1 ml (12.98 mmol) of TFA was added to a solution of 66 mg (0.28 mmol) of tert-butyl imidazo[1,5-a]pyridin-6-ylcarbamate in dichloromethane (2 ml), and the mixture was stirred at RT for 1 h. Subsequently, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. After phase separation, the aqueous phase was dried over sodium sulphate and concentrated under reduced pressure. Yield: 38.9 mg (69% pure, 72% of theory).

(143) LC/MS [Method 5]: R.sub.t=1.08 min, MS (ESIpos): m/z=134 (M+H).sup.+.

Example 2.1A

2,5-Dimethoxypyridin-4-ylboronic acid

(144) ##STR00066##

(145) 11.53 g (82.9 mmol) of 2,5-dimethoxypyridine were reacted according to General Method 1A. The desired product precipitated out after acidification of the aqueous phase. Yield: 9.53 g (61% of theory)

(146) 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

(147) ##STR00067##

(148) 7.87 g (purity 95%, 40.86 mmol) of 2,5-dimethoxypyridin-4-ylboronic acid and 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 were reacted according to General Method 2A. Yield: 6.23 g (92% pure, 51% of theory).

(149) 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

(150) ##STR00068##

(151) 7.23 g (purity 92%, 24.21 mmol) of 4-chloro-2-(2,5-dimethoxypyridin-4-yl)benzonitrile and pyridinium hydrochloride were reacted according to General Method 3A. Yield: 6.66 g (91% pure, 96% of theory).

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

(153) .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 2.1D

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

(154) ##STR00069##

(155) Under argon and at −78° C., 14.0 ml (1.0M in THF, 14.0 mmol, 1.05 eq.) of bis(trimethylsilyl)lithium amide were added dropwise 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 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 flash chromatography (340 g of silica gel, mobile phase: 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 without any cover, 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)

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

(157) .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 2.1E

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

(158) ##STR00070##

(159) 159 mg (purity 82%, 0.5 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.5 eq. of 2-bromobutanoic acid (racemate) were reacted according to General Method 4A at 50° C. Yield: 55 mg (32% of theory)

(160) LC/MS [Method 1]: R.sub.t=0.85 min; MS (ESIpos): m/z=347 (M+H).sup.+.

(161) Alternative Synthesis:

(162) Under argon and at RT, 7.8 ml (101.8 mmol, 10 eq.) of trifluoroacetic acid were added 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, 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. Once the reaction had gone to completion, the reaction mixture was concentrated under reduced pressure and the residue was co-evaporated in each case 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 strongly diluted aqueous sodium bicarbonate solution (where the pH of the washing water should not exceed pH 3-4 since otherwise the product is well soluble in water). The organic phase was subsequently dried (sodium sulphate), filtered and concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether, filtered, washed twice with methyl tert-butyl ether and dried under reduced pressure. Yield: 2.9 g (83% of theory)

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

(164) .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 2.1F

Methyl 2-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)imidazo[1,2-a]pyridine-6-carboxylate (racemate)

(165) ##STR00071##

(166) 72 mg (0.20 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 43 mg (0.22 mmol, 1.1 eq.) of methyl 2-aminoimidazo[1,2-a]pyridine-6-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 59 mg (56% of theory)

(167) LC/MS [Method 1]: R.sub.t=1.01 min; MS (ESIpos): m/z=520 (M+H).sup.+.

Example 2.2A

Ethyl 6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)imidazo[1,2-a]pyridine-2-carboxylate (racemate)

(168) ##STR00072##

(169) 87 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 59 mg (0.28 mmol, 1.1 eq.) of ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 86 mg (64% of theory)

(170) LC/MS [Method 1]: R.sub.t=0.96 min; MS (ESIpos): m/z=534 (M+H).sup.+,

(171) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.76 (s, 1H), 9.32 (s, 1H), 8.61 (s, 1H), 8.00 (d, 1H), 7.78-7.71 (m, 2H), 7.64 (d, 1H), 7.51 (s, 1H), 7.34 (dd, 1H), 6.55 (s, 1H), 5.65 (dd, 1H), 4.30 (q, 2H), 3.70 (s, 3H), 2.28-2.10 (m, 2H), 1.30 (t, 3H), 0.92 (t, 3H).

Example 2.3A

Ethyl 7-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)imidazo[1,2-a]pyridine-2-carboxylate (racemate)

(172) ##STR00073##

(173) 87 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 56 mg (0.28 mmol, 1.1 eq.) of ethyl 7-aminoimidazo[1,2-a]pyridine-2-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 18 mg (13% of theory)

(174) LC/MS [Method 8]: R.sub.t=1.11 min; MS (ESIpos): m/z=534 (M+H).sup.+.

Example 3.1A

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

(175) ##STR00074##

(176) 516 mg (purity 91%, 1.8 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.2 eq. of tert-butyl bromoacetate were reacted according to General Method 4B at 100° C. Yield: 464 mg (68% of theory)

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

Example 3.1B

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

(178) ##STR00075##

(179) 187 mg (500 μmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate and 770 μl (10.0 mmol) of TFA were reacted according to General Method 6A. Yield: 159 mg (93% of theory)

(180) LC/MS [Method 1]: R.sub.t=0.72 min; MS (ESIneg): m/z=317 (M−H).sup.−,

(181) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.1 (s, 1H), 8.00 (d, 1H), 7.74 (dd, 1H), 7.72 (s, 1H), 7.58 (s, 1H), 6.51 (s, 1H), 4.64 (s, 2H), 3.62 (s, 3H).

Example 3.1C

Ethyl 6-({[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetyl}amino)imidazo[1,2-a]pyridine-2-carboxylate

(182) ##STR00076##

(183) 130 mg (0.25 mmol) of [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetic acid and 56 mg (0.28 mmol, 1.1 eq.) of ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate were reacted according to General Method 5A. The crude product was purified by flash chromatography (silica gel (40-60 μm), dichloromethane/methanol 10:1). Yield: 99 mg (48% of theory)

(184) LC/MS [Method 1]: R.sub.t=0.83 min; MS (ESIpos): m/z=506 (M+H).sup.+,

(185) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.65 (s, 1H), 9.30 (s, 1H), 8.62 (s, 1H), 8.01 (d, 1H), 7.70-7.71 (m, 2H), 7.65 (d, 1H), 7.61 (s, 1H), 7.33 (dd, 1H), 6.52 (s, 1H), 4.84 (s, 2H), 4.30 (q, 2H), 3.64 (s, 3H), 1.31 (t, 3H).

Example 4.1A

Ethyl 3-cyclobutyl-2-hydroxypropanoate (racemate)

(186) ##STR00077##

(187) 359 mg (14.8 mmol, 1.1 eq.) of magnesium turnings were covered with diethyl ether and etched by addition of a small piece of iodine for 3-4 min Under argon and at RT, 5 ml of a solution of 2.0 g (13.4 mmol) of (bromomethyl)cyclobutane in 30 ml of diethyl ether were added with stirring to this mixture, the mixture was stirred for 5 min (until the reaction is initiated) and the remainder of the (bromomethyl)cyclobutane/diethyl ether solution is added dropwise over a further 10 min. The reaction mixture was stirred under reflux for 1 h, cooled under a stream of argon and, with ice-water cooling, added dropwise to a solution of 2.4 ml (12.1 mmol, 0.9 eq.) of ethyl glyoxylate (50% in toluene). The reaction mixture was stirred at RT for 1 h, carefully quenched to pH 7 with 20 ml of a potassium citrate/citric acid solution (pH 5) and then adjusted to pH 4-5 with aqueous hydrochloric acid (1N). After phase separation, the aqueous phase was extracted with diethyl ether. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel 50, mobile phase: cyclohexane/ethyl acetate 20%-33%). Yield: 110 mg (purity 94%, 5% of theory)

(188) LC-MS [Method 8]: R.sub.t=3.37 min; MS (ESIpos): m/z=172 (M).sup.+.

Example 4.1B

Ethyl 3-cyclobutyl-2-{[(trifluoromethyl)sulphonyl]oxy}propanoate (racemate)

(189) ##STR00078##

(190) 110 mg (purity 94%, 0.60 mmol) of ethyl 3-cyclobutyl-2-hydroxypropanoate (racemate) and 142 μl (0.84 mmol, 1.4 eq.) of trifluoromethanesulphonic anhydride in the presence of 105 μl (0.90 mmol, 1.5 eq.) of 2,6-dimethylpyridine were reacted according to General Method 7A. The crude product was reacted in the next step without further purification.

Example 4.1C

Ethyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoate (racemate)

(191) ##STR00079##

(192) 122 mg (purity 87%, 0.41 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile in the presence of 1.3 eq. of sodium hydride and 161 mg (0.53 mmol, 1.3 eq.) of ethyl 3-cyclobutyl-2-{[(trifluoromethyl)sulphonyl]oxy}propanoate (racemate) were reacted at RT according to General Method 4C. The crude product was purified by flash chromatography (KP-SIL, cyclohexane/ethyl acetate 15-33%). Yield: 140 mg (82% of theory)

(193) LC/MS [Method 1]: R.sub.t=1.15 min; MS (ESIpos): m/z=415 (M+H).sup.+,

(194) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.99 (d, 1H), 7.78-7.69 (m, 2H), 7.42 (s, 1H), 6.48 (s, 1H), 5.12 (dd, 1H), 4.21-4.07 (m, 2H), 3.64 (s, 3H), 2.38-2.24 (m, 1H), 2.23-2.11 (m, 2H), 2.05-1.93 (m, 1H), 1.89-1.61 (m, 4H), 1.60-1.47 (m, 1H), 1.18 (t, 3H).

Example 4.1D

(195) 2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoic acid (racemate)

(196) ##STR00080##

(197) 138 mg (0.33 mmol) of ethyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoate (racemate) were hydrolysed with lithium hydroxide according to General Method 6B. Yield: 104 mg (82% of theory)

(198) LC/MS [Method 1]: R.sub.t=0.95 min; MS (ESIpos): m/z=387 (M+H).sup.+.

Example 4.1E

Ethyl 6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoyl}amino)imidazo[1,2-a]pyridine-2-carboxylate (racemate)

(199) ##STR00081##

(200) 109 mg (0.28 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]cyclobutylpropanoic acid (racemate) and 64 mg (0.31 mmol, 1.1 eq.) of ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 69 mg (43% of theory)

(201) LC/MS [Method 1]: R.sub.t=1.08 min; MS (ESIpos): m/z=574 (M+H).sup.+.

Example 5.1A

2-Bromo-4-chlorophenyl difluormethyl ether

(202) ##STR00082##

(203) 36 ml of aqueous potassium hydroxide solution (6M) were added to a solution of 3.5 g (16.9 mmol) of 2-bromo-4-chlorophenol in 36 ml of acetonitrile, the mixture was cooled in an ice bath and 6.5 ml (26.9 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 dropwise with vigorous stirring. The reaction mixture was stirred for 5 min and diluted with 200 ml of water. The aqueous phase was extracted twice with in each case 150 ml of diethyl ether. The combined organic phases were dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. The aqueous phase was once more extracted with diethyl ether. The organic phase was dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. Yield of the two combined residues: 3.4 g (80% of theory)

(204) LC/MS [Method 9]: R.sub.t=3.51 min; MS (ESIpos): m/z=256 (M+H).sup.+,

(205) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.91 (d, 1H), 7.55 (dd, 1H), 7.37 (d, 1H), 7.30 (t, 1H).

Example 5.1B

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

(206) ##STR00083##

(207) 417 mg (2.19 mmol, 1.2 eq.) of 2,5-dimethoxypyridin-4-ylboronic acid and 494 mg (1.82 mmol) of 2-bromo-4-chlorophenyl difluormethyl ether in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. The crude product was purified by flash chromatography (KP-SIL, petroleum ether/ethyl acetate 15-20%). Yield: 170 mg (90% pure, 27% of theory)

(208) LC/MS [Method 1]: R.sub.t=1.16 min; MS (ESIpos): m/z=316 (M+H).sup.+,

(209) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.96 (s, 1H), 7.57 (dd, 1H), 7.45 (d, 1H), 7.30 (d, 1H), 7.11 (t, 1H), 6.74 (s, 1H), 3.83 (s, 3H), 3.75 (s, 3H).

Example 5.1C

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

(210) ##STR00084##

(211) 170 mg (purity 90%, 0.49 mmol) of 4-[5-chloro-2-(difluoromethoxy)phenyl]-2,5-dimethoxypyridine and pyridinium hydrobromide were reacted according to General Method 3A. Yield: 127 mg (87% of theory)

(212) LC/MS [Method 1]: R.sub.t=0.84 min; MS (ESIpos): m/z=302 (M+H).sup.+.

Example 5.1D

Ethyl 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridine-1(2H)-yl}butanoate (racemate)

(213) ##STR00085##

(214) Under argon and at RT, 105 mg (2.64 mmol, 1.3 eq.) of sodium hydride (60% in mineral oil) were added to a solution of 618 mg (2.03 mmol) of 4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxypyridin-2(1H)-one in 25 ml of tetrahydrofuran, the mixture was stirred at RT for 60 min, 871 mg (2.64 mmol, 1.3 eq.) of ethyl 2-{[(trifluoromethyl)sulphonyl]oxy}butanoate (racemate) [J. Castells et al. Tetrahedron, 1994, 50, 13765-13774] were then added dropwise and the mixture was stirred at RT for 1 h. A further 38 mg (0.96 mmol) of sodium hydride (60% in mineral oil) were added, the mixture was stirred at RT for 5 min, a further 871 mg (2.64 mmol, 1.3 eq.) of ethyl 2-{[(trifluoromethyl)sulphonyl]oxy}butanoate (racemate) were added dropwise, and the reaction mixture was stirred at RT for 15 min and then quenched with water. After phase separation, the aqueous phase was extracted twice 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 residue was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate gradient). Yield: 415 mg (48% of theory)

(215) LC/MS [Method 1]: R.sub.t=1.08 min; MS (ESIpos): m/z=416 (M+H).sup.+.

Example 5.1E

2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridine-1(2H)-yl}butanoic acid (racemate)

(216) ##STR00086##

(217) 415 mg (0.97 mmol) of ethyl 2-{4-[5-Chloro-2-(difluormethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}butanoate (racemate) were hydrolysed with lithium hydroxide according to General Method 6B. Yield: 348 mg (93% of theory)

(218) LC/MS [Method 1]: R.sub.t=0.91 min; MS (ESIpos): m/z=388 (M+H).sup.+,

(219) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=12.96 (br. s, 1H), 7.57 (dd, 1H), 7.50 (d, 1H), 7.34-7.25 (m, 2H), 7.12 (t, 1H), 6.35 (s, 1H), 5.06 (dd, 1H), 3.58 (s, 3H), 2.20-2.06 (m, 2H), 0.82 (t, 3H).

Example 5.1F

Ethyl 6-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}butanoyl)amino]-imidazo[1,2-a]pyridine-2-carboxylate (racemate)

(220) ##STR00087##

(221) 116 mg (0.30 mmol) of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}butanoic acid (racemate) and 69 mg (0.33 mmol, 1.1 eq.) of ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate were reacted according to General Method 5A. Yield: 198 mg (quant.)

(222) LC/MS [Method 1]: R.sub.t=1.03 min; MS (ESIpos): m/z=575 (M+H).sup.+.

Example 6.1A

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

(223) ##STR00088##

(224) 10.0 g of 5-chloro-2-methoxypyridine were initially charged in 225 ml of THF, and 41.8 ml (83.6 mmol) of lithium diisopropylamide (2M in THF/heptane/ethylbenzene) were added at −78° C. The mixture was stirred at −78° C. for 4 h, and 32.6 ml (141 mmol) of triisopropyl borate were then added rapidly. The reaction mixture was stirred at −78° C. for 3 h and then warmed to room temperature overnight. The procedure was then repeated, and a further 20.9 ml (41.8 mmol) of lithium diisopropylamide (2M in THF/heptane/ethylbenzene) and 16.1 ml (69.7 mmol) of triisopropyl borate were added. The reaction mixture was poured into 500 ml of water and THF was removed under reduced pressure. The aqueous phase was extracted three times with ethyl acetate. The aqueous phase was acidified with hydrochloric acid (2N) and the precipitate was filtered off. The filtrate was extracted twice with ethyl acetate, the organic phase was dried and filtered, the solvent was removed under reduced pressure and the residue, together with the precipitate, was dried under high vacuum. Yield: 10.4 g (91% pure, 73% of theory).

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

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

Example 6.1B

5-Chloro-4-[5-chloro-2-(difluoromethoxy)phenyl]-2-methoxypyridine

(227) ##STR00089##

(228) At 60° C., 4.17 g (16.2 mmol) of 2-bromo-4-chloro-1-(difluoromethoxy)benzene, 3.04 g (16.2 mmol) of (5-chloro-2-methoxypyridin-4-yl)boronic acid, 561 mg (486 μmol) of CATAXCium A precatalyst and 133 ml of aqueous potassium phosphate solution (0.5N) were stirred in 73 ml of THF for 1 h. The reaction mixture was then diluted with 125 ml of water and 125 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted with 125 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. Purification by column chromatography of the crude product (100 g silica cartridge, flow rate: 50 ml/min, cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 2.80 g (86% pure, 46% of theory).

(229) LC/MS [Method 1]: R.sub.t=1.20 min; MS (ESIpos): m/z=320 (M+H).sup.+.

Example 6.1C

5-Chloro-4-[5-chloro-2-(difluoromethoxy)phenyl]pyridin-2(1H)-one

(230) ##STR00090##

(231) 2.80 g (8.75 mmol) of 5-chloro-4-[5-chloro-2-(difluoromethoxy)phenyl]-2-methoxypyridine and 28.0 g (175 mmol) of pyridinium hydrobromide were dissolved in 93.5 ml of dimethylformamide, and the mixture was stirred at 100° C. for 6 h. The solvent was removed under reduced pressure and the residue stirred with 253 ml of water. The precipitate was filtered off with suction, washed with water and then dried. Yield: 2.60 g (81% pure, 79% of theory).

(232) LC/MS [Method 1]: R.sub.t=0.85 min; MS (ESIpos): m/z=306 (M+H).sup.+,

(233) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=11.99 (br. s, 1H), 7.81 (s, 1H), 7.61 (dd, 1H), 7.49 (d, 1H), 7.34 (d, 1H), 7.20 (t, 1H), 6.44 (s, 1H).

Example 6.1D

tert-Butyl {5-chloro-4-[5-chloro-2-(difluoromethoxy)phenyl]-2-oxopyridin-1(2H)-ylacetate

(234) ##STR00091##

(235) 2.60 g (81% pure, 6.88 mmol) of 5-chlor-4-[5-chloro-2-(difluormethoxy)phenyl]pyridin-2(1H)-one and 1.2 eq. of tert-butyl bromoacetate in the presence of 1.5 eq. of potassium carbonate were reacted according to General Method 4B at 100° C. Yield: 2.44 g (84% of theory)

(236) LC/MS [Method 8]: R.sub.t=1.41 min; MS (ESIneg): m/z=418 (M−H).sup.−,

(237) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.09 (s, 1H), 7.63 (dd, 1H), 7.51 (d, 1H), 7.35 (d, 1H), 7.23 (t, 1H), 6.50 (s, 1H), 4.62 (s, 2H), 1.44 (s, 9H).

Example 6.1E

{5-Chloro-4-[5-chloro-2-(difluoromethoxy)phenyl]-2-oxopyridin-1(2H)-yl}acetic acid

(238) ##STR00092##

(239) 126 mg (0.30 mmol) of tert-butyl {5-chloro-4-[5-chloro-2-(difluoromethoxy)phenyl]-2-oxopyridin-1(2H)-ylacetate and 0.46 ml (6.0 mmol) of TFA were reacted according to General Method 6A. Yield: 101 mg (92% of theory)

(240) LC/MS [Method 1]: R.sub.t=0.85 min; MS (ESIpos): m/z=364 (M+H).sup.+.

Example 6.1F

Ethyl 6-[({5-chloro-4-[5-chloro-2-(difluoromethoxy)phenyl]-2-oxopyridin-1(2H)-yl}acetyl)amino]imidazo[1,2-a]pyridine-2-carboxylate

(241) ##STR00093##

(242) 101 mg (0.28 mmol) of {5-chloro-4-[5-chloro-2-(difluoromethoxy)phenyl]-2-oxopyridin-1(2H)-yl}acetic acid and 63 mg (0.31 mmol, 1.1 eq.) of ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate were reacted according to General Method 5A. Yield: 99 mg (65% of theory)

(243) LC/MS [Method 1]: R.sub.t=0.93 min; MS (ESIpos): m/z=551 (M+H).sup.+.

Example 7.1A

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

(244) ##STR00094##

(245) 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)

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

(247) .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 7.1B

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

(248) ##STR00095##

(249) Enantiomer separation of 41.9 g of the racemate from Example 7.1A gave 16.7 g of the title compound Example 7.1B (enantiomer 1): Chiral HPLC: R.sub.t=5.28 min; 99% ee, purity 93%.

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

(251) Separating method: Column: OD-H 5 μm 250 mm×20 mm; mobile phase: 95% isohexane, 5% 2-propanol; temperature: 25° C.; flow rate: 25 ml/min; UV detection: 210 nm.

(252) Analysis: Column: OD-H 5 μm 250 mm×4.6 mm; mobile phase: 95% isohexane, 5% 2-propanol; flow rate: 1 ml/min; UV detection: 220 nm.

Example 7.2B

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

(253) ##STR00096##

(254) Enantiomer separation of 41.9 g of the racemate from Example 7.1A gave 17.0 g of the title compound Example 7.2B (enantiomer 2): Chiral HPLC: R.sub.t=7.36 min; 96% ee, purity 96%.

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

(256) Separating method: Column: OD-H 5 μm 250 mm×20 mm; mobile phase: 95% isohexane, 5% 2-propanol; temperature: 25° C.; flow rate: 25 ml/min; UV detection: 210 nm.

(257) Analysis: Column: OD-H 5 μm 250 mm×4.6 mm; mobile phase: 95% isohexane, 5% 2-propanol; flow rate: 1 ml/min; UV detection: 220 nm.

Example 7.1C

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

(258) ##STR00097##

(259) 3.51 g (3.30 mmol) of palladium on carbon (10%) were added to a solution of 17.0 g (82.4 mmol) of (S)-2-[(benzyloxy)methyl]tetrahydro-2H-pyran (96% ee, purity 96%) in 120 ml of ethanol, and the mixture was hydrogenated at room temperature and under standard pressure overnight. Another 1.75 g (1.65 mmol) of palladium on carbon (10%) were then added, and the mixture was hydrogenated 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 chromatographically (silica, dichloromethane/methanol gradient) and the product fractions were freed from the solvent at <25° C. and >50 mbar. Yield: 8.23 g (86% of theory)

(260) 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.

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

(262) .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 7.1D

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

(263) ##STR00098##

(264) 330 mg (2.84 mmol) of (2S)-tetrahydro-2H-pyran-2-ylmethanol and 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 were reacted according to General Method 7A. The crude product was reacted in the next step without further purification.

(265) .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 7.1E

tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoate (mixture of enantiomerically pure diastereomers)

(266) ##STR00099##

(267) 4.10 g (10.9 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 4.07 g (16.4 mmol) of (2S)-tetrahydro-2H-pyran-2-ylmethyl trifluoromethanesulphonate and 12.0 ml (12.0 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 90 ml of THF were reacted according to General Method 8A. After aqueous work-up, the crude product was purified by flash chromatography (340 g silica cartridge, flow rate: 100 ml/min, cyclohexane/ethyl acetate gradient). Yield: 4.2 g (81% of theory)

(268) LC/MS [Method 1]: R.sub.t=1.15 min; MS (ESIpos): m/z=473 (M+H).sup.+.

Example 7.1F

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoic acid (mixture of enantiomerically pure diastereomers)

(269) ##STR00100##

(270) 9.8 g (20.7 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoate (mixture of enantiomerically pure diastereomers) in 245 ml of dichloromethane and 59.9 ml (777 mmol) of TFA were reacted according to General Method 6A. Yield: 8.7 g (73% pure, 74% of theory).

(271) LC/MS [Method 1]: R.sub.t=0.92 min; MS (ESIpos): m/z=417 (M+H).sup.+.

Example 7.1G

Ethyl 6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)imidazo[1,2-a]pyridine-2-carboxylate (mixture of enantiomerically pure diastereomers)

(272) ##STR00101##

(273) 126 mg (0.30 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoic acid (mixture of enantiomerically pure diastereomers) and 68 mg (0.33 mmol, 1.1 eq.) of ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate were reacted according to General Method 5A. After removal of the dimethylformamide under reduced pressure, it was possible to crystallize the title compound from the residue using water. The precipitate was filtered off, washed with water and dried under reduced pressure. Yield: 162 mg (89% of theory) LC/MS [Method 1]: R.sub.t=0.99 min; MS (ESIpos): m/z=604 (M+H).sup.+.

Example 8.1A

2-Methoxyethyl trifluoromethanesulphonate

(274) ##STR00102##

(275) 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 8.1B

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

(276) ##STR00103##

(277) 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 bis(trimethylsilyl)lithiumamide (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 flash chromatography (silica gel 50, cyclohexane/ethyl acetate gradient). Yield: 7.87 g (95% pure, 80% of theory).

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

(279) 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 8.1C

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

(280) ##STR00104##

(281) 7.87 g (95% pure, 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% pure, 84% of theory)

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

(283) .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 9.1A

Ethyl trans-4-hydroxycyclohexanecarboxylate

(284) ##STR00105##

(285) 4.00 g (27.7 mmol) of trans-4-hydroxycyclohexanecarboxylic acid were initially charged in 50.2 ml of ethanol, and 2 ml of concentrated sulphuric acid were added at room temperature. The reaction solution was subsequently stirred at 80° C. for 10 h. The reaction solution was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with 200 ml of ethyl acetate, the organic phase was dried and filtered and the solvent was removed under reduced pressure. Yield: 4.3 g (90% of theory)

(286) GC/MS [Method 9]: R.sub.t=4.17 min; MS: m/z=172 (M).sup.+,

(287) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=4.56 (d, 1H), 4.03 (q, 2H), 3.39-3.29 (m, 1H), 2.22-2.13 (m, 1H), 1.88-1.78 (m, 4H), 1.40-1.27 (m, 2H), 1.21-1.09 (m, 2H), 1.16 (t, 3H).

Example 9.1B

Ethyl trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate

(288) ##STR00106##

(289) 4.3 g (25 mmol) of ethyl trans-4-hydroxycyclohexanecarboxylate were initially charged in 20 ml of dimethylformamide. 4.5 g (30 mmol) of tert-butyldimethylsilyl chloride and 4.2 g (62 mmol) of imidazole were then added, and the mixture was stirred at 35° C. for another 12 h. 200 ml of ethyl acetate were added and the reaction solution was extracted three times with 100 ml of water. The organic phase was dried and filtered and the solvent was removed under reduced pressure. Yield: 7.8 g (quantitative)

(290) GC/MS [Method 9]: R.sub.t=5.04 min; MS: m/z=286 (M).sup.+,

(291) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=4.00 (q, 2H), 3.59-3.50 (m, 1H), 2.24-2.14 (m, 1H), 1.86-1.71 (m, 4H), 1.41-1.29 (m, 2H), 1.27-1.16 (m, 2H), 1.13 (t, 3H), 0.82 (s, 9H), 0.00 (s, 6H).

Example 9.1C

(trans-4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)methanol

(292) ##STR00107##

(293) 12.5 ml (29.9 mmol) of lithium aluminium hydride (2.4M in THF) were initially charged in 90 ml of methyl tert-butyl ether, and a solution of 7.8 g (27.2 mmol) of ethyl trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate in 90 ml of methyl tert-butyl ether was added at room temperature. The mixture was then stirred at 40° C. for 4 h. The reaction was terminated by addition of 7 ml of water and 7 ml of 15% strength aqueous potassium hydroxide solution. The organic phase was decanted, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. Yield: 6.3 g (95% of theory)

(294) GC/MS [Method 9]: R.sub.t=4.74 min; MS: m/z=244 (M).sup.+,

(295) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=4.35 (t, 1H), 3.52-3.44 (m, 1H), 3.15 (t, 2H), 1.80-1.72 (m, 2H), 1.71-1.62 (m, 2H), 1.29-1.09 (m, 3H), 0.92-0.80 (m, 2H), 0.82 (s, 9H), 0.00 (s, 6H).

Example 9.1D

(trans-4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)methyl trifluoromethanesulphonate

(296) ##STR00108##

(297) 6.30 g (25.8 mmol) of (trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)methanol were initially charged in 90 ml of dichloromethane and, at 0° C., reacted with 4.50 ml (38.7 mmol) of lutidine and 6.54 ml (38.7 mmol) of trifluoromethanesulphonic anhydride, where the internal temperature should not exceed 5° C. The mixture was stirred for 1 h. The reaction solution was then diluted with 630 ml of methyl tert-butyl ether and successively washed three times with a mixture of aqueous hydrochloric acid (1N)/saturated aqueous sodium chloride solution (1:3) and saturated aqueous sodium bicarbonate solution. The organic phase was dried and filtered and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification. Yield: 9.7 g (quantitative)

Example 9.1E

tert-Butyl 3-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoate (racemate)

(298) ##STR00109##

(299) 4.90 g (12.3 mmol) of tert.-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate were initially charged in 98 ml of THF, and 13.6 ml (13.6 mmol) of bis(trimethylsilyl)lithiumamide (1M in THF) were added at −78° C. The mixture was stirred at −78° C. for 15 min, and 6.97 g (18.5 mmol) of (trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)methyl trifluoromethanesulphonate were then added. The mixture was stirred at −78° C. for 15 min and at room temperature for 2 h. The reaction was terminated by addition of saturated aqueous ammonium chloride solution, and the phases were separated. The aqueous phase was extracted three times with 174 ml of methyl tert-butyl ether. The combined organic phases were dried and filtered, and the solvent was removed under reduced pressure. Purification by column chromatography of the crude product (100 g silica cartridge, flow rate: 50 ml/min, cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 3.10 g (42% of theory)

(300) LC/MS [Method 1]: R.sub.t=1.59 min; MS (ESIpos): m/z=601 (M+H).sup.+.

Example 9.1F

3-(trans-4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoic acid (racemate)

(301) ##STR00110##

(302) 3.10 g (5.16 mmol) of tert-butyl 3-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoate (racemate) were initially charged in 32.4 ml of THF, 16.2 ml of ethanol and 16.2 ml of water, and 1.08 g (25.8 mmol) of lithium hydroxide monohydrate were added. The mixture was stirred at room temperature for 6 h and then acidified with aqueous hydrochloric acid (1N) (pH=4-5). The mixture was extracted three times with 129 ml of ethyl acetate. The combined organic phases were dried and filtered, and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification. Yield: 2.8 g (75% pure, quantitative)

(303) LC/MS [Method 1]: R.sub.t=1.37 min; MS (ESIpos): m/z=545 (M+H).sup.+.

Example 9.1G

3-(trans-4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(imidazo[1,2-a]pyridin-6-yl)propanamide (racemate)

(304) ##STR00111##

(305) 100 mg (183 μmol, 75% pure) of 3-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoic acid (racemate), 24.4 mg (183 μmol) of imidazo[1,2-a]pyridine-6-amine and 26.1 mg (183 mmol) of ethyl cyano(hydroxyimino)ethanoate were initially charged in 1.84 ml of dimethylformamide, and the solution was degassed for 10 min 29.0 μl (183 μmol) of N,N′-diisopropylcarbodiimide were then added dropwise, and the resulting reaction solution was shaken at 40° C. overnight. The solvent was removed under reduced pressure and the residue was taken up in a little dichloromethane, giving, after purification by column chromatography (24 g silica cartridge, flow rate: 35 ml/min, dichloromethane/methanol gradient), the title compound. Yield: 63.1 mg (purity 57%, 52% of theory)

(306) LC/MS [Method 1]: R.sub.t=1.11 min; MS (ESIpos): m/z=660 (M+H).sup.+.

Example 10.1A

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

(307) ##STR00112##

(308) 5.36 g (purity 91%, 26.03 mmol) of 5-chloro-2-methoxypyridin-4-ylboronic acid and 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 were reacted according to General Method 2A. After work-up, the crude product was then purified by flash chromatography (silica gel 60, cyclohexane/dichloromethane mixtures). Yield: 4.11 g (91% pure, 52% of theory).

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

Example 10.1B

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

(310) ##STR00113##

(311) 6.34 g (purity 93%, 21.12 mmol) of 4-chloro-2-(5-chloro-2-methoxypyridin-4-yl)benzonitrile and pyridinium hydrochloride were reacted according to General Method 3A. Yield: 4.23 g (76% of theory)

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

Example 10.1C

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

(313) ##STR00114##

(314) 3.1 g (11.46 mmol) of 4-chloro-2-(5-chloro-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.2 eq. of tert-butyl bromoacetate were reacted according to General Method 4B at 100° C. Yield: 3.65 g (84% of theory)

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

(316) .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 10.1D

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

(317) ##STR00115##

(318) 2.0 g (5.27 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate in the presence of 7.12 ml (7.12 mmol, 1.35 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 1.33 g (95% pure, 6.06 mmol, 1.15 eq.) of 2-methoxyethyl trifluoromethanesulphonate were reacted according to General Method 8A. Yield: 2.10 g (94% pure, 86% of theory).

(319) LC/MS [Method 1]: R.sub.t=1.14 min; MS (ESIpos): m/z=437 (M+H).sup.+,

(320) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.16-8.10 (m, 1H), 8.09-8.02 (m, 1H), 7.73-7.84 (m, 2H), 6.64 (s, 1H), 5.25-5.07 (m, 1H), 3.44-3.36 (m, 1H), 3.22-3.12 (m, 4H), 2.41-2.27 (m, 2H).

Example 10.1E

2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoate (racemate)

(321) ##STR00116##

(322) 2.1 g (94% pure, 4.51 mmol) of tert-butyl 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoate (racemate) were reacted according to General Method 6A. Yield: 1.89 g (quant.)

(323) LC/MS [Method 1]: R.sub.t=0.85 min; MS (ESIpos): m/z=381 (M+H).sup.+,

(324) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.19 (br. s, 1H), 8.15 (s, 1H), 8.05 (d, 1H), 7.82 (d, 1H), 7.81-7.76 (m, 1H), 6.63 (s, 1H), 5.31-5.13 (m, 1H), 3.46-3.35 (m, 1H), 3.22-3.08 (m, 4H), 2.43-2.27 (m, 2H).

Example 11.1A

Pyridin-2-ylmethyl methanesulphonate

(325) ##STR00117##

(326) Under argon and at 0° C., a solution of 2.84 ml (36.65 mmol, 1 eq.) of methanesulphonyl chloride in 24 ml of tetrahydrofuran was added 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, 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 normal phase chromatography (mobile phase: cyclohexane/ethyl acetate (20-50%) mixtures). Yield: 4.72 g (68% of theory)

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

(328) .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 11.1B

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

(329) ##STR00118##

(330) Under argon and at −78° C., 4.60 ml (1.0M in THF, 1.15 eq.) of bis(trimethylsilyl)lithium amide were added dropwise 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, 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.

(331) 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 normal phase chromatography (mobile phase: dichloromethane/methanol (2-5%) mixtures). Yield 1.99 g (93% pure, 99% of theory)

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

Example 11.1C

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

(333) ##STR00119##

(334) 1.99 g (purity 93%, 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 and 20 ml (259.6 mmol) of TFA were reacted according to General Method 6A. Yield: 220 mg (purity 93%, 13% of theory)

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

(336) .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 12.1A

5-(Bromomethyl)-1,3-oxazole

(337) ##STR00120##

(338) Under argon and at 0° C., 1.02 ml (13.12 mmol, 1.3 eq.) of methanesulphonyl chloride were added dropwise 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, 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 normal phase chromatography (mobile phase: dichloromethane). Yield 1.23 g (80% pure, 60% of theory)

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

Example 12.1B

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

(340) ##STR00121##

(341) 1.5 g (4.00 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate and 1.78 g (51% pure, 5.60 mmol, 1.4 eq.) of 5-(bromomethyl)-1,3-oxazole were reacted according to General Method 8B. Yield: 1.89 g (60% pure, 62% of theory).

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

Example 12.1C

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

(343) ##STR00122##

(344) 1.89 g (purity 60%, 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 and 14 ml (435 mmol) of TFA were reacted according to General Method 6A. Yield: 597 mg (purity 80%, 48% of theory)

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

(346) .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 13.1A

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

(347) ##STR00123##

(348) 610 mg (1.61 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate and 1.57 g (23% pure, 2.25 mmol, 1.4 eq.) of 5-(bromomethyl)-1,3-oxazole were reacted according to General Method 8B. Yield: 468 mg (purity 83%, 52% of theory)

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

Example 13.1B

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

(350) ##STR00124##

(351) 468 mg (purity 83%, 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 and 4.5 ml (58.4 mmol) of TFA were reacted according to General Method 6A. Yield: 290 mg (purity 85%, 72% of theory)

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

(353) .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 14.1A

6-Methoxypyridin-3-ol

(354) ##STR00125##

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

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

(357) .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 14.1B

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

(358) ##STR00126##

(359) 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)

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

Example 14.1C

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

(361) ##STR00127##

(362) At −78° C., 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 were added 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, 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 warm 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% pure, 82% of theory).

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

Example 14.1D

4-Iodo-6-methoxypyridin-3-ol

(364) ##STR00128##

(365) 50 ml (3 molar, 150 mmol) of hydrochloric acid were added to a solution of 25.1 g (purity 82%, 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, 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% pure, 81% of theory).

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

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

Example 14.1E

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

(368) ##STR00129##

(369) 4.8 ml of aqueous potassium hydroxide solution (6M) were added to a solution of 600 mg (93% pure, 2.22 mmol) of 4-iodo-6-methoxypyridin-3-ol in 4.8 ml of acetonitrile, the mixture was cooled in an ice bath and 863 μl (75% pure, 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 in each case 40 ml 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 (purity 90%, 55% of theory)

(370) .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 14.1F

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

(371) ##STR00130##

(372) 460 mg (purity 90%, 1.38 mmol) of 5-(difluoromethoxy)-4-iodo-2-methoxypyridine and 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 were reacted according to General Method 2A. The crude product was purified by flash chromatography (silica gel, petroleum ether/ethyl acetate (10-15%) mixtures). Yield: 230 mg (purity 80%, 43% of theory)

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

(374) .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 14.1G

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

(375) ##STR00131##

(376) 230 mg (purity 80%, 0.59 mmol) of 4-chloro-2-[5-(difluoromethoxy)-2-methoxypyridin-4-yl]benzonitrile and pyridinium hydrobromide were reacted according to General Method 3A. The crude product was purified by flash chromatography (silica gel, dichloromethane/methanol (3-25%) mixtures). Yield: 167 mg (95% of theory)

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

(378) .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 14.1H

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

(379) ##STR00132##

(380) 1.19 g (purity 92%, 3.69 mmol) of 4-chloro-2-[5-(difluoromethoxy)-2-oxo-1,2-dihydropyridin-4-yl]benzonitrile and 1.2 eq. of tert-butyl bromoacetate were reacted according to General Method 4B at 100° C. Yield: 1.30 g (95% pure, 81% of theory).

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

(382) .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 14.1I

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

(383) ##STR00133##

(384) 600 mg (1.39 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]acetate and 421 mg (80% pure, 2.08 mmol, 1.5 eq.) of 5-(bromomethyl)-1,3-oxazole were reacted according to General Method 8B. Yield: 320 mg (47% of theory)

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

(386) .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 14.1J

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

(387) ##STR00134##

(388) 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 and 5 ml (64.9 mmol) of TFA were reacted according to General Method 6A. Yield: 290 mg (quant.)

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

(390) .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 15.1A

4-(Bromomethyl)-1,3-oxazole

(391) ##STR00135##

(392) Under argon and at 0° C., 1.06 ml (13.72 mmol, 1.3 eq.) of methanesulphonyl chloride were added dropwise 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, 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 work-up. Yield 1.97 g (50% pure, 58% of theory)

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

Example 15.1B

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

(394) ##STR00136##

(395) 813 mg (2.17 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate and 983.8 mg (50% pure, 3.04 mmol, 1.4 eq.) of 4-(bromomethyl)-1,3-oxazole were reacted according to General Method 8B. Yield: 655 mg (65% of theory)

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

(397) .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 15.1C

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

(398) ##STR00137##

(399) 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 and 7 ml (90.86 mmol) of TFA were reacted according to General Method 6A. Yield: 403 mg (70% of theory)

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

(401) .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 16.1A

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

(402) ##STR00138##

(403) 600 mg (1.58 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate and 717.6 mg (50% pure, 2.22 mmol, 1.4 eq.) of 4-(bromomethyl)-1,3-oxazole were reacted according to General Method 8B. Yield: 530 mg (73% of theory)

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

(405) .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 16.1B

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

(406) ##STR00139##

(407) 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 and 6 ml (77.9 mmol) of TFA were reacted according to General Method 6A. Yield: 359 mg (77% of theory)

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

(409) .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, 1H).

Example 17.1A

Dibenzyl 1,3-acetonedicarboxylate

(410) ##STR00140##

(411) 14.1 g (81.0 mmol) of dimethyl 1,3-acetonedicarboxylate and 16.8 ml (162 mmol) of benzyl alcohol were combined at room temperature. The mixture was stirred at 170-180 C, and methanol formed was distilled off. The mixture was then first cooled to room temperature, and excess methanol and benzyl alcohol were then distilled off at 1 mbar and at most 150° C. The residue was separated by flash chromatography (500 g silica cartridge, cyclohexane/ethyl acetate gradient), giving the title compound. Yield 9.0 g (74% pure, 25% of theory)

(412) LC/MS [Method 3]: R.sub.t=2.38 min; MS (ESIneg): m/z=325 (M−H).sup.−.

Example 17.1B

Benzyl 1-(1-tert-butoxy-1-oxobutan-2-yl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (racemate)

(413) ##STR00141##

(414) 1.00 g (74% pure, 2.27 mmol) of dibenzyl 1,3-acetonedicarboxylate and 515 mg (3.17 mmol) of diethoxymethyl acetate were heated under reflux at 100° C. for 2.5 h. The mixture was cooled to room temperature and the reaction mixture was codistilled three times with toluene. The residue was dissolved in 8 ml of ethanol and a solution of 387 mg (2.38 mmol) of tert-butyl 2-aminobutanoate in 2 ml of ethanol was added at 0° C. The mixture was stirred at room temperature for 1 h, and 0.53 ml (2.3 mmol) of sodium ethoxide (21% in ethanol) was then added dropwise. After 30 min at room temperature, a further 0.26 ml (1.2 mmol) of sodium ethoxide (21% in ethanol) was added and the mixture was stirred for another 30 min. The reaction was terminated by addition of 50 ml of saturated aqueous ammonium chloride solution and 25 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was separated by flash chromatography (100 g silica cartridge, cyclohexane/ethyl acetate gradient), giving the title compound. Yield 0.46 g (75% pure, 39% of theory)

(415) LC/MS [Method 1]: R.sub.t=1.13 min; MS (ESIpos): m/z=388 (M+H).sup.+.

Example 17.1C

2-{5-[(Benzyloxy)carbonyl]-4-hydroxy-2-oxopyridin-1(2H)-yl}butanoic acid (racemate)

(416) ##STR00142##

(417) At 0° C. (ice bath cooling), 0.92 ml (12 mmol) of trifluoroacetic acid was added to a solution of 460 mg (1.19 mmol) of benzyl 1-(1-tert-butoxy-1-oxobutan-2-yl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (racemate) in 1.2 ml of dichloromethane. The mixture was warmed to room temperature and then stirred for another 3 h. The solvent was removed under reduced pressure and the residue was then codistilled three times with 10 ml of toluene. The crude product was purified by preparative HPLC (column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.05%-formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90% acetonitrile)], giving the title compound. Yield: 193 mg (49% of theory)

(418) LC/MS [Method 1]: R.sub.t=0.85 min; MS (ESIpos): m/z=332 (M+H).sup.+,

(419) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.0 (br. s, 1H), 10.9 (s, 1H), 8.38 (s, 1H), 7.48-7.32 (m, 5H), 5.70 (s, 1H), 5.37-5.28 (m, 2H), 5.07 (dd, 1H), 2.16-1.93 (m, 2H), 0.78 (t, 3H).

Example 17.1D

Benzyl 4-hydroxy-6-oxo-1-[1-oxo-1-(pyrazol[1,5-a]pyridin-5-ylamino)butan-2-yl]-1,6-dihydropyridine-3-carboxylate (racemate)

(420) ##STR00143##

(421) 193 mg (583 μmol.) of 2-{5-[(benzyloxy)carbonyl]-4-hydroxy-2-oxopyridin-1(2H)-yl}butanoic acid (racemate) and 116 mg (874 μmol, 1.5 eq.) of pyrazol[1,5-a]pyridine-5-amine were reacted according to General Method 5D. Yield: 233 mg (purity 94%, 84% of theory)

(422) LC/MS [Method 1]: R.sub.t=0.95 min; MS (ESIpos): m/z=447 (M+H).sup.+.

Example 17.1E

Benzyl 6-oxo-1-[1-oxo-1-(pyrazol[1,5-a]pyridin-5-ylamino)butan-2-yl]-4-{[(trifluoromethyl)sulphonyl]-oxy}-1,6-dihydropyridine-3-carboxylate (racemate)

(423) ##STR00144##

(424) 233 mg (94% pure, 491 μmol) of benzyl 4-hydroxy-6-oxo-1-[1-oxo-1-(pyrazol[1,5-a]pyridin-5-ylamino)butan-2-yl]-1,6-dihydropyridine-3-carboxylate (racemate) were dissolved in 5 ml of dichloromethane, and the reaction solution was cooled to −78° C. At −78° C., 171 μl (1.23 mmol) of triethylamine and 303 mg (736 μmol) of 1-{bis[(trifluoromethyl)sulphonyl]methyl}-4-tert-butylbenzene were added, and the mixture was stirred at room temperature overnight. 3 ml of dimethylformamide were then added dropwise, and the mixture was stirred at room temperature for another 1 h. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (cyclohexane/ethyl acetate gradient), giving the title compound. Yield: 185 mg (65% of theory)

(425) LC/MS [Method 1]: R.sub.t=1.15 min; MS (ESIpos): m/z=579 (M+H).sup.+.

Example 17.1F

Benzyl 4-(5-chloro-2-cyanophenyl)-6-oxo-1-[1-oxo-1-(pyrazol[1,5-a]pyridin-5-ylamino)butan-2-yl]-1,6-dihydropyridine-3-carboxylate (racemate)

(426) ##STR00145##

(427) 133 mg (959 μmol) of potassium carbonate were dried in the reaction vessel, and 185 mg (320 μmol) of benzyl 6-oxo-1-[1-oxo-1-(pyrazol[1,5-a]pyridin-5-ylamino)butan-2-yl]-4-{[(trifluoromethyl)sulphonyl]-oxy}-1,6-dihydropyridine-3-carboxylate (racemate), 67 mg (0.37 mmol) of 5-chloro-2-cyanophenylboronic acid and 4 ml of dioxane were then added. The suspension was degassed, 37 mg (32 μmol) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was shaken at 110° C. for 1 h. The reaction was terminated by addition of water and ethyl acetate. The mixture was acidified to pH=6 using 1N hydrochloric acid, and the phases were separated. The aqueous phase was extracted three times with ethyl acetate, 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 flash chromatography (cyclohexane/ethyl acetate gradient), giving the title compound. Yield: 147 mg (80% of theory)

(428) LC/MS [Method 1]: R.sub.t=1.11 min; MS (ESIpos): m/z=566 (M+H).sup.+.

WORKING EXAMPLES

General Method 1: Amide Coupling Using HATU/DIEA

(429) Under argon and at RT, the appropriate amine (1.1 eq.), N,N-diisopropylethylamine (DIEA) (2.2 eq.) and a solution of HATU (1.2 eq.) in a little dimethylformamide were added to a solution of the appropriate carboxylic acid (1.0 eq.) in dimethylformamide (about 7-15 ml/mmol). 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 normal phase chromatography (mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or by preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

General Method 2: Hydrolysis of a Methyl or Ethyl Ester with Lithium Hydroxide

(430) At RT, lithium hydroxide (2-4 eq.) was added to a solution of the appropriate ester (1.0 eq.) in a mixture of tetrahydrofuran/water (3:1, about 7-15 ml/mmol), and the mixture was stirred at RT. The reaction mixture was then adjusted to pH 1 using aqueous hydrochloric acid solution (1N). After addition of water/ethyl acetate, 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 normal phase chromatography (mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or by preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

General Method 3: Hydrolysis of a Tert-Butyl Ester or a Boc-Protected Amine Using TFA

(431) At RT, TFA (20 eq.) was added to a solution of the appropriate tert-butyl ester derivative or a Boc-protected amine (1.0 eq.) in dichloromethane (about 25 ml/mmol), and the mixture was stirred at RT for 1-8 h. Subsequently, the reaction mixture was concentrated under reduced pressure. The residue was co-evaporated repeatedly with dichloromethane and/or toluene. The crude product was then purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient or water/methanol gradient).

General Method 4: Amide Coupling with OXIMA/DIC

(432) N,N′-Diisopropylcarbodiimide (DIC) (1 eq.) was added dropwise to a degassed solution of the appropriate carboxylic acid (1 eq.), aniline (0.1 eq.) and ethyl hydroxyiminocyanoacetate (Oxima) (0.1-1 eq.) in dimethylformamide (0.1M), and the resulting reaction solution was stirred at RT to 40° C. for 8-24 h. The solvent was removed under reduced pressure. The residue was either admixed with water and the desired product was filtered off or purified by normal phase chromatography (cyclohexane/ethyl acetate gradient) or preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

General Method 5: Amide Coupling Using T3P/DIEA

(433) Under argon and at 0° C., N,N-diisopropylethylamine (3 eq.) and propylphosphonic anhydride (T3P, 50% in dimethylformamide, 3 eq.) were added dropwise to a solution of the carboxylic acid and the appropriate amine (1.1-1.5 eq.) in dimethylformamide (0.15-0.05 mmol). The reaction mixture was stirred at RT and then concentrated under reduced pressure. After addition of water/ethyl acetate and phase separation, the aqueous phase was extracted twice 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 flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or by preparative HPLC (Reprosil C18, water/acetonitrile gradient or water/methanol gradient).

General Method 6: Amide Coupling Using T3P/Pyridine

(434) A solution of the appropriate carboxylic acid (1 eq.) and the appropriate amine (1.1-1.5 eq.) in pyridine (about 0.1M) was heated to 60° C., and T3P (50% in ethyl acetate, 15 eq.) was added dropwise. Alternatively, T3P was added at RT and the mixture was then stirred at RT or heated to 60 to 90° C. After 1-20 h, the reaction mixture was cooled to RT, and water and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous buffer solution (pH=5), with saturated aqueous sodium bicarbonate 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 normal phase chromatography (mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or by preparative RP-HPLC (water/acetonitrile gradient or water/methanol gradient).

Example 1

2-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)imidazo[1,2-a]pyridine-6-carboxylic acid (racemate)

(435) ##STR00146##

(436) 59 mg (0.11 mmol) of methyl 2-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)imidazo[1,2-a]pyridine-6-carboxylate (racemate) were hydrolysed with lithium hydroxide according to General Method 2. After acidification with aqueous hydrochloric acid (1N), the desired product could be isolated as precipitate. Yield: 45 mg (75% of theory)

(437) LC/MS [Method 1]: R.sub.t=0.88 min; MS (ESIpos): m/z=506 (M+H).sup.+,

(438) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.19 (s, 1H), 11.34 (s, 1H), 9.25 (s, 1H), 8.29 (s, 1H), 8.00 (d, 1H), 7.79-7.70 (m, 2H), 7.63 (dd, 1H), 7.54-7.46 (m, 2H), 6.53 (s, 1H), 5.75 (dd, 1H), 3.70 (s, 3H), 2.28-2.10 (m, 2H), 0.89 (t, 3H).

Example 2

6-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)imidazo[1,2-a]pyridine-2-carboxylic acid (racemate)

(439) ##STR00147##

(440) 86 mg (0.16 mmol) of ethyl 6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)imidazo[1,2-a]pyridine-2-carboxylate (racemate) were hydrolysed with lithium hydroxide according to General Method 2. After aqueous work-up, the crude product was purified by preparative RP-HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 16 mg (19% of theory)

(441) LC/MS [Method 1]: R.sub.t=0.74 min; MS (ESIpos): m/z=506 (M+H).sup.+,

(442) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.75 (s, 1H), 9.32 (s, 1H), 8.54 (s, 1H), 8.01 (d, 1H), 7.78-7.70 (m, 2H), 7.62 (d, 1H), 7.52 (s, 1H), 7.32 (dd, 1H), 6.55 (s, 1H), 5.66 (dd, 1H), 3.70 (s, 3H), 2.28-2.10 (m, 2H), 0.92 (s, 3H).

Example 3

7-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)imidazo[1,2-a]pyridine-2-carboxylic acid (racemate)

(443) ##STR00148##

(444) 18 mg (0.03 mmol) of ethyl 7-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)imidazo[1,2-a]pyridine-2-carboxylate (racemate) were hydrolysed with lithium hydroxide according to General Method 2. After aqueous work-up, the crude product was purified by preparative RP-HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 8 mg (45% of theory)

(445) LC/MS [Method 8]: R.sub.t=0.95 min; MS (ESIpos): m/z=506 (M+H).sup.+,

(446) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.82 (s, 1H), 8.48 (d, 1H), 8.32 (s, 1H), 8.04-7.97 (m, 2H), 7.78-7.70 (m, 2H), 7.51 (s, 1H), 7.11 (dd, 1H), 6.55 (s, 1H), 5.62 (dd, 1H), 3.70 (s, 3H), 2.31-2.13 (m, 2H), 0.92 (s, 3H).

Example 4

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(imidazo[1,2-a]pyridin-6-yl)butanamide (racemate)

(447) ##STR00149##

(448) 87 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 44 mg (0.30 mmol, 1.2 eq.) of imidazo[1,2-a]pyridine-6-amine were reacted according to General Method 1. After aqueous work-up, the crude product was purified by preparative RP-HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 8 mg (7% of theory)

(449) LC/MS [Method 8]: R.sub.t=0.93 min; MS (ESIpos): m/z=462 (M+H).sup.+,

(450) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.64 (s, 1H), 9.25 (s, 1H), 8.03-7.97 (m, 2H), 7.77-7.71 (m, 2H), 7.57 (d, 1H), 7.54 (d, 2H), 7.23 (dd, 1H), 6.55 (s, 1H), 5.66 (dd, 1H), 3.70 (s, 3H), 2.28-2.19 (m, 2H), 0.92 (t, 3H).

Example 5

6-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoyl}-amino)imidazo[1,2-a]pyridine-2-carboxylic acid (racemate)

(451) ##STR00150##

(452) 69 mg (0.12 mmol) of ethyl 2-({6-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoyl}amino)imidazo[1,2-a]pyridine-2-carboxylate (racemate) were hydrolysed with lithium hydroxide according to General Method 2. After aqueous work-up, the crude product was purified by preparative RP-HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 38 mg (58% of theory)

(453) LC/MS [Method 1]: R.sub.t=0.88 min; MS (ESIpos): m/z=546 (M+H).sup.+,

(454) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.74 (s, 1H), 9.32 (s, 1H), 8.54 (s, 1H), 8.00 (d, 1H), 7.78-7.70 (m, 2H), 7.62 (d, 1H), 7.53 (s, 1H), 7.34 (dd, 1H), 6.53 (s, 1H), 5.75-5.66 (m, 1H), 3.69 (s, 3H), 2.35-2.18 (m, 3H), 2.02-1.90 (m, 2H), 1.86-1.61 (m, 4H).

Example 6

6-({[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetyl}amino)imidazo[1,2-a]pyridine-2-carboxylic acid

(455) ##STR00151##

(456) 99 mg (0.20 mmol) of ethyl 6-({[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetyl}amino)imidazo[1,2-a]pyridine-2-carboxylate were hydrolysed with lithium hydroxide according to General Method 2. After acidification with aqueous hydrochloric acid (1N), the desired product could be isolated as precipitate and purified further by stirring with acetonitrile/water (2:1). Yield: 42 mg (45% of theory)

(457) LC/MS [Method 1]: R.sub.t=0.69 min; MS (ESIpos): m/z=478 (M+H).sup.+,

(458) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.87 (s, 1H), 9.42 (s, 1H), 8.70 (s, 1H), 8.00 (d, 1H), 7.79-7.68 (m, 3H), 7.62 (s, 1H), 7.56 (d, 1H), 6.52 (s, 1H), 4.86 (s, 2H), 3.64 (s, 3H).

Example 7

6-[(2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}butanoyl)amino]-imidazo[1,2-a]pyridine-2-carboxylic acid (racemate)

(459) ##STR00152##

(460) 198 mg (0.28 mmol) of ethyl 6-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}butanoyl)amino]imidazo[1,2-a]pyridine-2-carboxylate (racemate) were hydrolysed with lithium hydroxide according to General Method 2. After aqueous work-up, the crude product was purified by preparative RP-HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 85 mg (56% of theory)

(461) LC/MS [Method 1]: R.sub.t=0.85 min; MS (ESIpos): m/z=547 (M+H).sup.+,

(462) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.74 (s, 1H), 9.32 (s, 1H), 8.55 (s, 1H), 7.63 (d, 1H), 7.58 (dd, 1H), 7.50 (dd, 1H), 7.41 (s, 1H), 7.37-7.26 (m, 2H), 7.14 (t, 1H), 6.41 (s, 1H), 5.64 (dd, 1H), 3.64 (s, 3H), 2.27-2.05 (m, 2H), 0.91 (t, 3H).

Example 8

6-[({5-Chloro-4-[5-chloro-2-(difluoromethoxy)phenyl]-2-oxopyridin-1(2H)-yl}acetyl)amino]imidazo[1,2-a]pyridine-2-carboxylic acid

(463) ##STR00153##

(464) 99 mg (0.18 mmol) of ethyl 6-[({5-chloro-4-[5-chloro-2-(difluoromethoxy)phenyl]-2-oxopyridin-1(2H)-yl}acetyl)amino]imidazo[1,2-a]pyridine-2-carboxylate were hydrolysed with lithium hydroxide according to General Method 2. After aqueous work-up, the crude product was purified by preparative RP-HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 26 mg (28% of theory)

(465) LC/MS [Method 1]: R.sub.t=0.77 min; MS (ESIpos): m/z=523 (M+H).sup.+,

(466) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.73 (s, 1H), 9.31 (s, 1H), 8.60 (s, 1H), 8.13 (s, 1H), 7.68 (d, 1H), 7.64 (dd, 1H), 7.52 (d, 1H), 7.42-7.34 (m, 2H), 7.26 (t, 1H), 6.52 (s, 1H), 4.85 (s, 2H).

Example 9

6-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)imidazo[1,2-a]pyridine-2-carboxylic acid (mixture of enantiomerically pure diastereomers)

(467) ##STR00154##

(468) 162 mg (0.27 mmol) of ethyl 6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)imidazo[1,2-a]pyridine-2-carboxylate (mixture of enantiomerically pure diastereomers) were hydrolysed with lithium hydroxide according to General Method 2. After aqueous work-up, the crude product was purified by preparative RP-HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 61 mg (40% of theory)

(469) LC/MS [Method 1]: R.sub.t=0.81 min; MS (ESIpos): m/z=576 (M+H).sup.+,

(470) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.69/10.58 (2×s, 1H), 9.31/9.28 (2×s, 1H), 8.56-8.51 (m, 1H), 8.03-7.97 (m, 1H), 7.77-7.70 (m, 2H), 7.63-7.57 (m, 1H), 7.54/7.50 (2×s, 1H), 7.42-7.33 (m, 1H), 6.53/6.52 (2×s, 1H), 5.85/5.77 (t/dd, 1H), 3.93-3.79 (m, 1H), 3.69 (s, 3H), 3.25-3.15 (m, 1H), 3.14-3.05 (m, 1H), 2.40-2.09 (m, 2H), 1.80-1.71 (m, 1H), 1.68-1.56 (m, 1H), 1.48-1.35 (m, 3H), 1.34-1.20 (m, 1H).

Example 10

Ethyl 6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)imidazo[1,2-a]pyridine-3-carboxylate (racemate)

(471) ##STR00155##

(472) According to General Method 6, 80 mg (0.21 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 65 mg (0.32 mmol, 1.5 eq.) of ethyl 6-aminoimidazo[1,2-a]pyridine-3-carboxylate were initially charged in pyridine at 60° C. and reacted with one another by addition of T3P. The crude product was purified by preparative HPLC (Chromatorex 125 mm×30 mm, 10 μm, mobile phase: water/acetonitrile, gradient 10-90% acetonitrile). Yield: 66 mg (55% of theory)

(473) LC/MS [Method 1]: R.sub.t=0.96 min; MS (ESIpos): m/z=564 (M+H).sup.+,

(474) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.81 (s, 1H), 10.09 (d, 1H), 8.25 (s, 1H), 8.00 (d, 1H), 7.80 (d, 1H), 7.76-7.71 (m, 2H), 7.66 (dd, 1H), 7.54 (s, 1H), 6.54 (s, 1H), 5.78 (dd, 1H), 4.35 (q, 2H), 3.71 (s, 3H), 3.46-3.39 (m, 1H), 3.30-3.25 (m, 1H), 3.22 (s, 3H), 2.49-2.36 (m, 2H), 1.34 (t, 3H).

Example 11

Ethyl 7-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)imidazo[1,2-a]pyridine-2-carboxylate (racemate)

(475) ##STR00156##

(476) According to General Method 6, 75 mg (0.20 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 53 mg (0.26 mmol, 1.3 eq.) of ethyl 7-aminoimidazo[1,2-a]pyridine-2-carboxylate were initially charged in pyridine at 60° C. and reacted with one another by addition of T3P. The crude product was purified by preparative HPLC (Chromatorex 125 mm×30 mm, 10 μm, mobile phase: gradient water/acetonitrile: 10-90% acetonitrile). Yield: 83 mg (74% of theory)

(477) LC/MS [Method 1]: R.sub.t=0.91 min; MS (ESIpos): m/z=564 (M+H).sup.+,

(478) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.69 (s, 1H), 9.32-9.29 (m, 1H), 8.60 (s, 1H), 8.02-7.98 (m, 1H), 7.76-7.72 (m, 2H), 7.64-7.60 (m, 1H), 7.52 (s, 1H), 7.38 (dd, 1H), 6.54 (s, 1H), 5.78 (dd, 1H), 4.30 (q, 2H), 3.69 (s, 3H), 3.45-3.38 (m, 1H), 3.30-3.25 (m, 1H), 3.22 (s, 3H), 2.48-2.36 (m, 2H), 1.31 (t, 3H).

Example 12

7-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)imidazo[1,2-a]pyridine-2-carboxamide (racemate)

(479) ##STR00157##

(480) According to General Method 6, 65 mg (0.17 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 44 mg (90% pure, 0.22 mmol, 1.3 eq.) of 7-aminoimidazo[1,2-a]pyridine-2-carboxamide were initially charged in pyridine at 60° C. and reacted with one another by addition of T3P. The crude product was purified by preparative HPLC (Chromatorex 125 mm×30 mm, 10 μm, mobile phase: gradient water/acetonitrile: 10%-90% acetonitrile) and then by further preparative HPLC (Kinetex 5 μm C18 150 mm×21.2 mm, gradient water/acetonitrile: 5%-50% acetonitrile). Yield: 8 mg (9% of theory)

(481) LC/MS [Method 1]: R.sub.t=0.77 min; MS (ESIpos): m/z=535 (M+H).sup.+,

(482) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.66 (s, 1H), 9.31-9.29 (m, 1H), 8.39 (s, 1H), 8.02-7.98 (m, 1H), 7.76-7.71 (m, 2H), 7.64-7.61 (m, 1H), 7.58 (d, 1H), 7.53 (s, 1H), 7.38-7.32 (m, 2H), 6.54 (s, 1H), 5.79 (dd, 1H), 3.69 (s, 3H), 3.45-3.38 (m, 1H), 3.28-3.24 (m, 1H), 3.22 (s, 3H), 2.48-2.38 (m, 2H).

Example 13

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(imidazo[1,2-a]pyridin-6-yl)-4-methoxybutanamide (racemate)

(483) ##STR00158##

(484) 200 mg (0.53 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 78 mg (0.58 mmol, 1.1 eq.) of imidazo[1,2-a]pyridine-6-amine were reacted according to General Method 1. The crude product was purified by flash chromatography (silica gel 50, dichloromethane/methanol gradient) and subsequent thick-layer chromatography (dichloromethane/methanol 10:1). Yield: 47 mg (purity 90%, 16% of theory)

(485) LC/MS [Method 2]: R.sub.t=1.80 min; MS (ESIpos): m/z=492 (M+H).sup.+,

(486) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.59 (s, 1H), 9.23 (s, 1H), 8.03-7.95 (m, 2H), 7.76-7.67 (m, 2H), 7.58-7.50 (m, 3H), 7.25 (dd, 1H), 6.54 (s, 1H), 5.79 (dd, 1H), 3.69 (s, 3H), 3.45-3.37 (m, 1H), 3.31-3.26 (m, 1H), 3.22 (s, 3H), 2.48-2.35 (m, 2H).

Example 14

2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-(imidazo[1,2-a]pyridin-6-yl)-4-methoxybutanamide (racemate)

(487) ##STR00159##

(488) 50 mg (0.13 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 28 mg (0.19 mmol, 1.5 eq.) of imidazo[1,2-a]pyridine-6-amine were reacted according to General Method 6. The crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 20 mg (32% of theory)

(489) LC/MS [Method 1]: R.sub.t=0.75 min; MS (ESIpos): m/z=496 (M+H).sup.+,

(490) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.66 (s, 1H), 9.23 (s, 1H), 8.23 (s, 1H), 8.09-8.04 (m, 1H), 7.98 (s, 1H), 7.84-7.76 (m, 2H), 7.60-7.50 (m, 2H), 7.24 (dd, 1H), 6.68 (s, 1H), 5.85-5.73 (m, 1H), 3.42 (dt, 1H), 3.29-3.24 (m, 1H), 3.21 (s, 3H), 2.46-2.38 (m, 2H).

Example 15

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutyl-N-(imidazo[1,2-a]pyridin-6-yl)propanamide (racemate)

(491) ##STR00160##

(492) 123 mg (94% pure, 0.30 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoic acid (racemate) and 47 mg (0.33 mmol, 1.1 eq.) of imidazo[1,2-a]pyridine-6-amine were reacted according to General Method 1. After aqueous work-up, the crude product was purified by preparative RP-HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 45 mg (30% of theory)

(493) LC/MS [Method 1]: R.sub.t=0.81 min; MS (ESIpos): m/z=502 (M+H).sup.+,

(494) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.63 (s, 1H), 9.24 (s, 1H), 8.03-7.97 (m, 2H), 7.77-7.70 (m, 2H), 7.59-7.50 (m, 3H), 7.24 (dd, 1H), 6.53 (s, 1H), 5.71 (t, 1H), 3.69 (s, 3H), 2.31-2.19 (m, 3H), 2.02-1.91 (m, 2H), 1.85-1.62 (m, 4H).

Example 16

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(trans-4-hydroxycyclohexyl)-N-(imidazo[1,2-a]pyridin-6-yl)propanamide (racemate)

(495) ##STR00161##

(496) 63 mg (96 μmol) of 3-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(imidazo[1,2-a]pyridin-6-yl)propanamide (racemate) were initially charged in 5 ml of dimethylformamide, and 0.5 ml of aqueous hydrochloric acid (1N) was added. The reaction solution was stirred at room temperature for 1 h and then separated by preparative HPLC (column: Chromatorex C18, 10 μm, 125 mm×30 mm, solvent: acetonitrile/0.1%-formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90% acetonitrile), giving the title compound. Yield: 25.3 mg (48% of theory)

(497) LC/MS [Method 1]: R.sub.t=0.69 min; MS (ESIpos): m/z=546 (M+H).sup.+,

(498) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.6 (s, 1H), 9.24-9.22 (m, 1H), 8.02-7.97 (m, 2H), 7.77-7.71 (m, 2H), 7.58-7.50 (m, 3H), 7.23 (dd, 1H), 6.55 (s, 1H), 5.85 (dd, 1H), 4.44 (d, 1H), 3.68 (s, 3H), 2.19-2.10 (m, 1H), 1.96-1.87 (m, 1H), 1.83-1.71 (m, 4H), 1.12-0.95 (m, 5H).

Example 17

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(3-chloroimidazo[1,2-a]pyridin-6-yl)butanamide (racemate)

(499) ##STR00162##

(500) At RT, 13 mg (0.10 mmol, 1.0 eq.) of N-chlorosuccinimide were added to a solution of 46 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(imidazo[1,2-a]pyridin-6-yl)butanamide (racemate) in 2 ml of ethanol, and the mixture was stirred at RT overnight. After addition of water/ethyl acetate and 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 residue was purified by preparative RP-HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 18 mg (36% of theory)

(501) LC/MS [Method 1]: R.sub.t=0.91 min; MS (ESIpos): m/z=496 (M+H).sup.+,

(502) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.84 (s, 1H), 9.09 (s, 1H), 8.00 (d, 1H), 7.77-7.71 (m, 2H), 7.70-7.65 (m, 2H), 7.52 (s, 1H), 7.36 (dd, 1H), 6.56 (s, 1H), 5.65 (dd, 1H), 3.70 (s, 3H), 2.30-2.12 (m, 2H), 0.93 (t, 3H).

Example 18

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-[2-(4-fluorophenyl)-imidazo[1,2-a]pyridin-6-yl]butanamide (racemate)

(503) ##STR00163##

(504) According to General Method 6, 80 mg (0.23 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 96 mg (82% pure, 0.35 mmol, 1.5 eq.) of 2-(4-fluorophenyl)imidazo[1,2-a]pyridine-6-amine were initially charged in pyridine at 60° C. and reacted with one another by addition of T3P. The crude product was purified by preparative HPLC (Chromatorex 125 mm×30 mm, 10 μm, mobile phase: water/acetonitrile, gradient 10-90% acetonitrile). Yield: 80 mg (62% of theory)

(505) LC/MS [Method 1]: R.sub.t=0.88 min; MS (ESIpos): m/z=556 (M+H).sup.+,

(506) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.68 (s, 1H), 9.23 (d, 1H), 8.43 (s, 1H), 8.00 (d, 1H), 7.98-7.93 (m, 2H), 7.76-7.72 (m, 2H), 7.59 (d, 1H), 7.53 (s, 1H), 7.30-7.23 (m, 3H), 6.56 (s, 1H), 5.67 (dd, 1H), 3.70 (s, 3H), 2.30-2.09 (m, 2H), 0.93 (t, 3H).

Example 19

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-[2-(4-fluorophenyl)-imidazo[1,2-a]pyridin-6-yl]-4-methoxybutanamide (racemate)

(507) ##STR00164##

(508) According to General Method 6, 75 mg (0.20 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 83 mg (82% pure, 0.30 mmol, 1.5 eq.) of 2-(4-fluorophenyl)imidazo[1,2-a]pyridine-6-amine were initially charged in pyridine at 60° C. and reacted with one another by addition of T3P. The crude product was purified by preparative HPLC (Chromatorex 125 mm×30 mm, 10 μm, mobile phase: water/acetonitrile, gradient: 10-90% acetonitrile). Yield: 53 mg (45% of theory)

(509) LC/MS [Method 1]: R.sub.t=0.86 min; MS (ESIpos): m/z=586 (M+H).sup.+,

(510) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.63 (s, 1H), 9.21 (d, 1H), 8.43 (s, 1H), 8.02-7.98 (m, 1H), 7.98-7.93 (m, 2H), 7.76-7.72 (m, 2H), 7.58 (d, 1H), 7.54 (s, 1H), 7.30 (dd, 1H), 7.28-7.23 (m, 2H), 6.55 (s, 1H), 5.80 (dd, 1H), 3.70 (s, 3H), 3.46-3.39 (m, 1H), 3.30-3.26 (m, 1H), 3.23 (s, 3H), 2.48-2.35 (m, 2H).

Example 20

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-([1,2,4]triazolo[4,3-a]pyridin-6-yl)butanamide (racemate)

(511) ##STR00165##

(512) 69 mg (0.19 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 29 mg (0.21 mmol, 1.1 eq.) of [1,2,4]triazolo[4,3-a]pyridine-6-amine were reacted according to General Method 1. After aqueous work-up, the crude product was purified by preparative RP-HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 58 mg (65% of theory)

(513) LC/MS [Method 1]: R.sub.t=0.87 min; MS (ESIpos): m/z=463 (M+H).sup.+,

(514) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.90 (s, 1H), 9.45 (s, 1H), 8.45 (s, 1H), 8.00 (d, 1H), 7.87 (d, 1H), 7.77-7.70 (m, 2H), 7.68 (dd, 1H), 7.52 (s, 1H), 6.56 (s, 1H), 5.64 (dd, 1H), 3.70 (s, 3H), 2.30-2.11 (m, 2H), 0.92 (t, 3H).

Example 21

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxy-N-([1,2,4]triazolo[4,3-a]pyridin-6-yl)butanamide (racemate)

(515) ##STR00166##

(516) 150 mg (0.398 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 59 mg (0.44 mmol, 1.1 eq.) of [1,2,4]triazolo[4,3-a]pyridine-6-amine were reacted according to General Method 1. Yield: 27 mg (14% of theory)

(517) LC/MS [Method 1]: R.sub.t=0.84 min; MS (ESIpos): m/z=493 (M+H).sup.+,

(518) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.8 (s, 1H), 9.44 (d, 1H), 8.45 (s, 1H), 8.02-7.98 (m, 1H), 7.86 (d, 1H), 7.76-7.71 (m, 3H), 7.53 (s, 1H), 6.55 (s, 1H), 5.77 (dd, 1H), 3.70 (s, 3H), 3.43 (dt, 1H), 3.31-3.26 (m, 1H), 3.22 (s, 3H), 2.49-2.36 (m, 2H).

Example 22

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxy-N-(3-methyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)butanamide (racemate)

(519) ##STR00167##

(520) 130 mg (0.35 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 76 mg (74% pure, 0.38 mmol, 1.1 eq.) of 3-methyl[1,2,4]triazolo[4,3-a]pyridine-6-amine were reacted according to General Method 1. The crude product was purified by flash chromatography (silica gel 50, dichloromethane/methanol gradient). Yield: 30 mg (purity 90%, 15% of theory)

(521) LC/MS [Method 2]: R.sub.t=2.29 min; MS (ESIpos): m/z=507 (M+H).sup.+,

(522) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.77 (s, 1H), 8.90 (s, 1H), 8.02-7.98 (m, 1H), 7.77-7.70 (m, 3H), 7.51 (s, 1H), 7.38 (dd, 1H), 6.54 (s, 1H), 5.78 (dd, 1H), 3.70 (s, 3H), 3.46-3.39 (m, 1H), 3.30-3.25 (m, 1H), 3.22 (s, 3H), 2.63 (s, 3H), 2.48-2.39 (m, 2H).

Example 23

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxy-N-(3-ethyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)butanamide (racemate)

(523) ##STR00168##

(524) 50 mg (0.13 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 26 mg (0.16 mmol, 1.2 eq.) of 3-ethyl[1,2,4]triazolo[4,3-a]pyridine-6-amine were initially charged in 1.5 ml of dimethylformamide, and 0.11 ml (81 mg, 6.0 eq.) of triethylamine was added. 237 μl (796 μmol, 3.0 eq.) of T3P (50% in ethyl acetate) were then added dropwise. The reaction mixture was left to stir at RT overnight, water and ethyl acetate were then added and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 50, dichloromethane/methanol gradient). Yield: 64 mg (89% of theory)

(525) LC/MS [Method 1]: R.sub.t=0.79 min; MS (ESIpos): m/z=521 (M+H).sup.+,

(526) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.76 (s, 1H), 8.92 (s, 1H), 8.03-7.97 (m, 1H), 7.78-7.71 (m, 3H), 7.51 (s, 1H), 7.38 (dd, 1H), 6.54 (s, 1H), 5.77 (dd, 1H), 3.70 (s, 3H), 3.46-3.38 (m, 1H), 3.31-3.25 (m, 1H), 3.22 (s, 3H), 3.03 (d, 2H), 2.44 (d, 2H), 1.36 (t, 3H).

Example 24

N-(3-Butyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanamide (racemate)

(527) ##STR00169##

(528) 100 mg (0.27 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 71 mg (85% pure, 0.32 mmol, 1.2 eq.) of 3-butyl[1,2,4]triazolo[4,3-a]pyridine-6-amine were initially charged in 3.0 ml of dimethylformamide, and 0.22 ml (161 mg, 6.0 eq.) of triethylamine was added. 474 μl (796 μmol, 3.0 eq.) of T3P (50% in ethyl acetate) were then added dropwise. The reaction mixture was left to stir at RT overnight, water and ethyl acetate were then added and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with aqueous saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 50, dichloromethane/methanol gradient) and subsequent preparative HPLC (Chromatorex 125 mm×30 mm, 10 μm, mobile phase: water/acetonitrile, gradient 10-90% acetonitrile). Yield: 17 mg (12% of theory)

(529) LC/MS [Method 1]: R.sub.t=1.01 min; MS (ESIpos): m/z=549 (M+H).sup.+,

(530) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.77 (s, 1H), 9.31 (dd, 1H), 8.02-7.98 (m, 1H), 7.76-7.70 (m, 3H), 7.66 (dd, 1H), 7.53 (s, 1H), 6.54 (s, 1H), 5.76 (dd, 1H), 3.69 (s, 3H), 3.45-3.38 (m, 1H), 3.28-3.25 (m, 1H), 3.21 (s, 3H), 2.78 (t, 2H), 2.47-2.37 (m, 2H), 1.77-1.68 (m, 2H), 1.36 (sxt, 2H), 0.91 (t, 3H).

Example 25

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-{3-[(dimethylamino)-methyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}-4-methoxybutanamide (racemate)

(531) ##STR00170##

(532) 75 mg (0.20 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 46 mg (0.24 mmol, 1.2 eq.) of 3-[(dimethylamino)methyl][1,2,4]triazolo[4,3-a]pyridine-6-amine were reacted according to General Method 1. The crude product was purified by preparative HPLC (Chromatorex 125 mm×30 mm, 10 μm, mobile phase: water/acetonitrile, gradient 10-90% acetonitrile). Yield: 96 mg (87% of theory)

(533) LC/MS [Method 1]: R.sub.t=1.01 min; MS (ESIpos): m/z=550 (M+H).sup.+,

(534) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.91 (s, 1H), 10.22 (br. s, 1H), 9.47 (dd, 1H), 8.02-7.98 (m, 1H), 7.93 (dd, 1H), 7.81 (dd, 1H), 7.73 (s, 2H), 7.51 (s, 1H), 6.55 (s, 1H), 5.74 (dd, 1H), 4.60 (s, 2H), 3.70 (s, 3H), 3.47-3.39 (m, 1H), 3.30-3.26 (m, 1H), 3.22 (s, 3H), 2.88 (s, 6H), 2.48-2.38 (m, 2H).

Example 26

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxy-N-[3-(morpholin-4-ylmethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]butanamide (racemate)

(535) ##STR00171##

(536) According to General Method 6, 75 mg (0.20 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 91 mg (77% pure, 0.30 mmol, 1.5 eq.) of 3-(morpholin-4-ylmethyl)[1,2,4]triazolo[4,3-a]pyridine-6-amine were initially charged in pyridine at 60° C. and reacted with one another by addition of T3P. The crude product was purified by flash chromatography (silica gel 50, mobile phase: dichloromethane/methanol mixtures). Yield: 31 mg (purity 92%, 24% of theory)

(537) LC/MS [Method 1]: R.sub.t=0.68 min; MS (ESIpos): m/z=592 (M+H).sup.+,

(538) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.81 (s, 1H), 9.37-9.35 (m, 1H), 8.00 (d, 1H), 7.80-7.68 (m, 4H), 7.53 (s, 1H), 6.54 (s, 1H), 5.76 (dd, 1H), 3.76-3.71 (m, 1H), 3.69 (s, 3H), 3.68-3.62 (m, 1H), 3.59-3.53 (m, 4H), 3.45-3.38 (m, 1H), 3.30-3.24 (m, 1H), 3.21 (s, 3H), 2.48-2.35 (m, 2H).

Example 27

2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-(imidazo[1,5-a]pyridin-6-yl)-4-methoxybutanamide (racemate)

(539) ##STR00172##

(540) 50 mg (90% pure, 0.12 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 33 mg (69% pure, 0.18 mmol, 1.5 eq.) of imidazo[1,5-a]pyridine-6-amine were reacted according to General Method 1. The crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 7.9 mg (13% of theory)

(541) LC/MS [Method 1]: R.sub.t=0.77 min; MS (ESIpos): m/z=496 (M+H).sup.+,

(542) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.57 (s, 1H), 9.07 (s, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 8.07 (d, 1H), 7.86-7.76 (m, 2H), 7.55 (d, 1H), 7.32 (s, 1H), 6.83-6.76 (m, 1H), 6.68 (s, 1H), 5.85-5.71 (m, 1H), 3.42 (dt, 2H), 3.30-3.25 (m, 1H), 3.20 (s, 3H), 2.42 (q, 2H).

Example 28

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(imidazo[1,2-a]pyridin-6-yl)-3-(pyridin-2-yl)propanamide (racemate)

(543) ##STR00173##

(544) 30 mg (93% pure, 0.068 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(pyridin-2-yl)propanoic acid (racemate) and 15.0 mg (90% pure, 0,102 mmol, 1.5 eq.) of imidazo[1,2-a]pyridine-6-amine were reacted according to General Method 6. The crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). The product was then dissolved in acetonitrile and filtered through a solid phase extraction cartridge (StratoSpheres SPE PL-HCO.sub.3 MP-Resin). The filtrate was lyophilised. Yield: 11 mg (31% of theory)

(545) LC/MS [Method 1]: R.sub.t=0.66 min; MS (ESIneg): m/z=523 (M−H).sup.−,

(546) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.68 (s, 1H), 9.23 (s, 1H), 8.49 (d, 1H), 8.05-7.92 (m, 2H), 7.76-7.63 (m, 3H), 7.62-7.47 (m, 3H), 7.34 (d, 1H), 7.28-7.17 (m, 2H), 6.43 (s, 1H), 6.16 (t, 1H), 3.69 (d, 2H), 3.64 (s, 3H).

Example 29

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(imidazo[1,2-a]pyridin-6-yl)-3-(1,3-oxazol-5-yl)propanamide (racemate)

(547) ##STR00174##

(548) 50 mg (80% pure, 0.10 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-5-yl)propanoic acid (racemate) and 26.6 mg (90% pure, 0.18 mmol, 1.8 eq.) of imidazo[1,2-a]pyridine-6-amine were reacted according to General Method 6. The crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 35 mg (68% of theory)

(549) LC/MS [Method 8]: R.sub.t=0.82 min; MS (ESIpos): m/z=515 (M+H).sup.+,

(550) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.66 (s, 1H), 9.32-9.14 (m, 1H), 8.24 (s, 1H), 8.05-7.93 (m, 2H), 7.77-7.65 (m, 2H), 7.64-7.50 (m, 3H), 7.23 (dd, 1H), 6.92 (s, 1H), 6.51 (s, 1H), 5.99 (dd, 1H), 3.82-3.70 (m, 1H), 3.70-3.59 (m, 4H).

Example 30

2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-(imidazo[1,2-a]pyridin-6-yl)-3-(1,3-oxazol-5-yl)propanamide (racemate)

(551) ##STR00175##

(552) 50 mg (85% pure, 0,105 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-5-yl)propanoic acid (racemate) and 26.5 mg (90% pure, 0,179 mmol, 1.7 eq.) of imidazo[1,2-a]pyridine-6-amine were reacted according to General Method 6. The crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 21 mg (purity 83%, 32% of theory)

(553) LC/MS [Method 2]: R.sub.t=1.87 min; MS (ESIpos): m/z=519 (M+H).sup.+,

(554) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.73 (s, 1H), 9.22 (s, 1H), 8.35 (s, 1H), 8.25 (s, 1H), 8.08-8.03 (m, 1H), 8.00 (s, 1H), 7.82-7.75 (m, 2H), 7.59-7.53 (m, 2H), 7.24-7.15 (m, 1H), 6.92 (s, 1H), 6.66 (s, 1H), 5.98 (dd, 1H), 3.78 (dd, 1H), 3.66 (dd, 1H).

Example 31

2-[4-(5-Chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]-N-(imidazo[1,2-a]pyridin-6-yl)-3-(1,3-oxazol-5-yl)propanamide (racemate)

(555) ##STR00176##

(556) 40 mg (0.092 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-5-yl)propanoic acid (racemate) and 20.4 mg (90% pure, 0,138 mmol, 1.5 eq.) of imidazo[1,2-a]pyridine-6-amine were reacted according to General Method 6. The crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 20 mg (40% of theory)

(557) LC/MS [Method 1]: R.sub.t=0.67 min; MS (ESIpos): m/z=551 (M+H).sup.+,

(558) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.79 (s, 1H), 9.24 (s, 1H), 8.25 (s, 1H), 8.19-8.11 (m, 1H), 8.09-7.99 (m, 2H), 7.81-7.71 (m, 2H), 7.65-7.54 (m, 2H), 7.30-7.20 (m, 1H), 6.92 (s, 1H), 6.84 (t, 1H), 6.63 (s, 1H), 5.99 (dd, 1H), 3.73 (dd, 1H), 3.64 (dd, 1H).

Example 32

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(imidazo[1,2-a]pyridin-6-yl)-3-(1,3-oxazol-4-yl)propanamide (racemate)

(559) ##STR00177##

(560) 40 mg (0.1 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-4-yl)propanoic acid (racemate) and 19.7 mg (0.15 mmol, 1.5 eq.) of imidazo[1,2-a]pyridine-6-amine were reacted according to General Method 6. The crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 43.8 mg (84% of theory)

(561) LC/MS [Method 1]: R.sub.t=0.65 min; MS (ESIpos): m/z=515 (M+H).sup.+,

(562) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.69 (s, 1H), 9.25 (s, 1H), 8.30 (s, 1H), 8.06-7.91 (m, 2H), 7.82 (s, 1H), 7.76-7.65 (m, 2H), 7.63-7.50 (m, 3H), 7.27 (dd, 1H), 6.48 (s, 1H), 6.00 (dd, 1H), 3.68 (s, 3H), 3.54 (dd, 1H), 3.42 (dd, 1H).

Example 33

2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-(imidazo[1,2-a]pyridin-6-yl)-3-(1,3-oxazol-4-yl)propanamide (racemate)

(563) ##STR00178##

(564) 40 mg (0.1 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-(1,3-oxazol-4-yl)propanoic acid (racemate) and 19.8 mg (0.15 mmol, 1.5 eq.) of imidazo[1,2-a]pyridine-6-amine were reacted according to General Method 6. The crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 41 mg (79% of theory)

(565) LC/MS [Method 1]: R.sub.t=0.70 min; MS (ESIpos): m/z=519 (M+H).sup.+,

(566) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.78 (s, 1H), 9.25 (s, 1H), 8.35-8.19 (m, 2H), 8.10-7.94 (m, 2H), 7.89-7.67 (m, 3H), 7.66-7.47 (m, 2H), 7.26 (d, 1H), 6.62 (s, 1H), 5.99 (dd, 1H), 3.57 (dd, 1H), 3.42 (dd, 1H).

Example 34

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(pyrazolo[1,5-a]pyridin-5-yl)butanamide (racemate)

(567) ##STR00179##

(568) 138 mg (0.39 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 47 mg (0.35 mmol) of pyrazolo[1,5-a]pyridine-5-amine [B. C. Baguley et al. Bioorganic and Medicinal Chemistry, 2012, 20, 69-85] were reacted according to General Method 5. After aqueous work-up, the crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate gradient). Yield: 82 mg (51% of theory)

(569) LC/MS [Method 1]: R.sub.t=0.97 min; MS (ESIpos): m/z=462 (M+H).sup.+,

(570) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.75 (s, 1H), 8.62 (d, 1H), 8.14 (d, 1H), 8.00 (d, 1H), 7.92 (d, 1H), 7.70-7.70 (m, 2H), 7.51 (s, 1H), 6.97 (dd, 1H), 6.55 (s, 1H), 6.50 (d, 1H), 5.64 (dd, 1H), 3.70 (s, 3H), 2.27-2.09 (m, 2H), 0.92 (t, 3H).

Example 35

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxy-N-(pyrazolo[1,5-a]pyridin-5-yl)butanamide (racemate)

(571) ##STR00180##

(572) 800 mg (2.12 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 424 mg (3.19 mmol, 1.5 eq.) of pyrazolo[1,5-a]pyridine-5-amine were reacted according to General Method 1. The crude product was purified by flash chromatography (silica gel 50, dichloromethane/methanol gradient), and the product was stirred with acetonitrile and filtered off with suction. Yield: 550 mg (53% of theory)

(573) LC/MS [Method 1]: R.sub.t=0.94 min; MS (ESIpos): m/z=492 (M+H).sup.+,

(574) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.70 (s, 1H), 8.61 (d, 1H), 8.14 (d, 1H), 8.02-7.98 (m, 1H), 7.92 (d, 1H), 7.76-7.72 (m, 2H), 7.53 (s, 1H), 7.00 (dd, 1H), 6.54 (s, 1H), 6.50 (dd, 1H), 5.77 (dd, 1H), 3.69 (s, 3H), 3.45-3.38 (m, 1H), 3.31-3.25 (m, 1H), 3.21 (s, 3H), 2.48-2.36 (m, 2H).

Example 36

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxy-N-(pyrazolo[1,5-a]pyridin-5-yl)butanamide (enantiomer 1)

(575) ##STR00181##

(576) Enantiomer separation of 45.3 mg of the racemate from Example 35 gave 12.3 mg of the title compound Example 36 (enantiomer 1) in addition to 14.4 mg of enantiomer 2.

(577) Chiral HPLC: enantiomer 1: R.sub.t=2.75 min; 100% ee [comparison: enantiomer 2: R.sub.t=1.71 min; 100% ee]

(578) Separating method: Column: Daicel IF 5 μm 250 mm×20 mm; mobile phase: 40% isohexane, 60% ethanol; temperature: 23° C.; flow rate: 20 ml/min; UV detection: 220 nm.

(579) Analysis: Column: Daicel Chiralpak IF 3 μm 50 mm×4.6 mm, mobile phase: 50% isohexane, 50% ethanol; flow rate: 1 ml/min; UV detection: 220 nm.

(580) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.70 (s, 1H), 8.61 (d, 1H), 8.14 (d, 1H), 8.02-7.87 (m, 1H), 7.92 (d, 1H), 7.76-7.72 (m, 2H), 7.53 (s, 1H), 7.00 (dd, 1H), 6.54 (s, 1H), 6.51-6.49 (m, 1H), 5.77 (dd, 1H), 3.69 (s, 3H), 3.45-3.38 (m, 1H), 3.31-3.25 (m, 1H), 3.21 (s, 3H), 2.48-2.36 (m, 2H).

Example 37

2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxy-N-(pyrazolo[1,5-a]pyridin-5-yl)butanamide (racemate)

(581) ##STR00182##

(582) 110 mg (0.26 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 51 mg (0.39 mmol, 1.5 eq.) of pyrazolo[1,5-a]pyridine-5-amine were reacted according to General Method 6. The crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 95 mg (74% of theory)

(583) LC/MS [Method 1]: R.sub.t=1.00 min; MS (ESIpos): m/z=496 (M+H).sup.+,

(584) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.76 (br. s, 1H), 8.62 (d, 1H), 8.23 (s, 1H), 8.11 (d, 1H), 8.07 (d, 1H), 7.92 (d, 1H), 7.84-7.76 (m, 2H), 6.98 (dd, 1H), 6.68 (s, 1H), 6.50 (d, 1H), 5.85-5.67 (m, 1H), 3.42 (dt, 1H), 3.27 (dt, 1H), 3.20 (s, 3H), 2.47-2.38 (m, 2H).

Example 38

2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxy-N-(pyrazolo[1,5-a]pyridin-5-yl)butanamide (enantiomer 1)

(585) ##STR00183##

(586) Enantiomer separation of 90 mg of the racemate from Example 37 gave 34 mg of the title compound Example 38 (enantiomer 1) in addition to 33 mg of enantiomer 2.

(587) Chiral HPLC: enantiomer 1: R.sub.t=7.88 min; 100% ee [comparison: enantiomer 2: R.sub.t=4.37 min; 100% ee]

(588) Separation method (SFC): Column: Daicel Chiralpak AZ-H 5 μm 250 mm×20 mm; mobile phase: 70% carbon dioxide, 30% 2-propanol; temperature: 40° C.; flow rate: 80 ml/min; UV detection: 210

(589) Analysis (SFC): Column: Daicel Chiralpak AZ-H 250 mm×4.6 mm; mobile phase: 60% carbon dioxide, 40% 2-propanol; flow rate: 3 ml/min, temperature: 30° C.; UV detection: 210 nm.

Example 39

4-(5-Chloro-2-cyanophenyl)-6-oxo-1-[1-oxo-1-(pyrazol[1,5-a]pyridin-5-ylamino)butan-2-yl]-1,6-dihydropyridine-3-carboxylic acid (racemate)

(590) ##STR00184##

(591) 147 mg (260 μmol) of benzyl 4-(5-chloro-2-cyanophenyl)-6-oxo-1-[1-oxo-1-(pyrazol[1,5-a]pyridin-5-ylamino)butan-2-yl]-1,6-dihydropyridine-3-carboxylate (racemate) were initially charged in 3 ml of tetrahydrofuran, and 14 mg (13 μmol) of palladium (10% on carbon) were added. The reaction mixture was hydrogenated at standard pressure for 3 h. The reaction mixture was then filtered off and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.05%-formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90% acetonitrile)], giving the title compound. Yield: 36 mg (29% of theory)

(592) LC/MS [Method 1]: R.sub.t=0.81 min; MS (ESIpos): m/z=476 (M+H).sup.+,

(593) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=12.9 (br. s, 1H), 10.9 (s, 1H), 8.62 (d, 1H), 8.59 (s, 1H), 8.12 (s, 1H), 7.95-7.90 (m, 2H), 7.69-7.64 (m, 2H), 6.95 (dd, 1H), 6.50 (d, 1H), 6.47 (s, 1H), 5.64 (dd, 1H), 2.29-2.19 (m, 1H), 2.14-2.01 (m, 1H), 0.94 (t, 3H).

Example 40

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(3-chloropyrazolo[1,5-a]pyridin-5-yl)butanamide (racemate)

(594) ##STR00185##

(595) At RT, 30 mg (0.22 mmol, 1.45 eq.) in total of N-chlorosuccinimide were added to a solution of 71 mg (0.15 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(pyrazolo[1,5-a]pyridin-5-yl)butanamide (racemate) in 2 ml of ethanol, and the mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure. After addition of water/ethyl acetate and 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, concentrated under reduced pressure and dried. Yield: 80 mg (quant.)

(596) LC/MS [Method 1]: R.sub.t=1.12 min; MS (ESIpos): m/z=496 (M+H).sup.+,

(597) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.91 (s, 1H), 8.66 (d, 1H), 8.14 (d, 1H), 8.09 (s, 1H), 8.00 (d, 1H), 7.77-7.71 (m, 2H), 7.50 (s, 1H), 7.01 (dd, 1H), 6.56 (s, 1H), 5.62 (dd, 1H), 3.71 (s, 3H), 2.29-2.12 (m, 2H), 0.92 (t, 3H).

Example 41

2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(3-chloropyrazolo[1,5-a]pyridin-5-yl)-4-methoxybutanamide (racemate)

(598) ##STR00186##

(599) 100 mg (90% pure, 0.18 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxy-N-(pyrazolo[1,5-a]pyridin-5-yl)butanamide (racemate) were dissolved in 3.0 ml of ethanol, 29 mg (0.20 mmol, 1.1 eq.) of N-chlorosuccinimide were added and the mixture was left to stir at RT overnight. A drop of dimethylformamide and a further 4.9 mg (37 μmol, 0.2 eq.) of N-chlorosuccinimide were then added, and the mixture was left to stir for a further 4 h. The reaction solution was then purified by preparative HPLC (Chromatorex 125 mm×30 mm, 10 μm, mobile phase: water/acetonitrile, gradient 10% acetonitrile to 90% acetonitrile). Yield: 16 mg (17% of theory)

(600) LC/MS [Method 1]: R.sub.t=1.02 min; MS (ESIpos): m/z=526/528 (M+H).sup.+,

(601) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=10.85 (s, 1H), 8.66 (dd, 1H), 8.14 (d, 1H), 8.09 (s, 1H), 8.02-7.99 (m, 1H), 7.76-7.72 (m, 2H), 7.52 (s, 1H), 7.05 (dd, 1H), 6.54 (s, 1H), 5.75 (dd, 1H), 3.70 (s, 3H), 3.46-3.38 (m, 1H), 3.30-3.25 (m, 1H), 3.21 (s, 3H), 2.48-2.40 (m, 2H).

(602) B) Assessment of Physiological efficacy

(603) The suitability of the compounds according to the invention for treating thromboembolic disorders can be demonstrated in the following assay systems:

(604) a) Test Descriptions (In Vitro)

(605) a.1) Measurement of FXIa Inhibition

(606) 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.

(607) 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). In each case 1 μl of the diluted substance solutions is placed into 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:

(608) TABLE-US-00001 TABLE A Example No. IC.sub.50 [nM] Example No. IC.sub.50 [nM] 1 32 2 2.3 3 6.6 4 65 5 1.0 6 11 7 12 8 380 9 0.5 10 36 11 20 12 3.1 13 16 14 31 15 41 16 11 17 65 18 220 19 33 20 86 21 21 22 28 23 53 24 63 25 20 26 24 27 96 28 12 29 16 30 96 31 500 32 92 33 310 34 21 35 4.0 36 3.6 37 29 38 15 39 180 40 140 41 26
a.2) Determination of the Selectivity

(609) To demonstrate the selectivity of the substances with respect to FXIa inhibition, the test substances are examined for their inhibition of other human serin proteases, such as factor Xa, trypsin and plasmin. To determine the enzymatic activity of factor Xa (1.3 nmol/1 from Kordia), trypsin (83 mU/ml from Sigma) and plasmin (0.1 μg/ml from Kordia), these enzymes are dissolved (50 mmol/1 of Tris buffer [C,C,C-tris(hydroxymethyl)aminomethane], 100 mmol/1 of NaCl, 0.1% BSA [bovine serum albumin], 5 mmol/1 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/1 of Boc-Ile-Glu-Gly-Arg-AMC from Bachem for factor Xa and trypsin, 5 50 μmol/1 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.

(610) a.3) Thrombin Generation Assay (Thrombogram)

(611) 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).

(612) 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.

(613) 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.

(614) a.4) Determination of Anticoagulatory Activity

(615) 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.

(616) 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.

(617) 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.

(618) a.5) Determination of the Plasma Kallikrein Activity

(619) 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.

(620) 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). In each case 1 μl of the diluted substance solutions is placed into 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.

(621) TABLE-US-00002 TABLE B Example No. IC.sub.50 [nM] Example No. IC.sub.50 [nM] 1 140 2 16 3 13 4 44 5 7.1 6 61 7 150 9 4.8 10 7.0 11 5.0 12 4.9 13 13 14 65 15 31 16 17 17 24 18 130 19 25 20 23 21 8.0 22 8.3 23 13 24 16 25 23 26 12 27 50 28 8.8 29 11 30 120 31 970 32 36 33 250 34 17 35 4.3 36 3.2 37 65 38 29 39 1800 40 51 41 11
a.6) Determination of Endothelium Integrity

(622) 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.

(623) a.7) Determination of the In Vitro Permeability of Endothelial Cells

(624) 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 membran; 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.

(625) b) Determination of Antithrombotic Activity (In Vivo)

(626) b.1) Arterial Thrombosis Model (Iron(II) Chloride-Induced Thrombosis) in Combination with Ear Bleeding Time in Rabbits

(627) 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

(628) 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.

(629) 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.

(630) 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.

(631) 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.

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

(633) c.1) Test of the Efficacy of Substances in the Laser-Induced Choroidal Neovascularization Model

(634) 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.

(635) 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.

(636) 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).

(637) 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.

(638) c.2) Test of the Efficacy of Substances in the Oxygen-Induced Retinopathy Model

(639) 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.

(640) 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 C57Bl/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.

(641) C) Working Examples of Pharmaceutical Compositions

(642) The substances according to the invention can be converted to pharmaceutical preparations as follows:

(643) Tablet:

(644) Composition:

(645) 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.

(646) Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm

(647) Production:

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

(649) Oral Suspension:

(650) Composition:

(651) 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.

(652) 10 ml of oral suspension correspond to a single dose of 100 mg of the compound of the invention.

(653) Production:

(654) 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.

(655) Solution or Suspension for Topical Administration to the Eve (Eye Drops):

(656) 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 percent by weight.