5,6,7,8-TETRAHYDRO[1,2,4]TRIAZOLO[4,3-A]PYRIDIN-3(2H)-ONES AND SUBSTITUTED 2,5,6,7-TETRAHYDRO-3H-PYRROLO[2,1-C][1,2,4]TRIAZOL-3-ONES AND THEIR USE

Description

[0001] The present application relates to novel substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3(2H)-ones and 2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-ones, processes for their preparation, their use alone or in combinations for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular for the treatment and / or prophylaxis of inflammatory lung diseases.

[0002] The enzyme prolyl endopeptidase (PREP, prolyl oligopeptidase, PE, POP) is a serine protease that cleaves peptides up to 30 amino acids long after the amino acid proline. [Moriyama et al., J. Biochem. 1988, 104:112-117]. PREP is constitutively expressed and secreted in all organs and tissues, including leukocytes and epithelial cells. Its release is increased upon contact with irritating, inflammatory substances. [Szul et al., Am. J. Respir. Cell Mol. Biol. 2016, 54:359-369] While PREP is involved in the degradation of peptide neurotransmitters in the central nervous system, PREP is an enzyme throughout the periphery, including the lungs, that cleaves collagen degradation products in degenerative or inflammatory processes, among other things. Due to the high content of proline and glycine in the amino acid sequence of collagen, tripeptides with the sequence proline-glycine-proline (PGP) are formed through the degradation of collagen fragments [Weathington et al., Nat. Med.2006, 12:317-323]. Significantly elevated PGP concentrations have been described in sputum from patients with chronic, inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF) [O'Reilly et al., Respir. Res. 2009, 10:38 doi:10.1186 / 1465-9921-10-38; Gaggar et al., J. Immunol. 2008, 180:5662-5669]. PGP, which is produced by PREP, is a chemokine for neutrophil granulocytes (neutrophils for short), meaning that PGP leads to neutrophil migration into tissues with elevated PGP concentrations. There is evidence that the mechanism of this attraction of neutrophils is based on a direct stimulation of neutrophils via PGP-sensitive receptors on the neutrophil cell membrane (e.g. CXCR1, CXCR2) or indirectly through the release of other chemokines, such as interleukins (e.g. interleukin-8, CXCL8) by other cell types (e.g.macrophages, epithelial cells). The chemokine effect of PGP on neutrophils has been demonstrated repeatedly in vitro and in vivo. [Weathington et al., Nat. Med. 2006, 12:317-323; De Kruijf et al., Eur. J. Pharmacol. 2010, 643:29-33; Overbeek et al., Eur. J. Pharmacol. 2011, 668:428-434; Braber et al., Eur. J. Pharmacol. 2011, 668:443-449] In animal experiments, the effect of PGP could be abolished by the administration of a complementary tripeptide (threonine-arginine-threonine, RTR) and by the application of a CXCR2 receptor blocker. It has been shown that repeated application of PGP into the lungs of mice can induce pulmonary emphysema. Furthermore, cigarette smoke increases the PGP concentration in the lungs of mice exposed to cigarette smoke. Concomitant administration of PGP-neutralizing RTR can reverse the above-mentioned cigarette smoke-induced effects [Braber et al., Eur J. Pharmacol. 2011, 668:443-449; Braber et al., Am. J.Physiol. Lung Cell Mol. Pysiol. 2011, 300:L255-L265].

[0003] Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by chronic bronchitis, shortness of breath, coughing, sputum production, and the destruction of lung tissue (emphysema). Lung function is increasingly impaired as the disease progresses due to obstructive changes in the bronchi and the loss of functional lung tissue. Overinflation of the lungs is common due to impaired exhalation.

[0004] The most common cause of COPD is chronic inhalation of cigarette smoke. Furthermore, worldwide, with regional variations, 10 to 40% of patients develop COPD that is not caused by cigarette smoke, but presumably due to exposure to environmental toxins, such as smoke from coal or wood fires or diesel exhaust [Salvi, Clin. Chest Med. 2014, 35:17-27].

[0005] Currently, COPD can only be treated symptomatically. COPD patients primarily receive bronchodilator medications to facilitate breathing. The use of anti-inflammatory medications has so far been limited.

[0006] In addition to the chronic symptoms described above, COPD patients often suffer from acute, temporary deteriorations of their already impaired health, necessitating additional treatment [Ewig, Klinikarzt 2013, 42:182-187]. Treatment of these flare-ups, known as acute exacerbations, has so far been limited to the administration of oxygen and systemically administered corticosteroids.

[0007] In a clinical COPD study, the anti-inflammatory drug roflumilast (PDE4 inhibitor) was shown to reduce PGP concentrations in the sputum and serum of treated COPD patients [Wells et al., Am. J. Respir. Crit. Care Med. 2015, 192:934-942].

[0008] Elevated, pro-inflammatory PGP concentrations have also been described in, among other conditions, shock lung (acute respiratory syndrome, ARDS) and corneal injury. [Hahn et al., Sci. Adv. 2015, 1: e1500175; Pfister et al., Invest. Ophthalmol. Vis. Sci. 1998, 39:1744-1750] Here, too, a pro-inflammatory influence of PGP is formulated, which leads, on the one hand, to increased vascular permeability and, on the other hand, as already described above, to increased recruitment of neutrophils (neutrophilia) and thus to increased inflammation. Since the formation of PGP in inflammatory processes is directly linked to tissue destruction, and PGP in turn promotes inflammation, involvement of PGP in self-sustaining, chronic inflammatory processes is likely. Of particular note here is COPD or acute exacerbating COPD (AE-COPD), which is caused by chronic inflammation [Russell et al., Curr Opin Pilm Med. 2016, 22:91-99; Anzueto, Eur. Respir. Rev. 2010, 19:113-118]. However, other chronic inflammatory diseases and wound healing disorders of the lungs and other tissues and organs, such as the skin, eyes, blood vessels, connective tissue, skeleton, or muscles, could also benefit from a reduction in PGP concentrations through PREP inhibition.

[0009] Potential areas of application for PREP inhibitors are acute and chronic pathological processes in which PREP or substrates and products of PREP are involved. Since this anti-inflammatory effect of PREP inhibition presumably does not directly interfere with the function of the immune system and therefore no immunosuppressive effect is to be expected, one advantage of PREP inhibition could be that fewer side effects could occur in treated patients than with classic immunomodulatory active principles. Since PGP is formed from collagen fragments via the constitutively expressed, i.e. constantly present, enzyme PREP, and PGP production is therefore not controlled or regulated by the immune system, it can be expected that the anti-inflammatory effect will also be effective in patients in whom the effectiveness against corticosteroids is reduced, for example due to resistance.Corticosteroid resistance has been described particularly in COPD patients during stable phases outside of acute exacerbations. Furthermore, additive or synergistic efficacy can be expected from the combination with corticosteroids, even when corticosteroids are fully effective, or when their effectiveness is limited or severely reduced. Combination with all other inflammatory mechanisms of action is also possible.

[0010] Since PGP, whose formation is prevented by PREP inhibition, probably plays a driving role in the inflammatory process in all diseases with inflammatory components and involvement of collagen or its fragments, PREP inhibition can have positive effects on many diseases such as autoimmune diseases, chronic inflammatory diseases such as rheumatoid diseases, infectious processes, and degenerative processes (skin, organs, bones, muscles).

[0011] The object of the present invention was to identify and provide novel, low-molecular-weight compounds that act as potent inhibitors of the enzyme prolyl endopeptidase (PREP, prolyl oligopeptidase, PE, POP) and, in acute or chronic, pathological or inflammatory-degenerative processes, reduce the recruitment of neutrophil granulocytes into organs, in particular the lungs, by reducing PREP-dependent PGP production.

[0012] Application WO2006052962A2 describes bicyclic triazoles for combating diseases that progress via integrin inhibition. 1,2-Dihydro-3H-indazol-3-ones as NOX inhibitors for combating diseases such as COPD, Alzheimer's disease, inflammatory or fibrotic diseases are known from WO2011062864A2. WO97007116A1 describes the use of prolyl endopeptidase inhibitors for combating neutrophil inflammation, and WO2008144748A1 describes proline derivatives as prolyl endopeptidase inhibitors for the treatment of CNS diseases.

[0013] The invention is defined by the claims. Any subject matter of the description that extends beyond the scope of the claims is disclosed as background knowledge and not part of the invention.

[0014] The present invention relates to compounds of the general formula (I) in which A represents (C 1 -C 4 )-alkylene or CD 2 , where (C 1 -C 4 )-alkylene may be substituted by hydroxy, (C 1 -C 4 )-alkoxy and up to five times by fluorine, or represents a group of the formula wherein n is 0 or 1, p is 0 or 1, q is 1 or 2, where # 1< marks the linkage to the nitrogen atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, * marks the linkage to R 1<, X stands for -CR 6< R 7< -, # 2< -CR 6< R 7< -CR 8< R 9< -**, # 2< -CR 6< =CR 8< -** or # 2< -CR 6< R 7< -CR 8< R 9< -CR 10< R 11< - **, where # 2< marks the linkage to the carbon atom of the CR 4< R 5< group, where ** marks the linkage to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring where R 6< represents hydrogen, fluorine, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, hydroxy, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino, where (C 1 -C 4 )-alkyl may be substituted with (C 1 -C 4 )-alkoxy, hydroxy, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino and up to five times with fluorine, R 7< represents hydrogen, fluorine or (C 1 -C 4 )-alkyl,wherein (C 1 -C 4 )-alkyl may be substituted up to five times by fluorine, or R 6< and R 7< together with the carbon atom to which they are attached form a carbonyl group, or R 6< and R 7< together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl ring or cyclopentyl ring, or R 6< and R 4< together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl ring or cyclopentyl ring, R 8< represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, fluorine, hydroxy, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino, wherein (C 1 -C 4 )-alkyl is substituted with (C 1 -C 4 )-alkoxy, hydroxy, Mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino and may be substituted up to five times by fluorine, R 9< represents hydrogen, fluorine or (C 1 -C 4 )-alkyl, wherein (C 1 -C 4 )-alkyl may be substituted up to five times by fluorine, or R 8< and R 9< together with the carbon atom to which they are attached,form a cyclopropyl, cyclobutyl or cyclopentyl ring, or R 7< and R 9< together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl or cyclopentyl ring, R 10< represents hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, fluorine, hydroxy, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino, in which (C 1 -C 4 )-alkyl may be substituted with (C 1 -C 4 )-alkoxy, hydroxy, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino and up to five times with fluorine, R 11< represents hydrogen, fluorine or (C 1 -C 4 )-alkyl, in which (C 1 -C 4 )-alkyl may be substituted up to five times by fluorine, or R 10< and R 11< together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl or cyclopentyl ring, R 1< represents phenyl or 5- to 6-membered heteroaryl, where phenyl is substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl,Trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylsulfanyl, methylsulfonyl, methylsulfonimidoyl, aminosulfonyl or methylsulfinyl, or wherein phenyl may be fused with cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein (cyclopentyl, cyclohexyl, (C 5 -C 6 )-heterocycyl and 5- to 6-membered heteroaryl may be substituted with 1 or 2 substituents methyl or ethyl, or wherein 5- to 6-membered heteroaryl may be substituted with 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, Methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, methylaminocarbonyl, tert-butylaminocarbonyl, dimethylaminocarbonyl, where 5- to 6-membered heteroaryl can be substituted with cyclopentyl, cyclohexyl,5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl may be fused, wherein 5- to 6-membered heteroaryl may be substituted with methyl, ethyl, chlorine, fluorine or methoxy, wherein cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl may be substituted with 1 or 2 (C 1 -C 4 )-alkyl substituents, R 2< represents a group of the formula , where # 3< marks the linkage to the carbonyl carbon atom, r stands for 0 or 1, Z stands for O, NR 18< , S, SO, SO 2 or CR 14A< R 14B<, where R 14A< stands for hydrogen, halogen, cyano, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl, trifluoromethyl, difluoromethyl, fluoromethyl, hydroxy, (C 1 -C 4 )-alkoxy, (C 3 - C 5 )-cycloalkoxy, difluoromethoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy, where (C 1 -C 4 )-alkyl may be substituted with hydroxy, amino, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino, R 14B< stands for hydrogen, Fluorine or (C 1 -C 4 )-alkyl, wherein (C 1 -C 4 )-alkyl may be substituted up to five times by fluorine, or R 14A< and R 14B< together with the carbon atom to which they are attached form a carbonyl group, R 18< represents hydrogen or methyl, R 12< represents hydrogen, cyano, (C 1 -C 4 )-alkyl, acetyl or formyl, wherein (C 1 -C 4 )-alkyl may be substituted by hydroxy or up to five times by fluorine,wherein acetyl may be substituted by hydroxy or up to three times by fluorine, R 13< represents hydrogen, fluorine or (C 1 -C 4 )-alkyl, or R 12< and R 13< are cyclopropyl- or cyclobutyl ring together with the carbon atoms to which they are attached, wherein the cyclopropyl or cyclobutyl ring may be substituted up to twice by fluorine, or R 13< and R 14A< are together with the carbon atoms to which they are attached, wherein the cyclopropyl or cyclobutyl ring may be substituted up to twice by fluorine, or R 14A< and R 14B< are together with the carbon atom to which they are attached, wherein the cyclopropyl or cyclobutyl ring may be substituted up to twice by fluorine, where R 13<, R 14A< and R 14B< are hydrogen if R 12< is not hydrogen, where R 12< is hydrogen if one of the substituents R 13< ,R 14A< or R 14B< does not represent hydrogen, or a group of the formula , where # 4< marks the link to the carbonyl carbon atom, Y stands for NR 15< , CR 16A< R 16B< , oxygen or sulfur, wherein R 15< stands for hydrogen or methyl, R 16A< stands for hydrogen or methyl, R 16B< stands for hydrogen or methyl, R 3< stands for hydrogen or (C 1 -C 4 )-alkyl, R 4< stands for hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, fluorine, hydroxy, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino, wherein (C 1 -C 4 )-alkyl is reacted with (C 1 -C 4 )-alkoxy, hydroxy, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino and up to may be substituted up to five times by fluorine, R 5< represents hydrogen or (C 1 -C 4 )-alkyl, wherein (C 1 -C 4 )-alkyl may be substituted up to five times by fluorine, or R 4< and R 5< together with the carbon atom to which they are attached form a carbonyl group, or R 4< and R 5< together with the carbon atom to which they are attached form a cyclopropyl,Form cyclobutyl ring or cyclopentyl ring, as well as the salts, solvates and solvates of the salts of the compounds of formula (I).

[0015] Compounds according to the invention are the compounds of formula (I) and their salts, solvates and solvates of the salts, the compounds encompassed by formula (I) of the formulas mentioned below and their salts, solvates and solvates of the salts, as well as the compounds encompassed by formula (I) and mentioned below as embodiments and their salts, solvates and solvates of the salts, insofar as the compounds encompassed by formula (I) and mentioned below are not already salts, solvates and solvates of the salts.

[0016] Preferred salts for the purposes of the present invention are physiologically acceptable salts of the compounds according to the invention. This also includes salts that are not suitable for pharmaceutical applications themselves, but can be used, for example, for the isolation or purification of the compounds according to the invention.

[0017] Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

[0018] Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 C atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

[0019] For the purposes of the invention, solvates are those forms of the compounds according to the invention that form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates in which coordination occurs with water. Hydrates are preferred solvates for the purposes of the present invention.

[0020] Depending on their structure, the compounds according to the invention can exist in different stereoisomeric forms, i.e., in the form of configurational isomers or, optionally, also as conformational isomers (enantiomers and / or diastereomers, including those in the case of atropisomers). The present invention therefore encompasses the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; chromatographic methods are preferably used for this purpose, in particular HPLC chromatography on an achiral or chiral phase. In the case of carboxylic acids as intermediates or end products, separation via diastereomeric salts can alternatively be carried out using chiral amine bases.

[0021] If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

[0022] The compounds of general formula (I) can exist as isotopic variants. The invention therefore encompasses one or more isotopic variants of the compounds of general formula (I), in particular deuterium-containing compounds of general formula (I).

[0023] The term "isotopic variant" of a compound or reagent is defined as a compound with an unnatural proportion of one or more of the isotopes from which such a compound is composed.

[0024] The term "isotopic variant of the compound of general formula (I)" is defined as a compound of general formula (I) with an unnatural proportion of one or more of the isotopes from which such a compound is composed.

[0025] The term "unnatural fraction" refers to a fraction of such an isotope that is higher than its natural abundance. The natural abundances of isotopes to be used in this context can be found in "Isotopic Compositions of the Elements 1997," Pure Appl. Chem., 70(1), 217-235, 1998.

[0026] Examples of such isotopes are stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2< H (deuterium), 3< H (tritium), 11< C, 13< C, 14< C, 15< N, 17< O, 18< O, 32< P, 33< P, 33< S, 34< S, 35< S, 36< S, 18< F, 36< Cl, 82< Br, 123< I, 124< I, 125< I, 129< I and 131< I respectively.

[0027] With regard to the treatment and / or prophylaxis of the disorders specified here, the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium ("deuterium-containing compounds of general formula (I)"). Isotopic variants of the compounds of general formula (I) into which one or more radioactive isotopes, such as 3< H or 14< C, are incorporated are useful, for example, in drug and / or substrate tissue distribution studies. These isotopes are particularly preferred because of their ease of incorporation and detectability. Positron-emitting isotopes such as 18< F or 11< C can be incorporated into a compound of general formula (I). These isotopic variants of the compounds of general formula (I) are suitable for use in in vivo imaging applications.Deuterium-containing and 13< C-containing compounds of general formula (I) can be used in mass spectrometry analyses in preclinical or clinical studies (HJ Leis et al., Curr. Org. Chem., 1998, 2, 131).

[0028] Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to those skilled in the art, such as those described in the schemes and / or examples described herein, by replacing a reagent with an isotopic variant of the reagent, preferably a deuterium-containing reagent. Depending on the desired deuteration sites, in some cases deuterium from D2O can be incorporated either directly into the compounds or into reagents that can be used for the synthesis of such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al., Chem. Eur. J., 2007, 13, 4052). Another useful reagent for incorporating deuterium into molecules is deuterium gas. A rapid route for the incorporation of deuterium is the catalytic deuteration of olefinic bonds (HJ Leis et al., Curr. Org. Chem., 1998, 2, 131; JR Morandi et al., J. Org. Chem., 1969, 34 (6), 1889) and acetylenic bonds (NHKhan, J. Am. Chem. Soc., 1952, 74 (12), 3018; S. Chandrasekhar et al., Tetrahedron Letters, 2011, 52, 3865). For the direct exchange of hydrogen for deuterium in functional group-containing hydrocarbons, metal catalysts (i.e., Pd, Pt, and Rh) in the presence of deuterium gas can also be used (J.G. Atkinson et al., US Patent 3,966,781). Various deuterated reagents and synthetic building blocks are commercially available from companies such as C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA. Further information regarding the state of the art with regard to deuterium-hydrogen exchange can be found, for example, in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; RP Hanzlik et al., Biochem. Biophys. Res. Commun. 160, 844, 1989; PJ Reider et al., J. Org. Chem. 52, 3326-3334, 1987; M. Jarman et al., Carcinogenesis 16(4), 683-688, 1995; J. Atzrodt et al., Angew. Chem., Int. Ed. 2007, 46, 7744; K. Matoishi et al., Chem. Commun. 2000, 1519-1520; K. Kassahun et al., WO2012 / 112363.

[0029] The term "deuterium-containing compound of general formula (I)" is defined as a compound of general formula (I) in which one or more hydrogen atoms are replaced by one or more deuterium atoms, and in which the abundance of deuterium in each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is approximately 0.015%. In particular, in a deuterium-containing compound of general formula (I), the abundance of deuterium in each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, preferably higher than 90%, 95%, 96%, or 97%, and even more preferably higher than 98% or 99% in that position(s). It is understood that the abundance of deuterium in each deuterated position is independent of the abundance of deuterium in other deuterated positions.

[0030] By selectively incorporating one or more deuterium atoms into a compound of general formula (I), the physico-chemical properties (such as acidity [CL Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490; A. Streitwieser et al., J. Am. Chem. Soc., 1963, 85, 2759;], basicity [CL Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641; CL Perrin, et al., J. Am. Chem. Soc., 2003, 125, 15008; CL Perrin in Advances in Physical Organic Chemistry, 44, 144], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271]) and / or alter the metabolic profile of the molecule, causing changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed. Such changes may lead to certain therapeutic advantages and may therefore be preferable under certain circumstances.Reduced metabolic rates and metabolic switching, in which the ratio of metabolites changes, have been reported (AE Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102; DJ Kushner et al., Can. J. Physiol. Pharmacol., 1999, 77, 79). These changes in exposure to the parent compound and metabolites can have important consequences regarding the pharmacodynamics, tolerability, and efficacy of a deuterium-containing compound of general formula (I). In some cases, deuterium replacement reduces or eliminates the formation of an undesirable or toxic metabolite and increases the formation of a desired metabolite (e.g., nevirapine: AM Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; efavirenz: AE Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases, the primary effect of deuterium replacement is to reduce the rate of systemic clearance.This increases the compound's biological half-life. Potential clinical benefits include the ability to maintain similar systemic exposure with reduced peak levels and increased trough levels. This could lead to fewer side effects and increased efficacy, depending on the pharmacokinetics / pharmacodynamics relationship of the respective compound. Examples of this deuterium effect include ML-337 (CJ Wenthur et al., J. Med. Chem., 2013, 56, 5208) and odanacatib (K. Kassahun et al., WO2012 / 112363). Other cases have also been reported in which reduced metabolism rates lead to an increase in drug exposure without changing the rate of systemic clearance (e.g., rofecoxib: F. Schneider et al., Arzneim. Forsch. / Drug. Res., 2006, 56, 295; telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993).Deuterated drugs that exhibit this effect may have reduced dosage requirements (e.g., fewer doses or lower dosage to achieve the desired effect) and / or result in lower metabolite burdens.

[0031] A compound of general formula (I) may have multiple potential targets for metabolism. To optimize the above-described effects on the physicochemical properties and metabolic profile, deuterium-containing compounds of general formula (I) can be selected with a specific pattern of one or more deuterium-hydrogen exchanges. In particular, the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is / are bonded to a carbon atom and / or is / are located in the positions of the compound of general formula (I) that are targets for metabolic enzymes such as cytochrome P450.

[0032] The term "prodrugs" refers to compounds which may be biologically active or inactive themselves, but which are converted into compounds of the invention during their residence time in the body (e.g. metabolically or hydrolytically).

[0033] In the context of the present invention, the substituents, unless otherwise specified, have the following meaning: Alkyl In the context of the invention, R represents a linear or branched alkyl radical having the specified number of carbon atoms. Examples and preferred radicals are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,4-dimethylpentyl, 4,4-dimethylpentyl, and 1,4,4-trimethylpentyl. AlkylcarbonylIn the context of the invention, represent a linear or branched alkyl radical having the specified number of carbon atoms and a carbonyl group attached to the carbon atom. Examples and preferred examples are: methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, and tert-butylcarbonyl. Alkoxy In the context of the invention, represents a linear or branched alkoxy radical with the specified number of carbon atoms. Examples and preferred examples are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and tert-butoxy. Cycloalkoxy In the context of the invention, represents a monocyclic, saturated alkyl radical with the specified number of ring carbon atoms, linked via an oxygen atom. Examples and preferred examples are: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Cycloalkyl or CarbocycleIn the context of the invention, R represents a monocyclic, saturated alkyl radical with the specified number of ring carbon atoms. Examples and preferred examples are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkylcarbonyl In the context of the invention, represent a monocyclic, saturated alkyl radical having the specified number of ring carbon atoms and a carbonyl group attached to the carbon atom. Examples and preferred examples are: cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, and cycloheptylcarbonyl. Alkoxycarbonyl In the context of the invention, represent a linear or branched alkoxy radical having the specified number of carbon atoms and a carbonyl group attached to the oxygen atom. Examples and preferred examples are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, and tert-butoxycarbonyl. Heterocycle or heterocyclylIn the context of the invention, represents a monocyclic or bicyclic, saturated heterocycle having the specified number of ring atoms, which contains one or two ring heteroatoms selected from the group consisting of N, O, S, SO, and / or SO2 and is linked via a ring carbon atom or, optionally, a ring nitrogen atom. Examples include: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl, and hexahydro-1,4-diazepinyl. Azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, and morpholinyl are preferred. Aza-heterocyclylIn the context of the invention, stands for a monocyclic or bicyclic, saturated or partially unsaturated heterocycle with the respectively specified number of ring atoms, which contains a nitrogen atom and may additionally contain one or two further ring heteroatoms from the series N, O, S, SO and / or SO 2 and is linked via a ring nitrogen atom. Examples include: pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, hexahydroazepinyl, hexahydro-1,4-diazepinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indolinyl, 8-azabicyclo[3.2.1]octanyl, 9-azabicyclo[3.3.1]nonanyl, 3-azabicyclo[4.1.0]heptanyl and quinuclidinyl. HeteroarylIn the context of the invention, represents a monocyclic or bicyclic aromatic heterocycle (heteroaromatic) with the specified number of ring atoms, which contains up to four identical or different ring heteroatoms selected from the group consisting of N, O, and / or S and is linked via a ring carbon atom or, optionally, via a ring nitrogen atom. Examples and preferred examples are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, quinolinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl. Mono-alkylaminocarbonyl In the context of the invention, represents an amino group linked via a carbonyl group and having a linear or branched alkyl substituent with the specified number of carbon atoms. Examples and preferred examples are: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n -Butylaminocarbonyl, tert .-Butylaminocarbonyl, n -Pentylaminocarbonyl and n -Hexylaminocarbonyl. Di-alkylaminocarbonyl In the context of the invention, represents an amino group linked via a carbonyl group and having two identical or different linear or branched alkyl substituents with the specified number of carbon atoms. Examples and preferred examples are: N,N -Dimethylaminocarbonyl, N,N -Diethylaminocarbonyl, N -Ethyl- N -methylaminocarbonyl, N- Methyl- N - n -propylaminocarbonyl, Nn- Butyl N- methylaminocarbonyl, N -tert.-butyl- N -methylaminocarbonyl, N - n -Pentyl- N -methylaminocarbonyl and N - n -Hexyl- N -methylaminocarbonyl. Mono-alkylaminosulfonylIn the context of the invention, represents an amino group linked via a sulfonyl group and having a linear or branched alkyl substituent with the specified number of carbon atoms. Examples and preferred examples are: methylaminosulfonyl, ethylaminosulfonyl, n- Propylaminosulfonyl, Isopropylaminosulfonyl, n -Butylaminosulfonyl, tert .-Butylaminosulfonyl, n- Pentylaminosulfonyl and n -Hexylaminosulfonyl. Di-alkylaminosulfonyl In the context of the invention, represents an amino group linked via a sulfonyl group and having two identical or different linear or branched alkyl substituents with the specified number of carbon atoms. Examples and preferred examples are: N,N -Dimethylaminosulfonyl, N , N -Diethylamino-sulfonyl, N -Ethyl- N -methylaminosulfonyl, N-methyl- Nn -propylaminosulfonyl, Nn- Butyl -N- methylaminosulfonyl, N- tert-butyl- N -methylaminosulfonyl, Nn -Pentyl- N -methylaminosulfonyl and N -n-Hexyl -N -methylaminosulfonyl. Mono-alkylamino In the context of the invention, represents an amino group which has a linear or branched alkyl substituent with the specified number of carbon atoms. Examples and preferred examples are: methylamino, ethylamino, n -Propylamino, Isopropylamino, n -Butylamino, tert .-Butylamino, n -Pentylamino and n -Hexylamino. Di-alkylamino In the context of the invention, represents an amino group having two identical or different linear or branched alkyl substituents with the specified number of carbon atoms. Examples and preferred examples are: N,N- Dimethylamino, N,N- Diethylamino, N -Ethyl- N -methylamino,N -Methyl- Nn -propylamino, Nn- Butyl N -methylamino, N - tert .-Butyl- N -methylamino, Nn -Pentyl- N -methylaminol and Nn -Hexyl- N -methylamino. halogen In the context of the invention, includes fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred. Oxo group In the context of the invention, represents an oxygen atom bonded to a carbon atom via a double bond.

[0034] In the formulas of the group which can be represented by A, X and R 2<, the end point of the line at which a symbol # 1< or # 2< or # 3< or # 4< or # 5< or * or ** or *** stands does not represent a carbon atom or a CH 2 group, but is part of the bond to the respective designated atom to which A or X or R 2< is bonded.

[0035] If radicals in the compounds according to the invention are substituted, the radicals may be mono- or polysubstituted, unless otherwise specified. For the purposes of the present invention, all radicals that occur multiple times are independent of one another. Substitution with one or two identical or different substituents is preferred. Substitution with one substituent is very particularly preferred.

[0036] For the purposes of the present invention, the term "treatment" or "treat" encompasses inhibiting, delaying, stopping, alleviating, attenuating, limiting, reducing, suppressing, repressing, or curing a disease, ailment, illness, injury, or health disorder, the development, course, or progression of such conditions, and / or the symptoms of such conditions. The term "therapy" is understood here as synonymous with the term "treatment."

[0037] The terms "prevention", "prophylaxis" or "prevention" are used synonymously in the context of the present invention and refer to avoiding or reducing the risk of getting, experiencing, suffering or having a disease, ailment, illness, injury or health disorder, the development or progression of such conditions and / or the symptoms of such conditions.

[0038] The treatment or prevention of a disease, condition, illness, injury or health disorder may be partial or complete.

[0039] Disclosed, but not part of the present invention, are compounds of general formula (I) in which A represents (C 1 -C 4 )-alkylene, where (C 1 -C 4 )-alkylene may be substituted by hydroxy, methoxy and up to three times by fluorine, or a group of the formula wherein n is 1, p is 0, q is 1, where # 1< marks the linkage to the nitrogen atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, * marks the linkage to R 1<, X stands for -CR 6< R 7< - or # 2< -CR 6< R 7< -CR 8< R 9< -**, where # 2< marks the linkage to the carbon atom of the CR 4< R 5< group, where ** marks the linkage to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where R 6< is hydrogen, fluorine, methyl, ethyl, methoxy, ethoxy, trifluoromethoxy, hydroxy, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino wherein methyl and ethyl may be substituted up to three times by fluorine, R 7< represents hydrogen, fluorine or methyl, wherein methyl may be substituted up to three times by fluorine, or R 6< and R 7< together with the carbon atom to which they are attached form a carbonyl group, or R 6< and R 7< together with the carbon atom to which they are attached,form a cyclopropyl or cyclobutyl ring, or R 6< and R 4< together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl ring, R 8< represents hydrogen, fluorine, methyl, ethyl, methoxy, ethoxy, trifluoromethoxy, hydroxy, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino, in which methyl and ethyl may be substituted up to three times by fluorine, R 9< represents hydrogen, fluorine or methyl, in which methyl may be substituted up to three times by fluorine, or R 8< and R 9< together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, R 1< represents (C 5 -C 6 )-cycloalkyl, phenyl or 5- to 10-membered heteroaryl, in which (C 5 -C 6 )-cycloalkyl may be substituted by 1 to 3 substituents independently selected from the group consisting of fluorine, cyano, trifluoromethyl, methyl, ethyl, methoxy and ethoxy, wherein methyl and ethyl may be substituted up to three times by fluorine,where phenyl with 1 to 4 substituents is independently selected from the group of halogen, cyano, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, (C 3 -C 5 )-cycloalkoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl, (C 1 -C 4 )-alkylsulfanyl, (C 1 -C 4 )-alkylsulfonyl, (C 1 -C 4 )-alkylsulfonimidoyl, aminosulfonyl, mono-(C 1 -C 4 )-alkylaminosulfonyl, Di-(C 1 -C 4 )-alkylaminosulfonyl, (C 1 -C 4 )-alkylsulfinyl, amino, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino, or wherein phenyl may be fused with cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein phenyl may be substituted with methyl, ethyl, chlorine, fluorine or methoxy, wherein cyclopentyl, cyclohexyl,5- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl having 1 or 2 substituents may be substituted by methyl or ethyl, wherein methyl and ethyl may be substituted by methoxy, hydroxy, mono-methylamino or di-ethylamino and up to three times by fluorine, or wherein 5- to 10-membered heteroaryl having 1 to 4 substituents independently selected from the group consisting of halogen, cyano, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, (C 3 -C 5 )-cycloalkoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 ), Di-(C 1 -C 4 )-alkylaminosulfonyl, (C 1 -C 4 )-alkylsulfinyl, amino, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino may be substituted,or wherein 5- to 10-membered heteroaryl may be fused with cyclopentyl, cyclohexyl or 5- to 6-membered heterocyclyl, wherein 5- to 10-membered heteroaryl may be substituted with methyl, ethyl, chlorine, fluorine or methoxy, wherein cyclopentyl, cyclohexyl and 5- to 6-membered heterocyclyl may be substituted with 1 or 2 (C 1 -C 4 )-alkyl substituents, wherein (C 1 -C 4 )-alkyl may be substituted with (C 1 -C 4 )-alkoxy, hydroxy, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino and up to five times with fluorine, R 2< represents a group of the formula , where # 3< marks the linkage to the carbonyl carbon atom, r is 0 or 1, Z is S, SO, SO 2 or CR 14A< R 14B<, where R 14A< is hydrogen, halogen, cyano, (C 1 -C 4 )-alkyl, cyclopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, hydroxy, methoxy, ethoxy, cyclopropoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, hydroxycarbonyl, aminocarbonyl or amino, where (C 1 -C 4 )-alkyl may be substituted with hydroxy, amino, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino, R 14B< is hydrogen, fluorine, methyl or trifluoromethyl, or R 14A< and R 14B< together with the carbon atom, that they are bonded to form a carbonyl group, R 12< represents hydrogen, cyano, methyl, ethyl, acetyl or formyl, wherein methyl may be substituted by hydroxy or up to five times by fluorine, wherein acetyl is substituted by hydroxy or up to three times by fluorine, R 13< represents hydrogen, fluorine or methyl,or R 12< and R 13< together with the carbon atoms to which they are attached form a cyclopropyl ring, wherein the cyclopropyl ring may be substituted up to twice by fluorine, or R 13< and R 14A< together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl ring, wherein the cyclopropyl or cyclobutyl ring may be substituted up to twice by fluorine, or R 14A< and R 14B< together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein the cyclopropyl or cyclobutyl ring may be substituted up to twice by fluorine, where R 13< , R 14A< and R 14B< are hydrogen when R 12< is not hydrogen, where R 12< is hydrogen when one of the substituents R 13< , R 14A< or R 14B< does not represent hydrogen, or a group of the formula , where # 4< marks the link to the carbonyl carbon atom, Y stands for NR 15< , CR 16A< R 16B< , oxygen or sulfur, wherein R 15< stands for hydrogen or methyl, R 16A< stands for hydrogen or methyl, R 16B< stands for hydrogen or methyl, R 3< stands for hydrogen or methyl, R 4< stands for hydrogen, fluorine, methyl, ethyl, methoxy, ethoxy, trifluoromethoxy, hydroxy, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino, wherein methyl and ethyl may be substituted up to three times by fluorine, R 5< stands for hydrogen, fluorine or methyl, wherein methyl may be substituted up to three times by fluorine, or R 4< and R 5< together with the carbon atom to which they are attached form a cyclopropyl ring, as well as the salts, solvates and solvates of Salts of the compounds of formula (I). Particularly preferred within the scope of the present invention are compounds of general formula (I) in which A represents -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 -,# 5< -CH 2 CH(CH 3 )-***, # 5< -CH 2 C(CH 3 ) 2 -***, # 5< -CH 2 CHF-*** or # 5< -CH 2 CF 2 -***, where # 5< marks the linkage to the nitrogen atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where *** marks the linkage to the R 1< group, X stands for - # 2< -CR 6< R 7< -CR 8< R 9< -**, where # 2< marks the linkage to the carbon atom of the CR 4< R 5< group, where ** marks the linkage to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where R 6< stands for hydrogen, fluorine, methyl, trifluoromethyl or hydroxy, R 7< stands for represents hydrogen, fluorine or methyl, or R 6< and R 7< together with the carbon atom to which they are attached form a cyclopropyl ring, R 8< represents hydrogen, fluorine, methyl or trifluoromethyl, R 9< represents hydrogen, fluorine or methyl, R 1< represents phenyl or 5- to 6-membered heteroaryl, where phenyl is substituted by 1 to 3 substituents as defined in claim 2,or wherein phenyl may be fused with cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein (cyclopentyl, cyclohexyl, (C 5 -C 6 )-heterocycyl and 5- to 6-membered heteroaryl may be substituted with 1 or 2 substituents methyl or ethyl, or wherein 5- to 6-membered heteroaryl may be substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, methylaminocarbonyl, tert-butylaminocarbonyl, dimethylaminocarbonyl, wherein 5- to 6-membered heteroaryl may be substituted with cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, wherein 5- to 6-membered heteroaryl may be substituted with methyl, ethyl, chlorine, fluorine or methoxy, wherein cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl,Phenyl and 5- to 6-membered heteroaryl may be substituted with 1 or 2 substituents (C 1 -C 4 )-alkyl, R 2< represents a group of the formula , where # 3< marks the linkage to the carbonyl carbon atom, r stands for 0 or 1, Z stands for S or CR 14A< R 14B< when r stands for 0, Z stands for S, SO, SO 2 or CR 14A< R 14B< when r stands for 1, wherein each R 14A< stands for hydrogen, fluorine, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, hydroxy, methoxy, difluoromethoxy or trifluoromethoxy, R 14B< stands for hydrogen or fluorine, or R 14A< and R 14B< together with the carbon atom to which they are attached form a carbonyl group, R 12< stands for hydrogen, cyano, methyl, acetyl or formyl, wherein acetyl is substituted by hydroxy or up to three times by fluorine, R 13< stands for hydrogen, fluorine or methyl, or R 12< and R 13< together with the carbon atoms to which they are attached form a cyclopropyl ring, or R 13< and R 14A< together with the carbon atom to which they are attached form a cyclopropyl ring,wherein the cyclopropyl ring may be substituted up to twice by fluorine, or R 14A< and R 14B< together with the carbon atom to which they are attached form a cyclopropyl ring, wherein the cyclopropyl ring may be substituted up to twice by fluorine, where R 13< , R 14A< and R 14B< are hydrogen if R 12< is not hydrogen, where R 12< is hydrogen if one of the substituents R 13< , R 14A< or R 14B< is not hydrogen, R 3< is hydrogen, R 4< is hydrogen, fluorine or methyl, R 5< is hydrogen, , as well as the salts, solvates and solvates of the salts of the compounds of formula (I).

[0040] Particularly preferred in the context of the present invention are compounds of the general formula (I) in which A stands for -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 -, # 5< -CH 2 CH(CH 3 )-***, # 5< -CH 2 C(CH 3 ) 2 -***, # 5< -CH 2 CHF-*** or # 5< -CH 2 CF 2 -***, where # 5< marks the linkage to the nitrogen atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where *** marks the linkage to the R 1< group, X stands for - # 2< -CR 6< R 7< -CR 8< R 9< -**, where # 2< marks the linkage to the carbon atom of the CR 4< R 5< group, where ** marks the linkage to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring where R 6< represents hydrogen, fluorine, methyl, trifluoromethyl or hydroxy, R 7< represents hydrogen, fluorine or methyl, or R 6< and R 7< together with the carbon atom to which they are attached form a cyclopropyl ring, R 8< represents hydrogen, fluorine, methyl or trifluoromethyl, R 9< represents hydrogen, fluorine or methyl, R 1< represents phenyl or 5- to 6-membered heteroaryl,wherein phenyl is substituted by 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylsulfanyl, methylsulfonyl, methylsulfonimidoyl, aminosulfonyl or methylsulfinyl, or wherein phenyl may be fused with cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein (cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl may be substituted by 1 or 2 substituents methyl or ethyl, or wherein 5- to 6-membered heteroaryl may be substituted by 1 to 3 substituents independently selected from the group fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, methylaminocarbonyl, tert-butylaminocarbonyl,Dimethylaminocarbonyl, wherein 5- to 6-membered heteroaryl may be fused with cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, wherein 5- to 6-membered heteroaryl may be substituted with methyl, ethyl, chlorine, fluorine or methoxy, wherein cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl may be substituted with 1 or 2 (C 1 -C 4 )-alkyl substituents, R 2< represents a group of the formula , where # 3< marks the linkage to the carbonyl carbon atom, r stands for 0 or 1, Z stands for S or CR 14A< R 14B< when r stands for 0, Z stands for S, SO, SO 2 or CR 14A< R 14B< when r stands for 1, wherein each R 14A< stands for hydrogen, fluorine, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, hydroxy, methoxy, difluoromethoxy or trifluoromethoxy, R 14B< stands for hydrogen or fluorine, or R 14A< and R 14B< together with the carbon atom to which they are attached form a carbonyl group, R 12< stands for hydrogen, cyano, methyl, acetyl or formyl, wherein acetyl is substituted by hydroxy or up to three times by fluorine, R 13< stands for hydrogen, fluorine or methyl, or R 12< and R 13< together with the carbon atoms to which they are attached form a cyclopropyl ring, or R 13< and R 14A< together with the carbon atom to which they are attached form a cyclopropyl ring,wherein the cyclopropyl ring may be substituted up to twice by fluorine, or R 14A< and R 14B< together with the carbon atom to which they are attached form a cyclopropyl ring, wherein the cyclopropyl ring may be substituted up to twice by fluorine, where R 13< , R 14A< and R 14B< are hydrogen if R 12< is not hydrogen, where R 12< is hydrogen if one of the substituents R 13< , R 14A< or R 14B< is not hydrogen, R 3< is hydrogen, R 4< is hydrogen, fluorine or methyl, R 5< is hydrogen, , as well as the salts, solvates and solvates of the salts of the compounds of formula (I).

[0041] Particularly preferred in the context of the present invention are compounds of the general formula (I) in which A stands for -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 -, # 5< -CH 2 CH(CH 3 )-***, # 5< -CH 2 C(CH 3 ) 2 -***, # 5< -CH 2 CHF-*** or # 5< -CH 2 CF 2 -***, where # 5< marks the linkage to the nitrogen atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where *** marks the linkage to the R 1< group, X stands for - # 2< -CR 6< R 7< -CR 8< R 9< -**, where # 2< marks the linkage to the carbon atom of the CR 4< R 5< group, where ** marks the linkage to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring where R 6< represents hydrogen, fluorine, methyl, trifluoromethyl or hydroxy, R 7< represents hydrogen, fluorine or methyl, or R 6< and R 7< together with the carbon atom to which they are attached form a cyclopropyl ring, R 8< represents hydrogen, fluorine, methyl or trifluoromethyl, R 9< represents hydrogen, fluorine or methyl, R 1< represents phenyl, pyrazolyl, imidazolyl, thiazolyl, thiophenyl, oxazolyl, oxadiazolyl or pyridyl,wherein phenyl is substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylsulfanyl, methylsulfonyl, methylsulfonimidoyl, aminosulfonyl or methylsulfinyl, or wherein phenyl may be fused with cyclopentyl, cyclohexyl, pyrazolyl or pyridyl, wherein (cyclopentyl, cyclohexyl, pyrazolyl or pyridyl may be substituted with 1 or 2 substituents by methyl or ethyl, or wherein pyrazolyl, imidazolyl, thiazolyl, thiophenyl, oxazolyl, oxadiazolyl or pyridyl may be substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, Trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, methylaminocarbonyl, tert-butylaminocarbonyl, dimethylaminocarbonyl,may be substituted, wherein pyrazolyl, imidazolyl, thiazolyl, thiophenyl, oxazolyl, oxadiazolyl or pyridyl may be fused with cyclopentyl, cyclohexyl, phenyl or pyrdiyl, wherein pyridyl may be substituted with methyl, ethyl, chlorine, fluorine or methoxy, wherein cyclopentyl, cyclohexyl, phenyl and pyridyl may be substituted with 1 or 2 (C 1 -C 4 )-alkyl substituents, R 2< represents a group of the formula , where # 3< marks the linkage to the carbonyl carbon atom, r stands for 0 or 1, Z stands for S or CR 14A< R 14B< when r stands for 0, Z stands for S, SO, SO 2 or CR 14A< R 14B< when r stands for 1, wherein each R 14A< stands for hydrogen, fluorine, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, hydroxy, methoxy, difluoromethoxy or trifluoromethoxy, R 14B< stands for hydrogen or fluorine, or R 14A< and R 14B< together with the carbon atom to which they are attached form a carbonyl group, R 12< stands for hydrogen, cyano, methyl, acetyl or formyl, wherein acetyl is substituted by hydroxy or up to three times by fluorine, R 13< stands for hydrogen, fluorine or methyl, or R 12< and R 13< together with the carbon atoms to which they are attached form a cyclopropyl ring, or R 13< and R 14A< together with the carbon atom to which they are attached form a cyclopropyl ring,wherein the cyclopropyl ring may be substituted up to twice by fluorine, or R 14A< and R 14B< together with the carbon atom to which they are attached form a cyclopropyl ring, wherein the cyclopropyl ring may be substituted up to twice by fluorine, where R 13< , R 14A< and R 14B< are hydrogen if R 12< is not hydrogen, where R 12< is hydrogen if one of the substituents R 13< , R 14A< or R 14B< is not hydrogen, R 3< is hydrogen, R 4< is hydrogen, fluorine or methyl, R 5< is hydrogen, , as well as the salts, solvates and solvates of the salts of the compounds of formula (I).

[0042] Also preferred in the context of the present invention are compounds of formula (I) in which A stands for -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 -, # 5< -CH 2 CH(CH 3 )-***, # 5< -CH 2 C(CH 3 ) 2 -***, # 5< -CH 2 CHF-*** or # 5< -CH 2 CF 2 -***, where # 5< marks the linkage to the nitrogen atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where *** marks the linkage to the R 1< group, as well as their solvates, salts and solvate salts.

[0043] Particularly preferred in the context of the present invention are also compounds of formula (I) in which A stands for -CH 2 -, -CH(CH 3 )- or -CH 2 CH 2 -, as well as their solvates, salts and solvate salts.

[0044] Particularly preferred in the context of the present invention are also compounds of formula (I) in which A stands for -CH 2 -, as well as their solvates, salts and solvate salts.

[0045] Also preferred in the context of the present invention are compounds of formula (I) in which X stands for -# 2< -CR 6< R 7< -CR 8< R 9< -**, where # 2< marks the linkage to the carbon atom of the CR 4< R 5< group, where ** marks the linkage to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where R 6< stands for hydrogen, fluorine, methyl, trifluoromethyl or hydroxy, R 7< stands for hydrogen, fluorine or methyl, or R 6< and R 7< together with the carbon atom to which they are attached form a cyclopropyl ring, as well as their solvates, salts and solvate salts.

[0046] Also preferred in the context of the present invention are compounds of formula (I) in which X stands for - # 2< -CR 6< R 7< -CR 8< R 9< -**, where # 2< marks the linkage to the carbon atom of the CR 4< R 5< group, where ** marks the linkage to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where R 6< stands for hydrogen, fluorine, methyl, trifluoromethyl or hydroxy, R 7< stands for hydrogen, fluorine or methyl, or R 6< and R 7< together with the carbon atom to which they are attached form a cyclopropyl ring, R 8< stands for hydrogen, fluorine, methyl or trifluoromethyl, R 9< stands for hydrogen, fluorine or methyl, as well as their solvates, salts and solvate salts.

[0047] Particularly preferred in the context of the present invention are also compounds of formula (I) in which X stands for - # 2< -CR 6< R 7< -CR 8< R 9< -**, where # 2< marks the linkage to the carbon atom of the CR 4< R 5< group, where ** marks the linkage to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where R 6< stands for hydrogen, fluorine, methyl or trifluoromethyl, R 7< stands for hydrogen, as well as their solvates, salts and solvate salts.

[0048] Particularly preferred in the context of the present invention are also compounds of formula (I) in which X stands for - # 2< -CR 6< R 7< -CR 8< R 9< -**, where # 2< marks the linkage to the carbon atom of the CR 4< R 5< group, where ** marks the linkage to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where R 6< stands for trifluoromethyl, R 7< stands for hydrogen, R 8< stands for hydrogen, R 9< stands for hydrogen, as well as their solvates, salts and solvate salts.

[0049] Also preferred in the context of the present invention are compounds of formula (I) in which X stands for - # 2< -CR 6< R 7< -CR 8< R 9< -**, where # 2< marks the linkage to the carbon atom of the CR 4< R 5< group, where ** marks the linkage to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where R 6< stands for hydrogen, R 7< stands for hydrogen, R 8< stands for hydrogen, fluorine, methyl or trifluoromethyl, R 9< stands for hydrogen, fluorine or methyl, as well as their solvates, salts and solvate salts.

[0050] Particularly preferred in the context of the present invention are also compounds of formula (I) in which X stands for - # 2< -CR 6< R 7< -CR 8< R 9< -**, where # 2< marks the linkage to the carbon atom of the CR 4< R 5< group, where ** marks the linkage to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where R 6< stands for hydrogen, R 7< stands for hydrogen, R 8< stands for fluorine, R 9< stands for fluorine, as well as their solvates, salts and solvate salts.

[0051] Particularly preferred in the context of the present invention are also compounds of formula (I) in which X stands for - # 2< -CR 6< R 7< -CR 8< R 9< -**, where # 2< marks the linkage to the carbon atom of the CR 4< R 5< group, where ** marks the linkage to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where R 6< stands for hydrogen, R 7< stands for hydrogen, R 8< stands for hydrogen, R 9< stands for hydrogen, as well as their solvates, salts and solvate salts.

[0052] The present invention relates to compounds of formula (I) in which R 1< represents phenyl or 5- to 6-membered heteroaryl, where phenyl is substituted by 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylsulfanyl, methylsulfonyl, methylsulfonimidoyl, aminosulfonyl or methylsulfinyl, or where phenyl can be fused with cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl, where (cyclopentyl, cyclohexyl, (C 5 -C 6 )-heterocycyl and 5- to 6-membered heteroaryl with 1 or 2 substituents are methyl or Ethyl may be substituted, or wherein 5- to 6-membered heteroaryl having 1 to 3 substituents independently selected from the group fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,Methylaminocarbonyl, tert-butylaminocarbonyl, dimethylaminocarbonyl, wherein 5- to 6-membered heteroaryl may be fused with cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, wherein 5- to 6-membered heteroaryl may be substituted with methyl, ethyl, chlorine, fluorine or methoxy, wherein cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl may be substituted with 1 or 2 (C 1 -C 4 )-alkyl substituents, as well as their solvates, salts and solvate salts.

[0053] Also preferred in the context of the present invention are compounds of formula (I) in which R 1< represents 5- to 6-membered heteroaryl, where 5- to 6-membered heteroaryl may be substituted by 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, methylaminocarbonyl, tert-butylaminocarbonyl, dimethylaminocarbonyl, where 5- to 6-membered heteroaryl may be fused with cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, where 5- to 6-membered heteroaryl may be substituted with methyl, ethyl, chlorine, fluorine or methoxy, where cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl may be substituted with 1 or 2 (C 1 -C 4 )-alkyl substituents, as well as their solvates, salts and solvate salts.

[0054] Also preferred in the context of the present invention are compounds of formula (I) in which R 1< represents phenyl, pyrazolyl, imidazolyl, thiazolyl, thiophenyl, oxazolyl, oxadiazolyl or pyridyl, where phenyl is substituted by 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylsulfanyl, methylsulfonyl, methylsulfonimidoyl, aminosulfonyl or methylsulfinyl, or where phenyl can be fused with cyclopentyl, cyclohexyl, pyrazolyl or pyridyl, where (cyclopentyl, cyclohexyl, pyrazolyl or pyridyl can be substituted by 1 or 2 substituents methyl or ethyl, or where pyrazolyl, imidazolyl, thiazolyl, thiophenyl, Oxazolyl, oxadiazolyl or pyridyl having 1 to 3 substituents independently selected from the group fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, methylaminocarbonyl, tert-butylaminocarbonyl, dimethylaminocarbonyl, wherein pyrazolyl, imidazolyl, thiazolyl, thiophenyl, oxazolyl, oxadiazolyl or pyridyl may be annelated with cyclopentyl, cyclohexyl, phenyl or pyrdiyl, wherein pyridyl may be substituted with methyl, ethyl, chlorine, fluorine or methoxy, wherein cyclopentyl, cyclohexyl, phenyl and pyridyl may be substituted with 1 or 2 (C 1 -C 4 )-alkyl substituents, as well as their solvates, salts and solvate salts.

[0055] Also preferred in the context of the present invention are compounds of formula (I) in which R 1< represents phenyl, where phenyl is substituted by 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylsulfanyl, methylsulfonyl, methylsulfonimidoyl, aminosulfonyl or methylsulfinyl, or where phenyl may be fused with cyclopentyl, cyclohexyl, pyrazolyl or pyridyl, where (cyclopentyl, cyclohexyl, pyrazolyl or pyridyl may be substituted by 1 or 2 methyl or ethyl substituents, as well as their solvates, salts and solvate salts.

[0056] Particularly preferred in the context of the present invention are also compounds of formula (I) in which R 1< represents pyrazolyl, imidazolyl, thiazolyl, thiophenyl, oxazolyl or oxadiazolyl, where phenyl may be fused with cyclopentyl, cyclohexyl, pyrazolyl or pyridyl, wherein (cyclopentyl, cyclohexyl, pyrazolyl or pyridyl may be substituted by 1 or 2 methyl or ethyl substituents, where pyrazolyl, imidazolyl, thiazolyl, thiophenyl, oxazolyl, oxadiazolyl or may be substituted by 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, methylaminocarbonyl, tert-butylaminocarbonyl, dimethylaminocarbonyl, where pyrazolyl, imidazolyl, thiazolyl, thiophenyl, oxazolyl, oxadiazolyl or pyridyl may be fused with cyclopentyl, cyclohexyl, phenyl or pyrdiyl, wherein pyridyl may be substituted with methyl, ethyl, chlorine, fluorine or methoxy, wherein cyclopentyl, cyclohexyl,Phenyl and pyridyl may be substituted by 1 or 2 (C 1 -C 4 )-alkyl substituents, as well as their solvates, salts and solvate salts.

[0057] Particularly preferred in the context of the present invention are also compounds of formula (I) in which R 1< represents pyridyl, where pyridyl may be substituted by 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, trifluoromethyl and methoxy, as well as their solvates, salts and solvate salts.

[0058] Also preferred in the context of the present invention are compounds of formula (I) in which R 2< for a group of the formula where # 3< marks the linkage to the carbonyl carbon atom, r stands for 0 or 1, Z stands for S or CR 14A< R 14B< when r stands for 0, Z stands for S, SO, SO 2 or CR 14A< R 14B< when r stands for 1, wherein each R 14A< stands for hydrogen, fluorine, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, hydroxy, methoxy, difluoromethoxy or trifluoromethoxy, R 14B< stands for hydrogen or fluorine, or R 14A< and R 14B< together with the carbon atom to which they are attached form a carbonyl group, R 12< stands for hydrogen, cyano, methyl, acetyl or formyl, wherein acetyl is substituted by hydroxy or up to three times by fluorine, R 13< stands for hydrogen, fluorine or methyl, or R 12< and R 13< together with the carbon atoms to which they are attached form a cyclopropyl ring, or R 13< and R 14A< together with the carbon atoms to which they are attached form a cyclopropyl ring,wherein the cyclopropyl ring may be substituted up to twice by fluorine, R 12< and R 13< or R 14A< and R 14B< together with the carbon atom to which they are attached form a cyclopropyl ring, wherein the cyclopropyl ring may be substituted up to twice by fluorine, where R 13< , R 14A< and R 14B< are hydrogen if R 12< does not represent hydrogen, where R 12< is hydrogen if one of the substituents R 13< , R 14A< or R 14B< is not hydrogen, as well as their solvates, salts and solvate salts.

[0059] Also preferred in the context of the present invention are compounds of formula (I) in which R 3< stands for hydrogen, as well as their solvates, salts and solvate salts.

[0060] Also preferred in the context of the present invention are compounds of formula (I) in which R 4< represents hydrogen, fluorine or methyl, as well as their solvates, salts and solvate salts.

[0061] Also preferred in the context of the present invention are compounds of formula (I) in which R 5< stands for hydrogen, as well as their solvates, salts and solvate salts.

[0062] The invention further relates to a process for preparing the compounds of formula (I) according to the invention, characterized in that [A] a compound of formula (II) in which R 3< , R 4< , R 5< and X each have the meanings given in claim 1, and T 1< is (C 1 -C 4 )-alkyl or benzyl, in an inert solvent in the presence of a suitable base with a compound of formula (III) in which A' represents -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 -, # 5< -CH 2 CH(CH 3 )-***, # 5< -CH 2 C(CH 3 ) 2 -***, # 5< -CH 2 CHF-*** or # 5< -CH 2 CF 2 -***, where # 5< marks the link to X 1<, where *** marks the link to the R 1< group, R 1< has the meanings given in claim 1, and X 1< stands for a suitable leaving group, in particular chlorine, bromine, iodine, mesylate {(methylsulfonyl)oxy}, triflate {[(trifluoromethyl)sulfonyl]oxy}, nonaflate {[(nonafluorobutyl)sulfonyl]oxy}, nosylate {[(4-nitrophenyl)sulfonyl]oxy} or tosylate {[(4-methylphenyl)sulfonyl]oxy}, to a Compound of formula (IV) in which A 1< , R 1< , R 3< , R 4< , R 5< , X each have the meanings given above, and T 1< is (C 1 -C 4 )-alkyl or benzyl, which is then converted into a compound of formula (V) by removing the group "T 1< " in an inert solvent in the presence of a suitable base or acid in which A 1< , R 1< , R 3< , R 4< , R 5< and X each have the meanings given in claim 1, and then reacting these in an inert solvent under amide coupling conditions with an amine of the formula (VI-A) or (VI-B), in which r, Y, Z, R 12< and R 13< each have the meanings given in claim 1, and then splitting off any protective groups present by methods known to the person skilled in the art, and converting the resulting compounds of the formula (I) into their solvates, salts and / or solvates of the salts, if appropriate with the corresponding (i) solvents and / or (ii) acids or bases, or [B] a compound of the formula (II) in which R 3< , R 4< , R 5< and X each have the meanings given in claim 1, and T 1< is (C 1 -C 4 )-alkyl or benzyl, in an inert solvent in the presence of a suitable base with an amine of the formula (VI-A) or (VI-B), in which r, Y, Z, R 12< and R 13< each have the meanings given above, to a compound of formula (XXIII-A) or (XXIII-B), in which r, R 3< , R 4< , R 5< , R 12< , R 13< , X, Y and Z each have the meanings given in claim 1, reacting this in an inert solvent in the presence of a suitable base with a compound of formula (III) in which A'represents -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 -, # 5< -CH 2 CH(CH 3 )-***, # 5< -CH 2 C(CH 3 ) 2 -***, # 5< -CH 2 CHF-*** or # 5< -CH 2 CF 2 -***, where # 5< marks the link to X 1<, where *** marks the link to the R 1< group, R 1< has the meanings given above, and X 1< stands for a suitable leaving group, in particular chlorine, bromine, iodine, mesylate {(methylsulfonyl)oxy}, triflate {[(trifluoromethyl)sulfonyl]oxy}, nonaflate {[(nonafluorobutyl)sulfonyl]oxy}, nosylate {[(4-nitrophenyl)sulfonyl]oxy} or tosylate {[(4-methylphenyl)sulfonyl]oxy}, and then any protective groups present are removed by methods known to the person skilled in the art, and the resulting compounds of formula (I) are optionally converted into their solvates, salts and / or solvates of the salts using the appropriate (i) solvents and / or (ii) acids or bases, or [C] a compound of formula (VII) in which R 3< , R 4< , R 5< and X each have the meanings given in claim 1 and T 1< is (C 1 -C 4 )-alkyl or benzyl, T 2< is 4-methoxybenzyl, benzyl, allyl, β-(trimethylsilyl)ethoxymethyl (SEM), methoxymethyl (MOM) or benzyloxymethyl, by hydrolysis of the ester group in an inert solvent in the presence of a suitable base or acid into a compound of formula (VIII) in which R 3< , R 4< , R 5< and X each have the meanings given in claim 1 and above, and T 2< is 4-methoxybenzyl, benzyl, allyl, β-(trimethylsilyl)ethoxymethyl (SEM), methoxymethyl (MOM) or benzyloxymethyl, which are then reacted in an inert solvent under amide coupling conditions with an amine of the formula (VI-A) in which r, Y, Z, R 12< and R 13< each have the meanings given in claim 1, to a compound of formula (IX-A) or (IX-B), in which r, R 3< , R 4< , R 5< , R 12< , R 13< , T 2< , X, Y and Z each have the meanings given above, the protecting group "T 2< " is removed in an inert solvent in the presence of a suitable base or acid or optionally in the presence of a suitable palladium catalyst and the resulting compound of formula (XA) or (XB), in which r, R 3< , R 4< , R 5< , R 12< , R 13< , X, Y and Z each have the meanings given in claim 1, in an inert solvent in the presence of a suitable base with a compound of formula (III) in which A'represents -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 -, # 5< -CH 2 CH(CH 3 )-***, # 5< -CH 2 C(CH 3 ) 2 -***, # 5< -CH 2 CHF-*** or # 5< -CH 2 CF 2 -***, where # 5< marks the link to X 1<, where *** marks the link to the R 1< group, R 1< has the meanings given above, and X 1< stands for a suitable leaving group, in particular chlorine, bromine, iodine, mesylate {(methylsulfonyl)oxy}, triflate {[(trifluoromethyl)sulfonyl]oxy}, nonaflate {[(nonafluorobutyl)sulfonyl]oxy}, nosylate {[(4-nitrophenyl)sulfonyl]oxy} or tosylate {[(4-methylphenyl)sulfonyl]oxy}, and then any protective groups present are removed by methods known to the person skilled in the art, and the resulting compounds of formula (I) are optionally converted into their solvates, salts and / or solvates of the salts using the appropriate (i) solvents and / or (ii) acids or bases.

[0063] The compounds of formulas (III), (VI-A) and (VI-B) are commercially available, known from the literature or can be prepared analogously to processes known from the literature.

[0064] Inert solvents for process step (II) + (III) -> (IV) or (X) + (III) → (I) are, for example, halogenated hydrocarbons such as dichloromethane, carbon tetrachloride, trichloroethylene or chlorobenzene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2,2,2-trifluoroethanol or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N,N -Dimethylformamide, N,N- dimethyl acetamide, dimethyl sulfoxide, N , N '-Dimethylpropyleneurea(DMPU), NMethylpyrrolidone (NMP) or pyridine. Mixtures of these solvents can also be used. Dimethylformamide or acetonitrile are preferred.

[0065] Suitable bases for process step (II) + (III) -> (IV) or (X) + (III) → (I) are the usual inorganic or organic bases. These preferably include lithium, sodium, potassium, alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alcoholates such as potassium tert-butoxide, methanolate, ethanolate, alkali metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, optionally with the addition of an alkali metal iodide such as sodium iodide or potassium iodide, or organic amines such as triethylamine, N -Methylmorpholine, N -Methylpiperidine, N , NDiisopropylethylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or 1,4-diazabicyclo[2.2.2]octane (DABCO ®< ). Cesium carbonate is preferred.

[0066] The reaction generally takes place in a temperature range from 0°C to +120°C, preferably from +20°C to +80°C, most preferably at room temperature, optionally in a microwave. The reaction can be carried out at normal, elevated, or reduced pressure (e.g., from 0.5 to 5 bar).

[0067] The hydrolysis of the esters of compounds (IV) to give compounds of formula (V) or of compounds (VII) to give compounds of formula (VIII) is carried out by conventional methods by treating the esters with acids or bases in inert solvents. In the latter case, the initially formed salts are converted into the free carboxylic acids by treatment with acid. In the case of tert-butyl esters, the ester cleavage is preferably carried out with acids.

[0068] Suitable inert solvents for these reactions are water or the organic solvents commonly used for ester cleavage. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, dioxane, or glycol dimethyl ether, or other solvents such as acetone, dichloromethane, dimethylformamide, or dimethyl sulfoxide. Mixtures of the solvents mentioned can also be used. In the case of basic ester hydrolysis, mixtures of water with dioxane, tetrahydrofuran, methanol, and / or ethanol and / or n-propanol are preferred. In the case of the reaction with trifluoroacetic acid, dichloromethane is preferred, and in the case of the reaction with hydrogen chloride, tetrahydrofuran, diethyl ether, dioxane, or water are preferred.

[0069] Conventional inorganic bases are suitable as bases. These preferably include alkali or alkaline earth hydroxides such as sodium, lithium, potassium, or barium hydroxide, or alkali or alkaline earth carbonates such as sodium, potassium, or calcium carbonate. Sodium or lithium hydroxide are particularly preferred.

[0070] Acids generally suitable for ester cleavage are sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid, or trifluoromethanesulfonic acid, or mixtures thereof, optionally with the addition of water. Hydrogen chloride or trifluoroacetic acid are preferred for tert-butyl esters, and hydrochloric acid for methyl esters.

[0071] The ester cleavage generally takes place in a temperature range from 0°C to +100°C, preferably at +0°C to +50°C, particularly preferably at room temperature.

[0072] The reactions mentioned can be carried out at normal, elevated, or reduced pressure (e.g., from 0.5 to 5 bar). Generally, the reaction is carried out at normal pressure.

[0073] Inert solvents for the amide coupling (V) + (VI-A) → (I) or (V) + (VI-B) → (I) or (VIII) + (VI-A) → (IX-A) or (VIII) + (VI-B) → (IX-B) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N'-Dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). Mixtures of these solvents can also be used. Preferred solvents are dichloromethane, tetrahydrofuran, dimethylformamide, or mixtures of these solvents.

[0074] Suitable condensation agents for the amide formation v or (VIII) + (VI-A) -> (IX-A) or (VIII) + (VI-B) -> (IX-B) are, for example, carbodiimides such as N,N'-diethyl-, N,N'-dipropyl-, N,N'-diisopropyl-, N,N'-dicyclohexylcarbodiimide (DCC) or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N,N'-carbonyldiimidazole (CDI), 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or isobutyl chloroformate, Propanephosphonic anhydride (T3P), 1-chloro-N,N,2-trimethylprop1-en-1-amine, cyanophosphonic acid diethyl ester, bis-(2-oxo-3-oxazolidinyl)-phos-phoryl chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, Benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), O -(Benzotriazol-1-yl)- N , N , N ', N'-tetramethyluronium tetrafluoroborate (TBTU), O -(Benzotriazol-1-yl)- N , N , N ', N '-tetramethyluronium hexafluorophosphate (HBTU), 2-(2-oxo-1-(2 H )-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O -(7-Azabenzotriazol-1-yl)- N,N,N',N -tetramethyl uronium hexafluorophosphate (HATU) or O -(1 H -6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU), optionally in combination with other excipients such as 1-hydroxybenzotriazole (HOBt) or N -Hydroxysuccinimide (HOSu), and as bases alkali carbonates, e.g. sodium or potassium carbonate or hydrogen carbonate, or organic bases such as trialkylamines, e.g. triethylamine, N -Methylmorpholine, N -Methylpiperidine or N,N- Diisopropylethylamine. HATU is preferred.

[0075] The condensation (V) + (VI-A) -> (I) or (V) + (VI-B) -> (I) or (VIII) + (VI-A) -> (IX-A) or (VIII) + (VI-B) -> (IX-B) is generally carried out in a temperature range from -20°C to +100°C, preferably from 0°C to +60°C. The reaction can be carried out at atmospheric, elevated, or reduced pressure (e.g., from 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.

[0076] Alternatively, the carboxylic acid of formula (V) or (VIII) can also first be converted into the corresponding carboxylic acid chloride, which can then be reacted directly or in a separate reaction with an amine of formula (VI) to give the compounds of the invention. The formation of carboxylic acid chlorides from carboxylic acids takes place by methods known to the person skilled in the art, for example by treatment with thionyl chloride or oxalyl chloride in the presence of a suitable base, for example in the presence of pyridine, and optionally with the addition of dimethylformamide, optionally in a suitable inert solvent.

[0077] The cleavage of the protecting group in reaction step (IX) -> (X) is carried out according to customary methods known from protecting group chemistry, preferably by reaction with acid such as trifluoroacetic acid in dichloromethane, by base such as ammonia in methanol, hydrogenolysis in the presence of a palladium catalyst, such as palladium on activated carbon, in an inert solvent such as ethanol or ethyl acetate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or ammonium cerium(IV) nitrate (CAN) [see also e.g. TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999].

[0078] Inert solvents for the reaction (II) + (VI-A) -> (XXIII-A) or (II) + (VI-B) -> (XXIII-B) include pyrrolidine, toluene, acetonitrile, tetrahydrofuran, or dichloromethane. Pyrrolidine is preferred.

[0079] The reaction (II) + (VI-A) -> (XXIII-A) or (II) + (VI-B) -> (XXIII-B) is generally carried out in a temperature range from 20°C to +200°C, preferably from 80°C to +200°C. The reaction can be carried out at normal or elevated pressure (e.g., from 1 to 5 bar). Generally, the reaction is carried out at normal pressure.

[0080] The compounds of formula (II) in which X represents # 2< -CR 6< R 7< -CR 8< R 9< -** and R 3< , R 7< and R 9< represent hydrogen, can be prepared by reacting a compound of formula (XI) in which T 1< represents (C 1 -C 4 )-alkyl or benzyl, X 2< represents fluorine, chlorine, bromine or iodine, and R 4<, R 6< and R 8< each have the meanings given above,

[0081] in an inert solvent in the presence of a suitable base and optionally a palladium catalyst with a compound of formula XII, in which T 3< represents benzyl or tert-butyl, to a compound of formula (XIII), in which R 4< , R 6< , R 8< , T 1< and T 3< each have the meanings given above, the protecting group T 3< is cleaved in a suitable inert solvent by hydrogenolysis in the presence of a palladium catalyst and the resulting compound of formula (XIV) in which R 4< , R 6< , R 8< and T 1< each have the meanings given above, in a suitable solvent with a phosgene derivative to give a compound of formula (XV), in which R 4< , R 6< , R 8< and T 1< each have the meanings given above, are cyclized and then hydrogenated in a suitable solvent in the presence of a palladium catalyst in a hydrogen atmosphere, and the resulting compounds of formula (II) are optionally converted into their solvates, salts and / or solvates of the salts with the appropriate (i) solvents and / or (ii) acids or bases.

[0082] The compounds of formula (II) or (IV) in which X represents # 2< -CR 6< R 7< -CR 8< R 9< -** can be prepared by reacting a compound of formula (XVI), in which T 1< represents (C 1 -C 4 )-alkyl or benzyl, and R 3< , R 4< , R 5< , R 6< , R 7< , R 8< and R 9< each have the meanings given above, in a suitable solvent in the presence of trimethyloxonium tetrafluoroborate with a compound of the formula (XVII-A) or (XVII-B), in which T 2< is 4-methoxybenzyl, T 4< is methyl or ethyl, and A 1< and R 1< each have the meanings given above, to a compound of formula (XVIII-A) or (XVIII-B) in which A 1< , R 1< , R 3< , R 4< , R 5< , R 6< , R 7< , R 8< , R 9< T 1< , T 2< and T 4< each have the meanings given above, reacting these in a suitable solvent to a compound of the formula (XIX-A) or (XIX-B), in which A 1< , R 1< , R 3< , R 4< , R 5< , R 6< , R 7< , R 8< , R 9< T 1< and T 2< each have the meanings given above, and for the compounds of the formula (XIX-A) the T 2< protecting group is then removed in an inert solvent in the presence of a suitable acid, and the resulting compounds of the formula (II) are optionally converted into their solvates, salts and / or solvates of the salts using the appropriate (i) solvents and / or (ii) acids or bases.

[0083] The compounds of formula (XIX-B) correspond to the compounds of formula (IV) if in formula (IV) X stands for # 2< -CR 6< R 7< -CR 8< R 9< -**.

[0084] The compounds of formula (VII) correspond to the compounds of formula (XIX) if in formula (VII) X stands for # 2< -CR 6< R 7< -CR 8< R 9< -**.

[0085] The compounds of formula (II) in which X is -CR 6< R 7< - can be prepared by reacting a compound of formula (XX), in which T 1< represents (C 1 -C 4 )-alkyl or benzyl, and R 3< , R 4< , R 5< , R 6< and R 7< each have the meanings given above, in a suitable solvent first in the presence of trimethyloxonium tetrafluoroborate and then with a compound of the formula (XXI), in which T 4< is methyl, ethyl, tert-butyl or benzyl, to a compound of formula (XXII) In which R 3< , R 4< , R 5< , R 6< , R 7< and T 1< each have the meanings given above.

[0086] The compounds of formulas (XI), (XII), (XVII-A), (XVII-B), (XX) and (XXI) are commercially available, known from the literature or can be prepared analogously to processes known from the literature.

[0087] The described procedures are illustrated by the following schemes (Schemes 1-3): a) tert-Butanol, pyridine, p-toluenesulfonyl chloride, RT; b) benzylcarbazate, cesium carbonate, 1,1'-bis(diphenylphosphino)ferrocene, bis(dibenzylideneacetone)palladium(0) in toluene 80°C; c) Pd / C 5%, 1 bar H2 in toluene / methanol, RT; d) Carbonyldiimidazole, THF, RT; e) Pd / C 5%, 34.5 bar H 2 in toluene / methanol, RT; f) Cesium carbonate, 1-(bromomethyl)-3,5-dichlorobenzene in acetonitrile, RT; g) HCl in 1,4-dioxane, RT; h) HATU, triethylamine, pyrrolidine in THF, RT. a)1.Methyl-(5RS)-6-oxopiperidine-2-carboxylate, trimethyloxonium tetrafluoroborate, dichloromethane, RT; 2. Methyl 1-(4-methoxybenzyl)hydrazine carboxylate, dichloromethane, RT; b) DMF, 150 °C; c) ) Lithium hydroxide, THF / water, RT; d) HATU, triethylamine, pyrrolidine in DMF, RT; e) Trifluoroacetic acid, 150 °C. a) 1. Trimethyloxonium tetrafluoroborate and methyl 5-oxo-L-prolinate in dichloromethane, RT; 2. Methyl hydrazinoformate, RT 3. DMF, 170 °C; b) Cesium carbonate, 1-(bromomethyl)-4-methylbenzene in acetonitrile, RT; c) Lithium hydroxide in water / THF, RT; d) HATU, diisopropylethylamine, pyrrolidine in DMF / dichloromethane, RT.

[0088] Process step (XI) + (XII) → (XIII) is carried out in a solvent that is inert under the reaction conditions. Suitable solvents include ethers such as 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, di- n-butyl ether, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as tert-butanol or amyl alcohols, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), toluene, or acetonitrile. It is also possible to use mixtures of the solvents mentioned. tert .-Butanol, 1,4-dioxane and toluene.

[0089] The process step (XI) + (XII) → (XIII) is carried out in the presence of a suitable palladium catalyst. Examples of suitable palladium catalysts include palladium on activated carbon, palladium(II) acetate, bis(dibenzylideneacetone)palladium(0), tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, bis(acetonitrile)palladium(II) chloride, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and the corresponding dichloromethane complex, optionally in combination with additional phosphine ligands such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), (2-biphenyl)di-tert-butylphosphine, dicyclohexyl[2',4',6'-tris(1-methylethyl)biphenyl-2-yl]phosphine (XPhos), Bis(2-phenylphosphinophenyl)ether (DPEphos) or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) [cf. e.g. Hassan J. et al., Chem. Rev.2002, 102, 1359-1469], 2-(Dicyclohexylphosphin)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1 '-biphenyl (BrettPhos), 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), 2-(Di-t-butylphosphino)-3-methoxy-6-methyl-2',4',6'-tri-i-propyl-1,1'-biphenyl (RockPhos) und 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (. tert-ButylXPhos) is suitable. Furthermore, it is possible to use corresponding precatalysts such as chloro-[2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)-phenyl]palladium(II) (BrettPhos precatalyst) [cf. e.g. SL Buchwald et al., Chem. Sci. 2013, 4, 916], optionally in combination with additional phosphine ligands such as 2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos). Preferred are bis(dibenzylideneacetone)palladium(0) in combination with 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) and chloro-[2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)-phenyl]palladium(II) (BrettPhos precatalyst).

[0090] The reaction (XI) + (XII) → (XIII) takes place in the presence of a suitable base. Suitable bases for this reaction are the usual inorganic or organic bases. These preferably include alkali or alkaline earth carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali or alkaline earth hydroxides such as sodium, potassium or barium hydroxide, alkali or alkaline earth phosphates such as potassium phosphate, alkali alkoxides such as sodium or potassium tert .-butoxide and sodium methoxide, alkali phenolates such as sodium phenolate, amides such as sodium amide, lithium, sodium, or potassium bis(trimethylsilyl)amide, or lithium diisopropylamide, or organic amines such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Preferred amines are cesium carbonate, potassium carbonate, sodium or potassium tert-butoxide, or lithium bis(trimethylsilyl)amide.

[0091] Process step (XI) + (XII) → (XIII) is generally carried out in a temperature range from 0°C to +200°C, preferably from +10°C to +150°C. The reactions can also be carried out in closed vessels (microwave tubes) in the microwave. The reaction can be carried out at atmospheric, elevated, or reduced pressure (e.g., from 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure or in closed vessels (microwave tubes) below or above the boiling point of the solvent used. Preference is given to reactions in closed vessels (microwave tubes), at temperatures above the boiling point of the solvent, and under elevated pressure, with or without the use of a microwave.

[0092] The cleavage of the protecting group in reaction step (XIII) → (XIV) is carried out according to conventional methods known from protecting group chemistry, preferably by reaction with acid such as trifluoroacetic acid, hydrogenolysis in the presence of a palladium catalyst, such as palladium on activated carbon, in an inert solvent such as ethanol or ethyl acetate [see also e.g. TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999].

[0093] Inert solvents for process step (XIV) → (XV) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide, N , N -Dimethylformamide, N,N- Dimethylacetamide, N,N' -Dimethylpropyleneurea (DMPU) or N -Methylpyrrolidone (NMP). Mixtures of the solvents mentioned can also be used. Dichloromethane, tetrahydrofuran, dimethylformamide, or mixtures of these solvents are preferred.

[0094] Suitable phosgene derivatives for process step (XIV) → (XV) are, for example, N , N'-Carbonyldiimidazole (CDI), trichloromethyl chlorocarbonic acid ester (diphosgene), bis(trichloromethyl)carbonate (triphosgene) or chloroformate acid aryl ester.Preferred is N,N' -Carbonyldiimidazole (CDI) is used.

[0095] Process step (XIV) → (XV) is generally carried out in a temperature range from -20°C to +100°C, preferably from 0°C to +60°C. The reaction can be carried out at atmospheric, elevated, or reduced pressure (e.g., from 0.5 to 5 bar). Generally, the reaction is carried out at atmospheric pressure.

[0096] Inert solvents for process step (XV) → (II) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone, ethyl acetate, acetonitrile, N , N -Dimethylformamide, N , N -Dimethylacetamide, N,N' -Dimethylpropyleneurea (DMPU) or N -Methylpyrrolidone (NMP). Mixtures of the solvents mentioned can also be used. Dichloromethane, tetrahydrofuran, dimethylformamide, or mixtures of these solvents are preferred.

[0097] Process step (XV) → (II) is generally carried out in a temperature range from -20°C to +100°C, preferably from 0°C to +60°C. The reaction can be carried out at normal or elevated hydrogen pressure (e.g., from 1.0 to 100 bar). Elevated hydrogen pressure is generally used.

[0098] Inert solvents for process step (XVI) + (XVII-A) → (XVIII-A) or (XVI) + (XVII-B) → (XVIII-B) or (XXI + (XXI) → (XXII) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as N , N -Dimethylformamide, N,N- Dimethylacetamide, N,N' -Dimethylpropyleneurea (DMPU) or N -Methylpyrrolidone (NMP). Mixtures of the solvents mentioned can also be used. Dichloromethane is preferred.

[0099] The process step (XVI) + (XVII-A) → (XVIII-A) or (XVI) + (XVII-B) → (XVIII-B) or (XXI + (XXI) -> (XXII) is generally carried out in a temperature range from -20°C to +100°C, preferably at 0°C to +60°C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.

[0100] Inert solvents for process step (XVI) + (XVII-A) → (XVIII-A) or (XVI) + (XVII-B) → (XVIII-B) or (XXI + (XXI) → (XXII) are, for example, ethers such as dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide, N , N -Dimethylformamide,N , N -Dimethylacetamide, N,N'- Dimethylpropylene urea (DMPU) or N -Methylpyrrolidone (NMP). It is also possible to use mixtures of the solvents mentioned. N , N -Dimethylformamide.

[0101] Process step (XVI) + (XVII-A) → (XVIII-A) or (XVI) + (XVII-B) → (XVIII-B) is generally carried out in a temperature range from 20°C to +100°C, preferably from 0°C to +60°C, from 20°C to +250°C, preferably from 100°C to +200°C. The reaction can be carried out at atmospheric, elevated, or reduced pressure (e.g., from 0.5 to 5 bar). Generally, the reaction is carried out at atmospheric pressure.

[0102] Inert solvents for process step (XVIII-A) → (XIX-A) or (XVIII-B) → (XIX-B) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide, N , N -Dimethylformamide, N,N -Dimethylacetamide, N , N '-Dimethylpropyleneurea (DMPU) or N -Methylpyrrolidone (NMP). Mixtures of the solvents mentioned can also be used. Dichloromethane and acetonitrile are preferred.

[0103] Process step (XVIII-A) → (XIX-A) or (XVIII-B) → (XIX-B) is generally carried out in a temperature range from 20°C to +250°C, preferably from 100°C to +200°C. The reaction can be carried out at atmospheric, elevated, or reduced pressure (e.g., from 0.5 to 5 bar). Generally, the reaction is carried out at atmospheric pressure.

[0104] Any hydroxy, amino and / or amido groups present in the starting compounds according to formula (II) and (VII) can, if appropriate or necessary, also be used in a temporarily protected form and then released again at the end of the respective reaction sequence [for the suitability, introduction and removal of such protecting groups see, for example, TWGreene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999).

[0105] Further compounds according to the invention can optionally also be prepared by converting functional groups of individual substituents, in particular those listed under R 3< , R 4< , R 5< , R 6< , R 7< , R 8< , R 9< , starting from the compounds of formula (I) obtained by the above processes. These conversions are carried out by customary methods known to the person skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, eliminations, alkylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of carboxamides, dehydrations and introduction and removal of temporary protecting groups.

[0106] Detailed instructions can also be found in the Experimental Part in the section on the preparation of starting compounds and intermediates. Explanations of the images:

[0107] Figure 1 : Example 237 in complex with pig PREP. Figure 2 : Example 358 in complex with pig PREP. Figure 3 : Example 454 in complex with pig PREP. Figure 4 : Example 108 in complex with pig PREP. Figure 5 : Example 113 in complex with pig PREP. Figure 6 : Example 157 in complex with pig PREP. Figure 7 : Example 026 in complex with pig PREP.

[0108] The compounds of the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

[0109] The compounds according to the invention are potent, chemically stable inhibitors of human prolyl endopeptidase (PREP, PE, prolyl oligopeptidase, POP) and are therefore suitable for the treatment and / or prevention of diseases and pathological processes, in particular those in which PREP or the PREP product PGP (proline-glycine-proline) is involved in the course of an infectious or non-infectious inflammatory process and / or tissue or vascular remodeling.

[0110] For the purposes of the present invention, these include in particular diseases of the respiratory tract and lungs, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), asthma and the group of interstitial lung diseases (ILD), as well as diseases of the cardiovascular system, such as arteriosclerosis and myocarditis.

[0111] The manifestations of COPD include, in particular, cigarette smoke-induced pulmonary emphysema, chronic bronchitis (CB), pulmonary hypertension in COPD (PH-COPD), bronchiectasis (BE) and combinations thereof, particularly in acute exacerbations of the disease (AE-COPD).

[0112] The manifestations of asthma include asthmatic diseases of varying severity with intermittent or persistent courses, such as refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and asthma induced by medication or dust.

[0113] The group of interstitial lung diseases (ILD) includes idiopathic pulmonary fibrosis (IPF), pulmonary sarcoidosis and acute interstitial pneumonia, non-specific interstitial pneumonias, lymphoid interstitial pneumonias, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonias, desquamative interstitial pneumonias and unclassifiable idiopathic interstitial pneumonias, as well as granulomatous interstitial lung diseases, interstitial lung diseases of known cause and other interstitial lung diseases of unknown cause.

[0114] The compounds according to the invention can also be used for the treatment and / or prevention of other diseases of the respiratory tract and lungs, such as pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), acute respiratory syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD) and cystic fibrosis (CF), various forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), bronchiectasis, pneumonia, farmer's lung and related diseases, infectious and non-infectious coughs and colds (chronic inflammatory cough, iatrogenic cough), nasal mucosal inflammations (including drug-induced rhinitis, vasomotor rhinitis and Seasonal allergic rhinitis, e.g. hay fever) and polyps.

[0115] The compounds according to the invention can furthermore be used for the treatment and / or prevention of cardiovascular diseases, such as high blood pressure (hypertension), heart failure, coronary heart disease, stable and unstable angina pectoris, renal hypertension, peripheral and cardiac vascular diseases, arrhythmias, atrial and ventricular rhythm disturbances and conduction disturbances such as grade I-III atrioventricular blocks, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV junctional extrasystoles, sick sinus syndrome, syncope, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart diseases (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies), boxer cardiomyopathy, aneurysms,Shock such as cardiogenic shock, septic shock and anaphylactic shock, furthermore for the treatment and / or prevention of thromboembolic diseases and ischemia, such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, pre-eclampsia, inflammatory cardiovascular diseases, spasms of the coronary arteries and peripheral arteries, edema formation such as pulmonary edema, cerebral edema, renal edema or heart failure-related edema, peripheral circulatory disorders, reperfusion injuries, arterial and venous thrombosis, microalbuminuria, heart muscle weakness, endothelial dysfunction, micro- and macrovascular damage (vasculitis), as well as for the prevention of restenosis, for example after thrombolysis therapies, percutaneous transluminal angioplasties (PTA), percutaneous transluminal Coronary angioplasties (PTCA), heart transplants and bypass operations.

[0116] For the purposes of the present invention, the term heart failure includes both acute and chronic manifestations of heart failure as well as specific or related disease forms thereof, such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, heart valve defects, heart failure in heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined heart valve defects, inflammation of the heart muscle (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic toxic Cardiomyopathy, cardiac storage diseases, and diastolic and systolic heart failure.

[0117] The compounds according to the invention are also suitable for the treatment and / or prevention of kidney diseases, in particular renal insufficiency and renal failure. For the purposes of the present invention, the terms renal insufficiency and renal failure encompass both acute and chronic manifestations thereof, as well as underlying or related kidney diseases, such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathic diseases such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as kidney transplant rejection and immune complex-induced kidney diseases, toxic-induced nephropathy, contrast-media-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, kidney cysts, nephrosclerosis,Hypertensive nephrosclerosis and nephrotic syndrome, which can be characterized diagnostically, for example, by abnormally reduced creatinine and / or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium, and / or creatinine, altered activity of renal enzymes such as glutamyl synthetase, altered urine osmolarity or urine volume, increased microalbuminuria, macroalbuminuria, lesions of glomeruli and arterioles, tubular dilation, hyperphosphatemia, and / or the need for dialysis. The present invention also encompasses the use of the compounds according to the invention for the treatment and / or prevention of sequelae of renal insufficiency, such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disturbances (e.g., hyperkalemia, hyponatremia), and disorders of bone and carbohydrate metabolism.

[0118] Furthermore, the compounds according to the invention are suitable for the treatment and / or prevention of diseases of the urogenital system, such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE), bladder emptying disorders (BOO), lower urinary tract syndromes (LUTS), neurogenic overactive bladder (OAB), incontinence such as mixed, urge, stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain as well as erectile dysfunction and female sexual dysfunction.

[0119] The compounds of the invention can also be used for the treatment of diseases of the female reproductive system, such as uterine fibroids, endometriosis, dysmenorrhea, and premature labor. Furthermore, they are suitable for the prophylaxis or treatment of hirsutism and hypertrichosis.

[0120] In addition, the compounds according to the invention have anti-inflammatory effects and can therefore be used as anti-inflammatory agents for the treatment and / or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic intestinal inflammation (IBD, Crohn's disease, ulcerative colitis), pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epidimytitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid diseases, osteoarthritis, inflammatory diseases of the central nervous system, multiple sclerosis, inflammatory skin diseases and inflammatory eye diseases.

[0121] The compounds according to the invention are also suitable for the treatment and / or prevention of fibrotic diseases of the internal organs, such as the lungs, heart, kidneys, bone marrow, and especially the liver, as well as dermatological fibroses and fibrotic diseases of the eye. For the purposes of the present invention, the term "fibrotic diseases" encompasses in particular diseases such as liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis, peritoneal fibrosis, and similar fibrotic diseases, scleroderma, morphea, keloids, hypertrophic scarring, nevi, diabetic retinopathy, proliferative vitroretinopathy, and connective tissue diseases (e.g., sarcoidosis).The compounds according to the invention can also be used to promote wound healing, to combat postoperative scarring, e.g. after glaucoma surgery, and for cosmetic purposes in aging or keratinizing skin.

[0122] The compounds of the invention can also be used for the treatment and / or prevention of anemias such as hemolytic anemias, in particular hemoglobinopathies such as sickle cell anemia and thalassemias, megaloblastic anemias, iron deficiency anemias, anemias due to acute blood loss, displacement anemias and aplastic anemias.

[0123] The compounds according to the invention are also suitable for the treatment of cancers, such as, for example, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, liver, pancreas, lung, kidney, ureter, prostate and genital tract, as well as malignant tumors of the lymphoproliferative system, such as, for example, Hodgkin's and non-Hodgkin's lymphoma.

[0124] In addition, the compounds according to the invention can be used for the treatment and / or prevention of arteriosclerosis, lipid metabolism disorders and dyslipidemias (hypolipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemias, hypercholesterolemia, abetalipoproteinemia, sitosterolemia), xanthomatosis, Tangier disease, obesity, metabolic diseases (metabolic syndrome, hyperglycemia, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance and diabetic late effects such as retinopathy, nephropathy and neuropathy), diseases of the gastrointestinal tract and abdomen (glossitis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, Proctitis, pruritis ani, diarrhea, celiac disease, hepatitis, liver fibrosis, liver cirrhosis, pancreatitis and cholecystitis),from diseases of the central nervous system and neurodegenerative disorders (stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, depression, multiple sclerosis), immune diseases, thyroid diseases (hyperthyroidism), skin diseases (psoriasis, acne, eczema, neurodermatitis, various forms of dermatitis such as dermatitis abacribus, dermatitis actinica, dermatitis allergica, dermatitis ammoniacalis, dermatitis artefacta, dermatitis autogenica, dermatitis atrophicans, dermatitis calorica, dermatitis combustionis, dermatitis congelationis, dermatitis cosmetica, dermatitis escharotica, dermatitis exfoliativa, dermatitis gangrenose, dermatitis haemostatica, dermatitis herpetiformis, dermatitis lichenoides, dermatitis linearis, dermatitis maligna, dermatitis medimencatosa, dermatitis palmaris et plantaris, dermatitis parasitaria, dermatitis photoallergica, Dermatitis phototoxica, dermatitis pustularis, dermatitis seborrheica,Dermatitis solaris, dermatitis toxica, ulcerative dermatitis, dermatitis veneata, infectious dermatitis, pyogenic dermatitis and rosacea-like dermatitis, as well as keratitis, bullosis, vasculitis, cellulitis, panniculitis, lupus erythematosus, erythema, lymphomas, skin cancer, Sweet's syndrome, Weber-Christian syndrome, scarring, wart formation, chilblains), inflammatory eye diseases (saccoidosis, blepharitis, conjunctivitis, iritis, uveitis, choroiditis, ophthalmitis), viral diseases (caused by influenza, adenoviruses and coronaviruses such as HPV, HCMV, HIV, SARS), diseases of the skeletal bones and joints as well as skeletal muscle (various forms of arthritis such as alcaptonuric arthritis, ankylosing arthritis, dysenteric arthritis, exudative arthritis, fungous arthritis, gonorrhoeal arthritis, arthritis mutilans, arthritis psoriatica, arthritis purulenta, arthritis rheumatica, arthritis serosa, arthritis syphilitica, arthritis tuberculosa, arthritis urica,Villonodular pigmentary arthritis, atypical arthritis, hemophilic arthritis, juvenile chronic arthritis, rheumatoid arthritis and metastatic arthritis, as well as Still's syndrome, Felty's syndrome, Sjörgen's syndrome, Clutton's syndrome, Poncet's syndrome, Pott's syndrome and Reiter's syndrome, various forms of arthropathies such as arthropathy deformans, arthropathy neuropathica, arthropathy ovaripriva, arthropathy psoriatica and arthropathy tabica, systemic sclerosis, various forms of inflammatory myopathies such as myopathy epidemica, myopathy fibrosa, myopathy myoglobinurica, myopathy ossificans, myopathy ossificans neurotica, myopathy ossificans progressiva multiplex, myopathy purulenta, myopathy rheumatica, myopathy trichinosa, myopathy tropica and myopathy typhosa, as well as Günther syndrome and Münchmeyer syndrome), from inflammatory arterial changes (various forms of arteritis such as endarteritis, mesarteritis, periarteritis,Polyarteritis, rheumatic arteritis, deforming arteritis, temporal arteritis, cranial arteritis, gigantocellular arteritis, and granulomatous arteritis, as well as Horton syndrome, Churg-Strauss syndrome, and Takayasu arteritis), Muckle-Well syndrome, Kikuchi disease, polychondritis, scleroderma, and other diseases with an inflammatory or immunological component, such as cataracts, cachexia, osteoporosis, gout, incontinence, leprosy, Sezary syndrome, and paraneoplastic syndrome, in rejection reactions after organ transplantation, and for wound healing and angiogenesis, particularly in chronic wounds.

[0125] Due to their biochemical and pharmacological property profile, the compounds according to the invention are particularly suitable for the treatment and / or prevention of inflammatory lung diseases, especially chronic obstructive pulmonary disease (COPD), pulmonary emphysema, chronic bronchitis, bronchiectasis, pulmonary hypertension in COPD (PH-COPD), acute exacerbation in COPD, cystic fibrosis (CF), asthma, as well as idiopathic pulmonary fibrosis (IPF), bronchiolitis obliterans syndrome (BOS), arteriosclerosis, myocarditis, as well as inflammatory skin and eye diseases or inflammatory diseases of the internal organs.

[0126] Due to their biochemical and pharmacological property profile, the compounds according to the invention are particularly suitable for the treatment and / or prevention of inflammatory lung diseases, in particular chronic obstructive pulmonary disease (COPD), pulmonary emphysema, chronic bronchitis, bronchiectasis, pulmonary hypertension in COPD (PH-COPD), acute exacerbation in COPD, cystic fibrosis (CF), asthma, as well as idiopathic pulmonary fibrosis (IPF) and bronchiolitis obliterans syndrome (BOS).

[0127] The aforementioned well-characterized human diseases can also occur in other mammals with comparable etiology and can also be treated there with the compounds of the present invention.

[0128] For the purposes of the present invention, the term "treatment" or "treat" encompasses inhibiting, delaying, stopping, alleviating, attenuating, limiting, reducing, suppressing, repressing, or curing a disease, ailment, illness, injury, or health disorder, the development, course, or progression of such conditions, and / or the symptoms of such conditions. The term "therapy" is understood here as synonymous with the term "treatment."

[0129] The terms "prevention", "prophylaxis" or "prevention" are used synonymously in the context of the present invention and refer to avoiding or reducing the risk of getting, experiencing, suffering or having a disease, ailment, illness, injury or health disorder, the development or progression of such conditions and / or the symptoms of such conditions.

[0130] The treatment or prevention of a disease, condition, illness, injury or health disorder may be partial or complete.

[0131] The present invention further relates to the use of the compounds according to the invention for producing a medicament for the treatment and / or prevention of diseases, in particular the diseases mentioned above.

[0132] The present invention further relates to a medicament containing at least one of the compounds according to the invention for the treatment and / or prevention of diseases, in particular the diseases mentioned above.

[0133] The compounds according to the invention can be used alone or, if necessary, in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesirable and unacceptable side effects. The present invention therefore further relates to medicaments containing at least one of the compounds according to the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases. Examples of suitable combination active ingredients include, but are not limited to: organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, as well as inhaled NO; compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, mirodenafil or lodenafil; NO- and heme-independent activators of soluble guanylate cyclase (sGC), such as in particular the compounds described in WO 01 / 19355, WO 01 / 19776, WO 01 / 19778, WO 01 / 19780, WO 02 / 070462 and WO 02 / 070510;NO-independent, but heme-dependent stimulators of soluble guanylate cyclase (sGC), such as in particular riociguat and the compounds described in WO 00 / 06568, WO 00 / 06569, WO 02 / 42301, WO 03 / 095451, WO 2011 / 147809, WO 2012 / 004258, WO 2012 / 028647 and WO 2012 / 059549; prostacyclin analogues and IP receptor agonists, such as, by way of example and with preference, iloprost, beraprost, treprostinil, epoprostenol or selexipag; endothelin receptor antagonists, such as, by way of example and with preference, bosentan, darusentan, ambrisentan or sitaxsentan; Compounds that inhibit human neutrophil elastase (HNE), such as, by way of example and preference, sivelestat or DX-890 (Reltran);compounds which inhibit the signal transduction cascade, by way of example and with preference from the group of kinase inhibitors, in particular from the group of tyrosine kinase and / or serine / threonine kinase inhibitors, such as by way of example and with preference nintedanib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, semaxanib or tandutinib; Compounds that inhibit the degradation and remodeling of the extracellular matrix, for example and preferably inhibitors of matrix metalloproteases (MMPs), in particular inhibitors of stromelysin, collagenases, gelatinases and aggrecanases (especially MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) as well as metalloelastase (MMP-12);Compounds that block the binding of serotonin to its receptor, by way of example and preferably antagonists of the 5-HT 2B receptor such as PRX-08066; antagonists of growth factors, cytokines and chemokines, by way of example and preferably antagonists of TGF-β, CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrins; compounds that inhibit Rho kinase, by way of example and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049; Compounds that inhibit soluble epoxide hydrolase (sEH), such as N,N'-dicyclohexylurea, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid or 1-adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}-urea; compounds that influence cardiac energy metabolism, such as, by way of example and preference, etomoxir, dichloroacetate, ranolazine or trimetazidine;Anti-obstructive agents, such as those used, for example, to treat chronic obstructive pulmonary disease (COPD) or bronchial asthma, for example and preferably from the group of inhaled or systemically administered β-adrenergic receptor agonists (β-mimetics) and inhaled anti-muscarinic substances; anti-inflammatory, immunomodulatory, immunosuppressive and / or cytotoxic agents, for example and preferably from the group of systemically or inhaled corticosteroids such as acetylcysteine, montelukast, azathioprine, cyclophosphamide, hydroxycarbamide, azithromycin, pirfenidone or etanercept;Antifibrotic agents, such as, by way of example and preferably, adenosine A2b receptor antagonists, sphingosine 1-phosphate receptor 3 (S1P3) antagonists, autotaxin inhibitors, lysophosphatidic acid receptor 1 (LPA-1) and lysophosphatidic acid receptor 2 (LPA-2) antagonists, lysyl oxidase (LOX) inhibitors, lysyl oxidase-like 2 inhibitors, CTGF inhibitors, IL-13 antagonists, α v β 6 integrin antagonists, TGF-β antagonists, inhibitors of the Wnt signaling pathway, or CCR2 antagonists; antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants, and profibrinolytic substances; blood pressure lowering agents, for example and preferably from the group of calcium antagonists, angiotensin antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, α-receptor blockers, β-receptor blockers, mineralocorticoid receptor antagonists and diuretics;Active substances that modify lipid metabolism, for example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as, for example and preferably, HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-α, PPAR-γ and / or PPAR-δ agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein(a) antagonists; and / or chemotherapeutic agents, such as those used, for example, for the treatment of neoplasms of the lungs or other organs.

[0134] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a β-adrenergic receptor agonist, such as, by way of example and by way of preference, albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, reproterol, salbutamol or salmeterol.

[0135] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an anti-muscarinic substance, such as, by way of example and by way of preference, ipratropium bromide, tiotropium bromide or oxitropium bromide.

[0136] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a corticosteroid, such as, by way of example and by way of preference, prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone.

[0137] Antithrombotic agents are preferably understood to mean compounds from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances.

[0138] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.

[0139] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, melagatran, dabigatran, bivalirudin or clexane.

[0140] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and preferably, tirofiban or abciximab.

[0141] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a factor Xa inhibitor, such as, by way of example and with preference, rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

[0142] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

[0143] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as, by way of example and preferably, coumarin.

[0144] Antihypertensive agents are preferably understood to be compounds from the group of calcium antagonists, angiotensin antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, α-receptor blockers, β-receptor blockers, mineralocorticoid receptor antagonists and diuretics.

[0145] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and preferably, nifedipine, amlodipine, verapamil or diltiazem.

[0146] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an α 1 receptor blocker, such as, by way of example and preferably, prazosin.

[0147] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a β-receptor blocker, such as, by way of example and with preference, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

[0148] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin all-antagonist, such as, for example and preferably, losartan, candesartan, valsartan, telmisartan, embursartan, irbesartan, olmesartan, eprosartan or azilsartan or a dual angiotensin all-antagonist / NEP inhibitor, such as, for example and preferably, LCZ696 (valsartan / sacubitril).

[0149] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor, such as, by way of example and with preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

[0150] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist, such as, by way of example and preferably, bosentan, darusentan, ambrisentan or sitaxsentan.

[0151] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a renin inhibitor, such as, by way of example and by way of preference, aliskiren, SPP-600 or SPP-800.

[0152] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as, by way of example and preferably, spironolactone, eplerenone or finerenone.

[0153] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a diuretic, such as, by way of example and with preference, furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

[0154] Lipid metabolism-altering agents are preferably understood to mean compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-α, PPAR-γ and / or PPAR-δ agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein(a) antagonists.

[0155] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as, by way of example and preferably, torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).

[0156] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thyroid receptor agonist, such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

[0157] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as, by way of example and with preference, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

[0158] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as, by way of example and preferably, BMS-188494 or TAK-475.

[0159] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as, by way of example and by way of preference, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

[0160] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor, such as, by way of example and by way of preference, implitapide, BMS-201038, R-103757 or JTT-130.

[0161] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-γ agonist, such as, by way of example and preferably, pioglitazone or rosiglitazone.

[0162] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-δ agonist, such as, by way of example and preferably, GW 501516 or BAY 68-5042.

[0163] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as, by way of example and preferably, ezetimibe, tiqueside or pamaqueside.

[0164] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, by way of example and preferably, orlistat.

[0165] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a polymeric bile acid adsorber, such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.

[0166] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a bile acid reabsorption inhibitor, such as, by way of example and preferably, ASBT (= IBAT) inhibitors such as, for example, AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

[0167] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipoprotein(a) antagonist, such as, by way of example and preferably, Gemcabene calcium (CI-1027) or nicotinic acid.

[0168] Particularly preferred are combinations of the compounds according to the invention with one or more further active ingredients selected from the group consisting of PDE 5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogues, IP receptor agonists, endothelin antagonists, compounds inhibiting the signal transduction cascade and pirfenidone.

[0169] The present invention further relates to medicaments which contain at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and to their use for the aforementioned purposes.

[0170] The compounds of the invention can act systemically and / or locally. For this purpose, they can be administered in a suitable manner, such as orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically, or as an implant or stent.

[0171] For these routes of administration, the compounds according to the invention can be administered in suitable administration forms.

[0172] For oral administration, suitable dosage forms which function according to the state of the art and release the compounds according to the invention rapidly and / or in a modified form and which contain the compounds according to the invention in crystalline and / or amorphized and / or dissolved form are used, such as tablets (uncoated or coated tablets, for example with gastro-resistant or delayed-dissolving or insoluble coatings which control the release of the compound according to the invention), tablets or films / wafers which disintegrate rapidly in the oral cavity, films / lyophilisates, capsules (for example hard or soft gelatin capsules), coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

[0173] Parenteral administration can be performed without an absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with absorption (e.g., inhalation, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). Suitable forms for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates, or sterile powders.

[0174] Other routes of administration include, for example, inhalation dosage forms (including powder inhalers, nebulizers, metered dose aerosols), nasal drops, solutions or sprays, lingual, sublingual or buccally administered tablets, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. plasters), milk, pastes, foams, powders, implants or stents.

[0175] Oral and parenteral administration are preferred, especially oral, intravenous and intrapulmonary (inhalation) administration.

[0176] The compounds according to the invention can be converted into the stated application forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include, among others, carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants such as ascorbic acid), dyes (e.g., inorganic pigments such as iron oxides), and flavor and / or odor correctors.

[0177] In general, it has proven advantageous to administer amounts of approximately 0.001 to 1 mg / kg, preferably approximately 0.01 to 0.5 mg / kg body weight, for parenteral administration to achieve effective results. For oral administration, the dosage is approximately 0.01 to 100 mg / kg, preferably approximately 0.01 to 20 mg / kg, and most preferably 0.1 to 10 mg / kg body weight. For intrapulmonary administration, the amount is generally approximately 0.1 to 50 mg per inhalation.

[0178] Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual response to the active ingredient, type of preparation, and time or interval at which administration takes place. In some cases, it may be sufficient to administer less than the aforementioned minimum amount, while in other cases the stated upper limit must be exceeded. When administering larger amounts, it may be advisable to distribute them into several individual doses throughout the day.

[0179] The following examples illustrate the invention. The invention is not limited to the examples.

[0180] The present invention further relates to medicaments and pharmaceutical compositions which contain at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and to their use for the aforementioned purposes.

[0181] The compounds of the invention can act systemically and / or locally. For this purpose, they can be administered in a suitable manner, such as orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, vaginally, dermally, transdermally, conjunctivally, otically, or as an implant or stent.

[0182] For these routes of administration, the compounds according to the invention can be administered in suitable administration forms.

[0183] For oral administration, suitable dosage forms which function according to the state of the art and release the compounds according to the invention rapidly and / or in a modified form and which contain the compounds according to the invention in crystalline and / or amorphized and / or dissolved form are used, such as tablets (uncoated or coated tablets, for example with gastro-resistant or delayed-dissolving or insoluble coatings which control the release of the compound according to the invention), tablets which disintegrate rapidly in the oral cavity or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

[0184] Parenteral administration can be performed without an absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, intravitreal, or intraperitoneal). Suitable administration forms for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates, or sterile powders.

[0185] Other routes of application include, for example, inhalation dosage forms (including powder inhalers, nebulizers), nasal drops, solutions, sprays; tablets, films / wafers or capsules for lingual, sublingual or buccal application, suppositories, eye drops, eye ointments, eye baths, ocular inserts, ear drops, sprays, powders, rinses, tampons, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, emulsions, microemulsions, ointments, creams, transdermal therapeutic systems (such as plasters), milk, pastes, foams, powdered powders, implants or stents.

[0186] The compounds according to the invention can be converted into the stated application forms. This can be done in a conventional manner by mixing with pharmaceutically suitable excipients. These excipients include, among others: Fillers and carriers (e.g. cellulose, microcrystalline cellulose such as Avicel ®< , lactose, mannitol, starch, calcium phosphates such as Di-Cafos ®< ), ointment bases (e.g. petrolatum, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), suppository bases (e.g. polyethylene glycols, cocoa butter, hard fat), solvents (e.g. water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglycerides, fatty oils, liquid polyethylene glycols, paraffins), surfactants, emulsifiers, dispersing or wetting agents (e.g. sodium dodecyl sulfate, lecithin, phospholipids, fatty alcohols such as Lanette ®< , sorbitan fatty acid esters such as Span ®< , polyoxyethylene sorbitan fatty acid esters such as Tween ®< , polyoxyethylene fatty acid glycerides such as Cremophor ®< , polyoxethlyene fatty acid esters, polyoxethlyene fatty alcohol ethers, glycerol fatty acid esters, poloxamers such asPluronic ®< ), buffer substances as well as acids and bases (e.g. phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide, ammonium carbonate, trometamol, triethanolamine), isotonic agents (e.g. glucose, sodium chloride), adsorbents (e.g. highly dispersed silicon dioxide), viscosity-increasing agents, gelling agents, thickeners or binders (e.g. polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, starch, carbomers, polyacrylic acids such as Carbopol ®< , alginates, gelatin), disintegrants (e.g. modified starch, carboxymethylcellulose sodium, sodium starch glycolate such as Explotab ®< , cross-linked polyvinylpyrrolidone, croscarmellose sodium such as AcDiSol ®< ), flow regulators, lubricants, glidants and Mould release agents (e.g. magnesium stearate, stearic acid, talc, highly dispersed silicon dioxides such asAerosil ®< ), coating agents (for example sugar, shellac) and film-forming agents for rapidly dissolving or modified dissolving films or diffusion membranes (for example polyvinylpyrrolidones such as Kollidon ®< , polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as Eudragit ®< ), capsule materials (for example gelatin, hydroxypropylmethylcellulose), synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates such as Eudragit ®< , polyvinylpyrrolidones such as Kollidon ®< , polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and block copolymers), plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate), penetration enhancers, stabilizers (e.gAntioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate), preservatives (e.g. parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), dyes (e.g. inorganic pigments such as iron oxides, titanium dioxide), flavorings, sweeteners, taste and / or odor correctors.

[0187] Oral or parenteral administration is preferred, especially oral administration.

[0188] The compounds according to the invention can be converted into the stated application forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include, among others, carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants such as ascorbic acid), dyes (e.g., inorganic pigments such as iron oxides), and flavor and / or odor correctors.

[0189] In general, it has been shown to be advantageous to administer doses of approximately 0.1 to 6 mg / kg for parenteral administration to achieve effective results. For oral administration, the dosage is approximately 0.1 to 10 mg / kg body weight.

[0190] Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual response to the active ingredient, type of preparation, and time or interval at which administration takes place. In some cases, it may be sufficient to administer less than the aforementioned minimum amount, while in other cases the stated upper limit must be exceeded. When administering larger amounts, it may be advisable to distribute them into several individual doses throughout the day.

[0191] The following examples illustrate the invention. The invention is not limited to the examples.

[0192] Unless otherwise stated, percentages in the following tests and examples are by weight; parts are by weight. Solvent ratios, dilution ratios, and concentrations of liquid / liquid solutions are all by volume. A. Examples

[0193] Only examples that fall within the claims are part of the invention. Examples that do not fall within the claims, such as Examples 40 and 41, are disclosed for reference only and do not form part of the invention. Abbreviations and acronyms:

[0194] Ac Acetyl aq. aqueous, aqueous solution boc tert-butoxycarbonyl br.d broad doublet (NMR) br.m broad multiplet (NMR) br.s broad singlet (NMR) br.t broad triplet (NMR) c concentration cat. catalytic d Doublet (NMR) de Diastereomeric excess DC Thin-layer chromatography DCI direct chemical ionization (in MS) dd Doublet of doublets (NMR) ddd Doublet of duplicates of duplicates (NMR) distilled distilled DIAD Diisopropyl zaodicarboxylate DIEA N , N -Diisopropylethylamin DMAP 4- N,N -Dimethylaminopyridin DMF Dimethylformamide DMSO Dimethyl sulfoxide DSC Differential Scanning Thermography dt Doublet of triplets (NMR) d. Th. the theory (at yield) EDC N' -(3-Dimethylaminopropyl)- N -ethylcarbodiimid-Hydrochlorid ee Enantiomeric excess ent enantiomerically pure, enantiomer eq. Equivalent(s) IT I Electrospray ionization (for MS) Et Ethyl GC-MS Gas chromatography coupled mass spectrometry h Hours) HATU O -(7-Azabenzotriazol-1-yl)- N,N,N',N' -tetramethyluronium-hexafluorophosphat HBTU O -(Benzotriazol-1-yl)- N,N,N',N '-tetramethyluronium-hexafluorphosphat HOBt 1 -Hydroxy-1 H -benzotriazol-Hydrat HPLC High pressure, high performance liquid chromatography ID inner diameter iPr isopropyl J Coupling constant (NMR) conc. Concentrated LC-MS Liquid chromatography coupled mass spectrometry m Multiplet (NMR) Me methyl min Minute(s) MPLC Medium pressure liquid chromatography MS Mass spectrometry MTBE Methyl- tert .-butylether NMR Nuclear magnetic resonance spectrometry Pd / C Palladium on activated carbon Ph Phenyl PyBOP Benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate quant. quantitative (in yield) rac racemic, racemate RT Room temperature R t Retention time (for HPLC) Schmp. Melting point SFC Supercritical fluid chromatography t Triplet (NMR) tBu tert .-Butyl tert. Tertiary TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran TPPO Triphenylphosphine oxide UV Ultraviolet spectrometry cf. compare v / v Volume to volume ratio (of a solution) HPLC, GC-MS and LC-MS methods Method 1:

[0195] Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8 µ 50 x 2.1 mm; Eluent A: 1 l water + 0.25 ml 99% formic acid, Eluent B: 1 l acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 90% A ----> 0.3 min 90% A ----> 1.7 min 5% A → 3.0 min 5% A Oven: 50°C; Flow: 1.20 ml / min; UV detection: 205 - 305 nm. Method 2:

[0196] Instrument: Thermo DFS, Trace GC Ultra; Column: Restek RTX-35, 15 m x 200 µm x 0.33 µm; constant flow with helium: 1.20 ml / min; oven: 60°C; inlet: 220°C; gradient: 60°C, 30°C / min ----> 300°C (hold 3.33 min). Method 3:

[0197] MS instrument type: Thermo Scientific FT-MS; UHPLC+ instrument type: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 x 75 mm, C18 1.8 µm; Eluent A: 1 L water + 0.01% formic acid; Eluent B: 1 L acetonitrile + 0.01% formic acid; Gradient: 0.0 min 10% B - 2.5 min 95% B → 3.5 min 95% B; Oven: 50°C; Flow: 0.90 ml / min; UV detection: 210 nm / Optimum Integration Path 210-300 nm Method 4:

[0198] Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 µ 50 x 1 mm; Eluent A: 1 l water + 0.25 ml 99% formic acid, Eluent B: 1 l acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 90% A ----> 1.2 min 5% A ----> 2.0 min 5% A Oven: 50°C; Flow: 0.40 ml / min; UV detection: 208 - 400 nm. Method 5:

[0199] Instrument: HP 1100 Series with LC / MSD SL; Column: CS MultoKrom 100-3 C18 60x4.6 mm; Eluent A: 1 l water + 10 ml 99% formic acid, Eluent B: 1 l + 10 ml 99% formic acid; Gradient: 0.0 min 80% A -> 8.0 min 10% A -> 10.0 min 10% A; Flow: 1.00 ml / min; DAD detection: 120 - 800 nm. Method 6:

[0200] Instrument MS: Waters (Micromass) Quattro Micro; Instrument Waters UPLC Acquity; Column: Waters BEH C18 1.7 µ 50 x 2.1 mm; Eluent A: 1 l water + 0.01 mol ammonium formate, eluent B: 1 l acetonitrile; Gradient: 0.0 min 95% A → 0.1 min 95% A → 2.0 min 15% A → 2.5 min 15% A→ 2.51 min 10% A ----> 3.0 min 10% A; Oven: 40°C; Flow: 0.5ml / min; UV detection: 210 nm Method 7:

[0201] Instrument: Waters Acquity, Waters Acquity Autosampler; Column: XBridge BEH C18 2.5 µm 2.1 x 50 mm (UPLC LG 500 nm); Eluent A: 10 mM ammonium bicarbonate pH 10, Eluent B: acetonitrile; Gradient: 2-98% B in 0.80 min, hold at 98% B for 1.30 min. Method 8:

[0202] Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 µ 50 x 1 mm; Eluent A: 1 l water + 0.25 ml 99% formic acid, Eluent B: 1 l acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 95% A ----> 6.0 min 5% A ----> 7.5 min 5% A Oven: 50°C; Flow: 0.35 ml / min; UV detection: 210 - 400 nm. Method 9:

[0203] MS instrument type: ThermoFisherScientific LTQ-Orbitrap-XL; HPLC instrument type: Agilent 1200SL; Column: Agilent, POROSHELL 120, 3 x 150 mm, SB - C18 2.7 µm; Eluent A: 1 l water + 0.1% trifluoroacetic acid; Eluent B: 1 l acetonitrile + 0.1% trifluoroacetic acid; Gradient: 0.0 min 2% B → 0.3 min 2% B → 5.0 min 95% B → 10.0 min 95% B; Oven: 40°C; Flow: 0.75 ml / min; UV detection: 210 nm. Method 10:

[0204] Instrument: Waters Prep LC / MS System, Column: XBridge C18 5µm 100x30 mm; Eluent A: water, Eluent B: acetonitrile, Flow: 65 ml / min plus 5 ml 2% formic acid in water, room temperature, Wavelength 200-400 nm, At-column injection (complete injection); Gradient profile: 0 to 2 min 10% Eluent B, 2 to 2.2 min at 20% Eluent B, 2.2 to 7 min at 60% Eluent B, 7 to 7.5 min at 92% Eluent B, 7.5 to 9 min at 92% B. Method 11:

[0205] Instrument: Waters Prep LC / MS System, Column: XBridge C18 5µm 100x30 mm; Eluent A: water, Eluent B: acetonitrile, Flow: 65 ml / min plus 5 ml 2% formic acid in water, room temperature, Wavelength 200-400 nm, At-column injection (complete injection); Gradient profile: 0 to 2 min 7.5% Eluent B, 2 to 7 min to 35% Eluent B, 7 to 7.5 min to 92% Eluent B, 7.5 to 9 min at 92% B. Method 12:

[0206] Instrument: Waters Prep LC / MS System, Column: XBridge C18 5µm 100x30 mm; Eluent A: water, Eluent B: acetonitrile, Flow: 65 mL / min plus 5 mL 2% ammonia in water, room temperature, Wavelength 200-400 nm, At-column injection (complete injection); Gradient profile: 0 to 2 min 7.5% Eluent B, 2 to 7 min to 35% Eluent B, 7 to 7.5 min to 92% Eluent B, 7.5 to 9 min at 92% B. Method 13:

[0207] MS instrument: Waters SQD2; HPLC instrument: Waters UPLC; Column: Zorbax SB-Aq (Agilent), 50 mm x 2.1 mm, 1.8 µm; Eluent A: water + 0.025% formic acid, Eluent B: acetonitrile (ULC) + 0.025% formic acid; Gradient: 0.0 min 98%A - ​​0.9 min 25%A - 1.0 min 5%A - 1.4 min 5%A - 1.41 min 98%A - ​​1.5 min 98%A; Oven: 40°C; Flow: 0.600 ml / min; UV detection: DAD; 210 nm. Method 14:

[0208] Instrument: Waters Prep LC / MS System, Column: Phenomenex Kinetex C18 5µm 100x30 mm Eluent A: water, Eluent B: acetonitrile, Flow: 65 ml / min plus 5 ml 2% formic acid in water, room temperature, Wavelength 200-400 nm, At-column injection (complete injection) Gradient profile: 0 to 2 min 10% eluent B, 2 to 2.2 min at 20% eluent B, 2.2 to 7 min at 60% eluent B, 7 to 7.5 min at 92% eluent B, 7.5 to 9 min at 92% B. Method 15:

[0209] Instrument: Waters Single Quad MS System; Instrument Waters UPLC Acquity; Column: Waters BEH C18 1.7 µm 50 x 2.1 mm; Eluent A: 1 l water + 1.0 mL (25% ammonia) / L, eluent B: 1 l acetonitrile; Gradient: 0.0 min 92% A ----> 0.1 min 92% A ----> 1.8 min 5% A ----> 3.5 min 5% A; Oven: 50°C; Flow: 0.45 mL / min; UV detection: 210nm (208-400nm). More information:

[0210] For purification of compounds of the invention by chromatography, especially by column chromatography, prepacked silica gel cartridges, such as Biotage SNAP cartridges, KP-Sil ®<, or KP-NH ®<, are used in combination with a Biotage system (SP4 ®< or Isolera Four ®<). Gradients of hexane / ethyl acetate or dichloromethane / methanol are used as eluents.

[0211] When purifying compounds of the invention by preparative HPLC using the methods described above, in which the eluents contain additives such as trifluoroacetic acid, formic acid, or ammonia, the compounds of the invention can be obtained in salt form, for example as trifluoroacetate, formate, or ammonium salt, provided the compounds of the invention contain sufficient basic or acidic functionalities. Such a salt can be converted into the corresponding free base or acid by various methods known to those skilled in the art.

[0212] Furthermore, amidines can be present as free compounds or partially (depending on the preparation with the involvement of acetic acid) as acetate salts or acetate solvates.

[0213] If, in the synthesis intermediates and exemplary embodiments of the invention described below, a compound is listed in the form of a salt of the corresponding base or acid, the exact stoichiometric composition of such a salt, as obtained by the respective preparation and / or purification process, is generally unknown. Unless specified more precisely, names and structural formulas such as "hydrochloride," "trifluoroacetate," "sodium salt," or "x hydrochloric acid," "x CF 3 COOH," "x Na +<" are not to be understood as stoichiometric for such salts, but are purely descriptive of the salt-forming components present.

[0214] The same applies analogously in the case that synthesis intermediates or embodiments or salts thereof were obtained by the described preparation and / or purification processes in the form of solvates, such as hydrates, whose stoichiometric composition (if of a defined nature) is not known.

[0215] Furthermore, the secondary amides of the invention may exist as rotational isomers / isomer mixtures, particularly in NMR studies. Purity data generally refer to corresponding peak integrations in the LC / MS chromatogram, but may also have been determined with the aid of the 1< H NMR spectrum. If no purity is stated, it is usually 100% purity according to automatic peak integration in the LC / MS chromatogram, or the purity was not explicitly determined.

[0216] Yields in % of theory are generally purity-corrected if a purity of <100% is stated. For solvent-containing or contaminated batches, the yield may formally be ">100%"; in these cases, the yield is not solvent- or purity-corrected.

[0217] All data in 1< H-NMR spectra indicate the chemical shifts δ[ppm] = in ppm.

[0218] The multiplicities of proton signals in 1< H NMR spectra given in the following paragraphs reflect the observed signal shape and do not take higher-order signal phenomena into account. As a rule, the chemical shift refers to the center of the respective signal. For broad multiplets, an interval is given. Signals obscured by solvent or water have either been tentatively assigned or are not listed. Strongly broadened signals—e.g., caused by rapid rotation of molecular parts or due to exchanging protons—have also been tentatively assigned (often referred to as broad multiplets or broad singlets) or are not listed.

[0219] Melting points and melting ranges, where indicated, are uncorrected.

[0220] The 1< H-NMR data of selected synthesis intermediates and working examples are recorded in the form of 1< H-NMR peak lists. For each signal peak, the δ[ppm] = value in ppm is listed first, followed by the signal intensity in parentheses. The δ[ppm] = value-signal intensity pairs of different signal peaks are listed separated by commas. The peak list of an example therefore has the form: δ[ppm] = 1 (intensity 1 ), δ[ppm] = 2 (intensity 2 ), ... , δ[ppm] = i (intensity i ), ... , δ[ppm] = n (intensity n ).

[0221] The intensity of sharp signals correlates with the height of the signals in a printed example of an NMR spectrum in cm and, when compared to other signals, shows the true ratios of the signal intensities. For broad signals, multiple peaks or the center of the signal and their relative intensity compared to the most intense signal in the spectrum can be shown. The lists of 1< H NMR peaks are similar to classic 1< H NMR printouts and thus usually contain all peaks listed in a classic NMR interpretation. In addition, like classic 1< H NMR printouts, they can show solvent signals, signals from stereoisomers of the target compounds that are also subject of the invention, and / or peaks from impurities.The peaks of stereoisomers of the target compounds and / or impurity peaks usually have a lower average intensity than the peaks of the target compounds (e.g., with a purity of >90%). Such stereoisomers and / or impurities can be typical for the respective manufacturing process. Their peaks can thus help identify the reproduction of our manufacturing process based on "by-product fingerprints." An expert who calculates the peaks of the target compounds using known methods (MestreC, ACD simulation, or using empirically evaluated expected values) can isolate the peaks of the target compounds as needed, applying additional intensity filters if necessary. This isolation would be similar to the peak picking involved in classical 1< H NMR interpretation.A detailed description of the presentation of NMR data in the form of peak lists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (see Research Disclosure Database Number 605005, 2014, August 1, 2014, or http: / / www.researchdisclosure.com / searching-disclosures). In the peak picking routine described in Research Disclosure Database Number 605005, the "Minimum Height" parameter can be set between 1% and 4%. Depending on the type of chemical structure and / or the concentration of the compound to be measured, it may be useful to set the "Minimum Height" parameter to values ​​<1%.

[0222] For all reactants or reagents whose preparation is not explicitly described below, it is assumed that they were obtained commercially from publicly accessible sources. For all other reactants or reagents whose preparation is also not described below and which were not commercially available or were obtained from sources that are not publicly accessible, a reference to the published literature describing their preparation is provided.

[0223] In the intermediates and working examples described below, the designation "5RS" in the IUPAC name of the respective example in conjunction with the term "racemate" means that this is a racemic mixture of the 5 R-enantiomers (→1st letter after the position number in "5RS") with the corresponding 5S-enantiomer (→2nd letter after the position number) in . The designation "5RS" in conjunction with the terms "enantiomer 1" and "enantiomer 2" means that these are the two enantiomers in separate, isolated form where an assignment of the absolute configuration (5 R or 5 S ) to these enantiomers has not been carried out. Similar designations such as "5 SR ", which result from the changed priority and / or order of name components due to the IUPAC nomenclature rules, are to be interpreted analogously according to this guide

[0224] In the intermediates and working examples described below, a designation "5" in the IUPAC name of the example in question means RS ,7 RS " in conjunction with the term "Racemat" that this is a racemic mixture of the 5R ,7 R -enantiomers (→ 1st letter after the position number in "5 RS ,7 RS ") with the corresponding 5S,7S -enantiomer (→ 2nd letter after the position number). The designation "5 RS ,7 RS " in conjunction with the terms "Enantiomer 1" and "Enantiomer 2" means that these are the two enantiomers in separate, isolated form where an assignment of the absolute configuration (5 R ,7 R or 5 S ,7 S ) to these enantiomers has not been carried out. Similar designations such as "5 SR, 7 SR ", which result from the changed priority and / or order of name components due to the IUPAC nomenclature rules, are to be interpreted analogously according to these instructions.

[0225] The (5S) configuration was assigned based on crystal structure determination for examples 26, 108, 113, 157, 237, 358, and 454. Analogously, the (5S) configuration was assigned for examples 183-188, 190-219, 275-279, 342-402, 404-415, and 418-563. Starting compounds and intermediates: Intermediate 1 Methyl 3-fluoro-2-(trifluoromethyl)isonicotinate

[0226]

[0227] 3-Fluoro-2-(trifluoromethyl)isonicotinic acid (1.00 g, 4.78 mmol) was dissolved in methanol (10 mL) and sulfuric acid (310 µL, 5.7 mmol) was added. The reaction mixture was heated to 60 °C for 30 minutes and then stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate, and washed with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated. This gave 890 mg (70% purity, 58% of theory) of the title compound. LC-MS (Method 1): R t = 1.15 min; MS (ESIpos): m / z = 224 [M+H] +< Intermediate 2 [3-Fluoro-2-(trifluoromethyl)pyridin-4-yl]methanol

[0228]

[0229] Methyl 3-fluoro-2-(trifluoromethyl)isonicotinate (890 mg, purity 70%, 3.99 mmol) was dissolved in methanol (5.0 ml), and sodium borohydride (166 mg, 4.39 mmol) was added portionwise at 0°C. After stirring overnight at room temperature, the reaction mixture was treated with saturated aqueous ammonium chloride solution, and the methanol was removed in vacuo. The residue was treated with ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated. This gave 420 mg (54% of theory) of the title compound. The compound was further reacted directly. Intermediate 3 4-(Chloromethyl)-3-fluoro-2-(trifluoromethyl)pyridine hydrochloride

[0230]

[0231] [3-Fluoro-2-(trifluoromethyl)pyridin-4-yl]methanol (420 mg, 2.15 mmol) was dissolved in dichloromethane (10 ml), and thionyl dichloride (310 µl, 4.3 mmol) was added at room temperature. After the reaction mixture was stirred overnight at room temperature, thionyl dichloride (310 µl, 4.3 mmol) and a drop of dimethylformamide were added again. The reaction mixture was stirred for one hour at room temperature, and then thionyl dichloride (620 µl, 8.6 mmol) and a drop of dimethylformamide were added again. After stirring for another 2 hours at room temperature, the solvent was removed under vacuum. This gave 379 mg (70% of theory) of the title compound. GC-MS (Method 2): R t = 2.74 min; MS (ESIpos): m / z = 213 [M+H] +< Intermediate 4 5-Chloro-4-(trifluoromethyl)pyridin-2-yl]methanol

[0232]

[0233] Methyl 5-chloro-4-(trifluoromethyl)pyridine-2-carboxylate (412 mg, 1.72 mmol) was dissolved in methanol (20 ml), and sodium borohydride (78.1 mg, 2.06 mmol) was added portionwise at 0°C. After stirring overnight at room temperature, sodium borohydride (35 mg, 0.9 mmol) was added again to the reaction mixture. After stirring at room temperature for 2 days, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the methanol was removed in vacuo. The residue was treated with ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated. This gave 295 mg (77% of theory) of the title compound. LC-MS (Method 3): R t = 1.32 min; MS (ESIpos): m / z = 212 [M+H] +< Intermediate 5 5-Chloro-2-(chloromethyl)-4-(trifluoromethyl)pyridine hydrochloride

[0234]

[0235] [5-Chloro-4-(trifluoromethyl)pyridin-2-yl]methanol (295 mg, 1.39 mmol) was dissolved in dichloromethane (20 mL) and treated with thionyl dichloride (200 µL, 2.8 mmol) at room temperature. After the reaction mixture was stirred at room temperature for 72 hours, the solvent was removed under vacuum. 274 mg (85% purity, 63% of theory) of the title compound were obtained 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.42), 3.937 (2.06), 4.644 (1.11), 4.903 (16.00), 7.839 (0.47), 8.078 (5.73), 8.296 (0.43), 8.857 (0.51), 8.957 (5.04), 9.102 (0.45). Intermediate 6 4-(Chloromethyl)-2-(trifluoromethyl)quinoline hydrochloride

[0236]

[0237] [2-(Trifluoromethyl)quinolin-4-yl]methanol (350 mg, 1.54 mmol) was dissolved in dichloromethane (10 mL) and thionyl dichloride (220 µL, 3.1 mmol) was added at 0°C. After the reaction mixture was stirred overnight at room temperature, the solvent was removed under vacuum. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated under vacuum, yielding 336 mg (74% purity, 57% of theory) of the title compound. LC-MS (Method 4): R t = 1.06 min; MS (ESIpos): m / z = 246 [M+H] +< Intermediate 7 4-(Chloromethyl)-2-(trifluoromethyl)pyrimidine hydrochloride

[0238]

[0239] [2-(Trifluoromethyl)pyrimidin-4-yl]methanol (313 mg, 1.76 mmol) was dissolved in dichloromethane (10 ml) and treated with thionyl dichloride (260 µl, 3.5 mmol) at room temperature. After the reaction mixture was stirred at room temperature for 4 hours, the solvent was removed under vacuum. 134 mg (61% purity, 20% of theory) of the title compound were obtained.

[0240] 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.678 (0.60), 4.946 (16.00), 5.366 (0.57), 7.993 (2.80), 8.006 (2.88), 9.129 (3.11), 9.142 (3.06). Intermediate 8 Methyl 6-[1-(tert-butoxycarbonyl)hydrazino]pyridine-2-carboxylate

[0241]

[0242] Methyl 6-chloropyridine-2-carboxylate (32.5 g, 189 mmol), tert-butyl hydrazinecarboxylate (25.0 g, 189 mmol), and cesium carbonate (61.6 g, 189 mmol) were degassed with argon in toluene (325 ml) before [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.9 g, 10 mmol) was added. The reaction mixture was stirred overnight at 100°C. The reaction mixture was diluted with dichloromethane and filtered through kieselguhr. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (silica gel; mobile phase: methanol / dichloromethane 4 / 96). The product-containing fractions were concentrated in vacuo and triturated with methyl tert-butyl ether. 28.8 g (57% of theory) of the title compound were obtained. LC-MS (Method 5): R t = 3.45 min; MS (ESIpos): m / z = 268 [M+H] +< Intermediate 9 2-(Diazan-2-ium-1-yl)-6-(methoxycarbonyl)pyridinium dichloride

[0243]

[0244] Methyl 6-{1-[(benzyloxy)carbonyl]hydrazino}pyridine-2-carboxylate (29.8 g, 112 mmol) was dissolved in dioxane (150 ml) and treated with hydrochloric acid (112 ml, 446 mmol, 4 M in dioxane). The reaction mixture was stirred for 4 h at room temperature and diluted with methyl tert-butyl ether (500 ml). After stirring for 1 h, the solid was filtered off, washed with methyl tert-butyl ether, and dried. This gave 28.8 g (> 100%) of the title compound. LC-MS (Method 5): R t = 0.88 min; MS (ESIpos): m / z = 168 [M+H] +< Intermediate 10 Methyl 3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate

[0245]

[0246] 2-(Diazan-2-ium-1-yl)-6-(methoxycarbonyl)pyridinium dichloride (28.8 g, 112 mmol) was dissolved in THF (500 mL), and triethylamine (46 mL, 335 mmol) was added. The reaction mixture was stirred at room temperature for 15 min. Subsequently, 1,1-carbonyldiimidazole (19.9 g, 123 mmol) was added. The reaction mixture was stirred at 70°C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was taken up in dilute aqueous hydrochloric acid and extracted with dichloromethane / methanol 9 / 1. The combined organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was suspended in ethyl acetate and stirred overnight. After filtration and drying, 11.4 g (53% of theory) of the title compound were obtained. LC-MS (Method 5): R t = 1.40 min; MS (ESIpos): m / z = 194 [M+H] +< Intermediate 11 Methy-(5RS)--3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate)

[0247]

[0248] Methyl 3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (17.6 g, 91.1 mmol) and palladium on carbon (1.0 g, 10%) were suspended in methanol (500 ml) and stirred overnight at room temperature in a hydrogen atmosphere (10 bar). The reaction mixture was filtered through kieselguhr. The filtrate was concentrated, yielding 17.8 g (99% of theory) of the title compound. LC-MS (Method 5): R t = 1.35 min; MS (ESIpos): m / z = 198 [M+H] +< 1< H-NMR (500 MHz, MeOD) δ [ppm]= 1.64 - 1.74 (br, 1H), 1.89 - 1.97 (br, 1H), 2.15 - 2.29 (br, 2H), 2.60 - 2.69 (m, 1H), 2.77 (dt, 1H), 3.79 (s, 3H), 4.63 (dd, 1H). Intermediate 12 Methyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (enantiomer 1)

[0249]

[0250] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) was separated by chiral preparative SFC [sample preparation: 33.20 g dissolved in 200 mL methanol; injection volume: 4.0 mL; column: Daicel Chiralpak®< IC 20 µm, 360 x 50 mm; mobile phase: CO2 / i-propanol 80 / 20; flow rate: 400 g / min; temperature: 35°C; UV detection: 210 nm]. After separation, 15.7 g of enantiomer 1, which eluted first, and 15.8 g of enantiomer 2, which eluted later, were isolated. Enantiomer 1

[0251] Analytical chiral SFC: R t = 2.76 min, de = 100% [column: Daicel Chiralpak ®< IC 50 x 4.6 mm; mobile phase: CO 2 / i-propanol 80:20; flow rate: 3 ml / min; UV detection: 210 nm]. LC-MS (Method 3): R t = 0.54 min; MS (ESIpos): m / z = 198 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]= 1.45 - 1.60 (m, 1H), 1.75 - 1.84 (m, 1H), 1.98 - 2.17 (m, 2H), 2.48 - 2.58 (m, 1H), 2.59 - 2.68 (m, 1H), 3.69 (s, 3H), 4.51 (dd, 1H), 11.42 (s, 1H). Intermediate 13 Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (enantiomer 2)

[0252]

[0253] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) was separated by chiral preparative SFC [sample preparation: 33.20 g dissolved in 200 mL methanol; injection volume: 4.0 mL; column: Daicel Chiralpak®< IC 20 µm, 360 x 50 mm; mobile phase: CO2 / i-propanol 80 / 20; flow rate: 400 g / min; temperature: 35°C; UV detection: 210 nm]. After separation, 15.7 g of enantiomer 1, which eluted first, and 15.8 g of enantiomer 2, which eluted later, were isolated. Enantiomer 2

[0254] Analytical chiral SFC: R t = 3.90 min, de = 100% [column: Daicel Chiralpak ®< IC 50 x 4.6 mm; mobile phase: CO 2 / i-propanol 80:20; flow rate: 3 ml / min; UV detection: 210 nm]. LC-MS (Method 3): R t = 0.54 min; MS (ESIpos): m / z = 198 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]= 1.42 - 1.59 (m, 1H), 1.72 - 1.86 (m, 1H), 1.96 - 2.17 (m, 2H), 2.44 - 2.59 (m, 1H), 2.59 - 2.69 (m, 1H), 3.69 (s, 3H), 4.51 (dd, 1H), 11.42 (s, 1H).

[0255] The (5S) configuration was assigned based on crystal structure determination for examples 26, 108, 113, 157, 237, 358, and 454. Methyl (5S)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate Intermediate 14 Methyl 1-(4-methoxybenzyl)hydrazine carboxylate

[0256]

[0257] (4-Methoxybenzyl)hydrazine dihydrochloride (1.50 g, 80% purity, 5.33 mmol) was dissolved in dichloromethane (50 mL), triethylamine (2.6 mL, 19 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was then cooled to 0°C, and methyl carbonate (450 µL, 5.9 mmol) dissolved in dichloromethane (10 mL) was added. After stirring overnight at room temperature, the reaction mixture was treated with water. The organic phase was separated, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane / ethyl acetate gradient). The product-containing fractions were concentrated in vacuo and 1.04 g (92% purity, 85% of theory) of the title compound were obtained. LC-MS (Method 3): R t = 1.08 min; MS (ESIpos): m / z = 211 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.988 (0.46), 3.314 (7.32), 3.541 (0.79), 3.622 (16.00), 4.397 (7.56), 4.553 (4.94), 6.861 (0.47), 6.868 (3.43), 6.873 (1.30), 6.885 (1.38), 6.890 (3.96), 6.897 (0.47), 7.161 (3.22), 7.182 (2.79). Intermediate 15 Methyl (2S)-6-oxopiperidine-2-carboxylate (enantiomer)

[0258]

[0259] Methanol (15 ml) was initially charged, and at 0°C, thionyl dichloride (560 µl, 7.7 mmol) was added, followed by (2S)-6-oxopiperidine-2-carboxylic acid (1.00 g, 6.99 mmol). After stirring overnight at room temperature, the solvent was removed in vacuo, and the residue was treated with toluene and triethylamine (1.9 ml, 14 mmol). The mixture was stirred for 30 minutes at room temperature, then filtered and the filtrate concentrated. This yielded 805 mg (70% of theory) of the title compound. LC-MS (Methode 4): R t = 0.26 min; MS (ESIpos): m / z = 158 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.70), 0.008 (1.69), 1.541 (0.78), 1.550 (1.05), 1.560 (1.24), 1.566 (1.90), 1.575 (2.78), 1.584 (3.48), 1.591 (3.19), 1.594 (3.57), 1.600 (4.36), 1.610 (3.31), 1.619 (4.16), 1.628 (3.71), 1.636 (3.43), 1.644 (5.02), 1.652 (4.23), 1.660 (4.33), 1.668 (4.60), 1.676 (2.96), 1.684 (2.78), 1.693 (1.99), 1.702 (1.75), 1.708 (1.01), 1.717 (0.85), 1.745 (1.91), 1.754 (2.09), 1.759 (2.49), 1.768 (2.39), 1.778 (3.46), 1.787 (3.35), 1.793 (3.60), 1.802 (3.22), 1.810 (2.52), 1.819 (1.83), 1.901 (2.92), 1.910 (3.42), 1.916 (3.20), 1.925 (4.72), 1.935 (4.50), 1.941 (3.46), 1.949 (4.49), 1.959 (3.35), 1.968 (1.78), 1.974 (1.91), 1.983 (1.62), 2.097 (0.90), 2.113 (0.85), 2.128 (11.31), 2.141 (16.00), 2.148 (10.19), 2.156 (7.22), 2.164 (7.72), 2.188 (0.61), 2.192 (0.69), 2.208 (0.70), 2.289 (0.72), 2.306 (1.34), 2.324 (0.85), 2.523 (0.72), 3.168 (4.31), 3.311 (4.19), 3.409 (0.45), 3.480 (0.73), 3.581 (8.47), 3.635 (7.91), 3.849 (0.72), 4.049 (4.37), 4.055 (4.73), 4.063 (8.78), 4.069 (8.78), 4.077 (4.66), 4.083 (4.33), 7.542 (6.15). . Intermediate 16 Methyl-(5S)-2-(4-methoxybenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Enantiomer)

[0260]

[0261] Methyl (2S)-6-oxopiperidine-2-carboxylate (300 mg, 1.91 mmol) was dissolved in dichloromethane (6.0 mL, 93 mmol) (enantiomer) at room temperature under argon. Trimethyloxonium tetrafluoroborate (311 mg, 2.10 mmol) was then added, and the reaction mixture was stirred at room temperature for 2 days. The solvent was removed in vacuo, and DMF (5 mL) was added to the residue. Methyl 1-(4-methoxybenzyl)hydrazinecarboxylate (401 mg, 1.91 mmol) was then added, and the reaction mixture was stirred at 170 °C for 4 hours. Water and ethyl acetate were added to the reaction mixture. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated.The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 156 mg (26% of theory) of the title compound. LC-MS (Method 3): R t = 1.20 min; MS (ESIpos): m / z = 318 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.02), 1.784 (0.43), 1.795 (0.46), 2.045 (0.41), 2.055 (0.68), 2.068 (0.64), 2.076 (0.62), 2.084 (0.47), 2.092 (0.40), 2.100 (0.48), 2.112 (0.44), 2.120 (0.47), 2.128 (0.45), 2.564 (0.76), 2.578 (0.61), 2,603 ​​(0.56), 2.615 (1.06), 2.627 (0.59), 2.657 (0.47), 2.669 (0.42), 2.829 (0.43), 3.700 (14.01), 3.730 (16.00), 3.743 (0.70), 4.581 (0.93), 4.591 (1.04), 4.597 (1.20), 4.607 (0.91), 4.749 (6.71), 6.882 (3.25), 6.903 (3.86), 7.161 (3.37), 7.183 (2.94). Intermediate 17 Methyl (5S)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (enantiomer)

[0262]

[0263] Methyl (5S)-2-(4-methoxybenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (155 mg, 488 µmol) (enantiomer) was dissolved in trifluoroacetic acid (4.5 ml) and stirred for one hour at 150°C in a microwave oven. Saturated aqueous sodium chloride solution was added to the reaction mixture, and the solution was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution. Dichloromethane was added, and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, mobile phase: dichloromethane / methanol gradient). The product-containing fractions were concentrated in vacuo, treated with ethyl acetate, and filtered. The filtrate was concentrated to one milliliter, and the product was crystallized with 10 ml of petroleum ether. The solid was filtered off and dried in vacuo.53.1 mg (53% of theory) of the title compound with an ee of 88% was obtained. The enantiomeric excess is determined by analytical chiral HPLC: Comparative values ​​racemate:

[0264] Analytical chiral HPLC: Enantiomer 1 R t = 3.40, Enantiomer 2 R t = 4.09 min, ratio 1:1 [Column: Daicel Chiraltek ®< AY-3 3µm 50 x 4.6 mm; mobile phase: i-hexane / ethanol 1:1, flow rate: 1 ml / min; UV detection: 220 nm] Enantiomer:

[0265] Analytical chiral HPLC: Enantiomer 1 R t = 3.35, Enantiomer 2 R t = 4.01 min, ratio 6:94 [Column: Daicel Chiraltek ®< AY-3 3µm 50 x 4.6 mm; mobile phase: i-hexane / ethanol 1:1, flow rate: 1 ml / min; UV detection: 220 nm]

[0266] 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.506 (0.41), 1.540 (0.44), 1.774 (0.50), 1.787 (0.56), 1.800 (0.48), 1.808 (0.40), 2.026 (0.49), 2.037 (0.75), 2.050 (0.70), 2.061 (0.71), 2.069 (0.52), 2.077 (0.48), 2.085 (0.55), 2.096 (0.54), 2.105 (0.55), 2.113 (0.53), 2.560 (0.95), 2,574 (0.73), 2.601 (0.65), 2.613 (1.22), 2.626 (0.67), 2.655 (0.55), 2.669 (0.46), 3.586 (0.54), 3.687 (16.00), 4.496 (1.07), 4.506 (1.20), 4.511 (1.37), 4.521 (1.06), 11.424 (1.40).

[0267] The (5S) configuration was assigned based on crystal structure determination for examples 26, 108, 113, 157, 237, 358 and 454. Intermediate 18 Methyl-(5RS)-2-(4-methoxybenzyl)-5-methyl-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate)

[0268]

[0269] Methyl (5RS)-2-methyl-6-oxopiperidine-2-carboxylate (racemate) (500 mg, 93% purity, 2.72 mmol, CAS 89115-90-2) was initially dissolved in dichloromethane (10 mL) at room temperature under argon. Trimethyloxonium tetrafluoroborate (442 mg, 2.99 mmol) was then added, and the reaction mixture was stirred at room temperature for 2 days. The solvent was removed in vacuo, and the residue was treated with DMF (5 mL). Methyl 1-(4-methoxybenzyl)hydrazinecarboxylate (571 mg, 2.72 mmol, 92% purity) was then added, and the reaction mixture was stirred at 170 °C for 8 hours. Water and ethyl acetate were added to the reaction mixture. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated.The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 186 mg (91% purity, 19% of theory) of the title compound. LC-MS (Method 3): R t = 1.42 min; MS (ESIpos): m / z = 332 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.589 (0.43), 1.597 (0.42), 1.606 (0.51), 1.623 (0.42), 1.697 (11.51), 1.769 (0.47), 1.782 (0.56), 1.802 (0.43), 1.907 (0.40), 1.935 (0.74), 1.942 (0.63), 1.960 (0.63), 2.023 (0.59), 2.030 (0.65), 2.042 (0.59), 2,050 (0.53), 2.058 (0.40), 2.570 (2.79), 2.586 (1.50), 2.829 (3.14), 3.531 (0.70), 3.645 (0.69), 3.665 (13.44), 3.730 (16.00), 3.742 (4.13), 4.677 (0.71), 4.716 (2.98), 4.736 (2.97), 4.774 (0.71), 5.753 (5.67), 6.885 (3.42), 6.906 (4.16), 6.922 (0.90), 7.148 (3.49), 7.169 (3.14), 7.232 (0.92), 7.253 (0.84), 7.632 (0.93). Intermediate 19 Methyl-(5RS)-methyl-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0270]

[0271] Methyl 2-(4-methoxybenzyl)-5-methyl-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (186 mg, 560 µmol) was dissolved in trifluoroacetic acid (5.0 ml) and stirred for one hour at 150°C (microwave apparatus). Saturated aqueous sodium chloride solution was added to the reaction mixture, and the solution was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution. Dichloromethane was added, and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, mobile phase: dichloromethane / methanol gradient). The product-containing fractions were concentrated in vacuo and 40.5 mg (34% of theory) of the title compound were obtained. LC-MS (Methode 3): R t = 0.70 min; MS (ESIpos): m / z = 212 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.64), 0.008 (0.61), 1.622 (0.54), 1.631 (0.51), 1.640 (0.78), 1.654 (15.63), 1.757 (0.51), 1.771 (0.63), 1.777 (0.57), 1.785 (0.46), 1.792 (0.52), 1.880 (0.46), 1.887 (0.52), 1.903 (0.40), 1.915 (0.92), 1.922 (0.83), 1.938 (0.81), 1.946 (0.65), 1.990 (0.78), 1.998 (0.84), 2.010 (0.73), 2.018 (0.68), 2.025 (0.49), 2.033 (0.43), 2.045 (0.43), 2.568 (3.91), 2.584 (1.91), 3.309 (16.00), 11.369 (1.45). Intermediate 20 tert-Butyl-6-chlorpyridin-2-carboxylat

[0272]

[0273] 6-Chloropicolinic acid (80.0 g, 0.51 mol) was dissolved in pyridine (300 ml) and tert-butanol (1.60 l), then p-toluenesulfonyl chloride (194 g, 1.02 mol) was added portionwise. The reaction mixture was stirred overnight at room temperature. After addition of saturated aqueous sodium bicarbonate solution, the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to a volume of 1.50 l and diluted with heptane (500 ml), ethyl acetate (500 ml), and water (500 ml). The organic phase was separated, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and the filtrate was concentrated. 104 g (96% of theory) of the title compound were obtained.

[0274] 1< H-NMR (400 MHz, CDCl 3 ) δ [ppm] = 1.61 (s, 9H), 7.45 - 7.48 (dd, 1H), 7.74 - 7.77 (t, 1H), 7.93 - 7.95 (dd, 1H). Intermediate 21 tert-Butyl-6-{1-[(benzyloxy)carbonyl]hydrazino}pyridine-2-carboxylate

[0275]

[0276] tert-Butyl 6-chloropyridine-2-carboxylate (91.1 g, 0.43 mol), benzyl hydrazinecarboxylate (70.9 g, 0.43 mol), cesium carbonate (174 g, 0.53 mol), and 1,1'-bis(diphenylphosphino)ferrocene (17.1 g, 32.0 mmol) were suspended in toluene (1.00 L) under argon. Bis(dibenzylideneacetone)palladium(0) (9.76 g, 10.7 mmol) was added, and the reaction mixture was stirred at 80°C for 3 h. The reaction mixture was treated with water and ethyl acetate, filtered through kieselguhr, and rinsed with ethyl acetate. The organic phase was separated, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and filtered. The filtrate was treated with silica gel, stirred for 10 min, then filtered and washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography (silica gel; mobile phase: heptane / ethyl acetate 4 / 1, 2 / 1, 1 / 1).The product-containing fractions were concentrated in vacuo, yielding 112 g (77% of theory) of the title compound. LC-MS (Method 7): R t = 0.81 min; MS (ESIpos): m / z = 344 [M+H] +< 1< H-NMR (400 MHz, CDCl 3 ) δ [ppm]= 1.59 (s, 9H), 5.30 (s, 2H), 7.31 - 7.39 (m, 3H), 7.42 - 7.45 (m, 2H), 7.76 - 7.78 (m, 2H), 7.98 - 8.12 (dd, 1H). Intermediate 22 tert-Butyl-6-hydrazinopyridine-2-carboxylate

[0277]

[0278] tert-Butyl 6-{1-[(benzyloxy)carbonyl]hydrazino}pyridine-2-carboxylate (112 g, 0.33 mol) and palladium on carbon (11.2 g, 5%) were suspended in toluene (100 ml) and methanol (1.12 l) and stirred overnight at room temperature in a hydrogen atmosphere (1 bar). The reaction mixture was filtered through kieselguhr and washed with methanol. The solvent was removed under vacuum, yielding 79.9 g (>100%) of the title compound.

[0279] 1< H-NMR (400 MHz, CDCl 3 ) δ [ppm]= 1.61 (s, 9H), 6.92 - 6.95 (d, 1H), 7.38 - 7.41 (d, 1H), 7.53 - 7.58 (dd, 1H). Intermediate 23 tert-Butyl-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0280]

[0281] tert-Butyl 6-hydrazinopyridine-2-carboxylate (79.9 g, 0.33 mol) was dissolved in THF (1.40 L), and 1,1-carbonyldiimidazole (74.3 g, 0.46 mol) was added while stirring at room temperature. The reaction mixture was stirred overnight at room temperature. After addition of water (1.0 L), the mixture was stirred for 15 min, and volatile solvents were removed in vacuo. The aqueous residue was saturated with sodium chloride and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The organic phase was separated, dried over magnesium sulfate and silica gel, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (SiO2; mobile phase: heptane / ethyl acetate 4 / 1, 2 / 1, 1 / 1, 1 / 2). The product-containing fractions were concentrated in vacuo, and 62.4 g (80% of theory) of the product were obtained.over two stages) of the title connection. . LC-MS (Method 7): R t = 0.50 min; MS (ESIpos): m / z = 180 [M+H] +< 1< H-NMR (400 MHz, CDCl 3 ) δ [ppm] = 1.62 (s, 9H), 6.62 - 6.64 (dd, 1H), 7.00 - 7.06 (dd, 1H), 7.15 - 7.19 (dd, 1H), 10.86 (br s, 1H). Intermediate 24 tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate)

[0282]

[0283] tert-Butyl 3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (34.5 g, 0.15 mol) and palladium on carbon (6.90 g, 5%) were suspended in toluene (60 ml) and methanol (500 ml) and stirred for 24 h at room temperature in a hydrogen atmosphere (34.5 bar). The reaction mixture was filtered through kieselguhr and washed with dichloromethane / methanol 9 / 1. The filtrate was concentrated, and the residue was stirred with ethyl acetate for 30 min, then filtered and dried. 36.8 g (89% of theory) of the title compound were obtained. LC-MS (Method 7): R t = 1.28 min; MS (ESIpos): m / z = 240 [M+H] +< 1< H-NMR (400 MHz, CDCl 3 ) δ [ppm] = 0.53 (s, 9H), 0.74 - 0.91 (m, 1H), 1.01 - 1.13 (m, 1H), 1.21 - 1.32 (m, 1H), 1.47 - 1.56 (m, 1H), 1.88 - 2.00 (m, 1H), 2.17 - 2.26 (dt, 1H), 4.29 - 4.34 (dd, 1H), 11.9 (br s, 1H). Intermediate 25 tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (enantiomer 2)

[0284] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate

[0285] (racemate) was separated by chiral preparative SFC [sample preparation: 6.00 g dissolved in 88 ml methanol; injection volume: 4.5 ml; column: Daicel Chiralpak ®< IC 20 µm, 370 x 50 mm; mobile phase: CO 2 / i-propanol: 0.0 min 35% i-propanol, flow: 200 g / min; 14.0 min 35% isopropanol, flow: 200 g / min; 15.0 min 60% i-propanol, flow: 115 g / min; 37.0 min 60% i-propanol, flow: 115 g / min; 38.0 min, 35% i-propanol, flow: 200 g / min; 42.0 min, 35% i-propanol, flow: 200 g / min; temperature: 38°C; UV detection: 210 nm]. After separation, 2.78 g of enantiomer 1, which eluted first, and 2.79 g of enantiomer 2, which eluted later, were isolated. Enantiomer 2

[0286] Analytical chiral SFC: R t = 4.20 min, de = 100% [column: Daicel Chiralpak ®< IC 50 x 4.6 mm; mobile phase: CO 2 / i-propanol 70:30; flow rate: 3 ml / min; UV detection: 210 nm]. LC-MS (Method 4): R t = 0.60 min; MS (ESIpos): m / z = 239 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]= 1.41 (s, 9H), 1.49 (dq, 1H), 1.72 - 1.84 (m, 1H), 1.95 - 2.10 (m, 2H), 2.46 - 2.56 (m, 1H), 2.59 - 2.68 (m, 1H), 4.35 (t, 1H), 11.36 (s, 1H).

[0287] The (5S) configuration was assigned based on crystal structure determination for examples 26, 108, 113, 157, 237, 358 and 454. tert-Butyl-(5S)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate Intermediate 26 tert-Butyl-(5RS)3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (enantiomer 1)

[0288] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate

[0289] (racemate) was separated by chiral preparative SFC [sample preparation: 6.00 g dissolved in 88 ml methanol; injection volume: 4.5 ml; column: Daicel Chiralpak ®< IC 20 µm, 370 x 50 mm; mobile phase: CO 2 / i-propanol: 0.0 min 35% i-propanol, flow: 200 g / min; 14.0 min 35% isopropanol, flow: 200 g / min; 15.0 min 60% i-propanol, flow: 115 g / min; 37.0 min 60% i-propanol, flow: 115 g / min; 38.0 min, 35% i-propanol, flow: 200 g / min; 42.0 min, 35% i-propanol, flow: 200 g / min; temperature: 38°C; UV detection: 210 nm]. After separation, 2.78 g of enantiomer 1, which eluted first, and 2.79 g of enantiomer 2, which eluted later, were isolated. Enantiomer 1

[0290] Analytical chiral SFC: R t = 1.67 min, de = 100% [column: Daicel Chiralpak ®< IC 50 x 4.6 mm; mobile phase: CO 2 / i-propanol 70:30; flow rate: 3 ml / min; UV detection: 210 nm]. LC-MS (Methode 4): R t = 0.60 min; MS (ESIpos): m / z = 239 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]= 1.41 (s, 9H), 1.49 (dq, 1H), 1.81 (dt, 1H), 2.00 - 2.10 (m, 2H), 2.45 - 2.56 (m, 1H), 2.58 - 2.67 (m, 1H), 4.35 (t, 1H), 11.36 (s, 1H). Intermediate 27 tert-Butyl-6-chlor-4-methylpyridin-2-carboxylat

[0291]

[0292] 6-Chloro-4-methylpyridine-2-carboxylic acid (2.50 g, 14.6 mmol) was dissolved in pyridine (10 ml) and tert-butanol (50 ml, 520 mmol), and 4-methylbenzenesulfonyl chloride (5.56 g, 29.1 mmol) was added. The reaction mixture was stirred overnight at room temperature and diluted with saturated aqueous sodium bicarbonate solution and cyclohexane / ethyl acetate 90 / 10. The organic phase was separated, and the aqueous phase was extracted with cyclohexane / ethyl acetate 90 / 10. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. 2.89 g (87% purity, 75% of theory) of the title compound were obtained.

[0293] 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.325 (0.86), 1.340 (0.86), 1.553 (16.00), 7.614 (0.68), 7.830 (0.80). Intermediate 28 tert-Butyl-6-{1-[(benzyloxy)carbonyl]hydrazino}-4-methylpyridine-2-carboxylate

[0294]

[0295] Under argon, tert-butyl 6-chloro-4-methylpyridine-2-carboxylate (2.89 g, 12.7 mmol) and benzyl hydrazinecarboxylate (2.32 g, 14.0 mmol) were dissolved in toluene (32 ml), and 1,1'-bis(diphenylphosphino)ferrocene (657 mg, 635 µmol), tris(dibenzylideneacetone)dipalladium chloroform complex (704 mg, 1.27 mmol), and cesium carbonate (4.96 g, 15.2 mmol) were added. The reaction mixture was stirred at 80°C for 4 h, then water and ethyl acetate were added. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica gel; mobile phase: isocratic, methanol / dichloromethane 4 / 96). The product-containing fractions were concentrated in vacuo, yielding 4.25 g (86% purity, 81% of theory) of the title compound. LC-MS (Method 3): R t = 1.96 min; MS (ESlpos): m / z = 358 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.317 (0.87), 1.329 (0.87), 1.549 (16.00), 2.387 (5.39), 5.192 (4.02), 5.277 (3.65), 7.314 (0.79), 7.331 (1.05), 7.344 (1.30), 7.360 (1.75), 7.380 (0.82), 7.421 (2.12), 7.440 (1.40), 7.618 (1.55), 7.649 (1.81). Intermediate 29 tert-Butyl-7-methyl-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate

[0296]

[0297] Under argon, palladium on carbon (299 mg, 10%) was added, and tert-butyl 6-{1-[(benzyloxy)carbonyl]hydrazino}-4-methylpyridine-2-carboxylate (1.80 g, 5.04 mmol) in methanol (20 ml) was added. The reaction mixture was stirred overnight at room temperature in a hydrogen atmosphere (1 bar). The suspension was diluted with methanol, filtered through diatomaceous earth, and washed with methanol. The reaction mixture was concentrated and immediately subjected to further reaction.

[0298] The residue was dissolved in THF (40 mL) and treated with di-1H-imidazol-1-ylmethanone (980 mg, 6.04 mmol). The reaction mixture was stirred at room temperature for 30 min. The solvent was removed under vacuum, and the residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated under vacuum, yielding 1.05 g (90% purity, 75% of theory) of the title compound. LC-MS (Method 1): R t = 0.98 min; MS (ESlneg): m / z = 248 [MH] -< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.536 (16.00), 1.553 (0.97), 2.218 (3.39), 3.318 (0.65), 6.597 (1.20), 7.051 (0.96), 12,345 (0.65). Intermediate 30 tert-Butyl-(5RS,7RS)-7-methyl-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (mixture of diastereomers; 4 isomers)

[0299]

[0300] Under argon, palladium on carbon (740 mg, 10%) was initially introduced, and tert-butyl 7-methyl-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (3.1 g, 12.44 mmol) in methanol (124 ml) was added. The reaction mixture was stirred overnight at room temperature in a hydrogen atmosphere (1 bar). The suspension was diluted with methanol, filtered through diatomaceous earth, and washed with methanol. The solvent was removed under vacuum. The residue was taken up in methanol (124 ml), and palladium on carbon (740 mg, 10%) was added. The reaction mixture was stirred for 48 h at room temperature in a hydrogen atmosphere (2 bar). The suspension was diluted with methanol, filtered through diatomaceous earth, and washed with methanol. The solvent was removed under vacuum and 2.71 g (86% of theory) of the title compound were obtained. LC-MS (Methode 3): R t = 1.24 min; MS (ESIpos): m / z = 507 [2M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.015 (2.13), 1.032 (2.20), 1.400 (0.73), 1.405 (1.16), 1.416 (16.00), 1.432 (0.48), 2.181 (0.46), 2.209 (0.56), 4.184 (0.45), 4.195 (0.43), 11.342 (0.73). Intermediate 31 Ethyl-6-{1-[(benzyloxy)carbonyl]hydrazino}-3-methylpyridin-2-carboxylat

[0301]

[0302] Under argon, ethyl 6-chloro-3-methylpyridine-2-carboxylate (970 mg, 4.86 mmol) and benzyl hydrazinecarboxylate (969 mg, 5.83 mmol) were dissolved in toluene (9.7 ml), and tris(dibenzylideneacetone)dipalladium chloroform complex (251 mg, 243 µmol), 1,1'-bis(diphenylphosphino)ferrocene (269 mg, 486 µmol), and cesium carbonate (1.90 g, 5.83 mmol) were added. The reaction mixture was stirred at 80°C for 4 h and then treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (SiO 2 ; mobile phase: isocratic, methanol / dichloromethane 8 / 92). The product-containing fractions were concentrated in vacuo, yielding 1.89 g (47% purity, 55% of theory) of the title compound. LC-MS (Method 4): Rt = 0.89 mins; MS (ESlpos): m / z = 330 [M+H] +< . Intermediate 32 Ethyl 6-hydrazino-3-methylpyridine-2-carboxylate dihydrochloride

[0303]

[0304] Under argon, palladium on carbon (232 mg, 10%) was initially charged, and ethyl 6-{1-[(benzyloxy)carbonyl]hydrazino}-3-methylpyridine-2-carboxylate (1.89 g, 5.74 mmol) in methanol (60 ml) was added. The reaction mixture was stirred overnight at room temperature in a hydrogen atmosphere (1 bar). The suspension was diluted with methanol, filtered through diatomaceous earth, and washed with methanol. The solvent was removed under vacuum, and the residue was taken up in dioxane, whereupon dioxane / hydrochloric acid (4M) was added. The precipitated solid was filtered, washed with methyl tert-butyl ether, and further reacted directly. Intermediate 33 Ethyl 6-methyl-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate

[0305]

[0306] Ethyl 6-hydrazino-3-methylpyridine-2-carboxylate dihydrochloride (419 mg, 1.56 mmol) was taken up in THF (12 ml), and di-1H-imidazol-1-ylmethanone (261 mg, 1.61 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Water and dichloromethane were added to the reaction mixture, and the mixture was basified with saturated aqueous sodium bicarbonate solution. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and the filtrate was concentrated. This gave 347 mg (89% purity, 104% of theory) of the title compound. LC-MS (Methode 1): R t = 0.77 min; MS (ESlneg): m / z = 220 [M-H] -< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.282 (5.00), 1.299 (10.60), 1.317 (5.79), 1.335 (0.84), 1.356 (2.69), 2.078 (16.00), 2.118 (0.45), 2.280 (0.45), 2.395 (0.71), 2.428 (0.75), 4.331 (1.67), 4.349 (4.92), 4.367 (4.80), 4.385 (1.58), 7.060 (2.57), 7.084 (3.35), 7.239 (3.24), 7.263 (2.51), 7.632 (0.45), 12.533 (1.43). Intermediate 34 Ethyl-(5RS,6RS)-6-methyl-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Diastereomerengemisch; 4 Isomere)

[0307]

[0308] Under argon, palladium on carbon (63 mg, 10%) was initially charged, and ethyl 6-methyl-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (297 mg, 1.34 mmol) in methanol (10 ml) was added. The reaction mixture was stirred overnight at room temperature in a hydrogen atmosphere (1 bar). The suspension was diluted with methanol, filtered through kieselguhr, and washed with methanol. The solvent was removed under vacuum, and the residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated under vacuum.

[0309] The residue was dissolved in methanol (5.0 ml), and after addition of palladium on carbon (25 mg, 10%), the reaction mixture was stirred overnight at room temperature in a hydrogen atmosphere (1 bar). The suspension was diluted with methanol, filtered through kieselguhr, and washed with methanol. The solvent was removed under vacuum, yielding 117 mg (39% of theory) of the title compound. LC-MS (Methode 3): R t = 0.93 min; MS (ESIpos): m / z = 226 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.015 (11.82), 1.033 (12.24), 1.175 (7.82), 1.193 (16.00), 1.211 (8.16), 1.236 (0.40), 1.428 (0.40), 1.441 (0.50), 1.459 (1.16), 1.473 (1.29), 1.492 (1.47), 1.505 (1.43), 1.522 (0.71), 1.536 (0.62), 1.691 (1.35), 1.698 (1.45), 1.706 (1.50), 1.717 (0.89), 1.724 (1.18), 1.732 (1.11), 1.739 (1.07), 2.246 (0.67), 2.252 (0.78), 2.263 (1.08), 2.269 (1.18), 2.278 (1.20), 2.284 (1.18), 2.292 (1.12), 2.299 (1.03), 2.309 (0.72), 2.316 (0.63), 2.557 (1.30), 2.569 (1.98), 2.584 (1.68), 2.600 (1.66), 2.615 (1.39), 2.656 (1.71), 2.661 (2.10), 2.669 (2.15), 2.675 (1.92), 2.698 (0.96), 2.703 (1.08), 2.711 (1.03), 2.717 (0.80), 4.098 (0.91), 4.107 (1.22), 4.116 (1.20), 4.125 (4.30), 4.134 (1.05), 4.142 (6.35), 4.151 (1.07), 4.160 (4.32), 4.169 (1.26), 4.178 (1.27), 4.187 (0.95), 4.419 (4.25), 4.435 (4.22), 11.412 (1.99). Intermediate 35 Ethyl-6-hydrazino-4-(trifluormethyl)pyridin-2-carboxylat

[0310]

[0311] Under argon, ethyl 6-chloro-4-(trifluoromethyl)pyridine-2-carboxylate (1000 mg, 3.94 mmol) and benzyl hydrazinecarboxylate (721 mg, 4.34 mmol) were dissolved in toluene (10 mL), and tris(dibenzylideneacetone)dipalladium chloroform complex (204 mg, 197 µmol), 1,1'-bis(diphenylphosphino)ferrocene (219 mg, 394 µmol), and cesium carbonate (1.54 g, 4.73 mmol) were added. The reaction mixture was stirred at 80°C for 4 h and treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (SiO2; mobile phase: isocratic, methanol / dichloromethane 8 / 92). The product-containing fractions were concentrated in vacuo, and the resulting residue was directly reacted.The residue was dissolved in methanol (50 ml) under argon, and palladium on carbon (223 mg, 10%) was added. The reaction mixture was stirred overnight at room temperature in a hydrogen atmosphere (1 bar). Further palladium on carbon (223 mg, 10%) was added and stirred overnight at room temperature in a hydrogen atmosphere (1 bar). The suspension was diluted with methanol, filtered through kieselguhr, and washed with methanol. The solvent was removed under vacuum, and the residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated under vacuum, yielding 385 mg (93% purity, 38% of theory) of the title compound. LC-MS (Method 1): R t = 0.91 min; MS (ESIpos): m / z = 250 [M+H] +< . Intermediate 36 Ethyl 3-oxo-7-(trifluoromethyl)-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate

[0312]

[0313] Ethyl 6-hydrazino-4-(trifluoromethyl)pyridine-2-carboxylate (384 mg, 1.54 mmol) was initially charged in THF (19 ml), treated with di-1H-imidazol-1-ylmethanone (300 mg, 1.85 mmol), and stirred overnight at room temperature. Water and dichloromethane were added to the reaction mixture. The organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and the filtrate was concentrated. This yielded 391 mg (94% purity, 87% of theory) of the title compound. LC-MS (Methode 4): R t = 0.71 min; MS (ESIpos): m / z = 276 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.299 (7.46), 1.316 (16.00), 1.334 (7.58), 1.345 (0.42), 1.357 (1.20), 1.363 (0.66), 2.525 (0.47), 4.336 (2.37), 4.354 (7.32), 4.371 (7.27), 4.389 (2.27), 7.044 (4.79), 7.048 (4.79), 7.954 (2.71), 7.957 (3.98), 7.960 (2.90). Intermediate 37 Ethyl-(5RS,7RS)-3-oxo-7-(trifluormethyl)-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Diastereomerengemisch; 4 Isomere)

[0314]

[0315] Under argon, palladium on carbon (30 mg, 10%) was initially charged, and ethyl 3-oxo-7-(trifluoromethyl)-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (100 mg, 363 µmol) in methanol (5.0 ml) was added. The reaction mixture was stirred for 40 h at room temperature in a hydrogen atmosphere (1 bar). The suspension was diluted with methanol, filtered through kieselguhr, and washed with methanol. The solvent was removed under vacuum, yielding 97.8 mg (87% purity, 84% of theory) of the title compound. LC-MS (Methode 4): R t = 0.64 min; MS (ESIpos): m / z = 280 [M+H] +< 1< H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.042 (1.06), 1.056 (2.04), 1.070 (1.10), 1.199 (8.42), 1.214 (16.00), 1.228 (8.00), 1.305 (0.45), 1.356 (1.36), 1.738 (1.02), 1.763 (2.47), 1.787 (2.58), 1.812 (1.20), 2.696 (1.56), 2.721 (2.08), 2.728 (2.47), 2.752 (2.57), 2.869 (2.23), 2.896 (1.50), 2.901 (1.51), 3.057 (1.19), 3.064 (1.13), 3.072 (1.13), 3.165 (1.54), 3.174 (1.56), 3.429 (0.48), 3.439 (0.55), 3.452 (0.48), 4.141 (0.78), 4.149 (1.47), 4.156 (2.22), 4.163 (4.00), 4.170 (4.33), 4.177 (4.39), 4.184 (3.95), 4.191 (2.27), 4.198 (1.47), 4.205 (0.83), 4.319 (0.42), 4.331 (0.60), 4.432 (2.24), 4.444 (2.52), 4.455 (2.47), 4.466 (2.20), 7.628 (0.41), 11.601 (3.48). brokered 38 Methyl-(2RS)-6-[(4-methoxybenzyl)(methoxycarbonyl)hydrazono]piperidin-2-carboxylat (Racemat)

[0316]

[0317] Trimethyloxonium tetrafluoroborate (678 mg, 95% purity, 4.36 mmol) was added to methyl (2RS)-6-oxopiperidine-2-carboxylate (racemate) (685 mg, 4.36 mmol) in dichloromethane (15 ml) under argon, and the reaction mixture was stirred overnight at room temperature. Methyl 1-(4-methoxybenzyl)hydrazinecarboxylate (1.29 g, 71% purity, 4.36 mmol) was then added, and the reaction mixture was stirred at room temperature for several days, occasionally monitoring the conversion. For workup, the volatiles were removed under vacuum. The remaining crude product (1.52 g, 100% of theory) was further reacted without additional purification. LC-MS (Method 4): R t = 0.51 min; MS (ESIpos): m / z = 350 [M+H] +< Intermediate 39 Methyl-(5RS)-2-(4-methoxybenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate)

[0318] Methyl (2RS)-6-[(4-methoxybenzyl)(methoxycarbonyl)hydrazono]piperidine-2-carboxylate

[0319] (Racemate) (1.52 g, 4.35 mmol) in DMF (5 ml) was stirred at 150°C overnight. For workup, the cooled mixture was added to approximately 50 ml of water, the mixture was alkalized to approximately pH 9 with aqueous sodium hydroxide solution, and extracted three times with 50 ml of dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by chromatography on silica gel (PuriFlash 50 g silica gel cartridge, dichloromethane 100% => dichloromethane: MeOH 80:1). Two fractions of the title compound were obtained: 327 mg in 60% purity (14% of theory) and 858 mg in 72% purity (45% of theory). Analytical results of the second fraction:

[0320] LC-MS (Methode 6): R t = 1.33 min; MS (ESIpos): m / z = 318 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.615 (0.90), 2.731 (9.35), 2.890 (12.58), 3.700 (13.65), 3.730 (16.00), 3.736 (6.83), 3.742 (2.33), 4.492 (1.54), 4.582 (0.85), 4.591 (0.94), 4.597 (1.08), 4.607 (0.82), 4.750 (5.88), 6.882 (3.29), 6.887 (2.11), 6.899 (1.66), 6.904 (4.11), 6.908 (1.73), 7.162 (3.09), 7.167 (1.04), 7.178 (1.35), 7.183 (3.40), 7.203 (1.01), 7.923 (0.79), 7.952 (1.25). Intermediate 40 (5RS)-2-(4-Methoxybenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carbonsäure (Racemat)

[0321]

[0322] Methyl (5RS)-2-(4-methoxybenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (320 mg, 60% purity, 605 µmol) was dissolved in water / THF (5 ml / 5 ml), lithium hydroxide (72.4 mg, 3.03 mmol) was added, and the reaction mixture was stirred at room temperature over a weekend. For workup, water was added, the mixture was adjusted to pH 3 with 1N aqueous hydrochloric acid, saturated with sodium chloride, and extracted three times with 30 ml of ethyl acetate each. The combined organic phases were dried with magnesium sulfate, filtered, and concentrated in vacuo. This yielded 250 mg (71% purity, 97% of theory) of the title compound. The resulting product was used without further purification.

[0323] In a second, analogous approach, 625 mg of the title compound (89% purity, 95% of theory) were obtained from 850 mg of methyl (5RS)-2-(4-methoxybenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (72% purity, 1.93 mmol). LC-MS (Method 3): R t = 1.00 min; MS (ESIpos): m / z = 304 [M+H] +< Intermediate 41 (5RS)-5-(Pyrrolidin-1-ylcarbonyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (racemate)

[0324] Variant a)

[0325] (5RS)-2-(4-Methoxybenzyl)-5-(pyrrolidin-1-ylcarbonyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (racemate) (670 mg, 1.88 mmol) was dissolved in trifluoroacetic acid (15 ml) and stirred in a microwave apparatus at 150°C for 1 h. For workup, the cooled mixture was concentrated, and the residue was purified in two injections by preparative HPLC (column: Chromatorex C18, 250x40mm 10µm. Flow: 50ml / min. Gradient (A=water + 0.1% formic acid, B=acetonitrile): 0min 10% B, 6min 10% B, 27min 95% B, 38min 95% B, 40min 10% B. Running time per separation: 40min. Detection: 210nm). Product fractions were concentrated and lyophilized. This gave 0.36g (80% of theory) of the title compound. Variant b)

[0326] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (500 mg, 2.54 mmol) was stirred with pyrrolidine (5.0 ml, 60 mmol) at 50 °C for 2 h, then for a further 18 h, and then for approximately 24 h at 60 °C (conversion monitored by HPLC / LC / MS). For workup, the reaction mixture was treated with water, diluted with ethyl acetate, and extracted. The aqueous phase was extracted twice more with ethyl acetate. The organic phases were discarded after LC / MS control. The product-containing aqueous phase was concentrated and dried in vacuo. By triturating the residue with ethyl acetate / methanol, concentrating the mother liquor and triturating it again with the solvent mixture, two fractions of the title compound were obtained: 45.7 mg (8%) and 112 mg (19%). Analytical data of the second fraction:

[0327] LC-MS (Methode 6): R t = 0.80 min; MS (ESIpos): m / z = 237 [M+H] +< 1< H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.147 (0.62), 1.662 (1.69), 1.673 (2.39), 1.682 (4.36), 1.690 (6.79), 1.700 (8.57), 1.710 (6.71), 1.720 (3.20), 1.757 (2.60), 1.771 (9.56), 1.784 (16.00), 1.798 (11.83), 1.812 (3.41), 1.894 (3.39), 1.907 (11.19), 1.921 (15.40), 1.935 (10.59), 1.948 (4.95), 1.956 (5.06), 1.965 (4.50), 1.972 (2.37), 1.978 (2.52), 1.990 (3.30), 1.999 (3.57), 2.007 (3.10), 2.019 (2.87), 2.036 (1.28), 2.049 (0.83), 2.472 (2.42), 2.518 (5.78), 2.524 (4.83), 2.571 (3.49), 2.580 (6.69), 2.590 (3.51), 2.604 (1.94), 2.613 (3.22), 2.623 (1.57), 2.636 (0.62), 3.013 (0.68), 3.027 (1.51), 3.041 (0.64), 3.225 (2.19), 3.238 (4.42), 3.248 (4.27), 3.262 (7.12), 3.276 (3.96), 3.288 (5.24), 3.324 (12.41), 3.333 (4.62), 3.338 (5.10), 3.347 (4.83), 3.362 (2.48), 3.375 (0.68), 3.437 (2.33), 3.451 (4.93), 3.457 (3.84), 3.465 (3.28), 3.471 (6.13), 3.485 (2.81), 3.579 (2.85), 3.593 (5.88), 3.599 (3.34), 3.606 (3.61), 3.612 (4.77), 3.626 (2.17), 4.637 (5.45), 4.644 (6.46), 4.650 (7.06), 4.657 (5.49), 11.270 (6.83). . Intermediate 42 Ethyl-2-isopropyliden-1-(4-methylbenzyl)hydrazincarboxylat

[0328]

[0329] Potassium hydroxide powder (4.11 g, 29.7 mmol) and tetra-n-butylammonium hydrogen sulfate (734 mg, 2.16 mmol) were added to ethyl 2-isopropylidenehydrazinecarboxylate (CAS 6637-60-1; 3.23 g, 22.4 mmol) in 55 mL of toluene under argon. 10 mL of toluene were added for improved stirrability. After warming to 50 °C, a solution of 1-(bromomethyl)-4-methylbenzene (5.00 g, 27.0 mmol) in 15 mL of toluene was slowly added dropwise. The mixture was heated to 80 °C and stirred for 2.5 h. For workup, water was added to the reaction mixture, and the organic phase was separated after extraction. The organic phase was extracted twice more with water, and the combined aqueous phases were then re-extracted once with toluene. The organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated and dried in vacuo.The crude product obtained was chromatographed on silica gel (instrument: Isolera column: 340g SNAP; mobile phase: cyclohexane and EtOAc; gradient: 0 min cyclohexane, 10 min cyclohexane, 35 min 30% EtOAc, 40 min 30% EtOAc). Product-containing fractions were combined, concentrated, and dried. This yielded 3.76 g (56% of theory) of the title compound. LC-MS (Method 4): R t = 0.96 min; MS (ESIpos): m / z = 249 [M+H] +< . Intermediate 43 Ethyl 1-(4-methylbenzyl)hydrazine carboxylate

[0330]

[0331] Ethyl 2-isopropylidene-1-(4-methylbenzyl)hydrazinecarboxylate (3.77 g, 15.2 mmol, according to LC / MS already partially hydrolyzed to the title compound) was dissolved in ethanol / water (100 ml / 66 ml), heated to reflux, and stirred for 3 h. For workup, the mixture was then largely concentrated, and the residue was taken up in dichloromethane / water and extracted. After separation of the phases, the aqueous phase was extracted twice more with dichloromethane, and the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated, and dried in vacuo. This yielded 3.25 g (87% purity, 89% of theory) of the title compound, which was further processed without further purification. LC-MS (Methode 6): R t = 1.53 min; MS (ESIpos): m / z = 209 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.159 (0.80), 1.168 (1.91), 1.185 (3.86), 1.203 (1.95), 1.667 (1.33), 1.927 (1.25), 2.267 (1.24), 2.275 (9.41), 4.035 (1.18), 4.053 (3.64), 4.071 (3.59), 4.088 (1.13), 4.425 (5.48), 4.548 (3.26), 7.126 (16.00). Intermediate 44 Methyl-(2RS)-6-[(ethoxycarbonyl)(4-methylbenzyl)hydrazono]piperidin-2-carboxylat (Racemat)

[0332]

[0333] Trimethyloxonium tetrafluoroborate (1.57 g, 95% purity, 10.1 mmol) was added to methyl (2RS)-6-oxopiperidine-2-carboxylate (racemate) (1.58 g, 10.1 mmol) in 20 mL of dichloromethane under argon, and the reaction mixture was stirred at room temperature for 18 h. Ethyl 1-(4-methylbenzyl)hydrazinecarboxylate (2.41 g, 87% purity, 10.1 mmol), dissolved in 10 mL of dichloromethane, was then added dropwise and stirred at room temperature for 26 h. For workup, the volatiles were removed under vacuum, and the residue was separated on silica gel. (Instrument: Isolera; Column: 100g SNAP cartridge. Mobile phase: cyclohexane and EtOAc / / EtOAc and MeOH. Gradient: 0 min 30% EtOAc, 3 min 30% EtOAc, 13 min 100% EtOAc, 18 min 100% EtOAc, 18.01 min 10% MeOH, 33 min 10% MeOH). Product-containing fractions were combined, concentrated, and dried in vacuo. 1.46 g (88% purity, 37% of theory) of the title compound were obtained, which was further reacted as desired. LC-MS (Methode 3): R t = 0.98 min; MS (ESIpos): m / z = 348 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.055 (0.58), 1.149 (1.00), 1.157 (1.01), 1.167 (1.78), 1.175 (1.73), 1.184 (0.92), 1.192 (0.87), 1.644 (0.91), 1.908 (0.76), 1.988 (2.45), 2.128 (2.05), 2.141 (2.19), 2.144 (2.23), 2.148 (1.42), 2.156 (0.95), 2.164 (0.99), 2.274 (3.39), 2.279 (4.35), 3.162 (0.90), 3.175 (0.90), 3.538 (3.77), 3.578 (0.99), 3.585 (1.56), 3.638 (3.98), 3.667 (16.00), 3.675 (1.67), 3.684 (2.39), 3.701 (3.26), 4.021 (0.67), 4.038 (0.81), 4.049 (1.01), 4.056 (1.07), 4.063 (1.50), 4.069 (1.44), 4.775 (1.21), 7.127 (1.68), 7.134 (2.17), 7.174 (1.17). Intermediate 45 Methyl-(5RS)-2-(4-methylbenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0334]

[0335] Methyl (2RS)-6-[(ethoxycarbonyl)(4-methylbenzyl)hydrazono]piperidine-2-carboxylate (racemate) (730 mg, 88% purity, 1.85 mmol) in 15 ml of DMF was stirred at 150°C overnight. For workup, the reaction mixture was added to water, made alkaline with 3N sodium hydroxide solution, and extracted with dichloromethane. The aqueous phase was saturated with sodium chloride and extracted twice more with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. This gave 288 mg (52% of theory) of the title compound. LC-MS (Methode 3): R t = 1.42 min; MS (ESIpos): m / z = 302 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.274 (12.04), 2.580 (0.80), 2.616 (1.19), 2.731 (10.86), 2.890 (12.92), 3.285 (1.12), 3.700 (16.00), 4.588 (1.05), 4.598 (1.19), 4.604 (1.34), 4.614 (1.04), 4.775 (6.63), 7.105 (0.94), 7.119 (1.09), 7.127 (7.35), 7.134 (6.83), 7.155 (1.02), 7.952 (1.56). Alternative Synthesis:

[0336] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (500 mg, 2.54 mmol) was initially dissolved in acetonitrile (10 mL). Cesium carbonate (909 mg, 2.79 mmol) and 1-(bromomethyl)-4-methylbenzene (493 mg, 2.66 mmol) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 560 mg (73% of theory) of the title compound. LC-MS (Methode 1): R t = 1.05 min; MS (ESIpos): m / z = 302 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.61), 0.008 (0.56), 1.787 (0.45), 1.798 (0.49), 1.812 (0.42), 2.050 (0.42), 2.060 (0.71), 2.072 (0.83), 2.080 (0.64), 2.088 (0.52), 2.096 (0.44), 2.104 (0.52), 2.108 (0.45), 2.116 (0.53), 2.124 (0.51), 2.132 (0.48), 2.274 (11.08), 2.523 (0.63), 2.566 (0.81), 2.580 (0.64), 2.605 (0.58), 2.616 (1.09), 2.629 (0.60), 2.659 (0.49), 3.701 (16.00), 4.588 (0.99), 4.598 (1.12), 4.604 (1.28), 4.614 (0.97), 4.775 (6.33), 7.106 (0.87), 7.127 (6.84), 7.134 (6.17), 7.154 (0.82). Intermediate 46 Methyl-(5RS)-2-(4-methylbenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Enantiomer 1)

[0337] Methyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0338] (Enantiomer 2) (700 mg, 3.55 mmol) was initially dissolved in acetonitrile (31 ml). Cesium carbonate (1.27 g, 3.90 mmol) and 1-(bromomethyl)-4-methylbenzene (690 mg, 3.73 mmol) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, 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 sulfate, filtered, and the filtrate was concentrated. 1.05 g (91% purity, 89% of theory) of the title compound were obtained. LC-MS (Method 3): R t = 1.46 min; MS (ESIpos): m / z = 302 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.497 (0.40), 1.519 (0.42), 1.524 (0.43), 1.532 (0.43), 1.788 (0.50), 1.797 (0.54), 1.811 (0.47), 1.821 (0.43), 1.988 (0.48), 2.049 (0.50), 2.060 (0.81), 2.073 (0.80), 2.080 (0.72), 2.087 (0.59), 2.095 (0.51), 2.104 (0.58), 2.115 (0.59), 2.124 (0.56), 2.131 (0.52), 2.273 (12.47), 2.292 (0.91), 2.523 (0.62), 2.566 (0.84), 2.580 (0.68), 2.604 (0.64), 2.616 (1.20), 2.628 (0.66), 2.658 (0.55), 3.310 (16.00), 3.683 (0.71), 4.588 (1.13), 4.598 (1.28), 4.604 (1.44), 4.614 (1.10), 4.674 (0.43), 4.775 (6.90), 7.106 (1.01), 7.127 (8.08), 7.133 (7.29), 7.154 (1.06).

[0339] The (5S) configuration was assigned based on crystal structure determination for examples 26, 108, 113, 157, 237, 358 and 454. Methyl (5S)-2-(4-methylbenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate Intermediate 47 Methyl-(5S)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-5-carboxylat (Enantiomer)

[0340]

[0341] Methyl 5-oxo-L-prolinate (24.0 g, 168 mmol, CAS 4931-66-2) was initially dissolved in dichloromethane (210 ml) at room temperature. Trimethyloxonium tetrafluoroborate (24.8 g, 168 mmol) was then added, and the reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo, and the residue was treated with DMF (240 ml). Methyl hydrazinecarboxylate (15.1 g, 168 mmol) was then added, and the reaction mixture was stirred overnight at 170 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, mobile phase: dichloromethane / methanol gradient). The product-containing fractions were concentrated in vacuo to yield 7.57 g (25% of theory) of the title compound. This was then further reacted directly. GC-MS (WUP-GC / MS): R t = 6.48 min; MS (ESIpos): m / z = 183 [M+H] +< Intermediate 48 Methyl-(5S)-2-(4-methylbenzyl)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate (enantiomer)

[0342]

[0343] Methyl (5S)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate (enantiomer) (250 mg, 1.36 mmol) was initially dissolved in acetonitrile (3.0 ml). Cesium carbonate (489 mg, 1.50 mmol) and 1-(bromomethyl)-4-methylbenzene (265 mg, 1.43 mmol, CAS 104-81-4) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. 412 mg (91% purity, 96% of theory) of the title compound were obtained. LC-MS (Methode 3): R t = 1.32 min; MS (ESIpos): m / z = 288 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.072 (1.11), 2.275 (9.70), 2.303 (0.99), 2.458 (0.51), 2.465 (0.54), 2.720 (1.21), 2.743 (1.93), 2.758 (1.66), 2.837 (0.42), 2.857 (0.41), 2.869 (0.51), 2.892 (0.49), 3.708 (1.25), 3.722 (12.20), 4.758 (2.95), 4.763 (3.01), 4.776 (1.05), 4.791 (1.07), 4.799 (0.95), 4.937 (0.40), 5.753 (0.46), 7.141 (16.00). Intermediate 49 Methyl-(5S)-2-[(6-chlorpyridin-3-yl)methyl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-5-carboxylat (Enantiomer)

[0344]

[0345] Methyl (5S)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate (enantiomer) (300 mg, 1.64 mmol) was initially dissolved in acetonitrile (10 ml). After stirring for 5 min, cesium carbonate (587 mg, 1.80 mmol) and 5-(bromomethyl)-2-chloropyridine (355 mg, 1.72 mmol, CAS 182924-36-3) were added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 430 mg (85% of theory) of the title compound. LC-MS (Method 1): R t = 0.80 min; MS (ESIpos): m / z = 309 [M+H] +< Intermediate 50 Methyl-(5S)-3-oxo-2-{[6-(trifluormethyl)pyridin-3-yl]methyl}-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-5-carboxylat (Enantiomer)

[0346]

[0347] Methyl (5S)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate (enantiomer) (300 mg, 1.64 mmol) was initially dissolved in acetonitrile (10 ml). Cesium carbonate (587 mg, 1.80 mmol) and 5-(bromomethyl)-2-(trifluoromethyl)pyridine (413 mg, 1.72 mmol, CAS 108274-33-5) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 441 mg (79% of theory) of the title compound. LC-MS (Method 1): R t = 0.92 min; MS (ESIpos): m / z = 343 [M+H] +<. Intermediate 51 Methyl-(5S)-2-(3-chlor-4-fluorbenzyl)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-5-carboxylat (Enantiomer)

[0348]

[0349] Methyl (5S)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate (enantiomer) (300 mg, 1.64 mmol) was initially dissolved in acetonitrile (530 µL). After stirring for 5 min, cesium carbonate (587 mg, 1.80 mmol) and 4-(bromomethyl)-2-chloro-1-fluorobenzene (384 mg, 1.72 mmol, CAS 192702-01-5) were added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 460 mg (86% of theory) of the title compound. LC-MS (Method 3): R t = 1.42 min; MS (ESIpos): m / z = 326 [M+H] +< . Intermediate 52 Methyl-(5S)-3-oxo-2-[3-(trifluormethyl)benzyl]-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-5-carboxylat (Enantiomer)

[0350]

[0351] Methyl (5S)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate (enantiomer) (150 mg, 819 µmol) was initially dissolved in acetonitrile (8.0 ml). After stirring for 5 min, cesium carbonate (294 mg, 901 µmol) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (206 mg, 860 µmol, CAS 402-23-3) were added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 150 mg (53% of theory) of the title compound. LC-MS (Method 1): R t = 1.09 min; MS (ESIpos): m / z = 342 [M+H] +< Intermediate 53 Methyl-(5S)-2-[(2-chlorpyridin-4-yl)methyl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-5-carboxylat (Enantiomer)

[0352]

[0353] Methyl (5S)-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylate (enantiomer) (150 mg, 819 µmol) was initially dissolved in acetonitrile (7.0 ml). After stirring for 5 min, cesium carbonate (294 mg, 901 µmol) and 4-(bromomethyl)-2-chloropyridine (178 mg, 860 µmol, CAS 83004-15-3) were added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 250 mg (99% of theory) of the title compound. LC-MS (Method 1): R t = 0.78 min; MS (ESIpos): m / z = 309 [M+H] +< Intermediate 54 Methyl-(5RS)-2-(4-chlorbenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0354]

[0355] Methyl (2RS)-6-[(tert-butoxycarbonyl)hydrazono]piperidine-2-carboxylate (racemate) (2.20 g, 7.21 mmol) in 15 mL of DMF was stirred at 150°C overnight. The reaction mixture (theoretical yield: 1.42 g) was divided into aliquots and used directly. Cesium carbonate (1.17 g, 3.60 mmol) and 1-(bromomethyl)-4-chlorobenzene (518 mg, 2.52 mmol) were added to an aliquot of the crude product methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (calculated as 473 mg, 2.40 mmol) in 5 mL of DMF. The reaction mixture was stirred overnight at room temperature. 1-(bromomethyl)-4-chlorobenzene (493 mg, 2.40 mmol) was then added and the mixture was stirred overnight at 50°C. For workup, the mixture was treated with water, extracted twice with 15 ml of ethyl acetate each time, and the combined organic phases were washed once with saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated in vacuo.The residue was separated into 2 portions via preparative HPLC (column: Chromatorex, 125x40mm 10µm. Flow: 50ml / min. Gradient (A= water + 0.1% formic acid, B= acetonitrile): 0min 10% B, 5min 10% B, 27min 98% B, 35min 98% B, 35.01min 10% B, 38min 10% B. Running time per separation: 38min. Detection: 210nm). Concentration of the product fractions yielded 80mg (96% purity, 9.6% of theory) of the title compound. LC-MS (Method 3): Rt = 1.78 min; MS (ESIpos): m / z = 388 [M+H] +< . Intermediate 55 tert-Butyl-(5RS)-2-(4-methylbenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (enantiomer 1)

[0356] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate

[0357] (Enantiomer 2) (1.77 g, 7.38 mmol) was initially dissolved in acetonitrile (71 ml). Cesium carbonate (2.40 g, 7.38 mmol) and 1-(bromomethyl)-4-methylbenzene (1.37 g, 7.38 mmol) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and the filtrate was concentrated. This gave 2.65 g (>100% of theory) of the title compound. LC-MS (Method 4): R t = 0.97 min; MS (ESIpos): m / z = 343 [M+H] +< brokered 56 tert-Butyl-(5RS)-2-[(5-chloropyridin-2-yl)methyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate)

[0358] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate

[0359] (Racemate) (300 mg, 1.25 mmol) was initially dissolved in acetonitrile (6.0 mL). Cesium carbonate (613 mg, 1.88 mmol) and 2-(bromomethyl)-5-chloropyridine (272 mg, 1.32 mmol, CAS 605681-01-4) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo and 306 mg (65% of theory) of the title compound were obtained. LC-MS (Methode 3): R t = 1.61 min; MS (ESIpos): m / z = 365 [M+H] +< 1< H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.410 (16.00), 2.078 (0.62), 2.085 (0.56), 2.637 (0.42), 4.453 (0.46), 4.459 (0.48), 4.463 (0.58), 4.469 (0.43), 4.932 (1.44), 4.947 (1.43), 7.232 (0.89), 7.246 (0.91), 7.928 (0.56), 7.932 (0.56), 7.942 (0.53), 7.946 (0.52), 8.578 (0.90), 8.582 (0.88). Intermediate 57 tert-Butyl-(5RS)-3-oxo-2-{[6-(trifluormethyl)pyridin-3-yl]methyl}-2,3,5,6,7,8-hexahydro-[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0360] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0361] (Racemate) (300 mg, 1.25 mmol) was initially dissolved in acetonitrile (6.0 ml). Cesium carbonate (613 mg, 1.88 mmol) and 5-(bromomethyl)-2-(trifluoromethyl)pyridine (316 mg, 1.32 mmol, CAS 108274-33-5) were then added. After stirring at room temperature for 48 h, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was suspended in diethyl ether, and the solid was filtered off and dried under reduced pressure. 345 mg (66% of theory) of the title compound were obtained. LC-MS (Methode 4): R t = 0.92 min; MS (ESIpos): m / z = 399 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.383 (16.00), 1.404 (0.51), 2.069 (0.60), 2.081 (0.48), 4.457 (0.62), 5.036 (2.03), 7.923 (1.20), 7.933 (0.73), 7.937 (0.70), 8.665 (0.72). Intermediate 58 tert-Butyl-(5RS)-2-(3,5-dichlorbenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0362] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0363] (Racemate) (300 mg, 1.25 mmol) was initially dissolved in acetonitrile (6.0 ml). Cesium carbonate (613 mg, 1.88 mmol) and 1-(bromomethyl)-3,5-dichlorobenzene (316 mg, 1.32 mmol, CAS 7778-01-0) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. This gave 445 mg (82% purity, 89% of theory) of the title compound. LC-MS (Method 3): R t = 2.12 min; MS (ESIpos): m / z = 342 [M+H] +< Intermediate 59 tert-Butyl-(5RS)-3-oxo-2-(pyridin-3-ylmethyl)-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate)

[0364] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate

[0365] (Racemate) (300 mg, 1.25 mmol) was initially dissolved in acetonitrile (6.0 ml). Cesium carbonate (1.02 g, 3.13 mmol) and 3-(bromomethyl)pyridine hydrobromide (333 mg, 1.32 mmol, CAS 4916-55-6) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. This gave 366 mg (88% of theory) of the title compound. LC-MS (Methode 4): R t = 0.58 min; MS (ESIpos): m / z = 331 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.390 (16.00), 1.405 (12.47), 2.037 (0.58), 2.050 (0.73), 2.060 (0.77), 2.070 (0.65), 2.523 (0.58), 2.617 (0.41), 2.627 (0.42), 4.348 (0.50), 4.444 (0.59), 4.526 (0.81), 4.896 (1.69), 7.359 (0.43), 7.371 (0.43), 7.378 (0.45), 7.391 (0.45), 7.642 (0.49), 7.661 (0.42), 8.483 (0.82), 8.500 (0.55), 8.504 (0.55), 8.513 (0.52). Intermediate 60 Methyl-(5RS)-2-[(5-methyl-1,2-oxazol-3-yl)methyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0366]

[0367] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (50.0 mg, 254 µmol) was initially dissolved in acetonitrile (3.6 ml). Cesium carbonate (124 mg, 380 µmol) and 3-(bromomethyl)-5-methyl-1,2-oxazole (46.9 mg, 266 µmol, CAS 130628-75-0) were then added. After stirring at room temperature for 24 h, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. 58.0 mg (93% purity, 73% of theory) of the title compound were obtained. LC-MS (Methode 1): R t = 0.78 min; MS (ESIpos): m / z = 293 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.58), 0.008 (0.51), 1.527 (0.40), 1.532 (0.40), 1.540 (0.42), 1.798 (0.45), 1.806 (0.50), 1.820 (0.43), 2.055 (0.46), 2.072 (3.66), 2.084 (0.69), 2.092 (0.58), 2.100 (0.46), 2.108 (0.53), 2.113 (0.51), 2.120 (0.49), 2.129 (0.51), 2.136 (0.47), 2.206 (1.02), 2.376 (10.50), 2.518 (0.88), 2.560 (0.90), 2.575 (0.76), 2.587 (0.75), 2.601 (0.66), 2.624 (0.60), 2.636 (1.04), 2.648 (0.59), 2.678 (0.48), 3.687 (1.59), 3.703 (16.00), 4.591 (0.92), 4.600 (1.03), 4.607 (1.24), 4.616 (0.92), 4.854 (7.94), 4.981 (0.43), 6.065 (2.10). Intermediate 61 tert-Butyl-(5RS)-2-(3,4-difluorbenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0368] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0369] (Racemate) (300 mg, 1.25 mmol) was initially dissolved in acetonitrile (10 ml). Cesium carbonate (429 mg, 1.32 mmol) and 4-(bromomethyl)-1,2-difluorobenzene (273 mg, 1.32 mmol, CAS 85118-01-0) were then added. The reaction mixture was stirred overnight at room temperature and for one hour at 90 °C. Water and ethyl acetate were then added to the reaction mixture. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. This gave 455 mg (99% of theory) of the title compound.

[0370] 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.57), 0.008 (0.51), 1.393 (16.00), 1.404 (3.82), 1.908 (1.06), 1.988 (0.61), 2.064 (0.60), 2.074 (0.56), 2.523 (0.73), 4.433 (0.44), 4.443 (0.41), 4.448 (0.56), 4.699 (0.90), 4.847 (1.99), 7.400 (0.49), 7.428 (0.45). Intermediate 62 tert-Butyl-(5RS)-2-(3-chlor-4-fluorbenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0371] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0372] (Racemate) (311 mg, 1.30 mmol) was initially dissolved in acetonitrile (10 ml). Cesium carbonate (445 mg, 1.36 mmol) and 4-(bromomethyl)-2-chloro-1-fluorobenzene (305 mg, 1.36 mmol, CAS 192702-01-5) were then added. The reaction mixture was stirred overnight at room temperature and for one hour at 90 °C. Water and ethyl acetate were then added to the reaction mixture. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. This gave 491 mg (90% purity, 89% of theory) of the title compound. LC-MS (Method 1): R t = 1.32 min; MS (ESIpos): m / z = 326 [M-tBu+H] +< Intermediate 63 Methyl-(5RS)-2-(3-chlorobenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate)

[0373]

[0374] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (50.0 mg, 254 µmol) was initially dissolved in acetonitrile (3.6 ml). Cesium carbonate (124 mg, 380 µmol) and 1-(bromomethyl)-3-chlorobenzene (54.7 mg, 266 µmol, CAS 766-80-3) were then added. After stirring at room temperature for 24 h, the reaction mixture was treated with water, 1N aqueous hydrochloric acid, and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 66.0 mg (81% of theory) of the title compound. LC-MS (Methode 4): R t = 0.82 min; MS (ESIpos): m / z = 322 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.42), 0.008 (1.25), 1.526 (0.41), 1.532 (0.41), 1.802 (0.49), 1.811 (0.51), 1.825 (0.45), 1.836 (0.42), 2.065 (0.46), 2.075 (0.77), 2.088 (0.74), 2.095 (0.70), 2.102 (0.56), 2.110 (0.46), 2.118 (0.54), 2.130 (0.51), 2.139 (0.53), 2.146 (0.50), 2.523 (1.49), 2.564 (1.03), 2.579 (0.83), 2.591 (0.83), 2.605 (0.68), 2.631 (0.63), 2.642 (1.16), 2.654 (0.67), 2.673 (0.53), 2.684 (0.51), 3.708 (16.00), 4.615 (1.04), 4.625 (1.16), 4.631 (1.33), 4.640 (1.01), 4.863 (5.05), 7.190 (1.12), 7.208 (1.43), 7.282 (1.86), 7.343 (0.46), 7.359 (1.33), 7.364 (2.10), 7.369 (2.85), 7.387 (1.85), 7.407 (0.62). Intermediate 64 tert-Butyl-(5RS)-2-[(2-methoxypyridin-4-yl)methyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0375] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0376] (Racemate) (357 mg, 1.49 mmol) was initially dissolved in acetonitrile (10 mL). Cesium carbonate (510 mg, 1.57 mmol) and 4-(bromomethyl)-2-methoxypyridine (381 mg, 83% purity, 1.57 mmol, CAS 120277-15-8) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water, 1N aqueous hydrochloric acid, and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 144 mg (27% of theory) of the title compound. LC-MS (Method 3): R t = 1.52 min; MS (ESIpos): m / z = 361 [M+H] +< Intermediate 65 tert-Butyl-(5RS)-2-(3-fluorbenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0377] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0378] (Racemate) (300 mg, 1.25 mmol) was initially dissolved in acetonitrile (10 mL). Cesium carbonate (429 mg, 1.32 mmol) and 1-(bromomethyl)-3-fluorobenzene (249 mg, 1.32 mmol, CAS 456-41-7) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water, 1N aqueous hydrochloric acid, and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo and 297 mg (68% of theory) of the title compound were obtained. LC-MS (Methode 1): R t = 1.23 min; MS (ESIpos): m / z = 291 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.11), 0.008 (0.97), 1.397 (16.00), 2.067 (0.49), 2.077 (0.52), 2.518 (1.08), 2.523 (0.83), 4.451 (0.57), 4.865 (1.75), 4.872 (1.37), 7.078 (0.48), 7.097 (0.65), 7.380 (0.40), 7.396 (0.42). Intermediate 66 tert-Butyl-(5RS)-2-(3-chlor-4-methoxybenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0379] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0380] (Racemate) (300 mg, 1.25 mmol) was initially dissolved in acetonitrile (6.0 mL). Cesium carbonate (613 mg, 1.88 mmol) and 4-(bromomethyl)-2-chloro-1-methoxybenzene (314 mg, 99% purity, 1.32 mmol, CAS 320407-92-9) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 365 mg (74% of theory) of the title compound. LC-MS (Method 4): R t = 0.96 min; MS (ESIpos): m / z = 393 [M] +< Intermediate 67 tert-Butyl-(5RS)-3-oxo-2-[3-(trifluormethyl)benzyl]-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0381] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0382] (Racemate) (300 mg, 1.25 mmol) was initially dissolved in acetonitrile (6.0 ml). Cesium carbonate (613 mg, 1.88 mmol) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (315 mg, 1.32 mmol, CAS 402-23-3) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was suspended in diethyl ether, the solid was filtered off, and the filtrate was dried in vacuo. 388 mg (75% of theory) of the title compound were obtained. LC-MS (Method 1): R t = 1.35 min; MS (ESIpos): m / z = 342 [M+H] +< Intermediate 68 tert-Butyl-(5RS)-2-(3-methoxybenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate)

[0383] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0384] (Racemate) (300 mg, 1.25 mmol) was initially dissolved in acetonitrile (6.0 mL). Cesium carbonate (613 mg, 1.88 mmol) and 1-(bromomethyl)-3-methoxybenzene (265 mg, 1.32 mmol, CAS 874-98-6) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 340 mg (94% purity, 71% of theory) of the title compound. LC-MS (Method 4): R t = 0.91 min; MS (ESIpos): m / z = 360 [M+H] +< Intermediate 69 tert-Butyl-(5RS)-2-[(1-methyl-1H-pyrazol-3-yl)methyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0385] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0386] (Racemate) (145 mg, 606 µmol) was initially dissolved in acetonitrile (6.0 ml). Cesium carbonate (207 mg, 636 µmol) and 3-(bromomethyl)-1-methyl-1H-pyrazole (106 mg, 606 µmol, CAS 102846-13-9) were then added. The reaction mixture was stirred overnight at room temperature and then for 3 h at 70 °C. The reaction mixture was cooled to room temperature and treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 150 mg (74% of theory) of the title compound. LC-MS (Method 1): R t = 0.97 min; MS (ESIpos): m / z = 278 [M-tBu+H] +< . Intermediate 70 tert-Butyl-(5RS)-3-oxo-2-(5,6,7,8-tetrahydronaphthalin-2-ylmethyl)-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0387] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0388] (Racemate) (400 mg, 1.67 mmol) was initially dissolved in acetonitrile (10 mL). Cesium carbonate (572 mg, 1.76 mmol) and 6-(chloromethyl)-1,2,3,4-tetrahydronaphthalene (317 mg, 1.76 mmol, CAS 17450-63-4) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 280 mg (43% of theory) of the title compound. LC-MS (Method 1): R t = 1.44 min; MS (ESIpos): m / z = 328 [M-tBu+H] +< Intermediate 71 tert-Butyl-(5RS)-3-oxo-2-(2,4,5-trifluorbenzyl)-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0389] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0390] (Racemate) (400 mg, 1.67 mmol) was initially dissolved in acetonitrile (10 mL). Cesium carbonate (572 mg, 1.76 mmol) and 1-(chloromethyl)-2,4,5-trifluorobenzene (317 mg, 1.76 mmol, CAS 243139-71-1) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 390 mg (61% of theory) of the title compound. LC-MS (Method 1): R t = 1.29 min; MS (ESIpos): m / z = 328 [M-tBu+H] +< Intermediate 72 tert-Butyl-(5RS)-2-[(2-chloropyridin-4-yl)methyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate)

[0391] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate

[0392] (Racemate) (370 mg, 1.54 mmol) was initially dissolved in acetonitrile (10 ml). Cesium carbonate (528 mg, 1.62 mmol) and 4-(bromomethyl)-2-chloropyridine (360 mg, 93% purity, 1.62 mmol, CAS 83004-15-3) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. This gave 490 mg (83% of theory) of the title compound. LC-MS (Methode 3): R t = 1.54 min; MS (ESIpos): m / z = 365 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.57), 0.008 (1.54), 1.405 (16.00), 2.084 (0.54), 2.094 (0.44), 2.523 (0.99), 2.568 (0.41), 2.669 (0.51), 4.476 (0.54), 4.944 (1.40), 4.949 (1.35), 7.240 (0.51), 7.250 (0.53), 7.328 (0.82), 8.377 (0.75), 8.389 (0.75). Intermediate 73 tert-Butyl-(5RS)-2-[(5-chlor-2-thienyl)methyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0393] tert-Butyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0394] (Racemate) (300 mg, 1.25 mmol) was initially dissolved in acetonitrile (10 ml). Cesium carbonate (429 mg, 1.32 mmol) and 2-chloro-5-(chloromethyl)thiophene (220 mg, 1.32 mmol, CAS 23784-96-5) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. This gave 414 mg (83% purity, 74% of theory) of the title compound. LC-MS (Methode 3): R t = 1.88 min; MS (ESIpos): m / z = 313 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.175 (0.45), 1.335 (0.71), 1.384 (16.00), 1.397 (0.99), 1.988 (0.79), 2.045 (0.50), 2.057 (0.51), 4.420 (0.56), 4.950 (2.59), 4.986 (2.46), 6.922 (0.61), 6.931 (0.84), 6.976 (1.11), 6.986 (0.79), 7.011 (0.48), 7.020 (0.65), 7.079 (0.51). Intermediate 74 Methyl-(5RS)-2-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0395]

[0396] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (300 mg, 1.52 mmol) was initially dissolved in acetonitrile (10 ml). Cesium carbonate (545 mg, 1.67 mmol) and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole (283 mg, 1.60 mmol, CAS 90507-32-7) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 281 mg (63% of theory) of the title compound. LC-MS (Method 3): R t = 1.06 min; MS (ESIpos): m / z = 294 [M+H] +< Intermediate 75 Methyl-(5RS)-2-[(6-methylpyridin-3-yl)methyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0397]

[0398] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (300 mg, 1.52 mmol) was initially dissolved in acetonitrile (10 ml). Cesium carbonate (1.24 g, 3.80 mmol) and 5-(chloromethyl)-2-methylpyridine hydrochloride (298 mg, 1.67 mmol, CAS 106651-81-4) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water, 1N aqueous hydrochloric acid, and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 236 mg (51% of theory) of the title compound. LC-MS (Methode 4): R t = 0.26 min; MS (ESIpos): m / z = 303 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.57), 0.008 (0.57), 1.511 (0.41), 1.517 (0.41), 1.525 (0.42), 1.787 (0.49), 1.798 (0.53), 1.812 (0.45), 1.822 (0.42), 2.051 (0.47), 2.061 (0.80), 2.073 (3.59), 2.086 (0.68), 2.095 (0.50), 2.103 (0.56), 2.107 (0.49), 2.115 (0.52), 2.123 (0.54), 2.131 (0.51), 2.439 (12.07), 2.523 (0.56), 2.557 (0.88), 2.569 (0.86), 2.583 (0.68), 2.609 (0.63), 2.621 (1.16), 2.633 (0.65), 2.663 (0.57), 3.700 (16.00), 4.594 (1.02), 4.603 (1.12), 4.610 (1.31), 4.619 (1.00), 4.835 (5.24), 7.216 (1.67), 7.236 (1.95), 7.506 (1.19), 7.512 (1.20), 7.526 (1.07), 7.532 (1.07), 8.337 (1.47), 8.342 (1.45). Intermediate 76 Methyl-(5RS)-2-[(6-methoxypyridin-3-yl)methyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0399]

[0400] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (300 mg, 1.52 mmol) was initially dissolved in acetonitrile (10 ml). Cesium carbonate (1.24 g, 3.80 mmol) and 5-(chloromethyl)-2-methoxypyridine hydrochloride (325 mg, 1.67 mmol, CAS 120276-36-0) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water, 1N aqueous hydrochloric acid, and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 206 mg (42% of theory) of the title compound. LC-MS (Methode 4): R t = 0.61 min; MS (ESIpos): m / z = 319 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.39), 0.008 (1.28), 1.795 (0.43), 2.073 (5.67), 2.091 (0.40), 2.099 (0.45), 2.111 (0.42), 2.120 (0.44), 2.127 (0.41), 2.523 (0.87), 2.568 (0.68), 2.582 (0.55), 2.608 (0.50), 2.620 (0.92), 2.631 (0.52), 2.662 (0.50), 3.698 (13.67), 3.828 (16.00), 3.851 (0.46), 4.585 (0.90), 4.594 (0.95), 4.600 (1.13), 4.610 (0.82), 4.794 (5.64), 6.793 (1.69), 6.815 (1.80), 7.560 (1.13), 7.566 (1.15), 7.582 (1.09), 7.588 (1.11), 8.066 (1.53), 8.071 (1.49). Intermediate 77 Methyl-(5RS)-2-[2,5-bis(trifluormethyl)benzyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0401]

[0402] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (300 mg, 1.52 mmol) was initially dissolved in acetonitrile (10 ml). Cesium carbonate (1.24 g, 3.80 mmol) and 2-(bromomethyl)-1,4-bis(trifluoromethyl)benzene (514 mg, 1.67 mmol, CAS 302911-98-4) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water, 1N aqueous hydrochloric acid, and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. 649 mg (95% of theory) of the title compound were obtained. LC-MS (Methode 4): R t = 1.00 min; MS (ESIpos): m / z = 424 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.90), 0.008 (0.79), 1.157 (0.56), 1.175 (1.14), 1.193 (0.59), 1.539 (0.40), 1.815 (0.51), 1.825 (0.49), 1.839 (0.42), 1.850 (0.43), 1.988 (2.13), 2.073 (0.47), 2.091 (0.47), 2.103 (0.89), 2.111 (1.07), 2.134 (0.56), 2.147 (0.48), 2.155 (0.51), 2.163 (0.47), 2.576 (0.89), 2.591 (0.71), 2.603 (0.74), 2.617 (0.61), 2.649 (0.57), 2.660 (1.10), 2.671 (0.76), 2.702 (0.47), 3.702 (16.00), 4.021 (0.51), 4.038 (0.50), 4.660 (1.05), 4.669 (1.11), 4.675 (1.37), 4.684 (1.00), 5.056 (0.60), 5.097 (1.96), 5.130 (2.04), 5.171 (0.61), 7.632 (2.12), 7.934 (0.89), 7.953 (1.38), 8.025 (1.90), 8.045 (1.28). Intermediate 78 Methyl-(5RS)-3-oxo-2-({5-[3-(trifluormethyl)phenyl]-1,2,4-oxadiazol-3-yl}methyl)-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0403]

[0404] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (300 mg, 1.52 mmol) was initially dissolved in acetonitrile (10 ml). Cesium carbonate (1.24 g, 3.80 mmol) and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (439 mg, 1.67 mmol) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water, 1N aqueous hydrochloric acid, and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. 642 mg (90% purity, 90% of theory) of the title compound were obtained. LC-MS (Methode 3): R t = 1.68 min; MS (ESIpos): m / z = 424 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.48), 0.008 (0.43), 1.158 (0.79), 1.175 (1.64), 1.193 (0.83), 1.530 (0.40), 1.563 (0.43), 1.802 (0.50), 1.814 (0.55), 1.828 (0.47), 1.989 (3.08), 2.067 (0.47), 2.077 (0.73), 2.090 (0.67), 2.105 (0.47), 2.113 (0.50), 2.121 (0.46), 2.129 (0.54), 2.141 (0.53), 2.149 (0.56), 2.157 (0.53), 2.577 (0.87), 2.592 (0.78), 2.603 (0.82), 2.617 (0.63), 2.640 (0.62), 2.652 (1.20), 2.665 (0.72), 2.695 (0.51), 3.311 (16.00), 3.701 (0.48), 4.021 (0.74), 4.039 (0.71), 4.632 (1.16), 4.641 (1.31), 4.647 (1.53), 4.657 (1.11), 5.001 (2.12), 5.074 (0.77), 5.115 (4.74), 5.128 (4.74), 5.168 (0.79), 7.878 (0.89), 7.897 (2.02), 7.917 (1.26), 8.101 (1.45), 8.120 (1.38), 8.334 (2.40), 8.391 (1.51), 8.410 (1.42). Intermediate 79 Methyl-(5RS)-2-(2-methylbenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0405]

[0406] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (200 mg, 1.01 mmol) was initially dissolved in acetonitrile (10 ml). Cesium carbonate (364 mg, 1.12 mmol) and 1-(bromomethyl)-2-methylbenzene (197 mg, 1.06 mmol, CAS 89-92-9) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 196 mg (93% purity, 60% of theory) of the title compound. LC-MS (Method 1): R t = 1.04 min; MS (ESIpos): m / z = 302 [M+H] +< Intermediate 80 Methyl-(5RS)-2-[4-fluor-3-(trifluormethyl)benzyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0407]

[0408] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (300 mg, 1.52 mmol) was initially dissolved in acetonitrile (10 ml). Cesium carbonate (1.24 g, 3.80 mmol) and 4-(bromomethyl)-1-fluoro-2-(trifluoromethyl)benzene (430 mg, 1.67 mmol, CAS 184970-26-1) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water, 1N aqueous hydrochloric acid, and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. 569 mg (90% purity, 90% of theory) of the title compound were obtained. LC-MS (Method 4): R t = 0.90 min; MS (ESIpos): m / z = 374 [M+H] +< Intermediate 81 Methyl-(5RS)-2-[4-methoxy-3-(trifluormethyl)benzyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0409]

[0410] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (200 mg, 1.01 mmol) was initially dissolved in acetonitrile (10 mL). Cesium carbonate (347 mg, 1.06 mmol) and 4-(bromomethyl)-1-methoxy-2-(trifluoromethyl)benzene (300 mg, 1.11 mmol, CAS 261951-89-7) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 316 mg (80% of theory) of the title compound. LC-MS (Methode 3): R t = 1.60 min; MS (ESIpos): m / z = 386 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.97), 0.008 (0.99), 1.492 (0.42), 1.513 (0.43), 1.519 (0.45), 1.526 (0.45), 1.789 (0.53), 1.798 (0.55), 1.813 (0.47), 1.823 (0.45), 2.052 (0.49), 2.062 (0.82), 2.073 (0.90), 2.096 (0.50), 2.104 (0.57), 2.116 (0.52), 2.125 (0.55), 2.132 (0.51), 2.560 (0.84), 2.572 (0.84), 2.587 (0.67), 2.613 (0.64), 2.625 (1.19), 2.637 (0.68), 2.668 (0.66), 3.696 (15.68), 3.873 (16.00), 4.600 (1.06), 4.609 (1.20), 4.615 (1.38), 4.625 (1.04), 4.844 (4.92), 7.239 (1.72), 7.260 (2.01), 7.489 (1.35), 7.510 (1.41), 7.520 (2.68). Intermediate 82 Methyl-(5RS)-2-[(1-methyl-1H-indazol-5-yl)methyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0411]

[0412] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (200 mg, 1.01 mmol) was initially dissolved in acetonitrile (10 ml). Cesium carbonate (347 mg, 1.06 mmol) and 5-(bromomethyl)-1-methyl-1H-indazole (251 mg, 1.11 mmol, CAS 1092961-01-7) were then added. After stirring at room temperature for 72 h, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 87.0 mg (25% of theory) of the title compound. LC-MS (Methode 3): R t = 1.10 min; MS (ESIpos): m / z = 342 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.77), 0.008 (1.59), 1.447 (0.66), 1.456 (0.44), 1.783 (0.44), 1.794 (0.48), 1.808 (0.41), 2.049 (0.42), 2.060 (0.69), 2.073 (0.71), 2.080 (0.63), 2.087 (0.51), 2.095 (0.41), 2.103 (0.49), 2.115 (0.45), 2.123 (0.48), 2.131 (0.44), 2.563 (0.85), 2.578 (0.63), 2.602 (0.59), 2.613 (1.08), 2.626 (0.61), 2.656 (0.49), 2.669 (0.50), 3.706 (14.99), 4.024 (16.00), 4.597 (0.97), 4.607 (1.09), 4.613 (1.27), 4.623 (0.94), 4.922 (6.84), 7.285 (1.33), 7.307 (1.37), 7.310 (1.55), 7.593 (1.89), 7.614 (3.97), 8.019 (3.08). Intermediate 83 Methyl-(5RS)-2-[(1-ethyl-1H-imidazol-2-yl)methyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0413]

[0414] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (200 mg, 1.01 mmol) was initially dissolved in acetonitrile (6.0 ml). Cesium carbonate (364 mg, 1.12 mmol) and 2-(chloromethyl)-1-ethyl-1H-imidazole (154 mg, 1.06 mmol, CAS 780722-30-7) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 54.0 mg (17% of theory) of the title compound. LC-MS (Method 1): R t = 0.29 min; MS (ESIpos): m / z = 306 [M+H] +< Intermediate 84 Methyl-(5RS)-2-[(1-methyl-1H-benzimidazol-2-yl)methyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0415]

[0416] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (200 mg, 1.01 mmol) was initially dissolved in acetonitrile (6.0 ml). Cesium carbonate (364 mg, 1.12 mmol) and 2-(bromomethyl)-1-methyl-1H-benzimidazole (240 mg, 1.06 mmol, CAS 136099-52-0) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 137 mg (40% of theory) of the title compound. LC-MS (Method 1): R t = 0.73 min; MS (ESIpos): m / z = 342 [M+H] +< Intermediate 85 Methyl-(5RS)-2-[3-chlor-4-(trifluormethoxy)benzyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0417]

[0418] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (200 mg, 1.01 mmol) was initially dissolved in acetonitrile (10 ml). Cesium carbonate (347 mg, 1.06 mmol) and 4-(bromomethyl)-2-chlorophenyl trifluoromethyl ether (323 mg, 1.11 mmol, CAS 261763-18-2) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 302 mg (73% of theory) of the title compound. LC-MS (Methode 3): R t = 1.81 min; MS (ESIpos): m / z = 406 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.94), 0.008 (0.87), 1.805 (0.43), 1.815 (0.45), 2.070 (0.41), 2.079 (0.69), 2.094 (0.77), 2.104 (0.63), 2.112 (0.43), 2.120 (0.49), 2.124 (0.42), 2.132 (0.44), 2.140 (0.47), 2.148 (0.44), 2.524 (0.61), 2.569 (0.83), 2.583 (0.70), 2.595 (0.73), 2.609 (0.58), 2.636 (0.54), 2.647 (1.01), 2.660 (0.61), 2.690 (0.45), 3.708 (16.00), 4.619 (0.97), 4.629 (1.06), 4.635 (1.29), 4.644 (0.95), 4.911 (5.85), 7.317 (1.07), 7.322 (1.12), 7.338 (1.27), 7.344 (1.31), 7.533 (2.04), 7.539 (1.93), 7.564 (1.23), 7.567 (1.21), 7.585 (1.04), 7.588 (1.02). Intermediate 86 Methyl-(5RS)-2-{[3-chlor-5-(trifluormethyl)pyridin-2-yl]methyl}-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0419]

[0420] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (200 mg, 1.01 mmol) was initially dissolved in acetonitrile (5.0 ml). Cesium carbonate (364 mg, 1.12 mmol) and 3-chloro-2-(chloromethyl)-5-(trifluoromethyl)pyridine (245 mg, 1.06 mmol, CAS 175277-52-8) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 293 mg (74% of theory) of the title compound. LC-MS (Method 1): R t = 1.08 min; MS (ESIpos): m / z = 391 [M+H] +< . Intermediate 87 Methyl-(5RS)-2-[3-fluor-4-(trifluormethoxy)benzyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0421]

[0422] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (200 mg, 1.01 mmol) was initially dissolved in acetonitrile (6.0 ml). Cesium carbonate (364 mg, 1.12 mmol) and 4-(bromomethyl)-2-fluorophenyl trifluoromethyl ether (291 mg, 1.06 mmol, CAS 886499-04-3) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 263 mg (66% of theory) of the title compound. LC-MS (Method 1): R t = 1.22 min; MS (ESIpos): m / z = 390 [M+H] +< . Intermediate 88 Methyl-(5RS)-2-{[2-methyl-4-(trifluormethyl)-1,3-thiazol-5-yl]methyl}-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0423]

[0424] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (200 mg, 1.01 mmol) was initially dissolved in acetonitrile (10 ml). Cesium carbonate (347 mg, 1.06 mmol) and 5-(bromomethyl)-2-methyl-4-(trifluoromethyl)-1,3-thiazole (290 mg, 1.11 mmol, CAS 1000339-73-0) were then added. After stirring at room temperature for 72 h, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. 384 mg (99% of theory) of the title compound were obtained. LC-MS (Methode 3): R t = 1.33 min; MS (ESIpos): m / z = 377 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.01), 0.008 (1.10), 1.157 (1.51), 1.175 (3.06), 1.193 (1.55), 1.793 (0.43), 1.804 (0.48), 1.818 (0.41), 1.988 (5.82), 2.051 (0.42), 2.062 (0.77), 2.073 (0.86), 2.086 (0.67), 2.094 (0.45), 2.102 (0.51), 2.114 (0.46), 2.122 (0.50), 2.130 (0.46), 2.524 (0.72), 2.568 (0.84), 2.583 (0.72), 2.594 (0.74), 2.608 (0.61), 2.639 (1.12), 2.651 (15.16), 2.668 (1.55), 2.679 (0.51), 2.687 (0.68), 3.697 (16.00), 4.003 (0.46), 4.021 (1.39), 4.038 (1.38), 4.056 (0.46), 4.594 (1.02), 4.603 (1.12), 4.609 (1.32), 4.619 (0.98), 5.171 (4.60). Intermediate 89 Methyl-(5RS)-2-[(3-methyl-1,2-oxazol-5-yl)methyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0425]

[0426] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (200 mg, 1.01 mmol) was initially dissolved in acetonitrile (10 ml). Cesium carbonate (347 mg, 1.06 mmol) and 5-(bromomethyl)-3-methyl-1,2-oxazole (196 mg, 1.11 mmol, CAS 36958-61-9) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. 259 mg (86% purity, 75% of theory) of the title compound were obtained. LC-MS (Methode 3): R t = 0.94 min; MS (ESIpos): m / z = 293 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.44), 1.174 (0.64), 1.510 (0.40), 1.531 (0.43), 1.536 (0.43), 1.544 (0.42), 1.798 (0.49), 1.809 (0.54), 1.824 (0.47), 1.988 (1.18), 2.042 (0.41), 2.055 (0.52), 2.065 (0.75), 2.071 (0.80), 2.078 (0.73), 2.087 (0.86), 2.096 (0.58), 2.104 (0.53), 2.112 (0.61), 2.117 (0.52), 2.124 (0.64), 2.133 (0.58), 2.141 (0.55), 2.205 (15.12), 2.218 (2.90), 2.518 (0.41), 2.524 (0.52), 2.567 (0.86), 2.581 (0.78), 2.593 (0.80), 2.607 (0.67), 2.629 (0.63), 2.641 (1.15), 2.653 (0.66), 2.683 (0.47), 3.687 (1.47), 3.691 (0.75), 3.703 (16.00), 4.596 (1.03), 4.606 (1.14), 4.612 (1.28), 4.622 (0.98), 4.773 (1.74), 4.981 (6.40), 6.237 (3.04), 6.458 (0.50). Intermediate 90 Methyl-(5RS)-2-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0427]

[0428] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (200 mg, 1.01 mmol) was initially dissolved in acetonitrile (11 ml). Cesium carbonate (793 mg, 2.43 mmol) and 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (187 mg, 1.11 mmol, CAS 135206-76-7) were then added. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 178 mg (74% purity, 44% of theory) of the title compound. LC-MS (Method 3): R t = 0.61 min; MS (ESIpos): m / z = 293 [M+H] +< . Intermediate 91 Methyl-(5RS)-2-[2-fluor-3-(trifluormethyl)benzyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0429]

[0430] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (200 mg, 1.01 mmol) was initially dissolved in acetonitrile (5.0 ml). Cesium carbonate (364 mg, 1.12 mmol) and 1-(bromomethyl)-2-fluoro-3-(trifluoromethyl)benzene (274 mg, 1.06 mmol, CAS 184970-25-0) were added after 5 min of stirring. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 184 mg (49% of theory) of the title compound. LC-MS (Method 1): R t = 1.16 min; MS (ESIpos): m / z = 374 [M+H] +< . Intermediate 92 Methyl-(5RS)-2-[3-fluor-5-(trifluormethyl)benzyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Racemat)

[0431]

[0432] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (200 mg, 1.01 mmol) was initially dissolved in acetonitrile (5.0 ml). Cesium carbonate (364 mg, 1.12 mmol) and 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (274 mg, 1.06 mmol, CAS 239087-09-3) were added after 5 min of stirring. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 154 mg (41% of theory) of the title compound. LC-MS (Method 1): R t = 1.19 min; MS (ESIpos): m / z = 374 [M+H] +< . Intermediate 93 Methyl-(5RS)-3-oxo-2-{[2-(trifluormethyl)pyridin-4-yl]methyl}-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Enantiomer 1)

[0433] Methyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0434] (Enantiomer 2) (200 mg, 1.01 mmol) was initially dissolved in acetonitrile (5.0 mL). Cesium carbonate (364 mg, 1.12 mmol) and 4-(chloromethyl)-2-(trifluoromethyl)pyridine hydrochloride (247 mg, 1.06 mmol) were added after 5 min of stirring. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo and 279 mg (77% of theory) of the title compound were obtained. LC-MS (Method 4): R t = 0.71 min; MS (ESIpos): m / z = 357 [M+H] +< The (5S) configuration was assigned based on crystal structure determination for examples 26, 108, 113, 157, 237, 358, and 454. Methyl-(5S)-3-oxo-2-{[2-(trifluoromethyl)pyridin-4-yl]methyl}-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate Intermediate 94 Methyl-(5RS)-2-{[3-fluoro-2-(trifluoromethyl)pyridin-4-yl]methyl}-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (enantiomer 1)

[0435] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate

[0436] (Enantiomer 2) (200 mg, 1.01 mmol) was initially dissolved in acetonitrile (5.0 mL). Cesium carbonate (364 mg, 1.12 mmol) and 4-(chloromethyl)-3-fluoro-2-(trifluoromethyl)pyridine hydrochloride (266 mg, 1.06 mmol) were then added. After stirring overnight at room temperature, the reaction mixture was again treated with cesium carbonate (199 mg, 0.61 mmol) and stirred at 60 °C for 2 hours. The reaction mixture was then cooled to room temperature and treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 181 mg (48% of theory).) of the title connection. . LC-MS (Method 3): R t = 1.42 min; MS (ESIpos): m / z = 375 [M+H] +< The (5S) configuration was assigned based on crystal structure determination for examples 26, 108, 113, 157, 237, 358, and 454. Methyl (5S)-2-{[3-fluoro-2-(trifluoromethyl)pyridin-4-yl]methyl}-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate Intermediate 95 Methyl-(5RS)-2-{[5-chloro-4-(trifluoromethyl)pyridin-2-yl]methyl}-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (enantiomer 1)

[0437] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate

[0438] (Enantiomer 2) (164 mg, 829 µmol) was initially dissolved in acetonitrile (4.0 ml). Cesium carbonate (594 mg, 1.82 mmol) and 5-chloro-2-(chloromethyl)-4-(trifluoromethyl)pyridine hydrochloride (274 mg, 85% purity, 871 µmol) were then added. The reaction mixture was stirred overnight at room temperature, for 5 h at 85 °C, and then again overnight at room temperature. Water and ethyl acetate were added to the reaction mixture. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. This gave 269 mg (93% purity, 77% of theory) of the title compound. LC-MS (Method 3): R t = 1.55 min; MS (ESIpos): m / z = 391 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.42), 0.008 (0.46), 1.157 (1.75), 1.175 (3.60), 1.193 (1.82), 1.352 (0.61), 1.534 (0.40), 1.540 (0.41), 1.807 (0.47), 1.816 (0.49), 1.830 (0.41), 1.989 (6.73), 2.074 (0.58), 2.086 (0.74), 2.098 (0.77), 2,119 (0.46), 2.126 (0.53), 2.131 (0.46), 2.139 (0.47), 2.148 (0.52), 2.155 (0.46), 2.520 (0.80), 2.563 (0.87), 2.578 (0.72), 2.590 (0.72), 2.604 (0.62), 2.630 (0.57), 2.642 (1.01), 2.654 (0.60), 2.671 (0.40), 2.684 (0.45), 3.688 (1.91), 3.704 (16.00), 3.936 (0.71), 4.003 (0.54), 4.021 (1.59), 4.039 (1.58), 4.057 (0.52), 4.628 (1.01), 4.637 (1.55), 4.643 (1.37), 4.652 (1.42), 5.074 (7.18), 7.727 (3.53), 7.832 (0.45), 8.858 (0.45), 8.910 (3.33). The (5S) configuration was assigned based on crystal structure determination for examples 26, 108, 113, 157, 237, 358, and 454. Methyl-(5S)-2-{[5-chlor-4-(trifluormethyl)pyridin-2-yl]methyl}-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat Intermediate 96 Methyl-(5RS)-3-oxo-2-{[2-(trifluormethyl)chinolin-4-yl]methyl}-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Enantiomer 1)

[0439] Methyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0440] (Enantiomer 2) (166 mg, 839 µmol) was initially dissolved in acetonitrile (4.1 ml). Cesium carbonate (301 mg, 923 µmol) and 4-(chloromethyl)-2-(trifluoromethyl)quinoline hydrochloride (336 mg, 74% purity, 881 µmol) were added after 5 min of stirring. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo and 111 mg (33% of theory) of the title compound were obtained. LC-MS (Method 1): R t = 1.19 min; MS (ESIpos): m / z = 407 [M+H] +< The (5S) configuration was assigned based on crystal structure determination for examples 26, 108, 113, 157, 237, 358, and 454. Methyl-(5S)-3-oxo-2-{[2-(trifluoromethyl)quinolin-4-yl]methyl}-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate Intermediate 97 Methyl-(5RS)-2-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (enantiomer 1)

[0441] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate

[0442] (Enantiomer 2) (200 mg, 1.01 mmol) was initially dissolved in acetonitrile (5.0 mL). Cesium carbonate (364 mg, 1.12 mmol) and 3-chloro-2-(chloromethyl)-5-(trifluoromethyl)pyridine (245 mg, 1.06 mmol, CAS 175277-52-8) were added after 5 min of stirring. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo and 216 mg (55% of theory) of the title compound were obtained. LC-MS (Method 3): R t = 1.49 min; MS (ESIpos): m / z = 391 [M+H] +< The (5S) configuration was assigned based on crystal structure determination for examples 26, 108, 113, 157, 237, 358, and 454. Methyl-(5S)-2-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate Intermediate 98 Methyl-(5RS)-3-oxo-2-[(3,5,6-trimethylpyrazin-2-yl)methyl]-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (enantiomer 1)

[0443] Methyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate

[0444] (Enantiomer 2) (250 mg, 1.27 mmol) was initially dissolved in acetonitrile (5.0 mL). Cesium carbonate (454 mg, 1.39 mmol) and 2-(bromomethyl)-3,5,6-trimethylpyrazine (286 mg, 1.33 mmol, CAS 79074-45-6) were added after 5 min of stirring. After stirring overnight at room temperature, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo, yielding 261 mg (62% of theory) of the title compound. LC-MS (Method 3): R t = 1.02 min; MS (ESIpos): m / z = 332 [M+H] +< Intermediate 99 Methyl-(5RS)-3-oxo-2-{[4-(trifluormethyl)pyridin-2-yl]methyl}-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Enantiomer 1)

[0445] Methyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0446] (Enantiomer 2) (300 mg, 1.52 mmol) was initially dissolved in acetonitrile (6.0 mL). Cesium carbonate (744 mg, 2.28 mmol) and 2-(chloromethyl)-4-(trifluoromethyl)pyridine hydrochloride (371 mg, 1.60 mmol, CAS 215867-87-1) were then added. After stirring at room temperature for 4 hours, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo and 282 mg (52% of theory) of the title compound were obtained. LC-MS (Method 3): R t = 1.35 min; MS (ESIpos): m / z = 357 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.50), 1.811 (0.48), 1.821 (0.49), 1.835 (0.42), 2.073 (0.44), 2.079 (0.46), 2.090 (0.74), 2.103 (0.69), 2.110 (0.66), 2.118 (0.53), 2.126 (0.46), 2.133 (0.53), 2.138 (0.46), 2.146 (0.48), 2.154 (0.50), 2.162 (0.46), 2.519 (0.45), 2.570 (0.85), 2.585 (0.73), 2.597 (0.75), 2.611 (0.61), 2.636 (0.59), 2.647 (1.03), 2.660 (0.59), 2.690 (0.44), 3.706 (16.00), 4.636 (1.03), 4.646 (1.11), 4.652 (1.26), 4.661 (0.93), 5.075 (7.03), 7.551 (2.03), 7.713 (1.09), 7.724 (1.09), 8.822 (1.50), 8.834 (1.43).

[0447] The (5S) configuration was assigned based on crystal structure determination for examples 26, 108, 113, 157, 237, 358 and 454. Methyl-(5S)-3-oxo-2-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate Intermediate 100 Methyl-(5RS)-3-oxo-2-{[2-(trifluormethyl)pyrimidin-4-yl]methyl}-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat (Enantiomer 1)

[0448] Methyl-(5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridin-5-carboxylat

[0449] (Enantiomer 2) (108 mg, 548 µmol) was initially dissolved in acetonitrile (2.0 mL). Cesium carbonate (268 mg, 822 µmol) and 4-(chloromethyl)-2-(trifluoromethyl)pyrimidine hydrochloride (134 mg, 575 µmol) were then added. After stirring overnight at room temperature and a further 2 hours under reflux, the reaction mixture was treated with water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Chromatorex C18, 10 µm, 125 mm x 30 mm; mobile phase: acetonitrile / water gradient). The product-containing fractions were concentrated in vacuo and 49.3 mg (25% of theory) of the title compound were obtained. LC-MS (Method 4): Rt = 0.69 min; MS (ESIpos): m / z = 358 [M+H] +< The (5S) configuration was assigned based on crystal structure determination for examples 26, 108, 113, 157, 237, 358, and 454. Methyl-(5S)-3-oxo-2-{[2-(trifluoromethyl)pyrimidin-4...

Claims

1. Compound of the formula (I) in which A is (C1-C4) -alkylene or CD2, where (C1-C4) -alkylene may be substituted by hydroxyl and (C1-C4) -alkoxy and up to pentasubstituted by fluorine, or is a group of the formula in which n is 0 or 1, p is 0 or 1, q is 1 or 2, where #1 marks the bond to the nitrogen atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, * marks the bond to R1, X is -CR6R7-, *2-CR6R7-CR8R9-**, #2-CR6=CR8-** or #2-CR6R7-CR8R9-CR10R11-**, where #2 marks the bond to the carbon atom of the CR4R5- group, where ** marks the bond to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where R6 is hydrogen, fluorine, (C1-C4) -alkyl, (C1-C4)-alkoxy, trifluoromethoxy, hydroxyl, mono- (C1-C4) -alkylamino or di-(C1-C4)-alkylamino, in which (C1-C4) -alkyl may be substituted by (C1-C4) -alkoxy, hydroxyl, mono- (C1-C4) -alkylamino or di-(C1-C4)-alkylamino and up to pentasubstituted by fluorine, R7 is hydrogen, fluorine or (C1-C4) -alkyl, in which (C1-C4)-alkyl may be up to pentasubstituted by fluorine or R6 and R7 together with the carbon atom to which they are bonded form a carbonyl group, or R6 and R7 together with the carbon atom to which they are bonded form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring, or R6 and R4 together with the carbon atom to which they are bonded form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring, R8 is hydrogen, (C1-C4) -alkyl, (C1-C4) -alkoxy, fluorine, hydroxyl, mono-(C1-C4)-alkylamino or di-(C1-C4)-alkylamino, in which (C1-C4) -alkyl may be substituted by (C1-C4) -alkoxy, hydroxyl, mono- (C1-C4) -alkylamino or di-(C1-C4)-alkylamino and up to pentasubstituted by fluorine, R9 is hydrogen, fluorine or (C1-C4)-alkyl, in which (C1-C4) -alkyl may be up to pentasubstituted by fluorine or R8 and R9 together with the carbon atom to which they are bonded form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring, or R7 and R9 together with the carbon atoms to which they are bonded form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring, R10 is hydrogen, (C1-C4) -alkyl, (C1-C4) -alkoxy, fluorine, hydroxyl, mono-(C1-C4)-alkylamino or di-(C1-C4)-alkylamino, in which (C1-C4) -alkyl may be substituted by (C1-C4) -alkoxy, hydroxyl, mono- (C1-C4) -alkylamino or di-(C1-C4)-alkylamino and up to pentasubstituted by fluorine, R11 is hydrogen, fluorine or (C1-C4) -alkyl, in which (C1-C4)-alkyl may be up to pentasubstituted by fluorine or R10 and R11 together with the carbon atom to which they are bonded form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring, R1 is phenyl or 5- to 6-membered heteroaryl, where phenyl is substituted by 1 to 3 substituents independently selected from the group of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, difluoro-methoxy, trifluoromethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylsulfanyl, methylsulfonyl, methylsulfonimidoyl, aminosulfonyl or methylsulfinyl, or where phenyl may be fused to cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl or 5-to 6-membered heteroaryl, in which cyclopentyl, cyclohexyl, (C5-C6)-heterocyclyl and 5- to 6-membered heteroaryl may be substituted by 1 or 2 methyl or ethyl substituents, or where 5- to 6-membered heteroaryl may be substituted by 1 to 3 substituents independently selected from the group of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, methylaminocarbonyl, tert-butylaminocarbonyl, dimethylaminocarbonyl, where 5- to 6-membered heteroaryl may be fused to cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, where 5- to 6-membered heteroaryl may be substituted by methyl, ethyl, chlorine, fluorine or methoxy, in which cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl may be substituted by 1 or 2 (C1-C4)-alkyl substituents, R2 is a group of the formula where #3 marks the bond to the carbonyl carbon atom, r is 0 or 1, Z is O, NR18, S, SO, SO2 or CR14AR14B, in which R14A is hydrogen, halogen, cyano, (C1-C4)-alkyl, (C3-C6)-cycloalkyl, trifluoromethyl, difluoromethyl, fluoromethyl, hydroxyl, (C1-C4)-alkoxy, (C3-C5)-cycloalkoxy, difluoromethoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy, in which (C1-C4) -alkyl may be substituted by hydroxyl, amino, mono-(C1-C4)-alkylamino or di-(C1-C4) -alkylamino, R14B is hydrogen, fluorine or (C1-C4)-alkyl, in which (C1-C4)-alkyl may be up to pentasubstituted by fluorine or R14A and R14B together with the carbon atom to which they are bonded form a carbonyl group, R18 is hydrogen or methyl, R12 is hydrogen, cyano, (C1-C4) -alkyl, acetyl or formyl, in which (C1-C4) -alkyl may be substituted by hydroxyl or up to pentasubstituted by fluorine, in which acetyl may be substituted by hydroxyl or up to trisubstituted by fluorine, R13 is hydrogen, fluorine or (C1-C4)-alkyl, or R12 and R13 together with the carbon atoms to which they are bonded form a cyclopropyl or cyclobutyl ring, in which the cyclopropyl or cyclobutyl ring may be up to disubstituted by fluorine, or R13 and R14A together with the carbon atoms to which they are bonded form a cyclopropyl or cyclobutyl ring, in which the cyclopropyl or cyclobutyl ring may be up to disubstituted by fluorine, or R14A and R14B together with the carbon atom to which they are bonded form a cyclopropyl or cyclobutyl ring, in which the cyclopropyl or cyclobutyl ring may be up to disubstituted by fluorine, where R13, R14A and R14B are hydrogen when R12 is not hydrogen, where R12 is hydrogen when one of the R13, R14A and R14B substituents is not hydrogen, or is a group of the formula where #4 marks the bond to the carbonyl carbon atom, Y is NR15, CR16AR16B, oxygen or sulfur, in which R15 is hydrogen or methyl, R16A is hydrogen or methyl, R16B is hydrogen or methyl, R3 is hydrogen or (C1-C4) -alkyl, R4 is hydrogen, (C1-C4) -alkyl, (C1-C4) -alkoxy, fluorine, hydroxyl, mono-(C1-C4)-alkylamino or di-(C1-C4) -alkylamino, in which (C1-C4)-alkyl may be substituted by (C1-C4)-alkoxy, hydroxyl, mono-(C1-C4)-alkylamino or di-(C1-C4)-alkylamino and up to pentasubstituted by fluorine, R5 is hydrogen or (C1-C4) -alkyl, in which (C1-C4) -alkyl may be up to pentasubstituted by fluorine or R4 and R5 together with the carbon atom to which they are bonded form a carbonyl group, or R4 and R5 together with the carbon atom to which they are bonded form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring, and the salts, solvates and solvates of the salts of the compounds of the formula (I).

2. Compound of the formula (I) according to Claim 1, in which A is -CH2-,-CH (CH3)-, -CH2CH2-, #5-CH2CH(CH3)-***, #5-CH2C(CH3)2-***, #5-CH2CHF-*** or #5-CH2CF2-***, where #5 marks the bond to the nitrogen atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where *** marks the bond to the R1 group, X is - #2-CR6R7-CR8R9-**, where #2 marks the bond to the carbon atom of the CR4R5- group, where ** marks the bond to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where R6 is hydrogen, fluorine, methyl, trifluoromethyl or hydroxyl, R7 is hydrogen, fluorine or methyl, or R6 and R7 together with the carbon atom to which they are bonded form a cyclopropyl ring, R8 is hydrogen, fluorine, methyl or trifluoromethyl, R9 is hydrogen, fluorine or methyl, R1 is phenyl or 5- to 6-membered heteroaryl, where phenyl is substituted by 1 to 3 substituents independently selected from the group of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, difluoro-methoxy, trifluoromethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylsulfanyl, methylsulfonyl, methylsulfonimidoyl, aminosulfonyl or methylsulfinyl, or where phenyl may be fused to cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl or 5-to 6-membered heteroaryl, in which cyclopentyl, cyclohexyl, (C5-C6)-heterocyclyl and 5- to 6-membered heteroaryl may be substituted by 1 or 2 methyl or ethyl substituents, or where 5- to 6-membered heteroaryl may be substituted by 1 to 3 substituents independently selected from the group of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, methylaminocarbonyl, tert-butylaminocarbonyl and dimethylaminocarbonyl, where 5- to 6-membered heteroaryl may be fused to cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, where 5- to 6-membered heteroaryl may be substituted by methyl, ethyl, chlorine, fluorine or methoxy, in which cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl may be substituted by 1 or 2 (C1-C4)-alkyl substituents, R2 is a group of the formula where #3 marks the bond to the carbonyl carbon atom, r is 0 or 1, Z is S or CR14AR14B when r is 0, Z is S, SO, SO2 or CR14AR14B when r is 1, in each of which R14A is hydrogen, fluorine, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, hydroxyl, methoxy, difluoromethoxy or trifluoromethoxy, R14B is hydrogen or fluorine, or R14A and R14B together with the carbon atom to which they are bonded form a carbonyl group, R12 is hydrogen, cyano, methyl, acetyl or formyl, in which acetyl is substituted by hydroxyl or up to trisubstituted by fluorine, R13 is hydrogen, fluorine or methyl, or R12 and R13 together with the carbon atoms to which they are bonded form a cyclopropyl ring, or R13 and R14A together with the carbon atom to which they are bonded form a cyclopropyl ring, in which the cyclopropyl ring may be up to disubstituted by fluorine, or R14A and R14B together with the carbon atom to which they are bonded form a cyclopropyl ring, in which the cyclopropyl ring may be up to disubstituted by fluorine, where R13, R14A and R14B are hydrogen when R12 is not hydrogen, where R12 is hydrogen when one of the R13, R14A and R14B substituents is not hydrogen, R3 is hydrogen, R4 is hydrogen, fluorine or methyl, R5 is hydrogen, and the salts, solvates and solvates of the salts of the compounds of the formula (I).

3. Compound of the formula (I) according to Claim 1 or 2, in which A is -CH2-,-CH (CH3)-, -CH2CH2-, #5-CH2CH(CH3)-***, #5-CH2C(CH3)2-***, #5-CH2CHF-*** or #5-CH2CF2-***, where #5 marks the bond to the nitrogen atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where *** marks the bond to the R1 group, X is - #2-CR6R7-CR8R9-**, where #2 marks the bond to the carbon atom of the CR4R5- group, where ** marks the bond to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where R6 is hydrogen, fluorine, methyl, trifluoromethyl or hydroxyl, R7 is hydrogen, fluorine or methyl, or R6 and R7 together with the carbon atom to which they are bonded form a cyclopropyl ring, R8 is hydrogen, fluorine, methyl or trifluoromethyl, R9 is hydrogen, fluorine or methyl, R1 is phenyl or 5- to 6-membered heteroaryl, where phenyl is substituted by 1 to 3 substituents independently selected from the group of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, hydroxy-carbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylsulfanyl, methylsulfonyl, methylsulfonimidoyl, aminosulfonyl and methylsulfinyl, or where phenyl may be fused to cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl or 5-to 6-membered heteroaryl, in which cyclopentyl, cyclohexyl, (C5-C6)-heterocyclyl and 5- to 6-membered heteroaryl may be substituted by 1 or 2 methyl or ethyl substituents, or where 5- to 6-membered heteroaryl may be substituted by 1 to 3 substituents independently selected from the group of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, methylaminocarbonyl, tert-butylaminocarbonyl and dimethylaminocarbonyl, where 5- to 6-membered heteroaryl may be fused to cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, where 5- to 6-membered heteroaryl may be substituted by methyl, ethyl, chlorine, fluorine or methoxy, in which cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl may be substituted by 1 or 2 (C1-C4)-alkyl substituents, R2 is a group of the formula where #3 marks the bond to the carbonyl carbon atom, ris 0 or 1, Zis S or CR14AR14B when r is 0, Zis S, SO, SO2 or CR14AR14B when r is 1, in each of which R14A is hydrogen, fluorine, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, hydroxyl, methoxy, difluoromethoxy or trifluoromethoxy, R14B is hydrogen or fluorine, or R14A and R14B together with the carbon atom to which they are bonded form a carbonyl group, R12 is hydrogen, cyano, methyl, acetyl or formyl, in which acetyl is substituted by hydroxyl or up to trisubstituted by fluorine, R13 is hydrogen, fluorine or methyl, or R12 and R13 together with the carbon atoms to which they are bonded form a cyclopropyl ring, or R13 and R14A together with the carbon atom to which they are bonded form a cyclopropyl ring, in which the cyclopropyl ring may be up to disubstituted by fluorine, or R14A and R14B together with the carbon atom to which they are bonded form a cyclopropyl ring, in which the cyclopropyl ring may be up to disubstituted by fluorine, where R13, R14A and R14B are hydrogen when R12 is not hydrogen, where R12 is hydrogen when one of the R13, R14A and R14B substituents is not hydrogen, R3 is hydrogen, R4 is hydrogen, fluorine or methyl, R5 is hydrogen, and the salts, solvates and solvates of the salts of the compounds of the formula (I).

4. Compound of the formula (I) according to Claim 1 or 2, in which A is -CH2-,-CH (CH3)-, -CH2CH2-, #5-CH2CH(CH3)-***, #5-CH2C(CH3)2-***, #5-CH2CHF-*** or #5-CH2CF2-***, where #5 marks the bond to the nitrogen atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where *** marks the bond to the R1 group, X is - #2-CR6R7-CR8R9-**, where #2 marks the bond to the carbon atom of the CR4R5- group, where ** marks the bond to the carbon atom of the 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl ring, where R6 is hydrogen, fluorine, methyl, trifluoromethyl or hydroxyl, R7 is hydrogen, fluorine or methyl, or R6 and R7 together with the carbon atom to which they are bonded form a cyclopropyl ring, R8 is hydrogen, fluorine, methyl or trifluoromethyl, R9 is hydrogen, fluorine or methyl, R1 is phenyl, pyrazolyl, imidazolyl, thiazolyl, thiophenyl, oxazolyl, oxadiazolyl or pyridyl, where phenyl is substituted by 1 to 3 substituents independently selected from the group of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, hydroxy-carbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylsulfanyl, methylsulfonyl, methylsulfonimidoyl, aminosulfonyl and methylsulfinyl, or where phenyl may be fused to cyclopentyl, cyclohexyl, pyrazolyl or pyridyl, in which cyclopentyl, cyclohexyl, pyrazolyl or pyridyl may be substituted by 1 or 2 methyl or ethyl substituents, or where pyrazolyl, imidazolyl, thiazolyl, thiophenyl, oxazolyl, oxadiazolyl or pyridyl may be substituted by 1 to 3 substituents independently selected from the group of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, methylaminocarbonyl, tert-butylaminocarbonyl and dimethylaminocarbonyl, where pyrazolyl, imidazolyl, thiazolyl, thiophenyl, oxazolyl, oxadiazolyl or pyridyl may be fused to cyclopentyl, cyclohexyl, phenyl or pyridyl, in which pyridyl may be substituted by methyl, ethyl, chlorine, fluorine or methoxy, in which cyclopentyl, cyclohexyl, phenyl and pyridyl may be substituted by 1 or 2 (C1-C4)-alkyl substituents, R2 is a group of the formula where #3 marks the bond to the carbonyl carbon atom, r is 0 or 1, Z is S or CR14AR14B when r is 0, Z is S, SO, SO2 or CR14AR14B when r is 1, in each of which R14A is hydrogen, fluorine, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, hydroxyl, methoxy, difluoromethoxy or trifluoromethoxy, R14B is hydrogen or fluorine, or R14A and R14B together with the carbon atom to which they are bonded form a carbonyl group, R12 is hydrogen, cyano, methyl, acetyl or formyl, in which acetyl is substituted by hydroxyl or up to trisubstituted by fluorine, R13 is hydrogen, fluorine or methyl, or R12 and R13 together with the carbon atoms to which they are bonded form a cyclopropyl ring, or R13 and R14A together with the carbon atom to which they are bonded form a cyclopropyl ring, in which the cyclopropyl ring may be up to disubstituted by fluorine, or R14A and R14B together with the carbon atom to which they are bonded form a cyclopropyl ring, in which the cyclopropyl ring may be up to disubstituted by fluorine, where R13, R14A and R14B are hydrogen when R12 is not hydrogen, where R12 is hydrogen when one of the R13, R14A and R14B substituents is not hydrogen, R3 is hydrogen, R4 is hydrogen, fluorine or methyl, R5 is hydrogen, and the salts, solvates and solvates of the salts of the compounds of the formula (I).

5. Compound of the formula (I) according to Claim 1 having the systematic name (5RS,7RS)-2-[(6-chloropyridin-3-yl)methyl]-5-{[(3R,4S)-3,4-difluoropyrrolidin-1-yl]carbonyl}-7-(trifluoro-methyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]-pyridin-3(2H)-one and of the structural formula 6. Compound of the formula (I) according to Claim 1 having the systematic name (5S,7R)-5-{[(3S)-3-fluoropyrrolidin-1-yl]carbonyl}-7-(trifluoro-methyl)-2-{[6-(trifluormethyl)pyridin-3-yl]-methyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]-pyridin-3(2H)-one and of the structural formula 7. Compound of the formula (I) according to Claim 1 having the systematic name (5S)-5-{[(3R,4S)-3,4-difluoropyrrolidin-1-yl]carbonyl}-2-{[3-fluoro-2-(trifluormethyl)pyridin-4-yl]methyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one and of the structural formula 8. Compound of the formula (I) according to Claim 1 having the systematic name (5S)-5-{[(3S)-3-fluoropyrrolidin-1-yl]carbonyl}-2-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one and of the structural formula 9. Compound of the formula (I) according to Claim 1 having the systematic name (5RS,7RS)-2-[(6-chloropyridin-3-yl)methyl]-5-{[(3S)-3-fluoro-pyrrolidin-1-yl]carbonyl}-7-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin- 3(2H)-one and of the structural formula 10. Process for preparing a compound as defined in Claims 1 to 5, characterized in that either [A] a compound of the formula (II) in which R3, R4, R5 and X each have the definitions given in Claim 1, and T1 is (C1-C4) -alkyl or benzyl, is reacted in an inert solvent in the presence of a suitable base with a compound of the formula (III) in which A1 is -CH2-, -CH (CH3)-, -CH2CH2-, #5-CH2CH (CH3)-***, #5-CH2C(CH3)2-***, #5-CH2CHF-*** or #5-CH2CF2-***, where #5 marks the bond to X1, where *** marks the bond to the R1 group, R1 has the definitions given in Claim 1, and X1 is a suitable leaving group, especially chlorine, bromine, iodine, mesylate {(methylsulfonyl)oxy}, triflate {[(trifluoromethyl)sulfonyl]oxy}, nonaflate {[(nonafluorobutyl)sulfonyl]-oxy}, nosylate {[(4-nitrophenyl)sulfonyl]oxy} or tosylate {[(4-methylphenyl)sulfonyl]oxy}, to give a compound of the formula (IV) in which A1, R1, R3, R4, R5 and X each have the definitions given in Claim 1 and T1 is (C1-C4) -alkyl or benzyl, then the latter are converted by removing the "T1" group in an inert solvent in the presence of a suitable base or acid to a compound of the formula (V) in which A1, R1, R3, R4, R5 and X each have the definitions given in Claim 1, and then the latter is reacted in an inert solvent under amide coupling conditions with an amine of the formula (VI-A) or (VI-B) in which Y, Z, R12 and R13 each have the definitions given in Claim 1, and then any protecting groups present are detached by methods known to those skilled in the art, and the resulting compounds of the formula (I) are optionally converted with the appropriate (i) solvents and / or (ii) acids or bases to the solvates, salts and / or solvates of the salts thereof, or [B] a compound of the formula (VII) in which A1, R1, R3, R4, R5 and X each have the definitions given in Claim 1, and T1 is (C1-C4) -alkyl or benzyl, is reacted in an inert solvent in the presence of a suitable base with an amine of the formula (VI-A) or (VI-B) in which r, Y, Z, R12 and R13 each have the definitions given in Claim 1, to give a compound of the formula (XXIII-A) or (XXIII-B) in which r, R3, R4, R5, R12, R13, X, Y and Z each have the definitions given in Claim 1, the latter is reacted in an inert solvent in the presence of a suitable base with a compound of the formula (III) in which A1 is -CH2-, -CH(CH3)-, -CH2CH2-, #5-CH2CH (CH3)-***, #5-CH2C(CH3)2-***, #5-CH2CHF-*** or #5-CH2CF2-***, where #5 marks the bond to X1, where *** marks the bond to the R1 group, R1 has the definitions given in Claim 1, and X1 is a suitable leaving group, especially chlorine, bromine, iodine, mesylate {(methylsulfonyl)oxy}, triflate {[(trifluoromethyl)sulfonyl]oxy}, nonaflate {[(nonafluorobutyl)sulfonyl]-oxy}, nosylate {[(4-nitrophenyl)-sulfonyl]oxy} or tosylate {[(4-methylphenyl)sulfonyl]oxy}, and then any protecting groups present are detached by methods known to those skilled in the art, and the resulting compounds of the formula (I) are optionally converted with the appropriate (i) solvents and / or (ii) acids or bases to the solvates, salts and / or solvates of the salts thereof, or [C] a compound of the formula (VII) in which R3, R4, R5 and X each have the definitions given in Claim 1 and T1 is (C1-C4) -alkyl or benzyl, T2 is 4-methoxybenzyl, benzyl, allyl, β-(trimethylsilyl)ethoxymethyl (SEM), methoxymethyl (MOM) or benzyloxymethyl, is converted by hydrolysis of the ester group in an inert solvent in the presence of a suitable base or acid to a compound of the formula (VIII) in which R3, R4, R5 and X each have the definitions given in Claim 1 and T2 is 4-methoxybenzyl, benzyl, allyl, β-(trimethylsilyl)ethoxymethyl (SEM), methoxymethyl (MOM) or benzyloxymethyl, then the latter is reacted in an inert solvent under amide coupling conditions with an amine of the formula (VI-A) in which r, Y, Z, R12 and R13 each have the definitions given in Claim 1, to give a compound of the formula (IX-A) or (IX-B) in which r, R3, R4, R5, R12, R13, T2, X, Y and Z each have the definitions given in Claim 1, the protecting group "T2" is removed in an inert solvent in the presence of a suitable base or acid or optionally in the presence of a suitable palladium catalyst and the resulting compound of the formula (X-A) or (X-B) or in which r, R3, R4, R5, R12, R13, X, Y and Z each have the definitions given in Claim 1, is reacted in an inert solvent in the presence of a suitable base with a compound of the formula (III) in which A1 is -CH2-, -CH (CH3)-, -CH2CH2-, #5-CH2CH(CH3)-***, #5-CH2C(CH3)2-***, #5-CH2CHF-*** or #5-CH2CF2-***, where #5 marks the bond to X1, where *** marks the bond to the R1 group, R1 has the definitions given in Claim 1, and X1 is a suitable leaving group, especially chlorine, bromine, iodine, mesylate {(methylsulfonyl)oxy}, triflate {[(trifluoromethyl)sulfonyl]oxy}, nonaflate {[(nonafluorobutyl)sulfonyl]-oxy}, nosylate {[(4-nitrophenyl)sulfonyl]oxy} or tosylate {[(4-methylphenyl)sulfonyl]oxy}, and then any protecting groups present are detached by methods known to those skilled in the art, and the resulting compounds of the formula (I) are optionally converted with the appropriate (i) solvents and / or (ii) acids or bases to the solvates, salts and / or solvates of the salts thereof.

11. Compound as defined in any of Claims 1 to 9 for treatment and / or prophylaxis of diseases.

12. Compound as defined in Claims 1 to 9 for use in a method for treatment and / or prophylaxis of lung inflammation disorders, particularly of chronic-obstructive lung disease (COPD), of pulmonary emphysema, of chronic bronchitis, of bronchiectasis, of pulmonary hypertension in COPD (PH-COPD), of acute exacerbation in COPD, of cystic fibrosis (mucoviscidosis, CF), of asthma, and idiopathic pulmonary fibrosis (IPF), of bronchiolitis obliterans syndrome (BOS), of arteriosclerosis, of myocarditis, and of inflammatory skin and eye disorders or inflammatory disorders of the internal organs.

13. Compound of the formula (I) as defined in Claims 1 to 9 for production of a medicament for treatment and / or prophylaxis of lung inflammation disorders, particularly of chronic-obstructive lung disease (COPD), of pulmonary emphysema, of chronic bronchitis, of bronchiectasis, of pulmonary hypertension in COPD (PH-COPD), of acute exacerbation in COPD, of cystic fibrosis (mucoviscidosis, CF), of asthma, and idiopathic pulmonary fibrosis (IPF), of bronchiolitis obliterans syndrome (BOS), of arteriosclerosis, of myocarditis, and of inflammatory skin and eye disorders or inflammatory disorders of the internal organs.

14. Medicament comprising a compound as defined in any of Claims 1 to 9 in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

15. Medicament comprising a compound as defined in any of Claims 1 to 9 in combination with one or more active ingredients selected from the group of the PDE 5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogues, IP receptor agonists, endothelin antagonists, compounds that inhibit the signal transduction cascade, and pirfenidone.

16. Medicament according to Claim 14 or 15 for treatment and / or prophylaxis of lung inflammation disorders, particularly of chronic-obstructive lung disease (COPD), of pulmonary emphysema, of chronic bronchitis, of bronchiectasis, of pulmonary hypertension in COPD (PH-COPD), of acute exacerbation in COPD, of cystic fibrosis (mucoviscidosis, CF), of asthma, and idiopathic pulmonary fibrosis (IPF), of bronchiolitis obliterans syndrome (BOS), of arteriosclerosis, of myocarditis, and of inflammatory skin and eye disorders or inflammatory disorders of the internal organs.