EP3126339A1

EP3126339A1 - 2,5-disubstituted cyclopentane carboxylic acids and use thereof

Info

Publication number: EP3126339A1
Application number: EP15712934.7A
Authority: EP
Inventors: Hartmut Beck; Volkhart Min-Jian Li; Yolanda Cancho Grande; Andreas Timmermann; Dirk Brohm; Hannah JÖRIßEN; Pamela BOGNER; Michael Gerisch; Dieter Lang
Original assignee: Bayer Pharma AG
Current assignee: Bayer Pharma AG
Priority date: 2014-04-03
Filing date: 2015-03-31
Publication date: 2017-02-08
Also published as: WO2015150363A1; US20170022171A1

Abstract

The invention relates to novel 2,5-disubstituted cyclopentane carboxylic acid derivatives, to methods for the preparation thereof, to the use thereof alone or in combination for the treatment and/or prevention of disorders, and to the use thereof for producing medicaments for the treatment and/or prevention of disorders, especially for treatment and/or prevention of diseases of the respiratory tract, lung and of the cardiovascular system.

Description

2,5-Disubstituted cyclopentanecarboxylic acids and their use

The present application relates to novel 2,5-disubstituted cyclopentanecarboxylic acid derivatives, processes for their preparation, their use alone or in combinations for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of respiratory, pulmonary and cardiovascular diseases.

Human macrophage elastase (HME, EC 3.4.24.65) belongs to the family of matrix metallo-peptidases (MMPs) and is also called human matrix metallo-peptidase 12 (hMMP-12). The protein is increased i.a. formed by macrophages after contact with "irritating" substances or particles, activated and released. Such substances and particles may, for example, be contained as impurities in suspended particles, as may be mentioned, inter alia. in cigarette smoke or industrial dusts. In a broader sense, endogenous and foreign body cell constituents and cellular debris are counted among these irritant particles, as they may be present in some cases in high concentrations in inflammatory processes. The highly active enzyme is capable of degrading a variety of connective tissue proteins, e.g. primarily the protein elastin (hence the name), as well as other proteins and proteoglycans such as collagen, fibronectin, laminin, chondroitin sulfate, heparan sulfate and others. This proteolytic activity of the enzyme enables macrophages to penetrate the basal membrane. Elastin, for example, occurs in high concentrations in all tissue types that exhibit high elasticity, e.g. in the lungs and arteries. In a variety of pathological processes, such as tissue injury, the HME plays an important role in tissue degradation (tissue remodeling). In addition, the HME is an important modulator in inflammatory processes. It is a key molecule in the recruitment of inflammatory cells, for example by releasing the central inflammatory mediator tumor necrosis factor-alpha (TNF-α) and interfering with the transforming growth factor -beta (TGF-ß) mediated signaling pathway [Hydrolysis of a Broad Spectrum of Extracellular Matrix Proteins by Human Macrophage Elastase, Gronski et al., J. Biol. Chem. 272, 12189-12194 (1997)]. MMP-12 also plays a role in host defense, particularly in the regulation of antiviral immunity, presumably through intervention in the interferon-alpha (IFN-α) -mediated signaling pathway [A new transcriptional role-matrix matrix metalloproteinase -12 in antiviral immunity, Marchant et al., Nature Med. 20, 493-502 (2014)].

It is therefore assumed that the HME plays an important role in many diseases, injuries and pathological changes, their emergence and / or progression with an infectious or non-infectious inflammatory event and / or a proliferative and hypertrophic tissue and vascular remodeling. These may be, in particular, diseases and / or damage to the lung, the kidney or the cardiovascular system, or these may be cancerous diseases or other inflammatory diseases [Macrophage metalloelasta.se (MMP-12) as a target for inflammatory respiratory diseases, Lagente et al., Expert Opin. Ther. Targets 13, 287-295 (2009); Macrophage Metalloelastase as a Major Factor for Glomerular Injury in Anti-Glomerular Basement Membrane Nephritis, Kaneko et al., J. Immunol. 170, 3377-3385 (2003); A Selective Matrix Metalloelastase-12 Inhibitor Retards Atherosclerotic Plaque Development in Apolipoprotein E Knock-out Mice, Johnson et al., Arterioscler. Thromb. Vase. Biol. 31, 528-535 (2011); Impaired Coronary Collateral Growth in the Metabolic Syndrome is Mediated by Matrix Metalloelastase 12-dependent Production of Endodontin and Angiostatin, Dodd et al., Arterioscler. Thromb. Vase. Biol. 33, 1339-1349 (2013); Carcinoma, Chetty et al., Pharmacogenomics 12, 535-546 (2011)]. Matrix metalloproteinase pharmacogenomics in non-small-cell lung carcinoma.

In this context to be named diseases and injuries of the lung are in particular the chronic obstructive pulmonary illness (COPD), the lung emphysema (lung emphysema), interstitial pulmonary diseases (interstitial lung diseases, ILD) such as the pulmonary fibrosis (ideopathic pulmonary fibrosis, IPF) and pulmonary sarcoidosis (pulmonary sareoidosis), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), cystic fibrosis (CF), also called cystic fibrosis). , Asthma and infectious, especially viral respiratory diseases. As other fibrotic diseases, liver fibrosis and systemic sclerosis are mentioned as examples. Diseases and injuries of the cardiovascular system in which the HME is involved are, for example, tissue and vascular changes in atherosclerosis, here in particular carotid arteriosclerosis, infective endocarditis, in particular viral myocarditis, cardiomyopathy Cardiac insufficiency, cardiogenic shock, acute coronary syndrome (ACS), aneurysms, myocardial infarct (AMI) reperfusion injury, ischemic damage to the kidney or retina, and chronic disease such as chronic kidney disease. chronic kidney disease, CKD) and Alport syndrome. Also mentioned here are the metabolic syndrome and obesity. Diseases associated with sepsis include systemic inflammatory response syndrome (SIRS), severe sepsis, septic shock and multi-organ dysfunction (MODF), as well as intravascular Coagulation (disseminated intravascular coagulation, DIC). Examples of tissue degradation and remodeling in cancer processes are the invasion of cancer cells into the healthy tissue (metastasis) and the reformation of supplying blood vessels (neo-angiogenesis). Other Inflammatory diseases in which the HME plays a role are rheumatoid diseases, for example rheumatoid arthritis, as well as chronic bowel inflammation (IBD; Crohn's disease, CD, ulcerative colitis, ulcerative colitis , UC). In general, it is believed that elastase-mediated pathological processes underlie a shifted balance between free elastase (HME) and the body's own elastase inhibitor protein (tissue inhibitor of metalloproteinase, ΤΓΜΡ). In various pathological, especially inflammatory processes, the concentration of free elastase (HME) is increased, so that locally the balance between protease and anti-protease is shifted in favor of the protease. A similar (in) equilibrium exists between the elastase of the neutrophil cells (human neutrophil elastase, HNE, a member of the serine protease family) and the endogenous anti-protease AAT (alpha-1 anti-trypsin, a member of the serine protease family). Inhibitors, SERPINs). Both equilibria are coupled with each other since HME cleaves and inactivates the HNE inhibitor and, conversely, HNE cleaves and inactivates the HME inhibitor, thereby additionally shifting the respective protease / anti-protease imbalances. In addition, in the environment of local inflammation, oxidative bursts prevail, further enhancing protease / anti-protease imbalance [Pathogenic triad in COPD: oxidative stress, protease-antiprotease imbalance, and inflammation, Fischer et al. , Int. J. COPD 6, 413-421 (2011)]. There are currently more than 20 known MMPs that are historically roughly classified into different classes in terms of their most prominent substrates, eg gelatinases (MMP-2, MMP-9), collagenases (MMP-1, MMP-8, MMP-13), stromelysins (MMP-3, MMP-10, MMP-11) and Matrilysins (MMP-7, MMP-26). HME (MMP-12) is so far the only representative of metallo-elastase. In addition, further MMPs are assembled into the group of so-called MT-MMPs (membrane-type MMPs), since they have a characteristic domain that anchors the protein in the membrane (MMP-14, MMP-15, MMP-16, MMP-17 , MMP-24, MMP-25). Common to all MMPs is a conserved zinc-binding region in the active site of the enzyme, which is important for catalytic activity and is also found in other metalloproteins (eg a disintegrin and metalloproteinase, ADAM). The complexed zinc is masked by a sulfhydryl group in the N-terminal pro-peptide domain of the protein, resulting in an enzymatically inactive pro-form of the enzyme. Only after cleavage of this pro-peptide domain is the zinc in the active center of the enzyme freed from this coordination and the enzyme thereby activated (so-called activation by cysteine switch) [matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases, Hu et al ., Nature Rev. Drug Discov. 6, 480-498 (2007)]. Most known synthetic MMP inhibitors have a zinc-complexing functional group, very often for example a hydroxamate, a carboxylate or a thiol [Recent Developments in the Design of Specific Matrix Metalloproteinase Inhibitors aided by Structural and Computational Studies, BG Rao , Curr. Pharm. Des. 11, 295-322 (2005)]. The scaffold of these inhibitors is often similar to peptides, one speaks of so-called peptidomimetics (usually with a poor oral bioavailability), or it has no similarity to peptides, one speaks more generally of small molecules (small molecules, SMOLs ). The physicochemical and pharmacokinetic properties of these inhibitors have, in general terms, a great influence on which targets and which undesired molecules (anti-targets, off-targets) are "hit" in which tissue and for what period to what extent ,

It is a major challenge to determine the specific role of a particular MMP in a disease process. This is compounded in particular by the fact that there are a large number of MMPs and other similar molecules (eg ADAMs), associated with a large number of physiological substrates that are possible in each case and thus possibly also associated inhibitory or activatory effects in a variety of signal transduction pathways. Numerous in vitro and preclinical in vz ^'vo experiments have contributed much to a better understanding of MMPs in different disease models (eg transgenic animals, knock-out animals and genetic data from human studies). The validation of a target with regard to a possible drug therapy can ultimately only be carried out in clinical trials on humans or patients. The first generation of MMP inhibitors has been clinically studied in cancer studies. At that time, only a few representatives of the MMP protein family were known. None of the tested inhibitors could clinically convince, since at effective dosages, the side effects were not tolerated. As it became clear in the course of the knowledge of further MMPs, the representatives of the first inhibitor generation were non-selective inhibitors, ie a large number of different MMPs were equally inhibited (pan-MMP inhibitors, pan-MMPIs). Presumably, the desired effect on one or more MMP targets has been masked by an undesired effect on one or more MMP anti-targets or by an undesired effect on another target site (off-target) [Validating matrix metalloproteinases as drug targets and anti-targets for Cancer Therapy, Coverall & Kleifeld, Nature Rev. Cancer 6, 227-239 (2006)].

Newer MMP inhibitors, which are characterized by increased selectivity, have now also been clinically tested, including compounds explicitly referred to as MMP-12 inhibitors, but so far also without any conclusive clinical success. At a closer Look here, too, the previously described as selective inhibitors have been found to be not so selective.

Thus, for the clinical test compound "MMP408" as a ΜΜΡ-12 inhibitor, a certain to marked selectivity in vitro over MMP-13, MMP-3, MMP-14, MMP-9, Agg-1, MMP-1, Agg-2 , MMP-7 and TACE [A Selective Matrix Metalloprotease 12 Inhibitor for Potential Treatment of Chronic Obstructive Pulmonary Disease (COPD): Discovery of (S) -2- (8- (methoxycarbonylamino) dibenzo [b, d] furan- 3-sulfonamido) -3-methylbutanoic acid (MMP408), Li et al., J. Med. Chem. 52, 1799-1802 (2009)]. In vitro micrographs of MMP-2 and MMP-8 indicate less favorable selectivity towards these two MMPs [matrix metalloproteinase-12 is a therapeutic target for asthma in children and young adults, Mukhopadhyay et al., J. Biol. Allergy Clin. Immunol. 126, 70-76 (2010)].

The same is true for the clinical test substance AZD1236 for the treatment of COPD, which is described as a dual MMP-9/12 inhibitor. [Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate / severe COPD: A randomized controlled trial, Dahl et al., Pulm. Pharmacol. Therap. 25, 169-177 (2012)]. The development of this compound was discontinued in 2012; here, too, a marked inhibition of MMP-2 and MMP-13 is cited [http://www.wipo.int/research/en/details.jsp?id=2301].

When assessing MMP selectivity, a cautious assessment of the predictive power of animal models is also indicated. For example, the test compound MMP408 shows a significantly decreased affinity for the mouse orthologous MMP-12 target: IC ₅₀ 2 nM (human MMP-12), IC ₅₀ 160 nM (murine MMP-12), IC ₅₀ 320 nm (MMP-12 of the Rat) [see above Li et al., 2009; Mukhopadhyay et al., 2010]. Information on the potency against other mouse MMPs has not been published. It seems similar with the test substance AZD1236 [see http: //www.wipo. int / research / en / details.jsp? id = 2301 for cross-reactivity in various animal species].

In addition to the selectivity profile across species boundaries, the potency at the target MMP-12 itself is very important. With a comparably similar pharmacokinetic profile, a highly potent compound will result in a lower therapeutic dose than a less potent compound, and generally a lower dose should be associated with a reduced likelihood of side effects. This is particularly true with the inclusion of the so-called "free fraction" (fraction unbound, f _u ) of a compound which can interact with the desired target or unwanted anti and off targets (the "free fraction" is defined as the available amount of one A compound that is not bound to components of the blood plasma, which are mainly blood protein components such as eg albumin). In addition to the MMP selectivity, the specificity is therefore of paramount importance.

Accordingly, novel macrophage elastase inhibiting agents should have high selectivity and specificity in order to be able to specifically inhibit HME. For this purpose, a good metabolic stability of the substances is necessary (low clearance). In addition, these compounds should be stable under oxidative conditions so as not to lose their inhibitory potency in disease.

Chronic obstructive pulmonary disease (COPD) is a slowly progressive lung disease characterized by obstruction of respiratory flow, which is caused by pulmonary emphysema and / or chronic bronchitis. The first symptoms of the disease usually appear from the fourth to fifth decade of life. In the following years, the shortness of breath is often aggravated and it manifests cough, associated with an extensive and sometimes purulent sputum and a stenosis breathing to a dyspnea. COPD is primarily a disease of smokers: smoking is responsible for 90% of all COPD cases and 80-90% of all COPD deaths. COPD is a major medical problem and is the sixth most common cause of death worldwide. About 4-6% of over 45's are affected.

Although the obstruction of the respiratory flow can be only partially and temporally limited, COPD is not curable. The aim of the treatment is thus to improve the quality of life, alleviate the symptoms, prevent acute worsening and slow down the progressive impairment of lung function. Existing pharmacotherapies, which have barely changed over the last two to three decades, include the use of bronchodilators to open blocked airways and, in certain situations, corticosteroids to control lung inflammation [Chronic Obstructive Pulmonary Disease, PJ. Barnes, N. Engl. J. Med. 343, 269-280 (2000)]. The chronic inflammation of the lungs, caused by cigarette smoke or other irritants, is the driving force of disease development. The underlying mechanism involves immune cells that release various chemokines during the inflammatory response of the lungs. As a result, neutrophilic cells and subsequently alveolar macrophages are lured to the lung connective tissue and lumen. Neutrophils secrete a protease cocktail containing mainly HNE and proteinase 3. Activated macrophages release the HME. As a result, the protease / antiprotease balance is shifted locally in favor of the proteases, which leads inter alia to an uncontrolled elastase activity and, as a consequence thereof, to an excessive degradation of the elastin of the alveolar bodies. This tissue breakdown causes a collapse of the bronchi. This goes hand in hand with a reduction in dermal elasticity of the lung, resulting in obstruction of the respiratory flow and impaired breathing. In addition, frequent and prolonged inflammation of the lungs may lead to bronchial remodeling and, as a consequence, to the formation of lesions. Such lesions contribute to the onset of chronic cough that marks chronic bronchitis.

Studies with human sputum samples have shown that the amount of HME protein is associated with smoking or COPD status: detectable HME levels are lowest in non-smokers, slightly higher in former smokers and smokers, and in COPD - Patients significantly increased [Elevated MMP-12 protein levels in induced sputum from patients with COPD, Demedts et al., Thorax 61, 196-201 (2006)]. Similar data were collected with human sputum samples and bronchial alveolar washing fluid (BALF). Here, HME could be detected and quantified on activated macrophages: HME amount COPD patient / smoker> COPD patient / former smoker> former smoker> Non-smoker [Patterns of airway inflammation and MMP-12 expression in smokers and ex-smokers with COPD, Babusyte et al., Respir. Res. 8, 81-90 (2007)].

One of the COPD-related inflammatory lung diseases is interstitial lung disease (ILD), in particular idiopathic pulmonary fibrosis (IPF) and sarcoidosis [Commonalities between the pro-fibrotic mechanisms in COPD and IPF, LA Murray, Pulm , Pharmacol. Therap. 25, 276-280 (2012); The pathogenesis of COPD and IPF: distinct horns of the same devil ?, Chilosi et al., Respir. Res. 13: 3 (2012)]. Again, the homeostasis of the extracellular matrix is disturbed. Data from genome-wide association studies suggest a special role of HME in the disease process of such fibro- genetic diseases [Gene Expression Profiling Identifies MMP-12 and ADAMDEC1 as Potential Pathogenic Mediators of Pulmonary Sarcoidosis, Crouser et al., Am. J. Respir. Crit. Care Med. 179, 929-938 (2009); Association of a Functional Polymorphism in the Matrix Metalloproteinase-12 Promoter Region with Systemic Sclerosis in an Italian Population, Manetti et al., J. Rheumatol. 37, 1852-1857 (2010); Increased serum levels and tissue expression of matrix metalloproteinase-12 in patients with systemic sclerosis: correlation with severity of skin and pulmonary fibrosis and vascular damage, Manetti et al., Ann. Rheum. Dis. 7J, 1064-1070 (2012)]. In addition, there is further preclinical evidence for a significant role of HME in ischemic-inflammatory disease processes [Macrophage Metalloelastase (MMP-12) Deficiency Mitigates Retinal Inflammation and Pathological Angiogenesis in Ischemic Retinopathy, Li et al., PLoS ONE 7 (12)]. , e52699 (2012)]. Significantly higher MMP-12 expression is also known in ischemic kidney injuries, as is the involvement of MMP-12 in further inflammatory kidney disease [JNK signaling in human and experimental renal ischemia / reperfusion injury, Kanellis et al., Nephrol. Dial. Transplant. 25, 2898-2908 (2010); Macrophage Metalloelastase as a Major Factor for Glomerular Injury in Anti-Glomerular Basement Membrane Nephritis, Kaneko et al., J. Immun. 170, 3377-3385 (2003); Role for macrophage metallo elastase in Glomerular Basement Membrane Damage Associated with Alport Syndrome, Rao et al., Am. J. Pathol. 169, 32-46 (2006); Differential regulation of metabolites in experimental chronic renal allograft rejection: potential markers and novel therapeutic targets, Berthier et al., Kidney Int. 69, 358-368 (2006); Macrophage infiltration and renal damage are independent of matrix metalloproteinase 12 (MMP-12) in the obstructed kidney, Abraham et al., Nephrology 17, 322-329 (2012)].

The object of the present invention was therefore to identify and provide new substances which act as potent, selective and specific inhibitors of human macrophage elastase (HME / MMP-12) and as such for the treatment and / or prevention of, in particular, respiratory diseases, the Lungs and the cardiovascular system are suitable. From the patent applications WO 96/15096-A1, WO 97/43237-A1, WO 97/43238-A1, WO 97/43239-A1, WO 97/43240-A1, WO 97/43245-A1 and WO 97/43247 A1 is 4-aryl- and 4-biaryl-substituted 4-oxobutanoic acid derivatives with inhibitory activity towards MMP-2, MMP-3, MMP-9 and, to a lesser extent, MMP-1; Because of this profile of action, the compounds have been found to be particularly suitable for the treatment of osteoarthritis, rheumatoid arthritis and tumor diseases. In WO 98/09940 A1 and WO 99/18079 A1 other biarylbutanoic acid derivatives have been disclosed as inhibitors of MMP-2, MMP-3 and / or MMP-13, which are suitable for the treatment of various diseases. WO 00/40539 A1 claims the use of 4-biaryl-4-oxobutanoic acids for the treatment of pulmonary and respiratory diseases, based on a different degree of inhibition of MMP-2, MMP-3, MMP-8, MMP-9, MMP-12 and MMP-13 through these compounds. Furthermore, WO 2012/014114-A1 describes 3-hydroxypropionic acid derivatives and WO 2012/038942-A1 describes oxy- or sulfonylacetic acid derivatives as dual MMP-9/12 inhibitors.

In view of the above-described object, however, it has been found that these prior art MMP inhibitors often have disadvantages, in particular an inadequate inhibitory potency for MMP-12, an insufficient selectivity for MMP-12 compared to others MMPs and / or limited metabolic stability.

Further arylalkanecarboxylic acid derivatives are described in WO 2004/092146-A2, WO 2004/099168-A2, WO 2004/099170-A2, WO 2004/099171-A2, WO 2006/050097-A1 and WO 2006/055625-A2 Inhibitors of protein tyrosine phosphatase 1B (PTP-1B) are described for the treatment of diabetes, cancers and neurodegenerative diseases.

It has now surprisingly been found that certain 2,5-disubstituted cyclopentanecarboxylic acid derivatives have a significantly improved profile with regard to their potency and selectivity with respect to the human macrophage elastase (HME / hMMP-12) in comparison to those of the prior art Technology known compounds. Moreover, many of the compounds of the invention to a low in vz ^'iro clearance and a good metabolic stability. Overall, this property profile makes it possible for the compounds according to the invention to have low dosability and, as a result of the more targeted mode of action, a reduced risk of the occurrence of undesired side effects in the therapy.

In addition, the compounds of the invention are characterized by a significant inhibitory activity and selectivity towards the rodent orthologous MMP-12 peptidases, such as mouse MMP-12 (also referred to as murine macrophage elastase, MME) and rat MMP-12. This allows a more comprehensive preclinical evaluation of the substances in various established animal models of the diseases described above.

The present invention relates to compounds of the general formula (I)

in which

A is -O- or -S-, straight-chain or branched (C3-Cv) -alkyl or a group of the formula

stands in which

* denotes the link to A, n denotes the number 1, 2 or 3, Cy (C ₃ -C 6) -cycloalkyl,

R is hydrogen, fluorine, chlorine, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, (trifluoromethyl) sulfanyl, methoxycarbonylamino or 2-oxo-l, 3-oxazolidin-3-yl, and

_R 3B is hydrogen, fluorine, chlorine, methyl or trifluoromethyl, and

R ^{2 is} hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl, and their salts, solvates and solvates of the salts. Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.

Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not suitable for pharmaceutical applications themselves, but can be used, for example, for the isolation, purification or storage of the compounds according to the invention. Physiologically acceptable salts of the compounds according to the invention include, in particular, the salts derived from customary bases, such as, by way of example and by way of preference, alkali metal salts (eg sodium and potassium salts), alkaline earth salts (eg calcium and magnesium salts), zinc 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, / V, / V-diisopropylethylamine, monoethanolamine, diethanolamine, triethanolamine, tromethamine, dimethylaminoethanol, diethylaminoethanol, choline, procaine, dicyclohexylamine, dibenzylamine, / V-methylmor - pholine, / V-methylpiperidine, arginine, lysine and 1,2-ethylenediamine.

In the context of the invention, solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates in which the co- Ordination with water takes place. As solvates, hydrates are preferred in the context of the present invention.

The compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or, if appropriate, also as conformational isomers (enantiomers and / or diastereomers, including those of atropisomers). The present invention therefore includes 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; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.

The term "enantiomerically pure" in the context of the present invention is understood to mean that the relevant compound is present in an absolute configuration of the chiral centers in an enantiomeric excess of more than 95%, preferably more than 98%. The enantiomeric excess (ene, ee value) is calculated here by evaluating the chromatogram of a HPLC analysis on a chiral phase according to the following formula:

Enantiomer 1 (area%) - enantiomer 2 (area%)

ee = x 100%

Enantiomer 1 (area%) + enantiomer 2 (area%)

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

The present invention also includes all suitable isotopic variants of the compounds according to the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature. Examples of isotopes which can be incorporated in a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as Ή (deuterium), Ή (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ 0, ¹⁸ 0, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic variants of a compound of the invention, such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or distribution of active ingredient in the body; Due to the comparatively easy production and detectability, compounds labeled with ³ H or ¹⁴ C isotopes in particular are suitable for this purpose. In addition, the incorporation of isotopes, such as from Deuterium, lead to certain therapeutic advantages as a result of greater metabolic stability of the compound, such as to prolong the half-life in the body or to a reduction of the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by generally customary processes known to the person skilled in the art, for example by the methods described below and the rules reproduced in the exemplary embodiments by using corresponding isotopic modifications of the respective reagents and / or starting compounds. In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" here denotes compounds which may themselves be biologically active or inactive, but are converted during their residence time in the body by, for example, metabolic or hydrolytic routes to compounds of the invention.

In particular, the present invention comprises, as prodrugs, hydrolyzable ester derivatives of the carboxylic acids of the formula (I) according to the invention. These are understood to mean esters which can be hydrolyzed in physiological media, under the conditions of the biological assays described below, and in particular in vivo enzymatically or chemically to the free carboxylic acids, as the main biologically active compounds. As such esters, preference is given to (C 1 -C -alkyl esters in which the alkyl group may be straight-chain or branched.) Particular preference is given to methyl, ethyl or ethyl-butyl esters.

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:

(C 1 -C 7) -alkyl in the context of the invention is a straight-chain or branched alkyl radical having 3 to 7 carbon atoms. Examples which may be mentioned by way of example and with preference being given to n-propyl, isopropyl, n-butyl, isobutyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, 3-methylbutyl, n-hexyl, 2-hexyl, 3-hexyl, 4-methylpentyl, n-heptyl and 5-methylhexyl. Preference is given to a straight-chain alkyl radical having 4 to 6 carbon atoms, such as n-butyl, n-pentyl and n-hexyl.

In the context of the invention, (C 3 -C 6) -cycloalkyl is a monocyclic, saturated cycloalkyl group having 3 to 6 ring carbon atoms. Examples which may be mentioned are: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferred is a cycloalkyl radical having 5 or 6 ring carbon atoms such as cyclopentyl and cyclohexyl.

In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. When radicals in the compounds according to the invention are present Unless otherwise specified, the radicals may be monosubstituted or polysubstituted. Substitution with one or two identical or different substituents is preferred. Particularly preferred is the substitution with a substituent.

Preferred in the context of the present invention are compounds of the formula (I) in which A is -O- or -S-,

R ^{1 is} n-butyl, n-pentyl or n-hexyl or a group of the formula

stands in which

* denotes the link to A, n denotes the number 1, 2 or 3,

Cy cyclopentyl or cyclohexyl means

R ^{3A is} hydrogen, chlorine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, methoxycarbonylamino or 2-oxo-1,3-oxazolidin-3-yl, and R ^{3B is} hydrogen, fluorine or chlorine, and

R ^{2 is} hydrogen, methyl or trifluoromethyl, and their salts, solvates and solvates of the salts.

A particular embodiment of the present invention comprises compounds of the formula (I) in which

A is -O-, and their salts, solvates and solvates of the salts. Another particular embodiment of the present invention comprises compound formula (I) in which

R ^{1 is} a group of the formula

wherein the linkage to A denotes the number 1 or 2 and

Cy cyclopentyl or cyclohexyl, as well as their salts, solvates and solvates of the salts.

Another particular embodiment of the present invention comprises compounds of the formula (I) in which

R ^{1 is} a group of the formula

where the linkage is to A, n is the number 1,

R ^{3A represents} chlorine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, methoxycarbonylamino or 2-oxo-1,3-oxazolidin-3-yl, and

R ^{3B is} hydrogen, fluorine or chlorine, and their salts, solvates and solvates of the salts. Another particular embodiment of the present invention comprises compounds of the formula (I) in which

R ^{2 is} methyl or trifluoromethyl, and their salts, solvates and solvates of the salts. Particularly preferred in the context of the present invention are compounds of the formula (I) in which

A is -O-, n-pentyl or n-hexyl or a group of the formula

where the linkage is A, n is 1 or 2,

Cyclopentyl or cyclohexyl means

R ^{3A is} hydrogen, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy, and

R ^{3B is} hydrogen, fluorine or chlorine, and is hydrogen, methyl or trifluoromethyl, and their salts, solvates and solvates of the salts.

Of particular importance in the context of the present invention are compounds of the formulas (IA) and (IB)

wherein A, R ¹ and R ^{2 have} the meanings defined above and the groups bonded to the central cyclopentane ring have a relative trans arrangement to each other, and mixtures of these compounds, where A, R ¹ and R ² in such mixtures of (IA) and (IB) are each identical, and the salts, solvates and solvates of the salts of these compounds and their mixtures. Preferred in the context of the present invention are the compounds of the formula (IA)

in which A, R ¹ and R ^{2 have} the meanings defined above and the groups bonded to the central cyclopentane ring in enantiomerically pure form have an arrangement as indicated (IS, 2S, 5R) to each other, and the salts, solvates and solvates of the salts of these compounds.

The residue definitions given in detail in the respective combinations or preferred combinations of residues are also replaced by residue definitions of other combinations, regardless of the particular combinations of the residues indicated.

Very particular preference is given to combinations of two or more of the abovementioned preferred ranges. Another object of the invention is a process for the preparation of the compounds of the invention, characterized in that

[A] a compound of the formula (II)

in which A and R ^{2 have} the meanings given above, in the presence of a base with a compound of the formula (III)

X (III) in which R ^{1 has} the meaning given above and

X is a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, to give a compound of the formula (IV)

in which A, R ¹ and R ^{2 have} the meanings given above, alkylated and then the 2- (trimethylsilyl) ethyl ester group with the aid of an acid or a fluoride reagent to the carboxylic acid of formula (I)

in which A, R ¹ and R ^{2 have} the meanings given above,

cleaves

or alternatively, when A in formula (I) is -S-,

a compound of the formula (II-A)

in which R ^{2 has} the meaning given above,

into the corresponding trifluoromethanesulfonate of the formula (V)

in which R ^{2 has} the meaning given above, this then in the presence of a suitable palladium catalyst with a thiol of the formula (VI)

R-SH (VI), in which R ^{1 has} the abovementioned meaning, to give a compound of the formula (IV-A)

in which R ¹ and R ^{2 have} the meanings given above, and then reacting the 2- (trimethylsilyl) ethyl ester group with the aid of an acid or a fluoride reagent to give the carboxylic acid of the formula (IC)

in which R ¹ and R ^{2 have} the abovementioned meanings, and if appropriate separates the compounds of the formula (I) or (IC) thus obtained into their enantiomers and / or diastereomers and / or with the corresponding (i) solvents and / or or (ii) bases are converted into their solvates, salts and / or solvates of the salts.

Suitable bases for the alkylation reaction (II) + (ΠΙ) -> (IV) are in particular alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium - or potassium ieri.-butoxide, alkali metal hydrides such as sodium or potassium hydride, amide bases such as lithium diisopropylamide or Lithium, sodium or potassium bis (trimethylsilyl) amide, or common organometallic bases such as phenyllithium or n-, sec- or ieri.-butyllithium. Preference is given to using potassium carbonate or potassium ieri-butoxide.

Suitable inert solvents for this reaction are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl ieri-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis (2-methoxyethyl) ether, hydrocarbons, such as benzene, toluene, Xylene, pentane, hexane or cyclohexane, or dipolar aprotic solvents such as acetonitrile, butyronitrile, dimethylformamide (DMF), Ν, Ν-dimethylacetamide (DMA), Ν, Ν'-dimethylpropyleneurea (DMPU), / V-methylpyrrolidinone ( NMP) or dimethyl sulfoxide (DMSO). Mixtures of such solvents can also be used. Preferably, acetonitrile or dimethylformamide (DMF) is used.

The reaction (II) + (ΠΙ) - (IV) is generally carried out in a temperature range from 0 ° C to + 120 ° C, depending on the reactivity of the components involved.

The cleavage of the 2- (trimethylsilyl) ethyl ester grouping in process step (IV) - (I) is carried out by customary methods with the aid of a strong acid, in particular trifluoroacetic acid, in an inert solvent such as dichloromethane or with the aid of a fluoride, in particular Tetrabutylammonium fluoride (TBAF), in an ethereal solvent such as tetrahydrofuran. The ester cleavage is usually carried out in a temperature range from -20 ° C to + 30 ° C. The preparation of trifluoromethanesulfonate (V) starting from the phenol (Π-Α) is carried out in the usual manner by reaction with trifluoromethanesulfonic anhydride in the presence of an amine base such as A ^ -Diisopropylethylamin or pyridine. As the inert solvent, chlorinated hydrocarbons such as dichloromethane or chloroform are generally used, and the reaction is usually carried out in a temperature range of -20 ° C to + 25 ° C. The coupling reaction (V) + (VI) - (IV-A) is carried out with the aid of a palladium catalyst. Suitable examples of these are palladium (II) acetate, palladium (II) chloride, bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (II) chloride, tetrakis (triphenylphosphine) palladium (0), bis ( dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) or [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) chloride, in each case in combination with a suitable phosphine ligand such as, for example, 2- Dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (X-phosphine), 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (S-phos), 1,2,3,4,5-pentaphenyl -l '- (di-ieri-butylphosphino) ferrocene (Q-Phos), 4,5-bis (diphenylphosphino) -9,9-dimethyl-xanthene (xantphos), 2,2'-bis (diphenylphosphino) -l , l'-binaphthyl (BINAP), 2-dicyclohexylphosphine phino-2 '- (A ^r, A ⁱ -dimethylarnino) biphenyl or 2-Di-fer tert-butylphosphino-2' - (A ^r, A ^{i-dimethylamino)} biphenyl.

The reaction is usually carried out in the presence of a base. As such are alkali metal carbonates such as sodium, potassium or cesium carbonate, alkali metal phosphates such as sodium or potassium phosphate, alkali fluorides such as potassium or cesium fluoride, alkali ieri.-butylates such as sodium or potassium ieri.-butoxide, tertiary amine bases such as triethylamine, / V-methylmorpholine / V-methylpiperidine, diisopropylethylamine, pyridine or 4-A ^i, A ^{r-dimethylaminopyridine,} or amide bases such as lithium, sodium or potassium bis (trimethylsilyl) amide. The reaction is carried out in an inert solvent such as, for example, toluene, xylene, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF) or dimethylacetamide (DMA). or mixtures thereof in a temperature range of + 50 ° C to + 150 ° C, wherein the use of a microwave apparatus may be advantageous.

For this coupling reaction, preference is given to using a catalyst / ligand / base system consisting of tris (dibenzylideneacetone) dipalladium (0), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (xanthophos) and A 1 -diisopropylethylamine, and 1,4-dioxane used as a solvent [cf. also M.S. Chambers et al, Int. Pat. Appl. WO 2006/059149-A1, page 9; C.-K. Pei and M. Shi, Tetrahedron: Asymmetry 22 (11), 1239-1248 (2011)].

The cleavage of the 2- (trimethylsilyl) ethyl ester grouping in process step (IV -A) - (I-C) is carried out in a manner analogous to that described above for reaction (IV) - (I). Compounds of formula (Π) wherein A is -O- [i.e. Compounds of the above formula (Π-Α)] can be prepared by reacting a compound of the formula (VII)

in which

PG is a temporary protecting group such as benzyl, in the presence of an alkyl or arylphosphine and an azodicarboxylate with a triazine-4 (3 /) -one derivative of the formula (VHT)

in which R ^{2 has} the abovementioned meaning, to give a compound of the formula (IX)

in which PG and R ^{2 have} the meanings given above, and then the protective group PG to give the compound of the formula (II-A)

which R ^{2 has} the meaning given above, splits off.

The reaction (VII) + (VIII) -> (IX) is carried out under the usual conditions of a "Mitsunobu reaction" in the presence of a phosphine and an azodicarboxylate [see eg D. L. Hughes, Org. Reactions 42, 335 (1992); DL Hughes, Org. Prep. Proced. Int. 28 (2), 127 (1996)]. Examples of suitable phosphine components are triphenylphosphine, tri-n-butylphosphine, 1,2-bis (diphenylphosphino) ethane (DPPE), diphenyl (2-pyridyl) phosphine, (4-dimethylaminophenyl) diphenylphosphine or tris (4 -dimethylaminophenyl) phosphine. As the azodicarboxylate, for example, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-ethyl-butyl azodicarboxylate, A ^ N-tetramethyl azodicarboxamide (TMAD), 1,1 '- (azodicarbonyl) dipiperidine (ADDP) or 4,7-dimethyl- 3,5,7-hexahydro-l, 2,4,7-tetrazocine-3,8-dione (DHTD). Preferably here tri-n-butylphosphine is used in conjunction with diethyl azodicarboxylate (DEAD). Inert solvents for this reaction are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl isl-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis (2-methoxyethyl) ether, hydrocarbons, such as benzene, Toluene, xylene, pentane, hexane or cyclohexane, or polar aprotic solvents such as acetonitrile, butyronitrile, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N, N'-dimethylpropyleneurea ( DMPU) or methylpyrrolidinone (NMP). Also, mixtures of such solvents can be used. Preference is given to using tetrahydrofuran, toluene or a mixture of these two.

The reaction (VII) + (VIII) - (IX) is generally carried out in a temperature range from -20 ° C to + 60 ° C, preferably at 0 ° C to + 40 ° C. Optionally, the use of a microwave len apparatus at this reaction be beneficial.

The removal of benzyl as a temporary protective group PG in process step (IX) - (II-A) is carried out in the usual manner by hydrogenation with gaseous hydrogen or, in the sense of a transfer hydrogenation, with the aid of a hydrogen donor such as Arnmoniumformiat, cyclohexene or cyclohexadiene, in each case in the presence of a suitable hydrogenation catalyst such as in particular palladium on activated carbon. The reaction is preferably carried out in an alcoholic solvent such as methanol or ethanol, in ethyl acetate or tetrahydrofuran or in a mixture of such solvents, optionally with the addition of water, in a temperature range from + 20 ° C to + 80 ° C [to possible alternative protecting groups and for introduction and removal of such protecting groups see also: TW Greene and P.G.M. Wuts, Protective Croups in Organic Synthesis, Wiley, New York, 1999].

Compounds of the formula (II) in which A is -S- can be prepared by reacting the above-described trifluoromethanesulfonate of the formula (V) in which R ^{2 has} the abovementioned meaning, in the presence of a suitable palladium catalyst with a trialkylsilanethiol, for example triisopropylsilanethiol, to give the compound of the formula (II-B)

in which R ^{2 has} the meaning given above, converts.

The transformation (V) - (II-B) is carried out in an analogous manner as described in detail above for the coupling reaction (V) + (VI) - (IV-A). The trialkylsilylsulfide initially formed by coupling with the trialkylsilanethiol is cleaved again under the conditions used for an aqueous reaction work-up and chromatographic product purification, so that the free thiophenol (II-B) is obtained directly [cf. M. Kreis and S. Bräse, Adv. Synth. Catal. 342 (2-3), 313-319 (2005)].

The individual process steps described above can be carried out at normal, at elevated or at reduced pressure (for example in the range from 0.5 to 5 bar); In general, one works at normal pressure. The compounds of the formula (VII), in turn, can be prepared in various ways, starting from compounds of the formula (X) or (XI), based on published synthesis processes.

(X) (xi),

wherein PG is as defined above and Hai is a halogen atom [see, e.g. the general preparative methods described in WO 96/15096-A1, pages 26-44, in particular the methods A, G, H and K].

In particular, compounds of formula (VII) which have a relative trans arrangement of the groups attached to the central cyclopentane ring, i. Compounds of the formulas (Vn-A) and (VE-B)

(VII-A) (VII-B), in which PG has the abovementioned meaning, can be prepared in analogy to published synthetic methods, for example by reacting e o-2- (trimethylsilyl) efhyl 2-oxobicyclo [2.2.1] heptane-7-carboxylate of the formula (II)

(Xii)

with a phenyl Grignard compound of the formula (ΧΙΠ) in which PG and Hai have the meanings given above, to the adduct of the formula (XIV)

in which PG has the abovementioned meaning, then reacting the tertiary hydroxy group via the corresponding mesylate to give the olefin of the formula (XV)

in which PG has the abovementioned meaning, this is then eliminated with A ^r -Mefhylmorpholin- / V-oxide together with Osmiumtetroxid as a catalyst to 1,2-diol of the formula (XVI)

PG (xvi), in which PG has the meaning given above, oxidizes, then this bicyclic diol using lead tetraacetate or sodium periodate to 2-formyl-5-keto-cyclopentanecarboxylic acid ester of the formula (XVII)

in which PG has the meaning given above, and finally with sodium borohydride to the hydroxymethyl compound of the formula (VII-A)

in which PG has the meaning given above, reduced [cf. WO 96/15096-A1, preparative method K (pages 42-44)].

In the synthetic sequence (XII) + (ΧΠΙ) -> (XIV) -> (XV) → (XVI) → (XVII) - (VII-A) described above, the relative configuration of the chiral centers has only been simplified in each case the structural formula of an enantiomer is reproduced, even if the compounds in question were used or obtained in racemic form; The actual end product of such a racemic preparation process is the racemic mixture of compounds (VII-A) and (VII-B). The 1,2,3-triazine-4 (3 //) -one derivatives of the formula (VIII) are easily prepared by treatment of aminoaminobenzamides of the formula (XVIII) (XVIII), in which R ^{2 has} the meaning given above, accessible with sodium nitrite in aqueous hydrochloric acid [see, eg, D. Fernandez-Forner et al, Tetrahedron 47 (42), 8917-8930 (1991)]. The separation of stereoisomers (enantiomers and / or diastereomers) of the compounds of the formula (I) according to the invention can be achieved by customary methods known to the person skilled in the art. Preferably, chromatographic methods for achiral or chiral separation phases are used for this purpose. Alternatively, it is also possible to carry out a separation via diastereomeric salts of the carboxylic acids of the formula (I) with chiral amine bases. A separation of the compounds according to the invention into the corresponding enantiomers and / or diastereomers may, if appropriate, also be carried out at the stage of the intermediates (II), (IV), (II-A), (IV-A), (VII). , (IX), (II-B) or (VII-A) / (VII-B), which are then further reacted in separated form according to the reaction sequence described above. For such a separation of the stereoisomers of intermediates, it is also preferred to use chromatographic methods on achiral or chiral separation phases.

The compounds of formulas (ΠΙ), (VI), (X), (XI), (ΧΠ), (ΧΙΠ) and (XVIII) are either commercially available or described as such in the literature, or they can be derived from others commercially available compounds, known in the art, literature methods are prepared. Numerous detailed regulations and further literature references are also to be found in the Experimental Section in the section on the Preparation of Starting Compounds and Intermediates.

The preparation of the compounds of the invention can be exemplified by the following reaction schemes: Scheme 1

(as a racemic mixture)

The compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals. The compounds of the invention are potent, non-reactive and selective inhibitors of human macrophage elastase (HME / hMMP-12), which have a significantly improved profile of potency and selectivity compared to the compounds known in the art. Moreover, many of the compounds of the invention to a low in vz ^'iro clearance and a good metabolic stability. Overall, this property profile makes it possible for the compounds according to the invention to have low dosability and, as a result of the more targeted mode of action, a reduced risk of the occurrence of undesired side effects in the therapy.

The compounds according to the invention are therefore particularly suitable for the treatment and / or prevention of diseases and pathological processes, in particular those in which, in the course of an infectious or non-infectious inflammatory event and / or a tissue or vascular remodeling, the macrophage elastase (HME / hMMP-12).

For the purposes of the present invention, these include, in particular, diseases of the respiratory tract and the lungs, such as chronic obstructive pulmonary disease (COPD), asthma and the group of interstitial lung diseases (ILD), and diseases of the cardiovascular system, such as arteriosclerosis and aneurysms ,

The manifestations of chronic obstructive pulmonary disease (COPD) include, in particular, pulmonary emphysema, e.g. Cigarette smoke-induced pulmonary emphysema, chronic bronchitis (CB), pulmonary hypertension in COPD (PH-COPD), bronchiectasis (BE) and combinations thereof, especially in acute exacerbating stages of the disease (AE-COPD).

Types of asthma include asthmatic diseases of varying degrees of severity with intermittent or persistent history, such as refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and medication-induced or dust-induced asthma.

The group of interstitial lung diseases (ILD) includes idiopathic pulmonary fibrosis (IPF), pulmonary sarcoidosis and acute interstitial pneumonia, non-specific interstitial pneumonia, lymphoid interstitial pneumonia, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonia, desquamative interstitialile Pneumonia and non-classifiable idiopathic interstitial pneumonia, granulomatous interstitial lung disease, interstitial lung disease of known cause and other interstitial lung diseases of unknown cause. The compounds of the invention may also be used for the treatment and / or prevention of other respiratory and pulmonary diseases, such as pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), of acute respiratory tract syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD) and cystic fibrosis (CF), of various forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis) , bronchiectasis, pneumonia, farmer lung and related diseases, infectious and non-infectious cough and cold diseases (chronic inflammatory cough, iatrogenic cough), nasal irritation (including medicinal rhinitis, vasomotor rhinitis and season-dependent allergic rhinitis, eg hay fever) and polyps ,

For the purposes of the present invention, the group of diseases of the cardiovascular system includes, in particular, arteriosclerosis and its secondary diseases, such as, for example, Stroke in arteriosclerosis of the cervical arteries (carotid arteriosclerosis), myocardial infarction in arteriosclerosis of the coronary arteries, peripheral arterial occlusive disease (PAOD) as a result of arteriosclerosis of the leg arteries, as well as aneurysms, in particular aneurysms of the aorta, e.g. as a result of atherosclerosis, hypertension, injuries and inflammations, infections (eg rheumatic fever, syphilis, Lyme disease), congenital connective tissue weaknesses (eg in Marfan syndrome and Ehlers-Danlos syndrome) or as a result of a volume burden of the aorta in congenital heart defects with right-left shunt or shunt-dependent perfusion of the lungs, as well as aneurysms of the coronary arteries in the course of a disease in Kawasaki syndrome and in brain areas in patients with a congenital malformation of the aortic valve.

The compounds of the invention may also be used for the treatment and / or prevention of other cardiovascular diseases, such as hypertension, heart failure, coronary heart disease, stable and unstable angina pectoris, renal hypertension, peripheral and cardial vascular diseases, arrhythmias, arrhythmias Atria and ventricles, as well as conduction disorders such as atrio-ventricular blockades of grade I-III, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, torsades de pointes tachycardia, extrasystoles of the atria and ventricles, AV junctional Extrasystoles, sick sinus syndrome, syncope, AV node reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), boxer cardiomyopathy, shock wi cardiogenic shock, septic shock and anaphylactic shock, as well as for the treatment and / or prevention of thrombo- embolic diseases and ischaemias, such as myocardial ischemia, cardiac hypertrophy, transitory 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 congestive heart failure edema, peripheral contusion bleeding disorders, reperfusion damage, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), as well as for the prevention of restenosis, for example after thrombolytic therapies, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA ), Heart transplants and bypass operations. For the purposes of the present invention, the term cardiac insufficiency includes both acute and chronic manifestations of heart failure, as well as specific or related 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 failure, 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 valvular insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic toxicity Cardiomyopathy, cardiac storage disorders and diastolic and systolic heart failure.

The compounds according to the invention are also suitable for the treatment and / or prevention of kidney diseases, in particular renal insufficiency and kidney failure. For the purposes of the present invention, the terms renal insufficiency and renal failure include both acute and chronic manifestations thereof as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as renal transplant rejection and Alport syndrome, immune complex-induced kidney disease, toxic-induced nephropathy, contrast-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive Nephrosclerosis and nephrotic syndrome, which are abnormally elevated diagnostically by, for example, abnormally decreased creatinine and / or water excretion increased blood concentrations of urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes such as glutamylsynthetase, altered urinary or urine output, increased microalbuminuria, Macroalbuminuria, glomerular and arteriolar lesions, 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, cardiac insufficiency, uremia, anemia, electrolyte disorders (eg hyperkalemia, hyponatremia) and disorders in the bone and carbohydrate. Metabolism.

In addition, 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 prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorders (BOO), lower urinary tract syndromes ( LUTS), neurogenic overactive bladder (OAB), incontinence such as mixed, urgency, stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, as well as erectile dysfunction and female sexual dysfunction.

In addition, the compounds of the invention have anti-inflammatory activity 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, epidymitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid diseases, inflammatory diseases of the central nervous system, multiple sclerosis, inflammatory skin diseases, and inflammatory ocular diseases. The compounds according to the invention are furthermore suitable for the treatment and / or prevention of fibrous diseases of the internal organs, such as, for example, the lung, the heart, the kidney, the bone marrow and in particular the liver, as well as dermatological fibroses and fibroid diseases of the eye , For the purposes of the present invention, the term fibrotic disorders includes in particular such diseases as liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis, peritoneal fibrosis and similar fibrotic disorders, scleroderma, Morphaea, keloids, hypertrophic scarring, nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis). The compounds of the invention may also be used to promote wound healing, to combat postoperative scarring, e.g. after glaucoma surgery, and for cosmetic purposes on aging or keratinizing skin.

Also, the compounds of the invention may be used for the treatment and / or prevention of anemias, such as hemolytic anemias, especially hemoglobinopathies such as Sickle cell anemia and thalassemia, megaloblastic anemia, iron deficiency anemia, anemia due to acute blood loss, displacement anemia and aplastic anemia.

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

In addition, the compounds according to the invention can be used for the treatment and / or prevention of lipid metabolism disorders and dyslipidemias (hypolipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemias, hypercholesterolemia, abetalipoproteinemia, sitosterolemia), xanthomatosis, Tangier's disease, obesity, obesity , metabolic disorders (metabolic syndrome, hyperglycaemia, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance and diabetic sequelae such as retinopathy, nephropathy and neuropathy), diseases of the gastrointestinal tract and of the 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), of Central nervous system disorders and neurodegenerative disorders (stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, depression, multiple sclerosis), immune diseases, thyroid disorders (hyperthyroidism), skin diseases (psoriasis, acne, eczema, neurodermatitis, various forms of dermatitis such as dermatitis abacribus, dermatitis actinica, dermatitis allergica, ammoniacal dermatitis, dermatitis artefacta, dermatitis autogenica, dermatitis atrophicans, dermatitis calorica, dermatitis combustionis, dermatitis congelationis, dermatitis cosmetica, dermatitis escharotica, dermatitis exfoliativa, dermatitis gangrenosis, Dermatitis haemostatica, dermatitis herpetiformis, dermatitis lichenoides, dermatitis linearis, malignant dermatitis, median catosis, dermatitis palmaris et plantaris, dermatitis parasitaria, dermatitis photoallergica, dermatitis phototoxica, dermatitis pustularis, dermatitis seborrhoica, dermatitis solaris, dermatitis toxica, ulcerative colitis, dermatitis veneata, infectious dermatitis, pyogenic dermatitis and rosacea-like dermatitis, as well as keratitis, bullosis, vasculitis, cellulitis, panniculitis, lupus erythematosus, erythema, lymphoma, skin cancer, sweet syndrome, Weber Christian disease Syndrome, scarring, wart formation, chilblains), inflammatory eye diseases (saccoidosis, blepharitis, conjunctivitis, iritis, uveitis, choroiditis, ophthalmitis), viral diseases (by influenza, adeno and coronaviruses, such as HPV, HCMV, HIV, SARS) , diseases of skeletal bone and joints and skeletal muscle (various forms of arthritis such as eg arthritis alcaptonurica, arthritis ankylosans, arthritis dysenterica, arthritis exsudativa, arthritis fungosa, arthritis gonorrhoica, arthritis mutilans, arthritis psoriatica, arthritis purulenta, arthritis rheumatica, arthritis serosa, arthritis syphilitica, arthritis tuberculosa, arthritis urica, arthritis villonodularis pigmentosa, atypical arthritis haemophilic arthritis, juvenile chronic arthritis, rheumatoid arthritis, and metastatic arthritis; Still syndrome, Felty syndrome, Sjörgen syndrome, Clutton syndrome, Poncet syndrome, Pott syndrome, and Reiter syndrome, various forms of arthropathies such as arthropathy deformans, arthropathy neuropathic, ovarian arthropathy, psoriatic arthropathy and arthropathy tabica, systemic sclerosis, multiple forms of inflammatory myopathies such as myopathy epidemica, myopathy fibrosa, myopathy myoglobinurica, myopathy ossificans, myopathy ossificans neurotica, myopathy ossificans progre ssiva multiplex, myopathy purulenta, myopathy rheumatica, myopathy trichinosa, myopathy tropica and myopathy typhosa, as well as the Günther syndrome and the Münchmeyer syndrome), of inflammatory arterial changes (various forms of arteritis such as endarteritis, mesarteritis, periarteritis, panarteritis, Rheumatoid arthritis, formaldehyde arteritis, temporal arteritis, cranial arteritis, gigantocellular arteryitis and granulomatous arteritis, as well as Horton's syndrome, Churg-Strauss syndrome and Takayasu's arteritis), MückleWell's syndrome, Kikuchi's disease, of polychondritis, scleroderma and other diseases with an inflammatory or immunological component, such as cataract, cachexia, osteoporosis, gout, incontinence, leprosy, Sezary syndrome and paranoid syndrome, rejection reactions after organ transplantation and wound healing and angiogenesis especially in chronic wounds.

Because of their property profile, the compounds according to the invention are particularly suitable for the treatment and / or prevention of respiratory and pulmonary diseases, especially chronic obstructive pulmonary disease (COPD), in particular pulmonary emphysema, chronic bronchitis (CB), pulmonary Hypertension in COPD (PH-COPD) and bronchiectasis (BE) as well as combinations of these diseases, especially in acute exacerbating stages of COPD disease (AE-COPD), asthma and interstitial lung diseases, in particular idiopathic pulmonary fibrosis ( IPF) and pulmonary sarcoidosis, diseases of the cardiovascular system, in particular atherosclerosis, especially carotid arteriosclerosis, as well as viral myocarditis, cardiomyopathy and aneurysms, including their sequelae such as stroke, myocardial infarction and peripheral arterial occlusive disease (PAD), as well as of chronic kidney diseases and the Alport syndrome. The aforementioned well-characterized human diseases of similar etiology may also be present in other mammals and also be treated there with the compounds of the present invention.

For the purposes of the present invention, the term "treatment" or "treating" includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the course or progression of such conditions and / or the symptoms of such conditions. The term "therapy" is understood to be synonymous with the term "treatment". The terms "prevention", "prophylaxis" or "prevention" are used interchangeably in the context of the present invention and denote the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions. The treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.

Another object of the present invention is the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases. Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is a pharmaceutical composition containing at least one of the compounds of the invention, for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is the use of the compounds of the invention in a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention. The compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects. A further subject of the present invention are therefore medicaments containing at least one of the compounds according to the invention and one or more further active compounds, in particular for the treatment and / or prevention of the aforementioned diseases. Suitable combination active ingredients for this purpose are by way of example and preferably mentioned:

Anti-obstructive / bronchodilatory agents, e.g. for the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, by way of example and preferably from the group of inhaled or systemically administered beta-adrenergic receptor agonists (beta-mimetics), the inhaled anti-muscarinic substances and the PDE 4 inhibitors;

• organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO; Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), for example inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 4 inhibitors such as roflumi last and PDE 5 inhibitors such as sildenafil, vardenafil, tadalafil, uddenafil, dasantafil, avanafil, mirodenafil or lodenafil; · NO and heme-independent activators of soluble guanylate cyclase (sGC), 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), in particular riociguat, as well as those 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;

Compounds which inhibit human neutrophil elastase (HNE), in particular Sivelastat, DX-890 (Reltran) and those described in WO 2004/020410, WO 2004/020412, WO 2004/024700, WO 2004/024701, WO 2005 / 080372, WO 2005/082863, WO 2005/082864, WO 2009/080199, WO 2009/135599, WO 2010/078953 and WO 2010/115548;

Prostacyclin analogs and IP receptor agonists, such as by way of example and preferably iloprost, beraprost, treprostinil, epoprostenol or NS-304; Endothelin receptor antagonists, such as by way of example and preferably bosentan, darusentan, ambrisentan or sitaxsentan; anti-inflammatory, immunomodulatory, immunosuppressant and / or cytotoxic agents, by way of example and preferably from the group of systemic or inhaled corticosteroids, and acetylcysteine, montelukast, azathioprine, cyclophosphamide, hydroxycarbamide, azithromycin, IFN-γ, pirfenidone or etanercept; antifibrotic agents, such as, by way of example and by way of preference, lysophosphatidic acid receptor 1 (LPA-1) antagonists, lysyl oxidase (LOX) inhibitors, lysyl oxidase like 2 inhibitors, vasoactive intestinal peptide (VIP), VIP analogs, α _v β6- Integrin antagonists, cholchicine, IFN-β, D-penicillamine, inhibitors of the WNT signaling pathway or CCR2 antagonists; lipid metabolism-altering agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein (a) antagonists; hypotensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid Receptor antagonists and diuretics; the signal transduction cascade inhibiting compounds, for example and preferably 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 preferably nintedanib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, Cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, semaxanib or tandutinib;

Compounds which block the binding of serotonin to its receptor, by way of example and preferably antagonists of the 5-HT2B 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; The Rho kinase inhibiting compounds, such as by way of example and preferably Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;

Compounds which inhibit the soluble epoxide hydrolase (sEH), such as N, N'-cycloalkyloxyurea, 12- (3-adamantan-1-yl-ureido) -dodecanoic acid or 1-adamantan-1-yl-3 { 5- [2- (2-ethoxyethoxy) ethoxy] pentyl} urea;

• the energy metabolism of the heart affecting compounds, such as by way of example and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine;

Antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances;

• chemotherapeutic agents, as e.g. used for the treatment of neoplasms of the lungs or other organs; and or

Antibiotics, in particular from the group of fluoroquinolonecarboxylic acids, such as by way of example and preferably ciprofloxacin or moxifloxacin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a beta-adrenergic receptor agonist such as, for example and preferably, albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, repro sterol, salbutamol or salmeterol.

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

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 preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone.

Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances.

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 by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole. 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.

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

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaraban, 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.

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

Among the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor Antagonists and diuretics understood.

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 by way of preference, nifedipine, amlodipine, verapamil or diltiazem. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, Carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucine dolol administered.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.

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 by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril. 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 by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.

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

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.

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 preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quineth- azon, acetazolamide, dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene. Among the lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR alpha- , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood. 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).

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) ,

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 preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

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.

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130. In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.

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

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.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat. In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.

In a preferred embodiment of the invention, the compounds of 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 e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

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.

Particularly preferred are combinations of the compounds according to the invention with one or more further active compounds selected from the group consisting of corticosteroids, beta-adrenergic receptor agonists, anti-muscarcinogenic substances, PDE 4 inhibitors, PDE 5 inhibitors, sGC activators, sGC Stimulants, HNE inhibitors, prostacyclin analogs, endothelin antagonists, statins, antifibrotic agents, antiinflammatory agents, immunomodulating agents, immunosuppressive agents and cytotoxic agents.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic, or as an implant or stent.

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

For oral administration are according to the prior art functioning, the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as tablets (uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control of the compound according to the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. Parenteral administration can be done bypassing a resorption step (eg intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or using absorption (for example by inhalation, intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). For parenteral administration, suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are suitable, for example Inhalation medicaments (including powder inhalers, nebulizers, metered dose aerosols), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (for example patches), milk, pastes, foams, scattering powders, implants or stents.

Preferred are oral, intrapulmonary (inhalative) and intravenous administration.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), Stabilizers (eg antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxides) and flavor and / or odoriferous.

In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 1 mg kg, preferably about 0.01 to 0.5 mg kg body weight, in order to achieve effective results. When administered orally, the dosage is about 0.01 to 100 mg kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg body weight. For intrapulmonary administration, the amount is generally about 0.1 to 50 mg per inhalation. Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The following embodiments illustrate the invention. The invention is not limited to the examples.

Examples

Abbreviations and acronyms: abs. absolutely

Ac acetyl

aq. aqueous, aqueous solution

br. wide (at NMR signal)

Example. Example

Bu Butyl

c concentration

about circa, about

cat. catalytic

CI chemical ionization (in MS)

d doublet (by NMR)

d day (s)

(dba) ₃ Pd ₂ tris (dibenzylideneacetone) dipalladium (0)

TLC thin layer chromatography

DCI direct chemical ionization (in MS)

dd doublet of doublet (by NMR)

DEAD Diethyl azodicarboxylate

DMF N, -dimethylamine

DMSO dimethyl sulfoxide

dt doublet of triplet (by NMR)

d. Th. Of theory (in chemical yield) ee enantiomeric excess

EI electron impact ionization (in MS)

ent enantiomerically pure, enantiomer

eq. Equivalent (s)

ESI electrospray ionization (in MS)

Et ethyl

h hour (s)

HPLC high pressure, high performance liquid chromatography

iPr isopropyl

concentrate concentrated (at solution)

LC liquid chromatography

LC / MS liquid chromatography-coupled mass spectrometry

Literature (position)

m multiplet (by NMR)

Me methyl

min minute (s)

MPLC medium pressure liquid chromatography (over silica gel; also "flash"

Called chromatography ")

Ms methanesulfonyl (mesyl)

MS mass spectrometry

NMO N-methylmorpholine N-oxide

NMR nuclear magnetic resonance spectrometry

Pd / C palladium on charcoal

Pr Propyl

q (or quart) quartet (by NMR)

qd Quartet by Dublett (by NMR)

quant. quantitative (at chemical yield)

quint quintet (by NMR)

rac racemic, racemate

Rf Retention Index (at DC)

RP reverse phase (reversed phase, for HPLC)

RT room temperature

R _t retention time (for HPLC, LC / MS)

s singlet (by NMR)

sept septet (by NMR)

SFC supercritical liquid chromatography t triplet (by NMR)

tBu teri-butyl

td triplet of doublet (by NMR)

TFA trifluoroacetic acid

THF tetrahydrofuran

UV ultraviolet spectrometry

v / v volume to volume ratio (of a solution)

Xantphos 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene

together

HPLC and LC / MS methods:

Method 1 (LC / MS):

Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ, 50 x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 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 2 (LC / MS):

Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 μ, 50 x 1 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 97% A-> 0.5 min 97% A-> 3.2 min 5% A -> 4.0 min 5% A; Oven: 50 ° C; Flow: 0.3 ml / min; UV detection: 210 nm.

Method 3 (LC / MS):

Instrument MS: Waters Micromass QM; Instrument HPLC: Agilent 1100 series; Column: Agilent ZORBAX Extend-C18 3.5 μ, 3.0 x 50 mm; Eluent A: 1 l of water + 0.01 mol of ammonium carbonate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 98% A -> 0.2 min 98% A -> 3.0 min 5% A -> 4.5 min 5% A; Oven: 40 ° C; Flow: 1.75 ml / min; UV detection: 210 nm.

Method 4 (preparative HPLC):

Column: Reprosil C18, 10 μm, 250 × 30 mm; Eluent: acetonitrile / water with 0.1% TFA; Gradient: 0-5.00 min 10:90, sample injection at 3.00 min; 5.00-23.00 min to 95: 5; 23.00-30.00 min 95: 5; 30.00-30.50 min to 10:90; 30.50-31.20 min 10:90. Method 5 (preparative HPLC):

Column: Reprosil C18, 10 μm, 250 × 30 mm; Eluent: acetonitrile / water with 0.1% TFA; Gradient: 0-5.00 min 10:90, sample injection at 3.00 min; 5.00-20.00 min to 95: 5; 20.00-30.00 min 95: 5; 30.00-30.50 min to 10:90; 30.50-31.20 min 10:90. Method 6 (preparative HPLC):

Column: Reprosil C18, 10 μm, 125 × 30 mm; Eluent: acetonitrile / water with 0.1% TFA; Gradient: 0-6.00 min 35:65, sample injection at 3.00 min; 6.00-27.00 min to 80:20; 27.00-30.00 min 95: 5; 30.00-33.00 min to 35:65.

Method 7 (preparative HPLC):

Column: Reprosil-Pur C18, 10 μιη; Eluent: water / methanol; Gradient: 70:30 -> 50:50 (to 6 min) -> 20:80 (to 22 min), to 75 min 20:80.

Method 8 (preparative HPLC):

Column: Reprosil-Pur C18, 10 μιη; Eluent: water / methanol; Gradient: 70:30 -> 50:50 (to 6 min) -> 20:80 (to 20 min), to 115 min 20:80. Method 9 (preparative HPLC):

Column: Reprosil-Pur C18, 10 μιη; Eluent: water / methanol; Gradient: 70:30 -> 50:50 (to 6 min) -> 20:80 (to 21 min), to 75 min 20:80.

Method 10 (preparative HPLC):

Column: Reprosil-Pur C18, 10 μιη; Eluent: water / methanol; Gradient: 70:30 -> 50:50 (to 6 min) -> 20:80 (to 25 min), to 75 min 20:80.

Method 11 (preparative HPLC):

Column: Reprosil-Pur C18, 10 μιη; Eluent: water / methanol; Gradient: 70:30 -> 50:50 (to 6 min) -> 20:80 (to 20 min), to 75 min 20:80.

More information:

The percentages in the following example and test descriptions are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume. Purity specifications usually refer to corresponding peak integrations in the LC / MS chromatogram, but may additionally have been determined with the help of the--NMR spectrum. If no purity is specified, it is usually a 100% purity according to automatic peak integration in the LC / MS chromatogram, or purity was not explicitly determined.

Data on yields in% d. Th. Are purity-corrected as a rule, provided that a purity of <100% is specified. For solvent-containing or contaminated batches, the yield may be formally "> 100%"; in these cases, the yield is not solvent or purity corrected. The following descriptions of the coupling patterns of ^ -NMR signals were partly taken directly from the suggestions of the ACD SpecManager (ACD / Labs Release 12.00, Product version 12.5) and not necessarily rigorously questioned. In part, the suggestions of the SpecManager were adapted manually. Manually customized descriptions are usually based on the visual appearance of the signals in question and do not necessarily correspond to a rigorous, physically correct interpretation. As a rule, the indication of the chemical shift refers to the center of the relevant signal. For wide multiplets, an interval is specified. Solvent or water concealed signals were either tentatively assigned or are not listed.

Melting points and melting ranges, where indicated, are not corrected. For all reactants or reagents, the preparation of which is not explicitly described below, it is true that they were obtained commercially from generally available sources. For all other reactants or reagents, the preparation of which is also not described below and which were not commercially available or obtained from sources that are not generally available, reference is made to the published literature describing their preparation ,

In the intermediates and exemplary embodiments described below, a designation "IRS, 2RS, 5SR" in the IUP AC name of the relevant example, in conjunction with the term "racemate", means that this is a racemic mixture of IR, 2R, 5S - Enantiomers (- each 1st letter after the position number in "IRS, 2RS, 5SR") with the appropriate lS, 2S, 5R-enantiomer (-> each 2nd letter after the position number) acts. The term "IRS, 2RS, 5SR" in connection with the statements "enantiomer 1" and "enantiomer 2" means that these are the two enantiomers in separated, isolated form, wherein an assignment of the absolute configuration (IR, 2R, 5S or IS, 2S, 5R) to these Enantiomers was not made. Similar terms such as "IRS, 2SR, 5RS", which result from the changed priority and / or order of parts of names due to the IUPAC nomenclature rules, shall be interpreted in an analogous manner according to this manual. In order to simplify the description of the relative stereochemical configuration of chiral centers, only the structural formula of one of the participating enantiomers is reproduced below in the structural formulas of racemic example compounds; As can be seen from the term "racemate" in the associated IUPAC name, in these cases the second enantiomer with the respectively opposite absolute configuration is always included.

Starting compounds and intermediates:

Example 1A

6- (trifluoromethyl) -l, 2,3-benzotriazin-4 (3 //) - one

To a suspension of 24.4 g (119.51 mmol) of 2-amino-5- (trifluoromethyl) benzamide in 174 ml of a 2: 1 mixture of water and conc. Hydrochloric acid at 0 ° C, a solution of 9.08 g (131.47 mmol) of sodium nitrite in 74 ml of water was added slowly, keeping the internal temperature below 5 ° C. After stirring for 30 minutes at a bath temperature of 0 ° C., 74 ml (0.74 mol) of 10 M sodium hydroxide solution were slowly added with further ice-bath cooling, the internal temperature rising to about 20 ° C. It first formed a solution from which then a suspension was formed, which was diluted for better stirrability with 100 ml of water. After stirring at RT for 1.5 h, the mixture was carefully poured with conc. Hydrochloric acid acidified (pH = 2). The precipitate formed was filtered off and washed three times with water. After drying in air and then in vacuo, 24.74 g (96% of theory) of the title compound were obtained. Ή NMR (400 MHz, DMSO-de): δ [ppm] = 15.31 (br.s, 1H), 8.46 (s, 1H), 8.40 (d, 2H).

LC / MS (Method 1, ESIpos): R _t = 0.78 min, m / z = 216 [M + H] Example 2A

6-Mefhyl-l, 2,3-benzotriazin-4 (3 //) - one

To a suspension of 32.0 g (213.08 mmol) of 2-amino-5-methylbenzamide in 300 ml of a 2: 1 mixture of water and conc. Hydrochloric acid at 0 ° C, a solution of 16.17 g (234.38 mmol) of sodium nitrite in 120 ml of water was added slowly, keeping the internal temperature below 5 ° C. After stirring for 30 minutes at 0 ° C. bath temperature, 120 ml (1.2 mol) of 10 M sodium hydroxide solution were slowly added with further cooling of the ice bath, during which the internal temperature rose to about 20 ° C. and the solid present went into solution. After stirring for 1 h at RT, the mixture was carefully poured with conc. Hydrochloric acid acidified (pH = 2). The precipitate formed was filtered off and washed three times with water. After drying in air and in vacuo, 33.80 g (98% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 14.85 (br.s, 1H), 8.08 (d, 1H), 8.02 (s, 1H), 7.90 (d, 1H). LC / MS (Method 3, ESIpos): R _t = 1.40 min, m / z = 162 [M + H] ⁺ . Example 3A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (benzyloxy) benzoyl] -5 - [(4-oxo-l, 2,3-benzotriazine - 3 (4 /) - yl) methyl] cyclopentanecarboxylate (racemate)

Step 1:

2- (trimethylsilyl) ethyl 2- [4- (benzyloxy) phenyl] -2-hydroxybicyclo [2.2.1] heptane-7-carboxylate

A solution of 24.30 g (95.52 mmol) of e o-2- (trimemylsilyl) ethyl 2-oxobicyclo [2.2.1] heptane-7-carboxylate [WO 96/15096, Example 360 / step 1] in 60 ml of THF was added at ca. .1 ° C internal temperature under argon slowly added to 114.62 ml (114.62 mmol) of a 1 M solution of 4- (benzyloxy) - phenylmagnesium bromide in THF, wherein the internal temperature rose to a maximum of 0 ° C. Subsequently, the cooling bath was removed and the mixture stirred for 1 h. The mixture was then treated with 200 ml of 5% citric acid solution and extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on 1 kg of silica gel (mobile phase cyclohexane / ethyl acetate 9: 1). There were obtained 28.70 g (66% of theory, purity 97%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.49-7.27 (m, 7H), 6.95 (d, 2H), 5.09 (s, 2H), 5.05 (s IH), 4.10-4.00 (m, 2H), 2.44-2.37 (m, IH), 2.33-2.24 (m, IH), 2.23-2.11 (m, IH), 1.78-1.60 (m IH), 1.52-1.26 (m, 4H), 0.95-0.80 (m, 2H), 0.00 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 3.15 min, m / z = 421 [M + HH ₂ 0] ⁺ .

2- (trimethylsilyl) ethyl 2- [4- (benzyloxy) phenyl] bicyclo [2.2.1] hept-2-ene-7-carboxylate

To a solution of 28.70 g (63.466 mmol) of the compound from Example 3A / step 1 in 150 ml of dichloromethane under argon was added at about 0 ° C, first 26.50 ml (190.40 mmol) of triethylamine and then slowly 9.82 ml (126.93 mmol) of methanesulfonyl chloride , wherein the internal temperature did not exceed 5 ° C. The mixture was then stirred at 0 ° C for 1.5 h. Thereafter, the mixture was diluted with dichloromethane and extracted with water. The organic phase was dried over magnesium sulfate and concentrated, and the residue was purified by flash chromatography on 1 kg of silica gel (mobile phase cyclohexane / ethyl acetate 95: 5). 20.06 g (75% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-de): δ [ppm] = 7.48-7.28 (m, 7H), 6.97 (d, 2H), 6.30 (d, 1H), 5.11 (s, 2H), 4.15-4.06 (m, 2H), 3.43 (brs s, 1H), 3.06 (brs s, 1H), 1.85-1.71 (m, 2H), 1.17-1.06 (m, 1H), 1.04-0.87 (m, 3H) , 0.04 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.61 min, m / z = 421 [M + H] ⁺ .

Step 3:

2- (trimethylsilyl) ethyl 2- [4- (benzyloxy) phenyl] -2,3-dihydroxybicyclo [2.2.1] heptane-7-carboxylate

To a degassed solution of 25.37 g (60.314 mmol, not purity-corrected) of the compound from Example 3A / step 2 in 150 ml of THF under argon at 0 ° C was a degassed solution of 15.90 g (135.71 mmol) / V-Methylmorpholin- / V oxide (NMO) in 42 ml of water under argon. 116 ml (9.05 mmol) of a 2.5% solution of osmium tetroxide in tert. Given -butanol. The mixture was then stirred at 0 ° C for 1 h. After a further 16 h stirring at RT, the mixture was diluted with 150 ml of ethyl acetate and extracted twice with 250 ml of 10% citric acid solution, twice with 300 ml of saturated sodium bicarbonate solution and twice with 300 ml of saturated sodium chloride solution. The organic phase was then dried over sodium sulfate and concentrated. There were obtained 27.51 g (75% of theory, purity 75%) of the title compound. LC / MS (Method 1, ESIpos): R _t = 1.40 min, m / z = 437 [M + HH ₂ O] ⁺ . Step 4:

2- (trimethylsilyl) ethyl (1RS, 2RS, 5SR) -2- [4- (benzyloxy) benzoyl] -5-formylcyclopentanecarboxylate

(Racemate)

Method A:

To a solution of 27.42 g (60.31 mmol, not purity-corrected) of the compound from Example 3A / step 3 in 170 ml of methanol under argon was added slowly at -15 ° C bath temperature 30.96 g (66.34 mmol, purity 95%) of lead tetraacetate. The mixture was stirred at -15 ° C for 1 h. After warming to RT, the mixture was filtered through Celite and the filtration residue washed three times with 50 ml of methanol. The filtrate was concentrated and the residue was taken up in 500 ml of dichloromethane and 500 ml of water, without any phase separation. The mixture was then filtered through silica gel and the silica gel washed with dichloromethane. After phase separation, the aqueous phase was extracted once more with 150 ml of dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated. There were obtained 27.1 g (86% of theory, purity 87%) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 9.72 (d, 1H), 8.02 (d, 2H), 7.53-7.34 (m, 5H), 7.18 (d, 2H), 5.25 ( s, 2H), 4.17 (q, 1H), 4.09 (dd, 2H), 3.74 (t, 1H), 3.23-3.14 (m, 1H), 2.24-2.13 (m, 1H), 2.08-1.88 (m, 2H), 1.61-1.49 (m, 1H), 0.87-0.79 (m, 2H), 0.00 (s, 9H). LC / MS (Method 1, ESIpos): R _t = 1.45 min, m / z = 425 [M + H-28]

Method B:

To a solution of 69.0 g (131 mmol, about 80% purity) of the compound from Example 3A / step 2 in a mixture of acetone / water / THF (3: 1: 1) were added at 0 ° C under argon first Add 76.87 g (656 mmol) of N-methylmorpholine N-oxide (NMO) and then 2.09 g (8.20 mmol) of a 4% solution of osmium tetroxide in water. The mixture was stirred at RT for 3 days. Subsequently, 105.26 g (492 mmol) of sodium periodate were added and the mixture was further stirred overnight at RT. After addition of ethyl acetate and 10% aqueous citric acid, the aqueous phase was separated and extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium bicarbonate solution and then stirred with magnesium silicate (Fluorisil). After filtration, the filter residue was washed with ethyl acetate. After concentration of the filtrate, the residue thus obtained was combined with the residues from two similar preliminary experiments [amounts used of the compound from Example 3A / step 2: 3.0 g (7.13 mmol) or 3.2 g (7.61 mmol)] and mixed together by flash chromatography. Purified by chromatography (silica gel, eluent petroleum ether / ethyl acetate 8: 2). This gave 53 g (58% of theory, taking into account preliminary tests, purity 89%) of the title compound.

Step 5:

2- (trimethylsilyl) ethyl (1RS, 2RS, 5SR) -2- [4- (benzyloxy) benzoyl] -5- (hydroxyethyl) cyclopentane carboxylate (racemate)

To a solution of 27.0 g (59.65 mmol, not purity-corrected) of the compound from Example 3A / step 4 in 135 ml of ethanol was added slowly at RT 677 mg (17.895 mmol) of sodium borohydride and the mixture was stirred at RT for 30 min. The mixture was then mixed with 400 ml of ammonium chloride solution and water and extracted twice with 300 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. This gave 21.90 g (70% of theory, purity 87%) of the title compound. Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.95 (d, 2H), 7.48-7.31 (m, 5H), 7.12 (d, 2H), 5.20 (s, 2H), 4.64 ( t, 1H), 4.07-3.98 (m, 3H), 3.53-3.45 (m, 1H), 3.40-3.34 (m, 1H), 2.94 (t, 1H), 2.34-2.23 (m, 1H), 2.12- 2.01 (m, 1H), 1.90-1.78 (m, 1H), 1.67-1.47 (m, 2H), 0.82-0.75 (m, 2H), 0.00 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.34 min, m / z = 455 [M + H] ⁺ . Step 6:

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (benzyloxy) benzoyl] -5 - [(4-oxo-l, 2,3-benzotriazine - 3 (4 //) - yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 500 mg (1.10 mmol, not purity corrected) of the compound of Example 3A / Step 5 in 6 mL of THF under argon was added 243 mg (1.65 mmol) of l, 2,3-benzotriazine-4 (3 /) -one and Add 1.11 g (5.50 mmol) of tributylphosphine. Subsequently, 1.50 ml (3.30 mmol) of a 40% solution of diethyl azodicarboxylate (DEAD) in toluene were added dropwise at 0 ° C. The mixture was stirred at RT for about 1 h, then diluted with ethyl acetate and extracted twice with 5 ml each of water and twice with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC (Method 6). There were obtained 334 mg (52% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.44 (dd, 1H), 8.38 (d, 1H), 8.27 (td, 1H), 8.15-8.08 (m, 3H), 7.65- 7.48 (m, 5H), 7.29 (d, 2H), 5.37 (s, 2H), 4.74-4.62 (m, 2H), 4.26 (q, 1H), 3.40 (t, 1H), 3.13-3.01 (m, 1H), 2.36-2.25 (m, 1H), 2.21-2.10 (m, 1H), 1.96-1.84 (m, 1H), 1.77-1.65 (m, 1H), 0.53-0.46 (m, 2H), 0.17 ( s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.51 min, m / z = 584 [M + H] ⁺ . Example 4A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- (4-hydroxybenzoyl) -5 - [(4-oxo-l, 2,3-benzotriazin-3 ( 4 /) - yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 270 mg (0.46 mmol) of the compound of Example 3A in 12 mL of ethyl acetate under argon was added 25 mg (0.024 mmol) of palladium on charcoal (10% Pd). The mixture was then hydrogenated under normal pressure for 42 h. The mixture was then filtered through kieselguhr, the filter residue washed with ethyl acetate and the filtrate was concentrated. The residue thus obtained was taken up in a little dichloromethane and purified by column chromatography (25 g of silica gel, mobile phase cyclohexane / ethyl acetate 7: 3). 165 mg (72% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.37 (d, 1H), 8.16 (d, 1H), 7.98-7.88 (m, 3H), 7.84-7.77 (m, 1H), 6.89 ( d, 2H), 6.67 (br s, 1H), 4.77-4.70 (m, 1H), 4.68-4.60 (m, 1H), 4.20-4.10 (m, 1H), 3.88-3.81 (m, 2H), 3.46 (t, 1H), 3.08-2.94 (m, 1H), 2.19-2.04 (m, 1H), 2.01-1.86 (m, 2H), 1.72- 1.64 (m, partially occluded, 1H), 0.63-0.55 ( m, 2H), -0.09 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.23 min, m / z = 494 [M + H] ⁺ .

Example 5A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(4-fluorobenzyl) oxy] benzoyl} -5 - [(4-oxo-l, 2,3-benzotriazine-3 (4 /) -yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 80 mg (0.16 mmol) of the compound from Example 4A in 1.8 ml of acetonitrile was added 45 mg (0.32 mmol) of potassium carbonate and 38 mg (0.19 mmol, purity 97%) of 4-fluorobenzyl bromide. The mixture was then stirred at reflux overnight. After cooling to RT, the mixture was diluted with water and extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC (Method 7). 50 mg (52% of theory, purity 100%) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 1.50 min, m / z = 602 [M + H] ⁺ . Example 6A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(3-chlorobenzyl) oxy] benzoyl} -5 - [(4-oxo-l, 2,3-benzotriazine-3 (4 /) -yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 80 mg (0.16 mmol) of the compound from Example 4A in 1.8 ml of acetonitrile were added 45 mg (0.32 mmol) of potassium carbonate and 41 mg (0.19 mmol, purity 97%) of 4-chlorobenzyl given bromide. The mixture was then stirred at reflux overnight. After cooling to RT, the mixture was diluted with water and extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC (Method 8). 55 mg (55% of theory, purity 100%) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 1.55 min, m / z = 618 [M + H] ⁺ .

Example 7A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(3,4-dichlorobenzyl) oxy] benzoyl} -5 - [(4-oxo- l, 2,3-benzotriazine-3 (4 //) - yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 80 mg (0.16 mmol) of the compound from Example 4A in 1.8 ml of acetonitrile were added 45 mg (0.32 mmol) of potassium carbonate and 48 mg (0.19 mmol, purity 98%) of 4- (bromomethyl) -1, 2- given dichlorobenzene. The mixture was then stirred at reflux overnight. After cooling to RT, the mixture was diluted with water and extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC (Method 9). 59 mg (55% of theory, purity 100%) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 1.59 min, m / z = 652 [M + H] ⁺ .

Example 8A 2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (cyclopentylmethoxy) benzoyl] -5 - [(4-oxo-l, 2,3 benzo-triazine-3 (4 /) -yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 80 mg (0.16 mmol) of the compound from Example 4A in 1.8 ml of acetonitrile was added 45 mg (0.32 mmol) of potassium carbonate and 32 mg (0.19 mmol) of (bromomethyl) cyclopentane and the mixture was stirred at reflux overnight. Thereafter, another 32 mg (0.19 mmol) of (bromomethyl) cyclopentane was added, and the mixture was stirred for a further 4 hours under reflux. After cooling to RT, the mixture was diluted with water and extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC (Method 7). 33 mg (36% of theory, purity 100%) of the title compound were obtained. LC / MS (Method 1, ESIpos): R _t = 1.61 min, m / z = 576 [M + H] ⁺ .

Example 9A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (2-cyclohexylethoxy) benzoyl] -5 - [(4-oxo-l, 2,3 benzo-triazine-3 (4 /) -yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 80 mg (0.16 mmol) of the compound from Example 4A in 1.8 ml of acetonitrile were added 45 mg (0.32 mmol) of potassium carbonate and 38 mg (0.19 mmol, purity 98%) of (2-bromoethyl) cyclohexane and the mixture was Stirred overnight under reflux. After cooling to RT The mixture was diluted with water and extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC (Method 7). 39 mg (39% of theory, purity 98%) of the title compound were obtained. LC / MS (Method 1, ESIpos): R _t = 1.68 min, m / z = 604 [M + H] ⁺ .

Example 10A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (hexyloxy) benzoyl] -5 - [(4-oxo-l, 2,3-benzotriazine - 3 (4 /) - yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 80 mg (0.16 mmol) of the compound from Example 4A in 1.8 ml of acetonitrile was added 45 mg (0.32 mmol) of potassium carbonate and 33 mg (0.19 mmol, purity 98%) of 1-bromohexane and the mixture was stirred at reflux overnight , After cooling to RT, the mixture was diluted with water and extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC (Method 9). 41 mg (44% of theory, purity 100%) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 1.62 min, m / z = 578 [M + H] ⁺ . Example IIA

2- (trimethylsilyl) ethyl (IR 5,25R, 5R 5) -2 - [(4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) -methyl] -5- [4- (pentyloxy) benzoyl ] cyclopentanecarboxylate (racemate)

To a solution of 80 mg (0.16 mmol) of the compound from Example 4A in 1.8 ml of acetonitrile was added 45 mg (0.32 mmol) of potassium carbonate and 30 mg (0.19 mmol, purity 99%) of 1-bromopentane and the mixture was stirred at reflux overnight , After cooling to RT, the mixture was diluted with water and extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC (Method 10). 30 mg (33% of theory, purity 99%) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 1.59 min, m / z = 564 [M + H] ⁺ . Example 12A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- (4-butoxybenzoyl) -5 - [(4-oxo-l, 2,3-benzotriazin-3 ( 4 /) - yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 80 mg (0.16 mmol) of the compound from Example 4A in 1.8 ml of acetonitrile was added 45 mg (0.32 mmol) of potassium carbonate and 27 mg (0.19 mmol) of 1-bromobutane and the mixture was stirred at reflux overnight. After cooling to RT, the mixture was diluted with water and extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC (Method 11). There were obtained 33 mg (37% of theory, purity 100%) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 1.53 min, m / z = 550 [M + H] ⁺ . Example 13A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, 5 _l ^S, R) -2- [4- (benzyloxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) - l , 2,3-Benzotriazine-3 (4 //) - yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 13.88 g (30.53 mmol, not purity corrected) of the compound of Example 3A / Step 5 in 200 mL of toluene under argon was added 7.88 g (36.64 mmol) of the compound from Example 1A and 9.88 g (48.85 mmol) of tributylphosphine. Subsequently, 13.90 ml (30.53 mmol) of a 40% solution of diethyl azodicarboxylate in toluene were added dropwise at 0 ° C. The mixture was stirred at RT for 1 day and then concentrated. The residue was purified by flash chromatography (1 kg silica gel, mobile phase cyclohexane / ethyl acetate 9: 1). 9.06 g (44% of theory, purity 98%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.47-8.43 (m, 2H), 7.95 (d, 2H), 7.48-7.30 (m, 5H), 7.12 (d, 2H), 5.20 (s, 2H), 4.60-4.50 (m, 2H), 4.10 (q, 1H), 3.65-3.49 (m, 2H), 3.25 (t, 1H), 2.96-2.83 ( m, 1H), 2.19-2.07 (m, 1H), 2.07-1.95 (m, 1H), 1.80-1.68 (m, 1H), 1.63-1.50 (m, 1H), 0.39-0.22 (m, 2H), -0.18 (s, 9H). LC / MS (Method 1, ESIpos): R _t = 1.57 min, m / z = 652 [M + H] ⁺ . Example 14A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, 5 _l ^S, R) -2- (4-hydroxybenzoyl) -5- {[4-oxo-6- (trifluoromethyl) -l, 2, 3-benzotriazine-3 (4 //) - yl] methyl} cyclopentanecarboxylate (racemate)

1.05 g (16.66 mmol) of ammonium formate and 369 mg (0.35 mmol) of palladium on activated carbon (10 % Pd). Subsequently, the mixture was stirred at 75 ° C for 1 h. Thereafter, a further 105 mg (1.67 mmol) of ammonium formate were added and the mixture was stirred for a further 30 min at 75.degree. After cooling to RT, the mixture was filtered through kieselguhr, the filter residue washed with ethyl acetate and ethanol and the filtrate was concentrated. There were obtained 7.86 g (100% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 10.40 (br.s, 1H), 8.52 (s, 1H), 8.47-8.42 (m, 2H), 7.85 (d, 2H), 6.84 (d, 2H), 4.60-4.51 (m, 2H), 4.05 (q, 1H), 3.64-3.48 (m, 2H), 3.23 (t, 1H), 2.96-2.82 (m, 1H), 2.17- 2.05 (m, 1H), 2.05-1.94 (m, 1H), 1.79-1.67 (m, 1H), 1.62-1.49 (m, 1H), 0.38-0.22 (m, 2H), -0.18 (s, 9H) ,

LC / MS (Method 1, ESIpos): R _t = 1.31 min, m / z = 562 [M + H] ⁺ .

Example 15A

2- (trimethylsilyl) ethyl (IR 5,2R ₁ S ^, 5S ^, R) -2- {4 - [(4-fluorobenzyl) oxy] benzoyl} -5- {[4-oxo-6- (trifluoro-) methyl) -l, 2,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 3 ml of DMF under argon was added 72 mg (0.64 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 93 mg (0.64 mmol) of 4-fluorobenzyl chloride were added and the mixture was stirred at 100 ° C. bath temperature for 1.5 h. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 60 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by column chromatography (25 g silica gel, eluent cyclohexane / ethyl acetate 85:15). 192 mg (54% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, IH), 8.45 (s, 2H), 7.96 (d, 2H), 7.54-7.48 (m, 2H), 7.27- 7.19 (m, 2H), 7.12 (d, 2H), 5.18 (s, 2H), 4.58-4.53 (m, 2H), 4.10 (q, IH), 3.64-3.49 (m, 2H), 3.25 (t, IH), 2.94-2.86 (m, IH), 2.18-2.07 (m, IH), 2.06-1.97 (m, IH), 1.79-1.68 (m, IH), 1.63-1.50 (m, IH), 0.38- 0.23 (m, 2H), -0.18 (s, 9H). LC / MS (Method 1, ESIpos): R _t = 1.56 min, m / z = 670 [M + H] ⁺ .

Example 16A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(3-methylbenzyl) oxy] benzoyl} -5- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 3 ml of DMF under argon was added 72 mg (0.64 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 118 mg (0.64 mmol) of 3-methylbenzyl bromide were added and the mixture was stirred for 10 min at 100 ° C. bath temperature. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (40 g silica gel, eluent cyclohexane / ethyl acetate 9: 1). 187 mg (53% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.95 (d, 2H), 7.26 (t, 3H), 7.18-7.08 ( m, 3H), 5.16 (s, 2H), 4.59-4.52 (m, 2H), 4.10 (q, 1H), 3.65-3.50 (m, 2H), 3.25 (t, 1H), 2.94-2.86 (m, 1H), 2.32 (s, 3H), 2.18-2.07 (m, 1H), 2.06-1.95 (m, 1H), 1.79-1.68 (m, 1H), 1.62-1.50 (m, 1H), 0.38-0.23 ( m, 2H), -0.18 (s, 9H). LC / MS (Method 1, ESIpos): R _t = 1.60 min, m / z = 666 [M + H] ⁺ .

Example 17A

2- (trimethylsilyl) ethyl (IRS, 2SR ^^

methyl} -5- (4- {[3- (trifluoromethyl) benzyl] oxy} benzoyl) cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 3 ml of DMF under argon was added 72 mg (0.64 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 153 mg (0.64 mmol) of 3- (trifluoromethyl) benzylbromide were added and the mixture was stirred for 10 min at 100 ° C. bath temperature. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (40 g silica gel, eluent cyclohexane / ethyl acetate 9: 1). 184 mg of the title compound were obtained (48% of theory, still containing solvent and slightly contaminated according to Ή-NMR).

Ή NMR (400 MHz, DMSO-de): δ [ppm] = 8.52 (s, IH), 8.45 (s, 2H), 7.97 (d, 2H), 7.83 (s, IH), 7.78 (d, IH ), 7.74-7.70 (m, IH), 7.68-7.62 (m, IH), 7.15 (d, 2H), 5.32 (s, 2H), 4.59-4.52 (m, 2H), 4.14-4.07 (m, IH ), 3.64-3.50 (m, 2H), 3.24 (t, IH), 2.95-2.86 (m, IH), 2.18-2.07 (m, IH), 2.06-1.96 (m, IH), 1.79-1.68 (m , IH), 1.68-1.60 (m, IH), 0.36-0.25 (m, 2H), -0.19 (s, 9H).

LC / MS (Method 2, ESIpos): R _t = 3.45 min, m / z = 720 [M + H] ⁺ .

Example 18A

2- (trimethylsilyl) ethyl (S lR5,2R _^l, ^5.S, R) -2- {4 - [(3-chlorobenzyl) oxy] benzoyl} -5- {[4-oxo-6- (trifluoro methyl) -l, 2,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 250 mg (0.45 mmol) of the compound from Example 14A in 2.5 ml of DMF under argon, 60 mg (0.53 mmol) of potassium feri.-butoxide were added. After stirring at RT for 5 min, 110 mg (0.53 mmol) of 3-chlorobenzyl bromide were added, and the mixture was stirred at 100 ° C. bath temperature for 15 min. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by column chromatography (25 g of silica gel, mobile phase cyclohexane / ethyl acetate 9: 1). There was obtained 113 mg of the title compound (37% of theory, still containing solvent and slightly contaminated with α-NMR).

Ή NMR (400 MHz, DMSO-de): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.96 (d, 2H), 7.55-7.52 (m, 1H), 7.45-7.40 (m, 3H), 7.13 (d, 2H), 5.23 (s, 2H), 4.59-4.53 (m, 2H), 4.14-4.06 (m, 1H), 3.63-3.51 (m, 2H), 3.28-3.21 (m, 1H), 2.95-2.86 (m, 1H), 2.18-2.07 (m, 1H), 2.07-1.95 (m, 1H), 1.78-1.69 (m, 1H), 1.69-1.60 (m, 1H) , 0.36-0.25 (m, 2H), -0.18 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.58 min, m / z = 686 [M + H] ⁺ .

Example 19A

2- (trimethylsilyl) ethyl (IRR ₁ S ^, 2R ₁ S ^, 5S ^, R) -2- {4 - [(4-chlorobenzyl) oxy] benzoyl} -5- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 3 ml of DMF under argon was added 72 mg (0.64 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 153 mg (0.64 mmol) of 4-chlorobenzyl bromide were added, and the mixture was stirred at 100 ° C. bath temperature for 1.5 h. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with 80 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (25 g silica gel, eluent cyclohexane / ethyl acetate 85:15). 112 mg (31% of theory, purity 100%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.96 (d, 2H), 7.51-7.44 (m, 4H), 7.12 ( d, 2H), 5.21 (s, 2H), 4.59-4.52 (m, 2H), 4.10 (q, 1H), 3.63-3.50 (m, 2H), 3.25 (t, 1H), 2.96-2.85 (m, 1H), 2.18-2.07 (m, 1H), 2.06-1.95 (m, 1H), 1.79-1.68 (m, 1H), 1.62-1.51 (m, 1H), 0.36-0.25 (m, 2H), -0.18 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.60 min, m / z = 686 [M + H] ⁺ .

Example 20A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(3,4-dichlorobenzyl) oxy] benzoyl} -5- {[4-oxo- 6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 3 ml of DMF under argon was added 72 mg (0.64 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 154 mg (0.64 mmol) of 3,4-dichlorobenzyl bromide were added, and the mixture was stirred at 100 ° C. bath temperature for 15 min. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with 80 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by column chromatography (25 g silica gel, eluent cyclohexane / ethyl acetate 85:15). There were obtained 222 mg (49% of theory, purity 85%) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.96 (d, 2H), 7.74 (d, 1H), 7.67 (d, 1H), 7.46 (dd, 1H), 7.13 (d, 2H), 5.23 (s, 2H), 4.59-4.53 (m, 2H), 4.10 (q, 1H), 3.64-3.50 (m, 2H), 3.25 (t, 1H), 2.96-2.85 (m, 1H), 2.18-2.07 (m, 1H), 2.07-1.95 (m, 1H), 1.79-1.68 (m, 1H), 1.64-1.50 (m, 1H) , 0.38-0.23 (m, 2H), -0.19 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.64 min, m / z = 720 [M + H] ⁺ .

Example 21A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4 - ({3 - [(methoxycarbonyl) amino] benzyl} oxy) benzoyl] -5- {[ 4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 3 ml of DMF under argon was added 72 mg (0.64 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 156 mg (0.64 mmol) of methyl [3- (bromomethyl) phenyl] carbamate were added and the mixture was stirred for 10 min at 100 ° C. bath temperature. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by column chromatography (25 g silica gel, mobile phase cyclohexane / ethyl acetate 7: 3). 189 mg (43% of theory, purity 87%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 9.70 (s, 1H), 8.52 (s, 1H), 8.45 (s, 2H), 7.95 (d, 2H), 7.57 (s, 1H), 7.41 (d, 1H), 7.29 (t, 1H), 7.13-7.04 (m, 3H), 5.16 (s, 2H), 4.59-4.52 (m, 2H), 4.14- 4.06 (m, 1H) , 3.65 (s, 3H), 3.62-3.52 (m, 2H), 3.25 (t, 1H), 2.95-2.85 (m, 1H), 2.17-2.06 (m, 1H), 2.05-1.94 (m, 1H) , 1.79-1.67 (m, 1H), 1.62-1.51 (m, 1H), 0.37-0.25 (m, 2H), -0.18 (s, 9H). LC / MS (Method 1, ESIpos): R _t = 1.48 min, m / z = 725 [M + H] ⁺ .

Example 22A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- (4- {[3- (2-oxo-l, 3-oxazolidin-3-yl) benzyl] oxy} benzoyl) - 5- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 3 ml of DMF under argon was added 72 mg (0.64 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 164 mg (0.64 mmol) of 3- [3- (bromomethyl) phenyl] -1,3-oxazolidin-2-one were added, and the mixture was stirred for 20 min at 100 ° C. bath temperature. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with 80 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (40 g silica gel, eluent cyclohexane / ethyl acetate 6: 4). 156 mg (39% of theory, purity 97%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.96 (d, 2H), 7.70 (s, 1H), 7.52 (dd, 1H ), 7.41 (t, 1H), 7.22 (d, 1H), 7.12 (d, 2H), 5.22 (s, 2H), 4.61-4.52 (m, 2H), 4.47-4.39 (m, 2H), 4.16- 4.01 (m, 3H), 3.66-3.49 (m, 2H), 3.25 (t, 1H), 2.99-2.82 (m, 1H), 2.19-2.07 (m, 1H), 2.06-1.94 (m, 1H), 1.80-1.68 (m, 1H), 1.62-1.50 (m, 1H), 0.39-0.22 (m, 2H), -0.18 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.41 min, m / z = 737 [M + H] ⁺ .

Example 23A

2- (trimethylsilyl) ethyl (IRS, 2SR ^^

methyl} -5- [4- (2-phenylethoxy) benzoyl] cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 3 ml of DMF under argon was added 72 mg (0.64 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 177 mg (0.64 mmol) of 2-phenylethyl 4-methylbenzenesulfonate were added, and the mixture was stirred at 100 ° C. bath temperature for 1.5 h. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with 80 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (25 g silica gel, eluent cyclohexane / ethyl acetate 9: 1). 240 mg (65% of theory, purity 96%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, IH), 8.45 (s, 2H), 7.93 (d, 2H), 7.35-7.27 (m, 4H), 7.26- 7.16 (m, IH), 7.04 (d, 2H), 4.59-4.50 (m, 2H), 4.28 (t, 2H), 4.09 (q, IH), 3.65-3.47 (m, 2H), 3.24 (t, IH), 3.05 (t, 2H), 2.97-2.83 (m, IH), 2.18-2.06 (m, IH), 2.06-1.94 (m, IH), 1.79-1.68 (m, IH), 1.61-1.50 ( m, IH), 0.38-0.21 (m, 2H), -0.19 (s, 9H).

LC / MS (Method 2, ESIpos): R _t = 3.43 min, m / z = 666 [M + H] ⁺ .

Example 24A

2- (trimethylsilyl) ethyl (IRS, 2SR ^^

methyl} -5- [4- (3-phenylpropoxy) benzoyl] cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 3 ml of DMF under argon was added 72 mg (0.64 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 319 mg (1.60 mmol) of (3-bromopropyl) benzene were added and the mixture was stirred for 2 h at 100 ° C. bath temperature. After cooling to RT, 30 ml of water and 30 ml of ethyl acetate were added to the mixture. After separation of the phases, the aqueous phase was extracted twice with 30 ml of ethyl acetate each time. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (40 g silica gel, eluent cyclohexane / ethyl acetate 9: 1). 37 mg (10% of theory, purity 98%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.94 (d, 2H), 7.32-7.14 (m, 5H), 7.03 ( d, 2H), 4.59-4.52 (m, 2H), 4.05 (t, 3H), 3.65-3.49 (m, 2H), 3.24 (t, 1H), 2.97-2.85 (m, 1H), 2.74 (t, 2H), 2.18-1.95 (m, 4H), 1.80-1.69 (m, 1H), 1.63-1.51 (m, 1H), 0.38-0.21 (m, 2H), -0.19 (s, 9H). LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 580 [M + H] ⁺ .

Example 25A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (cyclohexylmethoxy) benzoyl] -5- {[4-oxo-6- (trifluoro methyl) -l, 2,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 250 mg (0.45 mmol) of the compound from Example 14A in 4.5 ml of DMF under argon was added 60 mg (0.53 mmol) of potassium ferric acid-butylate. After stirring at RT for 5 min, 95 mg (0.53 mmol) (bromomethyl) cyclohexane were added, and the mixture was stirred for 1 h at a bath temperature of 100.degree. Thereafter, a further 95 mg (0.53 mmol) of (bromomethyl) cyclohexane were added, and the mixture was again stirred for 90 minutes at 100 ° C. bath temperature. After cooling to RT, 60 ml of water and 60 ml of ferric butyl methyl ether were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ferric butyl methyl ether and twice with 50 ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by column chromatography (25 g silica gel, mobile phase cyclohexane / ethyl acetate 9: 1). 174 mg (59% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.92 (d, 2H), 7.02 (d, 2H), 4.61-4.50 ( m, 2H), 4.09 (q, 1H), 3.87 (d, 2H), 3.64-3.47 (m, 2H), 3.22 (t, 1H), 2.97-2.84 (m, 1H), 2.18-1.96 (m, 2H), 1.85-1.61 (m, 8H), 1.33-1.13 (m, 3H), 1.11-0.95 (m, 2H), 0.35-0.23 (m, 2H), -0.19 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.71 min, m / z = 558 [M + H] ⁺ .

Example 26A 2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (cyclopentylmethoxy) benzoyl] -5- {[4-oxo-6- (trifluoro methyl) -l, 2,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound of Example 14A in 6 mL of acetonitrile under argon was added 180 mg (1.60 mmol) of potassium carbonate and 261 mg (1.60 mmol) of cyclopentylmethylbromide and the mixture was stirred at reflux for 6 h , Subsequently, an additional 261 mg (1.60 mmol) of cyclopentylmethylbromide were added and the mixture was further stirred at RT overnight. Thereafter, 30 ml of water and 30 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (25 g silica gel, eluent cyclohexane / ethyl acetate 9: 1). 217 mg (62% of theory, purity 98%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.93 (d, 2H), 7.03 (d, 2H), 4.60-4.50 ( m, 2H), 4.09 (q, 1H), 3.93 (d, 2H), 3.63-3.48 (m, 2H), 3.22 (t, 1H), 2.97-2.84 (m, 1H), 2.38-2.24 (m, 1H), 2.19-1.95 (m, 2H), 1.82-1.69 (m, 3H), 1.67-1.47 (m, 5H), 1.38-1.26 (m, 2H), 0.37-0.21 (m, 2H), -0.18 (s, 9H).

LC / MS (Method 2, ESIpos): R _t = 3.57 min, m / z = 644 [M + H] ⁺ .

Example 27A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (cyclobutylmethoxy) benzoyl] -5- {[4-oxo-6- (trifluoro methyl) -l, 2,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 3 ml of DMF under argon was added 72 mg (0.64 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 96 mg (0.64 mmol) (bromomethyl) cyclobutane were added, and the mixture was stirred at 100 ° C. bath temperature for 1.5 h. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with 80 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (25 g silica gel, eluent cyclohexane / ethyl acetate 9: 1). There were obtained 147 mg (41% of theory, purity 95%) of the title compound.

Ή NMR (400 MHz, DMSO-de): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.93 (d, 2H), 7.03 (d, 2H), 4.61-4.49 (m , 2H), 4.10 (q, 1H), 4.04 (d, 2H), 3.64-3.46 (m, 2H), 3.23 (t, 1H), 2.96-2.85 (m, 1H), 2.79-2.65 (m, 1H ), 2.19-1.97 (m, 4H), 1.96-1.68 (m, 5H), 1.63-1.49 (m, 1H), 0.38-0.22 (m, 2H), -0.18 (s, 9H).

LC / MS (Method 2, ESIpos): R _t = 3.50 min, m / z = 630 [M + H] ⁺ .

Example 28A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (cyclopropylmethoxy) benzoyl] -5- {[4-oxo-6- (trifluoro methyl) -l, 2,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 3 ml of DMF under argon was added 72 mg (0.64 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 117 mg (0.64 mmol) of (iodomethyl) cyclopropane were added and the mixture was stirred for 1 h at a bath temperature of 100.degree. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with 80 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (40 g silica gel, eluent cyclohexane / ethyl acetate 85:15). 150 mg (46% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.93 (d, 2H), 7.02 (d, 2H), 4.61-4.49 ( m, 2H), 4.09 (q, 1H), 3.91 (d, 2H), 3.66-3.47 (m, 2H), 3.23 (t, 1H), 2.97-2.83 (m, 1H), 2.19-2.07 (m, 1H), 2.06-1.96 (m, 1H), 1.80-1.68 (m, 1H), 1.62-1.49 (m, 1H), 1.29-1.18 (m, 1H), 0.62-0.54 (m, 2H), 0.37- 0.24 (m, 4H), -0.19 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.50 min, m / z = 616 [M + H] ⁺ .

Example 29A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (2-cyclohexylethoxy) benzoyl] -5- {[4-oxo-6- (trifluoro methyl) -l, 2,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 293 mg (0.36 mmol, purity 70%) of the compound from Example 14A in 2 ml of DMF under argon was added 49 mg (0.43 mmol) of potassium ieri. given butylate. After stirring at RT for 5 min, 83 mg (0.44 mmol) of (2-bromoethyl) cyclohexane were added and the mixture was stirred for 2 h at a bath temperature of 100.degree. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with 80 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by column chromatography (25 g silica gel, eluent cyclohexane / ethyl acetate 9: 1). 124 mg (51% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.93 (d, 2H), 7.03 (d, 2H), 4.64-4.48 ( m, 2H), 4.14-3.98 (m, 3H), 3.65-3.45 (m, 2H), 3.22 (t, 1H), 2.97-2.84 (m, 1H), 2.18- 2.06 (m, 1H), 2.05- 1.94 (m, 1H), 1.83-1.52 (m, 8H), 1.50-1.38 (m, 1H), 1.30-1.08 (m, 4H), 1.02-0.87 (m, 2H), 0.36-0.20 (m, 2H ), -0.19 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.74 min, m / z = 672 [M + H] ⁺ .

Example 30A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (2-cyclopentylethoxy) benzoyl] -5- {[4-oxo-6- (trifluoro methyl) -l, 2,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 293 mg (0.36 mmol, purity 70%) of the compound from Example 14A in 2 ml of DMF under argon was added 49 mg (0.43 mmol) of potassium ieri. given butylate. After stirring at RT for 5 min, 98 mg (0.44 mmol) of (2-iodoethyl) cyclopentane were added and the mixture was stirred for 2 h at a bath temperature of 100.degree. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with 80 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by column chromatography (25 g silica gel, eluent cyclohexane / ethyl acetate 9: 1). 119 mg (50% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.93 (d, 2H), 7.03 (d, 2H), 4.63-4.47 ( m, 2H), 4.15-4.02 (m, 3H), 3.65-3.47 (m, 2H), 3.22 (t, 1H), 2.97-2.84 (m, 1H), 2.17- 2.07 (m, 1H), 2.06- 1.86 (m, 2H), 1.83-1.70 (m, 5H), 1.64-1.43 (m, 5H), 1.20-1.07 (m, 2H), 0.35-0.24 (m, 2H), -0.18 (s, 9H) ,

LC / MS (Method 1, ESIpos): R _t = 1.69 min, m / z = 658 [M + H] ⁺ .

Example 31A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (3-cyclohexylpropoxy) benzoyl] -5- {[4-oxo-6- (trifluoro methyl) -l, 2,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 2 ml of DMF under argon was added 180 mg (1.60 mmol) of potassium ieri-butoxide. After stirring at RT for 5 min, 329 mg (1.60 mmol) of (3-bromopropyl) cyclohexane were added, and the mixture was stirred at 100 ° C. bath temperature for 1.5 h. After cooling to RT, 30 ml of water and 30 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (40 g silica gel, eluent cyclohexane / ethyl acetate 9: 1). There were obtained 84 mg (14% of theory, purity 63%) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 1.78 min, m / z = 686 [M + H] ⁺ .

Example 32A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (hexyloxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) - l , 2,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 3 ml of DMF under argon was added 72 mg (0.64 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 106 mg (0.64 mmol) of 1-bromohexane were added, and the mixture was stirred at 100 ° C. bath temperature for 1.5 h. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with 80 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (25 g silica gel, eluent cyclohexane / ethyl acetate 85:15). 169 mg (49% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.93 (d, 2H), 7.02 (d, 2H), 4.62-4.50 ( m, 2H), 4.15-4.00 (m, 3H), 3.65-3.45 (m, 2H), 3.22 (t, 1H), 2.97-2.83 (m, 1H), 2.18- 2.06 (m, 1H), 2.06- 1.95 (m, 1H), 1.82-1.67 (m, 3H), 1.63-1.50 (m, 1H), 1.46-1.36 (m, 2H), 1.35-1.25 (m, 4H), 0.91-0.84 (m, 3H ), 0.37-0.22 (m, 2H), -0.19 (s, 9H). LC / MS (Method 1, ESIpos): R _t = 1.67 min, m / z = 646 [M + H] ⁺ .

Example 33A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (3-methylbutoxy) benzoyl] -5- {[4-oxo-i

methyl) -l, 2,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 3 ml of DMF under argon was added 72 mg (0.64 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 97 mg (0.64 mmol) of 1-bromo-3-methylbutane were added, and the mixture was stirred for 1 h at a bath temperature of 100.degree. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were saturated once with 80 ml Sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (40 g silica gel, eluent cyclohexane / ethyl acetate 8: 2). There were obtained 249 mg (74% of theory, purity 100%) of the title compound. Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.93 (d, 2H), 7.03 (d, 2H), 4.63-4.45 ( m, 2H), 4.15-4.00 (m, 3H), 3.68-3.47 (m, 2H), 3.22 (t, 1H), 2.97-2.83 (m, 1H), 2.17- 2.06 (m, 1H), 2.05- 1.95 (m, 1H), 1.83-1.69 (m, 2H), 1.66-1.50 (m, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.37-0.23 (m, 2H), -0.18 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.61 min, m / z = 632 [M + H] ⁺ . Example 34A

2- (trimethylsilyl) ethyl (1RS, 2S ^

methyl} -5- [4- (pentyloxy) benzoyl] cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 3 ml of DMF under argon was added 72 mg (0.64 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 97 mg (0.64 mmol) of 1-bromopentane were added, and the mixture was stirred at 100 ° C. bath temperature for 1.5 h. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with 80 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by column chromatography (25 g silica gel, eluent cyclohexane / ethyl acetate 85:15). 181 mg (53% of theory, purity 99%) of the title compound were obtained. Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.93 (d, 2H), 7.02 (d, 2H), 4.63-4.48 ( m, 2H), 4.15-3.99 (m, 3H), 3.64-3.47 (m, 2H), 3.23 (t, 1H), 2.97-2.84 (m, 1H), 2.17- 2.07 (m, 1H), 2.06- 1.96 (m, 1H), 1.81-1.67 (m, 3H), 1.63-1.51 (m, 1H), 1.37 (d, 4H), 0.93-0.84 (m, 3H), 0.38-0.21 (m, 2H), -0.19 (s, 9H). LC / MS (Method 1, ESIpos): R _t = 1.64 min, m / z = 632 [M + H] ⁺ .

Example 35A

2- (trimethylsilyl) ethyl (1R5,2R5,55R) -2- (4-butoxybenzoyl) -5- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 //) -yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 3 ml of DMF under argon was added 72 mg (0.64 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 97 mg (0.64 mmol) of 1-bromobutane were added, and the mixture was stirred at 100 ° C. bath temperature for 1.5 h. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with 80 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by column chromatography (25 g silica gel, eluent cyclohexane / ethyl acetate 9: 1). There were obtained 235 mg (68% of theory, purity 96%) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.93 (d, 2H), 7.03 (d, 2H), 4.62-4.49 ( m, 2H), 4.14-3.99 (m, 3H), 3.65-3.46 (m, 2H), 3.23 (t, 1H), 2.99-2.81 (m, 1H), 2.18-2.07 (m, 1H), 2.06- 1.94 (m, 1H), 1.81-1.66 (m, 3H), 1.64-1.51 (m, 1H), 1.49-1.36 (m, 2H), 0.93 (t, 3H), 0.38-0.21 (m, 2H), -0.19 (s, 9H).

LC / MS (Method 2, ESIpos): R _t = 3.47 min, m / z = 618 [M + H] ⁺ . Example 36A

2- (trimethylsilyl) ethyl (IRS, 2SR, 5 ^

methyl} -5- (4-propoxybenzoyl) cyclopentanecarboxylate (racemate)

To a solution of 103 mg (0.18 mmol) of the compound from Example 14A in 2.0 ml of acetonitrile was added 51 mg (0.37 mmol) of potassium carbonate and 28 mg (0.22 mmol, purity 98%) of 1-bromopropane. The mixture was stirred at reflux overnight. Thereafter, a further 8 mg (0.07 mmol) of 1-bromopropane were added and stirred under reflux for a further 4 h. After cooling to RT, the mixture was diluted with water. The precipitated solid was filtered off and dried in vacuo. This crude product was then purified by preparative HPLC (Method 10). 69 mg (62% of theory, purity 100%) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 1.56 min, m / z = 604 [M + H] ⁺ . Example 37A 2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- (4-isobutoxybenzoyl) -5- {[4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.53 mmol) of the compound from Example 14A in 3 ml of DMF under argon was added 72 mg (0.64 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 88 mg (0.64 mmol) of 1-bromo-2-methylpropane were added, and the mixture was stirred for 2 h at a bath temperature of 100.degree. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with 80 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by column chromatography (40 g silica gel, eluent cyclohexane / ethyl acetate 85:15). There were obtained 92 mg (28% of theory, purity 100%) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.93 (d, 2H), 7.03 (d, 2H), 4.62-4.48 ( m, 2H), 4.14-4.04 (m, 1H), 3.83 (d, 2H), 3.67-3.47 (m, 2H), 3.22 (t, 1H), 2.97-2.83 (m, 1H), 2.18-1.95 ( m, 3H), 1.80-1.69 (m, 1H), 1.63-1.50 (m, 1H), 0.99 (s, 3H), 0.97 (s, 3H), 0.37-0.22 (m, 2H), -0.18 (s , 9H).

LC / MS (Method 1, ESIpos): R _t = 1.57 min, m / z = 618 [M + H] ⁺ .

Example 38A

2- (trimethylsilyl) ethyl (IRS, 2SR ^^

methyl} -5- (4- {[(trifluoromethyl) sulfonyl] oxy} benzoyl) cyclopentanecarboxylate (racemate)

0.25 ml (3.12 mmol) of pyridine and then, slowly, 0.45 ml (2.67 mmol) of trifluoromethanesulfonic anhydride were added at 0.degree. C. to a solution of 1.00 g (1.78 mmol) of the compound from Example 14A in 5.0 ml of dichloromethane under argon. The mixture was stirred for 1 h at 0 ° C, then treated with dichloromethane and washed once each with water and saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. 1.21 g (98% of theory, purity 100%) of the title compound were obtained.

LC / MS (Method 2, ESIpos): R _t = 3.41 min, m / z = 694 [M + H] ⁺ . Example 39A

2- (trimethylsilyl) ethyl (IRS, 2SR ^^

methyl} -5- (4-sulfanylbenzoyl) cyclopentanecarboxylate (racemate)

To a solution of 800 mg (1.15 mmol) of the compound from Example 38A in 10 ml of dioxane was successively 264 mg (1.38 mmol) of triisopropylsilanethiol, 298 mg (2.31 mmol) of N, N-diisopropylethylamine, 26 mg (0.03 mmol) of Tris (dibenzylideneacetone) dipalladium and 33 mg (0.06 mmol) of 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene (xanthphos). Subsequently, the degassed, purged with argon and stirred under reflux for 2.5 h. After cooling to RT, the mixture was treated with ethyl acetate and washed once with water. After a single extraction of the aqueous phase with ethyl acetate, the combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 4). The product-containing fractions were combined, neutralized with saturated aqueous sodium bicarbonate solution and concentrated to a small residual volume of water. After extracting this aqueous phase twice with dichloromethane, the combined organic phases were dried over magnesium sulfate, filtered, concentrated and the residue was dried in vacuo. 350 mg (35% of theory, purity 67%) of the title compound were obtained. According to LC / MS, it contained the corresponding disulfide (dimerized product, (+/-) - bis [2- (trimethylsilyl) ethyl] 2,2 '- [disulfandiylbis (benzene-4,1-diylcarbonyl)] bis ( 5- {[4-oxo-6- (trifluoromethyl) -1,2,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylate) at 25%.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.44 (s, 2H), 7.83 (d, 2H), 7.42 (d, 2H), 6.03 (br. s, 1H), 4.60-4.48 (m, 2H), 4.08 (q, 1H), 3.64-3.48 (m, 2H), 3.23 (t, 1H), 2.97-2.81 (m, 1H), 2.19-2.06 ( m, 1H), 2.06-1.94 (m, 1H), 1.79-1.67 (m, 1H), 1.62-1.48 (m, 1H), 0.37-0.22 (m, 2H), -0.18 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.44 min, m / z = 578 [M + H] ⁺ . Example 40A 2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (benzylsulfanyl) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) - l, 2,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 245 mg (0.35 mmol) of the compound from Example 38A in 3 ml of dioxane, 47 mg (0.38 mmol) of phenylmethanethiol, 91 mg (0.71 mmol) / V, / V-diisopropyl- ethylamine, 8 mg (0.01 mmol) of tris (dibenzylideneacetone) dipalladium and 10 mg (0.02 mmol) of 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene (xanthphos). It was degassed, purged with argon and then stirred under reflux for 2 h. After cooling to RT, the mixture was purified directly by preparative HPLC (Method 5). The product-containing fractions were combined, neutralized with saturated aqueous sodium bicarbonate solution and concentrated to a small residual volume of aqueous phase. After extracting this aqueous phase twice with dichloromethane, the combined organic phases were dried over magnesium sulfate, filtered, concentrated and the residue was dried in vacuo. 203 mg (86% of theory, purity 100%) of the title compound were obtained. Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.44 (s, 2H), 7.87 (d, 2H), 7.46-7.39 (m, 4H), 7.32 ( t, 2H), 7.25 (d, 1H), 4.61-4.49 (m, 2H), 4.37 (s, 2H), 4.09 (q, 1H), 3.65-3.48 (m, 2H), 3.24 (t, 1H) , 2.97-2.82 (m, 1H), 2.18-2.06 (m, 1H), 2.05-1.94 (m, 1H), 1.79-1.67 (m, 1H), 1.62-1.48 (m, 1H), 0.39-0.20 ( m, 2H), -0.18 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.55 min, m / z = 668 [M + H] ⁺ . Example 41A

2- (trimethylsilyl) ethyl (IR 5,2R ₁ S ^, 5S ^, R) -2- {4 - [(3-chlorobenzyl) sulfanyl] benzoyl} -5- {[4-oxo-6 (tri fluoromethyl) -1,3,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.43 mmol) of the compound from Example 38A in 4 ml of dioxane were successively 73 mg (0.46 mmol) of (3-chlorophenyl) methanethiol, 112 mg (0.87 mmol) of N, N-diisopropylethylamine, 10 mg (0.01 mmol) of tris (dibenzylideneacetone) dipalladium and 13 mg (0.02 mmol) of 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene (xanthphos). It was degassed, purged with argon and then stirred under reflux for 2 h. After cooling to RT and standing overnight, the mixture was purified directly by preparative HPLC (Method 5). The pro- containing fractions were combined, neutralized with saturated aqueous sodium bicarbonate solution and concentrated to a small residual volume of aqueous phase. After extracting this aqueous phase twice with dichloromethane, the combined organic phases were dried over magnesium sulfate, filtered, concentrated and the residue was dried in vacuo. There were obtained 255 mg (84% of theory, purity 100%) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.87 (d, 2H), 7.51-7.27 (m, 6H), 4.61- 4.48 (m, 2H), 4.39 (s, 2H), 4.10 (q, 1H), 3.65-3.47 (m, 2H), 3.24 (t, 1H), 2.97-2.83 (m, 1H), 2.18-2.06 ( m, 1H), 2.05-1.94 (m, 1H), 1.79-1.67 (m, 1H), 1.62-1.48 (m, 1H), 0.39-0.19 (m, 2H), -0.19 (s, 9H). LC / MS (Method 1, ESIpos): R _t = 1.59 min, m / z = 702 [M + H] ⁺ .

Example 42A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(3,4-dichlorobenzyl) sulfanyl] benzoyl} -5- {[4-0X0- 6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.43 mmol) of the compound from Example 38A in 4 ml of dioxane were successively 89 mg (0.46 mmol) of (3,4-dichlorophenyl) methanethiol, 112 mg (0.87 mmol) of N, N-diisopropylethylamine, 10 mg (0.01 mmol) of tris (dibenzylideneacetone) dipalladium and 13 mg (0.02 mmol) of 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene (xanthphos). It was degassed, purged with argon and then stirred under reflux for 2 h. After cooling to RT and standing overnight, the mixture was purified directly by preparative HPLC (Method 5). The product-containing fractions were combined, neutralized with saturated aqueous sodium bicarbonate solution and concentrated to a small residual volume of aqueous phase. After extracting this aqueous phase twice with dichloromethane, the pooled orga- dried over magnesium sulfate, filtered, concentrated and the residue dried in vacuo. There were obtained 266 mg (84% of theory, purity 100%) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.87 (d, 2H), 7.69 (d, 1H), 7.57 (d, 1H), 7.47-7.39 (m, 3H), 4.59-4.50 (m, 2H), 4.39 (s, 2H), 4.09 (q, 1H), 3.64-3.48 (m, 2H), 3.23 (t, 1H) , 2.96-2.82 (m, 1H), 2.17-2.06 (m, 1H), 2.05-1.94 (m, 1H), 1.80-1.67 (m, 1H), 1.62- 1.49 (m, 1H), 0.37-0.21 ( m, 2H), -0.20 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.63 min, m / z = 736 [M + H] ⁺ .

Example 43A

2- (trimethylsilyl) ethyl (1RS, 2S ^

methyl} -5- {4 - [(2-phenylethyl) sulfanyl] benzoyl] cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.43 mmol) of the compound from Example 38A in 4 ml of dioxane were successively 64 mg (0.46 mmol) of 2-phenylethanethiol, 112 mg (0.87 mmol) / V, / V-diisopropylethylamine, 10 mg ( 0.01 mmol) of tris (dibenzylideneacetone) dipalladium and 13 mg (0.02 mmol) of 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene (xanthphos). It was degassed, purged with argon and then stirred under reflux for 2 h. After cooling to RT and standing overnight, the mixture was purified directly by preparative HPLC (Method 5). The product-containing fractions were combined, neutralized with saturated aqueous sodium bicarbonate solution and concentrated to a small residual volume of aqueous phase. After extracting this aqueous phase twice with dichloromethane, the combined organic phases were dried over magnesium sulfate, filtered, concentrated and the residue was dried in vacuo. There were obtained 239 mg (81% of theory, purity 100%) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.90 (d, 2H), 7.43 (d, 2H), 7.34-7.26 ( m, 4H), 7.25-7.18 (m, 1H), 4.61-4.50 (m, 2H), 4.11 (q, 1H), 3.66-3.49 (m, 2H), 3.37- 3.30 (covert, 2H), 3.25 (t, 1H), 2.96-2.84 (m, 3H), 2.19-2.08 (m, 1H), 2.07-1.96 (m, 1H), 1.70 (m, 1H), 1.62 -1.51 (m, 1H), 0.40-0.23 (m, 2H), -0.19 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.62 min, m / z = 682 [M + H] ⁺ .

Example 44A

2- (trimethylsilyl) ethyl (IRR ₁ S ^, 2R ₁ S ^, 5S ^, R) -2- {4 - [(cyclohexylmethyl) sulfanyl] benzoyl} -5- {[4-oxo-6 (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 220 mg of the compound from Example 39A (0.38 mmol, not purity-corrected, containing about 25% corresponding disulfide) in 15 ml of DMF was added 105 mg (0.76 mmol) of potassium carbonate and the mixture was stirred at RT for 2 min. Subsequently, 148 mg (0.84 mmol) of (bromomethyl) cyclohexane, 135 mg (1.14 mmol) of sodium hydroxymethanesulfinate and 0.2 ml (0.11 mmol) of water were added, and stirring was continued at RT for a further 30 min. The mixture was then concentrated, and the residue was added with water and extracted twice with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. There were obtained 236 mg (87% of theory, purity 95%) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 1.73 min, m / z = 674 [M + H] ⁺ .

Example 45A

2- (trimethylsilyl) ethyl (1RS, 2S ^

methyl 1} -5 - [4- (pentylsulfonyl) benzoyl] cyclopentanecarboxylate (racemate)

To a solution of 300 mg (0.43 mmol) of the compound from Example 38A in 4 ml of dioxane were successively 48 mg (0.46 mmol) of pentane-1-thiol, 112 mg (0.87 mmol) / V, / V-Diisopropylefhyl- amine, 10 mg (0.01 mmol) of tris (dibenzylideneacetone) dipalladium and 13 mg (0.02 mmol) of 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene (xanthphos). It was degassed, purged with argon and then stirred under reflux for 2 h. After cooling to RT and standing overnight, the mixture was purified directly by preparative HPLC (Method 5). The product-containing fractions were combined, neutralized with saturated aqueous sodium bicarbonate solution and concentrated to a small residual volume of aqueous phase. After extracting this aqueous phase twice with dichloromethane, the combined organic phases were dried over magnesium sulfate, filtered, concentrated and the residue was dried in vacuo. There were obtained 233 mg (82% of theory, purity 98%) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.88 (d, 2H), 7.38 (d, 2H), 4.62-4.48 ( m, 2H), 4.10 (q, 1H), 3.66-3.47 (m, 2H), 3.23 (t, 1H), 3.05 (t, 2H), 2.97-2.83 (m, 1H), 2.20-2.06 (m, 1H), 2.06-1.95 (m, 1H), 1.81-1.71 (m, 1H), 1.67-1.51 (m, 3H), 1.44-1.19 (m, 4H), 0.86 (t, 3H), 0.39-0.20 ( m, 2H), -0.18 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.67 min, m / z = 648 [M + H] ⁺ .

Example 46A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (benzyloxy) benzoyl] -5 - [(6-methyl-4-oxo-l, 2 , 3-benzotriazine-3 (4 /) -yl) methyl] cyclopentanecarboxylate (racemate)

3.88 g (24.07 mmol) of the compound from Example 2A were added to a suspension of 9.60 g (20.06 mmol, purity 95%) of the compound from Example 3A / Step 5 in 110 ml of toluene under argon. Subsequently, 25.1 ml (100.30 mmol) of tributylphosphane and 27.4 ml (60.18 mmol) of a 40% solution of diethyl azodicarboxylate in toluene were added dropwise at 0 ° C. After stirring at RT for 2 h, the mixture was diluted with ethyl acetate and washed once with water. The aqueous phase was back-extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, eluent cyclohexane / ethyl acetate 85:15 → 80:20). There were obtained 6.28 g (51% of theory, purity 98%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.12-8.05 (m, 2H), 7.97-7.88 (m, 3H), 7.48-7.27 (m, 5H), 7.12 (d, 2H ), 5.20 (s, 2H), 4.56-4.42 (m, 2H), 4.08 (q, 1H), 3.61-3.46 (m, 2H), 3.22 (t, 1H), 2.96-2.83 (m, 1H), 2.55 (s, 3H), 2.17-2.05 (m, 1H), 2.03-1.92 (m, 1H), 1.78-1.67 (m, 1H), 1.59- 1.47 (m, 1H), 0.38-0.23 (m, 2H ), -0.17 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.49 min, m / z = 598 [M + H] ⁺ .

Example 47A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- (4-hydroxybenzoyl) -5 - [(6-methyl-4-oxo-l, 2,3- benzotriazine-3 (4 /) -yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 6.25 g (10.25 mmol, purity 98%) of the compound of Example 46A in a mixture of 50 mL of ethyl acetate and 50 mL of ethanol under argon was added 273 mg (0.26 mmol) of palladium on charcoal (10% Pd) and 969 mg (15.37 mmol) of ammonium formate. Subsequently, the mixture was stirred for 2 h at 70.degree. After cooling to RT, the mixture was filtered through kieselguhr, the filter residue was washed with ethyl acetate, the filtrate was concentrated and the residue was dried in vacuo. There were obtained 5.20 g (97% of theory, purity 97%) of the title compound.

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 10.40 (br.s, IH), 8.12-8.05 (m, 2H), 7.92 (dd, IH), 7.84 (d, 2H), 6.84 (d, 2H), 4.57-4.42 (m, 2H), 4.03 (q, IH), 3.62-3.46 (m, 2H), 3.21 (t, IH), 2.96- 2.83 (m, IH), 2.55 (s , 3H), 2.17-2.04 (m, IH), 2.03-1.91 (m, IH), 1.78-1.66 (m, IH), 1.60-1.48 (m, IH), 0.39-0.25 (m, 2H), 0.17 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.28 min, m / z = 508 [M + H] ⁺ .

Example 48A 2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(4-fluorobenzyl) oxy] benzoyl} -5 - [(6-methyl- 4-oxo-l, 2,3-benzotriazine-3 (4 //) - yl) -methyl] cyclopentanecarboxylate (racemate)

To a solution of 169 mg (0.27 mmol, purity 98%) of the compound from Example 47A in 2.1 ml of DMF under argon was added 51 mg (0.46 mmol) of potassium ieri-butoxide. After stirring at RT for 5 min, 87 mg (0.46 mmol) of 4-fluorobenzylbromide were added, and the mixture was stirred for 1 h at a bath temperature of 100.degree. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 60 ml of ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (40 g silica gel, eluent cyclohexane / ethyl acetate 85:15). 169 mg (71% of theory, purity 98%) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 1.48 min, m / z = 616 [M + H] ⁺ .

Example 49A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(3-methylbenzyl) oxy] benzoyl} -5 - [(6-methyl-4- oxol, 2,3-benzotriazine-3 (4 /) -yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 200 mg (0.38 mmol, purity 97%) of the compound from Example 47A in 2.1 ml of DMF under argon was added 51 mg (0.46 mmol) of potassium ieri-butoxide. After stirring at RT for 5 min, 85 mg (0.46 mmol) of 3-methylbenzyl bromide were added, and the mixture was stirred for 1 h at a bath temperature of 100.degree. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 60 ml of ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (40 g silica gel, eluent cyclohexane / ethyl acetate 85:15). 120 mg (51% of theory, purity 100%) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 1.53 min, m / z = 612 [M + H] ⁺ .

Example 50A

2- (trimethylsilyl) ethyl (IRS, 2SR ^^

(4- {[3- (trifluoromethyl) benzyl] oxy} benzoyl) cyclopentanecarboxylate (racemate)

To a solution of 500 mg (0.96 mmol, purity 97%) of the compound from Example 47A in 5.3 ml of DMF under argon, 129 mg (1.15 mmol) of potassium ieri. given butylate. After stirring for 5 min at RT, 274 mg (1.15 mmol) of 3- (trifluoromethyl) benzylbromide were added and the mixture was stirred for 2 h at 100 ° C bath temperature. Subsequently, a further 274 mg (1.15 mmol) of 3- (trifluoromethyl) benzyl bromide were added, and it was stirred for a further 2 h at 100 ° C bath temperature. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separation of the phases, the aqueous phase was extracted once with 60 ml of ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (90 g silica gel, eluent cyclohexane / ethyl acetate 8: 2). There were obtained 345 mg (53% of theory, purity 97%) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 1.58 min, m / z = 666 [M + H] ⁺ .

Example 51 A 2- (trimethylsilyl) ethyl (IRR ₁ S ^, 2R ₁ S ^, 5S ^, R) -2- {4 - [(3-chlorobenzyl) oxy] benzoyl} -5 - [(6-methyl 4-oxo-l, 2,3-benzotriazine-3 (4 /) - yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 500 mg (0.96 mmol, purity 97%) of the compound from Example 47A in 5.3 ml of DMF under argon, 129 mg (1.15 mmol) of potassium ieri. given butylate. After stirring at RT for 5 min, 236 mg (1.15 mmol) of 3-chlorobenzyl bromide were added, and the mixture was stirred for 1 h at 100 ° C. bath temperature. After cooling and standing overnight at RT, stirring was continued for a further 2 hours at 100 ° C. bath temperature. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (90 g silica gel, eluent cyclohexane / ethyl acetate 85:15). There were obtained 392 mg (65% of theory, purity 100%) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 1.58 min, m / z = 632 [M + H] ⁺ .

Example 52A 2- (trimethylsilyl) ethyl (1R ₁ S ^, 2R ₁ S ^, 5S ^, R) -2- {4 - [(3-methoxybenzyl) oxy] benzoyl} -5 - [(6-methyl) 4-oxo-l, 2,3-benzotriazine-3 (4 /) -yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 200 mg (0.38 mmol, purity 97%) of the compound from Example 47A in 2.1 ml of DMF under argon was added 51 mg (0.46 mmol) of potassium ieri-butoxide. After stirring at RT for 5 min, 92 mg (0.46 mmol) of 1- (bromomethyl) -3-methoxybenzene were added, and the mixture was stirred for 2 h at a bath temperature of 100.degree. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (40 g of silica gel, eluent cyclohexane / ethyl acetate 85:15). 115 mg (47% of theory, purity 98%) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 1.50 min, m / z = 628 [M + H] ⁺ .

Example 53A

2- (trimethylsilyl) ethyl (IRS, 2SR ^^

(4- {[3- (trifluoromethoxy) benzyl] oxy} benzoyl) cyclopentanecarboxylate (racemate)

To a solution of 200 mg (0.38 mmol, purity 97%) of the compound from Example 47A in 2.1 ml of DMF under argon was added 51 mg (0.46 mmol) of potassium ieri-butoxide. After stirring at RT for 5 min, 117 mg (0.46 mmol) of 1- (bromomethyl) -3- (trifluoromethoxy) benzene were added, and the mixture was stirred for 2 h at a bath temperature of 100.degree. Thereafter, another 117 mg (0.46 mmol) of 1- (bromomethyl) -3- (trifluoromethoxy) benzene were added, and the mixture was stirred for a further 2 hours at 100 ° C bath temperature. Then, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (40 g silica gel, eluent cyclohexane / ethyl acetate 85:15). There were obtained 95 mg (36% of theory, purity 100%) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 1.56 min, m / z = 682 [M + H] ⁺ . Example 54A

2- (trimethylsilyl) ethyl (IRS, 2SR ^^

[4- (2-phenylethoxy) benzoyl] cyclopentanecarboxylate (racemate)

To a solution of 500 mg (0.96 mmol, purity 97%) of the compound of Example 47A in 5 mL acetonitrile under argon was added 214 mg (1.91 mmol) potassium carbonate and 324 mg (1.15 mmol, purity 90%) of 2-phenylethyl trifluoromeflu sulfonate , The mixture was stirred for 4 h at RT. Then, the mixture was added with water and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (90 g silica gel, eluent cyclohexane / ethyl acetate 8: 2). There were obtained 347 mg (59% of theory, purity 100%) of the title compound. LC / MS (Method 1, ESIpos): R _t = 1.58 min, m / z = 612 [M + H] ⁺ . Example 55A

2- (trimethylsilyl) ethyl (IRS, 2SR, 5 ^

[4- (3-phenylpropoxy) benzoyl] cyclopentanecarboxylate (racemate)

To a solution of 200 mg (0.38 mmol, purity 97%) of the compound from Example 47A in 2.1 ml of DMF under argon was added 51 mg (0.46 mmol) of potassium ieri-butoxide. After 5 min Stirring at RT gave 91 mg (0.46 mmol) of (3-bromopropyl) benzene and the mixture was stirred for 2 h at 100 ° C bath temperature. Subsequently, a further 75 mg (0.38 mmol) of (3-bromopropyl) benzene were added, and the mixture was stirred for a further 2 hours at 100 ° C. bath temperature. Thereafter, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (40 g silica gel, eluent cyclohexane / ethyl acetate 85:15). There were obtained 44 mg (18% of theory, purity 100%) of the title compound. LC / MS (Method 1, ESIpos): R _t = 1.60 min, m / z = 626 [M + H] ⁺ .

Example 56A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (cyclohexylmethoxy) benzoyl] -5 - [(6-methyl-4-oxo-l, 2 , 3-benzotriazine-3 (4 /) -yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 200 mg (0.38 mmol, purity 97%) of the compound from Example 47A in 2.1 ml of DMF under argon was added 51 mg (0.46 mmol) of potassium ieri-butoxide. After stirring at RT for 5 min, 81 mg (0.46 mmol) (bromomethyl) cyclohexane were added, and the mixture was stirred for 2 h at 100 ° C. bath temperature. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (40 g silica gel, eluent cyclohexane / ethyl acetate 85:15). 163 mg (71% of theory, purity 100%) of the title compound were obtained. LC / MS (Method 1, ESIpos): R _t = 1.65 min, m / z = 604 [M + H] ⁺ . Example 57A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (cyclopentylmethoxy) benzoyl] -5 - [(6-methyl-4-oxo-l, 2 , 3-benzotriazine-3 (4 //) - yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 200 mg (0.38 mmol, purity 97%) of the compound from Example 47A in 2.1 ml of DMF under argon was added 51 mg (0.46 mmol) of potassium ieri-butoxide. After stirring at RT for 5 min, 75 mg (0.46 mmol) (bromomethyl) cyclopentane were added and the mixture was stirred at 100 ° C. bath temperature for 2 h. Thereafter, another 75 mg (0.46 mmol) of (bromomethyl) cyclopentane were added, and the mixture was stirred for a further 3.5 h at 100 ° C bath temperature. Then, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (40 g silica gel, eluent cyclohexane / ethyl acetate 85:15). 49 mg (13% of theory, purity 58%) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 1.64 min, m / z = 590 [M + H] ⁺ .

Example 58A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (hexyloxy) benzoyl] -5 - [(6-methyl-4-oxo-l, 2 , 3-benzotriazine-3 (4 /) -yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 200 mg (0.38 mmol, purity 97%) of the compound from Example 47A in 2.1 ml of DMF under argon was added 51 mg (0.46 mmol) of potassium ieri-butoxide. After stirring for 5 min at RT, 76 mg (0.46 mmol) of 1-bromohexane were added and the mixture was stirred for 2 h at 100 ° C bath temperature. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (40 g silica gel, eluent cyclohexane / ethyl acetate 85:15). There were obtained 140 mg (62% of theory, purity 100%) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 1.66 min, m / z = 592 [M + H] ⁺ . Example 59A

2- (trimethylsilyl) ethyl (IRS, 2SR ^^

[4- (pentyloxy) benzoyl] cyclopentanecarboxylate (racemate)

To a solution of 500 mg (0.96 mmol, purity 97%) of the compound from Example 47A in 5.3 ml of DMF under argon, 129 mg (1.15 mmol) of potassium ieri. given butylate. After stirring at RT for 5 min, 173 mg (1.15 mmol) of 1-bromopentane were added and the mixture was stirred for 1 h at a bath temperature of 100.degree. After cooling and standing overnight at RT, the mixture was stirred for a further 2 h at 100 ° C bath temperature. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (90 g of silica gel, eluent cyclohexane / ethyl acetate 85:15). 378 mg (60% of theory, purity 88%) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 1.58 min, m / z = 578 [M + H] ⁺ .

Exemplary embodiments:

example 1

(+/-) - (1R5,2R5,55R) -2- {4 - [(4-fluorobenzyl) oxy] benzoyl} -5 - [(4-oxo-1,2,3-benzotriazine-3 (4fl) -yl) - methyl] cyclopentanecarboxylic acid (racemate)

A solution of 49.8 mg (0.08 mmol) of the compound from Example 5A in 0.3 ml of dichloromethane was treated at 0 ° C. with 0.16 ml (2.07 mmol) of trifluoroacetic acid. The mixture was stirred for 3 h at 0 ° C and then stored at 5 ° C for about 72 h. Thereafter, the mixture was concentrated, the residue taken up in dichloromethane and the solution was concentrated again. This procedure was repeated several times. 37 mg (87% of theory, purity 99%) of the title compound were thus obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.26 (d, 1H), 8.20 (d, 1H), 8.08 (dd, 1H), 7.98 ( d, 2H), 7.93 (dd, 1H), 7.52 (dd, 2H), 7.23 (t, 2H), 7.12 (d, 2H), 5.19 (s, 2H), 4.58-4.48 (m, 2H), 4.11 (dd, 1H), 3.24 (dd, 1H), 2.92 (m, 1H), 2.15-2.06 (m, 1H), 1.93-1.85 (m, 1H), 1.70-1.62 (m, 1H), 1.56-1.46 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.17 min, m / z = 502 [M + H] ⁺ .

Example 2

(+/-) - (1R5,2R5,5S ^, R) -2- {4 - [(3-chlorobenzyl) oxy] benzoyl} -5 - [(4-oxo-1,2,3-benzotriazine) 3 (4 /) - yl) - methyl] cyclopentanecarboxylic acid (racemate)

A solution of 57 mg (0.09 mmol) of the compound from Example 6A in 0.36 ml of dichloromethane was admixed with 0.18 ml (2.29 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 5.5 h. Thereafter, the mixture was concentrated, the residue taken up in dichloromethane and the solution was concentrated again. This procedure was repeated several times. There were thus obtained 48 mg (100% of theory, purity 100%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.15 (br.s, 1H), 8.26 (d, 1H), 8.20 (d, 1H), 8.11-8.05 (m, 1H), 7.99 (d, 2H), 7.96-7.90 (m, 1H), 7.54 (s, 1H), 7.47-7.38 (m, 3H), 7.13 (d, 2H), 5.23 (s, 2H), 4.59-4.46 ( m, 2H), 4.16-4.04 (m, 1H), 3.24 (t, 1H), 2.94-2.80 (m, 1H), 2.18-2.03 (m, 1H), 1.95-1.82 (m, 1H), 1.73- 1.61 (m, 1H), 1.58-1.44 (m, 1H). LC / MS (Method 1, ESIpos): R _t = 1.22 min, m / z = 518 [M + H] ⁺ .

Example 3

(+/-) - (IR 5,2 R 5,5 ^, S ^, R) -2- {4 - [(3,4-dichlorobenzyl) oxy] benzoyl} -5 - [(4-oxo-l, 2,3- benzotriazine-3 (4 /) - yl) methyl] cyclopentanecarboxylic acid (racemate)

A solution of 54 mg (0.08 mmol) of the compound from Example 7A in 0.33 ml of dichloromethane was admixed with 0.16 ml (2.06 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 5.5 h. Thereafter, the mixture was concentrated, the residue taken up in dichloromethane and the solution was concentrated again. This procedure was repeated several times. 43 mg (95% of theory, purity 100%) of the title compound were thus obtained. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.26 (d, 1H), 8.20 (d, 1H), 8.08 (dd, 1H), 7.99 ( d, 2H), 7.93 (t, 1H), 7.76 (d, 1H), 7.68 (d, 1H), 7.46 (dd, 1H), 7.13 (d, 2H), 5.23 (s, 2H), 4.58-4.48 (m, 2H), 4.11 (q, 1H), 3.23 (t, 1H), 2.92-2.82 (m, 1H), 2.16-2.06 (m, 1H), 1.93-1.82 (m, 1H), 1.70-1.62 (m, 1H), 1.56-1.46 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.28 min, m / z = 552 [M + H] ⁺ . Example 4

(+/-) - (IR 5,2 R 5,55 R) -2 4- (cyclopentylmethoxy) benzoyl] -5 (4-oxo, 2,3-benzotriazine

methyl] cyclopentane carboxylic acid (racemate)

A solution of 33 mg (0.06 mmol) of the compound from Example 8A in 0.22 ml of dichloromethane was admixed at 0 ° C. with 0.11 ml (1.42 mmol) of trifluoroacetic acid. The mixture was stirred for 3 h at 0 ° C and then stored at 5 ° C for about 72 h. Then another 0.04 ml of trifluoroacetic acid were added and the mixture stirred for another 3 h at RT. Thereafter, the mixture was concentrated, the residue taken up in dichloromethane and the solution was concentrated again. This procedure was repeated several times. This gave 26 mg (93% of theory, purity 97%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.26 (d, 1H), 8.20 (d, 1H), 8.08 (dd, 1H), 7.96- 7.91 (m, 3H), 7.03 (d, 2H), 4.57-4.48 (m, 2H), 4.10 (dd, 1H), 3.94 (d, 2H), 3.23 (t, 1H), 2.92-2.82 (m, 1H), 2.37-2.28 (m, 1H), 2.15-2.06 (m, 1H), 1.93-1.85 (m, 1H), 1.81-1.73 (m, 2H), 1.70-1.46 (m, 6H), 1.37- 1.29 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.29 min, m / z = 476 [M + H] ⁺ .

Example 5

(+/-) - (1R5,2R5,55R) -2- [4- (2-Cyclohexylethoxy) benzoyl] -5 - [(4-oxo-1,2,3-benzotriazine-3 (4 /) -yl ) - methyl] cyclopentane carboxylic acid (racemate)

A solution of 38 mg (0.06 mmol) of the compound from Example 9A in 0.25 ml of dichloromethane was treated at 0 ° C with 0.12 ml (1.58 mmol) of trifluoroacetic acid. The mixture was added for 3 h Stirred 0 ° C, then stored for about 72 h at 5 ° C and then stirred again for 3 h at RT. The mixture was then concentrated, the residue taken up in dichloromethane and the solution concentrated again. This procedure was repeated several times. 31 mg (94% of theory, purity 96%) of the title compound were thus obtained. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.26 (d, 1H), 8.20 (d, 1H), 8.08 (dd, 1H), 7.96- 7.91 (m, 3H), 7.03 (d, 2H), 4.58-4.48 (m, 2H), 4.13-4.08 (m, 3H), 3.24 (dd, 1H), 2.92-2.82 (m, 1H), 2.15- 2.06 (m, 1H), 1.93-1.82 (m, 1H), 1.75-1.61 (m, 8H), 1.56-1.46 (m, 2H), 1.26-1.11 (m, 3H), 0.95 (dd, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.41 min, m / z = 504 [M + H] ⁺ . Example 6

(+/-) - (1R5,2R5,55R) -2- [4- (hexyloxy) benzoyl] -5 - [(4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) methyl ] - cyclopentane carboxylic acid (racemate)

A solution of 41 mg (0.07 mmol) of the compound from Example 10A in 0.28 ml of dichloromethane was admixed with 0.14 ml (1.76 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 5.5 h. Thereafter, the mixture was concentrated, the residue taken up in dichloromethane and the solution was concentrated again. This procedure was repeated several times. There were thus obtained 32 mg (95% of theory, purity 100%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.26 (d, 2H), 8.20 (d, 2H), 8.08 (dd, 1H), 7.97- 7.91 (m, 2H), 7.03 (d, 1H), 4.58-4.48 (m, 2H), 4.13-4.04 (m, 3H), 3.24 (t, 1H), 2.90-2.84 (m, 1H), 2.15- 2.06 (m, 1H), 1.93-1.85 (m, 1H), 1.76-1.62 (m, 3H), 1.56-1.51 (m, 1H), 1.44-1.37 (m, 2H), 1.33-1.23 (m, 4H ), 0.88 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.30 min, m / z = 478 [M + H] ⁺ .

Example 7 (+/-) - (IR 5,25R, 5R.S ^, ) -2 - [(4-Oxo-1,2,3-benzotriazine-3 (4 /) -yl) -methyl] -5- [4 - (pentyloxy) benzoyl] cyclopentane carboxylic acid (racemate)

A solution of 30 mg (0.05 mmol) of the compound from Example IA in 0.21 ml of dichloromethane was admixed with 0.10 ml (1.33 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 5.5 h. Thereafter, the mixture was concentrated, the residue taken up in dichloromethane and the solution was concentrated again. This procedure was repeated several times. This gave 26 mg (> 100% of theory, purity 99%) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (s, 1H), 8.26 (d, 1H), 8.20 (d, 1H), 8.08 (dd, 1H), 7.97-7.91 ( m, 3H), 7.03 (d, 2H), 4.58-4.48 (m, 2H), 4.14-4.01 (m, 3H), 3.24 (t, 1H), 2.92-2.82 (m, 1H), 2.15-2.06 ( m, 1H), 1.93-1.85 (m, 1H), 1.77-1.62 (m, 3H), 1.56-1.46 (m, 1H), 1.43-1.32 (m, 4H), 0.89 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.25 min, m / z = 464 [M + H] ⁺ .

Separation of the enantiomers:

18 mg of the racemic compound from Example 7 were dissolved in 7 ml of ethanol / isohexane and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 8 and 9) [column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 210 nm; Injection volume: 3.5 ml; Temperature: 40 ° C; Eluent: 30% isohexane / 70% ethanol + 0.2% TFA + 1% water; Total running time 14.1 min].

Example 8

(+) - (1R5,25R, 5R, S ^, ) -2 - [(4-oxo-l, 2,3-benzotriazine-3 (4 /) -yl) methyl] -5- [4- (pentyloxy) benzoyl] - cyclopentanecarboxylic acid (enantiomer 1)

Yield: 6 mg; former purity = 100%; ee value = 100%

[from ²⁰ = + 51.4 °, 589 nm, c = 0.07 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.11 (br.s, 1H), 8.26 (d, 1H), 8.20 (d, 1H), 8.08 (t, 1H), 8.00- 7.89 (m, 3H), 7.03 (d, 2H), 4.59-4.46 (m, 2H), 4.14-4.00 (m, 3H), 3.24 (t, 1H), 2.95-2.81 (m, 1H), 2.17- 2.03 (m, 1H), 1.95-1.82 (m, 1H), 1.79-1.60 (m, 3H), 1.57-1.45 (m, 1H), 1.45-1.27 (m, 4H), 0.89 (t, 3H). LC / MS (Method 1, ESIpos): R _t = 1.23 min, m / z = 464 [M + H] ⁺ . Example 9

(-) - (1R5,25R, 5R ^ -2 (4-oxo, 2,3-benzotriazine-3 (4 /) -yl) -methyl] -5- [4- (pentyloxy) benzoyl] -cyclopentanecarboxylic acid (enantiomer 2 Yield: 6 mg, former purity = 100%, ee value = 100%

[a] _D ²⁰ = -51.9 °, 589 nm, c = 0.09 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (br.s, 1H), 8.26 (d, 1H), 8.20 (d, 1H), 8.08 (t, 1H), 7.99- 7.88 (m, 3H), 7.03 (d, 2H), 4.59-4.46 (m, 2H), 4.15-4.01 (m, 3H), 3.23 (t, 1H), 2.94-2.79 (m, 1H), 2.18- 2.03 (m, 1H), 1.95-1.82 (m, 1H), 1.78-1.61 (m, 3H), 1.57-1.45 (m, 1H), 1.44-1.28 (m, 4H), 0.89 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.23 min, m / z = 464 [M + H] ⁺ .

Example 10

(+/-) - (1R5,2R5,5S ^, R) -2- (4-butoxybenzoyl) -5 - [(4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) methyl] cyclopentanecarboxylic acid (racemate)

A solution of 32 mg (0.06 mmol) of the compound from Example 12A in 0.23 ml of dichloromethane was admixed with 0.11 ml (1.45 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 5.5 h. Thereafter, the mixture was concentrated, the residue taken up in dichloromethane and the solution was concentrated again. This procedure was repeated several times. This gave 26 mg (100% of theory, purity 100%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.26 (d, 1H), 8.20 (d, 1H), 8.08 (td, 1H), 7.99- 7.89 (m, 3H), 7.03 (d, 2H), 4.53 (dd, 2H), 4.14-4.03 (m, 3H), 3.24 (t, 1H), 2.94-2.80 (m, 1H), 2.17-2.04 ( m, 1H), 1.95-1.82 (m, 1H), 1.77-1.60 (m, 3H), 1.57-1.37 (m, 3H), 0.93 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.19 min, m / z = 450 [M + H] ⁺ . Example 11

(+/-) - (IRS, 2RS, 5SR) -2- [4- (benzyloxy) benzoyl] -5- {^

3 (4 //) - yl] methylcyclopentanecarboxylic acid (racemate)

A solution of 82 mg (0.11 mmol, purity 85%) of the compound from Example 13A in 0.5 ml of dichloromethane was admixed at 0.degree. C. with 0.25 ml (3.24 mmol) of trifluoroacetic acid. The mixture was stirred for 4.5 h at 0 ° C and then concentrated. The residue was taken up in acetonitrile and purified by preparative HPLC (Method 4). There was obtained 42 mg (70% of theory, purity 98%) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.98 (d, 2H), 7.49-7.44 (m, 2H), 7.44-7.37 (m, 2H), 7.37-7.31 (m, 1H), 7.13 (d, 2H), 5.21 (s, 2H), 4.57 (d, 2H), 4.11 ( d, 1H), 3.24 (t, 1H), 2.95-2.79 (m, 1H), 2.17-2.05 (m, 1H), 1.99-1.87 (m, 1H), 1.72-1.61 (m, 1H), 1.59- 1.45 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.29 min, m / z = 552 [M + H] ⁺ . Example 12

(+/-) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(4-fluorobenzyl) oxy] benzoyl} -5- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 //) - yl] -methyl} cyclopentanecarboxylic acid (racemate)

A solution of 189 mg (0.28 mmol) of the compound from Example 15A in 1.6 ml of dichloromethane was admixed at 0 ° C. with 0.8 ml (10.46 mmol) of trifluoroacetic acid. The mixture was 2.5 h at Stirred 0 ° C and then concentrated. The residue was taken up in 2 ml of acetonitrile and purified by preparative HPLC (Method 4). There were obtained 140 mg (87% of theory, purity 100%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (s, IH), 8.51 (s, IH), 8.46-8.37 (m, 2H), 7.98 (d, 2H), 7.52 ( dd, 2H), 7.23 (t, 2H), 7.12 (d, 2H), 5.19 (s, 2H), 4.57 (d, 2H), 4.11 (dd, IH), 3.24 (t, IH), 2.94-2.79 (m, IH), 2.17-2.04 (m, IH), 2.00-1.87 (m, IH), 1.73-1.61 (m, IH), 1.59-1.45 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.25 min, m / z = 570 [M + H] ⁺ .

Separation of the enantiomers:

131 mg of the racemic compound from Example 12 were dissolved in 6 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 13 and 14) [column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm; Flow: 80 ml / min; Detection: 220 nm; Injection volume: 0.75 ml; Temperature: 40 ° C; Eluent: 70% carbon dioxide / 30% ethanol; Total running time 10 min]. Example 13

(+) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(4-fluorobenzyl) oxy] benzoyl} -5- {[4-oxo-6- (trifluoromethyl ) -l, 2,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 47 mg; ee value = 100%

[from ²⁰ = + 79.1 °, 589 nm, c = 0.32 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, IH), 8.51 (s , IH), 8.46-8.38 (m, 2H), 7.98 (d, 2H), 7.52 (dd, 2H), 7.23 (t, 2H), 7.12 (d, 2H), 5.19 (s, 2H), 4.57 ( d, 2H), 4.11 (dd, IH), 3.23 (t, IH), 2.94-2.79 (m, IH), 2.17-2.04 (m, IH), 1.99-1.86 (m, IH), 1.73-1.61 ( m, IH), 1.59-1.46 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.26 min, m / z = 570 [M + H] ⁺ . Example 14

(-) - _(l S ^lR5,2R, ^5.S, R) -2- {4 - [(4-fluorobenzyl) oxy] benzoyl} -5- {[4-oxo-6- (trifluoromethyl) -l , 2,3-benzotriazine-3 (4 //) - yl] -methyl} cyclopentanecarboxylic acid (enantiomer 2)

Yield: 49 mg; ee value = 100% [a] _D ²⁰ = -81.2 °, 589 nm, c = 0.38 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.98 (d, 2H), 7.52 (dd, 2H), 7.23 (t, 2H), 7.12 (d, 2H), 5.19 (s, 2H), 4.57 (d, 2H), 4.11 (dd, 1H), 3.24 (t, 1H), 2.94 -2.78 (m, 1H), 2.17-2.04 (m, 1H), 2.02-1.86 (m, 1H), 1.74-1.60 (m, 1H), 1.59-1.45 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.26 min, m / z = 570 [M + H] ⁺ . Example 15

(+/-) - _(l S ^lR5,2R, ^5.S, R) -2- {4 - [(3-methylbenzyl) oxy] benzoyl} -5- {[4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 //) - yl] -methyl} cyclopentanecarboxylic acid (racemate)

A solution of 182 mg (0.27 mmol) of the compound from Example 16A in 3 ml of dichloromethane was added at 0 ° C with 0.78 ml (10.12 mmol) of trifluoroacetic acid. The mixture was stirred for 1.5 h at 0 ° C and then concentrated. The residue was taken up in 3 ml of acetonitrile and purified by preparative HPLC (Method 4). 110 mg (71% of theory, purity 100%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 8.51 (s, 1H), 8.47-8.36 (m, 2H), 7.97 (d, 2H), 7.32-7.21 (m, 3H), 7.18-7.08 (m, 3H), 5.16 (s, 2H), 4.57 (d, 2H), 4.15-4.04 (m, 1H), 3.24 (t, 1H), 2.94- 2.80 (m, 1H), 2.32 (s, 3H), 2.18-2.05 (m, 1H), 1.99-1.87 (m, 1H), 1.72-1.61 (m, 1H), 1.59-1.43 (m, 1H). LC / MS (Method 1, ESIpos): R _t = 1.34 min, m / z = 566 [M + H] ⁺ .

Separation of the enantiomers:

101 mg of the racemic compound from Example 15 were dissolved in 4 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 16 and 17) [column: Daicel Chiralpak AZ-H, 5 μm, 250 mm × 20 mm; Flow: 80 ml / min; Detection: 220 nm; injection volume: 0.75 ml; Temperature: 35 ° C; Eluent: 65% carbon dioxide / 35% ethanol; Total running time 9 min].

Example 16

(+) - (1R5,2R5,55R) -2- {4 (3-methylbenzyl) oxy] benzoyl} -5- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 ( 4 //) - yl] methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 43 mg; ee value = 100%

[from ²⁰ = + 75.5 °, 589 nm, c = 0.38 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.97 (d, 2H), 7.31-7.22 (m, 3H), 7.18-7.09 (m, 3H), 5.16 (s, 2H), 4.57 (d, 2H), 4.15-4.06 (m, 1H), 3.24 (t, 1H), 2.93- 2.81 (m, 1H), 2.32 (s, 3H), 2.17-2.05 (m, 1H), 1.99-1.87 (m, 1H), 1.72-1.61 (m, 1H), 1.58-1.46 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.29 min, m / z = 566 [M + H] ⁺ . Example 17

(-) - _(l S ^lR5,2R, ^5.S, R) -2- {4 - [(3-methylbenzyl) oxy] benzoyl} -5- {[4-oxo-6- (trifluoromethyl) -l , 2,3-benzotriazine-3 (4 //) - yl] -methyl} cyclopentanecarboxylic acid (enantiomer 2)

Yield: 44 mg; ee value = 100%

[a] _D ²⁰ = -94.1 °, 589 nm, c = 0.36 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.97 (d, 2H), 7.32-7.22 (m, 3H), 7.18-7.09 (m, 3H), 5.16 (s, 2H), 4.57 (d, 2H), 4.15-4.05 (m, 1H), 3.24 (t, 1H), 2.93- 2.80 (m, 1H), 2.32 (s, 3H), 2.17-2.05 (m, 1H), 2.00-1.87 (m, 1H), 1.73-1.60 (m, 1H), 1.58-1.46 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.29 min, m / z = 566 [M + H] ⁺ . Example 18

(+/-) - (IR 5,25 R, 5 R 5) -2- {[4-Oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4-yl) methyl} -5- (4 - {[3- (trifluoromethyl) benzyl] oxy} benzoyl) cyclopentanecarboxylic acid (racemate)

A solution of 180 mg (0.25 mmol) of the compound from Example 17A in 1.4 ml of dichloromethane was treated at 0 ° C with 0.71 ml (9.23 mmol) of trifluoroacetic acid. The mixture was stirred for 1.5 h at 0 ° C and then concentrated. The residue was taken up in 3 ml of acetonitrile and purified by preparative HPLC (Method 4). There were obtained 128 mg (83% of theory, purity 100%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.99 (d, 2H), 7.84 (s, 1H), 7.79 (d, 1H), 7.75-7.70 (m, 1H), 7.68-7.61 (m, 1H), 7.15 (d, 2H), 5.32 (s, 2H), 4.57 (d, 2H), 4.16-4.06 (m, 1H), 3.24 (t, 1H), 2.95-2.80 (m, 1H), 2.18-2.05 (m, 1H), 1.99-1.87 (m, 1H), 1.72-1.61 ( m, 1H), 1.58-1.44 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.35 min, m / z = 620 [M + H] ⁺ .

Separation of the enantiomers:

120 mg of the racemic compound from Example 18 were dissolved in 4 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 19 and 20) [column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm; Flow: 220 ml / min; Detection: 220 nm; Injection volume: 0.50 ml; Temperature: 35 ° C; Eluent: 70% carbon dioxide / 30% ethanol; Total running time 6 min].

Example 19

(+) - (IRS, 2SR, 5RS) -2- {[4-oxo-6- (trifl ^^

(trifluoromethyl) benzyl] oxy} benzoyl) cyclopentanecarboxylic acid (enantiomer 1)

Yield: 52 mg; ee value = 100%

[a] _D ²⁰ = + 73.1 °, 589 nm, c = 0.37 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.99 (d, 2H), 7.84 (s, 1H), 7.79 (d, 1H), 7.75-7.69 (m, 1H), 7.68-7.61 (m, 1H), 7.15 (d, 2H), 5.32 (s, 2H), 4.57 (d, 2H), 4.16-4.05 (m, 1H), 3.24 (t, 1H), 2.93-2.80 (m, 1H), 2.17-2.06 (m, 1H), 2.00-1.87 (m, 1H), 1.73-1.61 (m, 1H), 1.59-1.45 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.30 min, m / z = 620 [M + H] ⁺ .

Example 20 (-) - (IRS, 2SR RS) -2- {[4-Oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4f) -yl] methyl} -5- (4 - {[3- (trifluoromethyl) benzyl] oxy} benzoyl) cyclopentanecarboxylic acid (enantiomer 2)

Yield: 52 mg; ee value = 100%

[from ²⁰ = -77.5 °, 589 nm, c = 0.37 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.99 (d, 2H), 7.84 (s, 1H), 7.79 (d, 1H), 7.75-7.70 (m, 1H), 7.68-7.63 (m, 1H), 7.15 (d, 2H), 5.32 (s, 2H), 4.57 (d, 2H), 4.16-4.07 (m, 1H), 3.24 (t, 1H), 2.93-2.82 (m, 1H), 2.18-2.05 (m, 1H), 2.02-1.87 (m, 1H), 1.73-1.61 ( m, 1H), 1.59-1.46 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.30 min, m / z = 620 [M + H] ⁺ .

Example 21 (+/-) - (IRS, 2RS, 5SR) -2- {4- [(3-chlorobenzyl) oxy] benzoyl} -5- {[4-oxo-6- (trifluoromethyl) -1, 2, 3-benzotriazine-3 (4 //) - yl] methyl} cyclopentanecarboxylic acid (racemate)

A solution of 108 mg (0.16 mmol) of the compound from Example 18A in 0.5 ml of dichloromethane was added at 0 ° C with 0.25 ml of trifluoroacetic acid. The mixture was stirred for 1.5 h at 0 ° C and then concentrated. The residue was purified by preparative HPLC (Method 4). There were obtained 71 mg (77% of theory, purity 100%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.98 (d, 2H), 7.54 ( s, 1H), 7.47-7.39 (m, 3H), 7.13 (d, 2H), 5.23 (s, 2H), 4.57 (d, 2H), 4.16-4.07 (m, 1H), 3.24 (t, 1H), 2.93-2.81 (m, 1H), 2.17-2.05 (m, 1H), 1.99-1.87 (m, 1H), 1.72-1.62 (m, 1H), 1.58- 1.46 (m, 1H ).

LC / MS (Method 1, ESIpos): R _t = 1.31 min, m / z = 586 [M + H] ⁺ .

Separation of the enantiomers:

62 mg of the racemic compound from Example 21 were dissolved in 6 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 22 and 23) [column: Daicel Chiralpak IC, 5 μm, 250 mm × 20 mm; Flow: 80 ml / min; Detection: 220 nm; Injection volume: 0.6 ml; Temperature: 40 ° C; Eluent: 70% carbon dioxide / 30% ethanol; Total running time 15 min]. Example 22

(-) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(3-chlorobenzyl) oxy] benzoyl} -5- {[4-oxo-6- (trifluoromethyl ) -l, 2,3-benzotriazine-3 (4 //) - yl] -methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 26 mg; ee value = 100%

[a] _D ²⁰ = -88.5 °, 589 nm, c = 0.39 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.14 (s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.98 (d, 2H), 7.54 (s, 1H), 7.48-7.37 (m, 3H), 7.13 (d, 2H), 5.23 (s, 2H), 4.57 (d, 2H), 4.15-4.05 (m, 1H), 3.24 (t, 1H), 2.94-2.80 (m, 1H), 2.17-2.04 (m, 1H), 1.99-1.87 (m, 1H), 1.72 -1.62 (m, 1H), 1.58- 1.44 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.31 min, m / z = 586 [M + H] ⁺ . Example 23

(+) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(3-chlorobenzyl) oxy] benzoyl} -5- {[4-oxo-6- (trifluoromethyl ) -l, 2,3-benzotriazine-3 (4 //) - yl] -methyl} cyclopentanecarboxylic acid (enantiomer 2)

Yield: 25 mg; ee value = 97%

[a] _D ²⁰ = + 80.0 °, 589 nm, c = 0.37 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.14 (br. s, 1H), 8.51 ( s, 1H), 8.46-8.37 (m, 2H), 7.98 (d, 2H), 7.54 (s, 1H), 7.47-7.37 (m, 3H), 7.13 (d, 2H), 5.23 (s, 2H) , 4.57 (d, 2H), 4.16-4.05 (m, 1H), 3.24 (t, 1H), 2.94-2.79 (m, 1H), 2.17-2.05 (m, 1H), 1.99-1.87 (m, 1H) , 1.72-1.61 (m, 1H), 1.58-1.46 (m, 1H). LC / MS (Method 1, ESIpos): R _t = 1.31 min, m / z = 586 [M + H] ⁺ . Example 24

(+/-) - (IRS, 2RS, 5SR) -2- {4- [(4-chlorobenzyl) oxy] benzoyl} -5- {[4-oxo-6- (tri-methyl) -1,3,3- benzotriazine-3 (4 //) - yl] methyl} cyclopentanecarboxylic acid (racemate)

A solution of 111.1 mg (0.16 mmol) of the compound from Example 19A in 0.9 ml of dichloromethane was treated at 0 ° C. with 0.46 ml (5.99 mmol) of trifluoroacetic acid. The mixture was stirred for 2.5 h at 0 ° C and then concentrated. The residue was taken up in 2 ml of acetonitrile and purified by preparative HPLC (Method 4). There were obtained 72 mg (75% of theory, purity 100%) of the title compound.

Ή NMR (400 MHz, DMSO-de): δ [ppm] = 12.14 (s, IH), 8.51 (s, IH), 8.46-8.38 (m, 2H), 7.98 (d, 2H), 7.51-7.44 (m, 4H), 7.12 (d, 2H), 5.21 (s, 2H), 4.57 (d, 2H), 4.14-4.07 (m, IH), 3.24 (t, IH), 2.93-2.79 (m, IH ), 2.17-2.05 (m, IH), 1.98-1.88 (m, IH), 1.72-1.61 (m, IH), 1.58-1.46 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.30 min, m / z = 586 [M + H] ⁺ . Separation of the enantiomers:

63 mg of the racemic compound from Example 24 were dissolved in 3 ml of acetonitrile / ethanol (2: 1) and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 25 and 26) [column: Daicel Chiralpak AD-H, 5 μιη , 250 mm x 20 mm; Flow: 20 ml / min; Detection: 220 nm; Injection volume: 0.25 ml; Temperature: 20 ° C; Eluent: t = 0-8 min 30% acetonitrile / 70% ethanol + 0.2% acetic acid].

Example 25

(+) - (lR _l ^S, 2R S _^l, 5 _l ^S, R) -2- {4 - [(4-chlorobenzyl) oxy] benzoyl} -5- {[4-oxo-6- (trifluoromethyl ) -l, 2,3-benzotriazine-3 (4 //) - yl] methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 22 mg; ee value = 100% [a] _D ²⁰ = + 80.0 °, 589 nm, c = 0.28 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.98 (d, 2H), 7.52-7.43 (m, 4H), 7.12 (d, 2H), 5.21 (s, 2H), 4.57 (d, 2H), 4.14-4.06 (m, 1H), 3.23 (t, 1H), 2.93-2.80 ( m, 1H), 2.17-2.05 (m, 1H), 1.99-1.86 (m, 1H), 1.72-1.61 (m, 1H), 1.58-1.46 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.35 min, m / z = 586 [M + H] ⁺ . Example 26

(-) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(4-chlorobenzyl) oxy] benzoyl} -5- {[4-oxo-6- (trifluoromethyl ) -l, 2,3-benzotriazine-3 (4 //) - yl] -methyl} cyclopentanecarboxylic acid (enantiomer 2) Yield: 27 mg; ee value = 97%

[a] _D ²⁰ = -85.5 °, 589 nm, c = 0.22 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.98 (d, 2H), 7.52-7.43 (m, 4H), 7.12 (d, 2H), 5.21 (s, 2H), 4.57 (d, 2H), 4.15-4.06 (m, 1H), 3.23 (t, 1H), 2.93-2.79 ( m, 1H), 2.17-2.05 (m, 1H), 1.99-1.86 (m, 1H), 1.72-1.61 (m, 1H), 1.58-1.45 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.35 min, m / z = 586 [M + H] ⁺ .

Example 27

(+/-) - _(l S ^lR5,2R, ^5.S, R) -2- {4 - [(3,4-dichlorobenzyl) oxy] benzoyl} -5- {[4-oxo-6- ( trifluoromethyl) -1,3,3-benzotriazine-3 (4 //) - yl] -methyl} cyclopentanecarboxylic acid (racemate)

A solution of 218 mg (0.30 mmol) of the compound from Example 20A in 1.7 ml of dichloromethane was added at 0 ° C with 0.9 ml (11.20 mmol) of trifluoroacetic acid. The mixture was stirred for 2.5 h at 0 ° C and then concentrated. The residue was taken up in 2 ml of acetonitrile and purified by preparative HPLC (Method 4). 170 mg (91% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, IH), 8.51 (s, IH), 8.46-8.38 (m, 2H), 7.99 (d, 2H), 7.75 (d, IH), 7.68 (d, IH), 7.46 (dd, IH), 7.13 (d, 2H), 5.23 (s, 2H), 4.57 (d, 2H), 4.15-4.07 (m, IH) , 3.24 (t, IH), 2.94-2.80 (m, IH), 2.17-2.04 (m, IH), 2.00-1.88 (m, IH), 1.72-1.60 (m, IH), 1.58-1.45 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.35 min, m / z = 520 [M + H] ⁺ . Separation of the enantiomers:

162 mg of the racemic compound from Example 27 were dissolved in 5 ml of methanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 28 and 29) [column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm; Flow: 80 ml / min; Detection: 220 nm; Injection volume: 0.75 ml; Temperature: 40 ° C; Eluent: 70% carbon dioxide / 30% ethanol; Total running time 10 min].

Example 28 (+) - _(l S ^lR5,2R, ^5.S, R) -2- {4 - [(3,4-dichlorobenzyl) oxy] benzoyl} -5- {[4-oxo-6- ( trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 72 mg; ee value = 100%

[from ²⁰ = + 77.4 °, 589 nm, c = 0.37 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, IH), 8.51 (s, IH), 8.46-8.38 (m, 2H), 7.99 (d, 2H), 7.75 (d, IH), 7.68 (d, IH), 7.46 (dd, IH), 7.13 (d, 2H), 5.23 (s, 2H), 4.57 (d, 2H), 4.15-4.06 (m, IH) , 3.24 (t, IH), 2.93-2.80 (m, IH), 2.18-2.04 (m, IH), 2.01-1.87 (m, IH), 1.73-1.61 (m, IH), 1.59-1.45 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.36 min, m / z = 520 [M + H] ⁺ . Example 29 (-) - _(l S ^lR5,2R, ^5.S, R) -2- {4 - [(3,4-dichlorobenzyl) oxy] benzoyl} -5- {[4-oxo-6- ( trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylic acid (enantiomer 2)

Yield: 73 mg; ee value = 100%

[a] _D ²⁰ = -80.8 °, 589 nm, c = 0.36 g / 100 ml, chloroform Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.99 (d, 2H), 7.75 (d, 1H), 7.67 (d, 1H), 7.46 (dd, 1H), 7.13 (d, 2H), 5.23 (s, 2H), 4.57 (d, 2H), 4.16-4.06 (m, 1H) , 3.24 (t, 1H), 2.94-2.80 (m, 1H), 2.19-2.04 (m, 1H), 1.99-1.87 (m, 1H), 1.73-1.61 (m, 1H), 1.58-1.45 (m, 1H). LC / MS (Method 1, ESIpos): R _t = 1.35 min, m / z = 520 [M + H] ⁺ .

Example 30

(+/-) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4 - ({3 - [(methoxycarbonyl) amino] benzyl} oxy) benzoyl] -5- {[ 4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylic acid (racemate)

A solution of 185 mg (0.26 mmol) of the compound from Example 21 A in 1.5 ml of dichloromethane was treated at 0 ° C with 0.73 ml (9.44 mmol) of trifluoroacetic acid. The mixture was stirred for 1.5 h at 0 ° C and then concentrated. The residue was taken up in 2 ml of acetonitrile and purified by preparative HPLC (Method 4). 113 mg (71% of theory, purity 100%) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 9.71 (s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.97 (d, 2H), 7.57 (s, 1H), 7.42 (d, 1H), 7.30 (t, 1H), 7.14-7.05 (m, 3H), 5.17 (s, 2H), 4.57 (d, 2H) , 4.15-4.06 (m, 1H), 3.66 (s, 3H), 3.24 (t, 1H), 2.94-2.81 (m, 1H), 2.18-2.05 (m, 1H), 1.99- 1.87 (m, 1H) , 1.73-1.61 (m, 1H), 1.58-1.45 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.19 min, m / z = 625 [M + H] ⁺ . Separation of the enantiomers:

104 mg of the racemic compound from Example 30 were dissolved in 5 ml of ethanol and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 31 and 32) [column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm; Flow: 12 ml / min; Detection: 220 nm; Injection volume: 1 ml; Temperature: 45 ° C; Eluent: t = 0-15 min 100% ethanol + 0.2% acetic acid]. Example 31

(+) - (IR 5,2 R 5,55 R) -2 4 - ({3 (methoxycarbonyl) amino] benzyl} oxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -1, 2, 3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 39 mg; ee value = 99% [a] _D ²⁰ = + 74.0 °, 589 nm, c = 0.38 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 9.70 (s, 1H), 8.51 (s, 1H), 8.45-8.38 (m, 2H), 7.97 (d, 2H), 7.56 (s, 1H), 7.42 (d, 1H), 7.30 (t, 1H), 7.14-7.05 (m, 3H), 5.17 (s, 2H), 4.57 (d, 2H) , 4.15-4.06 (m, 1H), 3.66 (s, 3H), 3.23 (t, 1H), 2.93-2.81 (m, 1H), 2.16-2.05 (m, 1H), 1.99- 1.87 (m, 1H) , 1.73-1.61 (m, 1H), 1.59-1.45 (m, 1H). LC / MS (Method 1, ESIpos): R _t = 1.19 min, m / z = 625 [M + H] ⁺ .

Example 32

(-) - (lRS, 2RS, 5SR) -2- [4- ({3 - [(methoxycarbonyl) amino] benzyl} oxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) - l, 2,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylic acid (enantiomer 2)

Yield: 35 mg; ee value = 99% [α] _D ²⁰ = -75.3 °, 589 nm, c = 0.32 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 9.70 (s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.97 (d, 2H), 7.56 (s, 1H), 7.42 (d, 1H), 7.30 (t, 1H), 7.14-7.05 (m, 3H), 5.17 (s, 2H), 4.57 (d, 2H) , 4.15-4.06 (m, 1H), 3.66 (s, 3H), 3.23 (t, 1H), 2.94-2.79 (m, 1H), 2.17-2.04 (m, 1H), 1.99- 1.87 (m, 1H) , 1.73-1.61 (m, 1H), 1.58-1.44 (m, 1H). LC / MS (Method 1, ESIpos): R _t = 1.19 min, m / z = 625 [M + H] ⁺ .

Example 33

(+/-) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- (4- {[3- (2-oxo-l, 3-oxazolidin-3-yl) benzyl] oxy} benzoyl) -5- {[4-OX0-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentane carboxylic acid (racemate)

A solution of 157 mg (0.21 mmol) of the compound from Example 22A in 1.2 ml of dichloromethane was treated at 0 ° C with 0.6 ml (7.87 mmol) of trifluoroacetic acid. The mixture was stirred for 1.5 h at 0 ° C and then concentrated. The residue was taken up in 2 ml of acetonitrile and purified by preparative HPLC (Method 4). 117 mg (87% of theory, purity 100%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.98 (d, 2H), 7.70 (s, 1H), 7.53 (d, 1H), 7.42 (t, 1H), 7.22 (d, 1H), 7.13 (d, 2H), 5.23 (s, 2H), 4.57 (d, 2H), 4.44 (t, 2H), 4.15-4.02 (m, 3H), 3.24 (t, 1H), 2.94-2.80 (m, 1H), 2.17-2.05 (m, 1H), 1.99-1.87 (m, 1H), 1.73 -1.61 (m, 1H), 1.59-1.45 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.15 min, m / z = 637 [M + H] ⁺ .

Separation of the enantiomers:

108 mg of the racemic compound from Example 33 were dissolved in 2 ml of acetonitrile / 4 ml of ethanol and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 34 and 35) [column: Daicel Chiralpak IC, 5 μm, 250 mm × 20 mm; Flow: 12 ml / min; Detection: 220 nm; Injection volume: 1.5 ml; Temperature: 45 ° C; Eluent: t = 0-25 min 100% ethanol + 0.2% acetic acid].

Example 34

(-) - _(l S ^lR5,2R, ^5.S, R) -2- (4- {[3- (2-oxo-l, 3-oxazolidin-3-yl) benzyl] oxy} benzoyl) - 5- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 46 mg; ee value = 99%

[from ²⁰ = -70.9 °, 589 nm, c = 0.42 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.98 (d, 2H), 7.70 (s, 1H), 7.53 (dd, 1H), 7.42 (t, 1H), 7.22 (d, 1H), 7.12 (d, 2H), 5.22 (s, 2H), 4.57 (d, 2H), 4.44 (t, 2H), 4.15-4.02 (m, 3H), 3.23 (t, IH), 2.93-2.80 (m, IH), 2.17-2.03 (m, IH), 1.99-1.86 (m, IH), 1.72-1.61 (m, IH), 1.59-1.46 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.16 min, m / z = 637 [M + H] ⁺ . Example 35 (+) - (IRS, 2RS, 5SR) -2- (4- {[3- (2-Oxo-1,3-oxazolidin-3-yl) benzyl] oxy} benzoyl) -5- {[4 -oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylic acid (enantiomer 2)

Yield: 50 mg; ee value = 99%

[from ²⁰ = + 70.3 °, 589 nm, c = 0.39 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, IH), 8.51 (s, IH), 8.46-8.37 (m, 2H), 7.98 (d, 2H), 7.70 (s, IH), 7.53 (dd, IH), 7.42 (t, IH), 7.22 (d, IH), 7.12 (d, 2H), 5.22 (s, 2H), 4.57 (d, 2H), 4.47 -4.40 (m, 2H), 4.14-4.02 (m, 3H), 3.22 (t, IH), 2.93-2.80 (m, IH), 2.17-2.04 (m, IH), 1.98-1.86 (m, IH) , 1.72-1.61 (m, IH), 1.58-1.45 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.16 min, m / z = 637 [M + H] ⁺ .

Example 36 (+/-) - (1R5,25R, 5R5) -2- {[4-Oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) - yl] methyl} -5 - [4- (2-phenylethoxy) benzoyl] cyclopentane carboxylic acid (racemate)

A solution of 236 mg (0.35 mmol) of the compound from Example 23A in 2 ml of dichloromethane was treated at 0 ° C with 1 ml (13.12 mmol) of trifluoroacetic acid. The mixture was stirred for 2 h at 0 ° C and then concentrated. The residue was taken up in 3 ml of acetonitrile and purified by preparative HPLC (Method 4). 150 mg (75% of theory, purity 100%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, IH), 8.50 (s, IH), 8.46-8.38 (m, 2H), 7.95 (d, 2H), 7.36-7.27 (m, 4H), 7.26-7.19 (m, IH), 7.05 (d, 2H), 4.57 (d, 2H), 4.29 (t, 2H), 4.14-4.05 (m, IH), 3.23 (t, IH), 3.06 (t, 2H), 2.93-2.81 (m, IH), 2.16-2.05 (m, IH), 1.99-1.87 (m, IH), 1.72-

1.60 (m, IH), 1.58-1.46 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 566 [M + H] ⁺ .

Separation of the enantiomers:

142 mg of the racemic compound from Example 36 were dissolved in 3 ml of ethanol and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 37 and 38) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 230 nm; Injection volume: 0.05 ml; Temperature: 25 ° C; Eluent: t = 0-12 min 86% acetonitrile / 10% ethanol / 4% 5% acetic acid in acetonitrile]. Example 37

(+) - (IRS, 2SR, 5RS) -2- {[4-oxo-6- (trifl ^^

phenylethoxy) benzoyl] cyclopentanecarboxylic acid (enantiomer 1)

Yield: 43 mg; ee value = 100%

[a] _D ²⁰ = + 77.5 °, 589 nm, c = 0.39 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, IH), 8.50 (s, IH), 8.46-8.38 (m, 2H), 7.95 (d, 2H), 7.36-7.27 (m, 4H), 7.26-7.19 (m, IH), 7.05 (d, 2H), 4.56 (i.e. , 2H), 4.29 (t, 2H), 4.14-4.05 (m, IH), 3.23 (t, IH), 3.06 (t, 2H), 2.93-2.80 (m, IH), 2.17-2.04 (m, IH ), 2.00-1.87 (m, IH), 1.73-

1.61 (m, IH), 1.58-1.45 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.28 min, m / z = 566 [M + H] ⁺ . Example 38

(-) - (lRS, 2 SR, 5 RS) -2- {

phenylethoxy) benzoyl] cyclopentanecarboxylic acid (enantiomer 2)

Yield: 34 mg; ee value = 99%

[a] _D ²⁰ = -84.3 °, 589 nm, c = 0.40 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, IH), 8.50 (s, IH), 8.46-8.37 (m, 2H), 7.95 (d, 2H), 7.36-7.28 (m, 4H), 7.26-7.19 (m, IH), 7.05 (d, 2H), 4.56 (i.e. , 2H), 4.29 (t, 2H), 4.15-4.04 (m, IH), 3.23 (t, IH), 3.06 (t, 2H), 2.93-2.80 (m, IH), 2.17-2.04 (m, IH ), 2.00-1.87 (m, IH), 1.72-1.60 (m, IH), 1.58-1.43 (m, IH). LC / MS (Method 1, ESIpos): R _t = 1.28 min, m / z = 566 [M + H] ⁺ . Example 39

(+/-) - (lRS, 2SR, 5RS) -2- {[4-oxo-6- (trffl ^^

phenylpropoxy) benzoyl] cyclopentanecarboxylic acid (racemate)

A solution of 37 mg (0.08 mmol) of the compound from Example 24A in 0.17 ml of dichloromethane was added at 0 ° C with 0.09 ml of trifluoroacetic acid. The mixture was stirred first at 0 ° C. for 15 minutes, then at RT for 1 h and then concentrated. The residue was purified by preparative HPLC (Method 4). 18 mg (58% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (s, 1H), 8.51 (s, 1H), 8.47-8.37 (m, 2H), 7.96 (d, 2H), 7.32- 7.14 (m, 5H), 7.04 (d, 2H), 4.57 (d, 2H), 4.14-4.02 (m, 3H), 3.24 (t, 1H), 2.94-2.81 (m, 1H), 2.75 (t, 2H), 2.18-1.99 (m, 3H), 1.99-1.88 (m, 1H), 1.73-1.61 (m, 1H), 1.59-1.45 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 580 [M + H] ⁺ . Example 40

(+/-) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (cyclohexylmethoxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -l , 2,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylic acid (racemate)

A solution of 175 mg (0.27 mmol) of the compound from Example 25 A in 0.9 ml of dichloromethane was added at 0 ° C with 0.45 ml (5.84 mmol) of trifluoroacetic acid. The mixture was stirred for 2.5 h at 0 ° C and then concentrated. The residue was taken up in 2 ml of acetonitrile. This precipitated a solid, which was filtered off and dried in vacuo. 97 mg (65% of theory, purity 99%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (s, IH), 8.51 (s, IH), 8.46-8.38 (m, 2H), 7.95 (d, 2H), 7.03 ( d, 2H), 4.57 (d, 2H), 4.14-4.04 (m, IH), 3.87 (d, 2H), 3.24 (t, IH), 2.93-2.80 (m, IH), 2.18-2.04 (m, IH), 1.99-1.87 (m, IH), 1.85-1.60 (m, 7H), 1.58-1.46 (m, IH), 1.32-1.11 (m, 3H), 1.11-0.97 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.40 min, m / z = 558 [M + H] ⁺ .

Separation of the enantiomers:

89 mg of the racemic compound from Example 40 were dissolved in 4 ml of ethanol while warm and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 41 and 42) [column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm; Flow: 15 ml / min; Detection: 220 nm; Injection volume: 1.4 ml; Temperature: 45 ° C; Eluent: t = 0-12 min 25% isohexane / 75% ethanol + 0.2% acetic acid].

Example 41

(+) - (lR _l ^S, 2R S _^l, 5 _l ^S, R) -2- [4- (cyclohexylmethoxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -l, 2 , 3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylic acid (enantiomer 1) Yield: 38 mg; ee value = 100%

[from ²⁰ = + 93.0 °, 589 nm, c = 0.11 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, IH), 8.51 (s, IH), 8.46-8.37 (m, 2H), 7.95 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.14-4.05 (m, IH), 3.87 (d, 2H), 3.23 (t, IH), 2.93-2.80 (m, IH), 2.17-2.03 ( m, IH), 2.00-1.87 (m, IH), 1.84-1.60 (m, 7H), 1.58-1.46 (m, IH), 1.32-1.12 (m, 3H), 1.11-0.97 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.45 min, m / z = 558 [M + H] ⁺ .

Example 42

(-) - (lR _l ^S, 2R S _^l, 5 _l ^S, R) -2- [4- (cyclohexylmethoxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -l, 2 , 3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylic acid (enantiomer 2) Yield: 39 mg; ee value = 100%

[a] _D ²⁰ = -86.6 °, 589 nm, c = 0.38 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.14 (br.s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.95 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.14-4.05 (m, 1H), 3.87 (d, 2H), 3.23 (t, 1H), 2.93-2.79 (m, 1H), 2.17-2.04 (m , 1H), 1.99-1.86 (m, 1H), 1.85-1.60 (m, 7H), 1.58-1.44 (m, 1H), 1.22 (d, 3H), 1.11-0.97 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.45 min, m / z = 558 [M + H] ⁺ .

Example 43

(+/-) - (1 ^, 2 ^, 5 ^) - 2- [4- (€ γο1ορεηΙγ ^ εώοχγ ^ εηζογ1] -5- {[4-οχο-6- (Ιπί1υο ™ εώγ1) -1,2 , 3-Benzotriazine-3 (4 //) - yl] methyl} cyclopentanecarboxylic acid (racemate)

A solution of 206 mg (0.31 mmol) of the compound from Example 26A in 1 ml of dichloromethane was treated at 0 ° C with 0.5 ml (6.88 mmol) of trifluoroacetic acid. The mixture was stirred first at 0 ° C. for 15 minutes, then at RT for 1 h and then concentrated. The residue was purified by preparative HPLC (Method 4). 173 mg (> 100% of theory, purity -100%, still solvent-containing) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.95 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.15-4.05 (m, 1H), 3.94 (d, 2H), 3.24 (t, 1H), 2.93-2.80 (m, 1H), 2.39-2.23 ( m, 1H), 2.18-2.04 (m, 1H), 2.00-1.87 (m, 1H), 1.83-1.72 (m, 2H), 1.72-1.46 (m, 6H), 1.38-1.26 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.34 min, m / z = 544 [M + H] ⁺ .

Separation of the enantiomers:

166 mg of the racemic compound from Example 43 were dissolved in 6 ml of acetonitrile / ethanol (1: 1) and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 44 and 45) [column: Daicel Chiralpak AD SFC, 5 μιη, 250 mm x 20 mm; Flow: 100 ml / min; detection: 220 nm; Injection volume: 0.2 ml; Temperature: 30 ° C; Eluent: 70% carbon dioxide / 30% ethanol; Total running time 11 min].

Example 44

(+) - (1 ^, 2 ^, 5 ^) - 2- [4- (€ γο1ορεηΙγ ^ εώοχγ ^ εηζογ1] -5- {[4-οχο-6- (ΙπίΊυο ™ εώγ1) -1,2,3 ^ εηζο-triazine-3 (4 //) - yl] -methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 76 mg; ee value = 100%

[from ²⁰ = + 85.1 °, 589 nm, c = 0.41 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.95 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.14-4.06 (m, 1H), 3.94 (d, 2H), 3.24 (t, 1H), 2.94-2.80 (m, 1H), 2.38-2.25 ( m, 1H), 2.16-2.04 (m, 1H), 2.00-1.87 (m, 1H), 1.83-1.72 (m, 2H), 1.72-1.45 (m, 6H), 1.38-1.27 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.34 min, m / z = 544 [M + H] ⁺ . Example 45

(-) - (1R ₁ S ^, 2R ₁ S ^, 5.S ^, R) -2- [4- (cyclopentylmethoxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -1, 2 , 3-benzotriazine-3 (4 //) - yl] -methyl} cyclopentanecarboxylic acid (enantiomer 2)

Yield: 76 mg; ee value = 100%

[a] _D ²⁰ = -84.5 °, 589 nm, c = 0.39 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.95 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.15-4.04 (m, 1H), 3.94 (d, 2H), 3.23 (t, 1H), 2.95-2.80 (m, 1H), 2.39-2.24 ( m, 1H), 2.17-2.04 (m, 1H), 2.00-1.86 (m, 1H), 1.82-1.73 (m, 2H), 1.72-1.46 (m, 6H), 1.38-1.27 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.34 min, m / z = 544 [M + H]

Example 46

(+/-) - (lR _l ^S, 2R S _^l, 5 _l ^S, R) -2- [4- (cyclobutylmethoxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -l , 2,3-benzotriazine-3 (4 //) - yl] -methyl} cyclopentanecarboxylic acid (racemate)

A solution of 141 mg (0.22 mmol) of the compound from Example 27A in 1.3 ml of dichloromethane was admixed at 0.degree. C. with 0.64 ml (8.26 mmol) of trifluoroacetic acid. The mixture was stirred for 1.5 h at 0 ° C and then concentrated. The residue was taken up in 3 ml of acetonitrile and purified by preparative HPLC (Method 5). There were obtained 93 mg (78% of theory, purity 100%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.95 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.14-4.06 (m, 1H), 4.04 (d, 2H), 3.24 (t, 1H), 2.93-2.81 (m, 1H), 2.79-2.66 ( m, 1H), 2.17-2.02 (m, 3H), 1.99-1.77 (m, 5H), 1.72-1.61 (m, 1H), 1.58-1.46 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.34 min, m / z = 530 [M + H] ⁺ . Separation of the enantiomers:

83 mg of the racemic compound from Example 46 were dissolved in 4 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 47 and 48) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Flow: 80 ml / min; Detection: 220 nm; Injection volume: 0.75 ml; Temperature: 40 ° C; Eluent: 65% carbon dioxide / 35% ethanol; Total running time 8 min].

Example 47

(+) - (lR _l ^S, 2R S _^l, 5 _l ^S, R) -2- [4- (cyclobutylmethoxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -l, 2 , 3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 35 mg; ee value = 100%

[a] _D ²⁰ = + 86.7 °, 589 nm, c = 0.32 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.14 (br.s, 1H), 8.51 (s, 1H), 8.46-8.36 (m, 2H), 7.95 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.14-4.06 (m, 1H), 4.04 (d, 2H), 3.23 (t, 1H), 2.93-2.81 (m, IH), 2.80-2.67 (m, IH), 2.16-2.01 (m, 3H), 1.99-1.76 (m, 5H), 1.72-1.61 (m, IH), 1.58-1.46 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.29 min, m / z = 530 [M + H] ⁺ . Example 48 (-) - (1 ^, 2 ^, 5 ^) - 2- [4- (€ γου υΙγ ^ εώοχγ ^ εηζογ1] -5- {[4-οχο-6 (Ιπί1υο ™ εώγ1) -1 , 2,3,3-εηζο-triazine-3 (4 //) - yl] methyl} cyclopentanecarboxylic acid (enantiomer 2)

Yield: 35 mg; ee value = 100%

[a] _D ²⁰ = -90.1 °, 589 nm, c = 0.33 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, IH), 8.51 (s, IH), 8.46-8.38 (m, 2H), 7.95 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.14-4.06 (m, IH), 4.04 (d, 2H), 3.23 (t, IH), 2.93-2.80 (m, IH), 2.78-2.65 ( m, IH), 2.17-2.00 (m, 3H), 1.99-1.76 (m, 5H), 1.67 (d, IH), 1.58-1.46 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.29 min, m / z = 530 [M + H] ⁺ .

Example 49

(+/-) - (S lR5,2R _^l, 5 _l ^S, R) -2- [4- (cyclopropylmethoxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -l, 2, 3-benzotriazine-3 (4 //) - yl] methyl} cyclopentanecarboxylic acid (racemate)

A solution of 150 mg (0.24 mmol) of the compound from Example 28A in 0.82 ml of dichloromethane was mixed at 0 ° C. with 0.41 ml (5.33 mmol) of trifluoroacetic acid. The mixture was stirred first at 0 ° C. for 15 minutes, then at RT for 1 h and then concentrated. The residue was purified by preparative HPLC (Method 4). 79 mg (63% of theory, purity 100%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, IH), 8.51 (s, IH), 8.46-8.38 (m, 2H), 7.95 (d, 2H), 7.02 (d, 2H), 4.57 (d, 2H), 4.14-4.05 (m, IH), 3.91 (d, 2H), 3.23 (t, IH), 2.93-2.80 (m, 1H), 2.17-2.04 (m, 1H), 2.00-1.86 (m, 1H), 1.73-1.61 (m, 1H), 1.58-1.46 (m, 1H), 1.29-1.19 (m, 1H), 0.61- 0.54 (m, 2H), 0.37-0.30 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.21 min, m / z = 516 [M + H] ⁺ .

Example 50 (+/-) - (1 ^, 2 ^, 5 ^) - 2- [4- (2- € γο ^ εχγ1εώοχγ ^ εηζογ1] -5- {[4-oo-6- (ΙπίΊυο ™ εώγ1) -1,2,3 ^ εηζο-triazine-3 (4 //) - yl] methyl} cyclopentanecarboxylic acid (racemate)

A solution of 121 mg (0.18 mmol) of the compound from Example 29A in 1 ml of dichloromethane was treated at 0 ° C with 0.5 ml (6.49 mmol) of trifluoroacetic acid. The mixture was stirred for 2.5 h at 0 ° C and then concentrated. The residue was taken up in 2 ml of acetonitrile and purified by preparative HPLC (Method 4). 97 mg (94% of theory, purity 100%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.95 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.14-4.05 (m, 3H), 3.24 (t, 1H), 2.94-2.81 (m, 1H), 2.17-2.05 (m, 1H), 2.00- 1.87 (m, 1H), 1.78-1.40 (m, 9H), 1.29-1.07 (m, 4H), 1.01-0.88 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.43 min, m / z = 572 [M + H] ⁺ .

Separation of the enantiomers:

89 mg of the racemic compound from Example 50 were dissolved in 5 ml of isopropanol and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 51 and 52) [column: Daicel Chiralcel OZ-H, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 230 nm; Injection volume: 0.3 ml; Temperature: 25 ° C; Eluent: t = 0-20 min. 50% isohexane / 50% isopropanol + 0.2% acetic acid].

Example 51

(-) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (2-cyclohexylethoxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -l , 2,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylic acid (enantiomer 1) Yield: 38 mg; ee value = 100%

[a] _D ²⁰ = -76.3 °, 589 nm, c = 0.34 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.14 (br.s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.95 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.14-4.05 (m, 3H), 3.23 (t, 1H), 2.94-2.80 (m, 1H), 2.17-2.04 (m, 1H), 2.00-1.86 (m, 1H), 1.78-1.40 (m, 9H), 1.31-1.07 (m, 4H), 1.04-0.86 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 3.20 min, m / z = 572 [M + H] ⁺ .

Example 52

(+) - _(l S ^lR5,2R, ^5.S, R) -2- [4- (2-cyclohexylethoxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -l, 2, 3-benzotriazine-3 (4 //) - yl] -methyl} cyclopentanecarboxylic acid (enantiomer 2) Yield: 38 mg; ee value = 100%

[from ²⁰ = + 72.3 °, 589 nm, c = 0.39 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.95 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.14-4.05 (m, 3H), 3.23 (t, 1H), 2.93-2.81 (m, 1H), 2.17-2.04 (m, 1H), 1.99- 1.87 (m, 1H), 1.78-1.40 (m, 9H), 1.31-1.07 (m, 4H), 1.03-0.87 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 3.20 min, m / z = 572 [M + H] ⁺ .

Example 53

(+/-) - _(l S ^lR5,2R, ^5.S, R) -2- [4- (2-cyclopentylethoxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 //) - yl] -methyl} cyclopentanecarboxylic acid (racemate)

A solution of 115.4 mg (0.18 mmol) of the compound from Example 30A in 1 ml of dichloromethane was treated at 0 ° C with 0.5 ml (6.49 mmol) of trifluoroacetic acid. The mixture was stirred for 2.5 h at 0 ° C and then concentrated. The residue was taken up in 2 ml of acetonitrile and purified by preparative HPLC (Method 4). There were obtained 92 mg (94% of theory, purity 100%) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, IH), 8.51 (s, IH), 8.45-8.38 (m, 2H), 7.96 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.14-4.03 (m, 3H), 3.24 (t, IH), 2.93-2.81 (m, IH), 2.17-2.05 (m, IH), 2.00- 1.86 (m, 2H), 1.83-1.41 (m, 10H), 1.25-1.06 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.39 min, m / z = 558 [M + H] ⁺ . Separation of the enantiomers:

84 mg of the racemic compound from Example 53 were dissolved in 3 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 54 and 55) [column: Daicel Chiralpak IC, 5 μm, 250 mm × 20 mm; Flow: 80 ml / min; Detection: 220 nm; Injection volume: 0.25 ml; Temperature: 40 ° C; Eluent: 60% carbon dioxide / 40% ethanol; Total running time 5 min].

Example 54

(-) - _(l S ^lR5,2R, ^5.S, R) -2- [4- (2-cyclopentylethoxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -l, 2, 3-benzotriazine-3 (4 //) - yl] -methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 30 mg; former purity = 100%; ee value = 100% [a] _D ²⁰ = -87.7 °, 589 nm, c = 0.37 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.13 (br.s, IH), 8.51 (s, IH), 8.46-8.36 (m, 2H), 7.96 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.15-4.03 (m, 3H), 3.23 (t, IH), 2.95-2.78 (m, IH), 2.18-2.03 (m, IH), 2.00-1.85 (m, 2H), 1.84-1.42 (m, 10H), 1.22-1.07 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 3.11 min, m / z = 558 [M + H] ⁺ . Example 55

(+) - (1R5,2R5,5S ^, R) -2- [4- (2-Cyclopentylethoxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzo - triazine-3 (4 //) - yl] -methyl} cyclopentane carboxylic acid (enantiomer 2)

Yield: 31 mg; former purity = 99%; ee value = 100%

[a] _D ²⁰ = + 77.2 °, 589 nm, c = 0.47 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, IH), 8.50 (s, IH), 8.46-8.37 (m, 2H), 7.96 (d, 2H), 7.02 (d, 2H), 4.61-4.51 (m, 2H), 4.16-4.00 (m, 3H), 3.22-3.13 (m, IH), 2.91-2.80 (m, IH), 2.18-2.01 (m, IH), 2.00-1.85 (m, 2H), 1.75 (d, 10H), 1.34-1.08 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 3.11 min, m / z = 558 [M + H] ⁺ . Example 56

(+/-) - (I R 5,2 R 5,5 ^, S ^, R) -2- [4- (3-cyclohexylpropoxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -l, 2,3 - benzotriazine-3 (4 //) - yl] methyl} cyclopentanecarboxylic acid (racemate)

A solution of 84 mg (0.08 mmol, purity 63%) of the compound from Example 31 A in 0.24 ml of dichloromethane was added at 0 ° C with 0.12 ml of trifluoroacetic acid. The mixture was stirred first at 0 ° C. for 15 minutes, then at RT for 1 h and then concentrated. The residue was purified by preparative HPLC (Method 4). 5 mg (12% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.95 (d, 2H), 7.02 (d, 2H), 4.57 (d, 2H), 4.15-3.99 (m, 3H), 3.24 (t, 1H), 2.93-2.81 (m, 1H), 2.17-2.04 (m, 1H), 1.98- 1.88 (m, 1H), 1.79-1.04 (m, 15H), 0.94-0.81 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.52 min, m / z = 586 [M + H] ⁺ . Example 57

(+/-) - (1R5,2R5,5S ^, R) -2- [4- (hexyloxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine - 3 (4 /) - yl] methylcyclopentanecarboxylic acid (racemate)

A solution of 164 mg (0.25 mmol) of the compound from Example 32A in 1.5 ml of dichloromethane was treated at 0 ° C with 0.72 ml (9.39 mmol) of trifluoroacetic acid. The mixture was stirred for 2.5 h at 0 ° C and then concentrated. The residue was taken up in 2 ml of acetonitrile and purified by preparative HPLC (Method 4). 112 mg (81% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (s, IH), 8.51 (s, IH), 8.46-8.38 (m, 2H), 7.95 (d, 2H), 7.03 ( d, 2H), 4.57 (d, 2H), 4.14-4.02 (m, 3H), 3.24 (t, IH), 2.93-2.81 (m, IH), 2.17-2.05 (m, IH), 2.00-1.87 ( m, IH), 1.77-1.61 (m, 3H), 1.58-1.46 (m, IH), 1.46-1.36 (m, 2H), 1.35-1.22 (m, 4H), 0.90-0.83 (m, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.37 min, m / z = 546 [M + H] ⁺ . Separation of the enantiomers:

103 mg of the racemic compound from Example 57 were dissolved in 6 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 58 and 59) [column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm; Flow: 80 ml / min; Detection: 220 nm; Injection volume: 0.75 ml; Temperature: 40 ° C; Eluent: 70% carbon dioxide / 30% ethanol; Total running time 5 min].

Example 58 (+) - (1R5,2R5,5S ^, R) -2- [4- (Hexyloxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine - 3 (4 /) - yl] methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 48 mg; ee value = 100%

[from ²⁰ = + 83.3 °, 589 nm, c = 0.29 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, IH), 8.51 (s, IH), 8.46-8.37 (m, 2H), 7.95 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.14-4.01 (m, 3H), 3.23 (t, IH), 2.94-2.80 (m, IH), 2.17-2.02 (m, IH), 2.00- 1.87 (m, IH), 1.78-1.60 (m, 3H), 1.58-1.47 (m, IH), 1.46-1.36 (m, 2H), 1.35-1.25 (m, 4H), 0.90-0.83 (m, 3H ).

LC / MS (Method 1, ESIpos): R _t = 1.43 min, m / z = 546 [M + H] ⁺ . Example 59 (-) - (I R 5,2 R _I S ', 5 _I S ^, R) -2- [4- (Hexyloxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -1, 2, 3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylic acid (enantiomer 2)

Yield: 51 mg; ee value = 100%

[a] _D ²⁰ = -91.8 °, 589 nm, c = 0.36 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.95 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.15-3.99 (m, 3H), 3.23 (t, 1H), 2.94-2.80 (m, 1H), 2.17-2.04 (m, 1H), 2.00- 1.87 (m, 1H), 1.78-1.60 (m, 3H), 1.59-1.47 (m, 1H), 1.46-1.37 (m, 2H), 1.35-1.21 (m, 4H), 0.91-0.82 (m, 3H ). LC / MS (Method 1, ESIpos): R _t = 1.43 min, m / z = 546 [M + H] ⁺ .

Example 60

(+/-) - (lR _l ^S, 2R S _^l, 5 _l ^S, R) -2- [4- (3-methylbutoxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 //) - yl] methyl} cyclopentanecarboxylic acid (racemate)

A solution of 249 mg (0.39 mmol) of the compound from Example 33A in 1.5 ml of dichloromethane was treated at 0 ° C with 0.75 ml (9.89 mmol) of trifluoroacetic acid. The mixture was stirred for 2 h at 0 ° C and then concentrated. The residue was taken up in 2 ml of acetonitrile and purified by preparative HPLC (Method 4). 168 mg (73% of theory, purity 91%) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.96 (d, 2H), 7.04 (d, 2H), 4.57 (d, 2H), 4.14-4.05 (m, 3H), 3.24 (t, 1H), 2.93-2.81 (m, 1H), 2.18-2.04 (m, 1H), 2.01- 1.87 (m, 1H), 1.84-1.72 (m, 1H), 1.72-1.59 (m, 3H), 1.58-1.46 (m, 1H), 0.94 (s, 3H), 0.92 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 532 [M + H] ⁺ . Separation of the enantiomers:

164 mg of the racemic compound from Example 60 were dissolved in 6 ml of ethanol and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 61 and 62) [column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm; Flow: 12 ml / min; Detection: 220 nm; Injection volume: 1.0 ml; Temperature: 45 ° C; Eluent: t = 0-12 min 100% ethanol + 0.2% acetic acid]. Example 61

(+) - (1 ^, 2 ^, 5 ^) - 2- [4- (3-Μεώγ ^ υΙοχγ ^ εηζογ1] -5- {[4-oo-6-one (ΙήΑυο ™ εώγ1) -1,2, 3 ^ εηζο-triazine-3 (4 //) - yl] methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 78 mg; former purity = 100%; ee value = 99% [α] _D ²⁰ = + 85.6 °, 589 nm, c = 0.33 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (s, IH), 8.51 (s, IH), 8.46-8.38 (m, 2H), 7.96 (d, 2H), 7.04 ( d, 2H), 4.57 (d, 2H), 4.14-4.04 (m, 3H), 3.24 (t, IH), 2.94-2.80 (m, IH), 2.17-2.04 (m, IH), 2.00-1.87 ( m, IH), 1.85-1.72 (m, IH), 1.72-1.59 (m, 3H), 1.59-1.46 (m, IH), 0.94 (s, 3H), 0.92 (s, 3H). LC / MS (Method 1, ESIpos): R _t = 1.37 min, m / z = 532 [M + H] ⁺ . Example 62

(-) - (1R5,2R5,55R) -2- [4- (3-methylbutoxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 //) - yl] methyl} cyclopentanecarboxylic acid (enantiomer 2)

Yield: 79 mg; former purity = 100%; ee value = 99% [α] _D ²⁰ = -92.8 °, 589 nm, c = 0.35 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (s, IH), 8.51 (s, IH), 8.46-8.38 (m, 2H), 7.96 (d, 2H), 7.04 ( d, 2H), 4.57 (d, 2H), 4.14-4.05 (m, 3H), 3.23 (t, IH), 2.93-2.80 (m, IH), 2.17-2.03 (m, IH), 1.99-1.87 ( m, IH), 1.85-1.72 (m, IH), 1.72-1.59 (m, 3H), 1.59-1.46 (m, IH), 0.94 (s, 3H), 0.92 (s, 3H). LC / MS (Method 1, ESIpos): R _t = 1.37 min, m / z = 532 [M + H] ⁺ . Example 63

(+/-) - (1R5,25R, 5R5) -2- {[4-Oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] methyl} -5- [ 4- (pentyloxy) benzoyl] cyclopentane carboxylic acid (racemate)

A solution of 177 mg (0.28 mmol) of the compound from Example 34A in 1.6 ml of dichloromethane was admixed at 0 ° C. with 0.8 ml (10.38 mmol) of trifluoroacetic acid. The mixture was stirred for 2.5 h at 0 ° C and then concentrated. The residue was taken up in 2 ml of acetonitrile and purified by preparative HPLC (Method 4). 122 mg (82% of theory, purity 100%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.95 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.14-4.02 (m, 3H), 3.24 (t, 1H), 2.94-2.79 (m, 1H), 2.17-2.04 (m, 1H), 1.99- 1.87 (m, 1H), 1.79-1.60 (m, 3H), 1.58-1.45 (m, 1H), 1.45-1.28 (m, 4H), 0.92-0.86 (m, 3H). LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 532 [M + H] ⁺ . Separation of the enantiomers:

114 mg of the racemic compound from Example 63 were dissolved in 6 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 64 and 65) [column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm; Flow: 80 ml / min; Detection: 220 nm; Injection volume: 0.75 ml; Temperature: 40 ° C; Eluent: 60% carbon dioxide / 40% ethanol; Total running time 8 min].

Example 64

(+) - (1R5,25R, 5R5) -2- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] methyl} -5- [4- (pentyloxy) benzoyl] cyclopentanecarboxylic acid (enantiomer 1) Yield: 52 mg; ee value = 100%

[a] _D ²⁰ = + 82.3 °, 589 nm, c = 0.35 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.95 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.14-4.01 (m, 3H), 3.23 (t, 1H), 2.93-2.81 (m, 1H), 2.17-2.04 (m, 1H), 1.99- 1.87 (m, 1H), 1.78-1.61 (m, 3H), 1.59-1.46 (m, 1H), 1.44-1.27 (m, 4H), 0.93-0.85 (m, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.32 min, m / z = 532 [M + H] ⁺ .

Example 65

(-) - (1R5,25R, 5R ^ -2- {[4-Oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) - yl] methyl} -5- [4- (pentyl-oxy) benzoyl] cyclopentanecarboxylic acid (enantiomer 2) Yield: 51 mg; ee value = 100%

[a] _D ²⁰ = -75.7 °, 589 nm, c = 0.34 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.13 (br.s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.95 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.15-4.00 (m, 3H), 3.23 (t, 1H), 2.95-2.77 (m, 1H), 2.17-2.03 (m, 1H), 2.00-1.85 (m, 1H), 1.79-1.60 (m, 3H), 1.59-1.46 (m, 1H), 1.45-1.27 (m, 4H), 0.93-0.84 (m, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.32 min, m / z = 532 [M + H] ⁺ .

Example 66

(+/-) - (1R5,2R5,55R) -2- (4-Butoxybenzoyl) -5- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylic acid (racemate)

A solution of 230 mg (0.37 mmol) of the compound from Example 35A in 2 ml of dichloromethane was admixed at 0 ° C. with 1 ml (13.79 mmol) of trifluoroacetic acid. The mixture was stirred for 1.5 h at 0 ° C and then concentrated. The residue was taken up in 3 ml of acetonitrile and purified by preparative HPLC (Method 4). 152 mg (79% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.96 (d, 2H), 7.03 ( d, 2H), 4.57 (d, 2H), 4.15-4.01 (m, 3H), 3.24 (t, 1H), 2.94-2.80 (m, 1H), 2.17-2.05 (m, 1H), 2.00-1.87 ( m, 1H), 1.77-1.61 (m, 3H), 1.59-1.37 (m, 3H), 0.93 (t, 3H). LC / MS (Method 1, ESIpos): R _t = 1.32 min, m / z = 518 [M + H] ⁺ .

Separation of the enantiomers:

142 mg of the racemic compound from Example 66 were dissolved in 4 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 67 and 68) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Flow: 80 ml / min; Detection: 220 nm; Injection volume: 0.75 ml; Temperature: 40 ° C; Eluent: 70% carbon dioxide / 30% ethanol; Total running time 7 min]. Example 67

(+) - (1R5,2R5,55R) -2- (4-Butoxybenzoyl) -5- {[4-oxo-6-trifluoromel], 2,3-benzotri

yl] methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 65 mg; ee value = 100% [α] _D ²⁰ = + 89.3 °, 589 nm, c = 0.40 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, IH), 8.51 (s, IH), 8.46-8.37 (m, 2H), 7.96 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.14-4.02 (m, 3H), 3.23 (t, IH), 2.94-2.80 (m, IH), 2.17-2.03 (m, IH), 2.00- 1.86 (m, IH), 1.77-1.60 (m, 3H), 1.58-1.38 (m, 3H), 0.93 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.27 min, m / z = 518 [M + H] ⁺ . Example 68

(-) - (IRS, 2RS, 5SR) -2- (4-butoxybenzoyl) -5- {[4-oxo-6- (ta ^

methylcyclopentanecarboxylic acid (enantiomer 2)

Yield: 56 mg; ee value = 100%

[a] _D ²⁰ = -94.2 °, 589 nm, c = 0.37 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.13 (br.s, IH), 8.51 ( s, IH), 8.46-8.37 (m, 2H), 7.96 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.16-4.00 (m, 4H), 3.24 (t, IH) , 2.94-2.79 (m, IH), 2.17-2.04 (m, IH), 1.99-1.86 (m, IH), 1.78-1.60 (m, 3H), 1.59-1.37 (m, 3H), 0.93 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.27 min, m / z = 518 [M + H] ⁺ .

Example 69 (+/-) - (1R5,25R, 5R5) -2- {[4-Oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) - yl] methyl} -5 - (4-propoxybenzoyl) cyclopentane carboxylic acid (racemate)

A solution of 63 mg (0.10 mmol) of the compound from Example 36A in 0.4 ml of dichloromethane was admixed at 0 ° C. with 0.2 ml (2.61 mmol) of trifluoroacetic acid. The mixture was stirred at 0 ° C for 8 h. Thereafter, the mixture was concentrated, the residue taken up in dichloromethane and the solution was concentrated again. This procedure was repeated several times. 51 mg (94% of theory, purity 96%) of the title compound were thus obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 8.51 (s, 1H), 8.45-8.39 (m, 2H), 7.96 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.10 (dd, 1H), 4.02 (t, 2H), 3.24 (dd, 1H), 2.92-2.82 (m, 1H), 2.16-2.07 (m, 1H), 1.97-1.89 (m, 1H), 1.79-1.70 (m, 1H), 1.70-1.63 (m, 2H), 1.57-1.48 (m, 1H), 0.98 (t, 3H). LC / MS (Method 1, ESIpos): R _t = 1.24 min, m / z = 504 [M + H] ⁺ . Separation of the enantiomers:

33 mg of the racemic compound from Example 69 were dissolved in 4 ml of methanol / isopropanol and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 70 and 71) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 280 nm; Injection volume: 1 ml; Temperature: 20 ° C; Eluent: t = 0-18 min 50% isohexane / 50% isopropanol + 0.2% trifluoroacetic acid].

Example 70

(+) - (1R5,25R, 5R5) -2- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] methyl} -5- (4- propoxybenzoyl) cyclopentanecarboxylic acid (enantiomer 1) Yield: 9 mg; former purity = 97%; ee value = 100%

[from ²⁰ = + 83.1 °, 589 nm, c = 0.24 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 8.51 (s, 1H), 8.45-8.39 (m, 2H), 7.96 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.10 (dd, 1H), 4.02 (t, 2H), 3.24 (dd, 1H), 2.92-2.84 (m, 1H), 2.16-2.07 (m, 1H), 1.97-1.89 (m, 1H), 1.79-1.70 (m, 1H), 1.70-1.63 (m, 2H), 1.57-1.48 (m, 1H), 0.98 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.25 min, m / z = 504 [M + H] ⁺ .

Example 71

(-) - (1R5,25R, 5R ^ -2- {[4-Oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 /) -yl] methyl} -5- (4- propoxybenzoyl) cyclopentanecarboxylic acid (enantiomer 2) Yield: 9 mg; former purity = 97%; ee value = 98% [α] _D ²⁰ = -71.3 °, 589 nm, c = 0.28 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.12 (br.s, 1H), 8.51 (s, 1H), 8.45-8.39 (m, 2H), 7.96 (d, 2H), 7.03 (d, 2H), 4.57 (d, 2H), 4.10 (dd, 1H), 4.02 (t, 2H), 3.24 (dd, 1H), 2.92-2.84 (m, 1H), 2.16-2.07 (m, 1H ), 1.97-1.89 (m, 1H), 1.79-1.70 (m, 1H), 1.70-1.63 (m, 2H), 1.57-1.48 (m, 1H), 0.98 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.25 min, m / z = 504 [M + H] ⁺ .

Example 72

(+/-) - (1R5,2R5,55R) -2- (4-isobutoxybenzoyl) -5- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine 3 (4 //) -yl] methyl} cyclopentanecarboxylic acid (racemate)

A solution of 92 mg (0.15 mmol) of the compound from Example 37A in 0.5 ml of dichloromethane was treated at 0.degree. C. with 0.25 ml (3.26 mmol) of trifluoroacetic acid. The mixture was stirred for 15 min at 0 ° C, then for 1.5 h at RT and then concentrated. The residue was purified by preparative HPLC (Method 4). There was obtained 62 mg (81% of theory, purity 100%) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.96 (d, 2H), 7.04 (d, 2H), 4.57 (d, 2H), 4.15-4.05 (m, 1H), 3.84 (d, 2H), 3.24 (t, 1H), 2.94-2.80 (m, 1H), 2.17-1.87 ( m, 3H), 1.73-1.61 (m, 1H), 1.59-1.45 (m, 1H), 0.99 (s, 3H), 0.97 (s, 3H). LC / MS (Method 1, ESIpos): R _t = 1.28 min, m / z = 518 [M + H] ⁺ .

Example 73

(+/-) - (lR _l ^S, 2R S _^l, 5 _l ^S, R) -2- [4- (Benzylsulfanyl) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -l , 2,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylic acid (racemate)

A solution of 150 mg (0.23 mmol) of the compound from Example 40A in 2 ml of dichloromethane was added at 0 ° C with 1 ml of trifluoroacetic acid. The mixture was stirred for 15 min at 0 ° C, then for 1.5 h at RT and then concentrated. The residue was purified by preparative HPLC (Method 4). 117 mg (92% of theory, purity 100%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.15 (s, 1H), 8.50 (s, 1H), 8.46-8.37 (m, 2H), 7.89 (d, 2H), 7.47- 7.39 (m, 4H), 7.35-7.29 (m, 2H), 7.28-7.21 (m, 1H), 4.59-4.54 (m, 2H), 4.37 (s, 2H), 4.14-4.04 (m, 1H), 3.23 (t, 1H), 2.94-2.79 (m, 1H), 2.17-2.04 (m, 1H), 1.99-1.87 (m, 1H), 1.72-1.60 (m, 1H), 1.58-1.45 (m, 1H ).

LC / MS (Method 1, ESIpos): R _t = 1.29 min, m / z = 568 [M + H] ⁺ .

Separation of the enantiomers:

98 mg of the racemic compound from Example 73 were dissolved in 4 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 74 and 75) [column: Daicel Chiralpak IC, 5 μm, 250 mm × 20 mm; Flow: 80 ml / min; Detection: 220 nm; Injection volume: 0.75 ml; Temperature: 40 ° C; Eluent: 70% carbon dioxide / 30% ethanol; Total running time 10 min].

Example 74

(-) - (1R5,2R5,55R) -2- [4- (Benzylsulfanyl) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine 3 (4 // ) -yl] -methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 43 mg; ee value = 100%

[a] _D ²⁰ = -87.6 °, 589 nm, c = 0.36 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.15 (br.s, 1H), 8.50 (s, 1H), 8.46-8.37 (m, 2H), 7.89 (d, 2H), 7.46-7.40 (m, 4H), 7.35-7.29 (m, 2H), 7.28-7.21 (m, 1H), 4.59-4.53 (m, 2H), 4.37 (s, 2H), 4.14-4.55 (m, 1H), 3.23 (t, 1H), 2.94-2.79 (m, 1H), 2.17-2.02 (m, 1H), 2.00-1.87 (m, 1H), 1.72-

1.59 (m, 1H), 1.58-1.45 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.29 min, m / z = 568 [M + H] ⁺ . Example 75 (+) - (IR 5,2 R 5,55 R) -2- [4- (Benzylsulfanyl) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) -l, 23-benzotriazine 3 (4 // ) -yl] methyl} cyclopentanecarboxylic acid (enantiomer 2)

Yield: 43 mg; ee value = 100%

[from ²⁰ = + 85.2 °, 589 nm, c = 0.38 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.15 (br.s, 1H), 8.50 (s, 1H), 8.45-8.37 (m, 2H), 7.89 (d, 2H), 7.47-7.40 (m, 4H), 7.36-7.29 (m, 2H), 7.28-7.21 (m, 1H), 4.60-4.53 (m, 2H), 4.37 (s, 2H),

4.15-4.55 (m, 1H), 3.23 (t, 1H), 2.93-2.80 (m, 1H), 2.16-2.04 (m, 1H), 1.99-1.86 (m, 1H), 1.72-

1.60 (m, 1H), 1.58-1.44 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.29 min, m / z = 568 [M + H] ⁺ . Example 76 (+/-) - (1R5,2R5,55R) -2- {4 - [(3-chlorobenzyl) sulfanyl] benzoyl} -5- {[4-oxo-6- (trifluoromethyl) -1, 2, 3-benzotriazine-3 (4 //) - yl] methyl} cyclopentanecarboxylic acid (racemate)

A solution of 255 mg (0.36 mmol) of the compound from Example 41A in 1.2 ml of dichloromethane was treated at 0 ° C with 0.6 ml (7.98 mmol) of trifluoroacetic acid. The mixture was stirred for 2 h at RT and then concentrated. The residue was purified by preparative HPLC (Method 4). 182 mg (83% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.15 (s, 1H), 8.50 (s, 1H), 8.46-8.38 (m, 2H), 7.90 (d, 2H), 7.50 ( s, 1H), 7.44 (d, 2H), 7.42-7.28 (m, 3H), 4.59-4.53 (m, 2H), 4.39 (s, 2H), 4.15-4.05 (m, 1H), 3.23 (t, 1H), 2.93-2.80 (m, 1H), 2.17-2.03 (m, 1H), 2.00-1.86 (m, 1H), 1.73-1.60 (m, 1H), 1.58-1.45 ( m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.38 min, m / z = 602 [M + H] ⁺ .

Separation of the enantiomers:

174 mg of the racemic compound from Example 76 were dissolved in 7 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 77 and 78) [column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm; Flow: 80 ml / min; Detection: 220 nm; Injection volume: 0.75 ml; Temperature: 40 ° C; Eluent: 60% carbon dioxide / 40% ethanol; Total running time 8 min]. Example 77

(+) - (IR 5,2 R 5,55 R) -2- {4 - [(3-chlorobenzyl) sulfanyl] benzoyl} -5- {[4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine] 3 (4 //) - yl] methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 80 mg; former purity = 100%; ee value = 100%

[from ²⁰ = + 72.9 °, 589 nm, c = 0.36 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.13 (br. s, 1H), 8.50 (s, 1H), 8.46-8.37 (m, 2H), 7.89 (d, 2H), 7.50 (s, 1H), 7.44 (d, 2H), 7.41-7.37 (m, 1H), 7.37-7.34 (m, 1H) , 7.33-7.28 (m, 2H), 4.58-4.54 (m, 2H), 4.39 (s, 2H), 4.14-4.06 (m, 1H), 3.22 (t, 1H), 2.91-2.83 (m, 1H) , 2.17-2.04 (m, 1H),

1.98-1.87 (m, 1H), 1.72-1.61 (m, 1H), 1.58-1.44 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 602 [M + H] ⁺ . Example 78

(-) - (1R5,2R5,5S ^, R) -2- {4 - [(3-chlorobenzyl) sulfanyl] benzoyl} -5- {[4-oxo-6- (trifluoromethyl) -1, 2, 3-benzotriazine-3 (4 //) - yl] -methyl} cyclopentanecarboxylic acid (enantiomer 2)

Yield: 80 mg; former purity = 100%; ee value = 100%

[a] _D ²⁰ = -80.7 °, 589 nm, c = 0.39 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.15 (br. s, 1H), 8.50 ( s, 1H), 8.46-8.37 (m, 2H), 7.90 (d, 2H), 7.50 (s, 1H), 7.44 (d, 2H), 7.42-7.38 (m, 1H), 7.37-7.34 (m, 1H), 7.34-7.28 (m, 2H), 4.60-4.52 (m, 2H), 4.39 (s, 2H), 4.15-4.05 (m, 1H), 3.23 (t, 1H), 2.93-2.80 (m, 1H), 2.17-2.04 (m, 1H),

1.99-1.86 (m, 1H), 1.71-1.60 (m, 1H), 1.58-1.45 (m, 1H). LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 602 [M + H] ⁺ . Example 79

(+/-) - (lRS, 2RS, 5SR) -2- {4 - [(3,4-Dicm ^

l, 2,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylic acid (racemate)

A solution of 266 mg (0.36 mmol) of the compound from Example 42A in 1.2 ml of dichloromethane was treated at 0 ° C with 0.6 ml (7.94 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1.5 h and then concentrated. The residue was purified by preparative HPLC (Method 4). There was obtained 204 mg (89% of theory, purity 100%) of the title compound. Ή NMR (400 MHz, DMSO-de): δ [ppm] = 12.15 (brs s, IH), 8.50 (s, IH), 8.46-8.37 (m, 2H), 7.90 (d, 2H), 7.70 (d, IH), 7.58 (d, IH), 7.47-7.40 (m, 3H), 4.59-4.53 (m, 2H), 4.40 (s, 2H), 4.16-4.04 (m, IH), 3.23 (t , IH), 2.93-2.79 (m, IH), 2.16-2.04 (m, IH), 1.99-1.87 (m, IH), 1.72-1.60 (m, IH), 1.58-1.45 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.42 min, m / z = 636 [M + H] ⁺ . Separation of the enantiomers:

195 mg of the racemic compound from Example 79 were dissolved in 7 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 80 and 81) [column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm; Flow: 80 ml / min; Detection: 220 nm; Injection volume: 0.15 ml; Temperature: 40 ° C; Eluent: 60% carbon dioxide / 40% ethanol; Total running time 8 min].

Example 80

(+) - (lRS, 2RS, 5SR) -2- {4 - [(3,4-dichlorobenzyl) sulfanyl] benzoyl} -5- {[4-oxo-6- (trifluoromethyl) -1,2,3- benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 86 mg; former purity = 100%; ee value = 100% [a] _D ²⁰ = + 52.9 °, 589 nm, c = 0.21 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.15 (br.s, IH), 8.50 (s, IH), 8.45-8.38 (m, 2H), 7.90 (d, 2H), 7.70 (d, IH), 7.58 (d, IH), 7.47-7.39 (m, 3H), 4.59-4.53 (m, 2H), 4.40 (s, 2H), 4.14-4.05 (m, IH), 3.23 ( t, IH), 2.93-2.80 (m, IH), 2.17-2.03 (m, IH), 2.00-1.87 (m, IH), 1.71-1.60 (m, IH), 1.58-1.44 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.42 min, m / z = 636 [M + H] ⁺ .

Example 81

(-) - (1R5,2R5,5 _l S ^, R) -2- {4 - [(3,4-dichlorobenzyl) sulfanyl] benzoyl} -5- {[4-oxo-6- (trifluoromethyl) -1] 2,3-benzotriazine-3 (4 //) - yl] -methyl} cyclopentanecarboxylic acid (enantiomer 2) Yield: 92 mg; former purity = 100%; ee value = 100%

[from ²⁰ = -73.7 °, 589 nm, c = 0.35 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, IH), 8.50 (s, IH), 8.46-8.36 (m, 2H), 7.90 (d, 2H), 7.70 (d, IH), 7.57 (d, IH), 7.47-7.38 (m, 3H), 4.60-4.52 (m, 2H), 4.39 (s, 2H), 4.15-4.05 (m, IH), 3.22 ( t, IH), 2.93-2.80 (m, IH), 2.16-2.03 (m, IH), 1.98-1.87 (m, IH), 1.72-1.61 (m, IH), 1.58-1.44 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.38 min, m / z = 636 [M + H] ⁺ .

Example 82

(+/-) - (IRS, 2SR, 5RS) -2- {[4-Oxo-6- (trifluoromethyl) -1,2,3-benzotriazine-3 (4 //) - yl] methyl} -5 - {4- [(2-phenylethyl) sulfanyl] benzoyl} cyclopentane carboxylic acid (racemate)

A solution of 239 mg (0.35 mmol) of the compound from Example 43A in 1.2 ml of dichloromethane was treated at 0 ° C with 0.6 ml (7.69 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1.5 h and then concentrated. The residue was purified by preparative HPLC (Method 4). There were obtained 92 mg (45% of theory, purity 100%) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.16 (br.s, IH), 8.51 (s, IH), 8.46-8.37 (m, 2H), 7.92 (d, 2H), 7.43 (d, 2H), 7.34-7.27 (m, 4H), 7.25-7.16 (m, IH), 4.61-4.53 (m, 2H), 4.17-4.05 (m, IH), 3.34 (t, 2H), 3.25 (t, IH), 2.97-2.81 (m, 3H), 2.19-2.07 (m, IH), 2.01-1.87 (m, IH), 1.74-1.62 (m, IH), 1.59-1.46 (m, IH ). LC / MS (Method 1, ESIpos): R _t = 1.37 min, m / z = 582 [M + H] ⁺ .

Separation of the enantiomers:

80 mg of the racemic compound from Example 82 were dissolved in 4 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 83 and 84) [column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm; Flow: 80 ml / min; Detection: 220 nm; Injection volume: 0.75 ml; Temperature: 40 ° C; Eluent: 60% carbon dioxide / 40% ethanol; Total running time 7 min].

Example 83

(+) - (IRS, 2SR, 5RS) -2- {[4-Oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 //) - yl] methyl} -5- {4 - [(2-phenylethyl) sulfanyl] benzoyl} cyclopentanecarboxylic acid (enantiomer 1) Yield: 35 mg; former purity = 97%; ee value = 100%

[from ²⁰ = + 77.8 °, 589 nm, c = 0.32 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.16 (br.s, IH), 8.51 (s, IH), 8.46-8.37 (m, 2H), 7.92 (d, 2H), 7.43 (d, 2H), 7.34-7.26 (m, 4H), 7.25-7.18 (m, IH), 4.62-4.52 (m, 2H), 4.16-4.06 (m, IH), 3.37-3.30 (obscured, 2H ), 3.24 (t, IH), 2.96-2.81 (m, 3H), 2.18-2.06 (m, IH), 2.00-1.86 (m, IH), 1.74-1.62 (m, IH), 1.60-1.45 (m , IH).

LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 582 [M + H] ⁺ .

Example 84

(-) - (lRS, 2SR, 5R ^ -2- {[4-oxo-6- (trifl ^^

phenylethyl) sulfanyl] benzoyl} cyclopentanecarboxylic acid (enantiomer 2) Yield: 36 mg; former purity = 100%; ee value = 100% [a] _D ²⁰ = -67.7 °, 589 nm, c = 0.30 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-de): δ [ppm] = 12.16 (br.s, IH), 8.51 (s, IH), 8.46-8.37 (m, 2H), 7.92 (d, 2H), 7.43 (d, 2H), 7.34-7.27 (m, 4H), 7.25-7.19 (m, IH), 4.60-4.54 (m, 2H), 4.16-4.04 (m, IH), 3.37-3.29 (obscured, 2H), 3.24 (t, IH), 2.96-2.81 (m, 3H), 2.19-2.05 (m, IH), 2.00-1.86 (m, 1.75-1.62 (m, IH), 1.59 -1.45 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 582 [M + H] ⁺ . Example 85

(+/-) - (IRS, 2RS, 5SR) -2- {4 - [(Cyclohexylmethyl) sulfanyl] benzoyl} -5- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine] 3 (4 /) - yl] methyl} cyclopentanecarboxylic acid (racemate)

A solution of 235 mg (0.33 mmol, purity 95%) of the compound from Example 44A in 3.5 ml of dichloromethane was treated at 0 ° C with 1.75 ml of trifluoroacetic acid. The mixture was initially stirred for 15 min at 0 ° C., then for 2 h at RT and then concentrated. The residue was purified by preparative HPLC (Method 4). There were obtained 184 mg (88% of theory, purity 91%) of the title compound.

Ή NMR (400 MHz, DMSO-de): δ [ppm] = 12.16 (br.s, IH), 8.51 (s, IH), 8.46-8.38 (m, 2H), 7.90 (d, 2H), 7.38 (d, 2H), 4.61-4.53 (m, 2H), 4.15-4.01 (m, IH), 3.24 (t, IH), 2.96 (d, 2H), 2.94-2.81 (m, IH), 2.18-2.06 (m, IH), 1.99-1.89 (m, IH), 1.88-1.80 (m, 2H), 1.77-1.42 (m, 6H), 1.36-0.79 (m, 5H).

LC / MS (Method 1, ESIpos): R _t = 1.43 min, m / z = 574 [M + H] ⁺ . Separation of the enantiomers:

174 mg of the racemic compound from Example 85 were dissolved in 3 ml of acetonitrile / 30 ml of ethanol and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 86 and 87) [column: Daicel Chiralpak AY-H, 5 μm, 250 mm x 20 mm; Flow: 12 ml / min; Detection: 220 nm; Injection volume: 0.75 ml; Temperature: 45 ° C; Eluent: t = 0-16 min 100% ethanol + 0.2% acetic acid]. Example 86

(+) - (IRS, 2RS, 5SR) -2- {4 - [(Cyclohexylmethyl) sulfanyl] benzoyl} -5- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 ( 4 /) - yl] methyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 64 mg; former purity = 100%; ee value = 99% [α] _D ²⁰ = + 84.9 °, 589 nm, c = 0.36 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.15 (br.s, IH), 8.51 (s, IH), 8.47-8.37 (m, 2H), 7.90 (d, 2H), 7.38 (d, 2H), 4.63-4.50 (m, 2H), 4.16-4.03 (m, IH), 3.24 (t, IH), 2.96 (d, 2H), 2.93-2.82 (m, IH), 2.17- 2.06 (m, IH), 2.00-1.89 (m, IH), 1.88-1.79 (m, 2H), 1.73-1.45 (m, 6H), 1.26-0.93 (m, 5H). LC / MS (Method 1, ESIpos): R _t = 1.47 min, m / z = 574 [M + H] ⁺ . Example 87

(-) - (IRS, 2RS, 5SR) -2- {4 - [(Cyclohexylmethyl) sulfanyl] benzoyl} -5- {[4-oxo-6- (trifluoromethyl) -1,2,3-benzotriazine-3 ( 4 //) - yl] methyl} cyclopentanecarboxylic acid (enantiomer 2)

Yield: 61 mg; former purity = 100%; ee value = 99% [α] _D ²⁰ = -87.3 °, 589 nm, c = 0.38 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.15 (br.s, IH), 8.51 (s, IH), 8.46-8.37 (m, 2H), 7.90 (d, 2H), 7.38 (d, 2H), 4.63-4.51 (m, 2H), 4.15-4.05 (m, IH), 3.24 (t, IH), 2.96 (d, 2H), 2.93-2.80 (m, IH), 2.18- 2.05 (m, IH), 1.99-1.89 (m, IH), 1.89-1.79 (m, 2H), 1.74-1.46 (m, 6H), 1.26-0.94 (m, 5H). LC / MS (Method 1, ESIpos): R _t = 1.47 min, m / z = 574 [M + H] ⁺ . Example 88

(+/-) - (1R5,25R, 5R5) -2- {[4-Oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] methyl} -5- [ 4- (pentylsulfanyl) benzoyl] cyclopentanecarboxylic acid (racemate)

A solution of 233 mg (0.35 mmol) of the compound from Example 45A in 1.2 ml of dichloromethane was treated at 0 ° C with 0.6 ml (7.75 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1 h and then concentrated. The residue was purified by preparative HPLC (Method 4). 150 mg (78% of theory, purity 100%) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.16 (br.s, IH), 8.51 (s, IH), 8.46-8.38 (m, 2H), 7.90 (d, 2H), 7.39 (d, 2H), 4.63-4.51 (m, 2H), 4.16-4.05 (m, IH), 3.24 (t, IH), 3.06 (t, 2H), 2.94-2.79 (m, IH), 2.18- 2.03 (m, IH), 2.00-1.86 (m, IH), 1.74-1.46 (m, 4H), 1.45-1.20 (m, 4H), 0.86 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.42 min, m / z = 548 [M + H] ⁺ .

Separation of the enantiomers:

140 mg of the racemic compound from Example 88 were dissolved in 7 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 89 and 90) [column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm; Flow: 80 ml / min; Detection: 220 nm; Injection volume: 0.25 ml; Temperature: 40 ° C; Eluent: 65% carbon dioxide / 35% ethanol; Total running time 7 min]. Example 89

(+) - (1R5,25R, 5R5) -2- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] methyl} -5- [4- (pentylsulfanyl) benzoyl] cyclopentanecarboxylic acid (enantiomer 1)

Yield: 64 mg; former purity = 100%; ee value = 100%

[from ²⁰ = + 91.2 °, 589 nm, c = 0.35 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.16 (br.s, IH), 8.51 (s , IH), 8.46-8.38 (m, 2H), 7.91 (d, 2H), 7.39 (d, 2H), 4.62-4.51 (m, 2H), 4.15-4.05 (m, IH), 3.24 (t, IH ), 3.06 (t, 2H), 2.93-2.80 (m, IH), 2.18-2.05 (m, IH), 2.00-1.87 (m, IH), 1.73-1.46 (m, 4H), 1.45-1.21 (m , 4H), 0.86 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.37 min, m / z = 548 [M + H] ⁺ .

Example 90 (-) - (IRS, 2SR, 5R ^ -2- {[4-oxo-6- (trifluorom ^

sulfanyl) benzoyl] cyclopentanecarboxylic acid (enantiomer 2)

Yield: 65 mg; former purity = 100%; ee value = 100%

[a] _D ²⁰ = -90.8 °, 589 nm, c = 0.41 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.16 (br.s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.90 (d, 2H), 7.39 (d, 2H), 4.63-4.51 (m, 2H), 4.15-4.06 (m, 1H), 3.24 (t, 1H), 3.06 (t, 2H), 2.94-2.80 (m, 1H), 2.18- 2.05 (m, 1H), 1.94 (d, 1H), 1.74-1.46 (m, 4H), 1.45-1.21 (m, 4H), 0.86 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.37 min, m / z = 548 [M + H] ⁺ . Example 91

(+/-) - _(l S ^lR5,2R, ^5.S, R) -2- [4- (benzyloxy) benzoyl] -5 - [(6-methyl-4-oxo-l, 2,3- benzotriazine-3 (4 /) - yl) - methyl] cyclopentanecarboxylic acid (racemate)

A solution of 155 mg (0.25 mmol, purity 98%) of the compound from Example 46A in 0.9 ml of dichloromethane was admixed at 0 ° C. with 0.4 ml (5.58 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1.5 h and then concentrated. The residue was purified by preparative HPLC (Method 6). There were obtained 102 mg (80% of theory, purity 100%) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (s, 1H), 8.12-8.04 (m, 2H), 7.98 (d, 2H), 7.90 (d, 1H), 7.49- 7.31 (m, 5H), 7.13 (d, 2H), 5.21 (s, 2H), 4.51 (d, 2H), 4.15-4.04 (m, 1H), 3.23 (t, 1H), 2.93-2.80 (m, 1H), 2.54 (s, 3H), 2.17-2.04 (m, 1H), 1.93-1.82 (m, 1H), 1.71-1.60 (m, 1H), 1.56- 1.44 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.18 min, m / z = 498 [M + H] ⁺ .

Separation of the enantiomers:

92 mg of the racemic compound from Example 91 were dissolved in a mixture of 1 ml of DMSO and 11 ml of ethanol / acetonitrile and separated by preparative SFC on chiral phase into the enantiomers (see Examples 92 and 93) [column: Phenomenex amylose, 5 μιη , 250 mm x 20 mm; Flow: 100 ml / min; Detection: 210 nm; Injection volume: 0.95 ml; Temperature: 40 ° C; Eluent: 70% carbon dioxide / 30% ethanol; Total running time 23 min]. Example 92

(+) - (1R5,2R5,55R) -2 4- (benzyloxy) benzoyl] -5 (6-methyl-oxo, 23-benzotriazine-3 (4 /) -yl) -methyl] -cyclopentanecarboxylic acid (enantiomer 1)

Yield: 37 mg; former purity = 100%; ee value = 100% [α] _D ²⁰ = + 64.4 °, 589 nm, c = 0.33 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.11 (br.s, IH), 8.12-8.05 (m, 2H), 7.97 (d, 2H), 7.90 (dd, IH), 7.49-7.31 (m, 5H), 7.13 (d, 2H), 5.21 (s, 2H), 4.51 (d, 2H), 4.14-4.05 (m, IH), 3.23 (t, IH), 2.93-2.80 ( m, IH), 2.55 (s, 3H), 2.16-2.04 (m, IH), 1.93-1.82 (m, IH), 1.71-1.60 (m, IH), 1.56-1.43 (m, IH). LC / MS (Method 1, ESIpos): R _t = 1.18 min, m / z = 498 [M + H] ⁺ .

Example 93

(-) - _(l S ^lR5,2R, ^5.S, R) -2- [4- (benzyloxy) benzoyl] -5 - [(6-methyl-4-oxo-l, 2,3-benzotriazin- 3 (4 /) - yl) - methyl] cyclopentanecarboxylic acid (enantiomer 2)

Yield: 34 mg; former purity = 100%; ee value = 100% [a] _D ²⁰ = -66.4 °, 589 nm, c = 0.34 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.10 (br.s, IH), 8.11-8.04 (m, 2H), 7.97 (d, 2H), 7.90 (dd, IH), 7.49-7.31 (m, 5H), 7.13 (d, 2H), 5.21 (s, 2H), 4.51 (d, 2H), 4.14-4.04 (m, IH), 3.23 (t, IH), 2.93-2.80 ( m, IH), 2.55 (s, 3H), 2.16-2.03 (m, IH), 1.93-1.82 (m, IH), 1.71-1.60 (m, IH), 1.56-1.44 (m, IH). LC / MS (Method 1, ESIpos): R _t = 1.18 min, m / z = 498 [M + H] ⁺ .

Example 94

(+/-) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(4-fluorobenzyl) oxy] benzoyl} -5 - [(6-methyl-4- oxo-l, 2,3-benzotriazine-3 (4 //) - yl) -methyl] cyclopentane carboxylic acid (Racemai)

A solution of 170 mg (0.27 mmol, purity 98%) of the compound from Example 48A in 0.9 ml of dichloromethane was treated at 0 ° C with 0.5 ml (5.95 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1.5 h and then concentrated. The residue was purified by preparative HPLC (Method 6). There were obtained 102 mg (73% of theory, purity 100%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (br.s, 1H), 8.12-8.04 (m, 2H), 7.98 (d, 2H), 7.90 (dd, 1H), 7.55-7.48 (m, 2H), 7.23 (t, 2H), 7.12 (d, 2H), 5.19 (s, 2H), 4.51 (d, 2H), 4.14-4.06 (m, 1H), 3.23 (t, 1H), 2.92-2.79 (m, 1H), 2.55 (s, 3H), 2.17-2.03 (m, 1H), 1.93-1.81 (m, 1H), 1.71-1.60 (m, 1H), 1.56-1.42 ( m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.18 min, m / z = 516 [M + H] ⁺ .

Separation of the enantiomers:

92 mg of the racemic compound from Example 94 were dissolved in 1 ml of DMSO and 9 ml of ethanol and separated by preparative SFC on chiral phase into the enantiomers (see Examples 95 and 96) [column: Phenomenex amylose II, 5 μιη, 250 mm x 20 mm; Flow: 100 ml / min; Detection: 210 nm; Injection volume: 0.8 ml; Temperature: 40 ° C; Eluent: 70% carbon dioxide / 30% ethanol; Total running time 18 min].

Example 95

(+) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(4-fluorobenzyl) oxy] benzoyl} -5 - [(6-methyl-4-oxo- l, 2,3-benzotriazine-3 (4 /) -yl) methyl] cyclopentane carboxylic acid (enantiomer 1)

Yield: 34 mg; former purity = 100%; ee value = 100%

[from ²⁰ = + 56.5 °, 589 nm, c = 0.32 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, 1H), 8.11-8.04 (m, 2H), 7.98 (d, 2H), 7.90 (dd, 1H), 7.52 (dd, 2H), 7.23 (t, 2H), 7.12 (d, 2H), 5.19 (s, 2H), 4.51 (d, 2H), 4.14-4.05 (m, 1H), 3.23 (t, IH), 2.93-2.79 (m, IH), 2.55 (s, 3H), 2.17-2.04 (m, IH), 1.94-1.81 (m, IH), 1.72-1.60 (m, IH), 1.57-1.43 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.18 min, m / z = 516 [M + H] ⁺ . Example 96 (-) - (IRR ₁ S ^, 2R ₁ S ^, 5S ^, R) -2- {4 - [(4-fluorobenzyl) oxy] benzoyl} -5 - [(6-methyl-4-) oxo-l, 2,3-benzotriazine-3 (4 //) - yl) methyl] cyclopentane carboxylic acid (enantiomer 2)

Yield: 37 mg; former purity = 100%; ee value = 100%

[a] _D ²⁰ = -64.6 °, 589 nm, c = 0.31 g / 100 ml, chloroform.

Example 97 (+/-) - (1R5,2R5,5S ^, R) -2- {4 - [(3-methylbenzyl) oxy] benzoyl} -5 - [(6-methyl-4-oxo-1, 2,3-benzotriazine-3 (4 //) - yl) methyl] cyclopentanecarboxylic acid (racemate)

A solution of 120 mg (0.20 mmol) of the compound from Example 49A in 0.7 ml of dichloromethane was treated at 0 ° C with 0.3 ml (4.30 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1.5 h and then concentrated. The residue was purified by preparative HPLC (Method 6). 68 mg (68% of theory, purity 100%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (br.s, IH), 8.12-8.04 (m, 2H), 7.97 (d, 2H), 7.90 (dd, IH), 7.31-7.21 (m, 3H), 7.18-7.08 (m, 3H), 5.16 (s, 2H), 4.51 (d, 2H), 4.14-4.05 (m, IH), 3.23 (t, IH), 2.93- 2.78 (m, IH), 2.55 (s, 3H), 2.32 (s, 3H), 2.17-2.03 (m, IH), 1.93-1.81 (m, IH), 1.71- 1.60 (m, IH), 1.56- 1.43 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.23 min, m / z = 512 [M + H] ⁺ . Separation of the enantiomers:

56 mg of the racemic compound from Example 97 were dissolved in 5 ml of acetonitrile / ethanol and separated by preparative SFC on chiral phase into the enantiomers (see Examples 98 and 99) [column: Daicel Chiralpak AY-H, 5 μm, 250 mm x 20 mm; Flow: 100 ml / min; Detection: 210 nm; Injection volume: 0.70 ml; Temperature: 40 ° C; Eluent: 70% carbon dioxide / 30% ethanol; Total running time 25 min].

Example 98

(+) - (IR 5,2 R ₁ S ', 5 _L S ^, R) -2- {4 - [(3-methylbenzyl) oxy] benzoyl} -5 - [(6-methyl-4-oxo-1,2-d , 3-benzotriazine-3 (4 /) -yl) methyl] cyclopentanecarboxylic acid (enantiomer 1) Yield: 42 mg; former purity = 100%; ee value = 100%

[from ²⁰ = + 57.7 °, 589 nm, c = 0.3 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.11 (br.s, IH), 8.11-8.04 (m, 2H), 7.97 (d, 2H), 7.90 (dd, IH), 7.31-7.22 (m, 3H), 7.18-7.08 (m, 3H), 5.16 (s, 2H), 4.51 (d, 2H), 4.14-4.05 (m, IH), 3.23 (t, IH), 2.93- 2.80 (m, IH), 2.55 (s, 3H), 2.32 (s, 3H), 2.17-2.03 (m, IH), 1.93-1.81 (m, IH), 1.72- 1.59 (m, IH), 1.57- 1.43 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.25 min, m / z = 512 [M + H] ⁺ .

Example 99

(-) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(3-methylbenzyl) oxy] benzoyl} -5 - [(6-methyl-4-oxo- l, 2,3-benzotriazine-3 (4 /) -yl) methyl] cyclopentanecarboxylic acid (enantiomer 2) Yield: 25 mg; former purity = 100%; ee value = 100%

[a] _D ²⁰ = -59.0 °, 589 nm, c = 0.35 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (br.s, IH), 8.12-8.04 (m, 2H), 7.97 (d, 2H), 7.91 (d, IH), 7.32-7.22 (m, 3H), 7.18-7.08 (m, 3H), 5.16 (s, 2H), 4.51 (d, 2H), 4.15-4.04 (m, IH), 3.23 (t, IH), 2.94- 2.78 (m, IH), 2.55 (s, 3H), 2.32 (s, 3H), 2.17-2.03 (m, IH), 1.93-1.81 (m, IH), 1.72- 1.59 (m, IH), 1.56- 1.43 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.25 min, m / z = 512 [M + H] Example 100

(+/-) - (lRS, 2SR, 5RS) -2 - [(6-methyl-4-oxo-l, 2,3-te ^

methyl) benzyl] oxy} benzoyl) cyclopentanecarboxylic acid (racemate)

A solution of 345 mg (0.50 mmol) of the compound from Example 50A in 1.7 ml of dichloromethane was added at 0 ° C with 0.85 ml (11.03 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1.5 h and then concentrated. The residue was purified by preparative HPLC (Method 4). 203 mg (71% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-de): δ [ppm] = 12.12 (brs s, IH), 8.12-8.04 (m, 2H), 7.99 (d, 2H), 7.90 (dd, IH), 7.84 (s, IH), 7.79 (d, IH), 7.74-7.70 (m, IH), 7.68-7.61 (m, IH), 7.15 (d, 2H), 5.32 (s, 2H), 4.51 (d, 2H ), 4.15-4.05 (m, IH), 3.23 (t, IH), 2.93-2.80 (m, IH), 2.55 (s, 3H), 2.17-2.03 (m, IH), 1.94-1.80 (m, IH ), 1.71-1.61 (m, IH), 1.57-1.44 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.25 min, m / z = 566 [M + H] ⁺ .

Separation of the enantiomers:

194 mg of the racemic compound from Example 100 were dissolved in 11 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 101 and 102) [column: Phenomenex amylose®, 5 μm, 250 mm × 20 mm; Flow: 100 ml / min; Detection: 210 nm; Injection volume: 0.30 ml; Temperature: 40 ° C; Eluent: 65% carbon dioxide / 35% ethanol; Total running time 7 min]. Example 101

(+) - (IR 5,25 R, 5 R 5) -2 - [(6-Methyl-4-oxo-1,2,3-benzotriazine-3 (4-yl-methyl) -5- (4- {[3 - (trifluoromethyl) benzyl] oxy} benzoyl) cyclopentanecarboxylic acid (enantiomer 1)

Yield: 76 mg; former purity = 100%; ee value = 100%

[from ²⁰ = + 61.0 °, 589 nm, c = 0.35 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, IH), 8.11-8.04 (m, 2H), 7.99 (d, 2H), 7.90 (dd, IH), 7.85 (s, IH), 7.79 (d, IH), 7.75-7.70 (m, IH), 7.69-7.62 (m, IH), 7.15 (d, 2H), 5.32 (s, 2H), 4.51 (d, 2H), 4.16-4.05 (m, IH), 3.23 (t, IH), 2.94-2.79 (m, IH), 2.56 (s, 3H), 2.17-2.04 (m, IH), 1.94-1.80 (m, IH), 1.72-1.60 (m, IH), 1.58-1.43 (m, IH). LC / MS (Method 1, ESIpos): R _t = 1.25 min, m / z = 566 [M + H] ⁺ .

Example 102

(-) - (1R5,25R, 5R ^ -2 - [(6-Methyl-4-oxo-l, 2,3-benzotriazine-3 (4 ^ -yl) methyl] -5- (4- {[3 (trifluoromethyl) benzyl] oxy} benzoyl) cyclopentanecarboxylic acid (enantiomer 2)

Yield: 77 mg; former purity = 100%; ee value = 92% [a] _D ²⁰ = -57.8 °, 589 nm, c = 0.36 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, IH), 8.12-8.04 (m, 2H), 7.99 (d, 2H), 7.90 (d, IH), 7.84 (s, IH), 7.79 (d, IH), 7.75-7.70 (m, IH), 7.69-7.63 (m, IH), 7.15 (d, 2H), 5.32 (s, 2H), 4.51 (d, 2H), 4.16-4.05 (m, IH), 3.23 (t, IH), 2.93-2.80 (m, IH), 2.17-2.04 (m, IH), 1.95-1.81 (m, IH), 1.73-1.60 ( m, IH), 1.56-1.44 (m, IH). LC / MS (Method 1, ESIpos): R _t = 1.25 min, m / z = 566 [M + H] ⁺ .

Example 103

(+/-) - (IRS, 2RS, 5SR) -2- {4- [(3-chlorobenzyl) oxy] benzoyl} -5- [(6-methyl-4-oxo-1,2,3-benzotriazine] 3 (4 //) - yl) methyl] cyclopentanecarboxylic acid (racemate)

A solution of 392 mg (0.62 mmol) of the compound from Example 51A in 2.1 ml of dichloromethane was admixed at 0 ° C. with 1.0 ml (13.62 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1 h and then concentrated. The residue was purified by preparative HPLC (Method 4). There were obtained 234 mg (71% of theory, purity 100%) of the title compound. Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (s, IH), 8.12-8.04 (m, 2H), 7.98 (d, 2H), 7.90 (dd, IH), 7.54 ( s, IH), 7.47-7.38 (m, 3H), 7.13 (d, 2H), 5.23 (s, 2H), 4.51 (d, 2H), 4.14-4.06 (m, IH), 3.23 (t, IH) , 2.93-2.80 (m, IH), 2.16-2.04 (m, IH), 1.93-1.82 (m, IH), 1.71-1.60 (m, IH), 1.56-1.44 (m, IH). LC / MS (Method 1, ESIpos): R _t = 1.25 min, m / z = 532 [M + H] ⁺ .

Separation of the enantiomers:

122 mg of the racemic compound from Example 103 were dissolved in 20 ml of methanol and 3 ml of dioxane and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 104 and 105) [column: Phenomenex amylose II, 5 μm, 250 mm × 30 mm; Flow: 100 ml / min; Detection: 210 nm; Injection volume: 0.90 ml; Temperature: 40 ° C; Eluent: 60% carbon dioxide / 40% ethanol; Total running time 15 min].

Example 104

(+) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(3-chlorobenzyl) oxy] benzoyl} -5 - [(6-methyl-4-oxo- l, 2,3-benzotriazine-3 (4 /) -yl) methyl] cyclopentanecarboxylic acid (enantiomer 1) Yield: 95 mg; former purity = 100%; ee value = 100%

[from ²⁰ = + 64.6 °, 589 nm, c = 0.40 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, IH), 8.11-8.04 (m, 2H), 7.98 (d, 2H), 7.90 (dd, IH), 7.54 (s, IH), 7.47-7.38 (m, 3H), 7.13 (d, 2H), 5.23 (s, 2H), 4.51 (d, 2H), 4.14-4.05 (m, IH), 3.23 (t, IH), 2.93-2.80 (m, IH), 2.55 (s, 3H), 2.17-2.03 (m, IH), 1.93-1.81 (m, IH), 1.72-1.60 (m, IH), 1.56-1.44 ( m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.24 min, m / z = 532 [M + H] ⁺ .

Example 105

(-) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(3-chlorobenzyl) oxy] benzoyl} -5 - [(6-methyl-4-oxo- l, 2,3-benzotriazine-3 (4 /) -yl) methyl] cyclopentanecarboxylic acid (enantiomer 2) Yield: 91 mg; former purity = 100%; ee value = 97%

[a] _D ²⁰ = -62.4 °, 589 nm, c = 0.27 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.13 (br.s, IH), 8.11-8.04 (m, 2H), 7.98 (d, 2H), 7.90 (d, IH), 7.54 (s, IH), 7.47-7.39 (m, 3H), 7.13 (d, 2H), 5.23 (s, 2H), 4.51 (d, 2H), 4.15-4.04 (m, 1H), 3.23 (t, 1H), 2.94-2.79 (m, 1H), 2.55 (s, 3H), 2.17-2.03 (m, 1H), 1.93-1.81 (m, 1H), 1.72-1.60 (m, 1H), 1.56-1.43 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.24 min, m / z = 532 [M + H] ⁺ . Example 106 (+/-) - (IRR ₁ S ^, 2R ₁ S ^, 5S ^, R) -2- {4 - [(3-methoxybenzyl) oxy] benzoyl} -5 - [(6-methyl- 4-oxo-l, 2,3-benzotriazine-3 (4 //) - yl) methyl] cyclopentanecarboxylic acid (racemate)

A solution of 115 mg (0.18 mmol) of the compound from Example 52A in 0.6 ml of dichloromethane was treated at 0 ° C with 0.3 ml (3.93 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1 h and then concentrated. The residue was purified by preparative HPLC (Method 6). 72 mg (75% of theory, purity 99%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (br.s, 1H), 8.12-8.04 (m, 2H), 7.97 (d, 2H), 7.90 (d, 1H), 7.34-7.28 (m, 1H), 7.12 (d, 2H), 7.05-7.00 (m, 2H), 6.93-6.87 (m, 1H), 5.18 (s, 2H), 4.51 (d, 2H), 4.14- 4.04 (m, 1H), 3.76 (s, 3H), 3.23 (t, 1H), 2.93-2.79 (m, 1H), 2.55 (s, 3H), 2.16-2.04 (m, 1H), 1.93-1.81 ( m, 1H), 1.71-1.59 (m, 1H), 1.57-1.43 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.17 min, m / z = 528 [M + H] ⁺ .

Separation of the enantiomers:

64 mg of the racemic compound from Example 106 were dissolved in 11 ml of ethanol / acetonitrile and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 107 and 108) [column: Phenomenex amylose®, 5 μm, 250 mm × 20 mm; Flow: 100 ml / min; Detection: 210 nm; Injection volume: 0.95 ml; Temperature: 40 ° C; Eluent: 70% carbon dioxide / 30% ethanol; Total running time 23 min]. Example 107

(+) - (1R5,2R5,55R) -2- {4 - [(3-methoxybenzyl) oxy] benzoyl} -5 - [(6-methyl-4-oxo-1,2,3-benzotriazine-3 ( 4 //) - yl) mefhyl] cyclopentanecarboxylic acid (enantiomer 1)

Yield: 25 mg; former purity = 100%; ee value = 100% [a] _D ²⁰ = + 61.8 °, 589 nm, c = 0.32 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.10 (br.s, IH), 8.12-8.04 (m, 2H), 7.97 (d, 2H), 7.90 (d, IH), 7.31 (t, IH), 7.12 (d, 2H), 7.05-7.00 (m, 2H), 6.91 (d, IH), 5.18 (s, 2H), 4.51 (d, 2H), 4.14-4.55 (m, IH), 3.76 (s, 3H), 3.23 (t, IH), 2.94-2.79 (m, IH), 2.55 (s, 3H), 2.16-2.04 (m, IH), 1.93- 1.82 (m, IH) , 1.72-1.60 (m, IH), 1.56-1.43 (m, IH). LC / MS (Method 1, ESIpos): R _t = 1.17 min, m / z = 528 [M + H] ⁺ .

Example 108

(-) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- {4 - [(3-methoxybenzyl) oxy] benzoyl} -5 - [(6-methyl-4-oxo- l, 2,3-benzotriazine-3 (4 //) - yl) -methyl] cyclopentane carboxylic acid (enantiomer 2)

Yield: 26 mg; former purity = 100%; ee value = 100% [α] _D ²⁰ = -62.5 °, 589 nm, c = 0.32 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.10 (br.s, IH), 8.12-8.04 (m, 2H), 7.97 (d, 2H), 7.90 (dd, IH), 7.31 (t, IH), 7.12 (d, 2H), 7.05-7.00 (m, 2H), 6.93-6.88 (m, IH), 5.18 (s, 2H), 4.51 (d, 2H), 4.14-4.04 ( m, IH), 3.76 (s, 3H), 3.23 (t, IH), 2.93-2.80 (m, IH), 2.55 (s, 3H), 2.16-2.04 (m, IH), 1.93-1.82 (m, IH), 1.72-1.59 (m, IH), 1.56-1.43 (m, IH). LC / MS (Method 1, ESIpos): R _t = 1.17 min, m / z = 528 [M + H] ⁺ .

Example 109

(+/-) - (1R5,25R, 5R5) -2 - [(6-methyl-4-oxo-1,2,3-benzotriazine-3 (4f) -yl) methyl] -5- (4- {[3- (trifluoromethoxy) benzyl] oxy} benzoyl) cyclopentanecarboxylic acid (racemate)

A solution of 95 mg (0.14 mmol) of the compound from Example 53A in 0.5 ml of dichloromethane was admixed at 0 ° C. with 0.2 ml (3.06 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1 h and then concentrated. The residue was purified by preparative HPLC (Method 6). 56 mg (69% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (s, 1H), 8.12-8.04 (m, 2H), 7.99 (d, 2H), 7.90 (dd, 1H), 7.58- 7.44 (m, 3H), 7.37-7.33 (m, 1H), 7.14 (d, 2H), 5.28 (s, 2H), 4.51 (d, 2H), 4.15-4.06 (m, 1H), 3.23 (t, 1H), 2.94-2.79 (m, 1H), 2.55 (s, 3H), 2.17-2.05 (m, 1H), 1.93-1.82 (m, 1H), 1.71-1.60 (m, 1H), 1.56-1.43 ( m, 1H). LC / MS (Method 1, ESIpos): R _t = 1.31 min, m / z = 582 [M + H] ⁺ .

Separation of the enantiomers:

48 mg of the racemic compound from Example 109 were dissolved in 8 ml of ethanol / acetonitrile and separated by means of preparative SFC on a chiral phase into the enantiomers (see Examples 110 and 111) [column: Phenomenex amylose®, 5 μm, 250 mm × 20 mm; Flow: 100 ml / min; Detection: 210 nm; Injection volume: 0.70 ml; Temperature: 40 ° C; Eluent: 70% carbon dioxide / 30% ethanol; Total running time 10 min].

Example 110

(+) - (IR 5,25 R, 5 R 5) -2 - [(6-Methyl-4-oxo-1,2,3-benzotriazine-3 (4-yl-methyl) -5- (4- {[3 - (trifluoromethoxy) benzyl] oxy} benzoyl) cyclopentanecarboxylic acid (enantiomer 1) Yield: 22 mg, former purity = 100%, ee value = 100%

[from ²⁰ = + 51.4 °, 589 nm, c = 0.33 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.10 (br.s, 1H), 8.12-8.04 (m, 2H), 7.99 (d, 2H), 7.90 (dd, 1H), 7.58-7.46 (m, 3H), 7.35 (d, 1H), 7.14 (d, 2H), 5.28 (s, 2H), 4.51 (d, 2H), 4.16-4.05 (m, 1H), 3.23 (t, 1H), 2.93-2.79 (m, 1H), 2.55 (s, 3H), 2.17-2.04 (m, 1H), 1.93-1.82 (m, 1H), 1.72-1.60 (m, 1H), 1.56-1.43 ( m, 1H). LC / MS (Method 1, ESIpos): R _t = 1.27 min, m / z = 582 [M + H] ⁺ . Example 111

(-MlRS, 2SR, 5RS) -2 (6-Metoyl-oxo ^

methoxy) benzyl] oxy} benzoyl) cyclopentanecarboxylic acid (enantiomer 2) Yield: 21 mg; former purity = 100%; ee value = 100% [α] _D ²⁰ = -34.5 °, 589 nm, c = 0.31 g / 100 ml, chloroform. Example 112

(+/-) - (IR 5,25 R, 5 R 5) -2 (6-methyl-4-oxo, 2,3-benzotriazine-3 (4 /) -yl) methyl] -5- [4- (2-phenyl - ethoxy) benzoyl] cyclopentanecarboxylic acid (racemate)

A solution of 347 mg (0.57 mmol) of the compound from Example 54A in 1.9 ml of dichloromethane was admixed at 0 ° C. with 1.0 ml (12.46 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1 h and then concentrated. The residue was purified by preparative HPLC (Method 4). 253 mg (87% of theory, purity 100%) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.11 (br.s, IH), 8.12-8.04 (m, 2H), 7.95 (d, 2H), 7.90 (dd, IH), 7.36-7.28 (m, 4H), 7.25-7.19 (m, IH), 7.04 (d, 2H), 4.51 (d, 2H), 4.29 (t, 2H), 4.13-4.05 (m, IH), 3.23 ( , IH), 3.06 (t, 2H), 2.93-2.79 (m, IH), 2.55 (s, 3H), 2.16-2.03 (m, IH), 1.93-1.82 (m, IH), 1.71-1.59 ( m, IH), 1.56-1.43 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.22 min, m / z = 512 [M + H] ⁺ . Separation of the enantiomers:

243 mg of the racemic compound from Example 112 were dissolved in 21 ml of methanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 113 and 114) [column: Phenomenex amylose®, 5 μm, 250 mm × 20 mm; Flow: 100 ml / min; Detection: 210 nm; Injection volume: 0.40 ml; Temperature: 40 ° C; Eluent: 65% carbon dioxide / 35% ethanol; Total running time 17 min]. Example 113

(+) - (1R5,25R, 5R5) -2 - [(6-Methyl-4-oxo-l, 23-benzotriazine-3 (4 /) -yl) methyl] -5- [4- (2-phenyl - ethoxy) benzoyl] cyclopentanecarboxylic acid (enantiomer 1)

Yield: 108 mg; former purity = 97%; ee value = 100% [a] _D ²⁰ = + 66.8 °, 589 nm, c = 0.39 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, IH), 8.11-8.04 (m, 2H), 7.95 (d, 2H), 7.89 (dd, IH), 7.36-7.28 (m, 4H), 7.26-7.18 (m, IH), 7.04 (d, 2H), 4.51 (d, 2H), 4.29 (t, 2H), 4.13-4.05 (m, IH), 3.22 ( t, IH), 3.06 (t, 2H), 2.93-2.79 (m, IH), 2.55 (s, 3H), 2.16-2.02 (m, IH), 1.93-1.80 (m, IH), 1.71-1.59 ( m, IH), 1.57-1.43 (m, IH). LC / MS (Method 1, ESIpos): R _t = 1.22 min, m / z = 512 [M + H] ⁺ .

Example 114

(-) - (1R5,25R, 5R ^ -2 - [(6-Methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) -methyl] -5- [4- (2 -phenylethoxy) - benzoyl] cyclopentanecarboxylic acid (enantiomer 2)

Yield: 112 mg; former purity = 100%; ee value = 99% [α] _D ²⁰ = -63.7 °, 589 nm, c = 0.40 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, IH), 8.11-8.04 (m, 2H), 7.95 (d, 2H), 7.89 (dd, IH), 7.36-7.27 (m, 4H), 7.26-7.19 (m, IH), 7.04 (d, 2H), 4.51 (d, 2H), 4.29 (t, 2H), 4.13-4.04 (m, IH), 3.22 ( t, IH), 3.06 (t, 2H), 2.93-2.79 (m, IH), 2.55 (s, 3H), 2.16-2.02 (m, IH), 1.93-1.80 (m, IH), 1.71-1.59 ( m, IH), 1.56-1.43 (m, IH). LC / MS (Method 1, ESIpos): R _t = 1.22 min, m / z = 512 [M + H] ⁺ .

Example 115

(+/-) - (1R5.2 _{l of} S ^, R, 5R.S ^, ) -2 - [(6-methyl-4-oxo-l, 2,3-benzotriazine-3 (4 /) -yl) methyl ] -5- [4- (3-phenyl-propoxy) benzoyl] cyclopentanecarboxylic acid (racemate)

A solution of 44 mg (0.07 mmol) of the compound from Example 55A in 0.2 ml of dichloromethane was admixed at 0 ° C. with 0.11 ml (1.55 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1 h and then concentrated. The residue was purified by preparative HPLC (Method 6). 23 mg (62% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (s, 1H), 8.12-8.05 (m, 2H), 7.96 (d, 2H), 7.90 (dd, 1H), 7.32- 7.15 (m, 5H), 7.04 (d, 2H), 4.51 (d, 2H), 4.14-4.03 (m, 3H), 3.23 (t, 1H), 2.87 (d, 1H), 2.75 (t, 2H) , 2.55 (s, 3H), 2.17-1.98 (m, 3H), 1.94-1.82 (m, 1H), 1.72-1.60 (m, 1H), 1.57-1.44 (m, 1H). LC / MS (Method 1, ESIpos): R _t = 1.32 min, m / z = 526 [M + H] ⁺ . Example 116

(+/-) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (cyclohexylmethoxy) benzoyl] -5 - [(6-methyl-4-oxo-l, 2 , 3-benzotriazine-3 (4 //) - yl) methyl] cyclopentanecarboxylic acid (racemate)

A solution of 163 mg (0.27 mmol) of the compound from Example 56A in 0.9 ml of dichloromethane was treated at 0 ° C with 0.5 ml (5.92 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1 h and then concentrated. The residue was purified by preparative HPLC (Method 6). There were obtained 106 mg (78% of theory, purity 100%) of the title compound.

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.12 (brs s, 1H), 8.11-8.04 (m, 2H), 7.95 (d, 2H), 7.90 (dd, 1H), 7.03 (d, 2H), 4.51 (d, 2H), 4.13-4.04 (m, 1H), 3.87 (d, 2H), 3.23 (t, 1H), 2.93-2.80 (m, 1H), 2.55 (s, 3H ), 2.17-2.02 (m, 1H), 1.93-1.59 (m, 7H), 1.56-1.44 (m, 1H), 1.32-0.97 (m, 6H). LC / MS (Method 1, ESIpos): R _t = 1.35 min, m / z = 504 [M + H]

Separation of the enantiomers:

98 mg of the racemic compound from Example 116 were dissolved in 10 ml of acetonitrile / ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 117 and 118) [column: Phenomenex amylose®, 5 μm, 250 mm × 20 mm; Flow: 100 ml / min; Detection: 210 nm; Injection volume: 0.80 ml; Temperature: 40 ° C; Eluent: 70% carbon dioxide / 30% ethanol; Total running time 17 min].

Example 117

(+) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (cyclohexylmethoxy) benzoyl] -5 - [(6-methyl-4-oxo-l, 2,3 benzotriazine 3 (4 /) -yl) methyl] cyclopentane carboxylic acid (enantiomer 1)

Yield: 40 mg; former purity = 100%; ee value = 100%

[a] _D ²⁰ = + 60.0 °, 589 nm, c = 0.32 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.11 (br.s, IH), 8.12-8.03 (m, 2H), 7.95 (d, 2H), 7.90 (dd, IH), 7.03 (d, 2H), 4.51 (d, 2H), 4.13-4.03 (m, IH), 3.87 (d, 2H), 3.23 (t, IH), 2.93-2.80 (m, IH), 2.55 (s, 3H), 2.10 (d, IH), 1.93-1.59 (m, 7H), 1.57-1.42 (m, IH), 1.35-0.97 (m, 6H).

LC / MS (Method 1, ESIpos): R _t = 1.35 min, m / z = 504 [M + H] ⁺ .

Example 118

(-) - (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (cyclohexylmethoxy) benzoyl] -5 - [(6-methyl-4-oxo-l, 2,3 benzotriazine-3 (4 /) -yl) methyl] cyclopentanecarboxylic acid (enantiomer 2) Yield: 37 mg; former purity = 100%; ee value = 100%

[a] _D ²⁰ = -68.5 °, 589 nm, c = 0.33 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (br.s, IH), 8.12-8.04 (m, 2H), 7.95 (d, 2H), 7.90 (dd, IH), 7.03 (d, 2H), 4.51 (d, 2H), 4.13-4.04 (m, IH), 3.87 (d, 2H), 3.23 (t, IH), 2.93-2.79 (m, IH), 2.55 (s, 3H), 2.15-2.03 (m, IH), 1.93-1.59 (m, 7H), 1.56-1.44 (m, IH), 1.35-0.96 (m, 6H). LC / MS (Method 1, ESIpos): R _t = 1.35 min, m / z = 504 [M + H] Example 119

(+/-) - (lRS, 2RS, 5SR) -2- [4- (cyclopentylmethoxy ^^

3 (4 //) - yl) methyl] cyclopentanecarboxylic acid (racemate)

A solution of 49 mg (0.049 mmol, purity 58%) of the compound from Example 57A in 0.16 ml of dichloromethane was admixed at 0 ° C. with 0.08 ml (1.07 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1 h and then concentrated. The residue was purified by preparative HPLC (Method 6). 18 mg (76% of theory, purity 100%) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (br.s, 1H), 8.11-8.04 (m, 2H), 7.95 (d, 2H), 7.90 (dd, 1H), 7.03 (d, 2H), 4.51 (d, 2H), 4.13-4.04 (m, 1H), 3.94 (d, 2H), 3.23 (t, 1H), 2.93-2.79 (m, 1H), 2.55 (s, 3H), 2.38-2.24 (m, 1H), 2.17-2.03 (m, 1H), 1.93-1.43 (m, 9H), 1.40-1.25 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.29 min, m / z = 490 [M + H] ⁺ .

Example 120 (+/-) - _(l S ^lR5,2R, ^5.S, R) -2- [4- (hexyloxy) benzoyl] -5 - [(6-methyl-4-oxo-l, 2, 3-benzotriazine-3 (4 /) - yl) - methyl] cyclopentanecarboxylic acid (racemate)

A solution of 140 mg (0.24 mmol) of the compound from Example 58A in 0.8 ml of dichloromethane was admixed at 0 ° C. with 0.4 ml (5.21 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1 h and then concentrated. The residue was purified by preparative HPLC (Method 6). 69 mg (59% of theory, purity 100%) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (br.s, IH), 8.12-8.04 (m, 2H), 7.95 (d, 2H), 7.90 (dd, IH), 7.03 (d, 2H), 4.51 (d, 2H), 4.13-4.02 (m, 3H), 3.23 (t, IH), 2.93-2.80 (m, IH), 2.55 (s, 3H), 2.16-2.03 ( m, IH), 1.93-1.82 (m, IH), 1.77-1.60 (m, 3H), 1.56-1.24 (m, 7H), 0.91-0.83 (m, 3H). LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 492 [M + H] ⁺ . Separation of the enantiomers:

60 mg of the racemic compound from Example 120 were dissolved in 11 ml of acetonitrile / ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 121 and 122) [column: Phenomenex amylose®, 5 μm, 250 mm × 20 mm; Flow: 100 ml / min; Detection: 210 nm; Injection volume: 0.6 ml; Temperature: 40 ° C; Eluent: 70% carbon dioxide / 30% ethanol; Total running time 11 min].

Example 121

(+) - (1R5,2R5,5S ^, R) -2- [4- (hexyloxy) benzoyl] -5 - [(6-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) - yl) - methyl] cyclopentanecarboxylic acid (enantiomer 1) Yield: 27 mg; former purity = 100%; ee value = 100%

[from ²⁰ = + 42.0 °, 589 nm, c = 0.35 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.09 (br.s, IH), 8.12-8.05 (m, 2H), 7.95 (d, 2H), 7.90 (dd, IH), 7.03 (d, 2H), 4.51 (d, 2H), 4.13-4.02 (m, 3H), 3.23 (t, IH), 2.93-2.79 (m, IH), 2.55 (s, 3H), 2.16-2.03 ( m, IH), 1.93-1.82 (m, IH), 1.78-1.60 (m, 3H), 1.56-1.22 (m, 7H), 0.91-0.83 (m, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.34 min, m / z = 492 [M + H] ⁺ . Example 122

(-) - (1R5,2R5,5S ^, R) -2- [4- (hexyloxy) benzoyl] -5 - [(6-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) - yl) - methyl] cyclopentanecarboxylic acid (enantiomer 2) Yield: 28 mg; former purity = 100%; ee value = 100%

[a] _D ²⁰ = -52.6 °, 589 nm, c = 0.36 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.09 (br.s, IH), 8.12-8.04 (m, 2H), 7.95 (d, 2H), 7.90 (dd, IH), 7.03 (d, 2H), 4.51 (d, 2H), 4.13-4.02 (m, 3H), 3.23 (t, IH), 2.92-2.80 (m, IH), 2.55 (s, 3H), 2.16-2.03 (m, 1H), 1.94-1.81 (m, 1H), 1.77-1.60 (m, 3H), 1.56-1.21 (m, 7H), 0.91-0.84 (m, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 492 [M + H] ⁺ . Example 123 (+/-) - (IR 5,25R, 5R 5) -2 - [(6-methyl-4-oxo-1,2-benzotriazine-3 (4 /) -yl) -methyl] -5- [4- (pentyloxy) benzoyl] cyclopentane carboxylic acid (racemate)

A solution of 378 mg (0.58 mmol, purity 88%) of the compound from Example 59A in 2.0 ml of dichloromethane was admixed at 0 ° C. with 1.0 ml (12.66 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1 h and then concentrated. The residue was purified by preparative HPLC (Method 6). 228 mg (83% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (s, 1H), 8.11-8.04 (m, 2H), 7.95 (d, 2H), 7.90 (dd, 1H), 7.03 ( d, 2H), 4.51 (d, 2H), 4.13-4.02 (m, 3H), 3.23 (t, 1H), 2.93-2.79 (m, 1H), 2.55 (s, 3H), 2.16-2.04 (m, 1H), 1.93-1.82 (m, 1H), 1.78-1.60 (m, 3H), 1.56-1.45 (m, 1H), 1.44-1.27 (m, 4H), 0.89 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.27 min, m / z = 478 [M + H] ⁺ . Separation of the enantiomers:

220 mg of the racemic compound from Example 123 were dissolved in 11 ml of ethanol while warm and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 124 and 125) [column: Phenomenex amylose II, 5 μm, 250 mm × 20 mm; Flow: 100 ml / min; Detection: 210 nm; Injection volume: 0.20 ml; Temperature: 40 ° C; Eluent: 70% carbon dioxide / 30% ethanol; Total running time 12 min].

Example 124 (+) - (IR 5,25R, 5R.S ^, ) -2 - [(6-Methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) methyl] -5- [4- (pentyloxy) benzoyl] cyclopentane carboxylic acid (enantiomer 1) Yield: 96 mg; former purity = 100%; ee value = 100% [a] _D ²⁰ = + 67.8 °, 589 nm, c = 0.37 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.13 (br.s, IH), 8.11-8.04 (m, 2H), 7.95 (d, 2H), 7.90 (dd, IH), 7.03 (d, 2H), 4.51 (d, 2H), 4.14-4.01 (m, 4H), 3.22 (t, IH), 2.93-2.80 (m, IH), 2.55 (s, 3H), 2.15-2.03 (m , IH), 1.92-1.82 (m, IH), 1.78-1.60 (m, 3H), 1.56-1.45 (m, IH), 1.44-1.28 (m, 4H), 0.92-0.86 (m, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.27 min, m / z = 478 [M + H] ⁺ . Example 125

(-) - (1R5,25R, 5R ^ -2 - [(6-Methyl-4-oxo-l, 2,3-benzotriazine-3 (4 /) -yl) methyl] -5- [4- (pentyloxy ) - benzoyl] cyclopentane carboxylic acid (enantiomer 2)

Yield: 98 mg; former purity = 100%; ee value = 99%

[a] _D ²⁰ = -68.1 °, 589 nm, c = 0.33 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, IH), 8.11-8.04 (m, 2H), 7.95 (d, 2H), 7.90 (dd, IH), 7.03 (d, 2H), 4.51 (d, 2H), 4.14-4.01 (m, 4H), 3.22 (t, IH), 2.93-2.79 (m, IH), 2.55 (s, 3H), 2.16-2.03 ( m, IH), 1.93-1.82 (m, IH), 1.78-1.60 (m, 3H), 1.56-1.45 (m, IH), 1.44-1.27 (m, 4H), 0.89 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.27 min, m / z = 478 [M + H] ⁺ .

B. Evaluation of Pharmacological Activity

The pharmacological activity of the compounds according to the invention can be detected by in vitro and in vzvo studies, as are known to those skilled in the art. The following application examples describe the biological activity of the compounds according to the invention without restricting the invention to these examples.

Abbreviations and acronyms:

APMA 4-aminophenyl mercuric acetate

Brij®- ³⁵ polyoxyethylene lauryl ether

BSA bovine serum albumin

CYP cytochrome P450

Dap (or Dpa) L-2,3-diaminopropionic acid (β-amino-L-alanine)

DMSO dimethyl sulfoxide

Dnp 2,4-dinitrophenyl

EDTA ethylenediaminetetraacetic acid

HEPES 2- [4- (2-hydroxyethyl) piperazin-1-yl] ethanesulfonic acid

HME human macrophage elastase

IC inhibitory concentration

Mca (7 -methoxycumarin-4-yl) acetyl

MMP matrix metallopeptidase

MTP microtiter plate

NADP ⁺ nicotinamide adenine dinucleotide phosphate (oxidized form)

NADPH nicotinic acid amide adenine dinucleotide phosphate (reduced form)

Nval Norvaline

PEG polyethylene glycol

Tris tris (hydroxymethyl) aminomethane

v / v volume to volume ratio (of a solution)

w / w weight to weight ratio (of a solution)

B-l. In vitro HME inhibition test

The potency of the compounds of the invention compared to HME (MMP-12) is determined in a in vi tro-inhibited st. The HME-mediated amidolytic cleavage of a suitable peptide substrate results here in a fluorescence light increase. The signal intensity of the fluorescent light is directly proportional to the enzyme activity. The effective concentration of a test compound, at Half of the enzyme is inhibited (50% signal intensity of the fluorescent light) is given as IC ₅ o value.

Standard in vitro HME inhibition test:

In a 384 well microtiter plate are used in a test volume of 41 μΐ of test buffer (0.1 M HEPES pH 7.4, 0.15M NaCl, 0.03M CaCl, 0.004 mM ZnCk, 0.02M EDTA, 0.005% Brij ^®), the enzyme ( 0.5 nM HME, R & D Systems, 917-MP, autocatalytic activation according to the manufacturer's instructions) and the intramolecularly quenched substrate [5 μM Mca-Pro-Leu-Gly-Leu-Glu-Glu-Ala-Dap (Dnp) -NH ₂ ; Bachem, M-2670] in the presence and absence of the test substance (as a solution in DMSO) for two hours at 37 ° C incubated. The fluorescent light intensity of the test mixtures is measured (excitation 323 nm, emission 393 nm). The IC 50 values are determined by plotting the fluorescent light intensity versus the drug concentration.

Highly sensitive in vitro HME inhibition test:

If subnanomolar IC values are obtained in the case of highly potent test substances in the standard HME inhibition test described above, a modified test is used for their more precise determination. In this case, a ten-fold lower enzyme concentration is used (final concentration, for example, 0.05 nM) in order to achieve an increased sensitivity of the test. The incubation time of the test is chosen to be longer (e.g., 16 hours).

In vitro HME inhibition test in the presence of serum albumin in the reaction buffer:

This test corresponds to the standard HME inhibition test described above, but using a modified reaction buffer. This reaction buffer additionally contains bovine serum albumin (BSA, fatty acid free, A6003, Sigma-Aldrich) of a final concentration of 2% (w / w), which corresponds approximately to half of the physiological serum albumin content. The enzyme concentration in this modified assay is slightly elevated (e.g., 0.75 nM), as is the incubation time (e.g., three hours).

Table 1 below shows for individual embodiments of the invention the IC 50 values from the standard or highly sensitive HME inhibition test (in part as averages of several independent individual determinations and rounded to two significant digits): Table 1: Inhibition of human macrophage elastase (HME / hMMP-12)

Example HME / hMMP-12 Example HME / hMMP-12 No. ICso [nM] No. ICso [nM]

1 0.052 28 0.036

2 0.51 29 4.1

3 0.055 30 0.037

4 0.049 31 0.012

5 0.070 33 0.13

6 0.17 34 160

7 0.26 35 0.013

8 0.21 36 0.13

9 145 37 0.080

10 0.36 38 350

11 0.014 39 0.044

12 0.019 40 0.048

13 0.018 41 0.010

14 10 42 39

15 0.050 43 0.039

16 0.064 44 0.024

17 48 45 4.1

18 0.11 46 0.034

19 0.027 47 0.025

20 4.6 48 290

21 0.045 49 0.14

22 170 50 0.036

23 0.032 51 30

24 0.015 52 0.017

25 0.013 53 0.027

26 1.0 54 22

27 0.032 55 0.037 Example HME / hMMP-12 Example HME / hMMP-12 No. ICso [nM] No. ICso [nM]

56 0.20 86 0.018

57 0.028 87 8.3

58 0.027 88 0.023

59 4.2 89 0.045

61 0.032 90 1.1

62 4.7 91 0.074

63 0.015 92 0.048

64 0.068 93 190

65 1.2 94 0.055

66 0.043 95 0.025

67 0.015 96 120

68 2.1 97 0.40

69 0.094 98 0.10

70 0.031 99 210

71 2.7 100 0.080

72 0.13 101 0.086

73 0.17 102 8.7

74 160 103 0.10

75 0.051 104 0.12

76 0.10 105 14

77 0.040 106 0.078

78 8.8 107 0.035

79 0.25 108 470

80 0.079 109 0.14

81 25 110 0.087

82 0.12 111 140

83 0.11 112 0.66

84 33 113 0.24

85 0.22 114 110 Example HME / hMMP-12 Example HME / hMMP-12

No. ICso [nM] No. ICso [nM]

115 0.13 121 0.078

116 0.093 122 190

117 0.014 123 0.088

118 150 124 0.062

119 0.048 125 6.7

120 0.10

B-2. In vitro MMP inhibition tests

The potency of the compounds of the invention over other MMPs (and thus its selectivity) is also determined in vz ^'iro inhibition assays. The MMP-mediated amidolytic cleavage of a suitable peptide substrate also leads here to a fluorescence light increase. The signal intensity of the fluorescent light is directly proportional to the enzyme activity. The effective concentration of a test compound in which half of the enzyme is inhibited (50% signal intensity of the fluorescent light) is given as IC 50 value. a) Human MMPs:

In vitro MMP-1 inhibition test:

Recombinant MMP-1 (R & D Systems, 901-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 2 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-1 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (for example over 120 minutes at a temperature of 32 ° C.).

In vitro MMP-2 inhibition test:

Recombinant MMP-2 (R & D Systems, 902-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentra- tion, for example, 2 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl, 150 mM NaCl, 0.05% Brij ^® -35) is 1 μΐ of the examined test compound (as a solution in DMSO, suitable concentrations, for example 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP). The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-2 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (for example over 120 minutes at a temperature of 32 ° C.).

In vitro MMP-3 inhibition test:

Recombinant MMP-3 (R & D Systems, 513-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 2 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCh, 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO , suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is carried out by adding the intramolecularly quenched substrate McA-Arg-Pro-Lys-Pro-Val-Glu-Nval-Trp-Arg-Lys (Dnp) -NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-002 ) so that a total test volume of 50 μΐ results. The course of the MMP-3 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.).

In vitro MMP-7 inhibition test:

Recombinant MMP-7 (R & D Systems, 907-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.5 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-7 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.). In vitro MMP-8 inhibition assay:

Recombinant MMP-8 (R & D Systems, 908-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.5 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCh, 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO , suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-8 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.).

In vitro MMP-9 inhibition test:

Recombinant MMP-9 (R & D Systems, 911-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-9 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (for example over 120 minutes at a temperature of 32 ° C.). In vitro ΜΜΡ-10 inhibition test:

Recombinant MMP-10 (R & D Systems, 910-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 2 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is carried out by adding the intramolecularly quenched substrate McA-Arg-Pro-Lys-Pro-Val-Glu-Nval-Trp-Arg-Lys (Dnp) -NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-002 ) so that a total test volume of 50 μΐ results. The course of the MMP-10 reaction is determined by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C).

In vitro ΜΜΡ-13 inhibition test:

Recombinant MMP-13 (R & D Systems, 511-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-13 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.). In vitro ΜΜΡ-14 inhibition test:

Recombinant MMP-14 (R & D Systems, 918-MP) is enzymatically activated according to the manufacturer's instructions by using recombinant furin (R & D Systems, 1503-SE). To 24 μΐ activated enzyme (final concentration eg 0.5 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as Solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by addition of the intramolecularly quenched substrate Mca-Lys-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH2 (final concentration eg 5 μΜ; R & D Systems, ES-010) a total test volume of 50 μΐ results. The course of the MMP-14 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (for example over 120 minutes at a temperature of 32 ° C.).

In vitro ΜΜΡ-16 inhibition test:

Recombinant MMP-16 (R & D Systems, 1785-MP) is enzymatically activated according to the manufacturer's instructions by using recombinant furin (R & D Systems, 1503-SE). To 24 μΐ activated enzyme (final concentration eg 1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is achieved by addition of the intramolecular quenched substrate Mca-Lys-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH2 (final concentration eg 5 μΜ, R & D Systems, ES-010) is started so that a total test volume of 50 μΐ results. The course of the MMP-16 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (for example over 120 minutes at a temperature of 32 ° C.). In the following Tables 2A and 2B, for representative embodiments of the invention, the IC 50 values from these assays for inhibiting human MMPs are reported (in part as averages of several independent determinations and rounded to two significant digits):

Table 2A: Inhibition of human MMPs

Example MMP-1 MMP-2 MMP-3 MMP-7 MMP-8

Nos. ICso [nM] ICso [nM] ICso [nM] ICso [nM] ICso [nM]

1 5200 9.3 170 1100 2.5

2> 40000 290 2100 5300 440

3 16000 190 1500 4900 260

4 28000 84 1100 2200 14

5> 40000 220 1500 2400 250

11 3800 210 100 87 3.2

12 2500 42 28 160 0.67

13 3300 80 62 120 0.88

15 8300 480 220 120 26

16 7100 970 350 190 65

18> 40000 2000 1000 910 61

19 37000 3800 3000 1600 130

23 24000 1600 540 500 56

25 2300 79 63 120 0.79

28 17000 700 250 300 43

31 5400 830 280 79 9.1

35 2100 450 400 31 2.0

39> 40000 4600 420 730 290

40 3800 440 180 260 6.3 Example MMP-1 MMP-2 MMP-3 MMP-7 MMP-8 No. ICso [nM] ICso [nM] ICso [nM] ICso [nM] ICso [nM]

41 3100 97 41 68 1.6

44 3600 270 140 140 1.1

52 6300 1600 380 340 38

55 15000 1300 440 260 30

56> 40000 2800 2000 1400 580

58 8400 580 300 180 16

67 5200 270 140 120 1.6

75 21000 4200 170 340 74

77 2900 970 100 150 41

79 15000 4000 800 1300 280

80 2500 1400 150 200 52

83> 40000 6700 450 160 260

86 27000 4800 1300 1000 150

88 2500 190 96 120 6.2

91 5700 100 190 190 3.0

92 3100 47 150 110 2.4

97> 40000 2300 2000 1500 310

98 9600 440 680 330 64

100> 40000 540 1500 1000 43

101 14000 380 880 720 29

103 9700 370 340 330 41

104 3900 220 260 270 31

106 12000 270 450 190 11

107 11000 300 730 200 19

109> 40000 1100 840 1700 87

110> 40000 850 920 1200 120

117 4400 97 110 100 4.0

121 13000 280 410 350 18

123 24000 170 540 390 11 Table 2B: Inhibition of human MMPs

Example MMP-9 MMP-10 MMP-13 MMP-14 MMP-16 No. ICso [nM] ICso [nM] ICso [nM] ICso [nM] ICso [nM]

1 4.7 33 11 24 130

2 480 310 400 480 1000

3 900 430 340 700 4000

4 130 110 58 33 170

5 960 93 350 620 2500

11 18 16 88 150 4500

12 5.9 15 39 78 86

13 4.4 22 33 150 170

15 230 26 640 180 520

16 440 37 1000 320 1700

18 940 200 1400 1000 4000

19 1000 270 2600 3000 5400

23 270 87 1500 1200 2200

25 3.0 19 45 230 290

28 260 130 620 1900 2200

31 2100 41 190 400 890

35 1400 53 53 170 300

39 780 170 1600 6400 14000

40 170 21 380 460 920

41 51 20 110 110 270

44 52 28 58 88 100

52 830 52 1600 3600 4600

55 940 50 1700 2400 5100

56 4900 250 2400> 40000> 40000

58 83 29 440 1300 2300

67 61 14 270 96 180

75 470 57 2300 1900 3600 Example MMP-9 MMP-10 MMP-13 MMP-14 MMP-16

Nos. ICso [nM] ICso [nM] ICso [nM] ICso [nM] ICso [nM]

77 550 30 770 1200 3800

79 3200 310 2700 8700> 40000

80 780 53 840 2600 5500

83 2100 120 2800 3900> 40000

86 1500 160 6600 3900 14000

88 55 22 230 440 670

91 21 21 50 68 1700

92 13 15 27 33 110

97 740 160 1500 870 4500

98 280 55 410 210 670

100 160 160 360 720 970

101 100 110 210 380 880

103 110 35 250 320 14000

104 110 50 200 230 540

106 76 39 120 180 190

107 89 52 150 290 650

109 150 100 190 670 3200

110 380 130 260 720 2100

117 54 26 74 88 260

121 57 93 300 820 1900

123 94 81 230 490 11000

Comparing the inhibition data presented in Tables 1 and 2A / 2B shows that the compounds according to the invention in general and their more active stereoisomers in particular have a very high inhibitory potency (frequently in the sub-nanomolar range) compared to HME and at the same time a high to very high Have selectivity (usually two to four orders of magnitude or more) against related human MMPs. b) MMPs of rodents:

In vitro MMP-2 inhibition test of the mouse:

Recombinant mouse MMP-2 (R & D Systems, 924-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-2 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.).

In vitro MMP-3 inhibition test of the mouse:

Recombinant mouse MMP-3 (R & D Systems, 548-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.5 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is carried out by addition of the intramolecularly quenched substrate Mca-Arg-Pro-Lys-Pro-Val-Glu-Nval-Trp-Arg-Lys (Dnp) -NH2 (final concentration eg 5 μΜ; R & D Systems, ES-002) so that a total test volume of 50 μΐ results. The course of the MMP-3 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.).

In vitro MMP-7 inhibition test of the mouse:

Recombinant mouse MMP-7 (R & D Systems, 2967-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.5 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCh, 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO , suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by addition of the intramolecularly quenched substrate Mca-Lys-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH2 (final concentration eg 5 μΜ; R & D Systems, ES-010) a total test volume of 50 μΐ results. The history The MMP-7 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.).

In vitro MMP-8 inhibition test of the mouse:

Recombinant mouse MMP-8 (R & D Systems, 2904-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 2 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by addition of the intramolecularly quenched substrate Mca-Lys-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH2 (final concentration eg 5 μΜ; R & D Systems, ES-010) a total test volume of 50 μΐ results. The course of the MMP-8 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.).

In vitro MMP-9 inhibition test of the mouse:

Recombinant mouse MMP-9 (R & D Systems, 909-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 5 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-9 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.).

In vitro ΜΜΡ-12 inhibition test of the mouse:

Recombinant mouse MMP-12 (R & D Systems, 3467-MP) is autocatalytically activated according to the manufacturer's instructions. To 24 μΐ activated enzyme (final concentration eg 1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is carried out by adding the intramolecularly quenched substrate Mca-Lys-Pro-Leu-Gly- Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 5 μΜ; R & D Systems, ES-010) was started, resulting in a total test volume of 50 μΐ. The course of the MMP-12 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (for example over 120 minutes at a temperature of 32 ° C.). Highly sensitive in vitro MMP-12 inhibition test of the mouse:

If subnanomolar IC values are obtained in the case of highly potent test substances in the mouse MMP-12 inhibition test described above, a modified test is used for more precise determination. Here, a tenfold lower enzyme concentration is used (final concentration, e.g., 0.1 nM) to achieve increased sensitivity of the assay. The incubation time of the test is chosen to be longer (e.g., 16 hours).

Rat in vitro MMP-2 inhibition test:

Recombinant rat MMP-2 (R & D Systems, 924-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-2 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.).

Rat in vitro MMP-8 inhibition test:

Recombinant rat MMP-8 (R & D Systems, 3245-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 2 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by addition of the intramolecularly quenched substrate Mca-Lys-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 5 μΜ; R & D Systems, ES-010) that a total test volume of 50 μΐ results. The course of the MMP-8 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (for example over 120 minutes at a temperature of 32 ° C.). In vitro rat MMP-9 inhibition test:

Recombinant mouse MMP-9 (R & D Systems, 5427-MM) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCh, 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO , suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 5 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-9 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.).

In vitro ΜΜΡ-12 inhibition test of the rat:

Rat MMP-12 (Uniprot NP_446415.1; construct L96-V277) is expressed with an additional N-terminal His tag and a TEV consecutive cleavage sequence using a pDEco7 vector in E. coli (BL21). The recombinantly expressed protein forms an intracellular insoluble protein complex (so-called inclusion body). This is solubilized after separation and intensive washing under denaturing conditions. For this purpose, the inclusion body pellet fraction from a 250 ml E. coli culture in a volume of 120 ml of buffer A (50 mM Tris pH 7.4, 100 mM NaCl, 0.03 mM ZnCl ₂ , 10 mM CaCl ₂ , 8 M urea). The soluble protein is renatured by dialysing each 60 ml of the sample several times at 4-8 ° C against buffer B (50 mM Tris pH 7.4, 100 mM NaCl, 0.03 mM ZnCh, 10 mM CaCk). After dialysis, the sample is centrifuged (25,000 xg). The refolded protein is in the supernatant with a yield of 3.7 mg per 250 ml-E. coli culture. The protein thus obtained is enzymatically active without further purification operations or protease-mediated cleavage processes.

To 24 μΐ MMP-12 protein (final concentration, for example 1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl _2, 150 mM NaCl, 0.05% Brij ^® -35) is 1 μΐ of the examined test compound ( as solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 5 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-12 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (for example over 120 minutes at a temperature of 32 ° C.). Table 1 below shows representative IC50 values from mouse MMP inhibition assays (in part as averages of several independent determinations and rounded to two significant digits) for representative embodiments of the invention:

Table 3: Inhibition of mouse MMPs

Example MMP-2 MMP-3 MMP-7 MMP-8 MMP-9 MMP-12 No. IC50 [nM] IC50 [nM] IC50 [nM] IC50 [nM] IC50 [nM] IC50 [nM]

1 14 160 46 18 31 0.61

2 400 1300 140 1400 1100 4.1

3 290 1900 430 810 2600 7.0

4 100 1300 160 42 61 1.4

5 270 1300 160 360 930 1.8

11 250 590 23 18 61 1.8

23 2400 8000 69 300 1700 6.5

28 1000 8200 140 120 2500 7.1

31 990 3900 44 89 4300 6.4

39 3800 9500 230 640> 40000 11

40 570 180 220 25 640 1.9

41 180 790 27 16 220 0.71

52 1800 6900 170 160 2800 10

56 5000> 40000 990 1100> 40000 21

75 4200 5900 120 410 2700 2.3

77 1400 1400 54 130 23000 2.0

79 5900 9300 1100 760 2100 35

80 1500 2500 130 130> 40000 4.3

83 8100 5900 82 1100> 40000 5.7

91 95 400 22 26 72 0.86

92 57 200 18 16 37 0.42

97 1900 4600 160 1300 1600 6.1

98 640 730 29 280 460 1.2

100 890 1800 150 250 1100 1.7 Example MMP-2 MMP-3 MMP-7 MMP-8 MMP-9 MMP-12 No. ICso [nM] ICso [nM] ICso [nM] ICso [nM] ICso [nM] ICso [nM]

101 490 1300 76 120 400 1.1

103 370 1100 28 270 550 2.3

104 290 490 20 130 330 1.1

109 1300 1100 250 450 910 3.0

110 1100 2400 220 420 1100 0.72

117 130 470 16 13 230 0.62

121 420 2700 100 120 880 4.0

123 370 1800 100 91 770 4.9

Comparing the inhibition data presented in Table 3 shows that the compounds according to the invention in general and their more active stereoisomers in particular have a very high inhibitory potency (frequently in the nanomolar or even sub-nanomolar range) in relation to mouse MMP-12 and at the same time have high selectivity (usually one to two orders of magnitude or more) over related murine MMPs.

B-3. Animal model of pulmonary emphysema

Elastase-induced pulmonary emphysema in mouse, rat or hamster is a widely used animal model of pulmonary emphysema [The Fas / Fas-ligand pathway does not mediate the apoptosis in elastase-induced emphysema in mice, Sawada et al., Exp. Lung Res. 33, 277-288 (2007)]. The animals receive orotracheal instillation of porcine pancreatic elastase. The treatment of the animals with the test substance starts on the day of the instillation of the porcine pancreatic elastase and extends over a period of 3 weeks. At the end of the study, lung compliance is determined and alveolar morphometry performed. B-4. Animal model of silica-induced lung inflammation

Orotracheal administration of silica to mouse, rat or hamster leads to lung inflammation [Involvement of leukotrienes in the pathogenesis of silica-induced pulmonary fibrosis in mice, Shimbori et al., Exp. Lung Res. 36, 292-301 ( 2010)]. The animals are treated with the test substance on the day of the instillation of the silica. After 24 hours bronchioalveolar lavage is performed to determine cell content and biomarkers. B-fifth Animal model of silica-induced pulmonary fibrosis

Mouse, rat, or hamster-induced lung induced fibrosis is a widely used animal model of pulmonary fibrosis in mice, Shimbori et al., Exp. Lung Res. 36, 292-301 (2010) )]. The animals receive oro-tracheal instillation of silica. The treatment of the animals with the test substance starts on the day of the instillation of the silica or therapeutically one week later and extends over a period of 6 weeks. At the end of the study, a bronchioalveolar lavage is performed to determine cell content and biomarkers, and a histological assessment of pulmonary fibrosis is performed. B-sixth Animal model of ATP-induced pulmonary inflammation

Intratracheal administration of ATP (adenosine triphosphate) to the mouse causes lung inflammation [ATP via the P2Y receptors: An experimental study, Matsuyama et al., Respir. Res. 9:79 (2008)]. The animals are treated with the test substance for 24 h on the day of instillation of ATP (by gavage, by addition in feed or drinking water, by osmotic minipump, by subcutaneous or intraperitoneal injection or by inhalation). At the end of the experiment a bronchio-alveolar lavage is performed to determine the cell content and the pro-inflammatory markers.

B. 7 CYP Inhibition Assay

The ability of substances to inhibit the human CYP enzymes CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in human is examined using pooled human liver microsomes as enzyme source in the presence of standard substrates (see above) which form CYP-specific metabolites. The inhibition effects are investigated at six different concentrations of the test compounds [2.8, 5.6, 8.3, 16.7, 20 (or 25) and 50 μΜ], compared with the extent of CYP-specific metabolite formation of the standard substrates in the absence of the test compounds and the corresponding IC 50 values calculated. A standard inhibitor that specifically inhibits a single CYP isoform is always incubated to make comparisons between different series comparable.

The incubation of phenacetin, diclofenac, tolbutamide, dextromethorphan or midazolam with human liver microsomes in the presence of six different concentrations each of a test compound (as a potential inhibitor) is performed on a workstation (Tecan, Genesis, Crailsheim, Germany). Standard incubation mixtures contain 1.3 mM NADP ⁺ , 3.3 mM MgC x 6 H ₂ O, 3.3 mM glucose-6-phosphate, glucose-6-phosphate dehydrogenase (0.4 U / ml) and 100 mM phosphate buffer (pH 7.4) in a total volume of 200 μΐ. Testverbin- tions are preferably dissolved in acetonitrile. 96-well plates are incubated for a defined time at 37 ° C with pooled human liver microsomes. The reactions are stopped by addition of 100 μL acetonitrile, which is a suitable internal standard. Precipitated proteins are separated by centrifugation, the supernatants are pooled and analyzed by LC-MS / MS.

B-eighth Hepatocyte assay for determination of metabolic stability

The metabolic stability of test compounds to hepatocytes is determined by incubating the compounds at low concentrations (preferably below or around 1 μΜ) and at low cell counts (preferably at 1 × 10 ⁶ cells / ml) to ensure the best possible linear kinetic conditions in the experiment , Seven samples from the incubation solution are taken at a fixed time interval for LC-MS analysis to determine the half-life (ie, degradation) of each compound. From this half-life different "clearance" parameters (CL) and "Fmax" values are calculated (see below).

The CL and Fmax values are a measure of the phase I and phase 2 metabolism of the compounds in the hepatocytes. In order to minimize the influence of the organic solvent on the enzymes in the incubation approaches, its concentration generally becomes high 1% (acetonitrile) or 0.1% (DMSO) limited.

For all species and breeds, a hepatocyte cell count in the liver of 1.1 * 10 ⁸ cells / g liver is expected. CL parameters based on half-lives much longer than the incubation period (typically 90 minutes) can only be considered as rough guidelines.

The calculated parameters and their meaning are:

Fmax well-stirred [] maximum bioavailability after oral administration

Calculation: (l-CLbi ₀₀ d well-stirred / QH) * 100

CLbiood well-stirred [L / (h * kg)] calculated blood clearance (well-stirred model)

Calculation: (QH * CL 'intrinsic) / (QH + CL intrinsic)

CL'mtrinsic [ml / (min * kg)] maximum ability of the liver (the hepatocytes) to metabolize a compound (assuming that the hepatic blood flow is not rate limiting)

Calculation: CL intrinsic, apparent * species-specific hepatocyte count [1.1 * 10 ⁸ / g liver] * species-specific liver weight [g / kg] CL'intrinsic, apparent [ml / (min * mg)] normalizes the elimination constant by dividing it by the hepatocyte cell number x (x * 10 ⁶ / ml) used. Calculation: k _e i [1 / min] / (cell number [x * 10 ⁶ ] / incubation volume [ml])

(QH = species-specific liver blood flow).

In Table 4 below, for representative embodiments of the invention, the CL and Fmax values from this assay are shown after incubation of the compounds with rat hepatocytes (in part as averages of several independent determinations): Table 4: Calculated blood clearance and bioavailability after incubation with rat hepatocytes

B. 9 Metabolism investigation

To determine the metabolism profile of the compounds according to the invention, they are incubated with liver microsomes or with primary fresh hepatocytes of various animal species (eg rat, dog) as well as of human origin in order to obtain information on the most complete hepatic phase I and phase II metabolism and on the Obtain and compare enzymes involved in metabolism.

The compounds of the invention are incubated at a concentration of about 1-10 μΜ. For this purpose, stock solutions of the compounds are prepared at a concentration of 0.1-1 mM in acetonitrile and then pipetted with a 1: 100 dilution in the incubation mixture. The liver microsomes are incubated in 50 mM potassium phosphate buffer pH 7.4 with and without NADPH-generating system consisting of 1 mM NADP ⁺ , 10 mM glucose-6-phosphate and 1 unit glucose-6-phosphate dehydrogenase at 37 ° C. Primary hepatocytes are also incubated in suspension in William's E medium at 37 ° C. After an incubation period of 0-4 h, the incubation mixtures are stopped with acetonitrile (final concentration about 30%) and the protein is added centrifuged about 15,000 xg. The thus stopped samples are either analyzed directly or stored at -20 ° C until analysis.

The analysis is carried out by means of high performance liquid chromatography with ultraviolet and mass spectrometric detection (HPLC-UV-MS / MS). For this purpose, the supernatants of the incubation samples are chromatographed using suitable C18 reverse-phase columns and variable eluent mixtures of acetonitrile and 10 mM aqueous ammonium formate solution or 0.05% aqueous formic acid. The UV chromatograms in combination with the mass spectrometric data serve to identify, structure elucidate and quantitatively estimate the metabolites and to quantitatively determine the metabolic decrease of the compounds according to the invention in the incubation mixtures.

B-tenth Pharmacokinetic studies in vivo

The substance to be tested is administered intravenously to rats or mice as a solution (eg in appropriate plasma with a small amount of DMSO or in a PEG / ethanolAmerge mixture), oral administration is carried out as a solution (eg in Solutol / ethanolAerger- or PEG /). Ethanol / water mixtures) or as a suspension (eg in Tylose) in each case via a gavage. After substance administration, the animals are bled at fixed times. This is heparinized, then plasma is recovered therefrom by centrifugation. The test substance is analytically quantified in the plasma via LC-MS / MS. From the plasma concentration-time curves determined in this way, the pharmacokinetic parameters are calculated using an internal standard and with the aid of a validated computer program, such as AUC (area under the concentration-time curve), Cmax (maximum plasma concentration), t (half-life), Vss (distribution volume) and CL (clearance) and the absolute and relative bioavailability F and F _re i (iv / po comparison or comparison of suspension to solution after po administration).

C. Embodiments of Pharmaceutical Compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet: composition:

100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm. production:

The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water. A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.

production:

The rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h. Orally administrable solution:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound according to the invention correspond to 20 g of oral solution. production:

The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention. i.v. solution: The compound of the invention is dissolved at a concentration below the saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

Claims

claims

Compound of the formula (I)

in which

where the linkage is to A, n is the number 1, 2 or 3,

(Cs-Ce denotes cycloalkyl,

Is hydrogen, fluorine, chlorine, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, (trifluoromethyl) sulfanyl, methoxycarbonylamino or 2-oxo-1,3-oxazolidin-3-yl, and

Hydrogen, fluorine, chlorine, methyl or trifluoromethyl, and

R ^{2 is} hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl, or a salt, solvate or solvate of a salt of this compound. 2. A compound of formula (I) according to claim 1, in which A is -O- or -S-, R ^{1 is} n-butyl, n-pentyl or n-hexyl or a group of the formula

where the linkage is to A, n is the number 1, 2 or 3,

Cyclopentyl or cyclohexyl means

R ^{3A is} hydrogen, chlorine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, methoxycarbonylamino or 2-oxo-1,3-oxazolidin-3-yl, and

Is hydrogen, fluorine or chlorine, and is hydrogen, methyl or trifluoromethyl, or a salt, solvate or solvate of a salt of this compound.

A compound of the formula (I) according to claim 1 or 2, in which

A is -O-, n-pentyl or n-hexyl or a group of the formula

where the linkage is A, n is 1 or 2, Cy cyclopentyl or cyclohexyl means

R ^{3A is} hydrogen, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy, and R ^{3B is} hydrogen, fluorine or chlorine, and

R ^{2 is} hydrogen, methyl or trifluoromethyl, or a salt, solvate or solvate of a salt of this compound. 4. A compound according to claim 1, 2 or 3 having the formula (IA) or (IB)

wherein A, R ¹ and R ^{2 have} the meanings defined in claim 1, 2 or 3 and the groups bound to the central cyclopentane ring have a relative irans arrangement to each other, or a mixture of these compounds, wherein A, R ¹ and R ² in such a mixture of (IA) and (IB) are each identical, or a salt, solvate or solvate of a salt of these compounds or their mixture.

5. A compound according to claim 1, 2, 3 or 4 having the formula (IA) wherein A, R ¹ and R ^{2 have} the meanings defined in claim 1, 2 or 3, and the groups bonded to the central cyclopentane ring in enantiomerically pure form have an arrangement as indicated (IS, 2S, 5R), or a salt, solvate or solvate of a salt of this compound.

Process for the preparation of a compound as defined in claims 1 to 5, characterized in that

[A] a compound of the formula (Π)

in the presence of a base with a compound of the formula (ΠΙ)

R-X (ΙΠ), in which R ^{1 has} the meaning given in claims 1 to 5, and

X is a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, to give a compound of the formula (IV) in which A, R ¹ and R ^{2 have} the meanings given in claims 1 to 5, followed by alkylation of the 2- (trimethylsilyl) ethyl ester group with the aid of an acid or a fluoride reagent to give the carboxylic acid of the formula (I)

in which A, R ¹ and R ^{2 have} the meanings given in claims 1 to 5, or alternatively, when A in formula (I) is -S-,

[B] a compound of the formula (Π-Α)

in which R ^{2 has} the meaning given in claims 1 to 5, into the corresponding trifluoromethanesulfonate of the formula (V)

R ² in which R ^{2 has} the meaning given in claims 1 to 5 transferred, this then in the presence of a suitable palladium Katalysati a thiol of the formula (VI)

R-SH (VI), in which R ^{1 has} the meaning given in claims 1 to 5, to give a compound of formula (IV-A)

in which R ¹ and R ^{2 have} the meanings given in claims 1 to 5, and subsequently reacting the 2- (trimethylsilyl) ethyl ester group with the aid of acid or a fluoride reagent to give the carboxylic acid of the formula (IC) in which R ¹ and R ^{2 have} the meanings given in claims 1 to 5, and optionally cleaving the compounds of the formula (I) or (IC) thus obtained into their

Enantiomers and / or diastereomers are separated and / or converted with the corresponding (i) solvents and / or (ii) bases into their solvates, salts and / or solvates of the salts.

A compound as defined in any one of claims 1 to 5 for the treatment and / or prevention of diseases. A compound as defined in any one of claims 1 to 5 for use in a method for the treatment and / or prevention of chronic obstructive pulmonary disease (COPD), pulmonary emphysema, chronic bronchitis, pulmonary hypertension in COPD (PH-COPD), Bronchiectasis, asthma, interstitial lung disease, idiopathic pulmonary fibrosis (IPF) and pulmonary sarcoidosis, atherosclerosis, carotid arteriosclerosis, viral myocarditis, cardiomyopathy and aneurysms, including their sequelae such as stroke, myocardial infarction and peripheral artery disease, as well as chronic kidney disease and Alport syndrome.

Use of a compound as defined in any one of claims 1 to 5 for the manufacture of a medicament for the treatment and / or prevention of chronic obstructive pulmonary disease (COPD), pulmonary emphysema, chronic bronchitis, pulmonary

Hypertension in COPD (PH-COPD), bronchiectasis, asthma, interstitial lung disease, idiopathic pulmonary fibrosis (IPF) and pulmonary sarcoidosis, atherosclerosis, carotid arteriosclerosis, viral myocarditis, cardiomyopathy and aneurysms, including their sequelae such as stroke, myocardial infarction and peripheral arterial Occlusive disease, as well as chronic kidney disease and the

Alport syndrome.

10. A medicament containing a compound as defined in any one of claims 1 to 5, in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.

11. A medicament comprising a compound as defined in any one of claims 1 to 5, in combination with one or more further active compounds selected from the group consisting of corticosteroids, beta-adrenergic receptor agonists, anti-muscarcinogenic substances, PDE 4 inhibitors, PDE 5 inhibitors, sGC activators, sGC stimulators, HNE inhibitors, prostacyclin analogs, endothelin antagonists, statins, antifibrotic agents, antiinflammatory agents, immunomodulating agents, immunosuppressive agents and cytotoxic agents.

12. Medicament according to claim 10 or 11 for the treatment and / or prevention of chronic obstructive pulmonary disease (COPD), pulmonary emphysema, chronic bronchitis, pulmonary hypertension in the COPD (PH-COPD), bronchiectasis, asthma, interstitial lung diseases, idiopathic pulmonary fibrosis (IPF ) and pulmonary sarcoidosis, atherosclerosis, carotid arteriosclerosis, viral myocarditis, cardiomyopathy and aneurysms, including their sequelae such as stroke, myocardial infarction and peripheral vascular disease, as well as chronic kidney disease and Alport syndrome.

13. A method for the treatment and / or prevention of chronic obstructive pulmonary disease (COPD), pulmonary emphysema, chronic bronchitis, pulmonary hypertension in COPD (PH-COPD), bronchiectasis, asthma, interstitial lung disease, idiopathic pulmonary fibrosis (IPF) and pulmonary sarcoidosis, of Atherosclerosis, carotid arteriosclerosis, viral myocarditis, cardiomyopathy and aneurysms, including their sequelae such as stroke, myocardial infarction and peripheral arterial disease, as well as chronic kidney disease and Alport syndrome in humans and animals by administering an effective amount of at least one compound, as in one of Claims 1 to 5, or a medicament as defined in any one of claims 10 to 12.