WO2015150366A1 - Cyclically substituted phenol ether derivatives and use thereof - Google Patents

Abstract

The invention relates to novel, cyclically substituted phenol ether derivatives, to methods for the production thereof, to the use thereof alone or in combination for treating and/or preventing illnesses, and to the use thereof for producing medications for treating and/or preventing illnesses, in particular for treating and/or preventing diseases of the respiratory tract, lungs and cardiovascular system.

Description

 Cyclic substituted phenol ether derivatives and their use

The present application relates to novel, cyclically substituted phenol ether 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 ofa 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 cyclic substituted phenol ether derivatives have a significantly improved profile of potency and selectivity to human macrophage elastase (HME / hMMP-12) compared to the compounds known in the art. In addition, many of the compounds of the present invention have low in vivo clearance and good metabolic stability. This property profile as a whole makes it possible for the compounds according to the invention to have low dosability and, as a consequence 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-, L is -CH ₂ - or -CH ₂ CH ₂ -,

Cy is a cyclic group of the formula

* denotes the linkage position to the group L, X denotes CH or N,

R ^{1 is} a substituent selected from the group fluorine, chlorine, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, (trifluoromethyl) sulfanyl, methoxycarbonylamino and 2-oxo-l, 3-oxazolidin-3-yl, where such a substituent may be bonded in the designated position 2, 3 and / or 4, m is the number 1 or 2, wherein in the event that the substituent R ¹ occurs twice, its individual meanings may be the same or different, and

R ^{2 is} hydrogen or fluorine, represents CH or N, is a substituent selected from the group fluorine, chlorine, methyl, fluoromethyl, difluoromethyl and trifluoromethyl, where such a substituent, if present, in the designated position 6, 7 and / or n is 0, 1 or 2, wherein, in the event that the substituent R ³ occurs twice, its individual meanings may be the same or different, 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 that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.

Depending on their structure, the compounds of the invention may exist in different stereoisomeric forms, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in 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 compound concerned with respect to the absolute configuration of the chiral center is present 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%) As long as the compounds of this invention can exist in tautomeric forms, the present invention encompasses all tautomeric forms.

The present invention also includes all suitable isotopic variants of the compounds of 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 into 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 C1, 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 drug distribution 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 deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing 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.

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

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 compounds of the formula (I) in which

L is -CH ₂ -, and their salts, solvates and solvates of the salts.

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

Cy is a cyclic group of the formula

stands in which

 * indicates the linkage position to the group L,

_R 1A is chlorine, methyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl

2-oxo-1,3-oxazolidin-3-yl, and

R ^{1B is} hydrogen, fluorine, chlorine, methyl, trifluoromethyl or trifluoromethoxy, and their salts, solvates and solvates of the salts.

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

Cy is a cyclic group of the formula

stands in which

* denotes the linking position to the group L, and their salts, solvates and solvates of the salts. Another particular embodiment of the present invention comprises compounds of the formula (I) in which

Y is CH, and their salts, solvates and solvates of the salts.

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

L is -CH ₂ - or -CH ₂ CH ₂ -,

Cy is a cyclic group of the formula

stands in which

indicates the linkage position to the group L,

Chloro, methyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl

2-oxo-1,3-oxazolidin-3-yl, and

R ^{1B is} hydrogen, chlorine, methyl, trifluoromethyl or trifluoromethoxy, Y is CH,

R ^{3 is} a substituent selected from the group consisting of fluoro, chloro, methyl and trifluoromethyl, such substituent, when present, being attached in the designated position 6, 7 or 8 and n being 0 or 1, and theirs Salts, solvates and solvates of salts.

Particularly preferred in the context of the present invention are compounds of the formula (I) in which

A is -O- or -S-,

L is -CH ₂ - or -CH ₂ CH ₂ -,

Cy is a cyclic group of the formula

stands in which

* denotes the linkage position to the group L, Y stands for CH,

R ^{3 is} a substituent selected from the group of chlorine, methyl and trifluoromethyl, which is bonded in the designated 6- or 7-position, and n is the number 1, and their salts, solvates and solvates of the salts. Likewise particularly preferred in the context of the present invention are compounds of formula (I) in which

A is -O-,

L is -CH ₂ -,

Cy is a cyclic group of the formula

stands in which

denotes the linking position to the group L, chlorine, methyl, trifluoromethyl or trifluoromethoxy,

R ^{1B is} hydrogen or chlorine,

Y stands for CH,

R ^{3 is} a substituent selected from the group of chlorine, methyl and trifluoromethyl, which is bonded in the designated 6- or 7-position, and n is the number 1, and their salts, solvates and solvates of the salts.

Of particular importance in the context of the present invention are compounds of the formula (I-A)

in which A, L, Cy, Y, R ³ and n have the meanings given above and the chiral carbon atom marked with * in enantiomerically pure form has the mapped configuration shown, and their salts, solvates and solvates of the salts.

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.

The invention further provides a process for the preparation of the compounds according to the invention, which comprises reacting di-ieri-butyl (2-hydroxyethyl) malonate of the formula (II)

in the presence of a phenylphosphine and an azodicarboxylate with a triazine-4 (3 /) -one derivative of the formula (ΙΠ)

in which R ³ , n and Y have the abovementioned meanings, to give a compound of the formula (IV)

in which R ³ , n and Y have the meanings given above, and then reacting the compound of formula (IV) either

[A] in the presence of a base with a compound of the formula (V)

in which A, L and Cy have the meanings given above, and

Z ^{1 represents} a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, to give a compound of the formula (VI)

in which A, L, Cy, R ³ , n and Y have the meanings given above, alkylated or

[B] first with a compound of the formula (VII)

in which A has the abovementioned meaning, is a temporary protective group such as, for example, acetyl or benzoyl and represents a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, in the presence of a base to give a compound of the formula (VIII)

in which A, PG, R ³ , n and Y have the meanings given above, followed by deprotection of the protective group PG and the resulting compound of the formula (IX)

in which A, R ³ , n and Y have the meanings given above, then in the presence of a base with a compound of the formula (X)

 in which L and Cy have the abovementioned meanings and represents a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, to the compound of the formula (VI)

in which A, L, Cy, R ³ , n and Y have the meanings given above, alkylated and the thus obtained by method [A] or [B] compound of formula (VI) finally by treatment with an acid and subsequent heating in the carboxylic acid of the formula (I)

If appropriate, the compounds of the formula (I) are separated into their enantiomers and / or diastereoisomers and / or if appropriate reacted with the appropriate (i) solvents and / or (ii) bases to give their solvates, salts and / or solvates of the salts ,

The reaction (II) + (III) - (IV) is carried out under the usual conditions of a "Mitsunobu reaction" in the presence of a phosphine and an azodicarboxylate [see, e.g. D.L. Hughes, Org. Reactions 42, 335 (1992); D.L. 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 azodicarboxylate, for example, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), Oi tert-butylazodicarboxylat, / V, / V, / VW tetramethylazodicarboxamide (TMAD), l, l '- (azodicarbonyl) di-piperidine (ADDP) or 4,7-dimethyl-3,5,7-hexahydro-l, 2,4,7-tetrazocine-3,8-dione (DHTD) can be used. Preference is given to using triphenylphosphine in combination with diisopropyl azodicarboxylate (DIAD).

Inert solvents for reaction (II) + (III) - (IV) are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl ferric butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis (2-methoxyethyl) ethers, hydrocarbons such as benzene, toluene, xylene, pentane, hexane or cyclohexane, or polar aprotic solvents such as acetonitrile, butyronitrile, dimethyl sulfoxide (DMSO), N-dimethylformamide (DMF), N-dimethylacetamide (DMA), Ν, Ν'-dimethylpropyleneurea (DMPU) or / V-methylpyrrolidinone (NMP). It is also possible to use mixtures of such solvents. Preference is given to using tetrahydrofuran.

The reaction (II) + (ΠΙ) - (IV) is usually 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 apparatus in this reaction may be advantageous.

Suitable bases for the alkylation reactions (IV) + (V) -> (VI) and (IV) + (Vit) -> (VIII) are particularly suitable alkali metal alcoholates such as sodium or potassium methoxide, sodium or Potassium ethoxide or sodium or potassium feri.-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as lithium diisopropylamide or lithium, sodium or potassium bis (trimethylsilyl) amide, or conventional organometallic bases such as phenyllithium or n-, sec- or ieri-butyllithium. Preferably, sodium hydride or potassium ieri.-butoxide is used. Suitable inert solvents for process steps (IV) + (V) -> (VI) and (IV) + (VII) -> (VIII) 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, A 1 -dimethylformamide (DMF) , Dimethylacetamide (DMA), Ν, Ν'-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP) or dimethylsulfoxide (DMSO). It is also possible to use mixtures of such solvents. Preferably, A 1 -dimethylformamide (DMF) is used.

The reactions (IV) + (V) - (VI) and (IV) + (VII) - (VIII) are generally in a temperature range from -70 ° C to + 100 ° C, preferably at 0 ° C to +60 ° C performed. The cleavage of an acetyl or benzoyl protective group PG in process step (VIII) - (IX) is preferably carried out with the aid of an alkali metal hydroxide, such as lithium, sodium or potassium hydroxide, or an alkali metal alkoxide, such as sodium or potassium methoxide or sodium or potassium. Suitable solvents for this reaction are, in particular, water, alcohols, such as methanol, ethanol, n-propanol or isopropanol, ethers, such as tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, or mixtures of these solvents. Sodium methoxide in a solvent mixture of methanol and tetrahydrofuran is preferably used for the cleavage. The reaction is generally carried out in a temperature range from 0 ° C to + 60 ° C.

Alternatively, a silyl group such as trimethylsilyl, triethylsilyl, triisopropylsilyl, feri.-butyldimethylsilyl or ieri.-butyldiphenylsilyl can be used as the temporary protective group PG in (VII). Their cleavage in process step (VIII) - (IX) is carried out in the usual way with the aid of a fluoride such as tetrabutylammonium fluoride (TBAF). Another possibility is the use of benzyl as protecting group PG; this can be removed by hydrogenolysis in a known way [see also T.W. Greene and P.G.M. Wuts, Protective Croups in Organic Synthesis, Wiley, New York, 1999].

Suitable bases for the alkylation reaction (IX) + (X) - (VI) 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, or alkali metal hydrides such as sodium or potassium hydride. Preferably, potassium carbonate is used.

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 acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N , N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP). It is also possible to use mixtures of such solvents. Preferably, acetonitrile is used. The reaction (ΓΧ) + (X) - (VI) is generally carried out in a temperature range of 0 ° C to + 100 ° C.

The ester cleavage and decarboxylation to the monocarboxylic acid in process step (VI) - (I) is achieved by treatment of the diester with a strong acid such as trifluoroacetic acid or hydrogen chloride and subsequent heating of the intermediately formed dicarboxylic acid. The reaction can be carried out in a one-pot process, without isolation of the intermediate, or in two stages. For the ester cleavage, in the case of the reaction with trifluoroacetic acid, preference is given to using dichloromethane and, in the case of reaction with hydrogen chloride, preferably 1,4-dioxane, in each case under anhydrous conditions, as solvent. The ester cleavage is usually carried out in a temperature range from 0 ° C to + 30 ° C. The subsequent decarboxylation is usually carried out in a temperature range from + 100 ° C. to + 150 ° C. in a correspondingly high-boiling inert solvent; Preferably, 1,4-dioxane is used for this purpose.

The 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 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. The 1,2,3-triazine-4 (3i7) -one derivatives of the formula (II) can be prepared in a simple manner by treatment of ori / amino aminocarboxamides of the formula (XI)

in which R ³ , n and Y have the meanings given above, accessible with sodium nitrite in aqueous hydrochloric acid [see, eg, D. Fernandez-Forner et al., Tetrahedron 47 (42), 8917-8930 (1991)]. The compounds of the formula (V) can be prepared starting from compounds of the formula (II) or (II)

 (xii) (ΧΠΙ), in which A, L and Cy have the meanings given above, are obtained by conventional methods for the α-halogenation of methyl ketones, the transformation of alcohols into halides or the formation of sulfonic acid esters from alcohols. The compounds of the formulas (XII) and (II) in turn can be prepared analogously to the above-described process step (IX) + (X) - (VI) by base-catalyzed alkylation of a compound of the formula (XIV) or (XV)

(XIV) (XV), in which A has the abovementioned meaning, with a compound of the formula (X)

(X) in which L, Cy and Z ^{3 have} the meanings given above, are prepared.

The compounds of formulas (II), (VII), (X), (XI), (XIV) and (XV) are either commercially available or described as such in the literature or, starting from other commercially available compounds, be prepared by the skilled person, known from the literature. Numerous detailed regulations and further references are also contained 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 2

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. In addition, many of the compounds of the invention have one low in vziro clearance and 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 interstitial pneumonia and unclassifiable 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 ), 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's lung and related diseases, infectious and non-infectious cough and cold diseases (chronic inflammatory cough, iatrogenic cough), nasal mucosal inflammation (including drug rhinitis , vasomotor rhinitis and season-dependent allergic rhinitis, eg hay fever) and of 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 atrium and ventricle, 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, and for the treatment and / or prevention of thromboembolic disorders and ischaemias, such as myocardial ischemia, cardiac hypertrophy, trans-oral and ischemic attacks, pre-eclampsia, inflammatory cardiovascular diseases, coronary artery spasm and peripheral arteries Edema such as pulmonary edema, cerebral edema, renal edema or congestive heart failure edema, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, Cardiac insufficiency, endothelial dysfunction, microvascular 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 renal enzyme activity such as glutamylsynthetase, altered urinary or urinary output, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilatation, hyperphosphatemia, and / or the need for dialysis can be characterized. The present invention also encompasses the use of the compounds according to the invention for the treatment and / or prevention of secondary effects of renal insufficiency, such as, for example, tonia, pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.

Moreover, the compounds according to the invention are suitable for the treatment and / or prevention of diseases of the genitourinary system, such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic hyperplasia (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 kidney 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 diseases (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 present invention can be used for the treatment and / or prevention of anemias, such as hemolytic anemias, especially hemoglobinopathies such as sickle cell anemia and thalassemias, megaloblastic anemias, iron deficiency anemias, acute blood loss anemia, crowding anaemias and aplastic anemias.

The compounds according to the invention are also suitable for the treatment of cancers, such as, for example, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemia, cancers, liposarcomas, carcinomas of the gastrointestinal tract, liver, pancreas, lung, kidney, ureter, prostate and genital tract, and 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 dyshpidemias (hypolipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemias, hypercholesterolemia, abetalipoproteinemia, sitosterolaemia), xanthomatosis, Tangier's disease, obesity (obesity), obesity , metabolic disorders (metabolic syndrome, hyperglycemia, 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 the abdomen (Glositis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, pruritis ani, diarrhea, celiac disease, hepatitis, liver fibrosis, liver cirrhosis, pancreatitis and cholecystitis), by Er diseases of the central nervous system and of 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, medermecotoxic dermatitis, palmaris et plantaris dermatitis, dermatitis parasitaria, dermatitis photoallergica, dermatitis phototoxica, dermatitis pustularis, seborrhoeic dermatitis, dermatitis sol aries, 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's syndrome, Weber's disease Christian syndrome, scarring, wart formation, frostbite), 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 the skeletal bone and joints and skeletal muscle (various forms of arthritis such as arthritis alcaptonurica, arthritis ankylosans, arthritis dysenterica, arthritis exsudativa, arthritis fungosa, arthritis gonorrhoica, arthritis mutilans, psoriatic arthritis, arthritis purulenta, arthritis rheumatica, Arthritis serosa, arthritis syphilitica, arthritis tuberculosa, arthritis urica, arthritis villonod ularis pigmentosa, atypical arthritis, haemophilic arthritis, juvenile chronic arthritis, rheumatoid arthritis and metastatic arthritis, in addition to the nursing syndrome, Felty Syndrome, Sjörgen syndrome, Clutton syndrome, Poncet syndrome, Pott syndrome and Reiter syndrome, multiple forms of arthropathies such as arthropathy deformans, arthropathy neuropathic, ovarian arthropod, arthropathy psoriatica and arthropathy tabica, systemic sclerosis, various forms of inflammatory myopathies such as myopathy epidemica, myopathy fibrosa, myopathy myoglobinurica, myopathy ossificans, myopathy ossificans neurotica, myopathy ossificans progressiva multiplex, myopathy purulenta, myopathy rheumatica, myopathy trichinosa, myopathy tropica and myopathy typhosa, as well as the gtther syndrome and Münchmeyer syndrome), inflammatory arterial changes (various forms of arteritis such as endarteritis, mesarteritis, periarteritis, panarteritis, rheumatoid arthritis, arteritis deforman, temporal arteritis, cranial arteritis, gigantocellular arteritis, granulomatous arteritis, and horton Syndrome, Churg-Stra uss syndrome and Takayasu's arteritis), Mückle -Well's syndrome, Kikuchi's disease, polychondritis, scleroderma and other diseases with an inflammatory or immunological component such as cataract, cachexia, osteoporosis, gout, incontinence, leprosy , Sezary syndrome and paraneoplastic syndrome, rejection 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 (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 (PAOD), 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 health disorder, the development, progression 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 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 comprising at least one of the compounds according to the invention and one or more further active ingredients, in particular for the purpose of 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 by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan; Antiinflammatory, 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; Anti-fibrotic 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 metabolizing 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 inhibitors 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; The 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, by way of 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 by way of illustration, nintedanib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, Pelitinib, semaxanib or tandutinib; Compounds that 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;

Compounds affecting the energy metabolism of the heart, 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 GPITb / nia antagonist, by way of example and preferably 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. For example, in some cases it may be sufficient to make do with less than the minimum amount mentioned above, while in other cases this 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.

A. 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)

 TLC thin layer chromatography

 DCI direct chemical ionization (in MS)

dd doublet of doublet (by NMR)

 DIAD diisopropyl 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

 GC gas chromatography

 GC / MS gas chromatography-coupled mass spectrometry 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

LDA lithium diisopropylamide

 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

 NMR nuclear magnetic resonance spectrometry

 Pd / C palladium on charcoal

 Ph phenyl

 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

R _f 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

 Triplet (by NMR)

tBu teri-butyl

td triplet of doublet (by NMR)

 Tf trifluoromethylsulfonyl (triflyl)

 TFA trifluoroacetic acid

 THF tetrahydrofuran

 Ts £> ara-tolylsulfonyl (tosyl)

 UV ultraviolet spectrometry

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

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, 30 x 2 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: 0.60 ml / min; UV detection: 208-400 nm.

Method 2 (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 3 (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 4 (LC / MS):

Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 μ, 50 x 1 mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 Acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A-> 0.1 min 90% A-> 1.5 min 10% A -> 2.2 min 10% A; Oven: 50 ° C; Flow: 0.33 ml / min; UV detection: 210 nm.

Method 5 (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 6 (preparative HPLC):

 Column: Reprosil C18, 10 μm, 250 × 40 mm; Eluent: acetonitrile / water with 0.1% TFA; Gradient: 0-6.00 min 10:90, sample injection at 3.00 min; 6.00-27.00 min to 95: 5; 27.00-38.00 min 95: 5; 38.00-39.00 min to 10:90; 39.00-40.20 min 10:90.

Method 7 (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 8 (preparative HPLC):

 Column: Reprosil C18, 10 μm, 250 × 40 mm; Eluent A: water with 0.1% formic acid, eluent B: acetonitrile; Gradient: 0 min 10% B, 6 min 10% B, 27 min 95% B, 38 min 95% B, 40 min 10% B; Flow: 50 ml / min; Running time per separation: 40 min; Detection: 210 nm. Method 9 (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 10 (preparative HPLC):

Column: Reprosil-Pur C18, 10 μιη; Eluent: water / acetonitrile; Gradient: 0-6 min 70:30, 6-22 min to 20:80, 22-46 min 20:80, 46-58 min to 70:30.

X-ray structure analysis:

Single crystal: obtained by crystallization from acetonitrile at RT; Diffractometer: Bruker diffractometer X8 Prospector, equipped with an Apex-II CCD area detector; Radiation: CuKa- Radiation 1.54178 Ä; Temperature: 100 K; Monochromator: mirror; Θ range: 3.26-67.72 °; Scan Type: fullsphere Data Collection Omega and Phi Scans; Scan area: 1 °; Index ranges: -8 <h <7, -22 <k <28, -32 <1 <32; collected reflexes: 39870; independent reflexes: 8188 [R (int) = 0.0310]; Completeness to Theta: 67.08 ° 99.5%. Structure Solution and Refinement: Structure Solution by Direct Method (SHELXS); Structural refinement: least-squares refinement, hydrogen atoms calculated in ideal positions and refined isotropically; Number of refined parameters: 716; final R-indices (obs data): Rl = 0.0323, wR2 = 0.0859; R-indices (all data): Rl = 0.0354, wR2 = 0.0875; Data-to-parameter ratio: 11.43; Goodness of Fit to F2: 1,039; Flack parameter: -0.07 (4). 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, a reference to the published literature is described in which their preparation is described.

Starting compounds and intermediates:

Example 1A

6-fluoro-l, 2,3-benzotriazin-4 (3 //) -

To a suspension of 13.23 g (85.83 mmol) of 2-amino-5-fluorobenzamide in 126 ml of a 2: 1 mixture of water and conc. Hydrochloric acid at 0 ° C, a solution of 6.51 g (94.41 mmol) of sodium nitrite in 53 ml of water was added slowly, keeping the internal temperature below 5 ° C. After stirring for 30 minutes, 53 ml (0.53 mol) of 10 M sodium hydroxide solution were slowly added with further cooling with ice bath, during which the internal temperature rose to about 20 ° C. and any solid present went into solution. After stirring for a further 30 minutes, 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 vacuo, 13.70 g (97% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 15.04 (br.s, 1H), 8.31 (dd, 1H), 8.08-7.82 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 0.53 min, m / z = 166 [M + H] ⁺ . Example 2A 6-Chloro-l, 2,3-benzotriazine-4 (3 /) -one

To a solution of 10.0 g (58.62 mmol) of 2-amino-5-chlorobenzamide in 140 ml of acetic acid at 10 ° C., 5.26 g (76.20 mmol) of sodium nitrite were added slowly in portions. After 1 h stirring at 10 ° C, the formed solid was filtered off and washed thoroughly with water. After drying in air and in vacuo, 7.26 g (65% of theory, purity 95%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 15.12 (br.s, 1H), 8.46-7.95 (m, 3H). LC / MS (Method 5, ESIpos): R _t = 1:35 min, m / z = 182 [M + H] ^+. Example 3A 6-Methyl-l, 2,3-benzotriazine-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 5, ESIpos): R _t = 1.40 min, m / z = 162 [M + H] Example 4A

6- (trifluoromethyl) -1,3,3-benzotriazine-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 0 ° C. bath temperature, 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-d ₆ ): δ [ppm] = 15.31 (br.s, 1H), 8.46 (s, 1H), 8.40 (d, 2H). LC / MS (Method 2, ESIpos): R _t = 0.78 min, m / z = 216 [M + H] ⁺ .

Example 5A

6,7-Difluoro-1,2,3-benzotriazine-4 (3 /) -one

To a suspension of 8.0 g (39.97 mmol, purity 86%) of 2-amino-4,5-difluorobenzamide in 39 ml of a 2: 1 mixture of water and conc. Hydrochloric acid at 0 ° C, a solution of 3.59 g (51.96 mmol) of sodium nitrite in 29 ml of water was added slowly, keeping the internal temperature below 5 ° C. After stirring for 30 min at 0 ° C bath temperature 29 ml (0.29 mol) of 10 M sodium hydroxide solution were added slowly with further ice bath cooling, the internal temperature rose to about 20 ° C and the solid went into solution. After 10 min stirring at RT the mixture was carefully mixed with conc. Hydrochloric acid acidified (pH = 4). The precipitate formed was filtered off and washed three times with water. After drying in air and in vacuo, 7.22 g (88% of theory, purity 89%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 15.15 (br.s, 1H), 8.24-8.17 (m, 1H), 8.15-8.07 (m, 1H).

LC / MS (Method 3, ESIpos): R _t = 1.42 min, m / z = 184 [M + H] ⁺ . Example 6A

7-fluoro-l, 2,3-benzotriazin-4 (3 //) - one

To a suspension of 5.0 g (32.44 mmol) of 2-amino-4-fluorobenzamide in 35 ml of a 2: 1 mixture of water and conc. Hydrochloric acid at 0 ° C, a solution of 2.46 g (35.68 mmol) of sodium nitrite in 16 ml of water was added slowly, keeping the internal temperature below 5 ° C. After stirring for 40 minutes at a bath temperature of 0 ° C., 16 ml (0.16 mol) of 10 M sodium hydroxide solution were slowly added with further cooling with ice bath, during which the internal temperature rose somewhat and the solid present went into solution. After stirring for 10 min at RT, the mixture was carefully poured with conc. Hydrochloric acid acidified (pH = 2). The precipitate formed was filtered off and washed with water. After drying in air and in vacuo, 5.13 g (96% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 15.09 (br.s, 1H), 8.30 (dd, 1H), 8.05 (dd, 1H), 7.79 (td, 1H).

LC / MS (Method 2, ESIpos): R _t = 0.53 min, m / z = 166 [M + H] ⁺ .

Example 7A

7-methyl-1,2,3-benzotriazine-4 (3 /) -one

To a suspension of 7.64 g (50.87 mmol) of 2-amino-4-methylbenzamide in 80 ml of a 2: 1 mixture of water and conc. Hydrochloric acid at 0 ° C, a solution of 3.86 g (55.96 mmol) of sodium nitrite in 32 ml of water was slowly added, the internal temperature was kept below 5 ° C. After stirring for 40 minutes at 0 ° C. bath temperature, 32 ml (0.32 mol) of 10 M sodium hydroxide solution were slowly added with further cooling with ice bath, during which the internal temperature rose to about 20 ° C. and any solid present went into solution. After the internal temperature had dropped back to about 5-10 ° C, the mixture was carefully added 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, 8.19 g (99% of theory) of the title compound were obtained.

Ή NMR (400 MHz, CDCL): δ [ppm] = 11.87 (br.s, 1H), 8.25 (d, 1H), 7.99 (s, 1H), 7.65 (d, 1H), 2.62 (s, 3H ).

LC / MS (Method 2, ESIpos): R _t = 0.57 min, m / z = 162 [M + H] ⁺ . Example 8A

7- (trifluoromethyl) -1,3,3-benzotriazine-4 (3 /) -one

To a suspension of 5.60 g (27.43 mmol) of 2-amino-4- (trifluoromethyl) benzamide in 40 ml of a 2: 1 mixture of water and conc. Hydrochloric acid at 0 ° C, a solution of 2.08 g (30.17 mmol) of sodium nitrite in 17 ml of water was added slowly, keeping the internal temperature below 5 ° C. After stirring for 40 minutes at 0 ° C. bath temperature, 17 ml (0.17 mol) of 10 M sodium hydroxide solution were slowly added with further ice-bath cooling, the internal temperature rising to about 30 ° C. After the internal temperature had dropped back to about 5-10 ° C, the suspension was carefully added with conc. Hydrochloric acid acidified (pH = 2). The solid was filtered off. triturated and washed three times with water. After drying in air and then in 5.64 g (93% of theory, purity 97%) of the title compound were obtained.

Ή-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 12.57 (br.s, 1H), 8.64-8.37 (m, 2H), 8.05 (d, 1H).

LC / MS (Method 2, ES Ineg): R _t = 0.73 min, m / z = 214 [MH] ^" .

Example 9A

8- (trifluoromethyl) -1,2,3-benzotriazine-4 (3 /) -one

Step 1:

 2-Amino-3- (trifluoromethyl) benzamide

1.1 g (5.91 mmol) of 2-amino-3- (trifluoromethyl) benzonitrile (US Pat. No. 3,976,633, Example 4) were admixed with 5 ml of conc. Hydrochloric acid and stirred at 50 ° C for 2 h. After cooling to rt, the mixture was diluted with water and carefully treated with conc. Sodium hydroxide solution adjusted to pH 9. It was then extracted several times with ethyl acetate. After combining the organic phases, removing the solvent and drying the residue in vacuo, 1.14 g (94% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm]

1H), 6.92 (brs s, 2H), 6.65 (t, 1H).

LC / MS (Method 1, ESIpos): R _t = 0.74 min, m / z = 205 [M + H] Step 2:

 8- (trifluoromethyl) -1,2,3-benzotriazine-4 (3 /) -one

To a suspension of 5.97 g (29.24 mmol) of the compound from Example 9A / Step 1 in 32 ml of a 2: 1 mixture of water and conc. Hydrochloric acid at 0 ° C, a solution of 2.22 g (32.17 mmol) of sodium nitrite in 15 ml of water was added slowly, keeping the internal temperature below 5 ° C. The difficult stirrable suspension was diluted with water until stirrable. After stirring for 40 minutes at 0 ° C. bath temperature, 15 ml (0.15 mol) of 10 M sodium hydroxide solution were slowly added with further ice-bath cooling, the internal temperature rising somewhat. After the internal temperature had dropped back to about 5-10 ° C, the suspension was carefully added with conc. Hydrochloric acid acidified (pH = 2). The solid was filtered off and washed three times with water. After drying in air and in vacuo, 5.38 g (86% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-de): δ [ppm] = 15.38 (br.s, 1H), 8.50 (d, 1H), 8.44 (d, 1H), 8.04 (t, 1H).

LC / MS (Method 2, ESIpos): R _t = 0.76 min, m / z = 216 [M + H] ⁺ . Example 10A

Pyrido [3,2-d] [1,2,3] triazine-4 (3 /) -one

To a suspension of 3.20 g (23.33 mmol) of 3-aminopyridine-2-carboxamide in 25 ml of a 2: 1 mixture of water and conc. Hydrochloric acid at 0 ° C, a solution of 1.78 g (25.67 mmol) of sodium nitrite in 11 ml of water was added slowly, keeping the internal temperature below 5 ° C. From the suspension, a solution was obtained, which was still 40 min at 0 ° C bath temperature was stirred. Then, with further ice-bath cooling, 11 ml (0.11 mol) of 10 M sodium hydroxide solution were added slowly, the internal temperature rising somewhat. After the internal temperature had dropped back to about 5-10 ° C, the resulting suspension was carefully mixed with conc. Hydrochloric acid acidified (pH = 2). The solid was filtered off, washed three times with water and stirred with diethyl ether. After drying in air and then in vacuo, 2.80 g (81% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 15.24 (br.s, 1H), 9.11 (dd, 1H), 8.61 (dd, 1H), 8.07 (dd, 1H).

LC / MS (Method 3, ESIpos): R _t = 0.38 min, m / z = 149 [M + H] ⁺ . Example IIA

Methyl [3- (bromomethyl) phenyl] carbamate

Step 1:

 Methyl [3- (hydroxymethyl) phenyl] carbamate

To a solution of 177 g (1.44 mol) of 3-aminobenzyl alcohol and 150 ml (0.86 mmol) of NN-diisopropylethylamine in 1.1 liters of THF at 0 ° C, a solution of 66.6 ml (0.86 mol) of methyl chloroformate in 40 ml of THF was added slowly , The mixture was stirred at 0 ° C. for 1 h and then at RT for 1 h. Then, the mixture was diluted with ethyl acetate and washed with water. The organic phase was concentrated and the residue was purified by flash chromatography (silica gel, eluent dichloromethane / ethyl acetate 10: 4). This gave 148 g (95% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 9.61 (br.s, 1H), 7.44 (s, 1H), 7.34 (d, 1H), 7.21 (t, 1H), 6.94 (i.e. , 1H), 5.18 (t, 1H), 4.45 (d, 2H), 3.66 (s, 3H). LC / MS (Method 2, ESIpos): R _t = 0.54 min, m / z = 182 [M + H] ⁺ . Step 2:

 Methyl [3- (bromomethyl) phenyl] carbamate

A solution of 13.1 ml (138 mmol) of phosphorus tribromide in 200 ml of dichloromethane was slowly added at RT to a solution of 50 g (276 mmol) of the compound from Example IA / step 1 in 1 liter of dichloromethane, the internal temperature not being 35 ° C. exceeded. The mixture was then stirred for a further 30 min at RT and then neutralized with 10% aqueous sodium bicarbonate solution. After separation of the organic phase, the aqueous phase was back-extracted once with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 57.4 g (85% of theory) of the title compound were obtained.

LC / MS (Method 2, ESIpos): R _t = 0.91 min, m / z = 244/246 [M + H] ⁺ . Example 12A

2-Bromo-1 - [4- (tetrahydro-2 / f-pyran-4-ylmethoxy) phenyl] efhanone

Step 1:

1- [4- (tetrahydro-2-pyran-4-ylmethoxy) phenyl] ethanone

To a solution of 5.00 g (36.72 mmol) of 4-hydroxyacetophenone in 75 ml of DMF under argon at RT 4.64 g (41.31 mmol) of potassium ieri.-butoxide were added. After stirring at RT for 5 min, 5.0 ml (36.72 mmol, purity 97%) of 4- (bromomethyl) tetrahydropyran were added at RT, and the mixture was then stirred at 60 ° C. for 3 h. Then another 1 ml (7.36 mmol) of 4- (bromomethyl) tetrahydropyran was added and the mixture was stirred at 60 ° C. for a further 28 h. After cooling to RT, the solvent was removed, and the residue was added with 100 ml of ethyl-butyl methyl ether and 100 ml of water. After phase separation, the organic phase was washed twice with 100 ml of 1 N sodium hydroxide solution and twice with 100 ml of water. Subsequently, the organic phase was dried over sodium sulfate, filtered and concentrated. There were obtained 5.74 g (63% of theory, purity 95%) of the title compound.

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 7.93 (d, 2H), 6.92 (d, 2H), 4.03 (dd, 2H), 3.87 (d, 2H), 3.45 (td, 2H) , 2.56 (s, 3H), 2.16-2.01 (m, 1H), 1.80-1.73 (m, 2H), 1.54-1.40 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.91 min, m / z = 234 [M + H] ⁺ .

Step 2:

2-Bromo-1 - [4- (tetrahydro-2 / f-pyran-4-ylmethoxy) phenyl] efhanone

3.81 g (10.13 mmol) of phenyltrimethylammonium tribromide were added at RT to a solution of 2.26 g (9.65 mmol) of the compound from Example 12A / step 1 in 60 ml of THF under argon. After stirring at RT for 4 h, a further 725 mg (1.93 mmol) of phenyltrimethylammonium tribromide were added, and the mixture was stirred at RT for a further 5 h. Then, a part of the solvent was removed, and 80 ml of ethyl acetate and 80 ml of water were added to the mixture. After phase separation, the aqueous phase was back-extracted once with 80 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in a little dichloromethane and purified by column chromatography (400 g of silica gel, mobile phase cyclohexane / ethyl acetate 7: 3, Buchi). 1.82 g (56% of theory, purity 93%) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 7.97 (d, 2H), 6.95 (d, 2H), 4.40 (s, 2H), 4.03

3.89 (d, 2H), 3.46 (td, 2H), 2.17-2.03 (m, 1H), 1.80-1.72 (m, 2H), 1.54-1.40 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 1.03 min, m / z = 313/315 [M + H] ⁺ .

Example 13A

Methyl (3- {[4- (bromoacetyl) phenoxy] methyl} phenyl) carbamate

Step 1:

 Methyl {3- [(4-acetylphenoxy) methyl] phenyl} carbamate

3.30 g (23.89 mmol) of potassium carbonate and 3.50 g (14.34 mmol) of the compound from Example 11A were added at RT to a solution of 1.63 g (11.95 mmol) of 4-hydroxyacetophenone in 25 ml of acetonitrile under argon. Subsequently, the mixture was stirred under reflux for 2 h. After cooling to RT, the solvent was removed and the residue was taken up in ethyl acetate and washed once each with water, saturated ammonium chloride solution and saturated sodium chloride solution. Subsequently, the organic phase was dried over sodium sulfate, filtered and concentrated. The residue was stirred in diethyl ether and the resulting solid was filtered off and dried in vacuo. There was obtained 3.48 g (97% of theory) of the title compound.

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 7.93 (d, 2H), 7.53 (br, s, 1H), 7.33 (d, 2H), 7.12 (t, 1H), 6.99 (d, 2H), 6.76 (br s, 1H), 5.11 (s, 2H), 3.78 (s, 3H), 2.55 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 0.96 min, m / z = 300 [M + H] ⁺ . Step 2:

Methyl (3- {[4- (bromoacetyl) phenoxy] methyl} phenyl) carbamate

3.45 g (9.18 mmol) of phenyltrimethylammonium tribromide were added at RT to a solution of 2.72 g (9.09 mmol) of the compound from Example 13A / Step 1 in 18 ml of THF. After stirring at RT for 16 h, the mixture was introduced into 40 ml of 1 N hydrochloric acid. It was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was stirred in a little diethyl ether and the resulting solid was filtered off and dried in vacuo. There was obtained 3.0 g (87% of theory) of the title compound.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 7.97 (d, 2H), 7.54 (br, s, 1H), 7.37-7.29 (m, 2H), 7.15-7.10 (m, 1H), 7.02 (d, 2H), 6.71 (brs s, 1H), 5.13 (s, 2H), 4.40 (s, 2H), 3.78 (s, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.05 min, m / z = 378/380 [M + H] ⁺ .

Example 14A

2-bromo-1 - {4 - [(tetrahydro-2-yl-pyran-4-ylmethyl) sulfanyl] -phenyl-jethanone

Step 1:

 1 - {4- [(Tetrahydro-2α-pyran-4-ylmethyl) sulfinyl] phenyl} ethanone

A suspension of 20 g (131.4 mmol) of 1- (4-sulfanylphenyl) ethanone and 10.5 g (262.78 mmol) of sodium hydride (60% dispersion in mineral oil) in 200 ml of THF was stirred at RT for 2 h. Subsequently, 16.2 g (87.6 mmol) of 4- (bromomethyl) tetrahydro-2i-7-pyran were slowly added. The reaction mixture was stirred at RT for 16 h and then filtered. The filtrate was concentrated and the residue was dissolved in dichloromethane, washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. There were obtained 9.5 g (26% of theory, purity 90%) of the title compound.

LC / MS (Method 2, ESIpos): R _t = 0.99 min, m / z = 251 [M + H] ⁺ .

Step 2:

2-bromo-1 - {4 - [(tetrahydro-2-yl-pyran-4-ylmethyl) sulfanyl] -phenyl-jethanone

11.89 g (31.63 mmol) of phenyltrimethylammonium tribromide were added in portions to a solution of 8.80 g (31.63 mmol) of the compound from Example 14A / step 1 in 350 ml of THF under argon at RT, and the mixture was then stirred at RT for 16 h. Subsequently, a further 2.38 g (6.30 mmol) of phenyltrimethylammonium tribromide were added and the mixture was stirred for a further 3 h at RT. Thereafter, the mixture was added with 1 N hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue was added with methanol, and the supernatant was decanted off from the solid and concentrated. There were obtained 13.0 g (80% of theory, purity 64%) of the title compound.

LC / MS (Method 2, ESIpos): R _t = 1.08 min, m / z = 329/331 [M + H] ⁺ . Example 15A

Di-ieri-butyl- (2- {4 - [(3-methylbenzyl) oxy] phenyl} -2-oxoethyl) [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) - yl) ethyl] malonate

A solution of 100 g (0.321 mol, purity 84%) of di-tert-butyl- (2-hydroxyethyl) malonate (US Pat. No. 6,900,194, intermediate 5E) in 1 liter of THF under argon was charged with 100.96 g (0.385 mol) of tri - Phenylphosphine and 56.63 g (0.385 mol) of l, 2,3-benzotriazine-4 (3 //) - added and then stirred for 20 min at RT. Subsequently, 75.8 ml (0.385 mol) of diisopropyl azodicarboxylate (DIAD) were slowly added, the internal temperature rising to about 30 ° C with slight cooling. The mixture was then stirred at RT overnight and then stirred into 5 liters of a 10% aqueous sodium chloride solution. After addition of 2 liters of ethyl acetate, the organic phase was separated, washed with 750 ml of 10% sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was taken up in a little dichloromethane, admixed with a little petroleum ether and purified by column chromatography (5 kg of silica gel, eluent petroleum ether / ethyl acetate 8: 2). There was obtained 109.4 g (88% of theory) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.26 (d, 1H), 8.19 (d, 1H), 8.09 (t, 1H), 7.93 (t, 1H), 4.43 (t, 2H), 3.40 (t, 1H), 2.25 (q, 2H), 1.37 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.28 min, m / z = 390 [M + H] ⁺ . Step 2:

 Di-fert \ butyl- {2- [4- (benzoyloxy) phenyl] -2-oxoethyl} P ^

malonate

To a mixture of 5.26 g (0.131 mol, 60% dispersion in mineral oil) of sodium hydride in 400 ml of DMF, a solution of 41.0 g (0.105 mol) of the compound from Example 15 A / Step 1 in 400 ml of DMF was slowly added at RT , It was then stirred until completion of the gas evolution, first at RT and then at 50 ° C. After cooling to RT, a solution of 36.96 g (0.115 mol) of 4- (bromoacetyl) phenylbenzoate in 400 ml of DMF was slowly added. The mixture was stirred for 5 h at RT and then allowed to stand overnight. After removing the solvent, the residue was added with water, made slightly acidic with 10% citric acid solution and extracted twice with dichloromethane. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. This gave 82.5 g (62% of theory, purity 50%) of the title compound, which was used directly in the subsequent reaction. An analogously prepared further batch of the title compound was purified to 82% purity by flash chromatography (silica gel, eluent cyclohexane / ethyl acetate 95: 5-> 90: 10-> 85:15).

Ή NMR (400 MHz, CDCL): δ [ppm] = 8.33-8.28 (m, 1H), 8.25-8.16 (m, 2H), 8.09 (dd, 3H), 7.94-7.88 (m, 1H), 7.79 -7.73 (m, 1H), 7.70-7.63 (m, 1H), 7.57-7.49 (m, 2H), 7.36-7.29 (m, 2H), 4.57-4.51 (m, 2H), 3.79 (s, 2H) , 2.73-2.66 (m, 2H), 1.48 (s, 18H).

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

Step 3:

Di-tert-butyl- [2- (4-hydroxyphenyl) -2-oxoethyl] [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) -malonate

To a solution of 82.5 g (65.72 mmol, purity 50%) of the compound of Example 15A / Step 2 in a mixture of 350 mL THF and 125 mL methanol was added 3.76 mL (19.72 mmol) of a 30% sodium methylate solution in methanol added at RT. The mixture was first stirred at 50 ° C for 4.5 h. Thereafter, an additional 1.9 ml (9.96 mmol) of the sodium methylate solution was added. The mixture was further stirred for a short time at 50 ° C, then allowed to stand at RT overnight and then stirred again at 50 ° C for 3 h. The mixture was then concentrated and the residue was purified by flash chromatography (1 kg silica gel, eluent cyclohexane / ethyl acetate 95: 5 → 90:10 → 80:20 → 70:30). After combining the product-containing fractions and removing the solvent, the residue was stirred with a little ethyl acetate, filtered off, washed once with pentane and dried in vacuo. This gave 25.6 g (74% of theory) of the title compound.

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.30 (d, IH), 8.11 (d, IH), 7.95-7.89 (m, IH), 7.86 (d, 2H), 7.77 (t, IH), 7.50-7.44 (m, IH), 6.83 (d, 2H), 4.57-4.50 (m, 2H), 3.72 (s, 2H), 2.73-2.67 (m, 2H), 1.48 (s, 18H) ,

LC / MS (Method 3, ESIpos): R _t = 2.54 min, m / z = 524 [M + H] ⁺ .

Step 4:

 Di-ieri-butyl- (2- {4 - [(3-methylbenzyl) oxy] phenyl} -2-oxoethyl) [2- (4-oxo-l, 2,3-benzotriazine-3 (4 //) yl) efhyl] malonate

To a solution of 500 mg (0.96 mmol) of the compound from Example 15A / Step 3 in 12 ml of acetonitrile was added 161 μΐ (1.15 mmol, purity 96%) of 3-methylbenzylbromide and 264 mg (1.91 mmol) of potassium carbonate and the resulting mixture 2 h stirred under reflux. After cooling to RT, water was added and stirred for a few minutes. The solid formed was filtered off, washed twice with water and a little pentane and then dried in air and in vacuo. There were obtained 538 mg (90% of theory) of the title compound.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.29 (d, 1H), 8.08 (d, 1H), 7.95 (d, 2H), 7.92-7.86 (m, 1H), 7.78-7.71 ( m, 1H), 7.32-7.20 (m, 3H), 7.16 (d, 1H), 6.98 (d, 2H), 5.09 (s, 2H), 4.56-4.49 (m, 2H), 3.72 (s, 2H) , 2.70-2.64 (m, 2H), 2.38 (s, 3H), 1.47 (s, 18H). LC / MS (Method 1, ESIpos): R _t = 1.53 min, m / z = 628 [M + H] ⁺ .

Example 16A

Di-ieri-butyl- [2- (4- {[3-chloro-4- (trifluoromethoxy) benzyl] oxy} phenyl) -2-oxoethyl] [2- (4-oxo-1,2,3-benzotriazine -3 (4 /) - yl) ethyl] malonate

To a solution of 500 mg (0.96 mmol) of the compound from Example 15A / Step 3 in 12 mL acetonitrile was added 332 mg (1.15 mmol) of 4- (bromomethyl) -2-chloro-1- (trifluoromethoxy) benzene and 264 mg (1.91 mmol) mmol) of potassium carbonate and the resulting mixture stirred for 2 h under reflux. After cooling to RT, water was added and stirred for a few minutes. The solid formed was filtered off, washed twice with water and a little pentane and then dried in air and in vacuo. 625 mg (85% of theory, purity 95%) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.20 (d, 1H), 8.14 (d, 1H), 8.08-8.02 (m, 1H), 7.95- 7.86 (m, 3H), 7.82 (d, 1H), 7.66-7.56 (m, 2H), 7.09 (d, 2H), 5.28-5.24 (m, 2H), 4.46-4.38 (m, 2H), 3.66 (s, 2H), 2.53- 2.47 (hidden, 2H), 1.38 (s, 18H).

LC / MS (Method 1, ESIpos): R _t = 1.57 min, m / z = 732 [M + H] ⁺ . Example 17A

Di-tert-butyl- [2- (4- {[4-chloro-3- (trifluoromethyl) benzyl] oxy} phenyl) -2-oxoethyl] [2- (4-oxo-1,2,3-benzotriazine -3 (4 //) - yl) efhyl] malonate

To a solution of 500 mg (0.96 mmol) of the compound from Example 15A / Step 3 in 12 ml of acetonitrile was added 313 mg (1.15 mmol) of 4- (bromomethyl) -1-chloro-2- (trifluoromethyl) benzene and 264 mg (1.91 mmol) mmol) of potassium carbonate and the resulting mixture stirred for 2 h under reflux. After cooling to RT, water was added and stirred for a few minutes. The solid formed was filtered off, washed twice with water and a little pentane and then dried in air and in vacuo. There was obtained 626 mg (91% of theory, purity 99%) of the title compound.

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 8.20 (d, 1H), 8.14 (d, 1H), 8.08-8.02 (m, 1H), 7.98 (s, 1H), 7.93 (i.e. , 3H), 7.83-7.76 (m, 2H), 7.11 (d, 2H), 5.31 (s, 2H), 4.49-4.31 (m, 2H), 3.66 (s, 2H), 2.53-2.47 (covert, 2H ), 1.38 (s, 18H).

LC / MS (Method 1, ESIpos): R _t = 1.56 min, m / z = 716 [M + H] ⁺ . Example 18A

Di-ieri-butyl- [2- (4- {[4-chloro-3- (trifluoromethoxy) benzyl] oxy} phenyl) -2-oxoethyl] [2- (4-oxo-1,2,3-benzotriazine -3 (4 /) - yl) ethyl] malonate

To a solution of 500 mg (0.96 mmol) of the compound of Example 15A / Step 3 in 12 mL of acetonitrile was added 331 mg (1.15 mmol) of 4- (bromomethyl) -1-chloro-2- (trifluoromethoxy) benzene and 264 mg (1.91 mmol) mmol) of potassium carbonate and the resulting mixture stirred for 2 h under reflux. After cooling to RT, water was added and stirred for a few minutes. The solid formed was filtered off, washed twice with water and a little pentane and then dried in air and in vacuo. 660 mg (94% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.20 (d, 1H), 8.14 (d, 1H), 8.08-8.02 (m, 1H), 7.95-7.87 (m, 3H), 7.82 (d, 1H), 7.65-7.56 (m, 2H), 7.10 (d, 2H), 5.26 (s, 2H), 4.46-4.38 (m, 2H), 3.66 (s, 2H), 2.53-2.48 ( hidden, 2H), 1.39 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.57 min, m / z = 732 [M + H] ⁺ .

Example 19A

Di-tert-butyl- [2- (4- {[4-methyl-3- (trifluoromethyl) benzyl] oxy} phenyl) -2-oxoethyl] [2- (4-oxo-1,2,3-benzotriazine -3 (4 /) - yl) ethyl] malonate

To a solution of 500 mg (0.96 mmol) of the compound from Example 15A / Step 3 in 12 ml of acetonitrile were added 299 mg (1.15 mmol) of 4- (bromomethyl) -l-methyl-2- (trifluoromethyl) benzene and 264 mg (1.91 mmol) of potassium carbonate were added and the resulting mixture was stirred under reflux for 1.5 h. After cooling to RT, water was added and stirred for a few minutes. The solid formed was filtered off, washed twice with water and a little pentane and then dried in air and in vacuo. 611 mg (92% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.20 (d, 1H), 8.14 (d, 1H), 8.08-8.02 (m, 1H), 7.95- 7.86 (m, 3H), 7.78 (s, 1H), 7.67 (d, 1H), 7.49 (d, 1H), 7.09 (d, 2H), 5.26 (s, 2H), 4.45-4.39 (m, 2H), 3.66 (s, 2H) , 2.53-2.48 (hidden, 2H), 2.45 (s, 3H), 1.39 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.57 min, m / z = 696 [M + H] ⁺ . Example 20A

Di-ieri-butyl- (2- {4- [(3,4-dichlorobenzyl) oxy] phenyl} -2-oxoethyl) [2- (4-oxo-1,2,3-benzotriazine-3 (4 / ) yl) ethyl] malonate

To a solution of 2.0 g (3.51 mmol, purity 92%) of the compound from Example 15A / Step 3 in 45 mL of acetonitrile was added 1.04 g (4.22 mmol, purity 97%) of 3,4-dichlorobenzylbromide and 971 mg (7.03 mmol) of potassium carbonate and the resulting mixture stirred for 2 h under reflux. After cooling to RT, water was added and stirred for a few minutes. The solid formed was filtered off, washed twice with water and a little pentane and then dried in air and in vacuo. 2.31 g (94% of theory, purity 98%) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.30 (d, 1H), 8.09 (d, 1H), 7.97 (d, 2H), 7.93-7.87 (m, 1H), 7.78-7.72 ( m, 1H), 7.55 (d, 1H), 7.48 (d, 1H), 7.29-7.27 (m, 1H), 6.96 (d, 2H), 5.11-5.04 (m, 2H), 4.55-4.49 (m, 2H), 3.73 (s, 2H), 2.70-2.64 (m, 2H), 1.47 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.56 min, m / z = 682 [M + H] ⁺ . Example 21A

Di-tert-butyl [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] [2-oxo-2- (4-one [6- (trifluoromethyl) pyridin-3-yl] methoxy} phenyl) ethyl] malonate

To a solution of 200 mg (0.36 mmol, purity 95%) of the compound from Example 15A / Step 3 in 5 ml of acetonitrile were added 106 mg (0.54 mmol) of 5- (chloromethyl) -2- (trifluoromethyl) -pyridine and 100 mg ( 0.73 mmol) of potassium carbonate and the resulting mixture was stirred at reflux for 2 h. After cooling to RT, it was diluted with about 20 ml of ethyl acetate, and the mixture was washed with 10 ml each of water, saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was dried in vacuo. 277 mg (62% of theory, purity 55%) of the title compound were obtained.

LC / MS (Method 2, ESIpos): R _t = 1.45 min, m / z = 683 [M + H] ⁺ .

Example 22A di-tert-butyl [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] {2-oxo-2- [4- (tetrahydro-2-yl) pyran-4-ylmethoxy) phenyl] ethyl} malonate

To a solution of 1.0 g (1.76 mmol, purity 92%) of the compound from Example 15A / Step 3 in 46 ml of acetonitrile was added 661 mg (3.69 mmol) of 4- (bromomethyl) tetrahydro-2i-7-pyran and 486 mg (3.51 mmol). Added potassium carbonate and the resulting mixture was stirred under reflux for 22 h. After cooling to RT, it was diluted with about 40 ml of ethyl acetate and the mixture was washed with 30 ml each of water, saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was stirred with diethyl ether, filtered off, washed with diethyl ether and dried in vacuo. There were obtained 239 mg (67% of theory, purity 96%) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.21-8.18 (m, 1H), 8.15-8.12 (m, 1H), 8.08-8.02 (m, 1H), 7.92-7.86 (m , 3H), 7.02-6.97 (m, 2H), 4.45-4.38 (m, 2H), 3.94-3.82 (m, 4H), 3.65 (s, 2H), 3.41-3.35 (m, 2H), 2.60-2.55 (obscured, 2H), 2.34-2.31 (m, 1H), 1.72-1.66 (m, 2H), 1.39 (s, 18H), 1.40-1.37 (obscured, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.44 min, m / z = 682 [M + H] ⁺ . Example 23A

[2- (6-Fluoro-4-oxo-l, 2,3-benzotriazine-3 (4 /) -yl) ethyl] {2- [4 - ({3 - [(methoxycarbonyl) amino] benzyl} oxy ) phenyl] -2-oxoethyl} malonic acid

Step 1:

Di-tert-butyl [2- (6-fluoro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) -malonate

A solution of 3.32 g (12.67 mmol) of triphenylphosphine in 35 ml of THF under argon was added at RT with 2.62 ml (12.67 mmol, purity 95%) of diisopropyl azodicarboxylate (DIAD) and stirred briefly. Subsequently, 1.90 g (11.51 mmol) of di-ieri-butyl- (2-hydroxyethyl) malonate (US Pat. No. 6,900,194, intermediate 5E) was added and the suspension was further stirred for about 5 minutes. Thereafter, 5.99 g (23.01 mmol) of the compound from Example 1A was added and the resulting mixture was stirred for 2 h at RT. It was then diluted with 100 ml of ethyl acetate and 100 ml of water and the phases were separated. The organic phase was washed once with 100 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (400 g silica gel, eluent cyclohexane / ethyl acetate 9: 1, Buchi). The title compound was obtained in two batches: 2.83 g (59% of theory, purity 97%) and 330 mg (7% of theory, purity 100%).

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.19 (dd, 1H), 7.97 (dd, 1H), 7.64 (td, 1H), 4.56 (t, 2H), 3.28 (t, 1H) , 2.42 (q, 2H), 1.45 (s, 18H). LC / MS (Method 2, ESIpos): R _t = 1.25 min, m / z = 408 [M + H]

Step 2:

 Di-ieri-butyl {2- [4- (benzoyloxy) phenyl] -2-oxoethyl} [2- (6-fluoro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl] ) ethyl] malonate

To a mixture of 398 mg (9.96 mmol, 60% dispersion in mineral oil) of sodium hydride in 25 ml of DMF under argon was slowly added a solution of 3.12 g (7.66 mmol) of the compound from Example 23A / step 1 in 25 ml of DMF RT added. It was then stirred for 10 min at RT and 30 min at 50 ° C until the evolution of gas. After cooling to RT, a solution of 2.44 g (7.66 mmol) of 4- (bromoacetyl) phenylbenzoate in 25 ml of DMF was added slowly and the mixture was stirred at RT for 2 h. After removing the solvent, the residue was added with 200 ml of water and 200 ml of ethyl acetate, and the phases were separated. The aqueous phase was back-extracted once with 150 ml of ethyl acetate, and the combined organic phases were washed once with 200 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was taken up in a little dichloromethane and purified by column chromatography (silica gel, mobile phase cyclohexane / ethyl acetate 90: 10-85: 15, Buchi). 2.83 g (57% of theory) of the title compound were obtained.

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.22 (d, 2H), 8.14 (dd, 1H), 8.07 (d, 2H), 7.92 (dd, 1H), 7.70-7.64 (m, 1H), 7.60 (td, 1H), 7.54 (t, 2H), 7.32 (d, 2H), 4.56-4.50 (m, 2H), 3.78 (s, 2H), 2.72- 2.65 (m, 2H), 1.48 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.53 min, m / z = 646 [M + H] ⁺ .

Step 3:

 Di-ieri-butyl- [2- (6-fluoro-4-oxo-l, 2,3-benzotriazine-3 (4 /) -yl) ethyl] [2- (4-hydroxyphenyl) -2-oxo] ethyl] malonate

To a solution of 2.79 g (4.32 mmol) of the compound from Example 23A / Step 2 in 60 ml of THF was added 0.25 ml (1.30 mmol) of a 30% sodium methylate solution in methanol at RT. The mixture was stirred for 12 h at 50 ° C bath temperature. After cooling to RT, the mixture was diluted with 300 ml of ethyl acetate and 300 ml of water, and the phases were separated. The aqueous phase was back-extracted with 200 ml of ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate. dried and concentrated. The residue was taken up in a little dichloromethane and purified by column chromatography (200 g silica gel, mobile phase cyclohexane / ethyl acetate 7: 3). There were obtained 2.07 g (89% of theory) of the title compound.

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.13 (dd, 1H), 7.91 (dd, 1H), 7.87 (d, 2H), 7.60 (td, 1H), 7.29-7.19 (m, 1H), 6.84 (d, 2H), 4.55-4.49 (m, 2H), 3.70 (s, 2H), 2.71-2.65 (m, 2H), 1.47 (s, 18H).

LC / MS (Method 4, ES Ineg): R _t = 1.44 min, m / z = 540 [MH] ^" .

Step 4:

 Di-tert-butyl [2- (6-fluoro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] {2- [4 - ({3 - [(methoxycarbonyl ) - amino] benzyl} oxy) phenyl] -2-oxoethyl} malonate

To a solution of 487 mg (0.90 mmol) of the compound of Example 23A / Step 3 in 10 mL of acetonitrile was added 263 mg (1.08 mmol) of the compound of Example IA and 249 mg (1.80 mmol) of potassium carbonate. The mixture was stirred at reflux for 1 h. After cooling to RT, 30 ml of ethyl acetate and 30 ml of water were added to the mixture and the phases were separated. The aqueous phase was back-extracted once with 30 ml of ethyl acetate, and the combined organic phases were washed once with 40 ml of sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was taken up in 4 ml of a mixture of cyclohexane and ethyl acetate (1: 1). The resulting precipitate was filtered off, washed twice with 2 ml of cyclohexane / ethyl acetate (1: 1) and dried in vacuo. 499 mg (79% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, CDCL): δ [ppm] = 8.14 (dd, 1H), 7.96 (d, 2H), 7.92 (dd, 1H), 7.61 (td, 1H), 7.53 (br. S, 1H ), 7.36 (d, 2H), 7.17-7.13 (m, 1H), 6.98 (d, 2H), 6.70 (br, s, 1H), 5.13 (s, 2H), 4.57-4.50 (m, 3H), 3.80 (s, 3H), 3.73 (s, 2H), 2.72-2.66 (m, 2H), 1.49 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.40 min, m / z = 705 [M + H] ⁺ . Step 5:

 [2- (6-Fluoro-4-oxo-1,2-benzotriazine-3 (4 /) -yl) ethyl] {2- [4 - ({3 - [(methoxycarbonyl) amino] benzyl} oxy) phenyl ] -2-oxo-ethyl} malonate

To a solution of 469 mg (0.67 mmol) of the compound from Example 23A / Step 4 in 7 ml of dioxane was added 7 ml of a 4 N solution of hydrogen chloride in dioxane and the mixture was stirred at RT for 18 h. Then, the solvent was removed, and the residue was added with 20 ml of ethyl acetate and 20 ml of water. After phase separation, the organic phase was dried over sodium sulfate and concentrated. 402 mg (99% of theory, purity 97%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.97 (br. S, 1H), 9.72 (br. S, 1H), 8.23 (dd, 1H), 7.94- 7.82 (m, 4H ), 7.58 (s, 1H), 7.43 (d, 1H), 7.31 (t, 1H), 7.09 (d, 1H), 7.04 (d, 2H), 5.15 (s, 2H), 4.43 (t, 2H) , 3.72-3.67 (m, 2H), 3.66 (s, 3H), 2.61-2.55 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.85 min, m / z = 593 [M + H] ⁺ . Example 24A

Di-tert-butyl [2- (6-fluoro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] {2-oxo-2- [4- (tetrahydroxy) 2-pyran-4-ylmethoxy) phenyl] ethyl} malonate

To a solution of 200 mg (0.37 mmol) of the compound of Example 23A / Step 3 in 5 mL of acetonitrile was added 132 mg (0.74 mmol) of 4- (bromomethyl) tetrahydropyran and 153 mg (1.11 mmol) of potassium carbonate. The mixture was stirred at reflux for 16 h. After cooling to RT, water was added and stirred for a few minutes. The solid formed was filtered off, washed twice with water and once with a little pentane and then dried in vacuo. This crude product was then purified by preparative HPLC (Method 7). The product-containing fractions were combined, neutralized with saturated sodium bicarbonate solution and concentrated to a small residual volume. The solid formed was filtered off, washed twice with water and once with pentane and dried in vacuo. 151 mg (64% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.13 (dd, 1H), 7.94 (d, 2H), 7.90 (dd, 1H), 7.59 (td, 1H), 6.89 (d, 2H) , 4.54-4.48 (m, 2H), 4.04 (dd, 2H), 3.86 (d, 2H), 3.71 (s, 2H), 3.46 (t, 2H), 2.70-2.64 (m, 2H), 2.16-2.03 (m, 1H), 1.77 (d, 2H), 1.54-1.46 (covert, 2H), 1.47 (s, 18H).

LC / MS (Method 1, ESIpos): R _t = 1.46 min, m / z = 640 [M + H] ⁺ . Example 25A

Di-ieri-butyl- (2- {4- [(3-chlorobenzyl) oxy] phenyl} -2-oxoethyl) [2- (6-chloro-4-oxo-1,2,3-benzotriazine-3 ( 4 /) - yl) ethyl] malonate

Step 1:

Di-tert-butyl [2- (6-chloro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) -malonate

A solution of 7.95 g (30.29 mmol) of triphenylphosphine in 90 ml of THF under argon was added at RT with 6.29 ml (30.29 mmol, purity 95%) of diisopropyl azodicarboxylate (DIAD) and briefly stirred. Subsequently, 5.0 g (27.54 mmol) of the compound from Example 2A were added in solid form and the suspension was stirred for a further 5 min. Thereafter, 10.75 g (41.30 mmol) of di-ieri-butyl (2-hydroxyethyl) malonate (US Pat. No. 6,900,194, intermediate 5E) was added. The resulting mixture was stirred at RT for a further 15 min and at 0 ° C bath temperature for 15 min. The solid formed was filtered off and treated with a little tert. -Butyl-methyl ether leached. The filtrate was concentrated and the residue was re-combined with the previously obtained solid. This material was then taken up in a little dichloromethane, applied to silica gel and purified by flash chromatography (silica gel, eluent cyclohexane / ethyl acetate 90: 10-> 85:15). There were obtained 8.96 g (77% of theory) of the title compound.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.32 (d, 1H), 8.09 (d, 1H), 7.87 (dd, 1H), 4.56 (t, 2H), 3.28 (t, 1H) , 2.42 (q, 2H), 1.45 (s, 18H). LC / MS (Method 1, ESIpos): R _t = 1.38 min, m / z = 424 [M + H] ⁺ .

Step 2:

 Di-ieri-butyl {2- [4- (benzoyloxy) phenyl] -2-oxoethyl} [2- (6-chloro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl] ) ethyl] malonate

To a mixture of 354 mg (8.85 mmol, 60% dispersion in mineral oil) of sodium hydride in 27 ml of DMF under argon was added a solution of 3.00 g (7.08 mmol) of the compound from Example 25A / Step 1 in 27 ml of DMF slowly at RT added. It was then stirred for 1 h at 50 ° C until the evolution of gas. After cooling to RT, a solution of 2.49 g (7.79 mmol) of 4- (bromoacetyl) phenyl benzoate in 27 ml of DMF was added and the mixture was stirred at RT for 15 min. After removing the solvent, the residue was added with water and ethyl acetate, whereupon a solid precipitated. The solid was filtered off and washed once each with water and ethyl acetate. The mother liquor was stored. Drying of the solid in vacuo gave 1.52 g (32% of theory) of a first batch of the title compound. The stored mother liquor was separated into the phases, and the aqueous phase was 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 recrystallized from ethyl acetate. After drying in vacuo, 1.21 g (26% of theory) of a second batch of the title compound were obtained. Ή NMR (400 MHz, CDCL): δ [ppm] = 8.26 (d, 1H), 8.22 (d, 2H), 8.09-8.02 (m, 3H), 7.84 (dd, 1H), 7.70-7.64 (m , 1H), 7.57-7.51 (m, 2H), 7.32 (d, 2H), 4.56-4.50 (m, 2H), 3.78 (s, 2H), 2.72-2.65 (m, 2H), 1.48 (s, 18H ).

LC / MS (Method 2, ESIpos): R _t = 1.54 min, m / z = 662 [M + H] ⁺ .

Step 3:

 Di-ieri-butyl- [2- (6-chloro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] [2- (4-hydroxyphenyl) -2-oxo] ethyl] malonate

To a solution of 2.70 g (4.08 mmol) of the compound from Example 25A / Step 2 in a mixture of 21 ml of THF and 7 ml of methanol was added 0.23 ml (1.22 mmol) of a 30% sodium methoxide solution in methanol at RT added. The mixture was stirred for 2.5 h at 50 ° C bath temperature. Subsequently, the solvent was removed and the residue in a Mixture of ethyl acetate and water was added. After phase separation, the aqueous phase was back-extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue was triturated with pentane, filtered off and dried in vacuo. 2.18 g (91% of theory, purity 95%) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.25 (d, 1H), 8.04 (d, 1H), 7.88-7.80 (m, 3H), 7.70 (br, s, 1H), 6.84 ( d, 2H), 4.55-4.49 (m, 2H), 3.69 (s, 2H), 2.70-2.65 (m, 2H), 1.47 (s, 18H).

LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 558 [M + H] ⁺ .

Step 4:

Di-ieri-butyl- (2- {4- [(3-chlorobenzyl) oxy] phenyl} -2-oxoethyl) [2- (6-chloro-4-oxo-1,2,3-benzotriazine-3 ( 4 /) - yl) ethyl] malonate

To a solution of 300 mg (0.51 mmol, purity 95%) of the compound from Example 25A / Step 3 in 6.5 ml of acetonitrile was added 130 mg (0.61 mmol, purity 97%) of 3-chlorobenzylbromide and 141 mg (1.02 mmol) of potassium carbonate. The mixture was stirred at reflux for 2 h. After cooling to RT, the mixture was treated with water and stirred for a few minutes. The precipitate formed was filtered off, washed twice with water and twice with a little pentane and dried in vacuo. There were obtained 346 mg (94% of theory, purity 95%) of the title compound. Ή NMR (400 MHz, CDCL): δ [ppm] = 8.24 (d, 1H), 8.03 (d, 1H), 7.95 (d, 2H), 7.82 (dd, 1H), 7.45 (s, 1H), 7.36-7.29 (m, 3H), 6.97 (d, 2H), 5.13-5.06 (m, 2H), 4.54-4.48 (m, 2H), 3.71 (s, 2H), 2.70-2.64 (m, 2H), 1.47 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.59 min, m / z = 682 [M + H] ⁺ . Example 26A

Di-i <2ri.-butyl- [2- (6-chloro-4-oxo-l, 2,3-benzotriazin-3 (^

pyran-4-ylmethoxy) phenyl] ethyl} malonate

To a solution of 300 mg (0.71 mmol) of the compound from Example 25 A / Step 1 in 4 ml of DMF under argon was added 51 mg (1.28 mmol, 60% dispersion in mineral oil) of sodium hydride. After stirring for 15 min at RT, 244 mg (0.78 mmol) of the compound from Example 12A were added at RT. The mixture was stirred at RT overnight. Subsequently, water and methanol were added to the mixture. The precipitate formed was filtered off, washed with methanol and dried in vacuo. This gave 183 mg (38% of theory, purity 97%) of a first batch of the title compound. The mother liquor was concentrated and the residue was treated with methanol and acetonitrile. The resulting solid was filtered off and dried in vacuo to give 81 mg (10% of theory, purity 58%) of a second crop of the title compound. LC / MS (Method 2, ESIpos): R _t = 1.46 min, m / z = 656 [M + H] ⁺ . Example 27A

Di-ieri-butyl {2- [4- ({3- [(methoxycarbonyl) amino] benzyl} oxy) phenyl] -2-oxoethyl} [2- (6-methyl-4-oxo-l, 2, 3-benzotriazine-3 (4 /) - yl) ethyl] malonate

Step 1:

 Di-ieri-butyl- [2- (6-methyl-4-oxo-l, 2,3-benzotriazine-3 (4 /) -yl) ethyl] malonate

A solution of 3.31 g (12.63 mmol) of triphenylphosphine in 35 ml of THF under argon was added at room temperature with 2.62 ml (12.63 mmol, purity 95%) of diisopropyl azodicarboxylate (DIAD) and stirred briefly. Subsequently, 1.85 g (11.50 mmol) of the compound from Example 3A were added and the suspension was stirred for a further 5 min. Thereafter, 3.59 g (13.78 mmol) of di-ethyl-butyl (2-hydroxyethyl) malonate (US Pat. No. 6,900,194, intermediate 5E) was added. The resulting mixture was stirred at RT for 18 h. Then the mixture was treated with 100 ml of ethyl acetate and 100 ml of water. After phase separation, the organic phase was washed once with 100 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (400 g silica gel, eluent cyclohexane / ethyl acetate 9: 1, Buchi). There were obtained 2.50 g (54% of theory) of the title compound. Ή NMR (400 MHz, CDCL): δ [ppm] = 8.14 (s, 1H), 8.03 (d, 1H), 7.74 (d, 1H), 4.55 (t, 2H), 3.29 (t, 1H), 2.57 (s, 3H), 2.42 (q, 2H), 1.45 (d, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.28 min, m / z = 404 [M + H] ⁺ .

Step 2:

Di-ieri-butyl {2- [4- (benzoyloxy) phenyl] -2-oxoethyl} [2- (6-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl] ) ethyl] malonate

To a mixture of 319 mg (7.97 mmol, 60% dispersion in mineral oil) of sodium hydride in 22 ml of DMF under argon was added a solution of 2.47 g (6.13 mmol) of the compound from Example 27A / Step 1 in 22 ml of DMF slowly at RT added. It was then stirred for 30 min at 50 ° C. After cooling to RT, a solution of 587 mg (1.84 mmol) of 4- (bromoacetyl) phenylbenzoate in 22 ml of DMF was added, and the mixture was stirred at RT for 45 min. Then another 587 mg (1.84 mmol) of 4- (bromoacetyl) phenylbenzoate were added and the mixture was stirred at RT for a further 2 h. Then, the mixture was added with 200 ml of water and 200 ml of ethyl acetate. After phase separation, the aqueous phase was back-extracted once with 100 ml of ethyl acetate. The combined organic phases were washed once with 300 ml of saturated sodium chloride solution. A precipitate formed, which was filtered off and, after drying in vacuo, yielded 380 mg (10% of theory, purity 98%) of a first batch of the title compound. The filtrate was dried over sodium sulfate, filtered and concentrated. The residue was taken up in a little dichloromethane and purified by column chromatography (400 g of silica gel, eluent cyclohexane / ethyl acetate 90:10 → 85:15, Buchi). This gave 1.54 g (37% of theory, purity 93%) of a second batch of the title compound.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.22 (d, 2H), 8.11-8.04 (m, 3H), 7.99 (d, 1H), 7.74-7.63 (m, 2H), 7.54 ( t, 2H), 7.32 (d, 2H), 4.56-4.46 (m, 2H), 3.79 (s, 2H), 2.72-2.65 (m, 2H), 2.55 (s, 3H), 1.48 (s, 18H) , LC / MS (Method 2, ESIpos): R _t = 1.57 min, m / z = 642 [M + H] ⁺ .

Step 3:

Di-ieri-butyl- [2- (4-hydroxyphenyl) -2-oxo-ethyl] [2- (6-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] malonate

To a solution of 1.90 g (2.96 mmol) of the compound from Example 27A / Step 2 in a mixture of 40 mL THF and 14 mL methanol was added 0.17 mL (0.89 mmol) of a 30% sodium methylate solution in methanol at RT , The mixture was stirred for 7 h at 50 ° C bath temperature. Then the solvent was removed and the residue was taken up in a mixture of 100 ml of ethyl acetate and 100 ml of water. After phase separation, the aqueous phase was back-extracted with 100 ml of ethyl acetate, and the combined organic phases were washed once with 150 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was recrystallized from about 20 ml of ethyl acetate, filtered off, washed twice with 10 ml of pentane and dried in vacuo. 878 mg (55% of theory) of a first batch of the title compound were obtained. The filtrate was concentrated and the residue was purified by column chromatography (120 g silica gel, cyclohexane / ethyl acetate 7: 3, Interchim). 406 mg (23% of theory, purity 92%) of a second batch of the title compound were obtained. Ή NMR (400 MHz, CDCL): δ [ppm] = 8.08 (s, 1H), 7.99 (d, 1H), 7.87 (d, 2H), 7.71 (d, 1H), 7.19-7.06 (m, 1H ), 6.83 (d, 2H), 4.54-4.47 (m, 2H), 3.72 (s, 2H), 2.72-2.65 (m, 2H), 2.55 (s, 3H), 1.48 (s, 18H).

LC / MS (Method 3, ESIpos): R _t = 2.62 min, m / z = 538 [M + H] ⁺ .

Step 4:

Di-ieri-butyl {2- [4- ({3- [(methoxycarbonyl) amino] benzyl} oxy) phenyl] -2-oxoethyl} [2- (6-methyl-4-oxo-l, 2, 3-benzotriazine-3 (4 /) - yl) ethyl] malonate

To a solution of 200 mg (0.37 mmol) of the compound from Example 27 A / Step 3 in 4.1 ml of acetonitrile were added 109 mg (0.45 mmol) of the compound from Example IA and 103 mg (0.74 mmol) of potassium carbonate. The mixture was stirred at reflux for 1 h. After cooling to RT, 30 ml of ethyl acetate and 30 ml of water were added to the mixture. After phase separation, the aqueous phase was back-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 a little dichloromethane and purified by column chromatography (50 g silica gel, eluent cyclohexane / ethyl acetate 8: 2, Biotage). 216 mg (83% of theory, purity 83%) of the title compound were obtained.

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.07 (s, 1H), 7.99-7.92 (m, 3H), 7.69 (dd, 1H), 7.50 (s, 1H), 7.34 (d, 2H), 7.16-7.10 (m, 1H), 6.97 (d, 2H), 6.63 (brs s, 1H), 5.11 (s, 2H), 4.53-4.47 (m, 2H), 3.78 (s, 3H) , 3.71 (s, 2H), 2.70-2.63 (m, 2H), 2.54 (s, 3H), 1.47 (s, 18H).

LC / MS (Method 1, ESIpos): R _t = 1.44 min, m / z = 701 [M + H] ⁺ . Example 28A

Di-tert-butyl [2- (6-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] [2-oxo-2- (4- {[3 - (2-oxo-1,3-oxazolidin-3-yl) benzyl] oxy} phenyl) ethyl] malonate

To a solution of 200 mg (0.37 mmol) of the compound from Example 27A / Step 3 in 4 ml of acetonitrile were added 114 mg (0.45 mmol) of 3- [3- (bromomethyl) phenyl] -1,3-oxazolidin-2-one ( described in WO 2008/049047, Example 228) and 102 mg (0.74 mmol) of potassium carbonate. The mixture was stirred at reflux for 1 h. After cooling to RT, 30 ml of ethyl acetate and 30 ml of water were added. After phase separation, the aqueous phase was back-extracted once with 30 ml of ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by column chromatography (50 g silica gel, mobile phase cyclohexane / ethyl acetate 3: 2, Biotage). There were obtained 233 mg (83% of theory, purity 95%) of the title compound. Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.07 (s, 1H), 7.99-7.93 (m, 3H), 7.70 (dd, 1H), 7.66 (s, 1H), 7.52 (dd, 1H), 7.42 (t, 1H), 7.22 (d, 1H), 6.97 (d, 2H), 5.15 (s, 2H), 4.54-4.44 (m, 4H), 4.13-4.05 (m, 2H), 3.72 (s, 2H), 2.69-2.62 (m, 2H), 2.54 (s, 3H), 1.47 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.41 min, m / z = 713 [M + H] ⁺ .

Example 29A di-tert-butyl [2- (6-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] {2-oxo-2- [4- ( tetrahydro-2-pyran-4-ylmethoxy) phenyl] ethyl} malonate

To a solution of 200 mg (0.37 mmol) of the compound from Example 27A / Step 3 in 4 mL of acetonitrile was added 80 mg (0.45 mmol) of 4- (bromomethyl) tetrahydro-2i-7-pyran and 102 mg (0.74 mmol) of potassium carbonate. The mixture was stirred at reflux for 24 h. After cooling to RT, 30 ml of ethyl acetate and 30 ml of water were added. After phase separation, the aqueous phase was back-extracted once with 30 ml of ethyl acetate, and 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 8: 2, Biotage). 196 mg (77% of theory, purity 93%) of the title compound were obtained. Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.07 (s, 1H), 8.00-7.93 (m, 3H), 7.70 (dd, 1H), 6.89 (d, 2H), 4.53-4.45 ( m, 2H), 4.04 (dd, 2H), 3.87 (d, 2H), 3.72 (s, 2H), 3.50-3.41 (m, 2H), 2.69-2.63 (m, 2H), 2.54 (s, 3H) , 2.17-2.02 (m, 1H), 1.77 (d, 2H), 1.55-1.49 (partially obscured, 2H).

LC / MS (Method 3, ESIpos): R _t = 2.94 min, m / z = 636 [M + H] ⁺ . Example 30A

Di-tert-butyl [2- (6-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] [2-oxo-2- (4- {[3 - (trifluoromethyl) benzyl] oxy} phenyl) ethyl] malonate

To a solution of 310 mg (0.58 mmol) of the compound from Example 27A / Step 3 in 6 mL of acetonitrile was added 165 mg (0.69 mmol) of 1- (bromomethyl) -3- (trifluoromethyl) benzene and 159 mg (1.15 mmol) of potassium carbonate , The mixture was stirred at reflux for 2 h. After cooling to RT, 7 ml of water were added and the mixture was stirred for a few minutes. Subsequently, the resulting solid was filtered off, washed twice with water and dried in vacuo. There were obtained 382 mg (95% of theory) of the title compound. Ή NMR (400 MHz, CDCL): δ [ppm] = 8.08 (s, 1H), 7.98 (dd, 3H), 7.74-7.67 (m, 2H), 7.66-7.59 (m, 2H), 7.57-7.49 (m, 1H), 6.99 (d, 2H), 5.17 (s, 2H), 4.53-4.46 (m, 2H), 3.73 (s, 2H), 2.70-2.63 (m, 2H), 2.54 (s, 3H ), 1.47 (s, 18H).

LC / MS (Method 3, ESIpos): R _t = 3.24 min, m / z = 696 [M + H] ⁺ . Example 31 A Di-tert-butyl- (2- {4- [(3-chlorobenzyl) oxy] phenyl} -2-oxoethyl) [2- (6-methyl-4-oxo-1,2,3-benzo - triazine-3 (4 //) - yl) ethyl] malonate

To a solution of 310 mg (0.58 mmol) of the compound of Example 27A / Step 3 in 6 mL of acetonitrile was added 142 mg (0.69 mmol) of 1- (bromomethyl) -3-chlorobenzene and 159 mg (1.15 mmol) of potassium carbonate. The mixture was stirred at reflux for 2 h. After cooling to RT, 7 ml of water were added and the mixture was stirred for a few minutes. Subsequently, the resulting solid was filtered off, washed twice with water and dried in vacuo. There were obtained 351 mg (92% of theory) of the title compound.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.08 (s, 1H), 7.99-7.94 (m, 3H), 7.69 (dd, 1H), 7.44 (s, 1H), 7.36-7.29 ( m, 3H), 6.97 (d, 2H), 5.10 (s, 2H), 4.53-4.47 (m, 2H), 3.72 (s, 2H), 2.70-2.63 (m, 2H), 2.54 (s, 3H) , 1.47 (s, 18H).

LC / MS (Method 3, ESIpos): R _t = 3.24 min, m / z = 662 [M + H] ⁺ .

Example 32A

{2-Oxo-2- [4- (tetrahydro-2-pyran-4-ylmethoxy) phenyl] ethyl} {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 ( 4 //) - yl] ethyl} malonic acid

Step 1:

Di-ieri-butyl {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] ethyl} malonate

A solution of 18.78 g (71.58 mmol) of triphenylphosphine in 210 ml of THF was added under argon at RT with 14.8 ml (71.58 mmol, purity 95%) of diisopropyl azodicarboxylate (DIAD) and briefly stirred. The internal temperature rose to 40 ° C and it formed a precipitate. Then, 14.0 g (65.08 mmol) of the compound from Example 4A were added and the mixture was stirred for a few more minutes. Subsequently, 18.64 g (71.58 mmol) of di-ieri-butyl (2-hydroxyethyl) malonate (US Pat. No. 6,900,194, intermediate 5E) was added, with the internal temperature rising to 60.degree. The solution was further stirred for 1 h. Thereafter, the solvent was removed and the residue was tert in 200 ml. -Butyl methyl ether added. The resulting solid was filtered off, with 30 ml of tert. -Butyl methyl ether washed and discarded. The filtrate was concentrated and the residue was purified by column chromatography (1 kg of silica gel, mobile phase cyclohexane / ethyl acetate 9: 1). There were obtained 26.44 g (89% of theory) of the title compound.

Ή NMR (400 MHz, CDCL): δ [ppm] = 8.65 (s, 1H), 8.28 (d, 1H), 8.15 (dd, 1H), 4.60 (t, 2H), 3.29 (t, 1H), 2.43 (q, 2H), 1.45 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.37 min, m / z = 457 [M + H] ⁺ .

Step 2:

Di-ieri-butyl {2- [4- (benzoyloxy) phenyl] -2-oxoethyl} {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (AH ) -yl] ethyl} malonate

To a solution of 24.44 g (53.43 mmol) of the compound from Example 32A / Step 1 in 400 ml of DMF under argon was slowly added in portions at RT 2.78 g (69.45 mmol, 60% dispersion in mineral oil) of sodium hydride. After stirring for 10 min at rt, the mixture was cooled to 0 ° C and a solution of 18.76 g (58.77 mmol) of 4- (bromoacetyl) phenylbenzoate in 100 ml of DMF was added. The mixture was stirred for 2 h at RT. After removing the solvent, the residue was added with 500 ml of water and 500 ml of ethyl acetate, and the phases were separated. The aqueous phase was extracted once with 500 ml of ethyl acetate, and the combined organic phases were washed once with 1 liter of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was mixed with about 200 ml ieri.-butyl methyl ether and stirred over the weekend. The solid present was filtered off and washed twice with 100 ml each of ferric butyl methyl ether. After drying in vacuo, 21.31 g (52% of theory, purity 91%) of a first batch of the title compound were obtained. The filtrate was concentrated and the residue was taken up in a little dichloromethane and then purified by flash chromatography (400 g silica gel, eluent cyclohexane / ethyl acetate 9: 1). This gave 840 mg (2% of theory, purity 99%) of a second batch of the title compound. Two further, partially purified fractions from column chromatography were combined, dissolved in 120 ml of THF and purified by preparative HPLC (column: Chromatorex C18, 10 μm, spring column 250 × 20 mm, flow: 250 ml / min, detection: 210 nm, injection volume 20 ml, temperature: 22 ° C, eluent: methanol / water gradient). There were obtained in this way 6.65 g (17% of theory, purity 97%) of a third batch of the title compound.

Ή-NMR (400 MHz, CDCh): δ [ppm] = 8.60 (s, 1H), 8.25-8.19 (m, 3H), 8.11 (dd, 1H), 8.07 (d, 2H), 7.70-7.63 (m , 1H), 7.58-7.51 (m, 2H), 7.32 (d, 2H), 4.61-4.54 (m, 2H), 3.78 (s, 2H), 2.74-2.67 (m, 2H), 1.49 (s, 18H ). LC / MS (Method 2, ESIpos): R _t = 1.54 min, m / z = 696 [M + H] Step 3:

 Di-ieri-butyl- [2- (4-hydroxyphenyl) -2-oxoethyl] {2- [4-oxo-6- (trifluoromethyl) -l, 23-benzotri 3 (4 /) -yl] ethyl} malonate

To a solution of 7.42 g (10.67 mmol) of the compound from Example 32A / Step 2 in a mixture of 150 ml of THF and 50 ml of methanol under argon was added 0.61 ml (0.58 mmol) of a 30% sodium methylate solution in methanol at RT added. The mixture was stirred for 2 h at 60 ° C bath temperature. After cooling to RT, 200 ml of ethyl acetate and 200 ml of water were added to the mixture, and the phases were separated. The aqueous phase was extracted with 100 ml Efhyl- acetate, and the combined organic phases were washed once with 300 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to a volume of about 70 ml. After cooling to 0 ° C. for 30 min, the solid formed was filtered off and washed twice with 5 ml of ethyl acetate each time. After drying in vacuo, 4.65 g (74% of theory) of a first batch of the title compound were obtained. The filtrate was concentrated and the residue was taken up in a little dichloromethane and then purified by column chromatography (silica gel, mobile phase cyclohexane / ethyl acetate 7: 3, Biotage system). This gave 0.89 g (14% of theory) of a second batch of the title compound.

Ή-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.58 (s, 1H), 8.22 (dd, 1H), 8.10 (dd, 1H), 7.86 (d, 2H), 6.86-6.83 (br. s, 1H), 6.83 (d, 2H), 4.59-4.53 (m, 2H), 3.70 (s, 2H), 2.72-2.66 (m, 2H), 1.48 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.31 min, m / z = 592 [M + H] ⁺ .

Step 4:

Di-tert-butyl {2-oxo-2- [4- (tetrahydro-2-pyran-4-ylmethoxy) -phenyl] -ethyl} {2- [4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 /) -yl] ethyl} malonate

Method A:

 To a solution of 198 mg (0.34 mmol) of the compound of Example 32A / Step 3 in 4 mL of acetonitrile was added 72 mg (0.40 mmol) of 4- (bromomethyl) tetrahydropyran and 93 mg (0.67 mmol) of potassium carbonate. The mixture was stirred at reflux for 24 h. Subsequently, a further 36 mg (0.20 mmol) of 4- (bromomethyl) tetrahydropyran were added and the mixture was stirred under reflux for a further 3 h. After cooling to RT, 30 ml of ethyl acetate and 30 ml of water were added to the mixture, and the phases were separated. The aqueous phase was back-extracted once with 30 ml of ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (25 g silica gel, eluent cyclohexane / ethyl acetate 8: 2, Biotage). 200 mg (87% of theory) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.57 (s, 1H), 8.22 (d, 1H), 8.09 (dd, 1H), 7.93 (d, 2H), 6.88 (d, 2H) , 4.59-4.52 (m, 2H), 4.03 (dd, 2H), 3.86 (d, 2H), 3.71 (s, 2H), 3.51-3.40 (m, 2H), 2.72-2.65 (m, 2H), 2.16 -2.01 (m, 1H), 1.77 (d, 2H), 1.54-1.45 (obscured, 2H), 1.47 (s, 18H).

LC / MS (Method 3, ESIpos): R _t = 1.31 min, m / z = 690 [M + H] ⁺ .

Method B:

31.9 g (284 mmol) of potassium ferric butylate were added at RT to a solution of 125.1 g (273 mmol) of the compound from Example 32A / Step 1 in 1.31 liter of DMF under argon, and the mixture was stirred at RT for 30 min , The mixture was then cooled to -60 ° C and cooled to -60 ° C solution of 68.5 g (219 mmol) of the compound of Example 12A in 660 ml of DMF was added dropwise. The mixture was stirred for 1 h at -60 ° C. Subsequently, 2.1 liters of ethyl acetate and 8.5 liters of a 10% sodium chloride solution were added. After phase separation, the aqueous phase was back-extracted with 2.1 liters of ethyl acetate, and the combined organic phases were washed with 2.1 liters of 10% sodium chloride solution, dried, filtered and concentrated. The residue was taken up in dichloromethane to give a concentrated solution and purified by column chromatography (4.5 kg Silica gel, eluent dichloromethane / ethyl acetate 95: 5 (50 liters) -> 90:10 (40 liters)). 115 g (76% of theory) of the title compound were obtained.

LC / MS (Method 2, ESIpos): R _t = 1.51 min, m / z = 690 [M + H] ⁺ .

Step 5:

{2-Oxo-2- [4- (tetrahydro-2-pyran-4-ylmethoxy) phenyl] ethyl} {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 ( 4 //) - yl] ethyl} malonic acid

100 ml of trifluoroacetic acid were added at RT to a solution of 7.25 g (9.68 mmol, purity 92%) of the compound from Example 32A / step 4 in 200 ml of dichloromethane, and the mixture was stirred at RT for 1 h. Then, solvent and trifluoroacetic acid were removed and the residue was dried in vacuo. This gave 7.65 g (> 100% of theory, purity 96%) of the title compound.

LC / MS (Method 2, ESIpos): R _t = 0.94 min, m / z = 578 [M + H] ⁺ . Example 33A Oi-tert. -butyl- {2- [4- ({3- [(methoxycarbonyl) amino] benzyl} oxy) phenyl] -2-oxoethyl} {2- [4-oxo-6- (trifluoromethyl) -l, 2,3- benzotriazine-3 (4 /) -yl] ethyl} malonate

94 mg (0.39 mmol) of the compound from Example 11A and 89 mg (0.64 mmol) were added to a solution of 190 mg (0.32 mmol) of the compound from Example 32A / Step 3 in 3.5 ml of acetonitrile. Given potassium carbonate. The mixture was stirred at reflux for 1 h. After cooling to RT, 30 ml of ethyl acetate and 30 ml of water were added, and after phase separation, the aqueous phase was back-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 (50 g of silica gel, mobile phase cyclohexane / ethyl acetate 8: 2, Biotage). 191 mg (79% of theory) of the title compound were obtained.

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.58 (s, 1H), 8.20 (d, 1H), 8.09 (dd, 1H), 7.93 (d, 2H), 7.51 (br. 1H), 7.33 (d, 2H), 7.15-7.10 (m, 1H), 6.96 (d, 2H), 6.63 (br s, 1H), 5.11 (s, 2H), 4.59- 4.51 (m, 2H) , 3.78 (s, 3H), 3.70 (s, 2H), 2.71-2.65 (m, 2H), 1.47 (s, 18H).

LC / MS (Method 1, ESIpos): R _t = 1.47 min, m / z = 755 [M + H] ⁺ .

Example 34A

(+/-) - {2-Oxo-2- [4- (tetrahydro-2-pyran-3-ylmethoxy) phenyl] ethyl} {2- [4-oxo-6- (trifluoromethyl) -1, 2 , 3-benzotriazin-3 (4 //) - yl] ethyl} malonic acid

Step 1:

 Di-ieri-butyl {2-oxo-2- [4- (tetrahydro-2-pyran-3-ylmethoxy) -phenyl] -ethyl} {2- [4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 /) -yl] ethyl} malonate

To a solution of 300 mg (0.51 mmol) of the compound from Example 32A / Step 3 in 6 ml of acetonitrile were added 109 mg (0.61 mmol) (+/-) - 3- (bromomethyl) -tetrahydro-2-i-pyran and 140 mg (1.01 mmol) of potassium carbonate. The mixture was stirred at reflux for 19 h. Subsequently, another 109 mg (0.61 mmol) of (+/-) - 3- (bromomethyl) tetrahydro-2i7-pyran were added and the mixture was stirred under reflux for a further 2 days. After cooling to RT, the mixture was treated with ethyl acetate and water. After phase separation, the aqueous phase was back-extracted once with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in a little acetonitrile and purified by preparative HPLC (Method 7). The product-containing fractions were combined and treated with saturated sodium bicarbonate solution and ethyl acetate. After phase separation, the organic phase was concentrated and the residue was dried in vacuo. There were obtained 76 mg (22% of theory) of the title compound.

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.57 (s, 1H), 8.21 (d, 1H), 8.09 (dd, 1H), 7.92 (d, 2H), 6.88 (d, 2H) , 4.58-4.52 (m, 2H), 4.05-3.99 (m, 1H), 3.91-3.83 (m, 3H), 3.71 (s, 2H), 3.53-3.45 (m, 1H), 3.39 (dd, 1H) , 2.72-2.65 (m, 2H), 2.20-2.11 (m, 1H), 1.95-1.87 (m, 1H), 1.73-1.63 (m, 2H), 1.48 (s, 18H).

LC / MS (Method 3, ESIpos): R _t = 3.18 min, m / z = 690 [M + H] ⁺ .

Step 2:

 (+/-) - {2-0x0-2- [4- (tetrahydro-2-pyran-3-ylmethoxy) phenyl] ethyl} {2- [4-oxo-6- (trifluoromethyl) -1,2] 3-benzotriazin-3 (4 //) - yl] ethyl} malonic acid

0.34 ml (4.35 mmol) of trifluoroacetic acid were added at RT to a solution of 75 mg (0.11 mmol) of the compound from Example 34 / Step 1 in 1 ml of dichloromethane, and the mixture was stirred at RT for 1 h. The mixture was then concentrated and the residue was dried in vacuo. There was obtained 62 mg (89% of theory, purity 90%) of the title compound.

LC / MS (Method 2, ESIpos): R _t = 3.02 min, m / z = 578 [M + H] ⁺ . Example 35A

Di-tert-butyl- (2-oxo-2- {4- [2- (tetrahydro-2-pyran-4-yl) -ethoxy] -phenyl} -ethyl) {2- [4-oxo-6- (tri fluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] ethyl} malonate

To a solution of 100 mg (0.17 mmol) of the compound from Example 32A / Step 3 in 3 ml of acetonitrile was added 98 mg (0.51 mmol) of 4- (2-bromoethyl) tetrahydro-2i-7-pyran and 70 mg (0.51 mmol) of potassium carbonate , The mixture was stirred for 16 h at 80 ° C bath temperature. After cooling to RT, ethyl acetate and water were added, and after phase separation, 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. 130 mg (98% of theory, purity 90%) of the title compound were obtained.

LC / MS (Method 2, ESIpos): R _t = 1.50 min, m / z = 704 [M + H] ⁺ . Example 36A (+/-) - di-ieri-butyl {2-oxo-2- [4- (tetrahydrofuran-3-ylmethoxy) phenyl] ethyl} {2- [4-oxo-6- (trifluoromethyl ) -l, 2,3-benzotriazine-3 (4 /) - yl] ethyl} malonate

To a solution of 100 mg (0.17 mmol) of the compound from Example 32A / Step 3 in 3 ml of acetonitrile were added 84 mg (0.51 mmol) of (+/-) -3- (bromomethyl) tetrahydrofuran and 70 mg (0.51 mmol) of potassium carbonate. The mixture was stirred for 16 h at 80 ° C bath temperature. After cooling to RT, ethyl acetate and water were added, and after phase separation, 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. 116 mg (93% of theory, purity 92%) of the title compound were obtained.

LC / MS (Method 2, ESIpos): R _t = 1.44 min, m / z = 676 [M + H] ⁺ . Example 37A

(+/-) - di-ieri-butyl {2-oxo-2- [4- (tetrahydrofuran-2-ylmethoxy) phenyl] ethyl} {2- [4-oxo-6- (trifluoromethyl) - l, 2,3-benzotriazine-3 (4 /) -yl] ethyl} malonate

To a solution of 100 mg (0.17 mmol) of the compound from Example 32A / Step 3 in 3 mL acetonitrile was added 84 mg (0.51 mmol) (+/-) - 2- (bromomethyl) tetrahydrofuran and 70 mg (0.51 mmol) potassium carbonate , The mixture was stirred for 32 h at 80 ° C bath temperature. After cooling to RT, ethyl acetate and water were added, and after phase separation, 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. 118 mg (75% of theory, purity 72%) of the title compound were obtained. LC / MS (Method 2, ESIpos): R _t = 1.45 min, m / z = 676 [M + H] ⁺ . Example 38A

(+/-) - di-ieri-butyl {2-oxo-2- [4- (tetrahydro-2-pyran-2-ylmethoxy) phenyl] ethyl} {2- [4-oxo-6 ( trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] ethyl} malonate

To a solution of 100 mg (0.17 mmol) of the compound of Example 32A / Step 3 in 3 ml of acetonitrile were added 91 mg (0.51 mmol) of (+/-) -2- (bromomethyl) tetrahydro-2i-7-pyran and 70 mg (0.51 mmol) of potassium carbonate. The mixture was stirred for 32 h at 80 ° C bath temperature. After cooling to RT, ethyl acetate and water were added, and after phase separation, 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. 125 mg (66% of theory, purity 62%) of the title compound were obtained. LC / MS (Method 2, ESIpos): R _t = 1.50 min, m / z = 690 [M + H] ⁺ . Example 39A

Di-ieri-butyl- (2- {4- [(4-fluorotetrahydro-2-yl-pyran-4-yl) -methyl] -phenyl} -2-oxo-ethyl) {2- [4-oxo-6- (trifluoromethyl) - l, 2,3-benzotriazine-3 (4 /) -yl] ethyl} malonate

To a solution of 100 mg (0.17 mmol) of the compound from Example 32A / Step 3 in 3 ml of acetonitrile were added 70 mg (0.51 mmol) of potassium carbonate and 90 mg (0.34 mmol) (4-fluorotetrahydro-2 / f-pyranitrile). 4-yl) methyl trifluoromefhansulfonate [Ref .: EP 2 090 570-A1, Reference Example 23, Step 1]. The mixture was stirred for 1.5 h at 80 ° C bath temperature. Subsequently, another 90 mg (0.34 mmol) (4-fluorotetrahydro-2 / f-pyran-4-yl) methyltrimidine were added twice in succession. Fluoromethanesulfonat added, each followed by 1.5 h stirring at 80 ° C bath temperature. After cooling to RT, the mixture was combined with another mixture obtained from a similar experiment (using DMF instead of acetonitrile, using 200 mg instead of 100 mg of the compound from Example 32A / Step 3) and worked up together. The combined mixtures were ethyl acetate and water, and after phase separation the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. A total of 77 mg of the title compound were obtained (26% of theory, based on a total of 300 mg of the compound used from Example 32A / step 3). LC / MS (Method 2, ESIpos): R _t = 1.47 min, m / z = 708 [M + H] ⁺ .

Example 40A

Di-tert-butyl- (2- {4- [(3-chlorobenzyl) oxy] phenyl} -2-oxoethyl) {2- [4-oxo-6- (trifluoromethyl)-1,2,3-benzotriazine] 3 (AH) -yl] ethyl} malonate

To a solution of 210 mg (0.31 mmol, purity 87%) of the compound from Example 32A / Step 3 in 4 mL of acetonitrile was added 85 mg (0.62 mmol) of potassium carbonate and 76 mg (0.37 mmol) of 3-chlorobenzyl bromide. The mixture was stirred at reflux for 1.5 h. After cooling to RT, 5 ml of water were added, and after stirring for a few minutes, the resulting solid was filtered off, washed twice with water and dried in vacuo. Subsequently, the solid was stirred in diethyl ether, filtered off and dried again in vacuo. 178 mg (80% of theory) of the title compound were obtained.

LC / MS (Method 2, ESIpos): R _t = 1.58 min, m / z = 716 [M + H] ⁺ .

Example 41A

Di-tert-butyl {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] ethyl} [2-oxo-2- (4- { [3- (trifluoromethyl) benzyl] oxy} phenyl) ethyl] malonate

To a solution of 750 mg (1.08 mmol, purity 85%) of the compound from Example 32A / Step 3 in 13 ml of acetonitrile was added 298 mg (2.16 mmol) of potassium carbonate and 309 mg (1.29 mmol) of 1- (bromomethyl) -3- ( trifluoromethyl) benzene. The mixture was stirred under reflux for 1.5 h. After cooling to RT, 5 ml of water were added, and after stirring for a few minutes, the resulting solid was filtered off, washed twice with water and dried in vacuo. The solid was then stirred in diethyl ether, filtered off and dried again in vacuo. 690 mg (85% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.41 (s, 1H), 8.35 (s, 2H), 7.89 (d, 2H), 7.85 (s, 1H), 7.79 (d, 1H), 7.73 (d, 1H), 7.69-7.64 (m, 1H), 7.08 (d, 2H), 5.30 (s, 2H), 4.49-4.42 (m, 2H), 3.64 (s, 2H), 2.58 -2.51 (obscured, 2H), 1.40 (s, 18H).

LC / MS (Method 3, ESIpos): R _t = 3.31 min, m / z = 750 [M + H] ⁺ .

Example 42A

Di-ieri-butyl- (2- {4- [(3,4-dichlorobenzyl) oxy] phenyl} -2-oxoethyl) {2- [4-oxo-6- (trifluoromethyl) -1,3,3- benzotriazine-3 (4 /) -yl] ethyl} malonate

To a solution of 750 mg (1.08 mmol, purity 85%) of the compound from Example 32A / Step 3 in 13 ml of acetonitrile were added 298 mg (2.16 mmol) of potassium carbonate and 310 mg (1.29 mmol) of 4- (bromomethyl) -1,2 given dichlorobenzene. The mixture was refluxed for 1.5 h. stir. After cooling to RT, 5 ml of water were added, and after stirring for a few minutes, the resulting solid was filtered off, washed twice with water and dried in vacuo. The solid was then stirred in diethyl ether, filtered off and dried again in vacuo. 802 mg (86% of theory) of the title compound were obtained. Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.42 (s, 1H), 8.36 (s, 2H), 7.90 (d, 2H), 7.76 (d, 1H), 7.69 (d, 1H), 7.47 (dd, 1H), 7.06 (d, 2H), 5.21 (s, 2H), 4.48-4.41 (m, 2H), 3.65 (s, 2H), 3.36-3.33 (obscured, 2H), 1.39 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.73 min, m / z = 750 [M + H] ⁺ . Example 43A di-tertiary-butyl- [2- (6,7-difluoro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] {2- [4- ({3 - [(methoxycarbonyl) amino] benzyl} oxy) phenyl] -2-oxoethyl} malonate

A solution of 2.36 g (9.01 mmol) of triphenylphosphine in 25 ml of THF under argon was added at RT with 1.87 ml (9.01 mmol, purity 95%) of diisopropyl azodicarboxylate (DIAD) and stirred briefly. Subsequently, 1.50 g (8.19 mmol) of the compound from Example 5A were added. Add and the suspension is stirred for about 5 min further. Thereafter, 4.27 g (16.28 mmol) of Oi-tert-butyl- (2-hydroxyethyl) malonate (US Pat. No. 6,900,194, intermediate 5E) was added and the mixture was stirred at RT for a further 3 h. Then, the mixture was added with 100 ml of ethyl acetate and 100 ml of water. After phase separation, the organic phase was washed once with 100 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (200 g of silica gel, eluent cyclohexane / ethyl acetate 85:15, Buchi). There were obtained 2.08 g (58% of theory, purity 98%) of the title compound.

Ή NMR (400 MHz, CDCL): δ [ppm] = 8.11 (dd, 1H), 7.93 (dd, 1H), 4.56 (t, 2H), 3.28 (t, 1H), 2.41 (q, 2H), 1.45 (s, 18H).

LC / MS (Method 4, ESIpos): R _t = 1.52 min, m / z = 426 [M + H] ⁺ .

Step 2:

 Di-ieri-butyl {2- [4- (benzoyloxy) phenyl] -2-oxoethyl} [2- (6,7-difluoro-4-oxo-1,2,3-benzotriazine] 3 (4 /) yl) ethyl] malonate

To a mixture of 244 mg (6.11 mmol, 60% dispersion in mineral oil) of sodium hydride in 15 ml of DMF under argon was slowly added a solution of 2.0 g (4.70 mmol) of the compound from Example 43A / Step 1 in 15 ml of DMF RT added. It was then stirred for 30 min at 50 ° C. After cooling to RT, a solution of 1.80 g (5.64 mmol) of 4- (bromoacetyl) phenylbenzoate in 15 ml of DMF was added and the resulting mixture was stirred at RT for 2 h. Then, the mixture was added with 200 ml of water and 200 ml of ethyl acetate. After phase separation, the aqueous phase was extracted once with 150 ml of ethyl acetate. The combined organic phases were washed once with 200 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was taken up in a little dichloromethane and purified by column chromatography (200 g of silica gel, mobile phase cyclohexane). hexane / ethyl acetate 85:15, Buchi). There were obtained 1.59 g (47% of theory, purity 91%) of the title compound.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.21 (d, 2H), 8.09-8.02 (m, 3H), 7.88 (dd, 1H), 7.70-7.63 (m, 1H), 7.57- 7.50 (m, 2H), 7.36-7.30 (m, 2H), 4.56-4.50 (m, 2H), 3.77 (s, 2H), 2.71-2.65 (m, 2H), 1.48 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.49 min, m / z = 664 [M + H] ⁺ .

Step 3:

 Di-tert-butyl- [2- (6,7-difluoro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] [2- (4-hydroxyphenyl) -2- oxoethyl] malonate

To a solution of 1.56 g (2.35 mmol) of the compound from Example 43A / Step 2 in 35 ml of THF was added 0.13 ml (0.71 mmol) of a 30% sodium methylate solution in methanol at RT. The mixture was stirred for 12 h at 50 ° C bath temperature. After cooling to RT, the mixture was treated with 100 ml of ethyl acetate and 100 ml of water. After phase separation, the aqueous phase was extracted with 100 ml of ethyl acetate, and the combined organic phases were washed once with 150 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was taken up in a little dichloromethane and purified by column chromatography (silica gel, mobile phase cyclohexane / ethyl acetate 7: 3, Buchi). 799 mg (61% of theory) of the title compound were obtained. Ή NMR (400 MHz, CDCL): δ [ppm] = 8.04 (t, 1H), 7.91-7.82 (m, 3H), 6.84 (d, 2H), 6.64 (br, s, 1H), 4.55-4.48 (m, 2H), 3.69 (s, 2H), 2.70-2.64 (m, 2H), 1.47 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.25 min, m / z = 560 [M + H] Step 4:

 Di-tert-butyl 2- (6-difluoro-oxo, 23-benzotriazine-3 (4 /) - yl) ethyl] {2 4 - ({3 (methoxycarbonyl) amino] benzyl} oxy) phenyl] 2-oxoethyl} malonate

To a solution of 383 mg (0.67 mmol) of the compound from Example 43A / Step 3 in 7.6 ml of acetonitrile was added 200 mg (0.82 mmol) of the compound from Example 12A and 189 mg (1.37 mmol) of potassium carbonate. The mixture was stirred at reflux for 1 h. After cooling to RT, 30 ml of ethyl acetate and 30 ml of water were added to the mixture. After phase separation, 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 a little dichloromethane and purified by column chromatography (50 g silica gel, mobile phase cyclohexane / ethyl acetate 7: 3, Buchi). There were obtained 383 mg (77% of theory) of the title compound.

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.04 (t, 1H), 7.93 (d, 2H), 7.86 (dd, 1H), 7.51 (br, s, 1H), 7.34 (d, 2H), 7.16-7.09 (m, 1H), 6.97 (d, 2H), 6.66 (brs s, 1H), 5.11 (s, 2H), 4.54-4.48 (m, 2H), 3.78 (s, 3H) , 3.70 (s, 2H), 2.69-2.63 (m, 2H), 1.47 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.41 min, m / z = 723 [M + H] ⁺ .

Example 44A

Di-tert-butyl [2- (7-fluoro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] {2- [4 - ({3 - [(methoxycarbonyl ) - amino] benzyl} oxy) phenyl] -2-oxoethyl} malonate

 Step 1:

 Di-ieri-butyl- [2- (7-fluoro-4-oxo-l, 2,3-benzotriazine-3 (4 /) - yl) ethyl] malonate

A solution of 3.15 g (12.11 mmol) of di-ferric butyl (2-hydroxyethyl) malonate (US Patent 6,900,194, Intermediate 5E), 3.97 g (15.14 mmol) of triphenyl phosphine and 2.50 g (15.14 mmol) of the compound from Example 6A in 110 ml of THF under argon was stirred for 30 min at RT and then slowly added at RT with 3.0 ml (15.14 mmol) of diisopropyl azodicarboxylate (DIAD). The mixture was then stirred at RT for 16 h. The solvent was then removed and the residue was purified directly by MPLC (silica gel, eluent cyclohexane / ethyl acetate 6: 1 → 4: 1). There were obtained 3.86 g (78% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 8.33 (dd, 1H), 8.08 (dd, 1H), 7.81 (td, 1H), 4.43 (t, 2H), 3.41 (t, 1H ), 2.24 (q, 2H), 1.37 (s, 18H).

LC / MS (Method 1, ESIpos): R _t = 1.32 min, m / z = 408 [M + H] ⁺ . Step 2:

Di-tert-butyl [2- (7-fluoro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] {2- [4 - ({3 - [(methoxycarbonyl ) - amino] benzyl} oxy) phenyl] -2-oxoethyl} malonate

To a mixture of 103 mg (2.58 mmol, 60% dispersion in mineral oil) of sodium hydride in 5 ml of DMF under argon was added slowly a solution of 1.0 g (2.45 mmol) of the compound from Example 44A / Step 1 in 5 ml of DMF. The mixture was stirred for 30 minutes until the evolution of gas and heat had subsided, and then 1.02 g (2.70 mmol) of the compound from Example 13A were added at RT. After stirring for 16 h at RT, the mixture was added to 30 ml of water and extracted three times 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 MPLC (silica gel, mobile phase cyclohexane / ethyl acetate 4: 1-> 2: 1). 1.0 g (58% of theory, purity 97%) of the title compound was obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 9.72 (br.s, 1H), 8.27 (dd, 1H), 8.01 (dd, 1H), 7.89 (d, 2H), 7.77 ( td, 1H), 7.58 (br s, 1H), 7.42 (d, 1H), 7.31 (t, 1H), 7.09 (d, 1H), 7.06 (d, 2H), 5.16 (s, 2H), 4.41 (t, 2H), 3.66 (s, 3H), 3.64 (s, 2H), 2.58-2.50 (obscured, 2H), 1.39 (s, 18H). LC / MS (Method 2, ESIpos): R _t = 1.39 min, m / z = 705 [M + H] ⁺ .

Example 45A

Di-tert-butyl [2- (7-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] {2-oxo-2- [4- (tetrahydroxy) 2-pyran-4-ylmethoxy) phenyl] ethyl} malonate

Step 1:

 Di-ieri-butyl- [2- (7-methyl-4-oxo-l, 2,3-benzotriazine-3 (4 /) -yl) ethyl] malonate

A solution of 12.46 g (47.50 mmol) of triphenylphosphine in 100 ml of THF under argon was added at RT with 9.85 ml (47.50 mmol, purity 95%) of diisopropyl azodicarboxylate (DIAD) and stirred briefly. For dilution, another 10 ml of THF was added. Subsequently, 6.96 g (43.19 mmol) of the compound from Example 7A were added and the suspension was stirred for a further 5 min. Then, a solution of 11.81 g (45.35 mmol) of di-feri-butyl- (2-hydroxyethyl) malonate (US Pat. No. 6,900,194, intermediate 5E) in 30 ml of THF was added slowly and the mixture was stirred at RT for 1 h. Thereafter, the mixture was concentrated, and the residue was stirred in 50 ml of a 10: 1 mixture of cyclohexane and ethyl acetate. After cooling to 0 ° C, the solid present was filtered off and discarded. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, eluent cyclohexane / ethyl acetate 95: 5 - 90: 10-85: 15). After concentration of the combined product-containing fractions, the residue was taken up in a little dichloromethane and treated with pentane, whereupon a solid precipitated. After stirring in the cold, the solid was filtered off and dried in vacuo. There were obtained 8.56 g (49% of theory) of the title compound.

Ή NMR (400 MHz, CDCL): δ [ppm] = 8.23 (d, 1H), 7.92 (s, 1H), 7.61 (d, 1H), 4.55 (t, 2H), 3.29 (td, 1H), 2.60 (s, 3H), 2.42 (q, 2H), 1.45 (s, 18H). LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 404 [M + H] ⁺ .

Step 2:

Di-ieri-butyl {2- [4- (benzoyloxy) phenyl] -2-oxoethyl} [2- (7-methyl-4-oxo-1,2,3-benzotriazine-3 (4/) -yl] ) ethyl] malonate

To a mixture of 1.05 g (26.33 mmol, 60% dispersion in mineral oil) of sodium hydride in 80 ml of DMF under argon, a solution of 8.50 g (21.07 mmol) of the compound from Example 45A / Step 1 in 80 ml of DMF slowly at RT added. It was then stirred until completion of the evolution of gas at RT and then at 50 ° C for about 10 min. After cooling to RT, a solution of 8.26 g (23.17 mmol, purity 90%) of 4- (bromoacetyl) phenylbenzoate in 80 ml of DMF was added rapidly, the temperature being kept at RT by further cooling. The mixture was then stirred for a further 15 min at RT. Thereafter, the mixture was taken up in ethyl acetate and water and adjusted to pH 4-5 with 10% citric acid solution. After phase separation, the aqueous phase was 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 90: 10-85: 15-80: 20). 11.80 g (87% of theory) of the title compound were obtained. Ή NMR (400 MHz, CDCb): δ [ppm] = 8.23-8.16 (m, 3H), 8.07 (d, 2H), 7.87 (s, 1H), 7.69-7.64 (m, 1H), 7.59-7.51 (m, 3H), 7.32 (d, 2H), 4.55-4.48 (m, 2H), 3.79 (s, 2H), 2.72-2.66 (m, 2H), 2.57 (s, 3H), 1.48 (s, 18H ).

LC / MS (Method 2, ESIpos): R _t = 1.51 min, m / z = 642 [M + H] ⁺ .

Step 3:

Di-tert-butyl- [2- (4-hydroxyphenyl) -2-oxoethyl] [2- (7-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) -ethyl ] malonate

To a solution of 3.10 g (4.44 mmol, purity 92%) of the compound from Example 45A / Step 2 in a mixture of 24 mL THF and 9 mL methanol was added 0.25 mL (1.33 mmol) of a 30% sodium methylate solution in methanol added at RT. The mixture was stirred for 4.5 h at 50 ° C bath temperature. Subsequently, a further 0.1 ml (0.52 mmol) of the 30% sodium methylate solution in methanol were added and the mixture was stirred for a further hour. After removing the solvent, the residue was taken up in a mixture of 100 ml of ethyl acetate, 200 ml of water and 150 ml of saturated sodium chloride solution. After phase separation, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was stirred in pentane and the resulting solid was filtered off and dried in vacuo. There were obtained 1.95 g (76% of theory, purity 93%) of the title compound.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.18 (d, 1H), 7.90-7.82 (m, 3H), 7.58 (d, 1H), 7.52 (s, 1H), 6.83 (d, 2H), 4.55-4.49 (m, 2H), 3.72 (s, 2H), 2.72-2.66 (m, 2H), 2.58 (s, 3H), 1.48 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.25 min, m / z = 538 [M + H] ⁺ .

Step 4:

Di-tert-butyl [2- (7-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] {2-oxo-2- [4- (tetrahydroxy) 2-pyran-4-ylmethoxy) phenyl] ethyl} malonate

To a solution of 200 mg (0.37 mmol) of the compound of Example 45A / Step 3 in 5 mL of acetonitrile was added 154 mg (1.12 mmol) of potassium carbonate and 133 mg (0.74 mmol) of 4- (bromomethyl) tetrahydro-2i-7-pyran , The mixture was stirred at reflux for 16 h. After cooling to RT, a few ml of water were added, and after stirring for a few minutes, the resulting solid was filtered off, washed twice with water and once with a little pentane and dried in vacuo. 201 mg (83% of theory, purity 98%) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.17 (d, 1H), 7.95 (d, 2H), 7.86 (s, 1H), 7.56 (d, 1H), 6.89 (d, 2H) , 4.53-4.45 (m, 2H), 4.03 (dd, 2H), 3.87 (d, 2H), 3.72 (s, 2H), 3.46 (t, 2H), 2.69-2.63 (m, 2H), 2.57 (s , 3H), 2.15-2.03 (m, 1H), 1.77 (d, 2H), 1.47 (s, 18H), 1.53-1.40 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.48 min, m / z = 636 [M + H] ⁺ .

Example 46A

Di-teri.-butyl- (2- {4 - [(3,4-dichlorobenzyl) oxy] phenyl} -2-oxoethyl) [2- (7-methyl-4-oxo-l, 2,3-benzo- triazine-3 (4 /) - yl) ethyl] malonate

To a solution of 800 mg (1.49 mmol) of the compound of Example 45A / Step 3 in 9 mL of acetonitrile was added 411 mg (2.97 mmol) of potassium carbonate and 441 mg (1.79 mmol, purity 97%) of 3,4-dichlorobenzyl bromide. The mixture was stirred at reflux overnight. To After cooling to RT, 5 ml of water were added, and after stirring for a few minutes, the resulting solid was filtered off, rinsed once with water and once with a little diethyl ether and dried in vacuo. 544 mg (49% of theory, purity 93%) of the title compound were obtained. LC / MS (Method 2, ESIpos): R _t = 1.60 min, m / z = 696 [M + H] ⁺ .

Example 47A

Di-tert-butyl {2- [4- ({3- [(methoxycarbonyl) amino] benzyl} oxy) phenyl] -2-oxoethyl} {2- [4-oxo-7- (trifluoromethyl)} -1, 2,3-benzotriazine-3 (4 /) -yl] ethyl} malonate

Step 1:

 Di-ieri-butyl {2- [4-oxo-7- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] -malonate

A solution of 14.31 g (54.56 mmol) of triphenylphosphine in 165 ml of THF under argon was treated at RT with 11.31 ml (54.57 mmol, purity 95%) of diisopropyl azodicarboxylate (DIAD) and stirred briefly. Subsequently, 11.0 g (49.60 mmol, purity 97%) of the compound from Example 8A were added and the suspension was stirred for a further 5 min. Thereafter, 15.49 g (59.52 mmol) of di-tertiary-butyl (2-hydroxyethyl) malonate (US Pat. No. 6,900,194, intermediate 5E) was added and the mixture was further stirred at RT for 1 h. Subsequently, the mixture was washed with 500 ml of ethyl acetate and washed once each with 500 ml of water and 500 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue was taken up in 150 ml of ethyl acetate and dissolved in the heat. After cooling to RT, a solid precipitated, which was washed twice with 70 ml of tert-butyl methyl ether and then discarded. The filtrate was concentrated and the residue was taken up in a little dichloromethane and then purified by flash chromatography (silica gel, eluent cyclohexane / ethyl acetate 9: 1). 2.85 g (12% of theory, purity 95%) of a first batch of the title compound and 13.19 g (58% of theory, purity 100%) of a second batch were obtained.

Ή NMR (400 MHz, CDCb): δ [ppm] = 8.49 (d, 1H), 8.43 (s, 1H), 8.00 (dd, 1H), 4.59 (t, 2H), 3.29 (t, 1H), 2.43 (q, 2H), 1.45 (s, 18H).

LC / MS (Method 3, ESIpos): R _t = 2.85 min, m / z = 458 [M + H] ⁺ .

Step 2:

 Di-ieri-butyl {2- [4- (benzoyloxy) phenyl] -2-oxoethyl} {2- [4-oxo-7- (trifluoromethyl) -1,3,3-benzotriazine-3 (AH ) -yl] ethyl} malonate

To a mixture of 1.50 g (37.48 mmol, 60% dispersion in mineral oil) of sodium hydride in 90 ml of DMF under argon was added a solution of 13.19 g (28.83 mmol) of the compound from Example 47A / Step 1 in 90 ml of DMF slowly at RT added. It was then stirred at 50 ° C for about 30 min. After cooling to RT, a solution of 10.12 g (31.72 mmol) of 4- (bromoacetyl) phenylbenzoate in 90 ml of DMF was added and the mixture was stirred at RT overnight. Then, the mixture was added with 400 ml of ethyl acetate and 400 ml of water. After phase separation, the aqueous phase was extracted once with 200 ml of ethyl acetate. The combined organic phases were washed once with 300 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (1 kg silica gel, eluent cyclohexane / ethyl acetate 9: 1). 6.16 g (30% of theory, purity 97%) of a first batch of the title compound were obtained. In addition, the partially purified product fractions were obtained, which were combined and subsequently purified by preparative HPLC (column: Daiso C18, 10 μm, Bio Dan 300 × 100 mm, flow: 250 ml / min, detection: 210 nm, injection volume 10 ml, temperature: 20 ° C. Eluent: isocratic methanol / water 90:10). This gave 3.37 g (17% of theory) of a second batch of the title compound.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.43 (d, 1H), 8.38 (s, 1H), 8.23-8.19 (m, 2H), 8.06 (d, 2H), 7.96 (dd, 1H), 7.70-7.64 (m, 1H), 7.54 (d, 2H), 7.31 (d, 2H), 4.60-4.54 (m, 2H), 3.78 (s, 2H), 2.74- 2.67 (m, 2H) , 1.49 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.60 min, m / z = 696 [M + H] ⁺ .

Step 3:

 Di-ieri-butyl- [2- (4-hydroxyphenyl) -2-oxoethyl] {2- [4-oxo-7- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 /) -yl] ethyl} malonate

To a solution of 6.20 g (8.02 mmol, purity 90%) of the compound from Example 47A / Step 2 in a mixture of 42 mL THF and 16 mL methanol was added 0.46 mL (2.41 mmol) of a 30% sodium methylate solution in methanol added at RT. The mixture was stirred for 4 h at 50 ° C bath temperature. It was then diluted with ethyl acetate and the solution was then washed once with water. The aqueous phase was extracted once with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to a small residual volume. The resulting solid was filtered off, washed twice with pentane and dried in vacuo. This gave 3.92 g (83% of theory) of a first batch of the title compound. The filtrate was concentrated, the residue was combined with 520 mg of a partially purified fraction from a previous experiment, then dissolved in a little dichloromethane and purified by column chromatography (120 g silica gel, eluent cyclohexane / ethyl acetate 7: 3, Interchim). There was thus obtained 1.25 g of a second batch of the title compound. Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.42 (d, 1H), 8.36 (s, 1H), 7.95 (dd, 1H), 7.85 (d, 2H), 6.85-6.79 (m, 3H), 4.59-4.53 (m, 2H), 3.70 (s, 2H), 2.73-2.66 (m, 2H), 1.48 (s, 18H).

LC / MS (Method 3, ESIpos): R _t = 2.78 min, m / z = 592 [M + H] ⁺ .

Step 4:

Oi-tert. -butyl {2- [4- ({3- [(methoxycarbonyl) amino] benzyl} oxy) phenyl] -2-oxoethyl} {2- [4-oxo-7- (trifluoromethyl) -l, 2,3- benzotriazine-3 (4 /) -yl] ethyl} malonate

To a solution of 750 mg (1.27 mmol) of the compound from Example 47 A / Step 3 in 15 ml of acetonitrile was added 371 mg (1.52 mmol) of the compound from Example IA and 350 mg (2.54 mmol) of potassium carbonate. The mixture was stirred at reflux for 2 h. After cooling to rt, the solvent was removed and the residue taken up in ethyl acetate and water. After phase separation, the aqueous phase was 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 column chromatography (120 g silica gel, eluent cyclohexane / ethyl acetate 8: 2, Interchim). There were obtained 741 mg (76% of theory, purity 99%) of the title compound.

Ή-NMR (400 MHz, CDCL): δ [ppm] = 8.42 (d, 1H), 8.36 (s, 1H), 7.96-7.90 (m, 3H), 7.53-7.49 (m, 1H), 7.34 (i.e. , 2H), 7.14-7.10 (m, 1H), 6.96 (d, 2H), 6.72 (brs s, 1H), 5.11 (s, 2H), 4.58-4.51 (m, 2H), 3.78 (s, 3H ), 3.71 (s, 2H), 2.71-2.65 (m, 2H), 1.47 (s, 18H). LC / MS (Method 2, ESIpos): R _t = 1.45 min, m / z = 755 [M + H] ⁺ .

Example 48A

Di-tert-butyl {2-oxo-2- [4- (tetrahydro-2-pyran-4-ylmethoxy) -phenyl] -ethyl} {2- [4-oxo-7- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 /) -yl] ethyl} malonate

To a solution of 500 mg (0.85 mmol) of the compound from Example 47A / Step 3 in 9 ml of acetonitrile were added 234 mg (1.69 mmol) of potassium carbonate and 182 mg (1.01 mmol) of 4- (bromomethyl) tetrahydro-2i-7-pyran given. The mixture was stirred at reflux for 16 h. Subsequently, a further 61 mg (0.34 mmol) of 4- (bromomethyl) tetrahydro-2i-7-pyran were added and the mixture was stirred for a further 20 h under reflux. After cooling to RT, 10 ml of water were added, and after stirring for a few minutes, the resulting solid was filtered off, washed twice with water and dried in vacuo. 548 mg (94% of theory) of the title compound were obtained. Ή-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.41 (d, 1H), 8.35 (s, 1H), 7.97-7.89 (m, 3H), 6.87 (d, 2H), 4.58-4.51 ( m, 2H), 4.03 (dd, 2H), 3.86 (d, 2H), 3.71 (s, 2H), 3.50-3.40 (m, 2H), 2.72-2.65 (m, 2H), 2.15-2.03 (m, 1H), 1.76 (d, 2H), 1.54-1.39 (covert, 2H), 1.47 (s, 18H).

LC / MS (Method 3, ESIpos): R _t = 3.07 min, m / z = 690 [M + H] ⁺ .

Example 49A di-tert-butyl- (2- {4- [(3-chlorobenzyl) oxy] phenyl} -2-oxoethyl) {2- [4-oxo-7- (trifluoromethyl) -1,3,3- benzotriazine-3 (AH) -yl] ethyl} malonate

To a solution of 500 mg (0.85 mmol) of the compound from Example 47 A / Step 3 in 9 ml of acetonitrile were added 234 mg (1.69 mmol) of potassium carbonate and 208 mg (1.01 mmol) of 3-chlorobenzyl given bromide. The mixture was stirred at reflux for 2 h. After cooling to RT, 10 ml of water were added, and after stirring for a few minutes, the resulting solid was filtered off, washed twice with water and dried in vacuo. 575 mg (95% of theory) of the title compound were obtained. Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.42 (d, 1H), 8.36 (s, 1H), 7.94 (d, 3H), 7.44 (s, 1H), 7.35- 7.28 (m, 3H), 6.97 (d, 2H), 5.10 (s, 2H), 4.58-4.52 (m, 2H), 3.71 (s, 2H), 2.72-2.65 (m, 2H), 1.47 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.67 min, m / z = 716 [M + H] ⁺ . Example 50A di-tert-butyl- (2- {4 - [(3-chloro-2-fluorobenzyl) oxy] phenyl} -2-oxoethyl) {2- [4-oxo-7- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 /) -yl] ethyl} malonate

To a solution of 500 mg (0.85 mmol) of the compound from Example 47 A / Step 3 in 9 ml of acetonitrile were added 234 mg (1.69 mmol) of potassium carbonate and 227 mg (1.01 mmol) of 1- (bromomethyl) -3-chloro Given 2-fluorobenzene. The mixture was stirred at reflux for 2 h. After cooling to RT, 10 ml of water were added, and after stirring for a few minutes, the resulting solid was filtered off, washed twice with water and dried in vacuo. 597 mg (96% of theory) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.42 (d, 1H), 8.36 (s, 1H), 7.95 (d, 4H), 7.44-7.36 (m, 2H), 7.13 (t, 1H), 6.98 (d, 2H), 5.20 (s, 2H), 4.59-4.50 (m, 2H), 3.72 (s, 2H), 2.72-2.65 (m, 2H), 1.48 (s, 18H).

LC / MS (Method 1, ESIpos): R _t = 1.59 min, m / z = 734 [M + H] Example 51 A

Di-tert-butyl {2- [4-oxo-7- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 //) - yl] ethyl} [2-oxo-2- (4- {[3- (trifluoromethyl) benzyl] oxy} phenyl) ethyl] malonate

To a solution of 500 mg (0.85 mmol) of the compound from Example 47A / Step 3 in 9 ml of acetonitrile were added 234 mg (1.69 mmol) of potassium carbonate and 242 mg (1.01 mmol) of 1- (bromomethyl) -3- (trifluoromethyl ) benzene. The mixture was stirred at reflux for 2 h. After cooling to RT, 10 ml of water were added, and after stirring for a few minutes, the resulting solid was filtered off, washed twice with water and dried in vacuo. 565 mg (89% of theory) of the title compound were obtained.

Ή NMR (400 MHz, CDCL): δ [ppm] = 8.42 (d, 1H), 8.36 (s, 1H), 7.98-7.91 (m, 3H), 7.71 (s, 1H), 7.66-7.58 (m , 2H), 7.56-7.49 (m, 1H), 6.98 (d, 2H), 5.17 (s, 2H), 4.59-4.51 (m, 2H), 3.72 (s, 2H), 2.73-2.64 (m, 2H ), 1.48 (s, 18H).

LC / MS (Method 3, ESIpos): R _t = 3.32 min, m / z = 750 [M + H] ⁺ . Example 52A

Di-ieri-butyl- (2- {4 - [(3,4-dichlorobenzyl) oxy] phenyl} -2-oxoethyl) {2- [4-oxo-7- (trifluoromethyl) -l, 2,3- benzotriazine-3 (4 /) -yl] ethyl} malonate

To a solution of 500 mg (0.85 mmol) of the compound from Example 47 A / Step 3 in 9 ml of acetonitrile were added 234 mg (1.69 mmol) of potassium carbonate and 243 mg (1.01 mmol) of 4- (bromomethyl) -1,2 given dichlorobenzene. The mixture was stirred at reflux for 2 h. After cooling to RT, 10 ml of water were added, and after stirring for a few minutes, the resulting solid was filtered off, washed twice with water and dried in vacuo. There were obtained 602 mg (93% of theory, purity 98%) of the title compound.

Ή-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.42 (d, 1H), 8.36 (s, 1H), 7.95 (d, 3H), 7.54 (d, 1H), 7.47 (d, 1H) , 7.29-7.23 (covert, 1H), 6.95 (d, 2H), 5.07 (s, 2H), 4.60-4.51 (m, 2H), 3.71 (s, 2H), 2.72-2.63 (m, 2H), 1.47 (s, 18H). LC / MS (Method 2, ESIpos): R _t = 1.62 min, m / z = 750 [M + H] ⁺ .

Example 53A

Di-tert-butyl- (2- {4 - [(3,4-dichlorobenzyl) oxy] phenyl} -2-oxoethyl) {2- [4-oxo-8- (trifluoromethyl) -l, 2,3- benzotriazine-3 (4 /) -yl] ethyl} malonate

A solution of 4.28 g (16.42 mmol) di-ferric butyl (2-hydroxyethyl) malonate (US Patent 6,900,194, Intermediate 5E), 6.46 g (24.64 mmol) triphenyl phosphine and 5.30 (24.64 mmol) of the compound from Example 9A in 170 ml of THF under argon was stirred for 30 min at RT, then slowly added at RT with 4.88 ml (24.64 mmol) of diisopropyl azodicarboxylate (DIAD) and then stirred overnight at RT. The solvent was then removed and the residue was purified directly by MPLC (silica gel, eluent cyclohexane / ethyl acetate 6: 1). There were obtained 3.47 g (43% of theory, purity 94%) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.53 (d, 1H), 8.44 (d, 1H), 8.05 (t, 1H), 4.46 (t, 2H), 3.45 (t, 1H), 2.27 (q, 2H), 1.37 (s, 18H). LC / MS (Method 2, ESIpos): R _t = 1.35 min, m / z = 458 [M + H] ⁺ .

Step 2:

 Di-ieri-butyl {2- [4- (benzoyloxy) phenyl] -2-oxoethyl} {2- [4-oxo-8- (trifluoromethyl) -1,3,3-benzotriazine-3 (AH ) -yl] ethyl} malonate

To a mixture of 319 mg (7.97 mmol, 60% dispersion in mineral oil) of sodium hydride in 20 ml of DMF under argon was slowly added a solution of 3.47 g (7.59 mmol) of the compound from Example 53A / Step 1 in 20 ml of DMF RT added (exothermic reaction). It was then stirred for about 30 min at 50 ° C until the evolution of gas subsided. After cooling to RT, a solution of 2.66 g (8.34 mmol) of 4- (bromoacetyl) phenylbenzoate in 20 ml of DMF was added and the mixture was stirred at RT overnight. Thereafter, a further 160 mg (3.98 mmol) of sodium hydride were added, and stirring was continued at RT for about 30 min. Then another 1.33 g (4.17 mmol) of the compound from Example 53A / Step 1 was added and the mixture was stirred again for 20 h at RT. Then the mixture was added to water and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. concentrated. The residue was purified by MPLC (silica gel, eluent cyclohexane / ethyl acetate 20: 1). 2.58 g (49% of theory) of the title compound were obtained.

LC / MS (Method 2, ESIpos): R _t = 1.52 min, m / z = 696 [M + H] ⁺ .

Step 3:

Di-ieri-butyl- [2- (4-hydroxyphenyl) -2-oxoethyl] {2- [4-oxo-8- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 //) -yl ] efhyl} malonate

To a solution of 2.58 g (3.71 mmol, not purity corrected) of the compound of Example 53A / Step 2 in a mixture of 30 ml of THF and 10 ml of methanol under argon was added 0.16 ml (0.86 mmol) of a 30% sodium methylate solution in Methanol added at RT. The mixture was stirred for 2.5 h at 50 ° C bath temperature. It was then diluted with ethyl acetate and the mixture was washed once with water. The aqueous phase was back-extracted once with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by MPLC (silica gel, eluent cyclohexane / ethyl acetate 6: 1-> 2: 1). 1.82 g (83% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 10.39 (br.s, 1H), 8.47 (d, 1H), 8.40 (d, 1H), 8.02 (t, 1H), 7.80 ( d, 2H), 6.80 (d, 2H), 4.48-4.40 (m, 2H), 3.61 (s, 2H), 2.52-2.49 (m, 2H), 1.39 (s, 18H).

LC / MS (Method 3, ESIpos): R _t = 2.72 min, m / z = 592 [M + H] ⁺ .

Step 4:

Di-tert-butyl- (2- {4 - [(3,4-dichlorobenzyl) oxy] phenyl} -2-oxoethyl) {2- [4-oxo-8- (trifluoromethyl) -l, 2,3- benzotriazine-3 (4 /) -yl] ethyl} malonate

To a solution of 300 mg (0.51 mmol) of the compound from Example 53A / Step 3 in 38 ml of acetonitrile was added 0.13 ml (1.07 mmol) of 3,4-dichlorobenzylbromide and 140 mg (1.01 mmol) of potassium carbonate. The mixture was stirred at reflux for 16 h. After cooling to RT, the mixture was diluted with ethyl acetate and washed once each with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by MPLC (silica gel, eluent cyclohexane / ethyl acetate 10: 1 to 4: 1). 333 mg (88% of theory) of the title compound were obtained. LC / MS (Method 2, ESIpos): R _t = 1.60 min, m / z = 750 [M + H] ⁺ .

Example 54A

Di-tert-butyl [2- (4-oxopyrido [3,2-d] [1,2,3] triazine-3 (4 /) -yl) ethyl] {2-oxo-2- [4- ( tetrahydro-2-pyran-4-ylmethoxy) phenyl] ethyl} malonate

Step 1:

Di-tert-butyl [2- (4-oxopyrido [3,2-d] [1,2,3] triazine-3 (4 /) -yl) -malonate

A mixture of 2.94 g (11.30 mmol) of di-ieri-butyl- (2-hydroxyethyl) malonate (US Patent 6,900,194, Intermediate 5E), 4.45 g (16.95 mmol) of triphenylphosphine and 2.51 (16.95 mmol) of the compound of Example 10A in 100 ml of THF under argon was stirred for 30 min at RT and then slowly added at RT with 3.36 ml (16.94 mmol) of diisopropyl azodicarboxylate (DIAD). After further stirring overnight, the solvent was removed, and the residue was added with 100 ml of cyclohexane and stirred for 30 minutes in the heat. The resulting solid was filtered off and the filtrate was concentrated. This residue was added again with 100 ml of cyclohexane and stirred again for 10 min in the heat. The solid was filtered off again and the filtrate was concentrated again. The resulting residue was then purified by MPLC (silica gel, eluent cyclohexane / ethyl acetate 20: 1). 4.40 g (99% of theory, still containing impurities) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 9.12 (dd, 1H), 8.62 (dd, 1H), 8.07 (dd, 1H), 4.46 (t, 2H), 3.44 (t, 1H), 2.26 (q, 2H), 1.39 (s, 18H). LC / MS (Method 2, ESIpos): R _t = 1.08 min, m / z = 391 [M + H] ⁺ .

Step 2:

 Di-ieri-butyl {2- [4- (benzoyloxy) phenyl] -2-oxoethyl} [2- (4-oxopyrido [3,2-d] [1,2,3] triazine 3 (4 / ) yl) ethyl] malonate

To a mixture of 133 mg (3.34 mmol, 60% dispersion in mineral oil) of sodium hydride in 10 ml of DMF under argon was slowly added a solution of 1.24 g (3.18 mmol) of the compound from Example 54A / Step 1 in 10 ml of DMF RT added (exothermic reaction). It was then stirred for about 30 min at RT until the evolution of gas subsided. Then a solution of 1.22 g (3.81 mmol) of 4- (bromoacetyl) phenylbenzoate in 10 ml of DMF was added and the mixture was stirred at RT for 1 h. Then the mixture was added to water and extracted three times 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 dichloromethane / methanol 100: 1). After combining the product-containing fractions and removing the solvent, the residue was stirred in diethyl ether. The resulting solid was filtered off and dried in vacuo. 1.07 g (53% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 9.11 (dd, 1H), 8.59 (dd, 1H), 8.17 (d, 2H), 8.09 (d, 2H), 8.05 (dd, 1H), 7.81-7.75 (m, 1H), 7.67-7.61 (m, 2H), 7.47 (d, 2H), 4.52-4.45 (m, 2H), 3.77 (s, 2H), 2.74-2.67 (obscured, 2H), 1.42 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.37 min, m / z = 629 [M + H] ⁺ .

Step 3:

 Di-tert-butyl- [2- (4-hydroxyphenyl) -2-oxoethyl] [2- (4-oxopyrido [3,2-d] [1,2,3] triazine-3 (4 /) -yl ) - ethyl] malonate

To a solution of 1.07 g (1.58 mmol, purity 93%) of the compound from Example 54 A / Step 2 in a mixture of 20 ml of THF and 70 ml of methanol under argon was added 90 μΐ (0.48 mmol) of a 30% sodium methylate. Solution in methanol at RT added. The mixture was stirred for 35 minutes at 50 ° C bath temperature. It was then diluted with ethyl acetate and the solution was washed once with water. The aqueous phase was extracted once with ethyl acetate. H, and the combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 905 mg (99% of theory, purity 92%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 10.40 (br.s, 1H), 9.09 (dd, 1H), 8.57 (dd, 1H), 8.04 (dd, 1H), 7.82 ( d, 2H), 6.82 (d, 2H), 4.46-4.40 (m, 2H), 3.61 (s, 2H), 2.56-2.45 (covert, 2H), 1.39 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.08 min, m / z = 525 [M + H] ⁺ . Step 4:

 Di-tert-butyl [2- (4-oxopyrido [3,2-d] [1,2,3] triazine-3 (4 /) -yl) ethyl] {2-oxo-2- [4- (tetrahydro-2-pyran-4-ylmethoxy) phenyl] ethyl} malonate

To a solution of 250 mg (0.48 mmol) of the compound of Example 54A / Step 3 in 35 ml of acetonitrile was added 179 mg (1.00 mmol) of 4- (bromomethyl) tetrahydropyran and 131 mg (0.95 mmol) of potassium carbonate. The mixture was stirred at reflux for 16 h. After cooling to RT, the mixture was diluted with ethyl acetate and washed once each with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. 344 mg (> 100% of theory, still contaminated) of the title compound were obtained.

LC / MS (Method 2, ESIpos): R _t = 1.29 min, m / z = 623 [M + H] ⁺ . Example 55A

Di-tert-butyl [2- (4-oxopyrido [3,2-d] [1,2,3] triazine-3 (4 /) -yl) ethyl] [2-oxo-2- (4- {[3- (trifluoromethyl) benzyl] oxy} phenyl) ethyl] malonate

To a solution of 250 mg (0.48 mmol) of the compound from Example 54A / Step 3 in 35 ml of acetonitrile was added 132 mg (0.95 mmol) of potassium carbonate and 239 mg (1.00 mmol) of 1- (bromomethyl) -3- (trifluoromethyl) given benzene. The mixture was refluxed overnight. After cooling to RT, ethyl acetate was added and the mixture was washed successively with water, saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 627 mg (> 100% of theory, still contaminated) of the title compound were obtained. LC / MS (Method 2, ESIpos): R _t = 1.47 min, m / z = 683 [M + H] ⁺ .

Example 56A

Di-tert-butyl- (2- {4- [(3-chlorobenzyl) oxy] phenyl} -2-oxoethyl) [2- (4-oxopyrido [3,2-d] [1,2,3] triazine - 3 (4 /) - yl) ethyl] malonate

To a solution of 250 mg (0.48 mmol) of the compound of Example 54A / Step 3 in 35 ml of acetonitrile were added 132 mg (0.95 mmol) of potassium carbonate and 206 mg (1.00 mmol) of 1- (bromomethyl) -3-chlorobenzene. The mixture was stirred at reflux overnight. After cooling to RT, ethyl acetate was added and the mixture was washed successively with water, saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by MPLC (silica gel, eluent cyclohexane / ethyl acetate 4: 1-1: 1). There were obtained 271 mg (88% of theory) of the title compound.

Ή NMR (400 MHz, DMSO-de): δ [ppm] = 9.09 (dd, 1H), 8.56 (dd, 1H), 8.03 (dd, 1H), 7.93 (d, 2H), 7.55 (s, 1H ), 7.47-7.39 (m, 3H), 7.09 (d, 2H), 5.23 (s, 2H), 4.48-4.41 (m, 2H), 3.66 (s, 2H), 2.55-2.47 (obscured, 2H), 1.40 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.43 min, m / z = 649 [M + H] ⁺ . Example 57A

Di-ieri-butyl {2- [4- ({3- [(methoxycarbonyl) amino] benzyl} oxy) phenyl] -2-oxoethyl} [2- (4-pyrido [3,2-d] [l , 2,3] triazin-3 (4 //) - yl) ethyl] malonate

To a solution of 250 mg (0.48 mmol) of the compound of Example 54A / Step 3 in 30 mL of acetonitrile was added 132 mg (0.95 mmol) of potassium carbonate and 244 mg (1.00 mmol) of the compound of Example IA. The mixture was stirred at reflux overnight. After cooling to RT, ethyl acetate was added and the mixture was washed successively with water, saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by MPLC (silica gel, eluent cyclohexane / ethyl acetate 1: 1- 1: 2-> 1: 4). 175 mg (51% of theory, purity 96%) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 9.73-9.70 (m, 1H), 9.09 (dd, 1H), 8.55 (dd, 1H), 8.03 (dd, 1H), 7.90 ( d, 2H), 7.58 (s, 1H), 7.42 (d, 1H), 7.31 (t, 1H), 7.11-7.03 (m, 3H), 5.16 (s, 2H), 4.47-4.41 ( _m , 2H) , 3.66 (s, 3H), 3.65 (s, 2H), 2.52-2.49 (m, 2H), 1.40 (s, 18H).

LC / MS (Method 1, ESIpos): R _t = 1.28 min, m / z = 688 [M + H] ⁺ . Example 58A

Di-ieri-butyl- (2-oxo-2- {4 - [(tetrahydro-2-pyran-4-ylmethyl) sulfanyl] phenyl} ethyl) {2- (trifluoromethyl) -1,3,3-benzotriazine -3 (4 /) - yl] ethyl} malonate

A solution of 1.94 g (4.24 mmol) of the compound from Example 32A / Step 1 in a mixture of 30 ml of THF and 5 ml of DMF under argon was stirred for 10 minutes with addition of molecular sieve. Subsequently, 212 mg (5.30 mmol, 60% dispersion in mineral oil) of sodium hydride were added and the mixture stirred for 30 minutes at RT. Then a solution of 2.15 g (4.24 mmol) of the compound from Example 14A in 10 ml of THF was added rapidly at RT and the mixture was stirred for a further 10 minutes. Thereafter, the mixture was added with methanol and concentrated. The residue was taken up in ethyl acetate, washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluent cyclohexane / ethyl acetate 20: 1). The combined product-containing fractions were concentrated and the residue was re-purified by preparative HPLC (mobile phase gradient acetonitrile / water 70: 30-50: 50). This gave 500 mg (17% of theory) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.43 (s, 1H), 8.40-8.32 (m, 2H), 7.83 (d, 2H), 7.36 (d, 2H), 4.50- 4.41 (m, 2H), 3.84 (dd, 2H), 3.66 (s, 2H), 3.31-3.20 (m, 2H), 3.01 (d, 2H), 2.55-2.48 (covert, 2H), 1.77-1.69 ( m, 3H), 1.40 (s, 18H), 1.34-1.22 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 1.55 min, m / z = 706 [M + H] ⁺ . Embodiments:

example 1

(+/-) - 4- {4- [(3-methylbenzyl) oxy] phenyl} -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 //) -yl) ethyl] butanoic acid

A solution of 508 mg (0.81 mmol) of the compound of Example 15A / Step 4 in 10 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was heated to reflux for 2 hours with stirring. After cooling to RT, the solvent was removed and the residue was triturated with acetonitrile. The solid formed was filtered off, washed with a little pentane and dried in vacuo. There were obtained 321 mg (80% of theory, purity 95%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, 1H), 8.26 (d, 1H), 8.21 (d, 1H), 8.12-8.06 (m, 1H), 7.98-7.90 (m, 3H), 7.32-7.23 (m, 3H), 7.16 (d, 1H), 7.11 (d, 2H), 5.17 (s, 2H), 4.58-4.43 (m, 2H), 3.47- 3.38 (m, 1H), 3.27-3.19 (m, 1H), 2.96-2.87 (m, 1H), 2.26-2.15 (m, 1H), 2.10-1.98 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.14 min, m / z = 472 [M + H] ⁺ . Separation of the enantiomers:

 216 mg of the compound from Example 1 were dissolved in 29 ml of a mixture of isopropanol, acetonitrile and acetone while warm and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 2 and 3) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 210 nm; Injection volume: 0.5 ml; Temperature: 40 ° C; Eluent: t = 0-6.4 min 30% acetonitrile + 0.2% acetic acid / 70% isopropanol + 0.2% acetic acid]:

Example 2

(-) - 4- {4 - [(3-methylbenzyl) oxy] phenyl} -4-oxo-2- [2- (4-oxo-l, 2,3-benzotriazin-3 (4ii) -yl) ethyl ] - butanoic acid (enantiomer 1) Yield: 87 mg; ee value = 100%

[a] _D ²⁰ = -28.2 °, 589 nm, c = 0.34 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.30 (br.s, IH), 8.25 (d, IH), 8.21 (d, IH), 8.12-8.06 (m, IH), 7.98 -7.90 (m, 3H), 7.32-7.22 (m, 3H), 7.16 (d, IH), 7.11 (d, 2H), 5.17 (s, 2H), 4.58-4.43 (m, 2H), 3.47-3.38 (m, IH), 3.27-3.18 (m, IH), 2.96-2.87 (m, IH), 2.26-2.15 (m, IH), 2.10-1.99 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.15 min, m / z = 472 [M + H] ⁺ . Example 3

(+) - 4- {4 - [(3-Methylbenzyl) oxy] phenyl} -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 //) -yl] ) efhyl] butanoic acid (enantiomer 2)

Yield: 90 mg; ee value = 96%

[a] _D ²⁰ = + 24.95 °, 589 nm, c = 0.33 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, IH), 8.26 (d, IH), 8.21 (d, IH), 8.12-8.06 (m, IH), 7.98-7.91 (m, 3H), 7.31-7.22 (m, 3H), 7.16 (d, IH), 7.11 (d, 2H), 5.17 (s, 2H), 4.57-4.43 (m, 2H), 3.46- 3.38 (m, IH), 3.27-3.19 (m, IH), 2.96-2.86 (m, IH), 2.26-2.15 (m, IH), 2.10-1.99 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.15 min, m / z = 472 [M + H] ⁺ . Example 4

(+/-) - 4- (4- {[3-chloro-4- (trifluoromethoxy) benzyl] oxy} phenyl) -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine - 3 (4 //) - yl) ethyl] butanoic acid

A solution of 493 mg (0.77 mmol, purity 95%) of the compound from Example 16A in 10 ml of a 4 N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently The mixture was heated to reflux with stirring for 3 hours. After cooling to RT, a solid crystallized out. It was added ieri.-butyl methyl ether and stirred for about 30 min. The solid was filtered off to give, after drying in vacuo, 253 mg (57% of theory) of the title compound. After concentration by recrystallization, a further 177 mg (35% of theory, purity 89%) of the title compound were obtained from the mother liquor.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, 1H), 8.27-8.24 (m, 1H), 8.21 (d, 1H), 8.09 (td, 1H), 8.00-7.91 (m, 4H), 7.82-7.76 (m, 2H), 7.14 (d, 2H), 5.32 (s, 2H), 4.58-4.43 (m, 2H), 3.48- 3.39 (m, 1H), 3.28-3.21 (m, 1H), 2.96-2.87 (m, 1H), 2.26-2.15 (m, 1H), 2.11-1.99 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.23 min, m / z = 576 [M + H] ⁺ . Separation of the enantiomers:

 318 mg of the compound from Example 4 were dissolved in 15 ml of a mixture of acetonitrile, methanol and acetone and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 5 and 6) [column: Daicel Chiralpak AD-H, 5 μιη, 250 mm x 20 mm; Flow: 25 ml / min; Detection: 210 nm; Injection volume: 1.5 ml; Temperature: 40 ° C; Eluent: t = 0-9 min 30% acetonitrile + 0.2% acetic acid / 70% methanol + 0.2% acetic acid]:

Example 5

(-) - 4- (4- {[3-Chloro-4- (trifluoromethoxy) benzyl] oxy} phenyl) -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) - yl) ethyl] butanoic acid (enantiomer 1)

Yield: 134 mg; ee value = 100% [a] _D ²⁰ = -24.0 °, 589 nm, c = 0.35 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.29 (br.s, 1H), 8.26 (dd, 1H), 8.21 (d, 1H), 8.09 (td, 1H), 8.00- 7.90 (m, 4H), 7.82-7.76 (m, 2H), 7.14 (d, 2H), 5.32 (s, 2H), 4.58-4.43 (m, 2H), 3.48-3.39 (m, 1H), 3.28- 3.19 (m, 1H), 2.96-2.87 (m, 1H), 2.26-2.14 (m, 1H), 2.10-1.99 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.26 min, m / z = 576 [M + H] ⁺ . Example 6

(+) - 4- (4- {[3-chloro-4- (trifluoromethoxy) benzyl] oxy} phenyl) -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) - yl) ethyl] butanoic acid (enantiomer 2)

Yield: 137 mg; ee value = 100% [a] _D ²⁰ = + 18.1 °, 589 nm, c = 0.32 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.27 (br.s, 1H), 8.27-8.24 (m, 1H), 8.21 (d, 1H), 8.12-8.06 (m, 1H ), 8.00-7.91 (m, 4H), 7.82-7.75 (m, 2H), 7.14 (d, 2H), 5.32 (s, 2H), 4.58-4.43 (m, 2H), 3.48-3.38 (m, 1H ), 3.28-3.20 (m, 1H), 2.97-2.86 (m, 1H), 2.27-2.15 (m, 1H), 2.10-1.99 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.24 min, m / z = 576 [M + H] ⁺ . Example 7

(+/-) - 4- (4- {[4-chloro-3- (trifluoromethyl) benzyl] oxy} phenyl) -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine - 3 (4 //) - yl) ethyl] butanoic acid

A solution of 595 mg (0.82 mmol, purity 99%) of the compound from Example 17A in 10 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. The mixture was then heated to reflux for 4.5 h with stirring. After cooling to RT, concentration and standing overnight, a solid had crystallized out. It was added acetonitrile and stirred for about 30 min. The solid was filtered off to give, after drying in vacuo, 306 mg (62% of theory, purity 94%) of the title compound.

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.31 (br.s, 1H), 8.26 (dd, 1H), 8.21 (d, 1H), 8.09 (td, 1H), 8.00-7.91 (m, 3H), 7.82 (d, 1H), 7.65-7.55 (m, 2H), 7.16-7.10 (m, 2H), 5.27 (s, 2H), 4.58-4.42 (m, 2H), 3.48-3.39 (m, 1H), 3.28-3.19 (m, 1H), 2.97-2.86 (m, 1H), 2.27-2.15 (m, 1H), 2.11-1.98 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.23 min, m / z = 560 [M + H] ⁺ . Separation of the enantiomers:

218 mg of the compound from Example 7 were dissolved in 18 ml of a mixture of acetonitrile, methanol and acetone in the heat and separated by preparative HPLC on a chiral phase into the enantiomers (see Examples 8 and 9) [column: Daicel Chiralpak AD- H, 5 μιη, 250 mm x 20 mm; Flow: 20 ml / min; Detection: 210 nm; Injection volume: 0.75 ml; Temperature: 40 ° C; Eluent: t = 0-6.7 min. 30% acetonitrile + 0.2% acetic acid / 70% methanol + 0.2% acetic acid]:

Example 8

(-) - 4- (4- {[4-Chloro-3- (trifluoromethyl) benzyl] oxy} phenyl) -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 //) - yl) ethyl] butanoic acid (enantiomer 1)

Yield: 98 mg; ee value = 100%

[a] _D ²⁰ = -23.2 °, 589 nm, c = 0.32 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.33 (br.s, IH), 8.26 (dd, IH), 8.21 (d, IH), 8.09 (td, IH), 8.00- 7.90 (m, 3H), 7.82 (d, IH), 7.65-7.55 (m, 2H), 7.13 (d, 2H), 5.27 (s, 2H), 4.58-4.42 (m, 2H), 3.48-3.38 ( m, IH), 3.28-3.19 (m, IH), 2.96-2.87 (m, IH), 2.27-2.14 (m, IH), 2.10-1.99 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.24 min, m / z = 560 [M + H] ⁺ . Example 9

(+) - 4- (4- {[4-Chloro-3- (trifluoromethyl) benzyl] oxy} phenyl) -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) - yl) ethyl] butanoic acid (enantiomer 2)

Yield: 106 mg; ee value = 97%

[from ²⁰ = + 20.3 °, 589 nm, c = 0.31 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, IH), 8.26 (dd, IH), 8.21 (d, IH), 8.09 (td, IH), 8.00- 7.90 (m, 3H), 7.82 (d, IH), 7.65-7.55 (m, 2H), 7.13 (d, 2H), 5.27 (s, 2H), 4.58-4.42 (m, 2H), 3.48-3.39 ( m, IH), 3.28-3.20 (m, IH), 2.96-2.86 (m, IH), 2.27-2.15 (m, IH), 2.11-1.98 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.24 min, m / z = 560 [M + H] ⁺ . Example 10

(+/-) - 4- (4- {[4-chloro-3- (trifluoromethoxy) benzyl] oxy} phenyl) -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine - 3 (4 /) - yl) ethyl] butanoic acid

A solution of 576 mg (0.79 mmol) of the compound from Example 18A in 10 ml of a 4 N solution of hydrogen chloride in dioxane was stirred at RT overnight. The mixture was then heated to reflux for 2.5 h with stirring. After cooling to RT and concentration, a little acetonitrile was added and the mixture allowed to stand overnight. The resulting solid was filtered off to give, after drying in vacuo, 398 mg (88% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, IH), 8.26 (dd, IH), 8.21 (d, IH), 8.09 (td, IH), 8.00- 7.91 (m, 3H), 7.82 (d, IH), 7.65-7.55 (m, 2H), 7.13 (d, 2H), 5.27 (s, 2H), 4.58-4.43 (m, 2H), 3.48-3.39 ( m, IH), 3.28-3.20 (m, IH), 2.96-2.87 (m, IH), 2.26-2.15 (m, IH), 2.11-1.99 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.26 min, m / z = 576 [M + H] ⁺ . Separation of the enantiomers:

 325 mg of the compound from Example 10 were dissolved in 8 ml of a mixture of ethanol and acetonitrile and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 11 and 12) [column: Daicel Chiralpak AD-H, 5 μιη, 250 mm x 20 mm; Flow: 20 ml / min; Detection: 280 nm; Injection volume: 0.10 ml; Temperature: 25 ° C; Eluent: t = 0-10 min 30% acetonitrile + 0.2% acetic acid / 70% methanol + 0.2% acetic acid]:

Example 11

(-) - 4- (4- {[4-Chloro-3- (trifluoromethoxy) benzyl] oxy} phenyl) -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) - yl) ethyl] butanoic acid (enantiomer 1)

Yield: 128 mg; after dissolving this material in dichloromethane and re-drying, 92 mg were obtained. ee value = 100%.

[a] _D ²⁰ = -21.1 °, 589 nm, c = 0.34 g / 100 ml, chloroform Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.19 (br.s, IH), 8.26 (d, IH), 8.21 (d, IH), 8.12-8.06 (m, IH), 8.00-7.90 (m, 3H), 7.82 (d, IH), 7.65-7.55 (m, 2H), 7.13 (d, 2H), 5.26 (s, 2H), 4.58-4.42 (m, 2H), 3.48- 3.38 (m, IH), 3.27-3.18 (m, IH), 2.96-2.84 (m, IH), 2.26-2.12 (m, IH), 2.11-1.97 (m, IH). LC / MS (Method 2, ESIpos): R _t = 1.25 min, m / z = 576 [M + H] ⁺ . Example 12

(+) - 4- (4- {[4-Chloro-3- (trifluoromethoxy) benzyl] oxy} phenyl) -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 //) - yl) ethyl] butanoic acid (enantiomer 2)

Yield: 123 mg; ee value = 99% [α] _D ²⁰ = + 15.2 °, 589 nm, c = 0.32 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.27 (brs s, IH), 8.26 (dd, IH), 8.21 (d, IH), 8.09 (td, IH), 8.00- 7.90 (m, 3H), 7.82 (d, IH), 7.65-7.55 (m, 2H), 7.13 (d, 2H), 5.26 (s, 2H), 4.58-4.42 (m, 2H), 3.48-3.39 ( m, IH), 3.27-3.18 (m, IH), 2.96-2.86 (m, 2H), 2.26-2.13 (m, IH), 2.10-1.98 (m, IH). LC / MS (Method 2, ESIpos): R _t = 1.25 min, m / z = 576 [M + H] ⁺ .

Example 13

(+/-) - 4- (4- {[4-Methyl-3- (trifluoromethyl) benzyl] oxy} phenyl) -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine - 3 (4 //) - yl) ethyl] butanoic acid

A solution of 566 mg (0.81 mmol) of the compound of Example 19A in 11 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was heated to reflux with stirring for 3 h. After cooling to RT and concentration, a little acetonitrile was added and the mixture allowed to stand overnight. The resulting solid was filtered off to give, after drying in vacuo, 325 mg (74% of theory) of the title compound. Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, IH), 8.26 (dd, IH), 8.21 (d, IH), 8.09 (td, IH), 7.99- 7.91 (m, 3H), 7.78 (s, IH), 7.66 (d, IH), 7.48 (d, IH), 7.12 (d, 2H), 5.27 (s, 2H), 4.58-4.33 (m, 2H) , 3.47-3.38 (m, IH), 3.28-3.20 (m, IH), 2.97-2.87 (m, IH), 2.45 (s, 3H), 2.26-2.15 (m, IH), 2.10-1.99 (m, IH). LC / MS (Method 2, ESIpos): R _t = 1.25 min, m / z = 540 [M + H] ⁺ .

Separation of the enantiomers:

 274 mg of the compound from Example 13 were dissolved in 18 ml of a mixture of acetonitrile, ethanol and dioxane and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 14 and 15) [column: Daicel Chiralpak AD-H, 5 μιη, 250 mm x 20 mm; Flow: 20 ml / min; Detection: 210 nm; Injection volume: 3.5 ml; Temperature: 40 ° C; Eluent: t = 0-8 min 30% acetonitrile + 0.2% acetic acid / 70% ethanol + 0.2% acetic acid]:

Example 14

(-) - 4- (4- {[4-Methyl-3- (trifluoromethyl) benzyl] oxy} phenyl) -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) - yl) ethyl] butanoic acid (enantiomer 1) Yield: 125 mg; ee value = 100%

[a] _D ²⁰ = -28.0 °, 589 nm, c = 0.30 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-de): δ [ppm] = 12.31 (br.s, IH), 8.26 (d, IH), 8.21 (d, IH), 8.12-8.06 (m, IH), 7.99 -7.90 (m, 3H), 7.78 (s, IH), 7.66 (d, IH), 7.48 (d, IH), 7.13 (d, 2H), 5.27 (s, 2H), 4.58-4.42 (m, 2H ), 3.48-3.38 (m, IH), 3.28-3.20 (m, IH), 2.96-2.87 (m, IH), 2.45 (s, 3H), 2.26- 2.15 (m, IH), 2.10-1.99 (m , IH).

LC / MS (Method 2, ESIpos): R _t = 1.28 min, m / z = 540 [M + H] ⁺ .

Example 15

(+) - 4- (4- {[4-Methyl-3- (trifluoromethyl) benzyl] oxy} phenyl) -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) - yl) ethyl] butanoic acid (enantiomer 2) Yield: 128 mg; ee value = 96%

[a] _D ²⁰ = + 22.9 °, 589 nm, c = 0.35 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (br.s, IH), 8.26 (dd, IH), 8.21 (d, IH), 8.09 (td, IH), 7.99- 7.91 (m, 3H), 7.78 (s, IH), 7.66 (d, IH), 7.48 (d, IH), 7.13 (d, 2H), 5.27 (s, 2H), 4.58- 4.42 (m, 2H), 3.47-3.39 (m, 1H), 3.28-3.20 (m, 1H), 2.96-2.87 (m, 1H), 2.45 (s, 3H), 2.26-2.15 (m, 1H), 2.10-1.99 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.28 min, m / z = 540 [M + H] ⁺ . Example 16 (+/-) - 4- {4- [(3,4-Dichlorobenzyl) oxy] phenyl} -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 ( 4 //) - yl) efhyl] butanoic acid

A solution of 2.25 g (3.23 mmol, purity 98%) of the compound from Example 20A in 33 ml of a 4 N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was heated to reflux with stirring for 3 h. After cooling to RT and concentration, the residue was dissolved in a little ethyl acetate and washed with tert. Butyl methyl ether. The solid which formed with stirring was filtered off after about 1 h and washed once with tert. -Butyl methyl ether washed. After drying in vacuo, 1.40 g (80% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (br.s, 1H), 8.26 (d, 1H), 8.21 (d, 1H), 8.12-8.06 (m, 1H), 7.99-7.90 (m, 3H), 7.76 (d, 1H), 7.68 (d, 1H), 7.47 (dd, 1H), 7.12 (d, 2H), 5.23 (s, 2H), 4.58-4.43 (m, 2H), 3.48-3.39 (m, 1H), 3.28-3.19 (m, 1H), 2.96-2.87 (m, 1H), 2.27-2.15 (m, 1H), 2.11-1.97 (m, 1H).

LC / MS (Method 3, ESIpos): R _t = 2.59 min, m / z = 526 [M + H] ⁺ . Separation of the enantiomers:

1.30 g of the compound from Example 16 were dissolved in a mixture of 20 ml of THF, 20 ml of acetone and 20 ml of acetonitrile and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 17 and 18) [column: Daicel Chiralpak IA, 5 μιη, 250 mm x 20 mm; Flow: 20 ml / min; Detection: 280 nm; Injection volume: 0.3 ml; Temperature: 25 ° C; Eluent: t = 0-8 min 30% acetonitrile / 70% acetone + 0.2% acetic acid]: Example 17

(-) - 4- {4 - [(3,4-Dichlorobenzyl) oxy] phenyl} -4-oxo-2- [2- (4-oxo-1,2-benzotriazine-3 (4 /) -yl) ethyl] butanoic acid (enantiomer 1)

There were obtained 650 mg of the title compound as an oil. The substance was dissolved in a little ethyl acetate and washed with tert. Butyl methacrylate. Trituration gave a solid which, after filtering and drying, gave 496 mg of the title compound. ee value = 100%.

[a] _D ²⁰ = -27.6 °, 589 nm, c = 0.32 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 11.99 (brs s, IH), 8.25 (d, IH), 8.21 (d, IH), 8.09 (t, IH), 7.99- 7.90 (m, 3H), 7.76 (s, IH), 7.68 (d, IH), 7.47 (d, IH), 7.12 (d, 2H), 5.23 (s, 2H), 4.59-4.41 (m, 2H) , 3.48-3.38 (m, IH), 3.27-3.17 (m, IH), 2.95-2.86 (m, IH), 2.27-2.14 (m, IH), 2.10-1.99 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.23 min, m / z = 526 [M + H] ⁺ . Example 18

(+) - 4- {4 - [(3,4-Dichlorobenzyl) oxy] phenyl} -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) - yl) ethyl] butanoic acid (enantiomer 2)

There were obtained 554 mg of the title compound as an oil. The substance was dissolved in a little ethyl acetate and washed with tert. Butyl methacrylate. Trituration gave a solid which, after filtering and drying, gave 501 mg of the title compound. ee value = 99%.

[a] _D ²⁰ = + 26.6 °, 589 nm, c = 0.32 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.18 (br.s, IH), 8.26 (d, IH), 8.21 (d, IH), 8.09 (t, IH), 8.00-7.89 (m, 3H), 7.76 (s, IH), 7.68 (d, IH), 7.47 (d, IH), 7.12 (d, 2H), 5.23 (s, 2H), 4.50 (dd, 2H), 3.48-3.37 (m, IH), 3.28-3.16 (m, IH), 2.96-2.83 (m, IH), 2.27- 2.14 (m, IH), 2.10-1.97 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.23 min, m / z = 526 [M + H] ⁺ . Example 19

(+/-) - 4-Oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4- (4- {[6- (trifluoromethyl ) pyridin-3-yl] -methoxy} phenyl) butanoic acid

To the 275 mg (0.40 mmol, not purity-corrected) compound of Example 21A was added 4 mL of a 1: 1 mixture of dichloromethane and trifluoroacetic acid cooled to 0 ° C. The mixture was stirred at RT for 1 h. After concentration, the residue was added twice in succession with toluene and concentrated again. The residue was then taken up in 4 ml of dioxane and heated to reflux with stirring for 3 h. After concentration, the residue was taken up in a little acetonitrile and purified by preparative HPLC (Method 8). 125 mg (59% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.32 (br.s, 1H), 8.89 (s, 1H), 8.26 (d, 1H), 8.23-8.16 (m, 2H), 8.12 -8.07 (m, 1H), 8.01-7.91 (m, 4H), 7.16 (d, 2H), 5.40 (s, 2H), 4.58-4.43 (m, 2H), 3.48- 3.39 (m, 1H), 3.29 -3.21 (m, 1H), 2.96-2.88 (m, 1H), 2.27-2.15 (m, 1H), 2.11-1.99 (m, 1H).

LC / MS (Method 4, ESIpos): R _t = 1.31 min, m / z = 527 [M + H] ⁺ .

Separation of the enantiomers:

 100 mg of the compound from Example 19 were dissolved in 10 ml of acetone and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 20 and 21) [column: Daicel Chiralpak IA, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 280 nm; Injection volume: 0.5 ml; Temperature: 25 ° C; Eluent: t = 0-10 min 70% acetonitrile / 30% acetone + 0.2% acetic acid]:

Example 20 (-) - 4-Oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4- (4- {[6- (trifluoromethyl ) pyridin-3-yl] -methoxy} phenyl) butanoic acid (enantiomer 1)

Yield: 35 mg; ee value = 100%

[a] _D ²⁰ = -4.6 °, 589 nm, c = 0.31 g / 100 ml, acetonitrile Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (br.s, 1H), 8.89 (s, 1H), 8.26 (d, 1H), 8.20 (t, 2H), 8.09 ( t, 1H), 8.01-7.90 (m, 4H), 7.16 (d, 2H), 5.40 (s, 2H), 4.58-4.43 (m, 2H), 3.48-3.39 (m, 1H), 3.28-3.20 ( m, 1H), 2.97-2.87 (m, 1H), 2.27-2.15 (m, 1H), 2.10-1.99 (m, 1H).

LC / MS (Method 3, ESIpos): R _t = 2.28 min, m / z = 527 [M + H] ⁺ . Example 21

(+) - 4-Oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4- (4- {[6- (trifluoromethyl) pyridine 3-yl] -methoxy} phenyl) butanoic acid (enantiomer 2)

Yield: 33 mg; ee value = 98%

[from ²⁰ = + 4.5 °, 589 nm, c = 0.31 g / 100 ml, acetonitrile Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.27 (br. s, 1H), 8.89 (s , 1H), 8.26 (d, 1H), 8.20 (t, 2H), 8.09 (t, 1H), 8.01-7.89 (m, 4H), 7.16 (d, 2H), 5.40 (s, 2H), 4.59- 4.41 (m, 2H), 3.49-3.39 (m, 1H), 3.29-3.18 (m, 1H), 2.97-2.87 (m, 1H), 2.28-2.15 (m, 1H), 2.11-1.99 (m, 1H ).

LC / MS (Method 3, ESIpos): R _t = 2.28 min, m / z = 527 [M + H] ⁺ .

Example 22 (+/-) - 4-Oxo-2- [2- (4-oxo-l, 2,3-benzotriazine-3 (4 /) -yl) ethyl] -4- [4- (tetrahydro-2ii pyran-4-ylmethoxy) phenyl] butanoic acid

To 635 mg (1.02 mmol) of the compound of Example 22A was added 11 mL of a 10: 1 mixture of dichloromethane and trifluoroacetic acid. The mixture was stirred at RT overnight. The mixture was then concentrated and the residue was taken up in 10 ml of dioxane and heated to reflux for 5 h with stirring. After cooling and concentration, the residue was purified by flash chromatography (silica gel, eluent cyclohexane / ethyl acetate 1: 2). There were obtained 349 mg (71% of theory, purity 97%) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.06 (br.s, 1H), 8.26 (d, 1H), 8.21 (d, 1H), 8.09 (t, 1H), 7.98- 7.90 (m, 3H), 7.03 (d, 2H), 4.58-4.41 (m, 2H), 3.93 (d, 2H), 3.88 (ddd, 2H), 3.47-3.30 (partially obscured, 3H), 3.27-3.18 (m, 1H), 2.96-2.87 (m, 1H), 2.27-2.14 (m, 1H), 2.10-1.98 (m, 2H), 1.68 (d, 2H), 1.41-1.27 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 0.92 min, m / z = 466 [M + H] ⁺ .

Separation of the enantiomers:

 350 mg of the compound from Example 22 were dissolved in a mixture of 5 ml of acetonitrile and 3 ml of acetone and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 23 and 24) [column: Daicel Chiralpak IA, 5 μm, 250 mm x 20 mm; Flow: 30 ml / min; Detection: 280 nm; Injection volume: 0.06 ml; Temperature: 25 ° C; Eluent: t = 0-12 min 50% isohexane / 50% acetone + 0.2% acetic acid]:

Example 23

(-) - 4-Oxo-2- [2- (4-oxo-l, 2,3-benzotriazine-3 (4 /) -yl) ethyl] -4- [4- (tetrahydro-2ii-pyran-4 -ylmethoxy) - phenyl] butanoic acid (enantiomer 1) Yield: 79 mg; ee value = 100%

[a] _D ²⁰ = -23.1 °, 589 nm, c = 0.39 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 11.51 (br.s, 1H), 8.25 (d, 1H), 8.20 (d, 1H), 8.09 (t, 1H), 7.97-7.90 (m, 3H), 7.03 (d, 2H), 4.58-4.41 (m, 2H), 3.93 (d, 2H), 3.88 (dd, 2H), 3.47-3.32 (partially occluded, 3H), 3.23-3.14 ( m, 1H), 2.93-2.84 (m, 1H), 2.26-2.14 (m, 1H), 2.09-1.97 (m, 2H), 1.68 (d, 2H), 1.40-1.27 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 0.95 min, m / z = 466 [M + H] ⁺ .

Single crystal X-ray analysis performed on this enantiomer gave an R configuration for the chiral carbon atom of the compound. The crystal data obtained here are given in the following table (for method description see introductory section of the Experimental Section). Crystal data from X-ray diffraction analysis for Example 23:

 Example 24

(+) - 4-Oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4- [4- (tetrahydro-2ii-pyran-4 -ylmethoxy) phenyl] butanoic acid (enantiomer 2)

Yield: 143 mg; ee value = 99%

[from ²⁰ = + 19.0 °, 589 nm, c = 0.40 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 11.72 (br.s, 1H), 8.25 (d, 1H), 8.22-8.18 (m, 1H), 8.09 (t, 1H), 7.97-7.89 (m, 3H), 7.03 (d, 2H), 4.57-4.41 (m, 2H), 3.93 (d, 2H), 3.88 (dd, 2H), 3.47-3.29 (m, 3H), 3.23- 3.13 (m, 1H), 2.92-2.84 (m, 1H), 2.24-2.13 (m, 1H), 2.08-1.96 (m, 2H), 1.68 (d, 2H), 1.41-1.23 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 0.95 min, m / z = 466 [M + H] ⁺ . Example 25

(+/-) - 2- [2- (6-Fluoro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) -4- [4 - ({3 - [( methoxycarbonyl) amino] - benzyl} oxy) phenyl] -4-oxobutanoic acid

A solution of 372 mg (0.62 mmol) of the compound from Example 23 A in 7.5 ml of dioxane was heated to reflux for 4 h with stirring. After cooling to RT and removal of the solvent, the residue was purified by column chromatography (120 g of silica gel, eluent dichloromethane / methanol 95: 5, Interchim). After drying in vacuo, 239 mg (67% of theory, purity 96%) of the title compound were obtained.

Ή-NMR (400 MHz, CDCb): δ [ppm] = 8.19 (ddd, 1H), 7.96 (dd, 1H), 7.91 (d, 2H), 7.64 (td, 1H), 7.50 (br. S, 1H ), 7.32 (d, 2H), 7.14-7.09 (m, 1H), 6.97 (d, 2H), 6.78 (br s, 1H), 5.10 (s, 2H), 4.62 (t, 2H), 3.78 ( s, 3H), 3.54-3.45 (m, 1H), 3.24-3.13 (m, 2H), 2.47-2.32 (m, 1H), 2.26-2.15 (m, 1H). LC / MS (Method 1, ESIpos): R _t = 1.01 min, m / z = 549 [M + H] ⁺ .

Separation of the enantiomers:

 190 mg of the compound from Example 25 were dissolved in 4 ml of acetonitrile and separated by preparative HPLC on a chiral phase into the enantiomers (see Examples 26 and 27) [column: Daicel Chiralpak IC, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 230 nm; Injection volume: 0.07 ml; Temperature: 40 ° C; Eluent: t = 0-8 min 3% methanol / 97% acetonitrile + 0.2% acetic acid]:

Example 26

(-) - 2- [2- (6-Fluoro-4-oxo-1,2,3-benzotriazine-3 (4 //) - yl) ethyl] -4- [4 - ({3 - [(methoxycarbonyl ) amino] - benzyl} oxy) phenyl] -4-oxobutanoic acid (enantiomer 1) Yield: 43 mg; ee value = 100%

[a] _D ²⁰ = -21.3 °, 589 nm, c = 0.40 g / 100 ml, chloroform

Ή NMR (400 MHz, CDCb): δ [ppm] = 8.20 (dd, 1H), 7.96 (dd, 1H), 7.92 (d, 2H), 7.64 (td, 1H), 7.52-7.49 (m, 1H ), 7.33 (d, 2H), 7.14-7.09 (m, 1H), 6.97 (d, 2H), 6.75 (br, s, 1H), 5.10 (s, 2H), 4.63 (t, 2H), 3.78 ( s, 3H), 3.55-3.45 (m, 1H), 3.24-3.11 (m, 2H), 2.46-2.34 (m, 1H), 2.26-2.14 (m, 1H). LC / MS (Method 3, ESIpos): R _t = 2.20 min, m / z = 549 [M + H] ⁺ . Example 27

(+) - 2- 2- (6-Fluorooxo-1,2,3-benzotriazine-3 (4 /) -yl) -4- [4 - ({3 - [(methoxycarbonyl) amino] benzyl } oxy) phenyl] -4-oxobutanoic acid (enantiomer 2) Yield: 42 mg; ee value = 98%

[from ²⁰ = + 16.1 °, 589 nm, c = 0.38 g / 100 ml, chloroform

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.20 (dd, 1H), 7.96 (dd, 1H), 7.92 (d, 2H), 7.64 (td, 1H), 7.53-7.47 (m, 1H), 7.33 (d, 2H), 7.14-7.09 (m, 1H), 6.97 (d, 2H), 6.75 (br s, 1H), 5.10 (s, 2H), 4.63 (t, 2H), 3.78 (s, 3H), 3.56-3.45 (m, 1H), 3.24-3.12 (m, 2H), 2.46-2.34 (m, 1H), 2.26-2.15 (m, 1H).

LC / MS (Method 3, ESIpos): R _t = 2.20 min, m / z = 549 [M + H] ⁺ . Example 28

(+/-) - 2- [2- (6-Fluoro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- [4- (tetrahydro -2ii-pyran-4-ylmethoxy) phenyl] butanoic acid

A solution of 130 mg (0.20 mmol) of the compound from Example 24A in 2.1 ml of a 4 N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was heated to reflux with stirring for 3 h. After cooling to RT and concentration, the residue was purified by preparative HPLC (Method 7). The product-containing fractions were combined and concentrated to a residual volume of aqueous phase. This aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was treated with a mixture of pentane and tert. Butyl methyl ether triturated. The resulting solid was filtered off and dried in vacuo. There were obtained 96 mg (97% of theory) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.29 (br.s, 1H), 8.37-8.29 (m, 1H), 8.02-7.89 (m, 4H), 7.03 (d, 2H ), 4.58-4.41 (m, 2H), 3.93 (d, 2H), 3.88 (dd, 2H), 3.42 (dd, 1H), 3.33 (t, 2H), 3.22 (dd, 1H), 2.96-2.87 ( m, 1H), 2.26-2.15 (m, 1H), 2.11-1.95 (m, 2H), 1.68 (d, 2H), 1.40-1.26 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 0.98 min, m / z = 484 [M + H] ⁺ . Separation of the enantiomers:

 77 mg of the compound from Example 28 were dissolved in a mixture of 10 ml of acetone and 10 ml of isohexane and separated by preparative HPLC on a chiral phase into the enantiomers (see Examples 29 and 30) [column: Daicel Chiralpak IA, 5 μm, 250 mm x 20 mm; Flow: 20 ml / min; Detection: 280 nm; Injection volume: 1 ml; Temperature: 25 ° C; Eluent: t = 0-12 min 50% isohexane / 50% acetone + 0.2% acetic acid]:

Example 29

(-) - 2- [2- (6-Fluoro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- [4- (tetrahydro-2ii -pyran-4-ylmethoxy) phenyl] butanoic acid (enantiomer 1) Yield: 30 mg; ee value = 100%

[a] _D ²⁰ = -20.5 °, 589 nm, c = 0.31 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-de): δ [ppm] = 12.28 (br.s, 1H), 8.36-8.30 (m, 1H), 8.01-7.90 (m, 4H), 7.03 (d, 2H) , 4.59-4.42 (m, 2H), 3.93 (d, 2H), 3.88 (dd, 2H), 3.46-3.38 (m, 1H), 3.37-3.29 (m, 2H), 3.22 (dd, 1H), 2.95 -2.86 (m, 1H), 2.26-2.14 (m, 1H), 2.13-1.97 (m, 2H), 1.72-1.63 (m, 2H), 1.40-1.27 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.96 min, m / z = 484 [M + H] ⁺ .

Example 30

(+) - 2- [2- (6-Fluoro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- [4- (tetrahydro-2ii -pyran-4-ylmethoxy) phenyl] butanoic acid (enantiomer 2) Yield: 27 mg; ee value = 100%

[a] _D ²⁰ = + 21.2 °, 589 nm, c = 0.31 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (br.s, 1H), 8.36-8.30 (m, 1H), 8.01-7.90 (m, 4H), 7.03 (d, 2H ), 4.57-4.40 (m, 2H), 3.93 (d, 2H), 3.88 (dd, 2H), 3.46-3.38 (m, 1H), 3.37-3.29 (m, 2H), 3.22 (dd, 1H), 2.96-2.86 (m, 1H), 2.27-2.14 (m, 1H), 2.10-1.96 (m, 2H), 1.72-1.63 (m, 2H), 1.40-1.27 ( m, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.96 min, m / z = 484 [M + H] ⁺ . Example 31 (+/-) - 4- {4 - [(3-Chlorobenzyl) oxy] phenyl} -2- [2- (6-chloro-4-oxo-1,2,3-benzotriazine-3 (4 / ) -yl) ethyl] -4-oxobutanoic acid

A solution of 324 mg (0.41 mmol, purity 95%) of the compound from Example 25A in 6.5 ml of a 4 N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was heated to reflux with stirring for 4 h. After cooling to RT and concentration, the residue was purified by preparative HPLC (Method 6). 200 mg (84% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, 1H), 8.24 (d, 1H), 8.22 (d, 1H), 8.13 (dd, 2H), 7.96 ( d, 2H), 7.55 (s, 1H), 7.46-7.39 (m, 3H), 7.12 (d, 2H), 5.23 (s, 2H), 4.57-4.43 (m, 2H), 3.47-3.38 (m, 1H), 3.27-3.19 (m, 1H), 2.96-2.87 (m, 1H), 2.26-2.15 (m, 1H), 2.10-1.99 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.25 min, m / z = 526 [M + H] ⁺ .

Separation of the enantiomers:

 150 mg of the compound from Example 31 were dissolved in a mixture of 10 ml of ethanol, 10 ml of acetonitrile and 10 ml of dioxane and then separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 32 and 33) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 210 nm; Injection volume: 1 ml; Temperature: 40 ° C; Eluent: t = 0-9 min 50% acetonitrile / 50% ethanol + 0.2% acetic acid]:

Example 32

(-) - 4- {4 - [(3-Chlorobenzyl) oxy] phenyl} -2- [2- (6-chloro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxobutanoic acid (enantiomer 1) Yield: 68 mg; ee value = 100%

[a] _D ²⁰ = -27.0 °, 589 nm, c = 0.33 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.30 (br.s, IH), 8.25 (d, IH), 8.22 (d, IH), 8.13 (dd, IH), 7.96 (i.e. , 2H), 7.55 (s, IH), 7.46-7.38 (m, 3H), 7.12 (d, 2H), 5.23 (s, 2H), 4.57-4.42 (m, 2H), 3.47-3.38 (m, IH ), 3.27-3.19 (m, IH), 2.96-2.87 (m, IH), 2.26-2.14 (m, IH), 2.10-1.99 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.23 min, m / z = 526 [M + H] ⁺ .

Example 33

(+) - 4- {4 - [(3-Chlorobenzyl) oxy] phenyl} -2- [2- (6-chloro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxobutanoic acid (enantiomer 2) Yield: 65 mg; ee value = 97%

[from ²⁰ = + 23.3 °, 589 nm, c = 0.43 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.29 (br.s, IH), 8.25 (d, IH), 8.22 (d, IH), 8.13 (dd, IH), 7.96 ( d, 2H), 7.55 (s, IH), 7.46-7.38 (m, 3H), 7.12 (d, 2H), 5.23 (s, 2H), 4.58-4.42 (m, 2H), 3.47-3.38 (m, IH), 3.27-3.18 (m, IH), 2.96-2.86 (m, IH), 2.26-2.15 (m, IH), 2.10-1.99 (m, IH). LC / MS (Method 2, ESIpos): R _t = 1.23 min, m / z = 526 [M + H] ⁺ .

Example 34

(+/-) - 2- [2- (6-Chloro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- [4- (tetrahydro -2ii-pyran-4-ylmethoxy) phenyl] butanoic acid

A solution of 182 mg (0.28 mmol) of the compound from Example 26A in 3 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. The mixture was then heated to reflux for 3.5 h with stirring. After cooling to RT and concentration, the Residue with dichloromethane and concentrated again. 133 mg (90% of theory, purity 94%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.27 (br.s, IH), 8.25 (d, IH), 8.22 (d, IH), 8.15-8.10 (m, IH), 7.93 (d, 2H), 7.03 (d, 2H), 4.57-4.41 (m, 2H), 3.93 (d, 2H), 3.91-3.83 (m, 2H), 3.46-3.33 (partially obscured, 3H), 3.26 -3.17 (m, IH), 2.97-2.86 (m, IH), 2.27-2.15 (m, IH), 2.09-1.97 (m, 2H), 1.68 (d, 2H), 1.40-1.27 (m, 2H) ,

LC / MS (Method 2, ESIpos): R _t = 1.07 min, m / z = 500 [M + H] ⁺ . Separation of the enantiomers:

 115 mg of the compound from Example 34 were dissolved in a mixture of 2 ml of ethanol and 3 ml of acetonitrile and separated by preparative HPLC on a chiral phase into the enantiomers (see Examples 35 and 36) [column: Daicel Chiralpak AY-H, 5 μιη, 250 mm x 20 mm; Flow: 20 ml / min; Detection: 250 nm; Injection volume: 1.5 ml; Temperature: 25 ° C; Eluent: t = 0-60 min 30% isohexane / 70% ethanol + 0.2% acetic acid]:

Example 35 (+) - 2- [2- (6-Chloro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- [4- (tetrahydro -2ii-pyran-4-ylmethoxy) phenyl] butanoic acid (enantiomer 1)

Yield: 34 mg; ee value = 100%

[from ²⁰ = + 28.4 °, 589 nm, c = 0.31 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.22 (br.s, IH), 8.24 (d, IH), 8.21 (d, IH), 8.15-8.09 (m, IH), 7.93 (d, 2H), 7.03 (d, 2H), 4.58-4.40 (m, 2H), 3.93 (d, 2H), 3.91-3.84 (m, 2H), 3.46-3.36 (partially obscured, 3H), 3.26 -3.15 (m, IH), 2.97-2.83 (m, IH), 2.27-2.14 (m, IH), 2.12-1.96 (m, 2H), 1.68 (d, 2H), 1.41-1.26 (m, 2H) ,

LC / MS (Method 2, ESIpos): R _t = 1.07 min, m / z = 500 [M + H] ⁺ . Example 36 (-) - 2- [2- (6-Chloro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- [4- (tetrahydro -2ii-pyran-4-ylmethoxy) phenyl] butanoic acid (enantiomer 2)

Yield: 36 mg; ee value = 100%

[a] _D ²⁰ = -30.5 °, 589 nm, c = 0.32 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.11 (br.s, IH), 8.27-8.19 (m, 2H), 8.15-8.09 (m, IH), 7.93 (d, 2H ), 7.03 (d, 2H), 4.57-4.42 (m, 2H), 3.93 (d, 2H), 3.91-3.84 (m, 2H), 3.46-3.35 (partially obscured, 3H), 3.26-3.14 (m, IH), 2.95-2.85 (m, IH), 2.27-2.13 (m, IH), 2.12-1.96 (m, 2H), 1.72-1.63 (m, 2H), 1.42-1.23 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 1.07 min, m / z = 500 [M + H] ⁺ .

Example 37

(+/-) - 4- [4- ({3- [(methoxycarbonyl) amino] benzyl} oxy) phenyl] -2- [2- (6-methyl-4-oxo-1,2,3-benzo) triazin-3 (4 //) - yl) efhyl] -4-oxobutanoic acid

A solution of 186 mg (0.27 mmol) of the compound of Example 27A in 2.9 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was heated to reflux for 2 hours with stirring. After cooling to RT and concentration, the residue was purified by column chromatography (silica gel, running dichloromethane / methanol 100: 2). 50 mg (33% of theory, purity 95%) of the title compound were obtained. Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.14 (s, IH), 8.05 (d, IH), 7.92 (d, 2H), 7.76 (dd, IH), 7.50 (br, s, IH), 7.33 (d, 2H), 7.14-7.08 (m, IH), 6.97 (d, 2H), 6.74 (br, s, IH), 5.10 (s, 2H), 4.70- 4.56 (m, 2H) , 3.78 (s, 3H), 3.56-3.45 (m, IH), 3.23-3.09 (m, 2H), 2.58 (s, 3H), 2.46-2.33 (m, IH), 2.27-2.14 (m, IH) ,

LC / MS (Method 2, ESIpos): R _t = 1.05 min, m / z = 545 [M + H] ⁺ . Separation of the enantiomers:

38 mg of the compound from Example 37 were dissolved in 4 ml of isopropanol in the heat and separated by preparative HPLC on chiral phase into the enantiomers (see Examples 38 and 39) [column: Daicel Chiralpak AD-H, 5 μιη, 250 mm x 20 mm; Flow: 15 ml / min; Detection: 220 nm; Injection volume: 1 ml; Temperature: 40 ° C; Eluent: t = 0-20 min 25% isohexane / 75% isopro panol + 0.2% acetic acid]: Example 38

(-) - 4- [4 - ({3 - [(Methoxycarbonyl) amino] benzyl} oxy) phenyl] -2- [2- (6-methyl-4-oxo-1,2,3-benzotriazine] 3 (4 //) - yl) efhyl] -4-oxobutanoic acid (enantiomer 1)

Yield: 15 mg; ee value = 99% [α] _D ²⁰ = -33.0 °, 589 nm, c = 0.30 g / 100 ml, chloroform

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.13 (s, IH), 8.05 (d, IH), 7.92 (d, 2H), 7.75 (dd, IH), 7.49 (br. IH), 7.33 (d, 2H), 7.14-7.09 (m, IH), 6.97 (d, 2H), 6.77 (br s, IH), 5.10 (s, 2H), 4.68- 4.57 (m, 2H) , 3.78 (s, 3H), 3.57-3.46 (m, IH), 3.23-3.11 (m, 2H), 2.57 (s, 3H), 2.45-2.33 (m, IH),

2.26- 2.14 (m, IH). LC / MS (Method 2, ESIpos): R _t = 1.05 min, m / z = 545 [M + H] ⁺ . Example 39

(+) - 4- [4 - ({3 - [(Methoxycarbonyl) amino] berizyl} oxy) pheriyl] -2- [2- (6-methyl-4-oxo-1,2,3-tricarboxylic 3 (4 /) - yl) ethyl] -4-oxobutanoic acid {enantiomer 2)

Yield: 17 mg; ee value = 99% [α] _D ²⁰ = + 33.1 °, 589 nm, c = 0.31 g / 100 ml, chloroform

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.13 (s, IH), 8.05 (d, IH), 7.92 (d, 2H), 7.75 (dd, IH), 7.49 (br. IH), 7.33 (d, 2H), 7.14-7.08 (m, IH), 6.97 (d, 2H), 6.77 (br, s, IH), 5.10 (s, 2H), 4.68- 4.55 (m, 2H) , 3.78 (s, 3H), 3.57-3.45 (m, IH), 3.22-3.10 (m, 2H), 2.58 (s, 3H), 2.45-2.33 (m, IH),

2.27- 2.14 (m, IH). LC / MS (Method 2, ESIpos): R _t = 1.02 min, m / z = 545 [M + H] ⁺ . Example 40

(+/-) - 2- [2- (6-Methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- (4- {[ 3- (2-oxo-1,3-oxazolidin-3-yl) benzyl] oxy} phenyl) butanoic acid

A solution of 208 mg (0.28 mmol) of the compound from Example 28A in 3.0 ml of a 4 N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was stirred under reflux for 2 h. After cooling to RT and concentration, the residue was purified by column chromatography (25 g of silica gel, mobile phase dichloromethane / methanol 100: 2). 42 mg (27% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.14 (s, 1H), 8.05 (d, 1H), 7.93 (d, 2H), 7.76 (dd, 1H), 7.66 (s, 1H) , 7.49 (dd, 1H), 7.40 (t, 1H), 7.20 (d, 1H), 6.98 (d, 2H), 5.14 (s, 2H), 4.69-4.56 (m, 2H), 4.53-4.46 (m , 2H), 4.11-4.04 (m, 2H), 3.57-3.47 (m, 1H), 3.23-3.10 (m, 2H), 2.58 (s, 3H), 2.46-2.33 (m, 1H), 2.27-2.15 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.02 min, m / z = 557 [M + H] ⁺ .

Separation of the enantiomers:

 33 mg of the compound from Example 40 were dissolved in 2 ml of acetonitrile and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 41 and 42) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 280 nm; Injection volume: 0.4 ml; Temperature: 25 ° C; Eluent: t = 0-30 min 50% methanol / 50% acetonitrile + 0.2% acetic acid]:

Example 41

(+) - 2- [2- (6-Methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- (4- {[3- (2-oxo-1,3-oxazolidin-3-yl) benzyl] oxy} phenyl) butanoic acid (enantiomer 1)

Yield: 11 mg; ee value = 100%

[from ²⁰ = + 31.0 °, 589 nm, c = 0.34 g / 100 ml, chloroform

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.14 (s, 1H), 8.05 (d, 1H), 7.92 (d, 2H), 7.75 (d, 1H), 7.66 (s, 1H) , 7.49 (d, 1H), 7.40 (t, 1H), 7.20 (d, 1H), 6.98 (d, 2H), 5.14 (s, 2H), 4.69-4.55 (m, 2H), 4.49 (t, 2H), 4.07 (t, 2H), 3.56-3.45 (m, 1H), 3.24-3.10 (m, 2H), 2.58 (s, 3H), 2.45-2.33 (m, 1H), 2.28- 2.15 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.00 min, m / z = 557 [M + H] ⁺ . Example 42 (-) - 2- [2- (6-Methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- (4- { 3- (2-oxo-1,3-oxazolidin-3-yl) benzyl] oxy} phenyl) butanoic acid (enantiomer 2)

Yield: 9 mg; ee value = 99%

[a] _D ²⁰ = -20.0 °, 589 nm, c = 0.29 g / 100 ml, chloroform

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.12 (s, 1H), 8.04 (d, 1H), 7.91 (d, 2H), 7.74 (d, 1H), 7.66 (s, 1H) , 7.49 (d, 1H), 7.40 (t, 1H), 7.20 (d, 1H), 6.97 (d, 2H), 5.13 (s, 2H), 4.61 (br, s, 2H), 4.49 (t, 2H ), 4.07 (t, 2H), 3.57-3.44 (m, 1H), 3.23-3.10 (m, 2H), 2.44-2.31 (m, 1H), 2.28-2.14 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.00 min, m / z = 557 [M + H] ⁺ .

Example 43

(+/-) - 2- [2- (6-Methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- [4- (tetrahydro -2ii-pyran-4-ylmethoxy) phenyl] butanoic acid

A solution of 177 mg (0.28 mmol) of the compound from Example 29A in 3.0 ml of a 4 N solution of hydrogen chloride in dioxane was stirred at RT for 20 h. Subsequently, the mixture was stirred under reflux for 2 h. After cooling to RT and concentration, the residue was purified by preparative HPLC (Method 7). 108 mg (80% of theory, purity 98%) of the title compound were obtained.

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.14 (s, 1H), 8.06 (d, 1H), 7.93 (d, 2H), 7.76 (dd, 1H), 6.90 (d, 2H) , 4.70-4.56 (m, 2H), 4.03 (dd, 2H), 3.86 (d, 2H), 3.57-3.40 (m, 3H), 3.23-3.10 (m, 2H), 2.58 (s, 3H), 2.46-2.33 (m, IH), 2.26-2.15 (m, IH), 2.15-2.01 (m, IH), 1.76 (d, 2H), 1.53-1.39 (m, 2H).

LC / MS (Method 3, ESIpos): R _t = 2.18 min, m / z = 480 [M + H] ⁺ .

Separation of the enantiomers:

97 mg of the compound from Example 43 were dissolved in 15 ml of acetone and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 44 and 45) [column: Daicel Chiralpak IA, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 280 nm; Injection volume: 0.2 ml; Temperature: 25 ° C; Eluent: t = 0-18 min. 60% acetonitrile / 40% acetone + 0.2% acetic acid]: Example 44

(-) - 2- [2- (6-Methyl-4-oxo-l, 23-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- [4- (tetrahydro-2ii-pyran -4-ylmethoxy) phenyl] butanoic acid (enantiomer 1)

Yield: 31 mg; ee value = 100%

[a] _D ²⁰ = -40.0 °, 589 nm, c = 0.30 g / 100 ml, chloroform Ή-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.14 (s, IH), 8.05 (d, IH ), 7.92 (d, 2H), 7.76 (d, IH), 6.90 (d, 2H), 4.70-4.55 (m, 2H), 4.03 (dd, 2H), 3.86 (d, 2H), 3.58-3.40 ( m, 3H), 3.24-3.10 (m, 2H), 2.58 (s, 3H), 2.47-2.32 (m, IH), 2.28-2.16 (m, IH), 2.15-2.02 (m, IH), 1.76 ( d, 2H), 1.54-1.40 (m, 2H).

LC / MS (Method 3, ESIpos): R _t = 2.19 min, m / z = 480 [M + H] ⁺ .

Example 45 (+) - 2- [2- (6-Methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- [4- (tetrahydro -2ii-pyran-4-ylmethoxy) phenyl] butanoic acid (enantiomer 2)

Yield: 35 mg; ee value = 100%

[from ²⁰ = + 36.0 °, 589 nm, c = 0.30 g / 100 ml, chloroform

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.14 (s, IH), 8.05 (d, IH), 7.92 (d, 2H), 7.76 (d, IH), 6.90 (d, 2H) , 4.70-4.54 (m, 2H), 4.03 (dd, 2H), 3.86 (d, 2H), 3.58-3.39 (m, 3H), 3.24-3.10 (m, 2H), 2.58 (s, 3H), 2.47 -2.33 (m, IH), 2.27-2.15 (m, IH), 2.15-2.01 (m, IH), 1.76 (d, 2H), 1.53-1.39 (m, 2H).

LC / MS (Method 3, ESIpos): R _t = 2.19 min, m / z = 480 [M + H] ⁺ . Example 46

(+/-) - 2- [2- (6-methyl-4-oxo-l, 2,3-benzotriazin-3 (4 / ^^

benzyl] oxy} phenyl) butanoic acid

A solution of 363 mg (0.52 mmol) of the compound from Example 30A in 5.6 ml of a 4 N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was stirred under reflux for 4 h. After cooling to RT and concentration, 301 mg (> 100% of theory, still containing dioxane) of the title compound were obtained.

Ή NMR (400 MHz, CDCL): δ [ppm] = 8.14 (s, IH), 8.06 (d, IH), 7.95 (d, 2H), 7.76 (dd, IH), 7.70 (s, IH), 7.64-7.59 (m, 2H), 7.56-7.49 (m, IH), 7.00 (d, 2H), 5.17 (s, 2H), 4.70-4.55 (m, 2H), 3.59-3.48 (m, IH), 3.24-3.11 (m, 2H), 2.58 (s, 3H), 2.47-2.33 (m, IH), 2.27-2.16 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.22 min, m / z = 540 [M + H] ⁺ .

Separation of the enantiomers:

 275 mg of the compound from Example 46 were dissolved in 30 ml of acetonitrile / acetone and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 47 and 48) [column: Daicel Chiralpak IA, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 270 nm; Injection volume: 0.15 ml; Temperature: 25 ° C; Eluent: t = 0-4.5 min 50% acetonitrile / 50% acetone + 0.2% acetic acid]:

Example 47 (-) - 2- [2- (6-Methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- (4- { 3- (trifluoromethyl) benzyl] oxy} phenyl) butanoic acid (enantiomer 1)

Yield: 105 mg; ee value = 100%

[a] _D ²⁰ = -46.8 °, 589 nm, c = 0.34 g / 100 ml, chloroform Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.14 (s, 1H), 8.05 (d, 1H), 7.95 (d, 2H), 7.75 (d, 1H), 7.71 (s, 1H) , 7.64-7.58 (m, 2H), 7.56-7.48 (m, 1H), 7.00 (d, 2H), 5.17 (s, 2H), 4.70-4.56 (m, 2H), 3.59- 3.48 (m, 1H) , 3.24-3.12 (m, 2H), 2.58 (s, 3H), 2.47-2.33 (m, 1H), 2.28-2.15 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.18 min, m / z = 540 [M + H] ⁺ . Example 48

(+) - 2- [2- (6-Methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- (4- {[3- (trifluoromethyl) benzyl] oxy} phenyl) butanoic acid (enantiomer 2)

Yield: 104 mg; ee value = 97%

[from ²⁰ = + 43.2 °, 589 nm, c = 0.35 g / 100 ml, chloroform Ή-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.14 (s, 1H), 8.05 (d, 1H), 7.95 (d, 2H), 7.75 (d, 1H), 7.71 (s, 1H), 7.65-7.59 (m, 2H), 7.56-7.49 (m, 1H), 7.00 (d, 2H), 5.17 (s, 2H), 4.71-4.54 (m, 2H), 3.59-3.47 (m, 1H), 3.23-3.10 (m, 2H), 2.58 (s, 3H), 2.47-2.33 (m, 1H), 2.28-2.14 ( m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.18 min, m / z = 540 [M + H] ⁺ .

Example 49 (+/-) - 4- {4 - [(3-Chlorobenzyl) oxy] phenyl} -2- [2- (6-methyl-4-oxo-1,2,3-benzotriazine-3 (4 / ) -yl) ethyl] -4-oxobutanoic acid

A solution of 331 mg (0.5 mmol) of the compound from Example 31A in 5.4 ml of a 4 N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was stirred under reflux for 4 h. After cooling to RT and concentration, 254 mg (about 98% of theory, still containing dioxane) of the title compound were obtained.

Ή NMR (400 MHz, CDCL): δ [ppm] = 8.14 (s, 1H), 8.06 (d, 1H), 7.94 (d, 2H), 7.76 (dd, 1H), 7.43 (s, 1H), 7.35-7.27 (m, 3H), 6.98 (d, 2H), 5.10 (s, 2H), 4.71-4.55 (m, 2H), 3.57-3.46 (m, 1H), 3.22-3.10 (m, 2H), 2.58 (s, 3H), 2.48-2.33 (m, 1H), 2.28-2.14 (m, 1H). LC / MS (Method 2, ESIpos): R _t = 1.21 min, m / z = 506 [M + H] ⁺ . Separation of the enantiomers:

 230 mg of the compound from Example 49 were dissolved in 50 ml of methanol / acetonitrile and separated by preparative HPLC on a chiral phase into the enantiomers (see Examples 50 and 51) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm ; Flow: 25 ml / min; Detection: 210 nm; Injection volume: 1 ml; Eluent: t = 0-18.3 min 30% acetonitrile / 70% methanol + 0.2% acetic acid]:

Example 50

(-) - 4- {4 - [(3-Chlorobenzyl) oxy] phenyl} -2- [2- (6-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxobutanoic acid (enantiomer 1)

Yield: 81 mg; ee value = 100%

[a] _D ²⁰ = -46.0 °, 589 nm, c = 0.35 g / 100 ml, chloroform

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.13 (s, IH), 8.05 (d, IH), 7.94 (d, 2H), 7.75 (d, IH), 7.43 (s, IH) , 7.34-7.28 (m, 3H), 6.98 (d, 2H), 5.10 (s, 2H), 4.66-4.58 (m, 2H), 3.58-3.47 (m, IH), 3.23-3.10 (m, 2H) , 2.58 (s, 3H), 2.46-2.33 (m, IH), 2.27-2.14 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.17 min, m / z = 506 [M + H] ⁺ .

Example 51

( ₊ ) -4- {4 - [(3-Chlorobenzyl) oxy] phenyl} -2- [2- (6-methyl-4-oxo-1,2,3-benzotriazine-3 (4ii) -yl) ethyl ] -4-oxobutanoic acid (enantiomer 2) Yield: 73 mg; ee value = 100%

[from ²⁰ = + 43.4 °, 589 nm, c = 0.36 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (br.s, IH), 8.10 (d, IH), 8.05 (s, IH), 7.96 (d, 2H), 7.91 ( d, IH), 7.55 (s, IH), 7.46-7.39 (m, 3H), 7.12 (d, 2H), 5.23 (s, 2H), 4.57-4.40 (m, 2H), 3.48-3.38 (m, IH), 3.27-3.17 (m, IH), 2.95-2.84 (m, IH), 2.25-2.13 (m, IH), 2.09-1.96 (m, IH). LC / MS (Method 2, ESIpos): R _t = 1.17 min, m / z = 506 [M + H] ⁺ . Example 52

(+/-) - 4-Oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 //) -yl] ethyl} -4- [4 - (tetrahydro-2-yl-pyran-4-ylmethoxy) phenyl] butanoic acid

Method A:

 A solution of 181 mg (0.26 mmol) of the compound from Example 32A / Step 4 in 2.8 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT for 20 h. Subsequently, the mixture was stirred under reflux for 2 h. After cooling to RT and concentration, the residue was purified by preparative HPLC (Method 7). 122 mg (85% of theory, purity 98%) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.64 (s, 1H), 8.30 (d, 1H), 8.15 (dd, 1H), 7.92 (d, 2H), 6.90 (d, 2H) , 4.67 (t, 2H), 4.03 (dd, 2H), 3.86 (d, 2H), 3.55-3.40 (m, 3H), 3.27-3.13 (m, 2H), 2.49- 2.36 (m, 1H), 2.27 -2.16 (m, 1H), 2.16-2.01 (m, 1H), 1.76 (d, 2H), 1.47 (m, 2H).

LC / MS (Method 3, ESIpos): R _t = 2.34 min, m / z = 534 [M + H] ⁺ . Method B:

 A solution of 6.65 g (8.63 mmol, purity 75%) of the compound from Example 32A / Step 5 in 90 ml of dioxane was stirred under reflux for 2 h. After cooling to RT and concentration, the residue was taken up in a little dichloromethane and purified by column chromatography (300 g of silica gel, eluent dichloromethane / methanol 100: 2, InterChim). There were obtained 4.54 g (94% of theory) of the title compound.

Separation of the enantiomers:

4.50 g of the compound from Example 52 were dissolved in 30 ml of DMSO and 30 ml of ethanol and separated by preparative SFC on chiral phase into the enantiomers (see Examples 53 and 54) [column: Daicel Chiralpak AY, 20 μιη, 250 mm x 30 mm ; Flow: 200 ml / min; Detection: 210 nm; Injection volume: 0.40 ml; Temperature: 38 ° C; Eluent: t = 0-14.5 min 78% carbon dioxide / 22% ethanol]: Example 53

(+) - 4-oxo-2- {2- [4-oxo-6- (trifluoromethyl) -l, 2,3-ben ^

pyran-4-ylmethoxy) phenyl] butaric acid (enantiomer 1)

Yield: 2.12 g; ee value = 100% [a] _D ²⁰ = + 20.3 °, 589 nm, c = 0.35 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (s, 1H), 8.49 (s, 1H), 8.45-8.36 (m, 2H), 7.93 (d, 2H), 7.03 ( d, 2H), 4.61-4.45 (m, 2H), 3.93 (d, 2H), 3.88 (dd, 2H), 3.47-3.30 (partially occluded, 3H), 3.27-3.16 (m, 1H), 2.99-2.88 (m, 1H), 2.29-2.17 (m, 1H), 2.13-1.95 (m, 2H), 1.68 (d, 2H), 1.40-1.26 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 1.08 min, m / z = 534 [M + H] ⁺ .

Example 54

(-) - 4-Oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4/) -yl] ethyl} -4- [4- (tetrahydro 2-pyran-4-ylmethoxy) phenyl] butanoic acid (enantiomer 2)

Yield: 2.11 g; ee value = 100% [α] _D ²⁰ = -23.5 °, 589 nm, c = 0.30 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (s, 1H), 8.49 (s, 1H), 8.45-8.37 (m, 2H), 7.93 (d, 2H), 7.03 ( d, 2H), 4.61-4.45 (m, 2H), 3.93 (d, 2H), 3.88 (dd, 2H), 3.48-3.29 (partially occluded, 3H), 3.27-3.17 (m, 1H), 2.99-2.87 (m, 1H), 2.29-2.16 (m, 1H), 2.13-1.95 (m, 2H), 1.68 (d, 2H), 1.40-1.26 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 1.08 min, m / z = 534 [M + H] ⁺ .

Example 55

(+/-) - 4- [4- ({3- [(methoxycarbonyl) amino] benzyl} oxy) phenyl] -4-oxo-2- {2- [4-oxo-6- (trifluoromethyl) - 1, 2,3-benzotriazine-3 (4 /) -yl] ethyl} butanoic acid

A solution of 165 mg (0.22 mmol) of the compound from Example 33A in 2.4 ml of a 4 N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was heated to reflux with stirring for 3 h. After cooling to RT and concentration, the residue was purified by column chromatography (25 g of silica gel, eluent dichloromethane / methanol 100: 2). 39 mg (29% of theory, purity 97%) of the title compound were obtained.

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.64 (s, IH), 8.29 (d, IH), 8.15 (dd, IH), 7.92 (d, 2H), 7.53-7.48 (m, IH), 7.36-7.29 (m, 3H), 7.14-7.09 (m, IH), 6.98 (d, 2H), 6.73 (br s, IH), 5.11 (s, 2H), 4.66 (t, 2H) , 3.78 (s, 3H), 3.55-3.44 (m, IH), 3.26-3.13 (m, 2H), 2.49-2.36 (m, IH), 2.27-2.14 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.11 min, m / z = 599 [M + H] ⁺ . Separation of the enantiomers:

 38 mg of the compound from Example 55 were dissolved in 2 ml of acetonitrile and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 56 and 57) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 280 nm; Injection volume: 0.1 ml; Temperature: 25 ° C; Eluent: t = 0-15 min 80% acetonitrile / 20% methanol + 0.2% acetic acid]:

Example 56 (+) - 4- [4 - ({3 - [(Methoxycarbonyl) amino] benzyl} oxy) phenyl] -4-0X0-2- {2- [4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 //) - yl] ethyl} butanoic acid (enantiomer 1)

Yield: 13 mg; ee value = 100%

[a] _D ²⁰ = + 15.0 °, 589 nm, c = 0.29 g / 100 ml, chloroform

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.63 (s, IH), 8.34-8.22 (m, IH), 8.19-8.08 (m, IH), 7.97- 7.83 (m, 2H), 7.54-7.46 (m, IH), 7.39-7.27 (m, 2H), 7.16-7.05 (m, IH), 7.01-6.91 (m, 2H), 6.79- 6.67 (m, IH), 5.10 (s, 2H), 4.72-4.59 (m, 2H), 3.78 (s, 3H), 3.56-3.41 (m, IH), 3.30-3.11 (m, 2H), 2.45- 2.36 (m, IH), 2.27-2.16 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.10 min, m / z = 599 [M + H] ⁺ . Example 57 (-) - 4- [4 - ({3 - [(Methoxycarbonyl) amino] benzyl} oxy) phenyl] -4-oxo-2- {2- [4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 //) - yl] ethyl} butanoic acid (enantiomer 2)

Yield: 14 mg; ee value = 100%

[from ²⁰ = -12.5 °, 589 nm, c = 0.34 g / 100 ml, chloroform

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.63 (s, IH), 8.28 (d, IH), 8.14 (d, IH), 7.91 (d, 2H), 7.53-7.45 (m, IH), 7.36-7.28 (m, 2H), 7.14-7.07 (m, IH), 6.97 (d, 2H), 6.77-6.67 (m, IH), 5.10 (s, 2H), 4.72-4.58 (m, 2H), 3.78 (s, 3H), 3.58-3.40 (m, IH), 3.26-3.12 (m, 2H), 2.46-2.34 (m, IH), 2.28- 2.15 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.10 min, m / z = 599 [M + H] ⁺ . Example 58 4-0x0-2- {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] ethyl} -4- {4- [tetrahydro-2 # - pyran-3-ylmefhoxy] phenyl butanedioic acid (mixture of stereoisomers)

A solution of 62 mg (0.11 mmol) of the compound from Example 34A in 1.0 ml of dioxane was heated to reflux for 1.5 h with stirring. After cooling to RT and concentration, the residue was taken up in a little acetonitrile and purified by preparative HPLC (Method 7). 30 mg (52% of theory, purity 100%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.32 (br.s, IH), 8.49 (s, IH), 8.45-8.36 (m, 2H), 7.93 (d, 2H), 7.03 (d, 2H), 4.62-4.43 (m, 2H), 4.00-3.83 (m, 3H), 3.79-3.70 (m, IH), 3.45-3.16 (m, 4H), 2.98-2.86 (m, IH ), 2.28-2.15 (m, IH), 2.13-1.96 (m, 2H), 1.91-1.78 (m, IH), 1.68-1.32 (m, 3H). LC / MS (Method 2, ESIpos): R _t = 1.11 min, m / z = 534 [M + H] ⁺ . Example 59

(+/-) - 4-Oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 //) - yl] ethyl} -4- {4 - [2- (tetrahydro-2i-pyran-4-yl) efhoxy] phenyl} butanoic acid

A solution of 130 mg (0.17 mmol) of the compound from Example 35A in 2 ml of a 4N solution of hydrogen chloride in dioxane and another 2 ml of dioxane was heated in the microwave at 150 ° C. for 10 min. The mixture was then concentrated and the residue was purified by preparative HPLC (Reprosil C18, eluent: acetonitrile / water + 0.2% trifluoroacetic acid). 45 mg (50% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.29 (br.s, 1H), 8.49 (s, 1H), 8.46-8.37 (m, 2H), 7.93 (d, 2H), 7.03 (d, 2H), 4.53 (d, 2H), 4.11 (t, 2H), 3.83 (dd, 2H), 3.42 (dd, 1H), 3.33-3.17 (m, 3H), 2.98-2.87 (m, 1H), 2.30-2.17 (m, 1H), 2.13-2.00 (m, 1H), 1.74-1.55 (m, 5H), 1.30-1.10 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.13 min, m / z = 548 [M + H] ⁺ . Example 60

4-Oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] ethyl} -4- {4- [tetrahydrofuran-3-ylmethoxy ] phenyl} butanoic acid (stereoisomer mixture)

A solution of 116 mg (0.16 mmol, purity 92%) of the compound of Example 36A in 2 ml of a 4N solution of hydrogen chloride in dioxane and another 2 ml of dioxane was heated in the microwave at 150 ° C. for 10 minutes. Then the mixture was concentrated and the residue purified by preparative HLPC (Reprosil C18, eluent: acetonitrile / water + 0.2% trifluoroacetic acid). There were obtained 28 mg (33% of theory, purity 95%) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (br.s, IH), 8.49 (s, IH), 8.46-8.37 (m, 2H), 7.94 (d, 2H), 7.04 (d, 2H), 4.61-4.45 (m, 2H), 4.08-3.93 (m, 2H), 3.79 (d, 2H), 3.70-3.61 (m, IH), 3.58- 3.50 (m, IH), 3.47-3.40 (m, IH), 3.28-3.18 (m, IH), 2.99-2.88 (m, IH), 2.74-2.61 (m, IH), 2.29-2.16 (m, IH), 2.13-1.97 (m , 2H), 1.73-1.60 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.04 min, m / z = 520 [M + H] ⁺ .

Example 61

4-Oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] ethyl} -4- {4- [tetrahydrofuran-2-ylmethoxy ] phenyl} butanoic acid (stereoisomer mixture)

A solution of 118 mg (0.13 mmol, purity 72%) of the compound from Example 37A in 2 ml of a 4 N solution of hydrogen chloride in dioxane and another 2 ml of dioxane was heated in the microwave at 150 ° C. for 10 min. The mixture was then concentrated and the residue was purified by preparative HPLC (Reprosil C18, eluent: acetonitrile / water + 0.2% trifluoroacetic acid). 33 mg (49% of theory, purity 96%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.29 (br.s, IH), 8.49 (s, IH), 8.46-8.37 (m, 2H), 7.94 (d, 2H), 7.04 (d, 2H), 4.61-4.44 (m, 2H), 4.22-4.13 (m, IH), 4.10-3.95 (m, 2H), 3.83-3.75 (m, IH), 3.72-3.63 (m, IH ), 3.46-3.37 (m, IH), 3.28-3.18 (m, IH), 2.98-2.87 (m, IH), 2.30-2.17 (m, IH), 2.14-1.96 (m, 2H), 1.95-1.77 (m, 2H), 1.74-1.61 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.06 min, m / z = 520 [M + H] ⁺ .

Example 62

4-Oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,2,3-benzotriazine-3 (4 /) -yl] ethyl} -4- {4- [tetrahydro-2 · pyran-2-ylmefhoxy] phenyl butanedioic acid (mixture of stereoisomers)

A solution of 118 mg (0.16 mmol, purity 91%) of the compound from Example 38A in 2 ml of a 4 N solution of hydrogen chloride in dioxane and another 2 ml of dioxane was heated in the microwave at 150 ° C. for 10 min. The mixture was then concentrated and the residue was purified by preparative HPLC (Reprosil C18, eluent: acetonitrile / water + 0.2% trifluoroacetic acid). 46 mg (55% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.29 (br.s, 1H), 8.49 (s, 1H), 8.46-8.37 (m, 2H), 7.93 (d, 2H), 7.03 (d, 2H), 4.61-4.45 (m, 2H), 4.00 (d, 2H), 3.93-3.85 (m, 1H), 3.69-3.59 (m, 1H), 3.39 (s, 2H), 3.28- 3.18 (m, 1H), 2.98-2.87 (m, 1H), 2.29-2.16 (m, 1H), 2.13-1.99 (m, 1H), 1.87-1.78 (m, 1H), 1.69-1.59 (m, 1H ), 1.49 (d, 3H), 1.39-1.25 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.14 min, m / z = 534 [M + H] ⁺ .

Example 63

(+/-) - 4- {4- [(4-fluorotetrahydro-2ii-pyran-4-yl) methoxy] phenyl} -4-oxo-2- {2- [4-oxo-6- (trifluoromethyl ) - 1, 2,3-benzotriazine-3 (4 /) - yl] ethyl} butanoic acid

A solution of 77 mg (0.11 mmol) of the compound from Example 39A in 1 ml of dichloromethane was treated with 0.5 ml (6.15 mmol) of trifluoroacetic acid and stirred at RT for 1.5 h. The reaction mixture was then concentrated and the residue taken up in 1 ml of dioxane. The solution was microwaved for 15 min at 150 ° C. The mixture was then concentrated and the residue was purified by preparative HPLC (Reprosil C18, eluent: acetonitrile / water + 0.2% trifluoroacetic acid). 39 mg (65% of theory, purity 100%) of the title compound were obtained. Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.64 (s, 1H), 8.30 (d, 1H), 8.15 (dd, 1H), 7.93 (d, 2H), 6.95 (d, 2H) , 4.67 (t, 2H), 4.04 (d, 2H), 3.93-3.86 (m, 2H), 3.84-3.74 (m, 2H), 3.56-3.45 (m, 1H), 3.28-3.14 (m, 2H) , 2.43 (dd, 1H), 2.22 (dd, 1H), 2.03-1.82 (m, 4H).

LC / MS (Method 2, ESIpos): R _t = 1.07 min, m / z = 552 [M + H] ⁺ . Example 64

(+/-) - 4- {4 - [(3-Chlorobenzyl) oxy] phenyl} -4-0X0-2- {2- [4-oxo-6- (trifluoromethyl) -l, 2, 3-benzotriazine 3 (4 /) - yl] ethyl jbutanoic acid

A solution of 454 mg (0.62 mmol, purity 98%) of the compound from Example 40A in 7 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. The mixture was then heated to reflux for 2.5 h with stirring. After cooling to RT and concentration, a little dioxane was added and concentrated again. From the residue obtained, 70 mg was taken out and stirred with a little methanol and acetonitrile. The resulting solid was filtered off and dried in vacuo. 54 mg (15% of theory, purity 98%) of a first batch of the title compound were obtained. The remaining amount of the residue previously obtained was dried in vacuo to give an additional 313 mg (79% of theory, purity 88%) of the title compound.

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.31 (br.s, 1H), 8.49 (s, 1H), 8.44-8.40 (m, 2H), 7.96 (d, 2H), 7.55 (s, 1H), 7.45-7.42 (m, 3H), 7.12 (d, 2H), 5.23 (s, 2H), 4.60-4.48 (m, 2H), 3.43 (dd, 1H), 3.24 (dd, 1H ), 2.98-2.89 (m, 1H), 2.28-2.19 (m, 1H), 2.12-2.02 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.24 min, m / z = 560 [M + H] ⁺ .

Separation of the enantiomers:

312 mg of the compound from Example 64 were dissolved in 13 ml of acetonitrile / ethanol and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 65 and 66) [column: Daicel Chiralpak AS-H, 5 μm, 250 mm × 20 mm ; Flow: 20 ml / min; Detection: 210 nm; Injection volume: 0.75 ml; Eluent: t = 0-15 min 30% acetonitrile / 70% ethanol + 0.2% acetic acid]:

Example 65

(-) - 4- {4- [(3-Chlorobenzyl) oxy] phenyl} -4-oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,2,3-benzotriazine-3 ( 4 //) - yl] efhyl} butanoic acid (enantiomer 1)

Yield: 86 mg; ee value = 98%

[a] _D ²⁰ = -24.6 °, 589 nm, c = 0.43 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, IH), 8.49 (s, IH), 8.44-8.40 (m, 2H), 7.96 (d, 2H), 7.55 (s, IH), 7.45-7.42 (m, 3H), 7.12 (d, 2H), 5.23 (s, 2H), 4.60-4.48 (m, 2H), 3.43 (dd, IH), 3.24 (dd, IH), 2.98-2.89 (m, IH), 2.28-2.19 (m, IH), 2.12-2.02 (m, IH).

LC / MS (Method 3, ESIpos): R _t = 2.69 min, m / z = 560 [M + H] ⁺ .

Example 66

(+) - 4- {4 - [(3-Chlorobenzyl) oxy] phenyl} -4-oxo-2- {2- [4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 ( 4 //) - yl] efhyl} butanoic acid (enantiomer 2) Yield: 73 mg; ee value = 99%

[from ²⁰ = + 28.3 °, 589 nm, c = 0.36 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, IH), 8.49 (s, IH), 8.44-8.40 (m, 2H), 7.96 (d, 2H), 7.55 (s, IH), 7.45-7.42 (m, 3H), 7.12 (d, 2H), 5.23 (s, 2H), 4.60-4.48 (m, 2H), 3.43 (dd, IH), 3.24 (dd, IH), 2.98-2.89 (m, IH), 2.28-2.19 (m, IH), 2.12-2.02 (m, IH). LC / MS (Method 3, ESIpos): R _t = 2.69 min, m / z = 560 [M + H] ⁺ .

Example 67

(+/-) - 4-oxo-2- {2- [4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 /) -yl] ethyl} -4- (4- {[3- (trifluoromethyl) benzyl] oxy} phenyl) butanoic acid

A solution of 670 mg (0.85 mmol, purity 95%) of the compound from Example 41A in 9 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was stirred under reflux for 2 h. After cooling to RT and concentration, a little dioxane was added and concentrated again. From the residue obtained, 79 mg were taken and stirred with a little acetonitrile. The resulting solid was filtered off and dried in vacuo. 55 mg (11% of theory, purity 96%) of a first batch of the title compound were obtained. The residual amount of the residue previously obtained was dried in vacuo to give an additional 460 mg (76% of theory, purity 83%) of the title compound. Ή NMR (400 MHz, DMSO-de): δ [ppm] = 12.30 (br.s, 1H), 8.49 (s, 1H), 8.45-8.39 (m, 2H), 7.96 (d, 2H), 7.85 (s, 1H), 7.79 (d, 1H), 7.73 (d, 1H), 7.67 (d, 1H), 7.14 (d, 2H), 5.32 (s, 2H), 4.60-4.48 (m, 2H), 3.44 (dd, 1H), 3.25 (dd, 1H), 2.98-2.90 (m, 1H), 2.28-2.19 (m, 1H), 2.11-2.04 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.28 min, m / z = 594 [M + H] ⁺ .

Separation of the enantiomers:

460 mg of the compound from Example 67 were dissolved in 15 ml of acetonitrile / methanol while warm and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 68 and 69) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 20 mm; Flow: 25 ml / min; Detection: 210 nm; Injection volume: 0.75 ml; Temperature: 40 ° C; Eluent: t = 0-6.8 min 30% acetonitrile / 70% methanol + 0.2% acetic acid]: Example 68

(-) - 4-Oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] ethyl} -4- (4- {[ 3- (trifluoromethyl) benzyl] oxy} phenyl) butanoic acid (enantiomer 1)

Yield: 145 mg; ee value = 100%

[a] _D ²⁰ = -7.9 °, 589 nm, c = 0.34 g / 100 ml, chloroform Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (br.s, IH), 8.49 (s, IH), 8.45-8.39 (m, 2H), 7.96 (d, 2H), 7.85 (s, IH), 7.79 (d, IH), 7.73 (d, IH), 7.67 (d, IH), 7.14 (d, 2H), 5.32 (s, 2H), 4.60-4.48 (m, 2H) , 3.44 (dd, IH), 3.25 (dd, IH), 2.98-2.90 (m, IH), 2.28-2.19 (m, IH), 2.11-2.04 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.25 min, m / z = 594 [M + H] ⁺ . Example 69

(+) - 4-Oxo-2- {2- [4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 //) - yl] efhyl} -4- (4- { [3- (trifluoromethyl) benzyl] oxy} phenyl) butanoic acid (enantiomer 2)

Yield: 146 mg; ee value = 99%

[from ²⁰ = + 8.8 °, 589 nm, c = 0.28 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (br.s, IH), 8.49 (s , IH), 8.45-8.39 (m, 2H), 7.96 (d, 2H), 7.85 (s, IH), 7.79 (d, IH), 7.73 (d, IH), 7.67 (d, IH), 7.14 ( d, 2H), 5.32 (s, 2H), 4.60-4.48 (m, 2H), 3.44 (dd, IH), 3.25 (dd, IH), 2.98-2.90 (m, IH), 2.28-2.19 (m, IH), 2.11-2.04 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.25 min, m / z = 594 [M + H] ⁺ .

Example 70 (+/-) - 4- {4- [(3,4-Dichlorobenzyl) oxy] phenyl} -4-oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,2, 3-benzotriazine-3 (AH) -yl] ethyl} butanoic acid

A solution of 780 mg (1.04 mmol) of the compound of Example 42A in 11 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was stirred under reflux for 2 h. After cooling to RT and concentration, 449 mg of a residue were obtained. Of these, 60 mg were taken, stirred with acetonitrile and the resulting solid was filtered off and dried. There was obtained 34 mg (5% of theory, purity 96%) of a first batch of the title compound. The remaining residue gave 389 mg (46% of theory, purity 73%) of a second crop of the title compound. Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (s, IH), 8.49 (s, IH), 8.45-8.39 (m, 2H), 7.96 (d, 2H), 7.76 ( s, IH), 7.68 (d, IH), 7.47 (d, IH), 7.12 (d, 2H), 5.23 (s, 2H), 4.59-4.47 (m, 2H), 3.43 (dd, IH), 3.24 (dd, IH), 2.97-2.88 (m, IH), 2.28-2.19 (m, IH), 2.11-2.02 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.30 min, m / z = 596 [M + H] ⁺ . Separation of the enantiomers:

 389 mg of the compound from Example 70 were dissolved in 50 ml of acetonitrile / methanol and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 71 and 72) [column: Daicel Chiralpak AD, 10 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 270 nm; Injection volume: 0.5 ml; Temperature: 25 ° C; Eluent: t = 0-6.8 min 70% acetonitrile + 0.2% acetic acid / 30% methanol + 0.2% acetic acid]:

Example 71

(-) - 4- {4 - [(3,4-dichlorobenzyl) oxy] phenyl} -4-oxo-2- {2- [4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazin- 3 (4 /) - yl] ethyl} butanoic acid (enantiomer 1)

Yield: 141 mg; ee value = 100% [a] _D ²⁰ = -5.3 °, 589 nm, c = 0.33 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (s, IH), 8.49 (s, IH), 8.45-8.39 (m, 2H), 7.96 (d, 2H), 7.76 ( s, IH), 7.68 (d, IH), 7.47 (d, IH), 7.12 (d, 2H), 5.23 (s, 2H), 4.59-4.47 (m, 2H), 3.43 (dd, IH), 3.24 (dd, IH), 2.97-2.88 (m, IH), 2.28-2.19 (m, IH), 2.11-2.02 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.30 min, m / z = 596 [M + H] ⁺ . Example 72

(+) - 4- {4- [(3,4-Dichlorobenzyl) oxy] phenyl} -4-oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,2,3-benzo triazine-3 (4 /) -yl] ethyl} butanoic acid (enantiomer 2)

Yield: 112 mg; ee value = 97%

[a] _D ²⁰ = + 8.0 °, 589 nm, c = 0.30 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (s, IH), 8.49 (s , IH), 8.45-8.39 (m, 2H), 7.96 (d, 2H), 7.76 (s, IH), 7.68 (d, IH), 7.47 (d, IH), 7.12 (d, 2H), 5.23 ( s, 2H), 4.59-4.47 (m, 2H), 3.43 (dd, IH), 3.24 (dd, IH), 2.97-2.88 (m, IH), 2.28-2.19 (m, IH), 2.11-2.02 ( m, IH). LC / MS (Method 2, ESIpos): R _t = 1.30 min, m / z = 596 [M + H] ⁺ . Example 73

(+/-) - 2 2- (6-Difluoro-oxo, 23-benzotriazine-3 (4 /) -yl) -4- [4 - ({3 - [(methoxycarbonyl) -amino] -benzyl} oxy ) phenyl] -4-oxobutanoic acid

A solution of 354 mg (0.49 mmol) of the compound from Example 43A in 5.0 ml of a 4 N solution of hydrogen chloride in dioxane was stirred at RT for 18 h. Subsequently, the mixture was heated to reflux with stirring for 3 h. After cooling to RT and concentration, the residue was purified by column chromatography (120 g of silica gel, eluent dichloromethane / methanol 100: 25). 200 mg (72% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.32 (br.s, 1H), 9.71 (s, 1H), 8.43 (dd, 1H), 8.31-8.21 (m, 1H), 7.95 (d, 2H), 7.57 (s, 1H), 7.42 (d, 1H), 7.30 (t, 1H), 7.13-7.05 (m, 3H), 5.17 (s, 2H), 4.58-4.39 (m, 2H), 3.66 (s, 3H), 3.47-3.37 (m, 1H), 3.27-3.15 (m, 1H), 2.96-2.84 (m, 1H), 2.26- 2.13 (m, 1H), 2.11-1.97 ( m, 1H). LC / MS (Method 1, ESIpos): R _t = 1.05 min, m / z = 567 [M + H] ⁺ .

Separation of the enantiomers:

 175 mg of the compound from Example 73 were dissolved in 20 ml of acetone and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 74 and 75) [column: Daicel Chiralpak IA, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 280 nm; Injection volume: 0.3 ml; Temperature: 25 ° C; Eluent: t = 0-20.68 min. 60% isohexane / 40% acetone + 0.2% acetic acid]:

Example 74

(-) - 2- [2- (6,7-Difluoro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4- [4 - ({3 - [( methoxycarbonyl) - amino] benzyl} oxy) phenyl] -4-oxobutanoic acid (enantiomer 1) The product obtained after enantiomer separation (61 mg) was taken up in acetonitrile and purified by preparative HPLC (Method 7). The product-containing fractions were combined and concentrated to a residual volume of aqueous phase. It was then extracted twice with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. After drying the residue in vacuo, 45 mg of the title compound were obtained. ee value = 100%.

[a] _D ²⁰ = -2.7 °, 589 nm, c = 0.31 g / 100 ml, acetonitrile

Ή NMR (400 MHz, CD ₃ CN): δ [ppm] = 8.11 (dd, 1H), 8.03 (dd, 1H), 7.93 (d, 2H), 7.73 (br, s, 1H), 7.57 (s , 1H), 7.41-7.36 (m, 1H), 7.35-7.28 (m, 1H), 7.12 (d, 1H), 7.04 (d, 2H), 5.15 (s, 2H), 4.52 (td, 2H), 3.70 (s, 3H), 3.44 (dd, 1H), 3.25-3.16 (m, 1H), 3.07-2.95 (m, 1H), 2.33-2.21 (m, 1H), 2.18-2.05 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.04 min, m / z = 567 [M + H] ⁺ . Example 75

(+) - 2- [2- (6,7-Difluoro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4- [4 - ({3 - [( methoxycarbonyl) - amino] benzyl} oxy) phenyl] -4-oxobutanoic acid (enantiomer 2)

The product obtained after enantiomer separation (66 mg) was taken up in acetonitrile and purified by preparative HPLC (Method 7). The product-containing fractions were combined and concentrated to a residual volume of aqueous phase. It was then extracted twice with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. After drying the residue in vacuo, 46 mg of the title compound were obtained. ee value = 96%.

[from ²⁰ = + 2.8 °, 589 nm, c = 0.31 g / 100 ml, acetonitrile

Ή NMR (400 MHz, CD ₃ CN): δ [ppm] = 8.11 (dd, 1H), 8.03 (dd, 1H), 7.93 (d, 2H), 7.73 (br, s, 1H), 7.57 (s , 1H), 7.42-7.36 (m, 1H), 7.35-7.28 (m, 1H), 7.12 (d, 1H), 7.04 (d, 2H), 5.15 (s, 2H), 4.52 (td, 2H), 3.70 (s, 3H), 3.48-3.39 (m, 1H), 3.25-3.16 (m, 1H), 3.06-2.95 (m, 1H), 2.33-2.21 (m, 1H), 2.17-2.06 (m, 1H ).

LC / MS (Method 1, ESIpos): R _t = 1.04 min, m / z = 567 [M + H] ⁺ . Example 76

 (+/-) - 2 2- (7-Fluorooxo, 23-benzotriazine-3 (4 /) - yl) ethyl] -4- [4 - ({3 - [(methoxycarbonyl) benzyl} oxy) phenyl] -4-oxobutanoic

A solution of 200 mg (0.28 mmol) of the compound from Example 44A in 2 ml of dichloromethane was admixed with 2 ml (25.96 mmol) of trifluoroacetic acid and stirred at RT overnight. Subsequently, the mixture was concentrated. The residue was redissolved in 5 ml of dioxane and stirred at reflux for 3 h. After cooling to RT and concentration, the residue was purified by preparative HPLC (eluent acetonitrile / water gradient). 130 mg (84% of theory, purity 96%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (br.s, 1H), 9.71 (s, 1H), 8.33 (dd, 1H), 8.09 (dd, 1H), 7.95 ( d, 2H), 7.81 (td, 1H), 7.57 (s, 1H), 7.44-7.39 (m, 1H), 7.30 (t, 1H), 7.13-7.05 (m, 3H), 5.17 (s, 2H) , 4.58-4.41 (m, 2H), 3.66 (s, 3H), 3.46-3.37 (m, 1H), 3.27-3.17 (m, 1H), 2.96-2.86 (m, 1H), 2.26-2.15 (m, 1H), 2.08-1.98 (m, 1H). LC / MS (Method 2, ESIpos): R _t = 0.99 min, m / z = 549 [M + H] ⁺ .

Separation of the enantiomers:

 423 mg of the compound from Example 76 were dissolved in a mixture of 20 ml of isopropanol, 10 ml of ethanol and 10 ml of isohexane and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 77 and 78) [column: Daicel Chiralpak AD-H , 5 μm, 250 mm × 20 mm; Flow: 15 ml / min; Detection: 230 nm; Injection volume: 6 ml; Temperature: 25 ° C; Eluent: t = 0-89 min 40% isohexane / 60% isopropanol + 0.2% trifluoroacetic acid]:

Example 77

(-) - 2- [2- (7-Fluoro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) -4- [4 - ({3 - [(methoxycarbonyl) amino] - benzyl} oxy) phenyl] -4-oxobutanoic acid (enantiomer 1) Yield: 186 mg; ee value = 100% [a] _D ²⁰ = -7.4 °, 589 nm, c = 0.37 g / 100 ml, methanol

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, 1H), 9.71 (s, 1H), 8.33 (dd, 1H), 8.09 (dd, 1H), 7.95 ( d, 2H), 7.81 (td, 1H), 7.57 (s, 1H), 7.42 (d, 1H), 7.30 (t, 1H), 7.13-7.05 (m, 3H), 5.17 (s, 2H), 4.58 -4.41 (m, 2H), 3.66 (s, 3H), 3.48-3.36 (m, 1H), 3.28-3.18 (occluded, 1H), 2.96-2.86 (m, 1H), 2.26-2.14 (m, 1H) , 2.10-1.97 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.03 min, m / z = 549 [M + H] ⁺ .

Example 78

(+) - 2- [2- (7-Fluoro-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) -4- [4 - ({3 - [(methoxycarbonyl) amino] - benzyl} oxy) phenyl] -4-oxobutanoic acid (enantiomer 2) Yield: 187 mg; ee value = 97%

[from ²⁰ = + 7.3 °, 589 nm, c = 0.41 g / 100 ml, methanol

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (br.s, 1H), 9.71 (s, 1H), 8.33 (dd, 1H), 8.09 (dd, 1H), 7.95 ( d, 2H), 7.81 (td, 1H), 7.57 (s, 1H), 7.42 (d, 1H), 7.30 (t, 1H), 7.12-7.06 (m, 3H), 5.17 (s, 2H), 4.57 -4.42 (m, 2H), 3.66 (s, 3H), 3.47-3.39 (m, 1H), 3.27-3.18 (partially occluded, 1H), 2.96-2.86 (m, 1H), 2.26-2.15 (m, 1H ), 2.09-1.98 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.03 min, m / z = 549 [M + H] ⁺ .

Example 79

(+/-) - 2- [2- (7-Methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- [4- (tetrahydro -2ii-pyran-4-ylmethoxy) phenyl] butanoic acid

A solution of 178 mg (0.28 mmol) of the compound of Example 45A in 3 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was stirred under reflux for 3 h. After cooling to RT and concentration, the residue was purified by preparative HPLC (Method 7). The product fractions were pooled and until concentrated to a small residual volume of aqueous phase. The solid present was filtered off, washed three times with water and twice with pentane and dried in vacuo. 98 mg (73% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (s, 1H), 8.14 (d, 1H), 8.01 (s, 1H), 7.93 (d, 2H), 7.76 (d, 1H), 7.03 (d, 2H), 4.56-4.40 (m, 2H), 3.93 (d, 2H), 3.88 (dd, 2H), 3.46-3.37 (m, 1H), 3.37- 3.28 (obscured, 2H) , 3.26-3.17 (m, 1H), 2.95-2.85 (m, 1H), 2.57 (s, 3H), 2.26-2.13 (m, 1H), 2.10- 1.95 (m, 2H), 1.68 (d, 2H) , 1.34 (qd, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.01 min, m / z = 480 [M + H] ⁺ .

Separation of the enantiomers:

742 mg of the compound from Example 79 were dissolved in 100 ml of acetone, admixed with 100 ml of isohexane and then separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 80 and 81) [column: Daicel Chiralpak IA, 5 μm, 250 mm x 20 mm; Flow: 20 ml / min; Detection: 270 nm; Injection volume: 7 ml; Temperature: 25 ° C; Eluent: t = 0-12 min 50% isohexane / 50% acetone + 0.2% acetic acid]: Example 80

(-) - 2- [2- (7-Methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- [4- (tetrahydro-2ii pyran-4-ylmethoxy) phenyl] butanoic acid (enantiomer 1)

The product obtained after enantiomer separation (376 mg) was stirred in pentane and the solid was filtered off and washed with a little pentane and tert. -Butyl methyl ether washed. There were obtained 286 mg of the title compound. ee value = 100%.

[from ²⁰ = -10.8 °, 589 nm, c = 0.32 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.28 (br.s, 1H), 8.14 (d, 1H), 8.01 (s, 1H), 7.94 (d, 2H), 7.76 ( d, 1H), 7.03 (d, 2H), 4.56-4.40 (m, 2H), 3.93 (d, 2H), 3.88 (dd, 2H), 3.46-3.38 (m, 1H), 3.37-3.29 (m, 2H), 3.26-3.18 (m, 1H), 2.96-2.85 (m, 1H), 2.57 (s, 3H), 2.27-2.12 (m, 1H), 2.09- 1.95 (m, 2H), 1.68 (d, 2H), 1.34 (qd, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.98 min, m / z = 480 [M + H] ⁺ .

Example 81

(+) - 2- [2- (7-Methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- [4- (tetrahydro-2ii -pyran-4-ylmethoxy) phenyl] butanoic acid (enantiomer 2) The product obtained after enantiomer separation (380 mg) was stirred in pentane and the solid was filtered off and washed with a little pentane and tert. -Butyl methyl ether washed. There were obtained 276 mg of the title compound. ee value = 100%.

[from ²⁰ = + 42.0 °, 589 nm, c = 0.32 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.29 (br. s, 1H), 8.14 (i.e. , 1H), 8.01 (s, 1H), 7.93 (d, 2H), 7.76 (d, 1H), 7.03 (d, 2H), 4.56-4.39 (m, 2H), 3.93 (d, 2H), 3.88 ( d, 2H), 3.47-3.37 (m, 1H), 3.37-3.29 (m, 2H), 3.26-3.17 (m, 1H), 2.94-2.85 (m, 1H), 2.57 (s, 3H), 2.26- 2.13 (m, 1H), 2.10-1.94 (m, 2H), 1.68 (d, 2H), 1.34 (qd, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.98 min, m / z = 480 [M + H] ⁺ . Example 82

(+/-) - 4- {4 - [(3 _; 4-Dichlorobenzyl) oxy] phenyl} -2- [2- (7-methyl-4-oxo-1,2,3-benzotriazine-3 (4 / ) -yl) ethyl] -4-oxobutanoic acid

A solution of 544 mg (0.73 mmol) of the compound of Example 46A in 8 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was stirred under reflux for 3 h. After cooling to RT, the mixture was concentrated and the residue was treated with dioxane. After re-concentration 399 mg of a residue were obtained. Of these, 70 mg were taken, stirred with a little acetonitrile and a few drops of methanol and the resulting solid was filtered off and dried. 54 mg (13% of theory, purity 95%) of a first batch of the title compound were obtained. The remaining residue gave 329 mg (69% of theory, purity 83%) of a second crop of the title compound.

Ή NMR (400 MHz, DMSO-de): δ [ppm] = 12.30 (s, 1H), 8.14 (d, 1H), 8.02 (s, 1H), 7.96 (d, 2H), 7.76 (d, 1H ), 7.55 (s, 1H), 7.45-7.41 (m, 2H), 7.12 (d, 2H), 5.23 (s, 2H), 4.55-4.42 (m, 2H), 3.42 (dd, 1H), 3.23 ( d, 1H), 2.95-2.86 (m, 1H), 2.57 (s, 3H), 2.26-2.14 (m, 1H), 2.08-2.00 (m, 1H). LC / MS (Method 1, ESIpos): R _t = 1.24 min, m / z = 540 [M + H] Separation of the enantiomers:

 328 mg of the compound from Example 82 were heat-dissolved in 82 ml of a mixture of acetonitrile, ethanol and dioxane and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 83 and 84) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 210 nm; Injection volume: 2 ml; Temperature: 40 ° C; Eluent: t = 0-11.2 min 70% acetonitrile / 30% ethanol + 0.2% acetic acid]:

Example 83

(-) - 4- {4 - [(3,4-Dichlorobenzyl) oxy] phenyl} -2- [2- (7-methyl-4-oxo-1,2,3-benzotriazine-3 (4 //) -yl) ethyl] -4-oxobutanoic acid (enantiomer 1) Yield: 117 mg; ee value = 100%

[a] _D ²⁰ = -39.5 °, 589 nm, c = 0.36 g / 100 ml, dichloromethane

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (s, IH), 8.14 (d, IH), 8.02 (s, IH), 7.96 (d, 2H), 7.76 (d, IH), 7.55 (s, IH), 7.45-7.41 (m, 2H), 7.12 (d, 2H), 5.23 (s, 2H), 4.55-4.42 (m, 2H), 3.42 (dd, IH), 3.23 (dd, IH), 2.95-2.86 (m, IH), 2.57 (s, 3H), 2.26-2.14 (m, IH), 2.08-2.00 (m, IH). LC / MS (Method 1, ESIpos): R _t = 1.27 min, m / z = 540 [M + H] ⁺ .

Example 84

(+) - 4- {4 - [(3,4-Dichlorobenzyl) oxy] phenyl} -2- [2- (7-methyl-4-oxo-l, 2,3-benzotriazine-3 (4 /) - yl) ethyl] -4-oxobutanoic acid (enantiomer 2)

Yield: 84 mg; ee value = 89% [α] _D ²⁰ = + 39.6 °, 589 nm, c = 0.32 g / 100 ml, dichloromethane

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (s, IH), 8.14 (d, IH), 8.02 (s, IH), 7.96 (d, 2H), 7.76 (d, IH), 7.55 (s, IH), 7.45-7.41 (m, 2H), 7.12 (d, 2H), 5.23 (s, 2H), 4.55-4.42 (m, 2H), 3.42 (dd, IH), 3.23 (dd, IH), 2.95-2.86 (m, IH), 2.57 (s, 3H), 2.26-2.14 (m, IH), 2.08-2.00 (m, IH).

LC / MS (Method 1, ESIpos): R _t = 1.28 min, m / z = 540 [M + H] ⁺ . Example 85

(+/-) - 4- [4- ({3- [(methoxycarbonyl) amino] benzyl} oxy) phenyl] -4-oxo-2- {2- [4-oxo-7- (trifluoromethyl) - 1, 2,3-benzotriazine-3 (4 /) - yl] ethyl jbutanoic acid

A solution of 700 mg (0.93 mmol) of the compound from Example 47A in 10 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was concentrated. The residue was stirred in water and the solid was filtered off, washed twice with a little water and dried in vacuo. There were obtained 568 mg of a solid (dicarboxylic acid intermediate). Of these, 537 mg were taken, taken up in 10 ml of dioxane and stirred under reflux for 2 h. After cooling to RT and concentration, the residue was stirred with water and the solid was filtered off again and dried. The crude product thus obtained was purified by column chromatography (silica gel, eluent dichloromethane / methanol 95: 5). 371 mg (66% of theory, purity 99%) of the title compound were obtained.

Ή NMR (400 MHz, CDCL): δ [ppm] = 8.48 (d, 1H), 8.44 (s, 1H), 8.00 (d, 1H), 7.91 (d, 2H), 7.53-7.45 (m, 1H ), 7.36-7.29 (m, 2H), 7.14-7.08 (m, 1H), 6.98 (d, 2H), 6.78 (br s, 1H), 5.10 (s, 2H), 4.66 (t, 2H), 3.78 (s, 3H), 3.56-3.43 (m, 1H), 3.26-3.14 (m, 2H), 2.48-2.34 (m, 1H), 2.26-2.15 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.10 min, m / z = 599 [M + H] ⁺ . Separation of the enantiomers:

 344 mg of the compound from Example 85 were dissolved in 8 ml of ethanol and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 86 and 87) [column: Daicel Chiralpak AZ-H, 5 μm, 250 mm × 20 mm; Flow: 15 ml / min; Detection: 220 nm; Injection volume: 2 ml; Temperature: 45 ° C; Eluent: t = 0-55 min 25% isohexane / 75% ethanol + 0.2% trifluoroacetic acid]:

Example 86

(+) - 4- [4 - ({3 - [(methoxycarbonyl) amino] benzyl} oxy) phenyl] -4-0X0-2- {2- [4-oxo-7- (trifluoromethyl) -1, 2, 3-benzotriazine-3 (4 /) -yl] ethyl} butanoic acid (enantiomer 1)

Yield: 143 mg; ee value = 99% [a] _D ²⁰ = + 19.0 °, 589 nm, c = 0.26 g / 100 ml, chloroform

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.48 (d, IH), 8.44 (s, IH), 8.00 (d, IH), 7.91 (d, 2H), 7.53-7.45 (m, IH), 7.36-7.29 (m, 2H), 7.14-7.08 (m, IH), 6.98 (d, 2H), 6.78 (br, s, IH), 5.10 (s, 2H), 4.66 (t, 2H) , 3.78 (s, 3H), 3.56-3.43 (m, IH), 3.26-3.14 (m, 2H), 2.48-2.34 (m, IH), 2.26-2.15 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.11 min, m / z = 599 [M + H] ⁺ . Example 87

(-) - 4- [4 - ({3 - [(Methoxycarbonyl) amino] benzyl} oxy) phenyl] -4-oxo-2- {2- [4-oxo-7- (trifluoromethyl) -1, 2, 3-benzotriazine-3 (4 //) -yi] ethyl} butanoic acid (enantiomer 2) Yield: 149 mg; ee value = 99%

[from ²⁰ = -18.0 °, 589 nm, c = 0.25 g / 100 ml, chloroform

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.48 (d, IH), 8.44 (s, IH), 8.00 (d, IH), 7.91 (d, 2H), 7.53-7.47 (m, IH), 7.36-7.29 (m, 2H), 7.14-7.09 (m, IH), 6.98 (d, 2H), 6.77 (br, s, IH), 5.10 (s, 2H), 4.69-4.61 (m, 2H), 3.78 (s, 3H), 3.56-3.42 (m, IH), 3.27-3.12 (m, 2H), 2.48-2.35 (m, IH), 2.27-2.15 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.11 min, m / z = 599 [M + H] ⁺ .

Example 88

(+/-) - 4-oxo-2- {2- [4-oxo-7- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 /) -yl] ethyl} -4- [4- (tetrahydro-2-yl-pyran-4-ylmethoxy) phenyl] butanoic acid

A solution of 505 mg (0.73 mmol) of the compound from Example 48A in 7.9 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was stirred under reflux for 5 h. After cooling to RT and concentration, the residue was was purified by preparative HPLC (Method 6). There were obtained 348 mg (89% of theory, purity 100%) of the title compound.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.49 (d, 1H), 8.44 (s, 1H), 8.01 (d, 1H), 7.92 (d, 2H), 6.90 (d, 2H) , 4.66 (t, 2H), 4.03 (dd, 2H), 3.86 (d, 2H), 3.56-3.40 (m, 3H), 3.26-3.15 (m, 2H), 2.48-2.36 (m, 1H), 2.28 -2.16 (m, 1H), 2.15-2.04 (m, 1H), 1.76 (dd, 1H), 1.47 (qd, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.10 min, m / z = 534 [M + H] ⁺ .

Separation of the enantiomers:

 310 mg of the compound from Example 88 were dissolved in 25 ml of acetone / isohexane and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 89 and 90) [column: Daicel Chiralpak IA, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 280 nm; Injection volume: 0.3 ml; Temperature: 25 ° C; Eluent: t = 0-10 min 50% isohexane / 50% acetone + 0.2% acetic acid]:

Example 89

(-) - 4-Oxo-2- {2- [4-oxo-7- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] ethyl} -4- [4- (tetrahydro 2-pyran-4-ylmethoxy) phenyl] butanoic acid (enantiomer 1)

Yield: 101 mg; Purity = 96%; ee value = 96%

[a] _D ²⁰ = -26.4 °, 589 nm, c = 0.34 g / 100 ml, chloroform

Ή NMR (400 MHz, CDCL): δ [ppm] = 8.49 (d, 1H), 8.44 (s, 1H), 8.01 (dd, 1H), 7.92 (d, 2H), 6.90 (d, 2H), 4.66 (t, 2H), 4.03 (dd, 2H), 3.86 (d, 2H), 3.55-3.39 (m, 3H), 3.27-3.13 (m, 2H), 2.48- 2.35 (m, 1H), 2.28- 2.16 (m, 1H), 2.15-2.02 (m, 1H), 1.76 (d, 2H), 1.47 (qd, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.10 min, m / z = 534 [M + H] ⁺ .

Example 90

(+) - 4-Oxo-2- {2- [4-oxo-7- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] ethyl} -4- [4- (tetrahydro -2-pyran-4-ylmethoxy) phenyl] butanoic acid (enantiomer 2) Yield: 100 mg; Purity = 100%; ee value = 100%

[a] _D ²⁰ = + 24.8 °, 589 nm, c = 0.36 g / 100 ml, chloroform Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.49 (d, 1H), 8.44 (s, 1H), 8.01 (dd, 1H), 7.92 (d, 2H), 6.90 (d, 2H) , 4.66 (t, 2H), 4.03 (dd, 2H), 3.86 (d, 2H), 3.55-3.39 (m, 3H), 3.27-3.13 (m, 2H), 2.48-2.36 (m, 1H), 2.27 -2.16 (m, 1H), 2.15-2.02 (m, 1H), 1.76 (dd, 2H), 1.47 (qd, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.10 min, m / z = 534 [M + H] ⁺ . Example 91

(+/-) - 4- {4 - [(3-Chlorobenzyl) oxy] phenyl} -4-0X0-2- {2- [4-oxo-7- (trifluoromethyl) -l, 2, 3-benzotriazine 3 (4 /) - yl] ethyl jbutanoic acid

A solution of 518 mg (0.72 mmol) of the compound of Example 49A in 8 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was heated to reflux with stirring for 3 h. After cooling to RT and concentration, the residue was taken up in 4 ml of warm acetonitrile and again allowed to cool slowly to RT. The solid formed was filtered off, washed with 1 ml of acetonitrile and dried in vacuo. 219 mg (54% of theory, purity 100%) of the title compound were obtained. Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (s, 1H), 8.63 (s, 1H), 8.45 (d, 1H), 8.23 (dd, 1H), 7.96 (d, 2H), 7.54 (s, 1H), 7.46-7.38 (m, 3H), 7.12 (d, 2H), 5.23 (s, 2H), 4.60-4.45 (m, 2H), 3.47- 3.39 (m, 1H) , 3.28-3.19 (m, 1H), 2.99-2.88 (m, 1H), 2.28-2.17 (m, 1H), 2.12-2.01 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.28 min, m / z = 560 [M + H] ⁺ .

Separation of the enantiomers:

200 mg of the compound from Example 91 were dissolved in 20 ml of acetone / acetonitrile and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 92 and 93) [column: Daicel Chiralpak IA, 5 μm, 250 mm × 20 mm ; Flow: 20 ml / min; Detection: 280 nm; Injection volume: 0.2 ml; Temperature: 25 ° C; Eluent: t = 0-4 min 50% acetonitrile / 50% acetone + 0.2% acetic acid]: Example 92

(-) - 4- {4 - [(3-Chlorobenzyl) oxy] phenyl} -4-oxo-2- {2- [4-oxo-7- (trifluoromethyl) -l, 2,3-benzotriazine-3 ( 4 //) - yl] efhyl} butanoic acid (enantiomer 1)

Yield: 80 mg; Purity = 97%; ee value = 100% [a] _D ²⁰ = -27.5 °, 589 nm, c = 0.32 g / 100 ml, chloroform

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.49 (d, 1H), 8.44 (s, 1H), 8.01 (dd, 1H), 7.93 (d, 2H), 7.43 (s, 1H) , 7.35-7.28 (m, 3H), 6.98 (d, 2H), 5.10 (s, 2H), 4.66 (t, 2H), 3.56-3.45 (m, 1H), 3.27-3.12 (m, 2H), 2.48 -2.35 (m, 1H), 2.28-2.15 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.27 min, m / z = 560 [M + H] ⁺ . Example 93

(+) - 4- {4 - [(3-Chlorobenzyl) oxy] phenyl} -4-oxo-2- {2- [4-oxo-7- (trifluoromethyl) -l, 2,3-benzotriazine-3 ( 4 //) - yl] efhyl} butanoic acid (enantiomer 2)

Yield: 91 mg; Purity = 100%; ee value = 99%

[from ²⁰ = + 27.9 °, 589 nm, c = 0.32 g / 100 ml, chloroform Ή-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.48 (d, 1H), 8.44 (s, 1H), 8.00 (d, 1H), 7.93 (d, 2H), 7.43 (s, 1H), 7.35-7.28 (m, 3H), 6.98 (d, 2H), 5.10 (s, 2H), 4.66 (t, 2H) , 3.56-3.44 (m, 1H), 3.27-3.11 (m, 2H), 2.49-2.36 (m, 1H), 2.27-2.15 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.27 min, m / z = 560 [M + H] ⁺ .

Example 94 (+/-) - 4- {4 - [(3-Chloro-2-fluorobenzyl) oxy] phenyl} -4-oxo-2- {2- [4-oxo-7- (trifluoromethyl) -l, 2,3-benzotriazine-3 (AH) -yl] ethyl} butanoic acid

A solution of 551 mg (0.75 mmol) of the compound of Example 50A in 8 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was stirred under reflux for 4 h. After cooling to RT and concentration, the residue was taken up in 4 ml of warm acetonitrile and again allowed to cool slowly to RT. The formed solid was filtered off, washed twice with 1 ml of acetonitrile and dried in vacuo. There were obtained 352 mg (81% of theory, purity 100%) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (s, 1H), 8.63 (s, 1H), 8.45 (d, 1H), 8.23 (dd, 1H), 7.97 (d, 2H), 7.65-7.59 (m, 1H), 7.59-7.52 (m, 1H), 7.28 (t, 1H), 7.15 (d, 2H), 5.30 (s, 2H), 4.62-4.44 (m, 2H) , 3.49-3.39 (m, 1H), 3.29-3.19 (m, 1H), 2.99-2.88 (m, 1H), 2.29-2.16 (m, 1H), 2.15-2.00 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.28 min, m / z = 578 [M + H] ⁺ .

Separation of the enantiomers:

 330 mg of the compound from Example 94 were dissolved in 10 ml of acetonitrile and 6 ml of methanol and then separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 95 and 96) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 20 mm; Flow: 25 ml / min; Detection: 230 nm; Injection volume: 0.4 ml; Temperature: 25 ° C; Eluent: t = 0-11 min 30% methanol / 70% acetonitrile + 0.2% acetic acid]:

Example 95

(+) - 4- {4 - [(3-Chloro-2-fluorobenzyl) oxy] phenyl} -4-oxo-2- {2- [4-oxo-7- (trifluoromethyl) -1,2,3- Benzotriazine-3 (4 /) -yl] ethyl} butanoic acid (enantiomer 1)

Yield: 138 mg; Purity = 95%; ee value = 100%

[from ²⁰ = + 25.6 °, 589 nm, c = 0.36 g / 100 ml, chloroform

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.48 (d, 1H), 8.44 (s, 1H), 8.00 (dd, 1H), 7.94 (d, 2H), 7.43.7.34 ( _m , 2H), 7.12 (td, 1H), 7.00 (d, 2H), 5.20 (s, 2H), 4.66 (t, 2H), 3.56-3.45 (m, 1H), 3.26- 3.13 (m, 2H), 2.48 -2.35 (m, 1H), 2.28-2.15 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.28 min, m / z = 578 [M + H] ⁺ .

Example 96

(-) - 4- {4- [(3-Chloro-2-fluorobenzyl) oxy] phenyl} -4-oxo-2- {2- [4-oxo-7- (trifluoromethyl) -1,3,3- benzotriazine-3 (4 /) -yl] ethyl} butanoic acid (enantiomer 2) Yield: 168 mg; Purity = 100%; ee value = 98% [a] _D ²⁰ = -26.0 °, 589 nm, c = 0.35 g / 100 ml, chloroform

Ή NMR (400 MHz, CDCb): δ [ppm] = 8.48 (d, 1H), 8.44 (s, 1H), 8.01 (d, 1H), 7.94 (d, 2H), 7.43-7.34 (m, 2H ), 7.12 (td, 1H), 7.00 (d, 2H), 5.20 (s, 2H), 4.66 (t, 2H), 3.57-3.44 (m, 1H), 3.27-3.14 (m, 2H), 2.48- 2.33 (m, 1H), 2.28-2.14 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.28 min, m / z = 578 [M + H] ⁺ .

Example 97

(+/-) - 4-Oxo-2- {2- [4-oxo-7- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 //) - yl] ethyl} -4- (4 - {[3- (trifluoromethyl) benzyl] oxy} phenyl) butanoic acid

A solution of 532 mg (0.71 mmol) of the compound from Example 51A in 7.5 ml of a 4 N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was heated to reflux with stirring for 4 h. After cooling to RT and concentration, the residue was dried in vacuo. 439 mg (> 100% of theory, still containing solvent) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.49 (d, 1H), 8.44 (s, 1H), 8.01 (dd, 1H), 7.95 (d, 2H), 7.70 (s, 1H) , 7.64-7.59 (m, 2H), 7.56-7.48 (m, 1H), 7.01 (d, 2H), 5.17 (s, 2H), 4.66 (t, 2H), 3.56- 3.45 (m, 1H), 3.28 -3.12 (m, 2H), 2.49-2.33 (m, 1H), 2.22 (dd, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.28 min, m / z = 594 [M + H] ⁺ .

Separation of the enantiomers:

410 mg of the compound from Example 97 were dissolved in 25 ml of acetone / isohexane and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 98 and 99) [column: Daicel Chiralpak IA, 5 μm, 250 mm × 20 mm ; Flow: 20 ml / min; Detection: 270 nm; Injection volume: 0.3 ml; Temperature: 25 ° C; Eluent: t = 0-4 min 40% acetonitrile / 60% acetone + 0.2% acetic acid]: Example 98

(-) - 4-oxo-2- {2- [4-oxo-7- (trifluoromethyl) -l, 2,3 ^^

methyl) benzyl] oxy} phenyl) butanoic acid (enantiomer 1)

Yield: 156 mg; Purity = 100%; ee value = 100% [a] _D ²⁰ = -24.6 °, 589 nm, c = 0.37 g / 100 ml, chloroform

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.49 (d, 1H), 8.44 (s, 1H), 8.00 (d, 1H), 7.95 (d, 2H), 7.70 (s, 1H) , 7.64-7.59 (m, 2H), 7.54 (d, 1H), 7.00 (d, 2H), 5.17 (s, 2H), 4.66 (t, 2H), 3.57-3.45 (m, 1H), 3.26-3.12 (m, 2H), 2.49-2.35 (m, 1H), 2.28-2.15 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.25 min, m / z = 594 [M + H] ⁺ . Example 99

(+) - 4-Oxo-2- {2- [4-oxo-7- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 /) -yl] ethyl} -4- (4- {[ 3- (trifluoromethyl) benzyl] oxy} phenyl) butanoic acid (enantiomer 2)

Yield: 157 mg; Purity = 100%; ee value = 100%

[from ²⁰ = + 22.9 °, 589 nm, c = 0.39 g / 100 ml, chloroform Ή-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.49 (d, 1H), 8.44 (s, 1H), 8.00 (d, 1H), 7.95 (d, 2H), 7.70 (s, 1H), 7.64-7.59 (m, 2H), 7.56-7.49 (m, 1H), 7.00 (d, 2H), 5.17 (s, 2H), 4.66 (t, 2H), 3.57-3.46 (m, 1H), 3.26-3.14 (m, 2H), 2.47-2.35 (m, 1H), 2.28-2.15 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.25 min, m / z = 594 [M + H] ⁺ .

Example 100 (+/-) - 4- {4 - [(3,4-Dichlorobenzyl) oxy] phenyl} -4-oxo-2- {2- [4-oxo-7- (trifluoromethyl) -1, 2, 3-benzotriazine-3 (AH) -yl] ethyl} butanoic acid

A solution of 562 mg (0.75 mmol) of the compound from Example 52A in 8 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was stirred under reflux for 3 h. After cooling to RT and concentration, the residue was dried in vacuo. 486 mg (> 100% of theory, still containing solvent) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.49 (d, 1H), 8.44 (s, 1H), 8.01 (d, 1H), 7.94 (d, 2H), 7.54 (d, 1H) , 7.47 (d, 1H), 7.26-7.23 (m, 1H), 6.97 (d, 2H), 5.08 (s, 2H), 4.66 (t, 2H), 3.56-3.45 (m, 1H), 3.26-3.13 (m, 2H), 2.50-2.36 (m, 1H), 2.28-2.15 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.33 min, m / z = 594 [M + H] ⁺ . Separation of the enantiomers:

 460 mg of the compound from Example 100 were dissolved in 20 ml of acetone / acetonitrile and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 101 and 102) [column: Daicel Chiralpak IA, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 270 nm; Injection volume: 0.15 ml; Temperature: 25 ° C; Eluent: t = 0-4.4 min 50% acetone + 0.2% acetic acid / 50% acetonitrile + 0.2% acetic acid]:

Example 101

(-) - 4- {4 - [(3,4-dichlorobenzyl) oxy] phenyl} -4-oxo-2- {2- [4-oxo-7- (trifluoromethyl) -l, 2,3-benzotriazin- 3 (4 /) - yl] ethyl} butanoic acid (enantiomer 1)

Yield: 167 mg; Purity = 100%; ee value = 100% [a] _D ²⁰ = -25.6 °, 589 nm, c = 0.34 g / 100 ml, chloroform

Ή NMR (400 MHz, CDCL): δ [ppm] = 8.49 (d, 1H), 8.44 (s, 1H), 8.01 (d, 1H), 7.94 (d, 2H), 7.54-7.52 (m, 1H ), 7.47 (d, 1H), 7.28-7.23 (m, 1H), 6.97 (d, 2H), 5.08 (s, 2H), 4.66 (t, 2H), 3.57-3.44 (m, 1H), 3.26- 3.13 (m, 2H), 2.48-2.36 (m, 1H), 2.27-2.15 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.31 min, m / z = 594 [M + H] ⁺ . Example 102

(+) - 4- {4 - [(3,4-Dichlorobenzyl) oxy] phenyl} -4-oxo-2- {2- [4-oxo-7- (trifluoromethyl) -l, 2,3-benzo triazine-3 (4 /) -yl] ethyl} butanoic acid (enantiomer 2)

Yield: 175 mg; Purity = 100%; ee value = 98% [from ²⁰ = + 24.9 °, 589 nm, c = 0.35 g / 100 ml, chloroform

Ή-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.48 (d, 1H), 8.44 (s, 1H), 8.01 (s, 1H), 7.94 (d, 2H), 7.55- 7.51 (m, 1H), 7.47 (d, 1H), 7.28-7.23 (m, 1H), 6.97 (d, 2H), 5.07 (s, 2H), 4.66 (t, 2H), 3.57-3.45 (m, 1H), 3.25 -3.13 (m, 2H), 2.48-2.34 (m, 1H), 2.27-2.15 (m, 1H). LC / MS (Method 2, ESIpos): R _t = 1.31 min, m / z = 594 [M + H] ⁺ .

Example 103

(+/-) - 4- {4- [(3,4-dichlorobenzyl) oxy] phenyl} -4-oxo-2- {2- [4-oxo-8- (trifluoromethyl) -1,3,3- benzotriazine-3 (AH) -yl] ethyl} butanoic acid

A solution of 330 mg (0.44 mmol) of the compound from Example 53A in 4 ml of dichloromethane was admixed with 2.4 ml (30.53 mmol) of trifluoroacetic acid and stirred at RT overnight. The mixture was then concentrated, the residue was taken up in 4 ml of dioxane and the mixture was stirred at reflux for 4 h. After cooling to RT and concentration, the residue was purified by preparative HPLC (eluent acetonitrile / water gradient). 182 mg (64% of theory, purity 92%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.33 (br.s, 1H), 8.53 (d, 1H), 8.45 (d, 1H), 8.06 (t, 1H), 7.96 ( d, 2H), 7.76 (d, 1H), 7.68 (d, 1H), 7.47 (dd, 1H), 7.12 (d, 2H), 5.23 (s, 2H), 4.61-4.43 (m, 2H), 3.49 -3.38 (m, 1H), 3.29-3.18 (m, 1H), 3.00-2.86 (m, 1H), 2.29-2.16 (m, 1H), 2.14-1.99 (m, 1H). LC / MS (Method 2, ESIpos): R _t = 1.35 min, m / z = 594 [M + H] ⁺ . Separation of the enantiomers:

172 mg of the compound from Example 103 were dissolved in 1 l of isopropanol and 1 ml of acetonitrile and then separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 104 and 105) [column: Daicel Chiralcel OZ-H, 5 μιη, 250 mm x 20 mm; Flow: 12 ml / min; Detek- tion: 220 nm; Injection volume: 0.5 ml; Temperature: 40 ° C; Eluent: t = 0-20 min 25% isohexane / 75% isopropanol + 0.1% trifluoroacetic acid]:

Example 104

(+) - 4- {4 - [(3,4-Dichlorobenzyl) oxy] phenyl} -4-oxo-2- {2- [4-oxo-8- (trifluoromethyl) -l, 2,3-benzo triazine-3 (4 //) - yl] efhyl} butanoic acid (enantiomer 1)

Yield: 77 mg; Purity = 96%; ee value = 99%

[from ²⁰ = + 16.7 °, 589 nm, c = 0.53 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.33 (br.s, IH), 8.53 (d, IH), 8.45 (d, IH), 8.06 (t, IH), 7.96 ( d, 2H), 7.76 (d, IH), 7.68 (d, IH), 7.47 (dd, IH), 7.12 (d, 2H), 5.23 (s, 2H), 4.61-4.43 (m, 2H), 3.49 -3.39 (m, IH), 3.28-3.19 (m, IH), 2.99-2.88 (m, IH), 2.29-2.17 (m, IH), 2.14-2.00 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.28 min, m / z = 594 [M + H] ⁺ . Example 105

(-) - 4- {4 - [(3,4-dichlorobenzyl) oxy] phenyl} -4-oxo-2- {2- [4-oxo-8- (trifluoromethyl) -l, 2,3-benzotriazin- 3 (4 //) - yl] efhyl} butanoic acid (enantiomer 2)

Yield: 67 mg; Purity = 100%; ee value = 99%

[a] _D ²⁰ = -23.3 °, 589 nm, c = 0.41 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.32 (br.s, IH), 8.53 (d, IH), 8.46 (s, IH), 8.06 (t, IH), 7.96 ( d, 2H), 7.76 (d, IH), 7.68 (d, IH), 7.47 (dd, IH), 7.12 (d, 2H), 5.23 (s, 2H), 4.61-4.43 (m, 2H), 3.43 (dd, IH), 3.24 (dd, IH), 3.00-2.88 (m, IH), 2.29-2.17 (m, IH), 2.13-1.99 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.28 min, m / z = 594 [M + H] ⁺ .

Example 106

(+/-) - 4-Oxo-2- [2- (4-oxopyrido [3,2-d] [l, 2,3] triazine-3 (4 /) -yl) ethyl] -4- [4 - (tetrahydro-2ii-pyran-4-yl-methoxy) phenyl] butanoic acid

A solution of 840 mg (1.35 mmol) of the compound from Example 54A in 2 ml of dichloromethane was admixed with 2 ml of trifluoroacetic acid and stirred at RT for 6 h. The mixture was then concentrated, the residue was taken up in 5 ml of dioxane and the mixture was stirred under reflux for 3 h. After cooling to RT and concentration, the residue was purified by preparative HPLC (eluent acetonitrile / water gradient). 371 mg (59% of theory, purity 100%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, 1H), 9.13 (dd, 1H), 8.63 (dd, 1H), 8.08 (dd, 1H), 7.94 ( d, 2H), 7.04 (d, 2H), 4.61-4.44 (m, 2H), 3.93 (d, 2H), 3.88 (dd, 2H), 3.47-3.38 (m, 1H), 3.36-3.29 (obscured, 2H), 3.27-3.20 (m, 1H), 2.99-2.88 (m, 1H), 2.29-2.16 (m, 1H), 2.12-1.97 (m, 2H), 1.68 (d, 2H), 1.34 (qd, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.85 min, m / z = 467 [M + H] ⁺ . Separation of the enantiomers:

 371 mg of the compound from Example 106 were dissolved in 8 ml of methanol / acetonitrile and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 107 and 108) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm ; Flow: 20 ml / min; Detection: 210 nm; Injection volume: 0.6 ml; Temperature: 40 ° C; Eluent: t = 0-9 min 50% acetonitrile / 50% methanol + 0.2% acetic acid]:

Example 107 (+) - 4-Oxo-2- [2- (4-oxopyrido [3,2-d] [l, 2,3] triazine-3 (4 /) -yl) ethyl] -4- [4 - (tetrahydro-2-pyran-4-ylmethoxy) phenyl] butanoic acid (enantiomer 1)

Yield: 117 mg; Purity = 100%; ee value = 100%

[a] _D ²⁰ = + 48.6 °, 589 nm, c = 0.37 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (br.s, 1H), 9.13 (dd, 1H), 8.63 (dd, 1H), 8.08 (dd, 1H), 7.94 ( d, 2H), 7.03 (d, 2H), 4.61-4.44 (m, 2H), 3.93 (d, 2H), 3.88 (dd, 2H), 3.46-3.38 (m, 1H), 3.37-3.29 (covert, 2H), 3.27-3.18 (m, 1H), 2.99-2.89 (m, 1H), 2.29-2.16 (m, 1H), 2.13-1.95 (m, 2H), 1.68 ( dd, 2H), 1.34 (qd, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.85 min, m / z = 467 [M + H] ⁺ . Example 108 (-) - 4-Oxo-2- [2- (4-oxopyrido [3,2-d] [l, 2,3] triazine-3 (4 /) -yl) ethyl] -4- [4 - (tetrahydro-2-pyran-4-ylmethoxy) phenyl] butanoic acid (enantiomer 2)

Yield: 131 mg; Purity = 100%; ee value = 100%

[from ²⁰ = -19.9 °, 589 nm, c = 0.48 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (br.s, 1H), 9.13 (dd, 1H), 8.63 (dd, 1H), 8.08 (dd, 1H), 7.94 ( d, 2H), 7.03 (d, 2H), 4.61-4.44 (m, 2H), 3.93 (d, 2H), 3.88 (dd, 2H), 3.47-3.38 (m, 1H), 3.38-3.29 (m, 2H), 3.27-3.19 (m, 1H), 2.98-2.89 (m, 1H), 2.29-2.17 (m, 1H), 2.13-1.96 (m, 2H), 1.68 (dd, 2H), 1.34 (qd, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.85 min, m / z = 467 [M + H] ⁺ . Example 109 (+/-) - 4-Oxo-2- [2- (4-oxopyrido [3,2-d] [l, 2,3] triazine-3 (4 /) -yl) ethyl] -4- (4- {[3- (trifluoromethyl) benzyl] oxy} phenyl) butanoic acid

A solution of 622 mg (0.91 mmol) of the compound from Example 55 A in 8 ml of dichloromethane was admixed with 4.9 ml of trifluoroacetic acid and stirred at RT overnight. The mixture was then concentrated, the residue dissolved in 8 ml of dioxane and the mixture was stirred under reflux for 3 h. After cooling to RT and concentration, the residue was purified by preparative HPLC (eluent acetonitrile / water gradient). 148 mg (31% of theory, purity 97%) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, IH), 9.13 (dd, IH), 8.63 (dd, IH), 8.08 (dd, IH), 7.98 ( d, 2H), 7.85 (s, IH), 7.79 (d, IH), 7.73 (d, IH), 7.66 (t, IH), 7.15 (d, 2H), 5.33 (s, 2H), 4.62-4.45 (m, 2H), 3.48-3.39 (m, IH), 3.29-3.21 (m, IH), 2.99-2.89 (m, IH), 2.30-2.17 (m, IH), 2.13-2.00 (m, IH) , LC / MS (Method 3, ESIpos): R _t = 2.32 min, m / z = 527 [M + H] ⁺ .

Separation of the enantiomers:

 141 mg of the compound from Example 109 were dissolved in 20 ml of acetonitrile and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 110 and 111) [column: Daicel Chiralpak IA, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 270 nm; Injection volume: 0.3 ml; Temperature: 25 ° C; Eluent: t = 0-10 min 30% acetone + 0.2% acetic acid / 70% acetonitrile + 0.2% acetic acid]:

Example 110

(-) - 4-Oxo-2- [2- (4-oxopyrido [3,2-d] [l, 2,3] triazine-3 (4 /) -yl) ethyl] -4- (4- { [3- (trifluoromethyl) benzyl] oxy} phenyl) butanoic acid (enantiomer 1) Yield: 63 mg; Purity = 100%; ee value = 100%

[a] _D ²⁰ = -19.4 °, 589 nm, c = 0.38 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-de): δ [ppm] = 12.28 (br.s, IH), 9.13 (dd, IH), 8.63 (dd, IH), 8.08 (dd, IH), 7.98 (i.e. , 2H), 7.85 (s, IH), 7.79 (d, IH), 7.73 (d, IH), 7.66 (t, IH), 7.15 (d, 2H), 5.33 (s, 2H), 4.62-4.46 ( m, 2H), 3.49-3.39 (m, IH), 3.30-3.21 (m, IH), 2.99-2.89 (m, IH), 2.30-2.17 (m, IH), 2.15-2.01 (m, IH).

LC / MS (Method 2, ESIpos): R _t = 1.06 min, m / z = 527 [M + H] ⁺ .

Example 111

(+) - 4-Oxo-2- [2- (4-oxopyrido [3,2-d] [l, 2,3] triazine-3 (4 /) -yl) ethyl] -4- (4- { [3- (trifluoromethyl) benzyl] oxy} phenyl) butanoic acid (enantiomer 2) Yield: 61 mg; Purity = 100%; ee value = 97%

[a] _D ²⁰ = + 18.4 °, 589 nm, c = 0.36 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (br.s, IH), 9.13 (dd, IH), 8.63 (dd, IH), 8.08 (dd, IH), 7.98 ( d, 2H), 7.85 (s, IH), 7.79 (d, IH), 7.73 (d, IH), 7.66 (t, IH), 7.15 (d, 2H), 5.33 (s, 2H), 4.61-4.45 (m, 2H), 3.48-3.39 (m, 1H), 3.29-3.21 (m, 1H), 2.99-2.88 (m, 1H), 2.29-2.17 (m, 1H), 2.14- 2.00 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.06 min, m / z = 527 [M + H] ⁺ . Example 112 (+/-) - 4- {4 - [(3-Chlorobenzyl) oxy] phenyl} -4-oxo-2- [2- (4-oxopyrido [3,2-d] [l, 2,3 ] triazine-3 (4 /) -yl) ethyl] butanoic acid

A solution of 268 mg (0.41 mmol) of the compound from Example 56A in 3.5 ml of dichloromethane was admixed with 2.2 ml (28.67 mmol) of trifluoroacetic acid and stirred at RT overnight. The mixture was then concentrated, the residue was dissolved in 3.5 ml of dioxane and the mixture was stirred under reflux for 4 h. After cooling to RT and concentration, the residue was purified by preparative HPLC (eluent acetonitrile / water gradient). 84 mg (40% of theory, purity 97%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (br.s, 1H), 9.13 (dd, 1H), 8.63 (dd, 1H), 8.08 (dd, 1H), 7.97 ( d, 2H), 7.55 (s, 1H), 7.46-7.39 (m, 3H), 7.12 (d, 2H), 5.24 (s, 2H), 4.61-4.45 (m, 2H), 3.48-3.38 (m, 1H), 3.28-3.20 (m, 1H), 2.98-2.87 (m, 1H), 2.28-2.16 (m, 1H), 2.13-1.98 (m, 1H).

LC / MS (Method 1, ESIpos): R _t = 1.02 min, m / z = 493 [M + H] ⁺ .

Separation of the enantiomers:

76 mg of the compound from Example 112 were dissolved in 4 ml of ethanol and 0.5 ml of acetonitrile and then separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 113 and 114) [column: Daicel Chiralpak IA, 5 μm, 250 mm × 20 mm; Flow: 15 ml / min; Detection: 220 nm; Injection volume: 0.5 ml; Temperature: 45 ° C; Eluent: t = 0-25 min 25% isohexane / 75% ethanol + 0.2% acetic acid]: Example 113

( ₊ ) -4- {4 - [(3-Chlorobenzyl) oxy] phenyl} -4-oxo-2 2- (4-oxo-pyrido [3,2-d] [l, 2,3] triazine-3 (4 /) - yl) - ethyl] butanoic acid (enantiomer 1)

Yield: 27 mg; ee value = 99%; Purity = 100% [α] _D ²⁰ = + 12.0 °, 589 nm, c = 0.26 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.32 (br.s, IH), 9.13 (dd, IH), 8.63 (dd, IH), 8.08 (dd, IH), 7.97 ( d, 2H), 7.55 (s, IH), 7.46-7.39 (m, 3H), 7.12 (d, 2H), 5.24 (s, 2H), 4.61-4.45 (m, 2H), 3.48-3.39 (m, IH), 3.28-3.20 (m, IH), 2.98-2.87 (m, IH), 2.29-2.17 (m, IH), 2.12-2.00 (m, IH). LC / MS (Method 2, ESIpos): R _t = 1.01 min, m / z = 493 [M + H] ⁺ . Example 114

(-) - 4- {4 - [(3-Chlorobenzyl) oxy] phenyl} -4-oxo-2- [2- (4-oxo-pyrido [3,2-d] [l, 2,3] -triazine-3 (4 /) - yl) - ethyl] butanoic acid (enantiomer 2)

Yield: 23 mg; ee value = 96%; Purity = 99% [α] _D ²⁰ = -20.4 °, 589 nm, c = 0.33 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, IH), 9.13 (dd, IH), 8.63 (dd, IH), 8.08 (dd, IH), 7.97 ( d, 2H), 7.55 (s, IH), 7.46-7.38 (m, 3H), 7.12 (d, 2H), 5.23 (s, 2H), 4.62-4.45 (m, 2H), 3.48-3.39 (m, IH), 3.28-3.19 (m, IH), 2.98-2.87 (m, IH), 2.29-2.17 (m, IH), 2.13-2.00 (m, IH). LC / MS (Method 2, ESIpos): R _t = 1.01 min, m / z = 493 [M + H] ⁺ .

Example 115

(+/-) - 4- [4- ({3- [(methoxycarbonyl) amino] benzyl} oxy) phenyl] -4-oxo-2- [2- (4-oxo-pyrido [3,2-d] - [ l, 2,3] triazin-3 (4 //) - yl) efhyi] butanoic acid

A solution of 174 mg (0.25 mmol) of the compound from Example 57 A in 2.2 ml of dichloromethane was admixed with 1.4 ml (17.57 mmol) of trifluoroacetic acid and stirred at RT overnight. The mixture was then concentrated, the residue dissolved in 2.2 ml of dioxane and the mixture was stirred for 4.5 h under reflux. After cooling to RT and concentration, the residue was purified by preparative HPLC (eluent acetonitrile / water gradient). 75 mg (55% of theory, purity 99%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, 1H), 9.71 (s, 1H), 9.13 (dd, 1H), 8.63 (dd, 1H), 8.08 ( d, 1H), 7.96 (d, 2H), 7.57 (s, 1H), 7.42 (d, 1H), 7.30 (t, 1H), 7.12-7.05 (m, 3H), 5.17 (s, 2H), 4.61 -4.45 (m, 2H), 3.66 (s, 3H), 3.47-3.38 (m, 1H), 3.28-3.20 (m, 1H), 2.99-2.88 (m, 1H), 2.28-2.16 (m, 1H) , 2.13-2.00 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 0.84 min, m / z = 532 [M + H] ⁺ . Separation of the enantiomers:

 69 mg of the compound from Example 115 were dissolved in 3 ml of ethanol / methanol and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 116 and 117) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 280 nm; Injection volume: 0.1 ml; Temperature: 25 ° C; Eluent: t = 0-10 min 25% methanol + 0.2% acetic acid / 75% acetonitrile + 0.2% acetic acid]:

Example 116 (+) - 4- [4 - ({3 - [(Methoxycarbonyl) amino] benzyl} oxy) phenyl] -4-oxo-2- [2- (4-oxopyrido [3,2-d] - [ l, 2,3] triazine-3 (4 /) -yl) ethyl] butanoic acid (enantiomer 1)

Yield: 22 mg; ee value = 100%; Purity = 100%

[a] _D ²⁰ = + 5.8 °, 589 nm, c = 0.24 g / 100 ml, methanol

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (br.s, 1H), 9.72 (s, 1H), 9.13 (dd, 1H), 8.63 (dd, 1H), 8.08 ( dd, 1H), 7.96 (d, 2H), 7.57 (s, 1H), 7.42 (d, 1H), 7.30 (t, 1H), 7.13-7.06 (m, 3H), 5.17 (s, 2H), 4.61-4.45 (m, 2H), 3.66 (s, 3H), 3.49-3.38 (m, 1H), 3.32-3.14 (m, 2H), 2.98-2.88 (m, 1H), 2.29 -2.15 (m, 1H), 2.12-1.99 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 0.84 min, m / z = 532 [M + H] ⁺ . Example 117 (-) - 4- [4 - ({3 - [(Methoxycarbonyl) amino] benzyl} oxy) phenyl] -4-oxo-2- [2- (4-oxopyrido [3,2-d] - [ l, 2,3] triazine-3 (4 //) - yl) efhyi] butanoic acid (enantiomer 2)

Yield: 29 mg; ee value = 88.5%; Purity = 100%

[a] _D ²⁰ = -6.7 °, 589 nm, c = 0.24 g / 100 ml, methanol

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.25 (br.s, 1H), 9.71 (s, 1H), 9.13 (dd, 1H), 8.63 (dd, 1H), 8.08 ( d, 1H), 7.96 (d, 2H), 7.57 (s, 1H), 7.42 (d, 1H), 7.30 (t, 1H), 7.13-7.05 (m, 3H), 5.17 (s, 2H), 4.61 -4.45 (m, 2H), 3.66 (s, 3H), 3.48-3.38 (m, 1H), 3.28-3.15 (m, 1H), 2.98-2.87 (m, 1H), 2.27-2.16 (m, 1H) , 2.12-2.00 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 0.84 min, m / z = 532 [M + H] ⁺ .

Example 118 (+/-) - 4-Oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 //) - yl] ethyl} -4- {4- [(tetrahydro-2i-pyran-4-ylmethyl) sulfanyl] phenyl} butanoic acid

A solution of 1.58 g (2.24 mmol) of the compound of Example 58A in 4 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was stirred under reflux for 4 h. After cooling to RT and concentration, the residue was combined three times in succession with dichloromethane and again concentrated each time. 1.23 g (95% of theory, purity 95%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, 1H), 8.49 (s, 1H), 8.45-8.38 (m, 2H), 7.89 (d, 2H), 7.41 (d, 2H), 4.62-4.45 (m, 2H), 3.84 (dd, 2H), 3.49-3.39 (m, 1H), 3.29-3.20 (m, 3H), 3.02 (d, 2H), 2.99-2.89 (m, IH), 2.29-2.17 (m, IH), 2.13-2.01 (m, IH), 1.80-1.68 (m, 3H), 1.34-1.20 (m, 2H) ,

LC / MS (Method 2, ESIpos): R _t = 1.14 min, m / z = 550 [M + H] ⁺ .

Separation of the enantiomers:

1.23 g of the compound from Example 118 were dissolved in 12 ml of ethanol and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 119 and 120) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 270 nm; Injection volume: 0.06 ml; Temperature: 25 ° C; Eluent: t = 0-20 min 70% ethanol / 22% acetonitrile / 8% 5% acetic acid in acetonitrile]: Example 119

(+) -4-Oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4/) -yl] ethyl} -4- {4 - [( tetrahydro-2-pyran-4-ylmethyl) sulfanyl] phenyl} butanoic acid (enantiomer 1)

The product obtained after enantiomer separation (376 mg) was partially purified by column chromatography (silica gel, mobile phase cyclohexane / ethyl acetate mixture) or by preparative HPLC (Method 10). A total of 282 mg of the title compound was obtained in three different lots. ee value = 100%; Purity = 96-100% (depending on the batch).

[from ²⁰ = + 20.1 °, 589 nm, c = 0.31 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, IH), 8.49 (s, IH), 8.45-8.38 (m, 2H), 7.89 (d, 2H), 7.41 (d, 2H), 4.62-4.45 (m, 2H), 3.84 (dd, 2H), 3.49-3.39 (m, IH), 3.29-3.20 (m, 3H), 3.02 (d, 2H), 2.99- 2.89 (m, IH), 2.29-2.17 (m, IH), 2.13-2.01 (m, IH), 1.80-1.68 (m, 3H), 1.34-1.20 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.14 min, m / z = 550 [M + H] ⁺ . Example 120

(-) - 4-Oxo-2- {2- [4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 /) -yl] ethyl} -4- {4 - [( tetrahydro-2-pyran-4-ylmethyl) sulfanyl] phenyl} butanoic acid (enantiomer 2)

Yield: 394 mg; ee value = 100%; Purity = 100%

[a] _D ²⁰ = -23.5 °, 589 nm, c = 0.32 g / 100 ml, chloroform Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.31 (br.s, 1H), 8.49 (s, 1H), 8.45-8.38 (m, 2H), 7.89 (d, 2H), 7.41 (d, 2H), 4.62-4.45 (m, 2H), 3.84 (dd, 2H), 3.49-3.39 (m, 1H), 3.29-3.20 (m, 3H), 3.02 (d, 2H), 2.99- 2.89 (m, 1H), 2.29-2.17 (m, 1H), 2.13-2.01 (m, 1H), 1.80-1.68 (m, 3H), 1.34-1.20 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 1.14 min, m / z = 550 [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 1.3 28 1.4

2 370 29 140

3 2.0 30 0.45

4 0.41 31 0.47

5 47 32 340

6 1.7 33 0.13

7 0.092 34 0.23

8 36 35 0.012

9 0.60 36 50

10 0.41 37 0.40

11 43 38 130

12 0.15 39 0.39

13 0.47 40 1.1

14 300 41 0.39

15 0.42 42 1.6

16 0.32 43 0.17

17 68 44 83

18 0.098 45 0.10

19 0.40 46 0.29

20 150 47 270

21 0.46 48 0.69

22 0.66 49 0.23

23 170 50 61

24 0.29 51 0.12

25 1.1 52 0.055

26 100 53 0.025

27 0.26 54 49 Example HME / hMMP-12 Example HME / hMMP-12 No. ICso [nM] No. ICso [nM]

55 0.15 84 0.15

56 0.095 85 0.77

57 14 86 0.50

58 0.19 87 210

59 0.088 88 0.17

60 1.0 89 30

61 0.80 90 0.13

62 0.19 91 0.51

63 0.026 92 540

64 0.17 93 0.31

65 21 94 0.86

66 0.067 95 0.62

67 0.46 96 93

68 86 97 0.66

69 0.17 98 330

70 0.20 99 0.33

71 34 100 0.20

72 0.055 101 96

73 0.86 102 0.13

74 41 103 0.81

75 0.38 104 0.34

76 0.61 105 290

77 350 106 0.46

78 0.48 107 0.59

79 0.96 108 140

80 160 109 0.72

81 0.35 110 170

82 0.31 111 0.47

83 140 112 0.73 Example HME / hMMP-12 Example HME / hMMP-12

 No. ICso [nM] No. ICso [nM]

 113 0.38 117 21

 114 52 118 0.027

 115 0.70 119 0.039

 116 0.17 120 1.7

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 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 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 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-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 test:

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). 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 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-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 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-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 concentra- tion, for example, 0.1 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-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 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-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 representative representative embodiments of the invention show the IC 50 values from these human MMP inhibition assays (partly as averages from 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> 30000 710 6700> 30000 6300

 3> 30000 470 4500 18000 5800

 4> 30000 1700> 30000> 30000 3600

 6> 30000 2600 24000> 30000 4600

 7> 30000 540 6700> 30000 24000

 9> 30000 890 10000> 30000 20000

 12> 40000 92 1600> 40000 2300

 18> 30000 140 1500> 30000 940

 24> 40000 510 7800 25000 120

 30> 40000 2000 10000> 30000 86

 33> 40000 1700 1100 4900 310

 35> 40000 1300 2500 2700 19

 37> 30000 2700 7100 5300 480

 40> 40000 5600 3800 3100 720

 45> 40000 2900 6900> 30000 55

 48> 40000 3800 7100 9300 250

 51> 30000 2100 4000 25000 1100

 53> 40000 3100 2200 7400 12

 59> 40000 2900 1800 2800 66

 69> 30000 28000 16000> 30000 1100

 72> 30000 7700 3500> 30000 1200

 79> 40000 19000 15000> 40000 160

81> 30000 11000 7300> 40000 92 Example MMP-1 MMP-2 MMP-3 MMP-7 MMP-8 No. ICso [nM] ICso [nM] ICso [nM] ICso [nM] ICso [nM]

84> 30000 4900 1800> 30000 750

90> 40000 2500 1800> 40000 12

91> 30000 14000 4500> 40000 1500

93> 30000 4300 2200> 30000 520

104> 30000 28000> 30000 1400 9800

112> 30000 230 3600> 30000 1700

113> 30000 270 2400> 30000 1200

118> 40000 5000 1400 1800 18

119> 40000 2400 810 1100 12

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 4500 2800 2900 1700 5300

3 1700 1400 1700 900 2500

4 12000 13000 4600 10000> 30000

6 14000 13000 4800 14000> 30000

7 1400 5700 320> 30000> 30000

9 1900 6000 210> 30000> 30000

12 330 910 68 6200> 40000

18 370 3000 470 1700 15000

24 2000 3200 670 1900 12000

30 2500 3200 870 4300> 30000

33 170 400 660 1200 1600

35 540 500 370 1100 5400

37 13000 2500 2400 4800 17000

40> 30000 1500 2100 6800 18000

45 1500 1900 1400 5000 24000 Example MMP-9 MMP-10 MMP-13 MMP-14 MMP-16

 Nos. ICso [nM] ICso [nM] ICso [nM] ICso [nM] ICso [nM]

 48 1500 2700 3000 4000 38000

 51 4100 1300 3900 18000> 30000

 53 950 710 1000 3900 6000

 59 1500 290 1600 8300 22000

 69 8700 6500 20000> 30000> 30000

 72 2100 4300 14000> 30000> 30000

 79 3200 1300 1700> 30000> 30000

 81 2000 600 1100 23000 13000

 84 460 410 780> 30000 9700

 90 290 160 480 7600 1000

 91 850 660 500> 30000 3600

 93 250 300 370 19000 1600

 104 18,000> 30,000> 30,000> 30,000> 30,000

 112 950 1500 1500 1700 12000

 113 700 1200 820 1200 9000

 118 750 500 2100 3000 21000

 119 760 3200 550 2000 4400

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 enantiomers in particular have a very high inhibitory potency (frequently in the sub-nanomolar range) over HME and at the same time a very high selectivity ( usually two to four orders of magnitude or more) relative to 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 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 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 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-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, 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 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 (for example 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 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-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. In this case, a tenfold lower enzyme concentration is used (final concentration, for example, 0.1 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).

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-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.).

Rat in vitro 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, for example 0.1 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 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 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 the to be examined testing procedures Binding (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-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

The compounds according to the invention thus have a high inhibitory potency (frequently in the nanomolar range) over MMP-12 of the mouse and at the same time a high selectivity (usually one to three 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 begins on the day of 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 causes 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 an orotracheal 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 leads to 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 CYP enzymes CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in humans is investigated using pooled human liver microsomes as the enzyme source in the presence of standard substrates (see below) that form CYP-specific metabolites. The inhibition effects are observed at six different concentrations of the test compounds. [2.8, 5.6, 8.3, 16.7, 20 (or 25) and 50 μΜ], was 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 were calculated. A standard inhibitor that specifically inhibits a single CYP isoform is always incubated to make results comparable between different series.

Incubation of phenacetin, diclofenac, tolbutamide, dextromethorphan or midazolam with human liver microsomes in the presence of six different concentrations of each 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 MgCl ₂ × 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. Test compounds 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) in order to obtain linear kinetic conditions in the Try to make sure. 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 apparent 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: I max well-stirred [] maximum bioavailability after oral administration

Calculation: (1-CLbiood well-stirred / QH) * 100

 CLbiood well-stirred [L / (h * kg)] calculated blood clearance (well-stirred model)

 Calculation: (QH * CL'intrinsic) / (QH + CL'intrinsic)

 CL'intrinsic [ml / (min * kg)] maximum ability of liver (hepatocytes) to metabolize a compound (assuming that hepatic blood flow is not rate limiting)

 Calculation: CL'intnnsic, apparent * species-specific hepatocyte count [1.1 * IC 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).

Table 4 below shows, for representative embodiments of the invention, the CL and Fmax values from this assay after incubation of the compounds with rat hepatocytes (partly as averages of several independent individual determinations):

Table 4: Calculated blood clearance and bioavailability after incubation with rat hepatocytes

Example no. CL _bl00d [L / (h * kg)] F _max []

 24 0.89 78.7

 27 0.78 81.4

 30 0.59 85.9

 33 1.49 64.4

 45 1.32 68.6

 48 1.34 68.1

 53 0.8 80.9

 63 0.52 87.6

 81 0.25 94.0

 107 0.02 99.5

111 0.27 93.5 Example no. CL _bl00d [L / (h * kg)] F _max []

 113 0.81 80.8

 118 1.53 63.6

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 centrifuged off at about 15,000 × g. 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), the 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. The pharmacokinetic parameters, such as AUC (area under the concentration-time curve), Cmax (maximum plasma concentration), tm (half-life) are calculated from the plasma concentration / time profiles determined using an internal standard and with the help of a validated computer program ), 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

1. Compound of formula (I)

in which

A is -O- or -S-,

L is -CH ₂ - or -CH ₂ CH ₂ -, for a cyclic group of the formula

indicates the linkage position to the group L,

X is CH or N, R ^{1 is} a substituent selected from the group fluorine, chlorine, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, (trifluoromethyl) sulfanyl, methoxycarbonylamino and 2-oxo-1,3-oxazolidin-3 -yl, where such a substituent may be attached in the designated position 2, 3 and / or 4, m is 1 or 2, and in the event that the substituent R ¹ occurs twice, its individual meanings may be the same or different can, and

R ^{2 is} hydrogen or fluorine, Y is CH or N,

R ^{3 is} a substituent selected from the group consisting of fluorine, chlorine, methyl, fluoromethyl, difluoromethyl and trifluoromethyl, where such substituent, when present, may be attached in the designated position 6, 7 and / or 8, and n is the number 0, 1 or 2, wherein, in the event that the substituent R ³ occurs twice, its individual meanings may be the same or different, and their salts, solvates and solvates of the salts.

A compound of the formula (I) according to claim 1, in which

A is -O- or -S-,

L is -CH ₂ - or -CH ₂ CH ₂ -,

Cy is a cyclic group of the formula

stands in which

* indicates the linkage position to the group L,

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

R ^{1B is} hydrogen, chlorine, methyl, trifluoromethyl or trifluoromethoxy,

Y stands for CH, R ^{3 is} a substituent selected from the group consisting of fluorine, chlorine, methyl and trifluoromethyl, such a substituent, if present, being bonded in the designated position 6, 7 or 8, and n is the number 0 or 1, and their salts, solvates and solvates of the salts.

A compound of the formula (I) according to claim 1 or 2, in which

A is -O- or -S-,

L is -CH ₂ - or -CH ₂ CH ₂ -,

Cy is a cyclic group of the formula

stands in which

* denotes the linkage position to the group L, Y stands for CH,

R ^{3 is} a substituent selected from the group chlorine, methyl and trifluoromethyl, which is bonded in the designated 6- or 7-position, and n is the number 1, and their salts, solvates and solvates of the salts.

A compound of the formula (I) according to claim 1 or 2, in which

A is -O-,

L is -CH ₂ -,

Cy is a cyclic group of the formula stands in which

* indicates the linkage position to the group L,

R ^{1A is} chlorine, methyl, trifluoromethyl or trifluoromethoxy, and

R ^{1B is} hydrogen or chlorine, Y is CH,

R ^{3 is} a substituent selected from the group of chlorine, methyl and trifluoromethyl, which is bonded in the designated 6- or 7-position, and n is the number 1, and their salts, solvates and solvates of the salts.

A compound according to claim 1, 2, 3 or 4 having the formula (I-A)

in which A, L, Cy, Y, R ³ and n have the meanings given in claim 1, 2, 3 or 4 and the chiral carbon atom marked with * in enantiomerically pure form has the ^-configuration shown, and also their salts, Solvates and solvates of salts.

6. A process for preparing a compound as defined in claims 1 to 5, characterized in that di-ieri.-butyl- (2-hydroxyethyl) malonate of the formula (Π)

in the presence of a phenylphosphine and an azodicarboxylate with a triazine-4 (3 //) -one derivative of the formula (ΠΙ)

in which R ³ , n and Y have the meanings given in claims 1 to 5, to give a compound of the formula (IV)

in which R ³ , n and Y have the meanings given in claims 1 to 5, and then reacting the compound of formula (IV) either

[A] in the presence of a base with a compound of the formula (V)

(V) in which A, L and Cy have the meanings given in claims 1 to 5 and

Z ^{1 represents} a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, to give a compound of the formula (VI)

in which A, L, Cy, R ³ , n and Y have the meanings indicated in claims 1 to 5, alkylated

first with a compound of the formula (VII)

in which A has the meaning given in claims 1 to 5,

PG is a temporary protecting group such as acetyl or benzoyl and

Z ^{2 represents} a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, in the presence of a base to give a compound of the formula (VIII)

in which A, PG, R ³ , n and Y have the meanings given above, followed by deprotection of the protective group PG and the resulting compound of the formula (IX)

in which A, R ³ , n and Y are as defined in claims 1 to 5, then in the presence of a base with a compound of formula (X)

in which L and Cy have the meanings given in claims 1 to 5 and represents a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, to the compound of the formula (VI)

in which A, L, Cy, R ³ , n and Y have the meanings given in claims 1 to 5, alkylated and the thus obtained by method [A] or [B] compound of formula (VI) finally by treatment with a Acid and subsequent heating in the carboxylic acid of the formula (I)

 have, converted and the compounds of formula (I) optionally separated into their enantiomers and / or diastereomers and / or optionally with the corresponding (i) solvents and / or (ii) bases to 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 diseases, idio- pathological 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.

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 atherosclerosis, viral myocarditis, cardiomyopathy and aneurysms, including their sequelae such as stroke, myocardial infarction and peripheral vascular disease, as well as chronic renal disease and Alport syndrome.

A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 5 in combination with one or more inert non-toxic pharmaceutically acceptable excipients.

A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 5 in combination with one or more other active ingredients selected from the group consisting of corticosteroids, beta-adrenergic receptor agonists, anti-muscarinergic 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.

A pharmaceutical composition 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 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 vascular disease, as well as chronic kidney disease and Alport syndrome.

Method 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 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; of chronic renal diseases and Alport syndrome in humans and animals by administering an effective amount of at least one compound as defined in any one of claims 1 to 5 or a pharmaceutical composition as defined in any one of claims 10 to 12.