1-ARYL-NAPHTYRIDIN-3-YLCARBOXAMIDES SUBSTITUTED AT POSITION 7 AND THEIR USE

Description

[0001] The present application relates to new 7-substituted 1-aryl-naphthyridine-3-carboxamides, processes for their production, their use alone or in combinations for the treatment and / or prevention of diseases and their use for the production of medicaments for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of cardiovascular diseases and / or kidney diseases.

[0002] Muscarinergic receptors are membrane-based receptors that bind the neurotransmitter acetylcholine (ACh) as an endogenous ligand (acetylcholine receptors), but can also be activated by muscarin. These G protein-coupled receptors exist as five subtypes (M1-M5) that are expressed in almost all tissues in the human organism. They are found in both the central and peripheral nervous systems as well as in many organs of the autonomic nervous system.

[0003] The M2 type (M2R) is predominantly expressed in the heart. At the cellular level, M2R stimulation by the agonist acetylcholine causes an inhibition of adenyl cyclase and an activation of the inwardly rectifying potassium channel (IKACh channel, GIRK: G protein activated inwardly rectifying K+ channel; also Kir3.x). This increases the potassium conductivity, which leads to hyperpolarization of the muscle cells. Accordingly, the cells become more difficult to depolarize, which leads to a negative chronotropic and dromotropic effect, so that the heart rate decreases. The M2R is the main mediator of the parasympathetic control of cardiac function, which is controlled by the vagus nerve. The right vagus nerve reduces the heart rate via the sinoatrial node, while the left predominantly increases the atrioventricular conduction time via the atrioventricular node (AV node). Overall, the influence of the vagus on the resting frequency of the heart predominates compared to the sympathetic nervous system. The effects of stimulation of M2R are therefore opposite to those of beta-adrenergic stimulation.

[0004] The activation of the M2 receptor by the endogenous agonist acetylcholine, but also by synthetic analogues such as carbachol, oxotremorin-M or Iperoxo (Schrage et al., Biochem. Pharmacol. 2014, 90(3), 307-319) occurs through the binding of the agonist to the so-called orthosteric binding site of the receptor and a resulting conformational change of the receptor or stabilization of the active receptor conformation. In addition to the endogenous agonist acetylcholine (ACh), the classic naturally occurring muscarinic receptor agonists include various plant alkaloids such as arecoline, muscarine and pilocarpine (Neubig et al., Pharmacol Rev., 2003, 55, 597-606). The orthosteric binding site of all muscarinic acetylcholine receptors is highly evolutionarily conserved and shows a high sequence and structural homology between the different subtypes. Therefore, many of the known agonists are nonselective towards the different subtypes of muscarinic acetylcholine receptors (Kruse et al., Mol Pharmacol., 2013, 84(4), 528-540). The M2R has an orthosteric as well as an allosteric binding site (Gregory et al., Current Neuropharmacol., 2007, 5(3), 157-167). The oldest known allosteric modulator is gallamine (Clark and Mitchelson, Br. J. Pharmac., 1976, 58, 323-331).

[0005] Allosteric modulators have clear differences compared to classic, orthosteric ligands. The allosteric modulator itself has no direct influence on receptor activation. The binding of the alloster results in a modulation of the binding affinity and / or effectiveness of the orthosteric agonist. The effect of an allosteric modulator can only develop in the presence of the endogenous ligand. This results in a spatial and temporal specificity of the allosteric effect (Conn et al., Nat. Rev. Drug Disc., 2009, 8, 41-54; Conn et al, Nat. Rev. Drug. Disc., 2014, 13, 692-708). Furthermore, the effect of an allosteric modulator is self-limiting if it stabilizes the binding of the agonist at high concentrations. This in turn generally results in a more favorable safety pharmacological profile compared to agonists, since toxic effects are limited due to receptor overactivation (Christopoulos, Mol. Pharmacol., 2014, 86, 463-478).

[0006] The mutual influence of allosteric and orthosteric ligands in terms of affinity and intrinsic activity, known as cooperativity, is determined by both ligands. In the case of a positive allosteric modulator of the M2R, the effects of the ACh (orthosteric ligand) are enhanced (positive cooperativity). Due to their ability to modulate receptor conformations in the presence of an orthosteric ligand, allosteric ligands can produce fine-tuning pharmacological effects (Wang et al., J. Pharmacol. Exp. Therap., 2009, 331, 340-348). In the case of the positive allosteric modulator of M2R, this can be expected to have an advantageous effect profile, a reduced risk of side effects and a starting point for the development of subtype-selective ligands compared to a full agonist.

[0007] From the positive allosteric M4R and M2R ligand LY2119620 (3-amino-5-chloro- N -cyclopropyl-4-methyl-6-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]thieno[2,3-b]pyridine-2-carboxamide), the crystal structure in complex with the M2R was published. The allosteric binding site of the M2R is spatially adjacent to, but clearly demarcated from, the orthosteric binding site and, in comparison to the other muscarinic receptor subtypes, shows less conservation or has larger sequence differences (Kruse et al., Nature, 2013, 504, 101- 106). LY2119620 has been described as a nonselective M2R / M4R positive allosteric modulator (Croy et al., Molecular Pharmacology, July 2014 86, 1, 106-115; Schober et al., Molecular Pharmacology, July 2014 86, 1, 116-123).

[0008] As a component of the autonomic nervous system, the M2R plays an important role in the pathogenesis and progression of cardiovascular diseases. Autonomic imbalance characterized by vagal (parasympathetic) attenuation and a dominance of the sympathetic nervous system is closely associated with increased morbidity and mortality. The clinical and prognostic significance of autonomic imbalance is well documented in various cardiovascular diseases, including heart failure (HF), cardiac arrhythmias, ischemia / reperfusion (I / R), hypertension (He et al., Br. J. Pharmacol. 2014 , Epub) and chronic kidney disease (Ranpuria et al., Nephrol Dial Transplant. 2008, 23(2), 444-4499). Particularly in patients with comorbidities such as diabetes, autonomic imbalance can contribute to increased morbidity and mortality (Vinik et al., Diabet Med., 2011, 28(6), 643-651). Baroreceptor reflex dysfunction, such as hypertensive crises or hypertension variability, as signs of autonomic nervous system dysfunction, often accompany the acute phase of ischemic or hemorrhagic stroke (Sykora et al., Stroke, 2009, 40(12), 678-682 ).

[0009] The often observed comorbidity between cardiovascular and mental illnesses, such as between heart failure and depression, is probably based on common pathomechanisms associated with autonomic imbalance (Halaris et al., Mod Trends Pharmacopsychiatri., 2013, 28, 144-161). Chronic stress shifts the homeostatic balance of the autonomic nervous system. Decreased vagal tone contributes to a pro-inflammatory status, with impaired neurotransmitter regulation, particularly serotonergic transmission. Other mental illnesses have also been associated with autonomic dysregulation, such as attention-deficit / hyperactivity disorder (ADHD), which is characterized by disinhibition, poor emotional self-control, inattention, and hyperactivity (Rash and Aguirre-Camacho, Atten Defic Hyperact Disord., 2012, 4(4), 167-177).

[0010] A strengthening of parasympathetic activity through a positive allosteric modulator including expected anti-inflammatory effects, increase in nitric oxide (NO), regulation of the redox state, improvement of mitochondrial function and calcium regulation could therefore represent a new therapeutic principle, especially in cardiovascular diseases. There is ample evidence that modulation of parasympathetic activity can be considered as a potential therapeutic target in chronic heart failure. Vagus nerve stimulation in dogs with healed myocardial infarction was able to significantly reduce the incidence of sudden cardiac death and mortality in chronic heart failure rats (De Ferrari, J. Cardiovasc. Transl. Res., 2014, 7(3), 310-320). In a dog model with heart failure (LVEF 35%) and an implanted vagal stimulator, it was demonstrated that the therapy group experienced a significant improvement in left ventricular ejection fraction (LVEF) and reduction in end-systolic and end-diastolic volumes (LVESV; LVEDV) compared to the sham group as well as a significant reduction in heart rate within 3 months. The described effect of VNS was additive to the administration of beta blockers (De Ferrari, J. Cardiovasc. Transl. Res., 2014, 7(3), 310-320). The plasma levels of TNF-α and IL-6 as well as their myocardial protein expression could be reduced by vagal stimulation in this animal model, which suggests that strengthening the parasympathetic nervous system has positive effects on pro-inflammatory cytokines in addition to the effects on LV remodeling.

[0011] Based on the experimental preclinical data, the first clinical studies on vagal stimulation in patients with chronic heart failure, as already established in the treatment of epilepsy and depression, have now been carried out. The effect of parasympathetic enhancement via direct vagus nerve stimulation (VNS) was evaluated in a non-randomized observational study of 32 patients with left ventricular (LV) systolic dysfunction, with results indicating that vagal stimulation improved quality of life, exercise tolerance, and LV function. Remodeling favorably influenced (De Ferrari GM et al., Eur. Heart J., 2011, 32, 847-855) In the multicenter open-label feasibility study ANTHEM-HF, the safety, tolerability and effectiveness of vagal stimulation in patients with chronic stable, symptomatic heart failure with reduced ejection fraction (HFrEF) in addition to standard therapy (Premchand RK et al., J. Card. Fail., 2014, 20(11), 808-816). Continuous vagal nerve stimulation used in this study resulted in improvements in ejection fraction, heart rate variability, NYHA class, and quality of life. The first placebo-controlled clinical study NECTAR-HF, however, was unable to show any significant effect of vagus nerve stimulation on the cardiac function of HF patients after 6 months (Zannad et al., Eur. Heart J., 2015, 36(7), 425-433) . Only the quality of life could be improved. The INOVATE-HF study with 650 HF patients was unable to show any effects of this therapy in terms of mortality and hospitalization. (Gold et al., J Am Coll Cardiol., 2016, Mar 29. pii: S0735-1097(16)32404-4. doi: 10.1016 / j.jacc.2016.03.525). Quality of life and walking distance were significantly improved.

[0012] In addition to the risk of infection and the potential risks of a surgical procedure, therapy using electrical stimulation of the vagus nerve is limited by side effects such as: dysphonia, cough and mouth / throat pain (Premchand RK et al., J. Card. Fail., 2014, 20(11 ), 808-816). Drug strengthening of the parasympathetic nervous system through a direct effect on the M2R could represent a new therapeutic option.

[0013] Atrial fibrillation is the most common persistent cardiac arrhythmia and its prevalence increases with age (Chen et al., Circ. Res., 2014, 114(9), 1500-1515). Atrial fibrillation and heart failure are often associated and reinforce each other. The prevalence of atrial fibrillation increases with the clinical severity of heart failure (Maisel and Stevenson, Am. J. Cardiol., 2003, 91, (suppl) 2D-8D). Clinical data suggest that patients in whom heart failure is accompanied by atrial fibrillation have a poor prognosis. Both mortality (overall mortality, sudden death and pump failure) and morbidity (hospitalization) were found to be significantly increased in this patient group.

[0014] When treating atrial fibrillation, a distinction is made between two treatment strategies: the so-called frequency control with adjustment and, if possible, normalization of the ventricular frequency in the context of atrial fibrillation, and the so-called rhythm control, which includes measures with which a sinus rhythm is to be established or maintained. An effective treatment consists of a combination of non-drug as well as drug or interventional measures (Levalter T, Advanced Training Program Pharmacy, 2011, 5, 106-127).

[0015] Beta blockers, class I and class III antiarrhythmics are used to control the rhythm with medication after cardioversion, depending on the underlying cardiac disease and the extent of the left ventricular pump function impairment. In patients with permanent atrial fibrillation as well as in oligosymptomatic (often older) patients with persistent or paroxysmal atrial fibrillation, pure frequency control while maintaining and leaving atrial fibrillation is often the treatment of choice. Medications that have an influence on the refractory period or the conduction capacity of the AV node are primarily used. In principle, this effect could be achieved by stimulating the M2R, which physiologically plays the key role at this point, e.g. with the help of a positive allosteric modulator. So far, beta blockers, digitalis, calcium antagonists and, in individual cases, amiodarone are available, which are used on an individual basis, taking into account the lifestyle, the underlying cardiac disease or any accompanying diseases. However, the options for drug therapy are inadequate, particularly in patients with reduced left ventricular pump function and severe heart failure. Calcium antagonists are contraindicated in this patient group. Digoxin therapy leads to increased mortality in patients with atrial fibrillation, as recent studies have shown (Leong-Sit and Tang, Curr. Opin. Cardiol., 2015 , EPub). A meta-analysis reported a lack of effectiveness for beta-blockers in patients with atrial fibrillation and heart failure (Leong-Sit and Tang, Curr. Opin. Cardiol., 2015 , EPub). The medical need for new, efficient and safe therapies for frequency control is correspondingly high. This could be achieved through drug stimulation of the M2R.

[0016] The object of the present invention is to identify and provide new substances which are potent, positive allosteric modulators of the muscarinic M2 receptor and as such are suitable for the treatment and / or prevention of, in particular, cardiovascular diseases and / or kidney diseases.

[0017] 1-Benzyl-substituted 4-oxo-1,4-dihydroquinolines-3-carboxylic acids are described as allosteric modulators of the M1 muscarinic receptor for the treatment of neurodegenerative diseases such as Alzheimer's and schizophrenia (Scammells et al., ACS Chem. Neurosci., 2013, 4 (7), 1026-1048; Mistry et al., J. Med. Chem. 2013, 56, 5151-5172). Pyridonecarboxylic acid derivatives which have antibacterial activity are known from EP 0945435 B1, among others. WO 2002 / 085886-A2, WO 2003 / 050107-A1 and WO 2005 / 026145-A2 describe 7-piperidino-substituted quinolone carboxylic acid derivatives, as well as various 7-pyrrolide in WO 2005 / 026165-A1 and WO 2005 / 049602-A1 ino -substituted quinolone carboxylic acid derivatives and in EP 1650192-A1 special 7-azetidinyl quinolone carboxylic acid derivatives with antimicrobial / antibacterial activity are claimed. Quinolone derivatives which can be used as platelet aggregation inhibitors are known from WO 2005 / 009971-A1 and JP 2005012561. In WO 2015 / 189560-A1, 1,4-dihydroquinoline derivatives are disclosed as NPRC agonists for the treatment of cardiovascular diseases. Quinolone carboxylic acid derivatives as MCT modulators are described in WO 2016 / 081464-A1 for the treatment of tumor diseases and inflammatory processes in particular.

[0018] The present invention relates to compounds of the general formula (I) in which X for halogen stands, r 1 <for hydrogen, or for -no. , where (C 2 -C 4 )-alkyl can be substituted with hydroxy or up to three times with fluorine and R 5 < (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, 3- to 6 -membered saturated heterocyclyl or (C 1 -C 4 )-alkylsulfonyl, where (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl and 3- to 6-membered saturated heterocyclyl, up to three times, identical or different, can be substituted with methyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxycarbonyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy, cyano and further up to four times with fluorine, or R 4< and R 5< form together with the nitrogen atom, to which they are bound, a saturated or partially unsaturated, 3- to 6-membered monocyclic or 6- to 10-membered bicyclic heterocycle, which contains one or two further, identical or different heteroatoms from the series N, O, S, SO and / or can contain SO 2 as ring members, the 3- to 6-membered monocyclic and the 6- to 10-membered bicyclic heterocycle each with 1 to 5 substituents being independently selected from the group (C 1 -C 4 )-alkyl, Difluoromethyl, trifluoromethyl, hydroxy, hydroxycarbonyl, oxo, (C 1 -C 3 )-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, (C 1 -C 3 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 3 )-alkylaminocarbonyloxy, -NHC(=O)R 14A<, -CH 2 NHC(=O)R 14B<, -OC(=O)R 15<, and further up to four times with fluorine, can be substituted, in which (C 1 -C 4)-Alkyl can be substituted once or twice, identically or differently, with hydroxy, (C 1 -C 3 )-alkoxy, and up to four times with fluorine, R 14A < and R 14B < independently of each other (C 1 - C 3 )-alkyl or cyclopropyl, and in which R 15< represents (C 1 -C 4 )-alkyl, R 2< represents a group of the formula where * marks the connection point with the N atom of the amide group, R 6A < hydrogen or (C 1 -C 4 )-alkyl, R 6B < hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl, Monofluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl or trifluoromethoxymethyl, R 7< means (C 1 -C 6 )-alkyl or (C 3 -C 5 )-cycloalkyl substituted up to four times with fluorine, where (C 1 -C 6 )- Alkyl can be substituted with amino, hydroxy, (C 1 -C 6 )-alkoxy and up to five times with fluorine, in which (C 1 -C 6 )-alkoxy can be substituted up to five times with fluorine L 1 < one bond or one Group of the formula -C(R 8A< R 8B< )-(C(R9 A< R 9< B)) m - means, in which m represents 0 or 1, R 8A< represents hydrogen or methyl, R 8B< hydrogen, represents methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl, R 9A< and R 9B< independently represent hydrogen or methyl, Ar 2< represents phenyl, where phenyl is one to three times, identical or different, with fluorine, chlorine, (C 1 -C 3)-Alkyl, difluoromethoxymethyl, trifluoromethoxymethyl and / or trifluoromethyl can be substituted, or for a 5- to 10-membered monocyclic, bicyclic or tricyclic carbocycle or heterocycle which contains one or two further, identical or different heteroatoms from the series N and / or or O as ring members, where the 5- to 10-membered monocyclic, bicyclic or tricyclic carbocycle or heterocycle is up to three times, identical or different, with (C 1 -C 3 )-alkyl, trifluoromethyl, (C 1 - C 4 )-alkoxycarbonyl and can further be substituted up to four times with fluorine, Ar 1< for a group of the formula is where *** marks the junction with the N atom, R 3A< stands for fluorine, chlorine, trifluoromethyl or methyl, R 3B< stands for hydrogen or fluorine and R 3C< stands for hydrogen, fluorine, chlorine or methyl, or represents a pyridine ring attached via a ring carbon atom, where the pyridine ring can be substituted once or twice with fluorine, chlorine, cyano, methyl or trifluoromethyl, as well as their N -oxides, salts, solvates, salts of the N -Oxides and solvates of the N -oxides and salts.

[0019] Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds of the following formulas included in formula (I) and their salts, solvates and solvates of the salts as well as those of formula (I), The compounds mentioned below as exemplary embodiments and their salts, solvates and solvates of the salts, insofar as the compounds included in formula (I) are not already salts, solvates and solvates of the salts.

[0020] Compounds according to the invention are also N -Oxides of the compounds of formula (I) and their salts, solvates and solvates of the salts.

[0021] In the context of the present invention, physiologically harmless salts of the compounds according to the invention are preferred as salts. Also included are salts that 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.

[0022] A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid addition salt of a compound of the present invention having a sufficiently basic nitrogen atom in a chain or ring, such as an acid addition salt with an inorganic acid or "mineral acid", for example hydrochloric acid , hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, disulfuric acid, phosphoric acid or nitric acid, or with an organic acid, such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2 -(4-Hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectic acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulf onic acid, benzenesulfonic acid, para-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, Aspartic acid, sulfosalicylic acid or thiocyanic acid.

[0023] Another suitable pharmaceutically acceptable salt of a sufficiently acidic compound of the present invention is also an alkali salt, for example a sodium or potassium salt, an alkaline earth salt, for example a calcium, magnesium or strontium salt, or an aluminum or zinc salt or an ammonium salt derived is of ammonia or an organic primary, secondary or tertiary amine with 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris (hydroxymethyl) aminomethane, procaine, dibenzylamine, N -Methylmorpholine, arginine, lysine, 1,2-ethylenediamine, N -Methylpiperidine, N -methylglucamine, N,N- dimethylglucamine, N -Ethylglucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt with a quaternary ammonium ion with 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra( n- propyl)ammonium, tetra( n -butyl)ammonium, N -Benzyl- N,N,N -trimethylammonium, choline or benzalkonium.

[0024] Furthermore, it is known to those skilled in the art that acid addition salts of the claimed compounds can be prepared by reacting the compounds with the corresponding inorganic or organic acid using a number of known methods. Alternatively, alkali metal and alkaline earth metal salts of the acidic compounds according to the invention are prepared by reacting the compounds according to the invention with the corresponding base using various known methods.

[0025] The present invention includes all possible salts of the compounds of the present invention as individual salts or as a mixture of these salts in any ratio.

[0026] When a compound is mentioned in the present text, especially in the experimental part, for the synthesis of intermediate products and examples of the present invention as a salt form with the corresponding base or acid, the exact stoichiometric composition of the salt form as determined by the respective preparation and / or or cleaning process was obtained is not known in most cases. Unless otherwise indicated, additions to chemical names or structural formulas that refer to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt" or "x HCl", "x CF 3 COOH", "x Na +< " a salt form, although the stoichiometry of this salt is not specified. This applies accordingly to cases in which synthesis intermediates or example compounds or salts thereof were obtained as solvates, for example as hydrates, according to the production and / or purification process described.

[0027] 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 through coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. Hydrates are preferred as solvates in the context of the present invention.

[0028] Depending on their structure, the compounds according to the invention can exist in different stereoisomeric forms, i.e. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers). The present invention therefore encompasses the enantiomers and diastereomers as well as their respective mixtures. The stereoisomerically uniform components can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers. Chromatographic methods are preferably used for this, in particular HPLC chromatography on achiral or chiral separation phases. In the case of carboxylic acids as intermediates or end products, a separation can alternatively be carried out via diastereomeric salts using chiral amine bases.

[0029] In the context of the present invention, the term “enantiomerically pure” is understood to mean that the compound in question is present in an enantiomeric excess of more than 95%, preferably more than 98%, with regard to the absolute configuration of the chiral centers. The enantiomeric excess enantiomeric excess, ee value) is calculated by evaluating the chromatogram of an HPLC analysis on a chiral phase using the following formula: ee = Enantiomer 1 Flächenprozent − Enantiomer 2 Flächenprozent Enantiomer 1 Flächenprozent − Enantiomer 2 Flächenprozent × 100 % .

[0030] To the extent that the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

[0031] The present invention also includes all suitable isotopic variants of the compounds according to the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is opposed to another atom of the same atomic number, but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature ("unnatural proportion") ) is replaced. The term “unnatural portion” means a portion of such an isotope that is higher than its natural abundance. The natural frequencies of isotopes to be used in this context can be found in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1), 217-235, 1998. Examples of isotopes that can be incorporated into a compound according to the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2< H (deuterium), 3< H (tritium), 13< C, 14< C, 15< N, 17< O, 18< O, 32< P, 33< P, 33< S, 34< S , 35<S, 36<S, 18<F, 36<Cl, 82<Br, 123<I, 124<I, 129<I and 131<I. Certain isotopic variants of a compound according to the invention, in particular those in which one or more radioactive isotopes are incorporated, can be of use, for example, for studying the mechanism of action or the distribution of active ingredients in the body; Because they are comparatively easy to produce and detect, compounds marked with 3<H or 14<C isotopes are particularly suitable for this purpose. In addition, the incorporation of isotopes such as deuterium can lead to certain therapeutic benefits as a result of greater metabolic stability of the compound, such as an extension of the half-life in the body or a reduction in the required effective dose; Such modifications of the compounds according to the invention may therefore also represent a preferred embodiment of the present invention. With regard to the treatment and / or prophylaxis of the disorders specified here, the isotopic variant(s) of the compounds of the general formula (I) preferably contain deuterium ("deuterium-containing compounds of the general formula (I)"). Isotopic variants of the compounds of general formula (I), into which one or more radioactive isotopes, such as 3<H or 14<C, are incorporated, are useful, for example, in drug and / or substrate tissue distribution studies. These isotopes are particularly preferred because of their easy incorporation and detectability. Positron-emitting isotopes such as 18<F or 11<C can be incorporated into a compound of the general formula (I). These isotopic variants of the compounds of general formula (I) are suitable for use in in vivo imaging applications. Deuterium-containing and 13<C-containing compounds of the general formula (I) can be used in mass spectrometry analyzes in the context of preclinical or clinical studies (H. J. Leis et al., Curr. Org. Chem., 1998, 2, 131). Isotopic variants of the compounds according to the invention can be prepared using commonly used methods known to those skilled in the art, for example using the methods described below and the instructions given in the exemplary embodiments, by using corresponding isotopic modifications of the respective reagents and / or starting compounds. Isotopic variants of the compounds of general formula (I) can generally be prepared according to methods known to those skilled in the art, as described in the schemes and / or examples described here, by replacing a reagent with an isotopic variant of the reagent, preferably a deuterium-containing reagent. Depending on the desired deuteration sites, in some cases deuterium from D 2 O can be incorporated either directly into the compounds or into reagents that can be used for the synthesis of such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al., Chem. Eur. J., 2007, 13, 4052). Deuterium gas is also a useful reagent for incorporating deuterium into molecules. A rapid route to incorporation of deuterium is the catalytic deuteration of olefinic bonds (H. J. Leis et al., Curr. Org. Chem., 1998, 2, 131; J. R. Morandi et al., J. Org. Chem., 1969, 34 (6), 1889) and acetylenic bonds (N. H. Khan, J. Am. Chem. Soc., 1952, 74 (12), 3018; S. Chandrasekhar et al., Tetrahedron, 2011, 52, 3865). To directly exchange hydrogen for deuterium in functional group-containing hydrocarbons, metal catalysts (i.e., Pd, Pt, and Rh) can also be used in the presence of deuterium gas (J. G. Atkinson et al., U.S. Patent 3,966,781). Various deuterated reagents and synthesis building blocks are commercially available from companies such as C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA. Further information regarding the state of the art with regard to deuterium-hydrogen exchange can be found, for example, in Hanzlik et al., J. Org. Chem., 1990, 55, 3992-3997; R.P. Hanzlik et al., Biochem. Biophys. Res. Commun., 1989, 160, 844; P. J. Reider et al., J. Org. Chem., 1987, 52, 3326-3334; M. Jarman et al., Carcinogenesis, 1993, 16(4), 683-688; J. Atzrodt et al., Angew. Chem., Int. Ed. 2007, 46, 7744; K. Matoishi et al., 2000, J. Chem. Soc, Chem. Commun., 1519-1520; K. Kassahun et al., WO 2012 / 112363.

[0032] The term "deuterium-containing compound of general formula (I)" is defined as a compound of general formula (I) in which one or more hydrogen atoms are replaced by one or more deuterium atoms and in which the abundance of deuterium in each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%. In particular, in a deuterium-containing compound of general formula (I), the abundance of deuterium in each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% in this position or these positions. It is understood that the abundance of deuterium in each deuterated position is independent of the abundance of deuterium in other deuterated positions.

[0033] By selectively incorporating one or more deuterium atoms into a compound of the general formula (I), the physicochemical properties (such as acidity [A. Streitwieser et al., J. Am. Chem. Soc., 1963, 85, 2759; C. L. Perrin et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin, et al., J. Am. Chem. Soc., 2003, 125, 15008; C. L. Perrin in Advances in Physical Organic Chemistry, 44, 144; C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19 (3), 271]) and / or the metabolic profile of the molecule is changed and changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed are caused. Such changes may result in certain therapeutic benefits and therefore may be preferred in certain circumstances. Decreased metabolic rates and metabolic switching, in which the ratio of metabolites changes, have been reported (D. J. Kushner et al., Can. J. Physiol. Pharmacol., 1999, 77, 79; A. E. Mutlib et al., Toxicol. Appl . Pharmacol., 2000, 169, 102). These changes in exposure to parent compound and metabolites may have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I). In some cases, deuterium replacement reduces or eliminates the formation of an undesirable or toxic metabolite and increases the formation of a desired metabolite (e.g. nevirapine: A. M. Sharma et al., Chem. Res.Toxicol., 2013, 26, 410; Uetrecht et al ., Chemical Research in Toxicology, 2008, 21, 9, 1862; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases, the main effect of deuteration is to reduce the rate of systemic clearance. This increases the biological half-life of the compound. Potential clinical benefits include the ability to maintain similar systemic exposure with reduced peak levels and increased trough levels. This could result in reduced side effects and increased efficacy depending on the pharmacokinetics / pharmacodynamics relationship of the compound in question. Examples of this deuterium effect are Indiplon (A. J. Morales et al., Abstract 285, The 15th North American Meeting of the International Society of Xenobiotics, San Diego, CA, October 12-16, 2008), ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208) and odanacatib (K. Kassahun et al., WO2012 / 112363). Other cases have also been reported in which reduced metabolic rates lead to an increase in drug exposure without changing the rate of systemic clearance (e.g. rofecoxib: F. Schneider et al., Arzneim. Forsch. Drug. Res., 2006, 56 , 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs that exhibit this effect may have reduced dosage requirements (e.g., lower number of doses or lower dosage to achieve the desired effect) and / or result in lower metabolite burdens.

[0034] A compound of general formula (I) may have several potential sites of attack for metabolism. To optimize the effects described above on the physicochemical properties and the metabolic profile, deuterium-containing compounds of the general formula (I) with a specific pattern of one or more deuterium-hydrogen exchanges can be selected. In particular, the cutcrium atom(s) of the cutcrium-containing compound (cn) of the general formula (I) is / are bound to a carbon atom and / or is / are in the positions of the compound of the general formula (I), which are attack sites for metabolic enzymes such as cytochrome P 450.

[0035] In the context of the present invention, unless otherwise specified, the substituents have the following meaning: Alkyl per se and "alk" and "alkyl" in alkoxy, alkylsulfonyl, alkylaminocarbonyloxy and alkoxycarbonyl represent a linear or branched alkyl radical with generally 1 to 6, preferably 1 to 4 or 1 to 3 carbon atoms, for example and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, iso-butyl, (2 -Methyl-prop-1-yl), n-pentyl and n-hexyl. Alkoxyrepresents, by way of example and preferably, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy. Alkylaminocarbonyloxy represents an alkylaminocarbonyloxy radical with one or two (independently chosen) alkyl substituents. (C 1 -C 3 )-Alkylaminocarbonyloxy represents, for example, a monoalkylaminocarbonyloxy radical having 1 to 3 carbon atoms or a dialkylaminocarbonyloxy radical each having 1 to 3 carbon atoms per alkyl substituent. By way of example and preferably, the following may be mentioned: methylaminocarbonyloxy, ethylaminocarbonyloxy, n-propylaminocarbonyloxy, isopropylaminocarbonyloxy, tert-butylaminocarbonyloxy, n-pentylaminocarbonyloxy, n-hexylaminocarbonyloxy, N,N -Dimethylaminocarbonyloxy, N,N -diethylaminocarbonyloxy, N -Ethyl- N- methylaminocarbonyloxy, N -Methyl- N -n-propylaminocarbonyloxy, N -Isopropyl- N -n-propylaminocarbonyloxy, N -tert-butyl- N -methylaminocarbonyl, N -Ethyl- N -n-pentylamino-carbonyl and N -n-Hexyl- N -methylaminocarbonyloxy. Alkylsulfonyl In the context of the invention, stands for a linear or branched alkyl radical with 1 to 4 carbon atoms, which is bonded via a sulfonyl group. By way of example and preferably its: methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl and tert-butylsulfonyl. Alkoxycarbonyl represents, for example and preferably, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. Carbocycle In the context of the invention, stands for a mono-, poly- or spirocyclic, preferably mono- or bicyclic, saturated carbocycle with a total of 3 to 6 ring atoms. A monocyclic, saturated carbocycle is referred to synonymously with cycloalkyl. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, bicyclo[1.1.1]pentyl , bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, tricyclo[3.3.1.13,7]decyl. Monocyclic cycloalkyl with 3 to 5 carbon atoms is preferred. Examples and preference which may be mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[2.2.1]heptyl, or bicyclo[1.1.1]pent-1-yl. Heterocyclyl represents a mono-, poly- or spirocyclic, preferably mono-, bi- or spirocyclic, non-aromatic heterocyclic radical with generally 3 to 10 ring atoms and up to 3, preferably up to 2 heteroatoms and / or heterogroups from the series N , S, SO, SO 2 . For the purposes of the present invention, bicyclic spirocyclic heterocyclyl radicals are intended to be encompassed by the definition of bicyclic heterocycle. The heterocyclyl residues can be saturated or partially unsaturated. Preferred are 4- to 6-membered monocyclic saturated heterocyclyl radicals with a nitrogen atom and those with a further heteroatom from the series N or and 6- to 7-membered bi- or spirocyclic saturated heterocyclyl radicals with a nitrogen atom. By way of example and preferably, the following may be mentioned: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, imidazolidinyl, morpholinyl, tetrahydropyrimidine, azabicyclo[3.1.0]hexyl, azaspiro[2.4]heptyl or 2-oxa-6-azaspiro[3.3]hept-6- yl. halogen stands for fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine.

[0036] In the formula of the group for which R 1< , R 2< , Ar 1< , or L 1< can stand, the end point of the line is where the sign # 1< ; *, ** and *** do not stand for a carbon atom or a CH 2 group, but are part of the bond to the designated atom to which R 1<, R 2<, Ar 1<, or L 1 < is bound.

[0037] If radicals in the compounds according to the invention are substituted, the radicals can be substituted once or more unless otherwise specified. In the context of the present invention, the meaning of all residues that occur multiple times is independent of one another. If radicals in the compounds according to the invention are substituted, the radicals can be substituted once or more unless otherwise specified. A substitution with one or with two identical or different substituents is preferred.

[0038] For the purposes of the present invention, the term “treatment” or “treat” includes inhibiting, delaying, stopping, alleviating, attenuating, limiting, reducing, suppressing, suppressing or curing an illness, disease, illness, injury or health disorder , the development, course or progression of such conditions and / or the symptoms of such conditions. The term “therapy” is understood to be synonymous with the term “treatment”.

[0039] The terms "prevention", "prophylaxis" or "prevention" are used synonymously in the context of the present invention and denote the avoidance or reduction of the risk of an illness, an illness, an illness, an injury or a health disorder, a development or a to develop, experience, suffer or have the progression of such conditions and / or the symptoms of such conditions.

[0040] The treatment or prevention of an illness, disease, illness, injury or health disorder may be partial or complete.

[0041] In the context of the present invention, preference is given to compounds of the formula (I), in which X for fluorine, chlorine or bromine stands for hydrogen, or for NR 4 <r 5 <stands, in which R 4 <hydrogen, methyl or ethyl means, and R 5 <up to four times substituted (C 1 - C 3 )-alkyl means, where (C 1 -C 3 )-alkyl can be substituted with hydroxy, or R 4 < and R 5 < together with the nitrogen atom to which they are bonded, a saturated 4- to 6-membered monocyclic or 6- to 9-membered bicyclic heterocycle, which can contain one or two further, identical or different heteroatoms from the series N and / or O as ring members, the 4- to 6-membered monocyclic and the 6- to 9 -membered bicyclic heterocycle each with 1 to 4 substituents independently selected from the group (C 1 -C 4 )-alkyl, difluoromethyl, trifluoromethyl, hydroxy, oxo, (C 1 -C 3 )-alkoxy, difluoromethoxy, trifluoromethoxy, (C 1 -C 3 )-alkoxycarbonyl, (C 1 -C 3 )-alkylaminocarbonyloxy, -OC(=O)R 15 <, and further up to four times substituted with fluorine, in which (C 1 -C 4 )-alkyl can be substituted once or twice, identically or differently, with hydroxy, (C 1 -C 3 )-alkoxy, and up to four times with fluorine, and in which R 15 <represents (C 1 -C 4 )-alkyl, R 2< for a group of the formula * stands, in which the connection point is marked with the N atom of the amide group, R 6A < hydrogen or (C 1 -C 4 )-alkyl, R 6B < methyl, ethyl, isopropyl, cyclopropyl, monofluoromethyl, difluoromethyl, or trifluoromethyl , means, and R 7< means (C 1 -C 4 )-alkyl substituted up to five times with fluorine, (C 3 -C 5 )-cycloalkyl substituted up to four times with fluorine, methoxymethyl or trifluoromethoxymethyl, L 1< means a bond or a group of the formula -CR 8A< R 8B< - means in which R 8A< represents hydrogen, R 8b< represents hydrogen, methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl, Ar 2< represents phenyl, where phenyl is one to three times, equal or can be substituted differently, with fluorine or chlorine, or represents a 5- to 7-membered bicyclic carbocycle or 5- or 6-membered monocyclic heterocycle which contains a nitrogen atom as a ring member, the 5- to 7-membered bicyclic Carbocycle or the 5- or 6-membered monocyclic heterocycle can each be substituted with (C 1 -C 4 )-alkoxycarbonyl and further up to four times with fluorine, Ar 1< for a group of the formula says what *** the connection point is marked with the N atom, R 3A< stands for fluorine, chlorine, trifluoromethyl or methyl, R 3B< stands for hydrogen or fluorine and R 3C< stands for hydrogen, fluorine, chlorine or methyl, or represents a pyridine ring connected via a ring carbon atom, where the pyridine ring can be substituted once or twice with fluorine, chlorine or cyano, as well as their salts, solvates and solvates of the salts.

[0042] Particularly preferred in the context of the present invention are compounds of the formula (I), in which X for fluorine, chlorine or bromine stands, r 1 <for nr 4 <r 5 <, in which R 4 <methyl or ethyl means, and R 5 <methyl, 2-hydroxyethyl or 2-hydroxypropyl means, or for one nitrogen -atom-bound heterocycle of the formula says what ** the connection point is marked with the rest of the molecule, R 10< represents fluorine, methyl, hydroxy, hydroxymethyl, methoxycarbonyl or acetyloxy, p represents the number 0, 1, or 2, in which case the substituents R 10< occur multiple times , the meanings of which can each be the same or different, Y 1 < represents -NH-, -N(CH 3 )- or -0-, R 2< for a group of the formula says what * the linking point is marked with the N atom of the amide group, R 6A < hydrogen, methyl or ethyl, R 6B < methyl, ethyl, trifluoromethyl, isopropyl or cyclopropyl, and R 7 < methyl, ethyl, difluoromethyl, trifluoromethyl , 2,2,2-trifluoroethyl, pentafluoroethyl, isopropyl, iso-butyl, methoxymethyl, trifluoromethoxymethyl or cyclopropyl means, R 11 < hydrogen, R 12 < methoxycarbonyl, R 13 < hydrogen or tert-butoxycarbonyl, L 1 < a Bond or a group of the formula -CR 8A< R 8B< - means in which R 8A< represents hydrogen, R 8b< represents hydrogen, methyl or trifluoromethyl, Ar 2< represents phenyl, where phenyl is one to two times, the same or different, can be substituted with fluorine or chlorine, Ar 1< for a group of the formula says what *** the connection point is marked with the N atom, R 3A< stands for fluorine or chlorine, and R 3C< stands for hydrogen or fluorine, as well as their salts, solvates and solvates of salts.

[0043] Very particularly preferred in the context of the present invention are compounds of the formula (I), in which X represents fluorine, R 1 < represents a heterocycle of the formula bonded via a nitrogen atom is where ** marks the junction with the rest of the molecule, R 2< represents a group of the formula is where * marks the connection point with the N atom of the amide group, R 7A < trifluoromethyl, ethyl or cyclopropyl, R 7B < methyl or ethyl, R 7C < trifluoromethyl or pentafluoroethyl, Ar 1 < for a group of formula stands, in which *** marks the point of connection with the N atom, as well as their salts, solvates and solvates of salts.

[0044] Very particularly preferred in the context of the present invention are compounds of the formula (I), in which X represents fluorine, R 1 < represents a heterocycle of the formula bonded via a nitrogen atom is where ** marks the junction with the rest of the molecule, R 2< represents a group of the formula says what *the connection point is marked with the N atom of the amide group, Ar 1< for a group of the formula where *** marks the point of connection with the N atom, as well as their salts, solvates and solvates of the salts.

[0045] A further particular embodiment of the present invention comprises compounds of formula (I), in which X represents fluorine, R 1 < represents a heterocycle of the formula bonded via a nitrogen atom where ** marks the junction point with the rest of the molecule, R 10<represents fluorine, methyl, hydroxy, hydroxymethyl, methoxycarbonyl or acetyloxy, p represents the number 0, 1, or 2, where in the case that the substituents R 10 < appear multiple times, the meanings of which can be the same or different, R 2< for a group of the formula is where * marks the point of connection with the N atom of the amide group, Ar 1< represents a group of the formula where *** marks the point of connection with the N atom, as well as their salts, solvates and solvates of the salts.

[0046] The present invention also relates to compounds of the general formula (I) in which X for halogen stands, r 1 <for hydrogen, or for -no. , where (C 2 -C 4 )-alkyl can be substituted with hydroxy or up to three times with fluorine and R 5 < (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, 3- to 6 -membered saturated heterocyclyl or (C 1 -C 4 )-alkylsulfonyl, where (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl and 3- to 6-membered saturated heterocyclyl, up to three times, identical or different, can be substituted with methyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxycarbonyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy, cyano and further up to four times with fluorine, or R 4< and R 5< form together with the nitrogen atom, to which they are bound, a saturated or partially unsaturated, 3- to 6-membered monocyclic or 6- to 10-membered bicyclic heterocycle, which contains one or two further, identical or different heteroatoms from the series N, S, SO and / or SO 2 can contain as ring members, the 3- to 6-membered monocyclic and the 6- to 10-membered bicyclic heterocycle each with 1 to 5 substituents being independently selected from the group (C 1 -C 4 )-alkyl, difluoromethyl, Trifluoromethyl, hydroxy, hydroxycarbonyl, oxo, (C 1 -C 3 )-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, (C 1 -C 3 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 3 )-alkylaminocarbonyloxy, -NHC (=O)R 14A<, -CH 2 NHC(=O)R 14B<, -OC(=O)R 15< and further can be substituted up to four times with fluorine, in which (C 1 -C 4 )- Alkyl can be substituted once or twice, identically or differently, with hydroxy, (C 1 -C 3 )-alkoxy, and up to four times with fluorine, R 14A< and R 14b< independently of one another (C 1 -C 3 ) -alkyl or cyclopropyl, and in which R 15< represents (C 1 -C 4 )-alkyl, R 2< represents a group of the formula is where * marks the connection point with the N atom of the amide group, R 6A < hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, iso-butyl, (2-methyl-prop-1- yl) or cyclopropyl, R 6B < hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, iso-butyl, (2-methyl-prop-1-yl), cyclopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, Methoxymethyl or trifluoromethoxymethyl, R 7< means (C 1 -C 6 )-alkyl or (C 3 -C 5 )-cycloalkyl substituted up to four times with fluorine, where (C 1 -C 6 )-alkyl with amino, hydroxy, (C 1 -C 6 )-alkoxy and can be substituted up to five times with fluorine, in which (C 1 -C 6 )-alkoxy can be substituted up to five times with fluorine L 1 < a bond or a group of the formula -C( R 8A < R 8B < )-(C(R 9A < R 9B < )) m - means where m represents 0 or 1, R 8A < represents hydrogen or methyl, R 8B < hydrogen, methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl represents, R 9A< and R 9B< independently represent hydrogen or methyl, Ar 2< represents phenyl, where phenyl is one to three times, identical or different, with fluorine, chlorine, (C 1 -C 3 )-alkyl, difluoromethoxymethyl, Trifluoromethoxymethyl and / or trifluoromethyl can be substituted, or for a 5- to 10-membered monocyclic, bicyclic or tricyclic carbocycle or heterocycle, which can contain one or two further, identical or different heteroatoms from the series N and / or O as ring members, stands, where the 5- to 10-membered monocyclic, bicyclic or tricyclic carbocycle or heterocycle is up to three times, identical or different, with (C 1 -C 3 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxycarbonyl and further can be substituted up to four times with fluorine, Ar 1< for a group of the formula is where *** marks the junction with the N atom, R 3A< stands for fluorine, chlorine, trifluoromethyl or methyl, R 3B< stands for hydrogen or fluorine and R 3C< stands for hydrogen, fluorine, chlorine or methyl, or represents a pyridine ring attached via a ring carbon atom, where the pyridine ring can be substituted once or twice with fluorine, chlorine, cyano, methyl or trifluoromethyl, as well as their N -oxides, salts, solvates, salts of the N -Oxides and solvates of the N -oxides and salts.

[0047] Preferred within the scope of the present invention are compounds of the formula (I), in which X represents fluorine, R 1 < represents a heterocycle of the formula bonded via a nitrogen atom is where ** marks the junction with the rest of the molecule, R 2< represents a group of the formula is where * marks the point of connection with the N atom of the amide group, Ar 1< represents a group of the formula says what ***marks the connection point with the N atom, as well as their salts, solvates and solvates of salts.

[0048] Preferred within the scope of the present invention are compounds of the formula (I), in which X represents fluorine, R 1 < represents a heterocycle of the formula bonded via a nitrogen atom is where ** marks the junction with the rest of the molecule, R 2< represents a group of the formula is where * marks the point of connection with the N atom of the amide group, Ar 1< represents a group of the formula stands, in which *** marks the point of connection with the N atom, as well as their salts, solvates and solvates of salts.

[0049] A further particular embodiment of the present invention comprises compounds of formula (I), in which X represents fluorine or chlorine, A further particular embodiment of the present invention comprises compounds of formula (I), in which X stands for fluorine, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0050] A further particular embodiment of the present invention comprises compounds of formula (I), in which X stands for chlorine, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0051] A further particular embodiment of the present invention comprises compounds of formula (I), in which X stands for bromine, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0052] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 1< stands for NR 4< R 5<, in which R 4< means methyl or ethyl, and R 5< means methyl, 2-hydroxyethyl or 2-hydroxypropyl, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0053] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 1 < for a heterocycle of the formula bonded via a nitrogen atom where ** marks the junction point with the rest of the molecule, R 10<represents fluorine, methyl, hydroxy, hydroxymethyl, methoxycarbonyl or acetyloxy, p represents the number 0, 1, or 2, where in the case that the substituents R 10 < occur multiple times, the meanings of which can be the same or different, Y 1< represents -NH-, -N(CH 3 )- or -0-, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0054] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 1 < for a heterocycle of the formula bonded via a nitrogen atom stands, where ** marks the point of connection with the rest of the molecule, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0055] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 1 < for a heterocycle of the formula bonded via a nitrogen atom stands, where ** marks the point of connection with the rest of the molecule, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0056] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 1 < for a heterocycle of the formula bonded via a nitrogen atom stands, where ** marks the point of connection with the rest of the molecule, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0057] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 1 < for a heterocycle of the formula bonded via a nitrogen atom stands, where ** marks the point of connection with the rest of the molecule, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0058] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 1< for trans -(3 R ,4 R )-3,4-Dihydroxypyrrolidin-1-yl of the formula stands, where ** marks the point of connection with the rest of the molecule, as well as their salts, solvates and solvates of salts.

[0059] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 1< for cis -( R,S )-3,4-Dihydroxypyrrolidin-1-yl of the formula where ** marks the point of attachment to the rest of the molecule, as well as its salts, solvates and solvates of the salts.

[0060] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 1 < for a heterocycle of the formula bonded via a nitrogen atom stands, where ** marks the junction with the rest of the molecule, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0061] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< for a group of the formula where * marks the connection point with the N atom of the amide group, R 6A < hydrogen, methyl or ethyl, R 6B < methyl, ethyl, trifluoromethyl, isopropyl or cyclopropyl, and R 7 < methyl, ethyl, Difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, isopropyl, iso-butyl, methoxymethyl, trifluoromethoxymethyl or cyclopropyl means, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0062] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< for a group of the formula is where * marks the connection point with the N atom of the amide group, R 6A < hydrogen, methyl or ethyl, R 6B < methyl, ethyl, trifluoromethyl, isopropyl, tert-butyl or cyclopropyl, and R 7 <Methyl, ethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, isopropyl, iso-butyl, methoxymethyl, trifluoromethoxymethyl or cyclopropyl means, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0063] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< stands for a group of the formula *-L'-Ar 2<, in which * marks the point of connection with the N atom of the amide group, L 1< represents a bond or a group of the formula -CR 8A< R 8B< - means in which R 8A< represents hydrogen, R 8B< represents hydrogen, methyl or trifluoromethyl, Ar 2< represents a group of the formula stands, where # 1 < marks the point of connection with the rest of the molecule, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0064] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< for a group of the formula is where * marks the connection point with the N atom of the amide group, R 7A < trifluoromethyl, ethyl or cyclopropyl, R 7B < methyl or ethyl, R 7C < trifluoromethyl or pentafluoroethyl, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0065] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< for a group of the formula stands, where * marks the point of connection with the N atom of the amide group, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0066] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< for a group of the formula stands, where * marks the point of connection with the N atom of the amide group, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0067] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< for a group of the formula stands, where * marks the point of connection with the N atom of the amide group, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0068] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< for a group of the formula is where * marks the connection point with the N atom of the amide group, R 7A< means trifluoromethyl, ethyl or cyclopropyl, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0069] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< for a group of the formula is where * marks the connection point with the N atom of the amide group, R 7B< means methyl or ethyl, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0070] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< for a group of the formula is where * marks the connection point with the N atom of the amide group, R 7C< means trifluoromethyl or pentafluoroethyl, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0071] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< for (2 S )-1,1,1-Trifluorobutan-2-yl of the formula stands, where * marks the point of connection with the N atom of the amide group, stands, as well as their salts, solvates and solvates of salts.

[0072] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< for (1 S )-1-Cyclopropyl-2,2,2-trifluoroethyl stands, where * marks the point of connection with the N atom of the amide group, as well as their salts, solvates and solvates of salts.

[0073] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< for a group of the formula stands, where * marks the point of connection with the N atom of the amide group, as well as their salts, solvates and solvates of salts.

[0074] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< for a group of the formula stands, where * marks the point of connection with the N atom of the amide group, as well as their salts, solvates and solvates of salts.

[0075] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< for a group of the formula stands, where * marks the point of connection with the N atom of the amide group, as well as their salts, solvates and solvates of salts.

[0076] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< for a group of the formula stands, where * marks the point of connection with the N atom of the amide group, as well as their salts, solvates and solvates of salts.

[0077] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< represents 1,1,1,3,3,3-hexafluoropropan-2-yl, as well as their salts, solvates and solvates of salts.

[0078] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< is 3,3,4,4,4-pentafluorobutan-2-yl, as well as their salts, solvates and solvates of salts.

[0079] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2< represents 1,1,1,2,2-pentafluoropentan-3-yl, as well as their salts, solvates and solvates of salts.

[0080] A further particular embodiment of the present invention comprises compounds of formula (I), in which R 2 < stands for 1,1,1-trifluoro-2-methylpropan-2-yl, as well as their salts, solvates and solvates of salts.

[0081] A further particular embodiment of the present invention comprises compounds of formula (I), in which Ar 1< for a group of the formula stands, in which *** marks the point of connection with the N atom, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0082] A further particular embodiment of the present invention comprises compounds of formula (I), in which Ar 1< for a group of the formula stands, in which *** marks the point of connection with the N atom, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0083] A further particular embodiment of the present invention comprises compounds of formula (I), in which Ar 1< for a group of the formula stands, in which *** marks the point of connection with the N atom, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0084] A further particular embodiment of the present invention comprises compounds of formula (I), in which Ar 1< for a group of the formula ▪ is where *** marks the point of connection with the N atom, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

[0085] The residue definitions specified in detail in the respective combinations or preferred combinations of residues are also replaced as desired by residue definitions of other combinations, regardless of the respective combinations of residues specified.

[0086] Combinations of two or more of the above-mentioned preferred ranges and embodiments are very particularly preferred.

[0087] The radical definitions mentioned as preferred, particularly preferred and very particularly preferred apply both to the compounds of the formula (I) and in a corresponding manner to all intermediate products.

[0088] The invention further provides a process for the preparation of compounds of the formula (I) according to the invention, characterized in that: [A] a compound of formula (II-A)

[0089] in which X, R 2< and Ar 1< have the meanings given above, and Hal represents fluorine, chlorine, bromine or iodine, preferably chlorine, with a compound of the formula (III) , in which R 1 < has the meaning given above, and where R 1 < does not mean hydrogen, to the carboxamide according to the invention of the formula (I-A) in which X, R 1<, R 2< and Ar 1< have the meanings given above, and where R 1< does not mean hydrogen, implements, or [B] a compound of formula (IV)

[0090] in which to the carboxamide of the formula (I) according to the invention in which X, R 1 , R 2 and Ar 1 have the meanings given above, implements, and optionally separates the compounds of formula (I) thus obtained into their enantiomers and / or diastereomers and / or with the corresponding ones (i) Solvents and / or (ii) Bases or acids are converted into their solvates, salts and / or solvates of the salts.

[0091] The reaction (II-A) + (III) → (I-A) can occur via a nucleophilic substitution reaction or a transition metal-mediated coupling reaction.

[0092] The nucleophilic substitution reaction is preferably carried out in the presence of a base. The usual inorganic or organic bases are suitable as bases for process step (II-A) + (III) → (I-A). These preferably include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali metal alcoholates such as lithium, sodium or potassium tert-butylate, alkali metal hydrides such as sodium - or potassium hydride, or organic amines such as N,N- Diisopropylethylamine (DIPEA), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Is preferred N,N -Diisopropylethylamine (DIPEA) is used. The reaction generally takes place in a temperature range from 0°C to +100°C, preferably at +23°C to +80°C.

[0093] Inert solvents for process step (II-A) + (III) → (I-A) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichlorethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide, N,N- dimethylformamide (DMF), N,N '-Dimethylpropylene urea (DMPU) or N -Methylpyrrolidone (NMP). It is also possible to use mixtures of the solvents mentioned. Dimethylformamide (DMF) or is preferred N -Methylpyrrolidone (NMP) is used.

[0094] In a preferred embodiment, the transition metal-mediated coupling reaction for process step (II-A) + (III) → (I-A) is carried out in the presence of a palladium catalyst. Suitable palladium catalysts are, for example, palladium (II) acetate, palladium (II) chloride, bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (II) chloride, tetrakis (triphenylphosphine) palladium (0), bis ( dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride, optionally in combination with a suitable phosphine ligand such as triphenylphosphine, tri- tert .-butylphosphine, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos), 2-dicyclohexylphosphino-2',6'-di-methoxybiphenyl (S-Phos), 1,2,3,4 ,5-Pentaphenyl-1'-(di- tert .-butylphosphino)ferrocene (Q-Phos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 2 -Dicyclohexylphosphino-2'-( N,N -dimethylamino)biphenyl or 2-di- tert .-butylphosphino-2'-( N,N- dimethylamino)biphenyl.

[0095] The palladium-catalyzed coupling reaction (II-A) + (III) → (I-A) is usually carried out in the presence of a base. Suitable as such are alkali metal carbonates such as sodium, potassium or cesium carbonate, alkali metal phosphates such as sodium or potassium phosphate, alkali metal fluorides such as potassium or cesium fluoride, or alkali metal tert .-butylates such as sodium or potassium tert .-butylate. The reaction takes place in an inert solvent such as toluene, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide (DMSO), N,N -Dimethylformamide (DMF), N,N -Dimethylacetamide (DMA) or mixtures thereof in a temperature range from +80°C to +200°C, preferably at +80°C to +150°C, whereby heating using a microwave apparatus can be advantageous.

[0096] A catalyst / ligand / base system consisting of palladium(II) acetate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) and cesium or potassium carbonate and 1,4-dioxane is preferably used for this coupling reaction used as a solvent.

[0097] In a further preferred embodiment, the coupling reaction (II-A) + (III) → (I-A) can also be carried out using a copper (I) catalyst, such as copper (I) oxide, bromide or iodide, in the presence of a copper Ligands, such as trans- N,N'- Dimethyl-1,2-cyclohexanediamine, 8-hydroxyquinoline or 1,10-phenanthroline, and an inorganic or organic carbonate base, such as potassium, cesium or bis (tetraethylammonium) carbonate. Toluene, xylene, 1,4-dioxane, acetonitrile, dimethyl sulfoxide (DMSO), are particularly suitable as inert solvents for this reaction. N,N- Dimethylformamide (DMF) or mixtures thereof, optionally with the addition of water. A system consisting of copper(I) iodide, trans- N,N' -Dimethyl-1,2-cyclohexanediamine and potassium carbonate are used in dimethylformamide. The reaction generally takes place in a temperature range from +50°C to +200°C, preferably at +60°C to +150°C.

[0098] The coupling reaction (IV) + (V) → (I) [amide formation] can take place either directly using a condensation or activating agent or via the intermediate stage of a carboxylic acid chloride, carboxylic acid ester or carboxylic imidazolide obtainable from (IV).

[0099] Carbodiimides such as, for example, are suitable as such condensation or activating agents N,N'- diethyl, N,N' -dipropyl-, N,N' -diisopropyl-, N,N' -Dicyclohexylcarbodiimide (DCC) or N -(3-Dimethylaminopropyl)- N '-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N,N' -Carbonyldiimidazole (CDI), isopropyl chloroformate or isobutyl chloroformate, 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or 2- tert .-Butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, α-chlorenamines such as 1-chloro- N,N ,2-trimethylprop-1-en-1-amine, 1,3,5-triazine derivatives such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, phosphorus -Connections like n -Propanephosphonic anhydride (T3P, PPACA), diethyl cyanophosphonate, diphenylphosphoryl azide (DPPA), bis-(2-oxo-3-oxazolidinyl) phosphoryl chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yloxy-tris (pyrrolidino)phosphonium hexafluorophosphate (PyBOP), or uronium compounds such as O -(Benzotriazol-l-yl)- N,N,N',N' -tetramethyluronium tetrafluoroborate (TBTU), O -(Benzotriazol-1-yl)- N,N,N;N' -tetramethyluronium hexafluorophosphate (HBTU), O -(1 H -6-Chlorobenzotriazol-l-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU), O -(7-Azabenzotriazol-1-yl)- N,N,N',N' -tetramethyluronium hexafluorophosphate (HATU) or 2-(2-oxo-1-(2 H )-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), optionally in combination with other excipients such as 1-hydroxybenzotriazole (HOBt) or N -Hydroxysuccinimide (HOSu), as well as alkali carbonates as bases, e.g. sodium or potassium carbonate, or tertiary amine bases such as triethylamine, N -Methylmorpholine (NMM), N -Methylpiperidine (NMP), N,N -Diisopropylethylamine (DIPEA), pyridine or 4- N,N -Dimethylaminopyridine (DMAP). Is preferred as a condensation or activating agent O -(7-Azabenzotriazol-1-yl)- N,N,N;N '-tetramethyluronium hexafluorophosphate (HATU) in combination with N,N- Diisopropylethylamine (DIPEA) as well n -Propanephosphonic anhydride (T3P, PPACA) in combination with N,N -Diisopropylethylamine (DIPEA).

[0100] The compounds of the formula (II-A) can be prepared by adding a carboxylic acid compound of the formula (VI-A) in which X, Hal and Ar 1 < have the meanings given above, with a compound of the formula (V) - II-A) in which X, Hal, R 2< and Ar 1< have the meanings given above, is implemented.

[0101] Compounds of the formula (I-B) can be prepared analogously to the reaction (VI-A) + (V) → (II-A) in that a carboxylic acid compound of the formula (VI-B) in which in which X, R 2< and Ar 1< have the meanings given above is implemented.

[0102] The coupling reaction (VI-A) + (V) → (II-A) or (VI-B) + (V) → (I-B) [amide formation] can be carried out either directly using a condensation or activating agent or via the intermediate stage of a carboxylic acid chloride, carboxylic acid ester or carboxylic imidazolide obtainable from (VI) takes place analogously to the conditions and reagents already described for the reaction (IV) + (V) → (I). If HATU is used as an activating agent in the coupling reaction to (II-A), it is possible that either a single, defined product of the general formula (II-A) is obtained, or a mixture with a "HATU adduct". In the present case, a “HATU adduct” refers to a pseudohalide compound, where the substituent Hal in the general formula (II-A) is in group 3 H -[1,2,3]Triazolo[4,5-b]pyridin-3-ol, also referred to as 1-hydroxy-7-azabenzotriazole, is replaced. Such a mixture of a halogen compound of the general formula (II-A) and a “HATU adduct” can also be used directly as a starting material for the subsequent reaction (according to (I) or (VIII)), analogous to the reaction described.

[0103] In a two-stage reaction using the carboxylic acid chlorides or carboxylic imidazolides obtainable from (VI), the coupling with the amine component (V) is carried out in the presence of a conventional base, such as sodium or potassium carbonate, triethylamine, DIPEA, N -Methylmorpholine (NMM), N -Methylpiperidine (NMP), pyridine, 2,6-dimethylpyridine, 4- N,N -Dimethylaminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0]non-5-ene (DBN), sodium or potassium methoxide, sodium - or potassium ethoxide, sodium or potassium tert-butylate or sodium or potassium hydride.

[0104] The carboxylic acid imidazolides themselves are prepared according to a known process by reacting (VI) with N,N'-carbonyldiimidazole (CDI) at elevated temperature (+60°C to +150°C) in a correspondingly higher-boiling solvent such as N,N-dimethylformamide (DMF ) available. The carboxylic acid chlorides are prepared in the usual way by treating (VI) with thionyl chloride or oxalic acid dichloride in an inert solvent such as dichloromethane or THF.

[0105] Depending on the process used, inert solvents for the coupling reactions mentioned are, for example, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis (2-methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane or cyclohexane, halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or polar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile, pyridine, dimethyl sulfoxide (DMSO), N,N -Dimethylformamide (DMF), N,N '-Dimethylpropylene urea (DMPU) or N- Methylpyrrolidinone (NMP). Mixtures of such solvents can also be used. Is preferred N,N -Dimethylformamide (DMF) and dichloromethane (DCM) used in combination with triethylamine. The couplings are generally carried out in a temperature range from 0°C to +130°C, preferably at +20°C to +30°C.

[0106] Depending on the respective substitution pattern, the compounds of the formula (IV-A) can be prepared by either [C] a compound of formula (VII-A)

[0107] in which X, Hal and Ar 1 < have the meanings given above, and T stands for (C 1 -C 4 )-alkyl or benzyl, in a first step with a compound of the formula (III) R 1 -H     (III), in which R 1 has the meaning given above, and where R 1 does not mean hydrogen, to a compound of the formula (VIII-A) in which X, T, R 1 and Ar 1 have the meanings given above, and where R 1 does not mean hydrogen, reacts, and optionally splits off the ester residue T in a second step to give the carboxylic acid of the formula (IV-A) according to the invention, in which X, R 1 and Ar 1 have the meanings given above, and where R 1 does not mean hydrogen, or [D] a compound of formula (VI-A)

[0108] in which means to the carboxylic acid according to the invention of the formula (IV-A), in which X, R 1< and Ar 1< have the meanings given above, and where R 1< does not mean hydrogen, implemented.

[0109] The reaction (VII-A) + (III) → (VIII-A) [path C] or the reaction (VI-A) + (III) → (IV-A) [path D] can each be carried out via a nucleophilic substitution reaction or a transition metal-mediated coupling reaction takes place analogously to the conditions and reagents already described for the reaction (II-A) + (III) → (I-A).

[0110] In a preferred embodiment, the reaction according to route C is carried out as a nucleophilic substitution reaction in the presence of a base, which is preferred N,N -Diisopropylethylamine (DIPEA) is used. Dimethylformamide (DMF) is preferred, N -Methylpyrrolidone (NMP) or acetonitrile used as solvent.

[0111] In a preferred embodiment, the reaction according to route D is carried out as a transition metal-mediated coupling reaction in the presence of a suitable palladium catalyst. A system consisting of palladium(II) acetate in combination with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), cesium or potassium carbonate and 1,4-dioxane is preferably used as a solvent.

[0112] The elimination of the ester group T in process step (VIII-A) → (IV-A) is carried out using customary methods by treating the ester in an inert solvent with an acid or base, with the latter variant being the initially formed salt Carboxylic acid is converted into free carboxylic acid by subsequent treatment with acid. In case of tert. -Butyl ester, the ester cleavage is preferably carried out with an acid. Alternatively, benzyl esters can also be split off by hydrogenation (hydrogenolysis) in the presence of a suitable catalyst, such as palladium on activated carbon.

[0113] Suitable solvents for these reactions are water and the organic solvents common for ester cleavage. These include in particular alcohols such as methanol, ethanol, n -propanol, isopropanol, n -butanol or tert .-Butanol, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, or other solvents such as dichloromethane, acetonitrile, N,N -Dimethylformamide or dimethyl sulfoxide. It is also possible to use mixtures of these solvents. In the case of basic ester hydrolysis, mixtures of water with tetrahydrofuran are preferably used.

[0114] The inorganic bases customary for a hydrolysis reaction are suitable as bases. These include in particular alkali or alkaline earth metal hydroxides such as lithium, sodium, potassium or barium hydroxide, or alkali or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate.

[0115] Suitable acids for ester cleavage are generally sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water. Aqueous hydrochloric acid (18 percent) is preferably used in a water / tetrahydrofuran mixture.

[0116] The ester cleavage is generally carried out in a temperature range from -20°C to +100°C, preferably at 23°C to +120°C.

[0117] The compounds of the formula (VI-A) and the formula (VII-A) can be prepared depending on the respective substitution pattern by using a 2,6, analogous to known processes (see, for example, EP 0607825 A1, pp. 25-26). -Dichloronicotinoyl acrylic acid ester derivative of the formula (IX-A) in which X, Hal and T have the meanings given above, and Y represents a leaving group such as dimethylamino, methoxy or ethoxy, as well in a first stage, preferably in the presence of a suitable base, with an aminopyridine compound of the formula (X) Ar 1 -NH 2 (X), in which type 1 which has the meanings given above, implements, and then in a second step in the presence of a suitable base to give the ester compound of the formula (VII-A) in which X, Hal, Ar 1 and T have the meaning given above, converted, and then, if necessary, under hydrolysis conditions in a further step, the ester compound (VII) into the carboxylic acid compound (VI-A) in which X, Hal and Ar 1< have the meanings given above, under the reaction conditions known in the literature.

[0118] Compounds of the formula (VI-B) and the formula (VII-B) can be prepared analogously to the reaction (IX-A) + (X) → (VII-A) → (VI-A) by analogously for known processes (see e.g. EP 0607825 A1, pp. 25-26) a 2,6-dichloronicotinoyl acrylic acid ester derivative of the formula (IX) in which X and T have the meanings given above, and Y represents a leaving group such as dimethylamino, methoxy or ethoxy, as well in a first stage, preferably in the presence of a suitable base, with an aminopyridine compound of the formula (X) Ar 1 -NH 2 (X), in which type 1 which has the meanings given above, implements, and then in a second step in the presence of a suitable base to give the ester compound of the formula (VII-B) in which X, Ar 1 and T have the meaning given above, converted, and then, if necessary, under hydrolysis conditions in a further step, the ester compound (VII-B) into the carboxylic acid compound (VI-B) in which X and Ar 1 have the meanings given above, transferred under the reaction conditions known in the literature.

[0119] The compounds of the formula (IX) are known from the literature (see, for example, EP 0607825 A1) or can be prepared in analogy to processes known from the literature. The compounds of the formula (III), (V) and (X) are commercially available or described as such in the literature, or they can be prepared in a manner obvious to the person skilled in the art in analogy to methods published in the literature. Numerous detailed regulations and literature references on the production of the respective starting materials can also be found in the experimental part in the section on the production of starting compounds and intermediates.

[0120] The separation of stereoisomers (enantio- and / or diastereomers) of the compounds of formula (I) according to the invention can be achieved using customary methods familiar to those skilled in the art. Chromatographic methods on achiral or chiral separation phases are preferably used for this purpose. A separation of the compounds according to the invention into the corresponding enantiomers and / or diastereomers can, if appropriate, also take place at the stage of the intermediates (II), (IV), or (VIII), which are then separated in the form described above Reaction sequence can be further implemented. For such a separation of the stereoisomers of intermediates, chromatographic methods on achiral or chiral separation phases are also preferably used. Alternatively, a separation can also be carried out using diastereomeric salts of the carboxylic acids of the formula (IV) with chiral amine bases.

[0121] The production of the compounds according to the invention can be exemplified by the following reaction schemes:

[0122] Further compounds of the formula (I) according to the invention can, if appropriate, also be prepared by converting functional groups of individual radicals and substituents, in particular those listed under R 1 < and R 2 <, from other compounds of the formula obtained by the above processes (I) or their precursors are assumed. These conversions are carried out using customary methods familiar to those skilled in the art and include, for example, reactions such as nucleophilic or electrophilic substitution reactions, transition metal-mediated coupling reactions, production and addition reactions of organometallics (e.g. Grignard compounds or lithium organyls), oxidation and reduction reactions, hydrogenation, halogenation ( e.g. fluorination, bromination), dehalogenation, amination, alkylation and acylation, the formation of carboxylic acid esters, carboxylic acid amides and sulfonamides, ester cleavage and hydrolysis as well as the introduction and removal of temporary protecting groups.

[0123] In a further aspect, the invention relates to intermediates of the general formula (II) in which X, R 2< and Ar 1< have the meanings given above for compounds of the formula (I) and Hal represents fluorine, chlorine, bromine or iodine, preferably chlorine.

[0124] The description relates in a further aspect to intermediates of the general formula (IV) in which X, R 1< and Ar 1< have the meanings given above for compounds of the formula (I).

[0125] The description relates in a further aspect to the use of a compound of the general formula (II) in which X, R 2< and Ar 1< have the meanings given above for compounds of the formula (I) and Hal represents fluorine, chlorine, bromine or iodine, preferably chlorine. or a compound of the general formula (IV) in which X, R 1 and Ar 1 have the meanings given above for compounds of formula (I), to prepare a compound of general formula (I) as defined above.

[0126] The compounds according to the invention show an unpredictable, valuable pharmacological and pharmacokinetic spectrum of activity.

[0127] They are therefore suitable for use as medicines for the treatment and / or prophylaxis of diseases in humans and animals. The compounds according to the invention have valuable pharmacological properties and can be used for the treatment and / or prophylaxis of diseases in humans and animals.

[0128] The compounds according to the invention represent positive allosteric modulators of the muscarinic M2 receptor and are therefore suitable for the treatment and / or prevention of diseases and pathological processes, in particular cardiovascular diseases and / or kidney diseases, in which there is a dysregulation of the autonomic nervous system or an imbalance The M2 receptor is involved between the activity of the sympathetic and parasympathetic parts of the autonomic nervous system.

[0129] The subject of the present invention are positive allosteric modulators of the muscarinic M2 receptor. Allosteric modulators have clear differences compared to classic, orthosteric ligands. The effect of an allosteric modulator is self-limiting if it stabilizes the binding of the agonist at high concentrations. Furthermore, the effect of an allosteric modulator can only develop in the presence of the endogenous ligand. The allosteric modulator itself has no direct influence on receptor activation. This results in spatial and temporal specificity of the allosteric effect. The mutual influence of allosteric and orthosteric ligands in terms of affinity and intrinsic activity, known as cooperativity, is determined by the two ligands. In the case of a positive allosteric modulator, the effects of the orthosteric ligand are enhanced (positive cooperativity). Because of their ability to modulate receptor conformations in the presence of an orthosteric ligand, allosteric ligands can produce fine-tuning of pharmacological effects.

[0130] For the purposes of the present invention, diseases of the cardiovascular system or cardiovascular diseases include, for example, the following diseases: acute and chronic heart failure, arterial hypertension, coronary heart disease, stable and unstable angina pectoris, myocardial ischemia, myocardial infarction, shock, atherosclerosis, cardiac hypertrophy, Cardiac fibrosis, atrial and ventricular arrhythmias, tachycardia, transient and ischemic attacks, stroke, preeclampsia, inflammatory cardiovascular diseases, peripheral and cardiac vascular diseases, peripheral circulatory disorders, arterial pulmonary hypertension, spasms of the coronary arteries and peripheral arteries, thrombosis, thromboembolic diseases, edema formation such as pulmonary edema, cerebral edema, renal edema or heart failure-related edema, as well as restenoses such as after thrombolytic therapies, percutaneous transluminal angioplasties (PTA), transluminal coronary angioplasties (PTCA), heart transplants and bypass operations, as well as micro- and macrovascular damage (vasculitis) , reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, peripheral and cardiac vascular diseases, peripheral circulatory disorders, heart failure-related edema, increased levels of fibrinogen and low-density LDL, and increased concentrations of plasminogen activator inhibitor 1 (PAI 1).

[0131] For the purposes of the present invention, the term heart failure also includes more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global heart failure, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, heart valve defects, heart failure in the case of heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valvular insufficiency, tricuspid stenosis, Tricuspid regurgitation, pulmonary valve stenosis, pulmonary valve insufficiency, combined heart valve defects, inflammation of the heart muscle (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcohol-toxic cardiomyopathy, cardiac storage diseases, heart failure with preserved systolic pump function (HFpEF), diastolic heart failure, and heart failure with reduced he systolic pump function (HfrEF), systolic heart failure.

[0132] For the purposes of the present invention, the term atrial and ventricular arrhythmias also includes more specific or related forms of disease such as: atrial fibrillation, paroxysmal atrial fibrillation, intermittent atrial fibrillation, permanent atrial fibrillation, atrial flutter, sinus arrhythmia, sinus tachycardia, passive heterotopia, active heterotopia, replacement systoles, extrasystoles, conduction disorders, sick sinus -Syndrome, hypersensitive carotid, tachycardia, AV node Reentrytrytachycardia, atriventricular reentrytachycardia, WPW syndrome (Wolff-Parkinson-White), Mahaim-Athykardia, Hidden Akcessorian Change Rail Atrial tachycardia, junctional ectope tachycardia, atriale Reentry tachycardia, ventricular tachycardia, ventricular flutter, ventricular fibrillation, sudden cardiac death.

[0133] For the purposes of the present invention, the term coronary heart disease also includes more specific or related forms of disease such as: ischemic heart disease, stable angina pectoris, acute coronary syndrome, unstable angina pectoris, NSTEMI (non-ST-segment elevation myocardial infarction), STEMI (ST-segment elevation myocardial infarction), ischemic myocardial injury, Cardiac arrhythmias and myocardial infarction.

[0134] The compounds according to the invention are further suitable for the prophylaxis and / or treatment of polycystic kidney disease (PCKD) and the syndrome of inappropriate ADH secretion (SIADH).

[0135] Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of kidney diseases, in particular acute and chronic kidney failure, as well as acute and chronic kidney failure.

[0136] For the purposes of the present invention, the term acute renal failure includes acute manifestations of kidney disease, kidney failure and / or kidney insufficiency with and without the need for dialysis, as well as underlying or related kidney diseases such as renal hypoperfusion, intradialytic hypotension, volume deficiency (e.g. dehydration, blood loss), shock, acute glomerulonephritis, hemolytic uremic syndrome (HUS), vascular catastrophe (arterial or venous thrombosis or embolism), cholesterol embolism, acute Bence-Jones kidney in plasmacytoma, acute supravesical or subvesical outflow obstructions, immunological kidney diseases such as kidney transplant rejection, immune complex-induced kidney diseases , tubular dilatation, hyperphosphatemia and / or acute kidney disease, which can be characterized by the need for dialysis, as well as partial resection of the kidney, dehydration due to forced diuresis, uncontrolled increase in blood pressure with malignant hypertension, urinary tract obstruction and infection and amyloidosis as well as systemic diseases with glomerular involvement, such as rheumatological-immunological systemic diseases such as lupus erythematosus, renal artery thrombosis, renal vein thrombosis, analgesic nephropathy and renal tubular acidosis, as well as X-ray contrast medium and drug-induced acute interstitial kidney diseases.

[0137] For the purposes of the present invention, the term chronic renal insufficiency includes chronic manifestations of renal disease, renal failure and / or renal insufficiency with and without the need for dialysis, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerular and tubular proteinuria, Renal edema, hematuria, primary, secondary and chronic glomerulonephritis, membranous and membrano-proliferative glomerulonephritis, Alport syndrome, glomerulosclerosis, tubulointerstitial diseases, nephropathic diseases such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as kidney transplant rejection, immune complex-induced kidney diseases, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, which are diagnosed, for example, by abnormally reduced creatinine and / or water excretion, abnormally increased blood concentrations of urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes such as glutamyl synthetase, altered urine osmolarity or urine volume, increased microalbuminuria, macroalbuminuria, lesions on glomeruli and arterioles, tubular dilatation, hyperphosphatemia and / or the need for dialysis, as well as in renal cell carcinoma, after partial resection of the kidney, dehydration due to forced diuresis , uncontrolled increase in blood pressure with malignant hypertension, urinary tract obstruction and infection and amyloidosis as well as systemic diseases with glomerular involvement, such as rheumatological-immunological systemic diseases such as lupus erythematosus, as well as renal artery stenosis, renal artery thrombosis, renal vein thrombosis, analgesic nephropathy and renal tubular acidosis. Furthermore, X-ray contrast medium and drug-induced chronic interstitial kidney diseases, metabolic syndrome and dyslipidemia. The present invention also includes the use of the compounds according to the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, heart failure, uremia, anemia, electrolyte disorders (e.g. hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.

[0138] Furthermore, the compounds according to the invention are also suitable for the treatment and / or prophylaxis of pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), acute respiratory syndrome (ARDS), acute lung injury ( ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (e.g. cigarette smoke-induced pulmonary emphysema), cystic fibrosis (CF), acute coronary syndrome (ACS), myocarditis and other autoimmune heart diseases (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies), cardiogenic shock, aneurysms, sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic intestinal inflammation (IBD, Crohn's Disease, UC), pancreatitis, peritonitis, rheumatoid diseases, inflammatory skin diseases and inflammatory eye diseases.

[0139] The compounds according to the invention can also be used for the treatment and / or prophylaxis of asthmatic diseases of varying degrees of severity with an intermittent or persistent course (refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, asthma induced by medications or by dust), of various types Forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), bronchiolitis obliterans, bronchiectasis, pneumonia, idiopathic interstitial pneumonia, farmer's lung and related diseases, cough and cold diseases (chronic inflammatory cough, iatrogenic cough), nasal mucosal inflammation (including drug rhinitis, vasomotor rhinitis and seasonal allergic rhinitis, e.g. hay fever) and polyps.

[0140] The compounds described in the present invention also represent active ingredients for combating diseases in the central nervous system characterized by disorders of the NO / cGMP system. In particular, they are suitable for improving perception, concentration performance, learning performance or memory performance after cognitive disorders, such as those that occur in particular in situations / diseases / syndromes such as "mild cognitive impairment", age-associated learning and memory disorders, age-associated memory losses, vascular dementia, craniocerebral disorder -Trauma, stroke, dementia that occurs after strokes ("post stroke dementia"), post-traumatic traumatic brain injury, general concentration disorders, concentration disorders in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies , dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelination, multiple sclerosis, thalamic degeneration, Creutzfeldt-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff psychosis. They are also suitable for the treatment and / or prevention of diseases of the central nervous system such as anxiety, tension and depression, bipolar disorder, central nervous system-related sexual dysfunctions and sleep disorders, as well as for regulating pathological disorders of food, recreational and addictive drug intake.

[0141] Furthermore, the compounds according to the invention are also suitable for the treatment and / or prophylaxis of urological diseases such as: urinary incontinence, in particular stress incontinence, urge incontinence, reflex incontinence and overflow incontinence, detrusor hyperactivity, neurogenic detrusor hyperactivity, idiopathic detrusor hyperactivity, benign prostatic hyperplasia (BPH syndrome), symptoms of the lower urinary tract (LUTS = lower urinary tract symptoms).

[0142] The compounds according to the invention are also suitable for the treatment and / or prevention of gastroenterological diseases such as esophageal diseases, vomiting, achalasia, gastroesophageal reflux disease, stomach diseases such as gastritis, intestinal diseases such as diarrhea, ostipation, malassimilation syndrome, bile acid loss syndrome, Crohn's disease, ulcerative colitis, microscopic colitis , and irritable bowel syndrome.

[0143] The compounds according to the invention are also suitable for the treatment and / or prevention of pain conditions, such as menstrual disorders, dysmenorrhea, endometriosis, premature birth, tocolysis.

[0144] Due to their biochemical and pharmacological property profile, the compounds according to the invention are particularly suitable for the treatment and / or prevention of heart failure, coronary heart disease, atrial and ventricular arrhythmias, renal insufficiency and nephropathies.

[0145] In addition, the compounds according to the invention can be used for the treatment and / or prophylaxis of primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, peripheral and autonomic neuropathies, diabetic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic ulcers of the extremities, gangrene, CREST syndrome, Erythematosis, onychomycosis, rheumatic diseases as well as to promote wound healing.

[0146] The compounds according to the invention are also suitable for the treatment and / or prevention of ophthalmological diseases, such as glaucoma, age-related macular degeneration (AMD), dry (non-exudative) AMD, wet (exudative, neovascular) AMD, choroidal neovascularization (CNV), and diabetes Retinopathy, atrophic changes in the retinal pigment epithelium (RPE), hypertrophic changes in the retinal pigment epithelium, macular edema, diabetic macular edema, retinal vein occlusion, choroidal retinal vein occlusion, macular edema due to retinal vein occlusion, angiogenesis at the front of the eye such as corneal angiogenesis, for example after keratitis, corneal transplantation or keratoplasty, corneal angiogenesis due to hypoxia (due to extensive contact lens wear), pterygium conjunctivae, subretinal edema and intraretinal edema. Furthermore, the compounds according to the invention are suitable for the treatment and / or prevention of elevated and high intraocular pressure as a result of traumatic hyphaema, periorbital edema, postoperative viscoelastic retention or intraocular inflammation.

[0147] In addition, the compounds according to the invention are suitable for the treatment and / or prophylaxis of hepatitis, neoplasm, osteoporosis, glaucoma and gastroparesis.

[0148] Furthermore, the compounds according to the invention are also suitable for regulating cerebral blood circulation and are effective agents for combating migraines. They are also suitable for prophylaxis and combating the consequences of cerebral infarction (apoplexia cerebri) such as stroke, cerebral ischemia and traumatic brain injury . The compounds according to the invention can also be used to combat pain, neuralgia and tinnitus.

[0149] The well-characterized human diseases mentioned above can also occur in other mammals with comparable etiology and can also be treated there with the compounds of the present invention.

[0150] For the purposes of the present invention, the term “treatment” or “treat” includes inhibiting, delaying, stopping, alleviating, attenuating, limiting, reducing, suppressing, suppressing or curing an illness, disease, illness, injury or health disorder , the development, course or progression of such conditions and / or the symptoms of such conditions. The term “therapy” is understood to be synonymous with the term “treatment”.

[0151] The terms "prevention", "prophylaxis" or "prevention" are used synonymously in the context of the present invention and denote the avoidance or reduction of the risk of an illness, an illness, an illness, an injury or a health disorder, a development or a to develop, experience, suffer or have the progression of such conditions and / or the symptoms of such conditions.

[0152] The treatment or prevention of an illness, disease, illness, injury or health disorder may be partial or complete.

[0153] A further subject of the present invention is therefore the use of the compounds according to the invention for the treatment and / or prevention of diseases, in particular the diseases mentioned above.

[0154] A further subject of the present invention is the use of the compounds according to the invention for producing a medicament for the treatment and / or prevention of diseases, in particular the diseases mentioned above.

[0155] The present invention further provides a medicament containing at least one of the compounds according to the invention for the treatment and / or prevention of diseases, in particular the diseases mentioned above.

[0156] A further subject of the present invention is the use of the compounds according to the invention in a method for the treatment and / or prevention of diseases, in particular the diseases mentioned above.

[0157] The present invention further provides a method for treating and / or preventing diseases, in particular the diseases mentioned above, using an effective amount of at least one of the compounds according to the invention.

[0158] The present invention further provides the compounds according to the invention for use in a method for the treatment and / or prevention of diseases, in particular the diseases mentioned above.

[0159] The compounds according to the invention can be used alone or, if necessary, in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesirable and unacceptable side effects. The present invention therefore also provides medicinal products containing at least one of the compounds according to the invention and one or more further active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases. Examples of suitable combination active ingredients for this are: Active ingredients that lower blood pressure, for example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, NEP inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha receptor blockers, beta receptors -Blockers, mineralocorticoid receptor antagonists, Rho kinase inhibitors and diuretics; antiarrhythmic active ingredients, such as and preferably sodium channel blockers, beta receptor blockers, potassium channel blockers, calcium channel blockers, If channel blockers, digitalis, parasympatholytics (vagolitics), sympathomimetics and other antiarrhythmics such as adenosine, adenosine receptor agonists and vernakalant. positive inotropic active ingredients, such as cardiac glycosides (dogoxin), beta-adrenergic and dopaminergic agonists, such as isoprenaline, adrenaline, norepinephrine, dopamine or dobutamine; Vasopressin receptor antagonists, such as and preferably conivaptan, tolvaptan, lixivaptan, mozavaptan, satavaptan, SR-121463, RWJ 676070 or BAY 86-8050, as well as those in WO 2010 / 105770, WO2011 / 104322 and WO 2016 / 071212 connections described ; Natriuretic peptides such as atrial natriuretic peptide (ANP), natriuretic peptide type B (BNP, nesiritide) natriuretic peptide type C (CNP) or urodilatin; Activators of cardiac myosin, such as Omecamtiv Mecarbil (CK-1827452); Calcium sensitizers, such as levosimendan, compounds affecting cardiac energy metabolism, such as, by way of example and preferably, etomoxir, dichloroacetate, ranolazine or trimetazidine, full or partial adenosine A1 receptor agonists such as GS-9667 (formerly known as CVT-3619), capadenoson, neladenoson and BAY 1067197; Compounds that affect heart rate, such as ivabradine; Compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil and Tadalafil, Udenafil, Desantafil, Avanafil, Mirodenafil, Lodenafil or PF-00489791; antithrombotic agents, for example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances; bronchodilator agents, for example and preferably from the group of beta-adrenergic receptor agonists, such as in particular albuterol, isoproterenol, metaproterenol, terbutaline, formoterol or salmeterol, or from the group of anticholinergics, such as in particular ipratropium bromide; anti-inflammatory agents, for example and preferably from the group of glucocorticoids, such as in particular prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone and the non-steroidal anti-inflammatory agents (NSAIDs), such as in particular acetylsalicylic acid (aspirin), ibuprofen and naproxen, 5-aminosalicylic acid derivatives, leukotriene antagonists, TNF-alpha inhibitors and chemokine receptor antagonists, such as CCR1, 2 and / or 5 inhibitors; Active ingredients that alter fat metabolism, for example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as, for example and preferably, HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha -, PPAR-gamma and / or PPAR-δ agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein (a) antagonists. Compounds inhibiting the signal transduction cascade, for example and preferably from the group of kinase inhibitors, in particular from the group of tyrosine kinase and / or serine / threonine kinase inhibitors; Compounds that inhibit the degradation and remodeling of the extracellular matrix, for example and preferably inhibitors of matrix metalloproteases (MMPs), in particular inhibitors of chymase, stromelysin, collagenases, gelatinases and aggrecanases (in particular MMP-1, MMP-3, MMP -8, MMP-9, MMP-10, MMP-11 and MMP-13) as well as metallo-elastase (MMP-12) and neutrophil elastase (HNE), such as e.g.Sivelestat or DX-890; Compounds that block the binding of serotonin to its receptor, for example and preferably antagonists of the 5-HT 2b receptor; organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, as well as inhaled NO; NO-independent but heme-dependent stimulators of soluble guanylate cyclase, such as in particular those 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 described compounds; NO- and heme-independent activators of soluble guanylate cyclase, such as in particular the compounds described in WO 01 / 19355, WO 01 / 19776, WO 01 / 19778, WO 01 / 19780, WO 02 / 070462 and WO 02 / 070510; Compounds that increase the synthesis of cGMP, such as sGC modulators, such as, by way of example and preferably, riociguat, cinaciguat, vericiguat or BAY 1101042; prostacyclin analogues, such as, by way of example and preferably, iloprost, beraprost, treprostinil or epoprostenol; Compounds that inhibit soluble epoxide hydrolase (sEH), such as. N,N' -Dicyclohexylurea, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid or 1-adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}-urea; Active ingredients that alter glucose metabolism, such as insulins, biguanides, thiazolidinediones, sulfonylureas, acarbose, DPP4 inhibitors, GLP-1 analogues or SGLT-1 inhibitors.

[0160] In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a kinase inhibitor, such as, for example and preferably, bortezomib, canertinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, lonafarnib, nintedanib, dasatinib, nilotinib, bosutinib, axitinib, telatinib, Imatinib, brivanib, pazopanib, pegaptinib, pelitinib, semaxanib, sorafenib, regorafenib, sunitinib, tandutinib, tipifarnib, vatalanib, fasudil, lonidamine, leflunomide, BMS-3354825 or Y-27632.

[0161] In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a serotonin receptor antagonist, such as, by way of example and preferably, PRX-08066.

[0162] Antithrombotic agents are preferably understood to mean compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.

[0163] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.

[0164] 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 preferably, dabigatran, ximelagatran, melagatran, bivalirudin or Clexane.

[0165] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, for example and preferably tirofiban or abciximab.

[0166] In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a factor N- 150, KFA-1982, EMD-503982, MC N -17, mLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

[0167] 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.

[0168] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, for example and preferably coumarin.

[0169] The blood pressure lowering agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha receptor blockers, beta receptor blockers, mineralocorticoid receptor antagonists , Rho kinase inhibitors and diuretics.

[0170] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, for example and preferably nifedipine, amlodipine, verapamil or diltiazem.

[0171] 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.

[0172] 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, metipranolol, nadolol, mepindolol, carazalol, sotalol, Metoprolol, Betaxolol, Celiprolol, Bisoprolol, Carteolol, Esmolol, Labetalol, Carvedilol, Adaprolol, Landiolol, Nebivolol, Epanolol or Bucindolol.

[0173] In a preferred embodiment of the invention, the compounds according to the invention are used in combination with an angiotensin AII antagonist, such as, by way of example and preferably, losartan, candesartan, valsartan, telmisartan or embursatan, irbesartan, olmesartan, eprosartan or azilsartan or a dual angiotensin AII antagonist / NEP- Inhibitor, such as and preferably Entresto (LCZ696, Valsartan / Sacubitril), administered.

[0174] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor, for example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

[0175] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist, such as, by way of example and preferably, bosentan, darusentan, ambrisentan, avosentan, macitentan, atrasentan or sitaxsentan.

[0176] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a TGFbeta antagonist, such as, for example and preferably, pirfenidone or fresolimumab.

[0177] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a TNFalpha antagonist, for example and preferably adalimumab.

[0178] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a renin inhibitor, such as, by way of example and preferably, aliskiren, SPP-600 or SPP-800.

[0179] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with HIF-PH inhibitors, such as, for example and preferably, molidustat or roxadustat.

[0180] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, for example and preferably spironolactone or eplerenone, finerenone.

[0181] In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a Rho kinase inhibitor, such as, by way of example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095, SB-772077, GSK-269962A or BA-1049.

[0182] In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a diuretic, such as furosemide, torasemide, bumetanide and piretanide, with potassium-sparing diuretics such as amiloride and triamterene, with aldosterone antagonists such as spironolactone, potassium canrenoate and eplerenone and thiazide diuretics such as for example hydrochlorothiazide, chlorthalidone, xipamide, and indapamide.

[0183] Among the agents that alter lipid metabolism, preference is given to compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR -gamma and / or PPAR-δ agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein (a) antagonists.

[0184] 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), anacetrapib, JJT-705 or CETP vaccine (Avant).

[0185] 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 preferably, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or Axitirome (CGS 26214).

[0186] 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.

[0187] 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.

[0188] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as, by way of example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

[0189] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor, such as, by way of example and preferably, Implitapide, BMS-201038, R-103757 or JTT-130.

[0190] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR gamma agonist, for example and preferably pioglitazone or rosiglitazone.

[0191] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-δ agonist, such as, by way of example and preferably, GW 501516 or BAY 68-5042.

[0192] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, for example and preferably ezetimibe, tiqueside or pamaqueside.

[0193] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, by way of example and preferably, orlistat.

[0194] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a polymeric bile acid adsorber, such as, by way of example and preferably, cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.

[0195] In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a bile acid reabsorption inhibitor, for example and preferably ASBT (= IBAT) inhibitors such as AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635, administered.

[0196] 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.

[0197] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with sGC modulators, such as, by way of example and preferably, riociguat, cinaciguat, vericiguat or BAY 1101042.

[0198] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an active ingredient that alters glucose metabolism, such as, for example and preferably, insulin, a sulfonylurea, acarbose, DPP4 inhibitors, GLP-1 analogues or SGLT-1 inhibitor.

[0199] Particularly preferred are combinations of the compounds according to the invention with one or more further active ingredients selected from the group consisting of active ingredients that lower blood pressure, antiarrhythmic active ingredients, vasopressin receptor antagonists, PDE 5 inhibitors, platelet aggregation inhibitors, sGC activators and sGC stimulators.

[0200] The present invention also provides medicinal products which contain at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the aforementioned purposes.

[0201] The compounds according to the invention can act systemically and / or locally. For this purpose, they can be applied in a suitable manner, such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

[0202] For these routes of administration, the compounds according to the invention can be administered in suitable application forms.

[0203] Suitable for oral administration are application forms that function according to the prior art and release the compounds according to the invention quickly and / or in a modified manner and which contain the compounds according to the invention in crystalline and / or amorphized and / or dissolved form, such as tablets (uncoated or coated Tablets, for example with gastro-resistant or delayed-dissolving or insoluble coatings which control the release of the compound according to the invention), tablets or films / wafers that quickly disintegrate in the oral cavity, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, Pellets, powders, emulsions, suspensions, aerosols or solutions.

[0204] Parenteral administration can occur bypassing an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or by involving absorption (e.g. inhalative, intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Suitable forms of application for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

[0205] Suitable for the other routes of application are, for example, inhalation dosage forms (including powder inhalers, nebulizers, metered dose aerosols), nasal drops, solutions or sprays, tablets to be administered lingually, sublingually or buccally, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous Suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. plasters), milk, pastes, foams, scattering powders, implants or stents.

[0206] Oral and parenteral administration are preferred, in particular oral, intravenous and intrapulmonary (inhalation) administration.

[0207] The compounds according to the invention can be converted into the application forms listed. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include, among others, carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g. sodium dodecyl sulfate, polyoxysorbitan oleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin) , stabilizers (e.g. antioxidants such as ascorbic acid), colorants (e.g. inorganic pigments such as iron oxides) and taste and / or odor correctors.

[0208] In general, it has proven to be advantageous to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight for parenteral administration 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.

[0209] Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on body weight, route of application, individual behavior towards the active ingredient, type of preparation and time or interval at which the application takes place. In some cases it may be sufficient to get by with less than the aforementioned minimum quantity, while in other cases the aforementioned upper limit must be exceeded. If larger quantities are applied, it may be advisable to distribute them in several individual doses throughout the day.

[0210] The following exemplary embodiments explain the invention. The invention is not limited to the examples. A. Examples Abbreviations and acronyms:

[0211] AAV general working instructions Section. absolutely AIBN Azobis(isobutyronitrile) aq. aqueous, aqueous solution br. wide (with NMR signal) E.g. Example Bu Butyl c concentration approx. approximately, approximately cat. catalytic CDI Carbonyldiimidazole CI chemical ionization (in MS) d Doublet (at NMR) d day(s) DCM Dichloromethane dd Doublet of doublet (in NMR) de Excess of diastereomers DEA Diethylamine dist. distilled DIPEA N,N-Diisopropylethylamine DMAP 4-N,N-Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide German Doublet of triplet (in NMR) d. Th. the theory (at chemical yield) ee Enantiomeric excess EGG Electron impact ionization (at MS) ent enantiomerically pure, enantiomer Äq. equivalent(s) IT I Electrospray ionization (at MS) Et Ethyl GC Gas chromatography GC / MS Gas chromatography-coupled mass spectrometry h Hours) HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HPLC High pressure, high performance liquid chromatography conc. concentrated (in solution) LC Liquid chromatography LC / MS Liquid chromatography-coupled mass spectrometry Lit. Literature (place) m Multiplet (at NMR) M molar (in solution) Me methyl min minute(s) MS Mass spectrometry NBS 1-Bromopyrrolidine-2,5-dione NMR Nuclear magnetic resonance spectrometry q (or quart) Quartet (at NMR) qd Quartet of doublet (at NMR) quant. quantitative (at chemical yield) fifth Quintet (at NMR) rac racemic, racemate RP reverse phase (reversal phase, for HPLC) RT Room temperature Rt Retention time (for HPLC, LC / MS) s Singlet (at NMR) Sept Septet (at NMR) SFC supercritical liquid chromatography t Triplet (at NMR) tBu tert-butyl td Triplet of doublet (in NMR) TFA Trifluoroacetic acid THF Tetrahydrofuran UV Ultraviolet spectrometry see. compare v / v Volume to volume ratio (of a solution) Xantphos 9,9-Dimethyl-4,5-bis-(diphenylphosphino)-xanthene add. together HPLC and LC / MS methods: Method 1:

[0212] Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 µ 50 x 1 mm; Eluent A: 11 water + 0.25 ml 99% formic acid, eluent B: 11 acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 90% A →1.2 min 5% A → 2.0 min 5% A Oven: 50°C; Flow: 0.40 ml / min; UV detection: 208 - 400 nm. Method 2:

[0213] Instrument MS: Waters (Micromass) QM; Instrument HPLC: Agilent 1100 series; Column: Agient ZORBAX Extend-C18 3.0x50mm 3.5-Micron; Eluent A: 11 water + 0.01 mol ammonium carbonate, eluent B: 11 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 3:

[0214] Device type MS: Thermo Scientific FT-MS; Device type UHPLC+: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 x 75 mm, C18 1.8 µm; Eluent A: 11 water + 0.01% formic acid; Eluent B: 11 acetonitrile + 0.01% formic acid; Gradient: 0.0 min 10% B → 2.5 min 95% B → 3.5 min 95% B; Oven: 50°C; Flow: 0.90 ml / min; UV detection: 210 nm / Optimum Integration Path 210-300 nm. Method 4:

[0215] Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 µ 50 x 1 mm; Eluent A: 11 water + 0.25 ml 99% formic acid, eluent B: 11 acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 95% A → 6.0 min 5% A → 7.5 min 5% A Oven: 50°C; Flow: 0.35 ml / min; UV detection: 210 - 400 nm. Method 5:

[0216] Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8 µ 50 x 2.1 mm; Eluent A: 11 water + 0.25 ml 99% formic acid, eluent B: 11 acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 90% A → 0.3 min 90% A → 1.7 min 5% A → 3.0 min 5% A Oven: 50°C; Flow: 1.20 ml / min; UV detection: 205 - 305 nm. Method 6:

[0217] Instrument: Thermo DFS, Trace GC Ultra; Column: Restek RTX-35, 15 m x 200 µm x 0.33 µm; constant flow with helium: 1.20 ml / min; Oven: 60°C; Inlet: 220°C; Gradient: 60°C, 30°C / min → 300°C (hold for 3.33 min). More information:

[0218] The percentages in the following example and test descriptions are percentages by weight unless otherwise stated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration information for liquid / liquid solutions each refer to the volume.

[0219] When purifying compounds according to the invention by preparative HPLC using the methods described, in which the eluents contain additives such as trifluoroacetic acid, formic acid or ammonia, the compounds according to the invention can be obtained in salt form, for example as trifluoroacetate, formate or ammonium salt, provided that the compounds according to the invention Compounds contain sufficient basic or acidic functionalities. Such a salt can be converted into the corresponding free base or acid using various methods known to those skilled in the art.

[0220] Purity information usually refers to corresponding peak integrations in the LC / MS chromatogram, but may also have been determined using the 1H NMR spectrum. If no purity is specified, it is usually 100% purity according to automatic peak integration in the LC / MS chromatogram or the purity was not explicitly determined.

[0221] Information on yields in % of theory. Th. are usually purity-corrected if a purity <100% is specified. For batches that contain solvents or are contaminated, the yield can formally be “>100%”; in these cases the yield is not corrected for solvent or purity.

[0222] The following descriptions of the coupling patterns of 1H-NMR signals were partly taken directly from the suggestions of the ACD SpecManager (ACD / Labs Release 12.00, Product version 12.5) and were not necessarily strictly questioned. In addition to these 1<H-NMR data, there may be additional widespread signals - due to the existing molecular dynamics (particularly in the range of 2.50 - 4.20 ppm) - which are not stated separately. Some of the SpecManager suggestions were adjusted manually. Manually adjusted or assigned descriptions are usually based on the visual appearance of the signals in question and do not necessarily correspond to a strict, physically correct interpretation. As a rule, the chemical shift information refers to the center of the signal in question. For wide multiplets, an interval is specified. Signals obscured by solvents or water were either tentatively assigned or are not listed. Strongly broadened signals - e.g. caused by rapid rotation of molecular parts or due to exchanging protons - have also been tentatively assigned (often referred to as broad multiplet or broad singlet) or are not listed.

[0223] The 1<H-NMR data of selected examples are recorded in the form of 1<H-NMR peak lists. For each signal peak, first the δ value is listed in ppm and then the signal intensity in round brackets. The δ -value signal intensity number pairs of different signal peaks are listed separated by commas. The peak list of an example therefore has the form: δ 1 (intensity 1 ), δ 2 (intensity 2 ), ... , δ i (intensity i ), ... , δ n (intensity n ).

[0224] The intensity of sharp signals correlates with the height of the signals in a printed example of an NMR spectrum in cm and shows the true ratios of the signal intensities when compared with other signals. For broad signals, multiple peaks or the center of the signal and their relative intensity compared to the most intense signal in the spectrum can be shown. The lists of H NMR peaks are similar to the classical 1< H NMR expressions and thus usually contain all the peaks listed in a classical NMR interpretation. In addition, like classic 1<H-NMR printouts, they can show solvent signals, signals from stereoisomers of the target compounds, which are also the subject of the invention, and / or peaks from impurities. The peaks of stereoisomers of the target compounds and / or peaks of impurities usually have, on average, a lower intensity than the peaks of the target compounds (for example with a purity of >90%). Such stereoisomers and / or impurities can be typical of the respective manufacturing process. Their peaks can thus help detect the reproduction of our manufacturing process using "by-product fingerprints". An expert who calculates the peaks of the target compounds using known methods (MestreC, ACD simulation, or using empirically evaluated expected values) can isolate the peaks of the target compounds as necessary, using additional intensity filters if necessary. This isolation would be similar to the relevant peak picking in the classical 1< H NMR interpretation. A detailed description of the representation of NMR data in the form of peak lists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. Research Disclosure Database Number 605005, 2014, August 1, 2014 or http: / / www. researchdisclosure.com / searching-disclosures). In the peak picking routine described in Research Disclosure Database Number 605005, the "MinimumHeight" parameter can be set between 1% and 4%. Depending on the type of chemical structure and / or depending on the concentration of the compound to be measured, it may make sense to set the "MinimumHeight" parameter to values ​​<1%.

[0225] Melting points and melting ranges, where stated, are not corrected.

[0226] All reactants or reagents whose preparation is not explicitly described below are deemed to have been obtained commercially from generally accessible sources. For all other reactants or reagents, the preparation of which is also not described below and which were not commercially available or were obtained from sources that are not generally accessible, a reference is provided to the published literature in which their preparation is described. General working regulations AAV1

[0227] A solution of the corresponding carboxylic acid (1 eq.) in DMF (0.08-0.12M) was mixed with N,N-diisopropylethylamine (1.4-1.5 eq. or 2.4-3.0 eq. if the amine was used as hydrochloride) and HATU (1.0 -1.65 eq.) and the mixture was stirred at RT for 30 min. The corresponding amine (1.04-1.5 eq.) was then added and the mixture was stirred for 0.15-2 h at room temperature. The reaction was then stopped by adding water and 1M aqueous hydrochloric acid. The precipitate was filtered off, taken up in DCM, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. Alternatively, after acidification, extraction was carried out with ethyl acetate, the combined organic phases were dried over magnesium sulfate or sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was then purified either using normal phase chromatography (silica gel, eluent: cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative RP-HPLC (water-acetonitrile gradient). Alternatively, the reaction mixture was diluted with a little acetonitrile, water and formic acid and the crude solution obtained was purified using RP-HPLC (water-acetonitrile gradient). Further alternatives for processing, if carried out, are described in the respective experiment. AAV2

[0228] Potassium or cesium carbonate (1.5-2.5 eq.) were baked in a vacuum in the reaction vessel. It was cooled to RT and flooded with argon. Palladium acetate (0.1-0.36 eq.), 9,9-dimethyl-4,5-bis-(diphenylphosphino)-xanthene (Xantphos, 0.18-0.36 eq.) and dioxane (0.04-0.12M) were added and the suspension was prepared for Degassed for 10 minutes at room temperature in an argon stream. The corresponding amide (1.0-10 eq.) and the corresponding 7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine (1.0 eq.) were then added. The mixture was stirred at 80-110° C. for 1 hour (or until complete conversion according to analytical HPLC or thin layer chromatography with appropriate solvent mixtures). It was then cooled to RT and all volatile components were removed under reduced pressure or, alternatively, the reaction mixture was poured onto water, the pH was adjusted to pH 1 with 1M aqueous hydrochloric acid, extracted with ethyl acetate, and the combined organic phases with saturated aqueous sodium chloride solution washed, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The crude product was then purified either using normal phase chromatography (eluent: cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative RP-HPLC (water-acetonitrile gradient). Alternatively, the reaction mixture was diluted with a little acetonitrile, water and formic acid or TFA and the resulting crude solution was purified using RP-HPLC (water-acetonitrile gradient). Further alternatives for processing, if carried out differently, are described in the respective experiment. AAV3

[0229] A solution of the corresponding 7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine in DMF (0.10-0.22M) was mixed with the corresponding amine (1.2 eq.) and DIPEA (1.5-3.5 eq.). offset. The reaction solution was stirred at RT overnight. The crude product was then purified either after aqueous processing and extraction with the appropriate organic solvent using normal phase chromatography (eluent: cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative RP-HPLC (water-acetonitrile gradient). Alternatively, the reaction mixture was diluted with a little acetonitrile, water and formic acid and the crude solution obtained was purified using RP-HPLC (water-acetonitrile gradient). Further alternatives for processing, if carried out, are described in the respective experiment. OUTPUT CONNECTIONS AND INTERMEDIATES: Example 1A 7-Chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester

[0230]

[0231] A solution of 6.00 g (17.8 mmol) of 2-[(2,6-dichloro-5-fluoropyridin-3-yl)carbonyl]-3-ethoxyacrylic acid ethyl ester (preparation described in US4840954 A, Example G, Stage 1, page 7) and 3.23 g (24.9 mmol) of 2,6-difluoroaniline in 30 ml of dichloromethane were mixed with 21.8 ml (125 mmol) of DIPEA and stirred at RT for 4 h. 2.47 g (17.8 mmol) of potassium carbonate were then added and refluxed overnight. The mixture was diluted with 200 ml of dichloromethane and washed twice with 150 ml of 1M aqueous hydrochloric acid. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. It was mixed with 80 ml tert. -Butyl methyl ether diluted, the precipitate was filtered off and mixed with 10 ml tert. -butyl methyl ether washed. 3.22 g (45% of theory, 95.7% purity) of the title compound were obtained. LC-MS (Method 1): R t = 0.96 min; MS (ESIpos): m / z = 383 [M+H]+. 1< H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.95 (s, 1H), 8.57 (d, 1H), 7.80-7.71 (m, 1H), 7.50-7.43 (m, 2H) , 4.25 (q, 2H), 1.26 (t, 3H). Example 2A 7-Chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

[0232]

[0233] 3.22 g (8.41 mmol) of 7-chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester were placed in 25.2 ml of water, with 25.2 ml 36 percent. aqueous hydrochloric acid and 25.2 ml THF were added and stirred at 110 ° C for 4 h. The reaction mixture was cooled to RT, the precipitate was filtered off with suction, washed twice with 30 ml of water and dried under high vacuum. 4.1 g (quantitative, 96.8% purity) of the title compound were obtained. LC-MS (Method 1): R t = 0.96 min; MS (ESIpos): m / z = 355 [M+H] +< . 1< H-NMR (400 MHz, DMSO-d6): δ [ppm] = 13.70 (s, 1H), 9.25 (s, 1H), 8.76 (d, 1H), 7.80-7.72 (m, 1H), 7.51 -7.43 (m, 2H). Example 3A 7-Chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo- N -[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

[0234]

[0235] According to AAV1, 1.00 g (2.82 mmol) of 7-chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid was mixed with 553 mg ( 3.38 mmol) (2 S )-1,1,1-trifluorobutane-2-amine hydrochloride was reacted in the presence of 1.29 g (3.38 mmol) HATU and 1.96 ml (11.3 mmol) DIPEA in 20 ml DMF. Stirring was continued for 1 minute and the reaction solution was added to a mixture of water, 1M aqueous hydrochloric acid and ethyl acetate. The phases were separated and the aqueous phase was extracted four times with 50 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was dissolved in a little ethyl acetate and purified using normal phase chromatography (cyclohexane-ethyl acetate, 5:1). The fractions were combined, concentrated in vacuo and the residue was lyophilized from acetonitrile overnight. 331 mg (25% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 3): R t = 2.32 min; MS (ESIpos): m / z = 464 [M+H] +< . 1< H-NMR (400 MHz, DMSO-d6): δ [ppm] = 9.84 (d, 1H), 9.12 (s, 1H), 8.72 (d, 1H), 7.80-7.72 (m, 1H), 7.51 -7.44 (m, 2H), 4.85-4.71 (m, 1H), 1.96-1.83 (m, 1H), 1.75-1.61 (m, 1H), 0.98 (t, 3H). Example 4A 7-Chloro-1-(2,4,6-trifluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester

[0236]

[0237] A solution of 12.0 g (35.7 mmol) of 2-[(2,6-dichloro-5-fluoropyridin-3-yl)carbonyl]-3-ethoxyacrylic acid ethyl ester (US4840954 A, Example G, Step 1, page 7) and 7.35 g ( 49.9 mmol) of 2,4,6-trifluoroaniline in 60 ml of dichloromethane were mixed with 43.5 ml (250 mmol) of DIPEA and stirred at RT for 4 h. 4.93 g (35.7 mmol) of potassium carbonate were then added and refluxed overnight. The mixture was then diluted with 200 ml of dichloromethane and washed three times with 150 ml of 1M aqueous hydrochloric acid. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. It was mixed with 100 ml tert. -Butyl methyl ether, the precipitate was filtered off with suction and washed three times with 20 ml of tert-butyl methyl ether and dried under high vacuum. 8.80 g (58% of theory, 94.6% purity) of the title compound were obtained. LC-MS (Method 1): R t = 1.01 min; MS (ESIpos): m / z = 401 [M+H]+. 1< H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.97 (s, 1H), 8.56 (d, 1H), 7.67-7.56 (m, 2H), 4.26 (q, 2H), 1.28 (t, 3H). Example 5A 7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

[0238]

[0239] 8.80 g (21.9 mmol) of 7-chloro-1-(2,4,6-trifluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester were dissolved in 66.2 ml of water presented, with 66.2 ml 36 percent. aqueous hydrochloric acid and 66.2 ml of THF were added and the mixture was stirred at 110° C. for 4 h. The reaction mixture was cooled to RT, the precipitate was filtered off with suction, washed four times with 40 ml of water and dried under high vacuum. 7.37 g (89% of theory, 99% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.84 min; MS (ESIpos): m / z = 373 [M+H] +< . 1< H-NMR (400 MHz, DMSO-d6): δ [ppm] = 13.67 (s, 1H), 9.28 (s, 1H), 8.76 (d, 1H), 7.68-7.59 (m, 2H). Example 6A 7-[(3 R ,4 R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

[0240]

[0241] Add a solution of 3.60 g (9.66 mmol) of 7-chloro-1-(2,4,6-trifluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 1.48 g (10.6 mmol) (3 R ,4 R )-Pyrrolidine-3,4-diol hydrochloride in 50 ml of DMF was added to 5.89 ml (33.8 mmol) of DIPEA at RT. Stirring was continued for 1 h at RT. The reaction mixture was then mixed with 150 ml of water and 100 ml of aqueous 1M hydrochloric acid and the resulting precipitate was filtered off with suction. The precipitate was washed with water and dried under high vacuum. 3.96 g (93% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.23 min; MS (ESIpos): m / z = 440 [M+H]+. 1< H-NMR (500 MHz, DMSO-d6): δ [ppm] = 15.01 (s, 1H), 9.05 (s, 1H), 8.07 (d, 1H), 7.64-7.54 (m, 2H), 5.30 -5.14 (m, 2H), 4.09-3.64 (m, 4H), 3.28-3.21 (m, 0.6H, partially under the water resonance), 3.15-3.01 (m, 1H). Example 7A 6-Fluoro-7-[(4 S )-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

[0242]

[0243] According to AAV2, 100 mg (268 µmol) 7-chloro-1-(2,4,6-trifluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with 32.6 mg (322 µmol) (4 S )-4-Hydroxypyrrolidin-2-one in the presence of 92.7 mg (671 µmol) potassium carbonate, 6.0 mg (27 µmol) palladium acetate and 33 mg (54 µmol) xantphos in 2.4 ml dioxane at 90 ° C for 1 h. The reaction mixture was diluted with 1 ml of aqueous 1M hydrochloric acid and 1 ml of DMSO and prepared directly using prep. HPLC (acetonitrile water with formic acid, C18 RP-HPLC). 61.7 mg (42% of theory, 80% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.19 min; MS (ESIpos): m / z = 438 [M+H] +< . Example 8A 7-[(3 S ,4 S )-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

[0244]

[0245] Add a solution of 240 mg (644 µmol) 7-chloro-1-(2,4,6-trifluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 73.0 mg (708 µmol) (3 S ,4 S )-Pyrrolidine-3,4-diol in 3.3 ml DMF was added to 280 µl (1.61 mmol) DIPEA at RT. Stirring was continued at RT for 1 hour. The reaction mixture was diluted with 0.4 ml of aqueous 1M hydrochloric acid and 1 ml of acetonitrile and prepared directly using prep. HPLC (acetonitrile water with formic acid, C18 RP-HPLC). 232 mg (74% of theory, 94.4% purity) of the title compound were obtained. LC-MS (Method 1): R t = 0.69 min; MS (ESIpos): m / z = 440 [M+H]+. 1< H-NMR (500 MHz, DMSO-d6): δ [ppm] = 15.01 (s, 1H), 9.05 (s, 1H), 8.07 (d, 1H), 7.64-7.55 (m, 2H), 5.33 -5.10 (m, 2H), 4.10-3.63 (m, 4H), 3.29-3.20 (m, 0.8H, partially under the water resonance), 3.15-3.00 (m, 1H). Example 9A 7-[(3 R ,4 S )-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

[0246]

[0247] Add a solution of 250 mg (671 µmol) 7-chloro-1-(2,4,6-trifluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 103 mg (738 µmol) cis -Pyrrolidine-3,4-diol hydrochloride in 3.5 ml DMF was added to 409 µl (2.35 mmol) DIPEA at RT. Stirring was continued for 1 h at RT. The reaction mixture was acidified with 7 ml of aqueous 1M hydrochloric acid, 15 ml of water was added and the precipitate was filtered off with suction. The residue was washed with water and lyophilized. 256 mg (86% of theory, 99% purity) of the title compound were obtained. LC-MS (Method 1): R t = 0.71 min; MS (ESIpos): m / z = 440 [M+H]+. 1< H-NMR (500 MHz, DMSO-d6): δ [ppm] = 15.0 (s, 1H), 9.05 (s, 1H), 8.05 (d, 1H), 7.63-7.54 (m, 2H), 5.15 -4.89 (m, 2H), 4.13-3.86 (m, 3H), 3.61 (br. s, 1H), 3.21 (br. s, 1H), 3.04 (br. s, 1H). Example 10A 6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridin-3- carboxylic acid

[0248]

[0249] 7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (800 mg, 2.15 mmol) was dissolved in 8 in DMF was introduced, (3S)-pyrrolidin-3-ol (206 mg, 2.36 mmol) and N,N-diisopropylethylamine (1.3 ml, 7.5 mmol) were added and the mixture was stirred at RT for 2 h. The reaction mixture was poured into water and 1M hydrochloric acid and ethyl acetate were added. The organic phase was separated off and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were once with sat. Washed sodium chloride solution, dried over sodium sulfate and concentrated. The product was stirred with acetonitrile, filtered off, washed with a little cold acetonitrile and dried. 770 mg (85% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 1): R t = 0.82 min; MS (ESIpos): m / z = 424 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.22), 0.008 (2.03), 1.909 (0.87) , 2,074 (16.00), 3,222 (0.71), 3,875 (0.53), 4,309 (0.50), 5,024 (1.35), 7,565 (2.70), 7,586 (4.97), 7,608 (2.81), 8,037 (5.77), 8,068 (5.70 ) , 9,043 (10.89), 15,025 (9.55). Example 11A N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-7-(3H-[1,2,3]triazolo[4,5-b]pyridine- 3-yloxy)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

[0250]

[0251] According to AAV1, 500 mg (1.34 mmol) of 7-chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid was mixed with 283 mg ( 1.61 mmol) (1 S )-1-Cyclopropyl-2,2,2-trifluoroethanamine hydrochloride was reacted in the presence of 612 mg (1.61 mmol) HATU and 935 µl (5.37 mmol) DIPEA in 10 ml DMF. The mixture was stirred at RT for 1 h and the reaction solution was added to a mixture of water and ethyl acetate. The phases were separated and the aqueous phase was extracted four times with 50 ml of ethyl acetate. The organic phases were combined, washed with 50 ml of pH-7 buffer and twice with 50 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The substance was dissolved in ethyl acetate and applied to silica gel and purified using normal phase chromatography (cyclohexane-ethyl acetate gradient). The fractions were combined, concentrated in vacuo and the residue was lyophilized from acetonitrile overnight. 534 mg (66% of theory, 99% purity) of the title compound were obtained. LC-MS (Method 3): R t = 2.21 min; MS (ESIpos): m / z = 594 [M+H] +< . 1< H-NMR (400 MHz, DMSO-d6): δ [ppm] = 10.01 (d, 1H), 8.96 (s, 1H), 8.88 (d, 1H), 8.74 (dd, 1H), 8.63 (dd , 1H), 7.65 (dd, 1H), 7.05-6.97 (m, 2H), 4.42-4.37 (m, 1H), 1.28-1.17 (m, 1H), 0.71-0.51 (m, 3H), 0.36-0.28 (m, 1H). Example 12A 6-Fluoro-4-oxo-7-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-N-[(2S)-1,1,1-trifluorobutane- 2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

[0252]

[0253] According to AAV1, 500 mg (1.34 mmol) of 7-chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid was mixed with 263 mg ( 1.61 mmol) (S)-1,1,1-trifluorobutane-2-amine hydrochloride was reacted in the presence of 612 mg (1.61 mmol) HATU and 935 µl (5.37 mmol) DIPEA in 9.5 ml DMF. The mixture was stirred at RT for 1 h and the reaction solution was added to a mixture of water and ethyl acetate. The phases were separated and the aqueous phase was extracted four times with 50 ml of ethyl acetate. The organic phases were combined, washed with 50 ml of buffer pH7 and twice with 50 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The substance was dissolved in ethyl acetate and applied to silica gel and purified using normal phase chromatography (cyclohexane-ethyl acetate gradient). The fractions were combined, concentrated in vacuo and the residue was lyophilized from acetonitrile overnight. 522 mg (66% of theory, 99% purity) of the title compound were obtained. LC-MS (Method 3): R t = 2.19 min; MS (ESIpos): m / z = 582 [M+H] +< . 1< H-NMR (400 MHz, DMSO-d6): δ [ppm] = 9.85 (d, 1H), 8.97 (s, 1H), 8.87 (d, 1H), 8.74 (dd, 1H), 8.63 (dd , 1H), 7.65 (dd, 1H), 7.06-6.96 (m, 2H), 4.81-4.66 (m, 1H), 1.94-1.81 (m, 1H), 1.73-1.59 (m, 1H), 0.96 (t , 3H). Example 13A tert-Butyl-4-[6-{[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-3-fluoro-5-oxo-8-(2,4,6-trifluorophenyl)- 5,8-dihydro-1,8-naphthyridin-2-yl]piperazine-1-carboxylate

[0254]

[0255] 7-Chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro- 1,8-naphthyridine-3-carboxamide (60.0 mg, 122 µmol) was placed in 1.2 ml of acetonitrile, with tert-butyl-piperazine-l-carboxylate (45.3 mg, 243 µmol) and N,N-diisopropylethylamine (74 µl, 430 µmol) and stirred at room temperature for 2 h. The reaction solution was concentrated in vacuo and used in the subsequent stage without further purification. 113 mg of the target compound (quantitative yield, purity approx. 69%) were obtained. LC-MS (Method 3): R t = 2.61 min; MS (ESIpos): m / z = 644 [M+H] +< Example 14A tert-Butyl-(2S)-4-[6-{[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-3-fluoro-5-oxo-8-(2,4,6 -trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]-2-methylpiperazine-1-carboxylate

[0256]

[0257] 7-Chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro- 1,8-naphthyridine-3-carboxamide (60.0 mg, 122 µmol) was placed in 1.2 ml of DMF, with tert-butyl-(2S)-2-methylpiperazine-1-carboxylate (34.1 mg, 170 µmol) and N,N -Diisopropylethylamine (74 µl, 430 µmol) was added and stirred at room temperature for 1 h. The reaction solution was taken up in ethyl acetate and washed three times with a semi-saturated ammonium chloride solution. shaken out. The combined aqueous phases were re-extracted once with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered off and concentrated in vacuo. 82 mg of the target compound (91% of theory, purity 90%) were obtained. LC-MS (Method 3): R t = 2.64 min; MS (ESIpos): m / z = 658 [M+H] +< Example 15A 7-Chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester

[0258]

[0259] A solution of 6.00 g (17.8 mmol) of 2-[(2,6-dichloro-5-fluoropyridin-3-yl)carbonyl]-3-ethoxyacrylic acid ethyl ester (US4840954, 1989, Example G, Stage 1, page 7) and 3.25 g (25.0 mmol) of 2-amino-3,5-difluoropyridine in 30 ml of dichloromethane was mixed with 21.8 ml (125 mmol) of DIPEA and stirred at RT for 4 h. 2.47 g (17.8 mmol, 1 eq.) of potassium carbonate were then added and refluxed overnight. Another equivalent of potassium carbonate was then added and continued refluxing overnight. Another equivalent of potassium carbonate was then added and further refluxed for 3d. The mixture was diluted with 200 ml of dichloromethane and washed twice with 200 ml of 1M aqueous hydrochloric acid. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. It was diluted with 80 ml of tert-butyl methyl ether and the precipitate was filtered off with suction with 10 ml tert.- Washed butyl methyl ether and dried under high vacuum. 3.73 g (54% of theory, 99% purity) of the title compound were obtained. LC-MS (Method 1): R t = 0.93 min; MS (ESIpos): m / z = 384 [M+H]+. 1< H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.92 (s, 1H), 8.66 (d, 1H), 8.56 (d, 1H), 8.44-8.37 (m, 1H), 4.26 (q, 2H), 1.28 (t, 3H). Example 16A 7-Chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

[0260]

[0261] 3.60 g (9.38 mmol) of 7-chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester were dissolved in 28.3 ml of water, with 28.3 ml 36 percent. aqueous hydrochloric acid and 28.3 ml THF were added and stirred at 110 ° C for 4 h. 28.3 ml of 36 percent were then added twice one after the other. aqueous hydrochloric acid was added and stirred for 2 d at 110 ° C. The reaction mixture was cooled to RT, the precipitate was filtered off with suction, washed with water and dried under high vacuum. 3.25 g (96% of theory, 99% purity) of the title compound were obtained. LC-MS (Method 1): R t = 0.90 min; MS (ESIpos): m / z = 356 [M+H] +< . 1< H-NMR (400 MHz, DMSO-d6): δ [ppm] = 13.71 (s, 1H), 9.18 (s, 1H), 8.76 (d, 1H), 8.68 (dd, 1H), 8.46-8.39 (m, 1H). Example 17A 1-(3,5-Difluoropyridin-2-yl)-7-[(3 R ,4 R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

[0262]

[0263] To a solution of 1.50 g (4.22 mmol) 7-chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridin-3- carboxylic acid and 648 mg (4.64 mmol) (3 R ,4 R )-Pyrrolidine-3,4-diol hydrochloride in 21 ml of DMF was added to 2.57 ml (14.8 mmol) of DIPEA at RT. Stirring was continued at RT for 2 h. It was acidified with 1M aqueous hydrochloric acid and then diluted with 100 ml of water and 50 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted twice with 50 ml of ethyl acetate. The combined organic phases were washed twice with 50 ml of a pH7 buffer solution and once with 50 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was mixed with 20 ml tert.- Butyl methyl ether was stirred, decanted and the precipitate was dried under high vacuum. 1.41 g (78% of theory, 99% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.07 min; MS (ESIpos): m / z = 423 [M+H]+. 1< H-NMR (500 MHz, DMSO-d6): δ [ppm] = 15.02 (s, 1H), 8.96 (s, 1H), 8.66-8.61 (m, 1H), 8.41-8.34 (m, 1H) , 8.07 (d, 1H), 5.34-5.06 (m, 2H), 4.14-3.59 (m, 4H), 3.44-3.20 (m, 1H, partially under the water resonance), 3.19-3.01 (m, 1H). Example 18A 1-(3,5-Difluoropyridin-2-yl)-6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine- 3 -carboxylic acid

[0264]

[0265] According to AAV3, 300 mg (843 μmol) of 7-chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 81 mg (928 µmol) of (S)-3-pyrrolidinol and 0.514 ml (2.95 mmol) of DIPEA were added to 3.1 ml of DMF and stirred at RT for 1 h. A further 20 mg (232 µmol) of (S)-3-pyrrolidinol were then added and the mixture was stirred at RT for 1 h. The reaction mixture was diluted with water and purified directly using preparative HPLC (acetonitrile-water with formic acid, C18 RP-HPLC). 244 mg (72% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.36 min; MS (ESIpos): m / z = 407 [M+H] +< . Example 19A 1-(3,5-Difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

[0266]

[0267] To a solution of 500 mg (1.41 mmol) 7-chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridin-3- carboxylic acid and 169 mg (1.55 mmol) 3-hydroxyazetidine hydrochloride in 7 ml DMF were added to 857 µl (4.92 mmol) DIPEA at RT. Stirring was continued at RT for 2.5 h. It was acidified with 1M aqueous hydrochloric acid and diluted with 30 ml of water and 30 ml of ethyl acetate. The precipitate was filtered off with suction (first product fraction). The phases were separated and the aqueous phase was extracted twice with 15 ml of ethyl acetate. The combined organic phases were washed twice with 15 ml of pH 7 buffer and once with 15 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was mixed with 10 ml tert. -Butyl methyl ether stirred, decanted and the precipitate dried under high vacuum (second product fraction). Combined, 476 mg (86% of theory, 99% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.35 min; MS (ESIpos): m / z = 393 [M+H] +< . 1< H-NMR (500 MHz, DMSO-d6): δ [ppm] = 14.98 (s, 1H), 8.95 (s, 1H), 8.62 (d, 1H), 8.39-8.31 (m, 1H), 8.05 (d, 1H), 5.80 (d, 1H), 4.81-3.50 (m, 5H). Example 20A 1-(3,5-Difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxy-3-methylazetidin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridin- 3 -carboxylic acid

[0268]

[0269] To a solution of 500 mg (1.41 mmol) 7-chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridin-3- carboxylic acid and 191 mg (1.55 mmol) 3-methylazetidin-3-ol hydrochloride in 7 ml DMF were added to 857 µl (4.92 mmol) DIPEA at RT. Stirring was continued at RT for 2 h. It was acidified with 1M aqueous hydrochloric acid, diluted with 40 ml of water and the precipitate was filtered off with suction. The precipitate was washed three times with 5 ml of water and dried under high vacuum. 534 mg (93% of theory, 99% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.43 min; MS (ESIpos): m / z = 407 [M+H] +< . 1< H-NMR (500 MHz, DMSO-d6): δ [ppm] = 14.98 (s, 1H), 8.95 (s, 1H), 8.62 (d, 1H), 8.39-8.32 (m, 1H), 8.06 (d, 1H), 5.72 (s, 1H), 4.48-3.49 (m, 4H), 1.38 (s, 3H). Example 21A Ethyl (2Z)-2-[(2,6-dichloro-5-fluoropyridin-3-yl)carbonyl]-3-ethoxyacrylate

[0270]

[0271] Ethyl 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxopropanoate (19.5 g, 69.6 mmol) and triethyl orthoformate (23.1 ml, 140 mmol) were placed in acetic anhydride (46 ml, 490 mmol). and the mixture was stirred at 140°C overnight. The reaction mixture was then concentrated in vacuo and reacted further without further workup for the subsequent stages. Quantitative sales were assumed. LC-MS (Method 1): R t = 1.00 min; MS (ESIpos): m / z = 336 [M+H] +< Example 22A Ethyl 7-chloro-1-(2-chloro-4,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (atropisomer mixture)

[0272]

[0273] Under argon, ethyl (2Z)-2-[(2,6-dichloro-5-fluoropyridin-3-yl)carbonyl]-3-ethoxyacrylate (24.0 g, 71.4 mmol) and 2-chloro-4,6-difluoroaniline were formed (16.3 g, 100 mmol) in 120 ml of dichloromethane and added at room temperature with N,N-diisopropylethylamine (87 ml, 500 mmol). The reaction solution was stirred at room temperature for 4 h. Potassium carbonate (9.87 g, 71.4 mmol) was then added and the mixture was stirred under reflux overnight. The reaction mixture was cooled, diluted with 300 ml of dichloromethane and washed three times with 180 ml of 1 M hydrochloric acid each time. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The suspension thus obtained was stirred in 150 ml of tert-butyl methyl ether. The solution was concentrated in vacuo. The crude product obtained was purified using silica gel chromatography (mobile phase: cyclohexane / ethyl acetate 10 / 1 to 5 / 1 to 2 / 1). 13.75 g of the target compound (46% of theory, purity 99%) were obtained. LC-MS (Method 3): R t = 1.98 min; MS (ESIpos): m / z = 417 [M+H] +< Example 23A 7-Chloro-1-(2-chloro-4,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (atropisomer mixture)

[0274]

[0275] Ethyl 7-chloro-1-(2-chloro-4,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (6.00 g, 99% purity , 14.2 mmol) was suspended in 43 ml THF. Water (43 ml) and concentrated. Hydrochloric acid (43 ml) was added and the mixture was allowed to stir at 110°C bath temperature for 4 h. The organic solvent was largely concentrated in vacuo. The suspension was mixed with 20 ml of water and the precipitate was filtered off. 5.12 g of the target compound (92% of theory, purity 99%) were obtained. LC-MS (Method 3): R t = 1.93 min; MS (ESIpos): m / z = 389 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.01), 0.008 (2.85), 2.327 (0.79) , 2,671 (0.75), 7.752 (1.44), 7.758 (2.19), 7.774 (2.10), 7.782 (6.12), 7.794 (2.31), 7.805 (5.86), 7.816 (1.78), 8.760 (8.43), 8.778 (8.40) , 9,250 (16.00), 13,654 (2.73). Example 24A 7-Chloro-1-(2-chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-1,4- dihydro-1,8-naphthyridine-3-carboxamide (atropisomer mixture)

[0276]

[0277] 7-Chloro-1-(2-chloro-4,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (atropisomer mixture, 1.50 g, 3.85 mmol) was presented in 34 ml DMF. Add HATU (1.47 g, 3.85 mmol) and N,N-diisopropylethylamine (1.6 ml, 9.3 mmol) and stir at room temperature for 30 min. (1S)-1-Cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (745 mg, 4.24 mmol) was then added and allowed to stir at room temperature for 2 minutes. The reaction was worked up directly without reaction control. The mixture was added to 340 ml of water. The solid that precipitated was filtered off and dried under a high vacuum. 2.13 g of the target compound (62% of theory, purity 57%) were obtained. LC-MS (Method 3): R t = 2.46 min; MS (ESIpos): m / z = 510 [M+H] +< Example 25A 1-(2-Chloro-4,6-difluorophenyl)-7-[(3 R ,4 R )-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3 -carboxylic acid (atropisomer mixture)

[0278]

[0279] To a solution of 500 mg (1.29 mmol) 7-chloro-1-(2-chloro-4,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3- carboxylic acid (atropisomer mixture) and 648 mg (4.64 mmol) of (3R,4R)-pyrrolidine-3,4-diol hydrochloride in 21 ml of DMF were added to 2.57 ml (14.8 mmol) of DIPEA at RT. Stirring was continued at RT for 12 h. It was stirred into 100 ml of water and the precipitate was filtered off with suction. The precipitate was washed with water and dried under high vacuum. 463 mg (78% of theory, 99% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.30 min; MS (ESIpos): m / z = 456 [M+H]+. 1< H-NMR (400 MHz, DMSO-d6): δ [ppm] = 15.04 (s, 1H), 9.01 (s, 1H), 8.07 (d, 1H), 7.80-7.69 (m, 1H),) , 5.22 (br. s, 2H), 4.09-3.64 (m, 4H), 3.28-3.17 (m, 1H), 3.11-2.94 (m, 1H). Example 26A 1-(2,6-Difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine- 3 -carboxylic acid

[0280]

[0281] To a solution of 1.00 g (2.82 mmol) 7-chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 433 mg (3.10 mmol) (3 R ,4 R )-Pyrrolidine-3,4-diol hydrochloride in 15.4 ml DMF was added to 1.72 ml (9.87 mmol) DIPEA at RT. Stirring was continued at RT for 2 h. The mixture was then acidified with 1M aqueous hydrochloric acid and diluted with 200 ml of water and 100 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted twice with 50 ml of ethyl acetate. The combined organic phases were washed twice with 25 ml of buffer pH 7, once with 50 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. 1.03 g (87% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.19 min; MS (ESIpos): m / z = 422 [M+H] +< . 1< H-NMR (400 MHz, DMSO-d6): δ [ppm] = 15.04 (s, 1H), 9.01 (s, 1H), 8.08 (d, 1H), 7.78-7.68 (m, 1H),) , 7.47-7.39 (m, 2H), 5.28-5.14 (m, 2H), 4.09-3.62 (m, 4H), 3.26-3.15 (m, 1H), 3.08-2.96 (m, 1H). Example 27A Ethyl (2Z)-3-ethoxy-2-[(2,5,6-trichloropyridin-3-yl)carbonyl]acrylate

[0282]

[0283] Ethyl 3-oxo-3-(2,5,6-trichloropyridin-3-yl) propanoate (1.6 g, 5.40 mmol) and (diethoxymethoxy) ethane (1.80 ml, 1.3 mmol) and acetic anhydride (3.31 ml, 35.1 mmol). ) admitted. The mixture was stirred overnight at 140 °C. The mixture was evaporated and reacted further without further purification (assuming 100% conversion). Example 28A Ethyl 6,7-dichloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate

[0284]

[0285] Under argon, ethyl (2Z)-3-ethoxy-2-[(2,5,6-trichloropyridin-3-yl)carbonyl]acrylate (assumption: 1.90 g, 5.39 mmol) was formed from the precursor and 2,4,6 -Trifluoroaniline (1.11 g, 7.54 mmol) in 50 ml of dichloromethane. N,N-Diisopropylethylamine (6.6 ml, 38 mmol) was added and the mixture was stirred at RT for 4 h. Potassium carbonate (745 mg, 5.39 mmol) was then added and the mixture was stirred at reflux overnight. The reaction mixture was diluted with 120 ml of dichloromethane and washed twice with 40 ml of 1M hydrochloric acid, dried and concentrated. The residue was purified over silica gel (mobile phase cyclohexane / ethyl acetate = 4:1). The product-containing fractions were concentrated. 0.298 g (13% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 1): R t = 1.08 min; MS (ESIpos): m / z = 417 [M+H] +< . Example 29A 6,7-Dichloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

[0286]

[0287] 292 mg of ethyl 6,7-dichloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate (700 μmol) were dissolved in THF (4.0 ml, 49 mmol), ethanol (2.0 ml, 34 mmol) and water (1.0 ml) and added at RT with conc. Hydrochloric acid was acidified (approx. 2 ml) and then stirred at 110 ° C for 4 days. The precipitate was filtered off, washed with water and dried under high vacuum overnight. 253 mg (90% of theory, 97% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.99 min; MS (ESIpos): m / z = 389 [M+H] +< . Example 30A 6-Chloro-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8- naphthyridine-3 carboxylic acid

[0288]

[0289] 253 mg of 6,7-dichloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (97% purity, 631 µmol) were dissolved in DMF (6.0 ml, 78 mmol) dissolved. (3R,4R)-pyrrolidine-3,4-diol hydrochloride (99.8 mg, 97% purity, 694 µmol) and N,N-diisopropylethylamine (384 µl, 2.2 mmol) were added and stirred at RT for 1 h. It was diluted with 20 ml water, 5 ml 1M hydrochloric acid and 20 ml ethyl acetate. The organic phases were separated and the aqueous phase was extracted three times with 20 ml of ethyl acetate. The united org. Phases were washed twice with 20 ml buffer (pH 7) and 20 ml sat. aqueous sodium chloride solution. washed, dried over magnesium sulfate, filtered and concentrated. 172 mg (57% of theory, 95% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.33 min; MS (ESIpos): m / z = 456 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.50), 0.008 (4.41), 0.146 (0.53) , 1.157 (0.75), 1.175 (1.193 (1.14), 1.211 (0.80), 1.229 (0.63), 1.263 (0.54), 1,988 (2.86), 2.327 (0.86), 2.366 (0.56), 2,670 (1.04) , 2,710 (0.65), 2,731 (7.25), 2,891 (9.16), 3,940 (5.63), 4.003 (0.85), 4.021 (1.18), 4.038 (1.09), 4.056 (0.63), 4.176 (0.54), 4.194 (0.51) , 5,210 (10.86), 5,216 (10.51), 5,754 (0.55), 7,582 (5.35), 7,604 (9.75), 7,626 (5.44), 7,952 (1.08), 8,314 (15.84), 9,065 (16.00), 14,776 ( 6.50) . Example 31A 7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbonyl chloride

[0290]

[0291] Add a solution of 300 mg (805 µmol) 7-chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid in 6 ml of THF were added to 180 µl (2.40 mmol) of thionyl chloride and stirred under reflux for 3 h and then all volatile components were removed under reduced pressure. The raw product was used in the next step without further processing (quantitative conversion was assumed). Example 32A 7-chlorine N -(2,6-dichlorophenyl)-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

[0292]

[0293] Add a solution of 314 mg (803 µmol) 7-chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbonyl chloride in 340 µl (2.40 mmol) of triethylamine and 156 mg (963 µmol) of 2,6-dichloroaniline were added to 20 ml of dichloromethane at RT. Stirring was continued for 30 min at RT and overnight at 50°C. The reaction mixture was concentrated and taken up in dichloromethane, washed twice with 1 M aqueous hydrochloric acid, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified using preparative HPLC (column: acetonitrile / water / 0.1% formic acid). 255 mg (61% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 1): R t = 1.28 min; MS (ESIpos): m / z = 516 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.50), -0.008 (5.02), 0.008 (4.03 ), 0.146 (0.49), 1.245 (0.63), 1.260 (0.75), 1.275 (0.44), 2.073 (11.19), 2.328 (0.67), 2,367 (0.63), 2.524 (2.670 (0.76), 2,710 (0.70 ), 2,891 (0.41), 7.381 (3.22), 7.402 (6.06), 7.422 (4.60), 7.596 (16.00), 7.608 (4.71), 7.616 (13.09), 7.629 (7.60), 7.652 (4.03), 8.767 (6.42 ), 8,786 (6.40), 9,250 (10.90), 11,287 (9.23). Example 33A Ethyl 2-[(2,5-dichloropyridin-3-yl)carbonyl]-3-(dimethylamino)acrylate

[0294]

[0295] 2.0 g (10.42 mmol) of 2,5-dichloronicotinic acid in 27 ml of dichloromethane were mixed with 1.34 ml (15.39 mmol) of oxalyl chloride and 4 drops of DMF at RT and stirred at RT for 1.5 h. The clear solution was then evaporated, mixed with toluene and evaporated again (twice). The intermediate product obtained was dissolved in 67 ml of toluene, and 2.17 ml (15.60 mmol) of triethylamine and 1.94 g (13.54 mmol) of ethyl (2E)-3-(dimethylamino) acrylate were added. The mixture was stirred at 90 ° C for 2.5 h, cooled, filtered and evaporated to dryness. The crude product was purified using silica gel chromatography (solvent: cyclohexane / ethyl acetate = 1:1). 4.10 g (quantitative yield, approx. 95% purity) of the title compound were obtained. LC-MS (Method 1): R t = 0.76 min; MS (ESIpos): m / z = 317 [M+H] +< Example 34A Ethyl 6-chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

[0296]

[0297] 770 µl (7.60 mmol) of 2,4- Difluoroaniline was added to 3.8 ml of THF and the reaction mixture was stirred at RT overnight. The solvent was then removed under reduced pressure, the residue was taken up in 20 ml of DMF and 1.31 g (9.48 mmol) of potassium carbonate was added. The suspension was then stirred at 100 ° C for 1 h, then cooled to RT and added to 50 ml of water. The precipitate was filtered off and washed three times with water. 1.06 g (46% of theory, 91% purity) of the title compound were obtained, which was used in the subsequent stage without further purification. LC-MS (Method 1): R t = 0.99 min; MS (ESIpos): m / z = 365 [M+H] +< 1< H NMR (400 MHz, DMSO- d 6 ): δ ppm = 8.80 (d, 1 H), 8.78 (s, 1 H), 8.59 (d, 1 H), 7.80 - 7.88 (m, 1 H), 7.57 - 7.65 (m, 1 H), 7.31 - 7.39 (m, 1 h), 4.24 (q, 2 h), 1.28 (t, 3 h). Example 35A 6-Chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

[0298]

[0299] Add a suspension of 1.10 g (3.02 mmol) of ethyl 6-chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate in 10 ml of THF and 127 mg (3.02 mmol) of lithium hydroxide monohydrate were added to 3.6 ml of water and the reaction mixture was stirred for 1 h at room temperature. It was then diluted with 20 ml THF and 20 ml water and the pH value was adjusted with 1M aqueous. Hydrochloric acid adjusted to pH 1. Ethyl acetate was added and the aqueous phase was extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in vacuo. 0.90 g (86% of theory, 97% purity) of the title compound were obtained. LC-MS (Method 1): R t = 0.96 min; MS (ESIpos): m / z = 337 [M+H] +< 1< H NMR (400 MHz, DMSO- d 6 ): δ ppm = 13.98 (br s, 1 H), 9.10 (s, 1 H), 8.95 (d, 1 H), 8.80 (d, 1 H), 7.80 - 7.89 (m, 1 H), 7.58 - 7.67 (m, 1 h), 7.26 - 7.47 (m, 1 h). Example 36A 6-Chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl chloride

[0300]

[0301] A solution of 150 mg (446 µmol) of 6-chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid in 3 ml of THF was added to 58 µl (670 µmol) oxalic acid dichloride and DMF (catalytic amounts) were added. The reaction mixture was stirred at room temperature for 1 h and under reflux for a further hour. All volatile components were then removed under reduced pressure. The raw product was used in the next step without further processing (quantitative conversion was assumed). Example 37A 7-Chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro- 1,8-naphthyridine-3-carboxamide

[0302]

[0303] 7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (100 mg, 268 µmol) was dissolved in 2.5 ml Acetonitrile was introduced, (1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (51.8 mg, 295 µmol) and N,N-diisopropylethylamine (190 µl, 1.1 mmol) were added. T3P solution (propanephosphonic acid cycloanhydride, 50% in ethyl acetate, 190 µl, 320 µmol) was then added. The reaction solution was stirred at room temperature overnight. Water was then added to the reaction mixture and the precipitated solid was filtered off and dried under high vacuum. 145 mg of the target compound (quantitative yield) were obtained. LC-MS (Method 3): R t = 2.42 min; MS (ESIpos): m / z = 494 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.74), 0.146 (0.69), 0.335 (4.38) , 0.348 (3.99), 0.359 (2.50), 0.567 (5.66), 0.579 (6.91), 0.590 (7.00), 0.624 (1.67), 0.651 (2.50), 0.670 (4.11), 0.687 (2.47), 1.224 (2.32) , 1.237 (3.75), 1.245 (3.07), 1.257 (3.55), 1.268 (2.06), 2.328 (1.49), 2,366 (1.19), 2.669 (1.43), 2,710 (1.01), 4.391 (3.66) , 4,411 (3.61), 4,433 (1.94), 5,754 (2.89), 7,602 (6.41), 7,624 (12.45), 7,647 (6.50), 8,709 (9.33), 8,728 (9.33), 9,157 (16.00), 9,972 (6.9 7) , 9,996 (6.88). Example 38A N -Benzyl-1,1,1,2,2-pentafluorobutane-3-amine (racemate)

[0304]

[0305] 5.40 ml (18.3 mmol) of titanium tetraisopropoxide and 2.66 ml (24.4 mmol) of benzylamine were added to a solution of 2.00 g (12.2 mmol) of 3,3,4,4,4-pentafluorobutan-2-one in 10 ml of dichloromethane at 0 ° C . Stirring was continued at RT for 90 min before cooling to 0°C again. 2.14 g (34.1 mmol) of sodium cyanoborohydride, 36 ml of methanol and 3Å molecular sieve were then added. The mixture was warmed to RT and stirred for 2 days. A little water and ethyl acetate were added to the reaction solution and filtered. The filtrate was washed twice with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified twice using normal phase chromatography (ethyl acetate / cyclohexane 1 / 20) and 1.65 g (48% of theory, 91% purity) of the title compound were obtained. LC-MS (Method 6): R t = 2.17 min; MS (ESIpos): m / z = 254 [M+H] +< . 1< H NMR (500 MHz, DMSO-d6): δ [ppm] = 7.28-7.36 (m, 4H), 7.20-7.27 (m, 1H), 3.83 (dd, 1H), 3.72 (dd, 1H), 3.22-3.30 (m, 1H), 2.43-2.48 (m, 1H), 1.20 (d, 3H). Example 39A 1,1,1,2,2-Pentafluorobutane-3 -amine hydrochloride (racemate)

[0306]

[0307] To a solution of 1.50 g (5.92 mmol) N- Benzyl-1,1,1,2,2-pentafluoropentan-3-amine in 27.4 ml of methanol, 150 mg of palladium on carbon (10%) were added and hydrogenated for 6 hours at normal pressure and room temperature. The reaction mixture was then filtered through a Millipore filter and the solvent was removed under reduced pressure. The template with the solvent distilled off was then transferred to a flask and mixed with 4N aqueous hydrochloric acid in dioxane and concentrated again. The residue was stirred with diethyl ether, the precipitate was filtered off with suction and dried under high vacuum. 456 mg (39% of theory, 100% purity) of the title compound were obtained. 1< H NMR (500 MHz, DMSO-d6): δ [ppm] = 9.21 (br. s, 3H), 4.40-4.29 (m, 1H), 1.41 (d, 3H). Example 40A N -Benzyl-1,1,1,2,2-pentafluoropentan-3-amine (racemate)

[0308]

[0309] 5.03 ml (17.0 mmol) of titanium tetraisopropoxide and 2.48 ml (22.7 mmol) of benzylamine were added to a solution of 2.00 g (11.4 mmol) of 1,1,1,2,2-pentafluoropentan-3-one in 10 ml of dichloromethane at 0 ° C . Stirring was continued at RT for 90 min before cooling to 0°C again. 2.00 g (31.8 mmol) of sodium cyanoborohydride, 36 ml of methanol and 3Å molecular sieve were then added. The mixture was warmed to RT and stirred for 2 days. A little water and ethyl acetate were then added to the reaction solution and filtered. The filtrate was washed twice with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified using normal phase chromatography (ethyl acetate / cyclohexane 1 / 20) and 989 mg (25% of theory, 76% purity) of the title compound were obtained. LC-MS (Method 1): R t = 1.27 min; MS (ESIpos): m / z = 268 [M+H] +< 1< H NMR (400 MHz, DMSO-d6): δ [ppm] = 7.21-7.36 (m, 5H), 3.73-3.85 (m, 2H), 3.05-3.20 (m, 1H), 1.63-1.75 (m, 1H), 1.49-1.61 (m, 1H), 1.15-1.20 (m, 1H), 0.96 (t, 3H). Example 41A 1,1,1,2,2-Pentafluoropentane-3 -amine hydrochloride (racemate)

[0310]

[0311] 75 mg of palladium on carbon (10%) were added to a solution of 980 mg (2.75 mmol, 75% purity) of the compound from Example 40A in 11.3 ml of methanol and hydrogenated for 6 h at normal pressure and room temperature. The reaction mixture was then filtered through a Millipore filter and the solvent was removed under reduced pressure. The template with the solvent distilled off was then transferred to a flask and mixed with 4 M aqueous hydrochloric acid in dioxane and concentrated again. The residue was stirred with diethyl ether, the precipitate was filtered off with suction and dried under high vacuum. 379 mg (65% of theory, 100% purity) of the title compound were obtained. 1< H NMR (400 MHz, DMSO-d6): δ [ppm] = 8.97 (br. s, 3H), 4.16-4.28 (m, 1H), 1.67-1.94 (m, 2H), 1.05 (t, 3H ). Example 41B 7-Chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester

[0312]

[0313] A solution of 12.1 g (38.0 mmol) of 2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-ethoxyacrylic acid ethyl ester (CAS 157373-27-8) and 7.83 g (53.2 mmol) of 2,4,6- Trifluoroaniline in 60.5 ml of DCM was mixed with 46.4 ml (266 mmol) of DIPEA and stirred at RT for 4 h. 5.26 g (38.0 mmol) of potassium carbonate were then added and heated under reflux overnight. It was diluted with 200 ml DCM and washed twice with 150 ml 1M aqueous hydrochloric acid. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The suspension obtained was mixed with 80 ml tert. -Butyl methyl ether stirred, the precipitate was filtered off with suction, with 10 ml tert. -Butyl methyl ether washed and dried in a high vacuum. 8.60 g (58% of theory, 99% purity) of the title compound were obtained. LC-MS (Method 1): R t = 0.97 min; 383 [M+H] +< . Example 41C 7-Chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

[0314]

[0315] 8.60 g (22.5 mmol) of 7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester (Example 100A) were dissolved in 67.7 ml of water presented, with 67.7 ml 36 percent. aqueous hydrochloric acid and 67.7 ml of THF were added and the mixture was stirred at 110° C. for 4.5 hours. The reaction mixture was cooled to RT. The precipitate was filtered off with suction, washed with water and dried under a high vacuum. 7.87 g (98% of theory, 99% purity) of the title compound were obtained. LC-MS (Method 1): R t = 0.95 min; MS (ESIpos): m / z = 355 [M+H] +< . 1< H NMR (400 MHz, DMSO-d6): δ [ppm] = 13.83 (s, 1H), 9.27 (s, 1H), 8.78 (d, 1H), 7.82 (d, 1H), 7.67-7.59 ( m, 2H). Example 42A 6-Fluoro-7-(morpholin-4-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

[0316]

[0317] Add a solution of 600 mg (1.61 mmol) of 7-chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 200 µl (2.30 mmol) morpholine in 8.0 ml DMF was added to 840 µl (4.80 mmol) DIPEA at RT. Stirring was continued overnight at RT. The reaction mixture was diluted with acetonitrile, some water and formic acid and the crude product was purified using preparative HPLC (column: acetonitrile / water / 0.1% formic acid). 658 mg (97% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.76 min; MS (ESIpos): m / z = 424 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.48), 0.146 (0.51), 2.328 (0.72) , 2,367 (0.64), 2,671 (0.77), 2,711 (0.64), 3,558 (12.72), 3,570 (14.98), 3,602 (16.00), 3,615 (13.62), 5,754 (1.56), 7,568 (4.70), 7,591 (8 .79) , 7,613 (4.66), 8,159 (7.09), 8,192 (7.01), 9,099 (13.11), 14,766 (1.97). Example 43A 7-chloro-6-fluoro N -(1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3 -carboxamide

[0318]

[0319] To a solution of 600 mg (1.61 mmol) 7-chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, 296 mg (1.77 mmol) of 1,1,1,3,3,3-hexafluoropropane-2-amine and 840 µl (4.80 mmol) of DIPEA in 14 ml of ethyl acetate were added to 3.8 ml (6.40 mmol) of 2,4,6-tripropyl- 1,3,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide (T3P, 50% in DMF) was added dropwise. Stirring was continued overnight at 80°C. The reaction mixture was poured onto water and ethyl acetate and the phases were separated. The organic phase was washed with water, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was dissolved in a little acetonitrile, filtered through a Millipore filter and purified in three runs using preparative HPLC (column: acetonitrile / water / 0.1% formic acid). 414 mg (49% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 3): R t = 2.47 min; MS (ESIpos): m / z = 522 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.77), -0.008 (7.00), 0.146 (0.77 ). ). 28 ). Example 44A 7-Chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro- N -(1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

[0320]

[0321] To a solution of 250 mg (703 µmol) 7-chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridin-3- carboxylic acid, 129 mg (773 µmol) 1,1,1,3,3,3-hexafluoropropane-2-amine and 370 µl (2.10 mmol) DIPEA in 10 ml ethyl acetate were 1.7 ml (2.80 mmol) 2,4,6- Tripropyl-1,3,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide (T3P, 50% in ethyl acetate) was added dropwise. Stirring was continued overnight at 80°C. 50 ml of water were added to the reaction mixture. The precipitate was filtered off with suction, washed with water and dried under a high vacuum. 259 mg (69% of theory, 94% purity) of the title compound were obtained. LC-MS (Method 3): R t = 2.34 min; MS (ESIpos): m / z = 505 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.14), 0.146 (1.21), 0.931 (1.84) , 0.949 (3.59), 0.967 (1.98), 1.175 (0.70), 1.243 (2.59), 1.260 (2.64), 1.273 (1.61), 1.298 (0.51), 1.487 (1.496 (1.19), 1.668 (0.58) , 1,988 (0.51), 2.328 (1.28), 2,366 (0.93), 2,670 (1.21), 2,710 (0.89), 6.406 (1.45), 6.424 (2.05), 6.448 (6.467 (1.38), 8.399 (2.33)) , 8.405 (2.89), 8.426 (4.48), 8.443 (2.54), 8.449 (2.66), 8.615 (0.49), 8.682 (10.68), 8.688 (9.63), 8.753 (9.52), 8.772 (9.52), 8.922 (0.42 ) , 9,184 (1.75), 9,217 (16.00), 9,284 (0.44), 10,705 (5.78), 10,731 (5.69). Example 45A 7-chloro-4-oxo- N -[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3 -carboxamide (racemate)

[0322]

[0323] To a solution of 250 mg (705 µmol) 7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, 166 mg (775 µmol ) 1,1,1,2,2-pentafluoropentane-3-amine hydrochloride (racemate) and 490 µl (2.80 mmol) DIPEA in 7.0 ml ethyl acetate became 1.6 ml (2.80 mmol) 2,4,6-tripropyl-1,3 ,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide (T3P, 50% in ethyl acetate) added dropwise. Stirring was continued overnight at 80°C. 50 ml of water were added to the reaction mixture. The aqueous phase was extracted twice with ethyl acetate. All organic phases were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. 360 mg (89% of theory, 90% purity) of the title compound were obtained. LC-MS (Method 3): R t = 2.45 min; MS (ESIpos): m / z = 514 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.93), -0.008 (7.96), 0.008 (8.00 ). ), 1,410 (15.56), 1.427 (15.60), 1.497 (0.62), 2.328 (1.15), 2.367 (0.93), 2.671 (1.07), 2.711 (0.83), 4.998 (0.77), 5.020 (1.35), 5.044 (1.59 ). 0 ). 5 ), 10,010 (5.94). Example 46A 7-[(3 R ,4 R )-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo- N -[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereomers)

[0324]

[0325] According to AAV3, 360 mg (700 µmol) 7-chloro-4-oxo- N -[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide with 81.9 mg ( 586 µmol) (3 R ,4 R )-Pyrrolidine-3,4-diol hydrochloride and 430 µl (2.50 mmol) DIPEA in 4 ml DMF were reacted. The reaction mixture was mixed with aqueous 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified using preparative HPLC (column: acetonitrile / water / 0.1% formic acid). 242 mg (60% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.86 min; MS (ESIpos): m / z = 581 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (2.01), 0.946 (7.17), 0.965 (16.00), 0.983 (7.77), 1.618 (0.90), 1.636 (1.25), 1.644 (1.05), 1.652 (1.50), 1.662 (1.35), 1.671 (1.20), 1.679 (1.40), 1.697 (1.00), 1.920 (1.30), 2.073 (0.80), 2.329 (0.80), 2.368 (0.70), 2.524 (2.46), 2.671 (0.85), 2.711 (0.75), 3.055 (2.76), 3.087 (3.71), 3.239 (2.36), 3.262 (1.76), 3.353 (3.76), 3.606 (2.06), 3.627 (1.71), 3.929 (3.46), 4.050 (3.46), 4.826 (0.80), 4.850 (1.15), 4.876 (1.10), 4.902 (0.85), 5.144 (4.97), 5,152 (4.97), 5,235 (5.02), 5,244 (4.87), 6,770 (7.32), 6,792 (7.52), 7,544 (2.71), 7,566 (4.82), 7,584 (2.76), 8,268 (8.58), 8,290 (8.13), 8,815 (14.50), 10,470 (4.97), 10,495 (4.76). Example 47A 7-chloro-4-oxo- N -[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3 -carboxamide (racemate)

[0326]

[0327] To a solution of 250 mg (705 µmol) 7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, 155 mg (775 µmοl ) 3,3,4,4,4-pentafluorobutane-2-amine hydrochloride (racemate) and 490 µl (2.80 mmol) DIPEA in 7.0 ml ethyl acetate became 1.6 ml (2.80 mmol) 2,4,6-tripropyl-1,3 ,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide (T3P, 50% in ethyl acetate) added dropwise. Stirring was continued at 80°C for 30 minutes. The solvent was removed under reduced pressure and the crude product was purified using preparative HPLC (column: acetonitrile / water / 0.1% formic acid). 325 mg (83% of theory, 90% purity) of the title compound were obtained. LC-MS (Method 3): R t = 2.37 min; MS (ESIpos): m / z = 500 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.17), -0.008 (16.00), 0.008 (8.86 ), 0.146 (1.23), 0.849 (0.84), 0.942 (1.10), 0.959 (0.65), 1.233 (1.59), 1.283 (0.62), 1.409 (11.07), 1.426 (10.77), 1.487 (0.55), 2.327 (1.53 ). ), 7.639 (4.35), 7.772 (8.18), 7.793 (8.31), 7.811 (0.97), 7.832 (1.04), 8.741 (8.18), 8.761 (7.89), 8.772, 8.793 (0.88), 9.142 (10.90 ), 9,272 (1.14), 9,985 (4.28), 10,009 (4.19). Example 48A 7-[(3 R ,4 R )-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo- N -[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereomers)

[0328]

[0329] According to AAV3, 325 mg (650 µmol) 7-chloro-4-oxo- N -[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (racemate) with 76.1 mg (545 µmol) (3 R ,4 R )-Pyrrolidine-3,4-diol hydrochloride and 400 µl (2.30 mmol) DIPEA in 3.7 ml DMF were reacted. The reaction mixture was mixed with aqueous 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified using preparative HPLC (column: acetonitrile / water / 0.1% formic acid). 239 mg (65% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.76 min; MS (ESIpos): m / z = 567 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.388 (15.08), 1.401 (16.00), 2.672 (0.88), 3,053 (3.67), 3,086 (4.68), 3,601 (3.82), 3,929 (6.14), 4,052 (6.04), 5,005 (2.33), 5,146 (6.42), 5,237 (6.35), 6,768 (5.34), 6,790 (5.44), 7,564 (8.09), 8,261 (5.29), 8,283 (5.16), 8,808 (8.64), 10,549 (4.91), 10,573 (4.81). Example 49A 7-chloro-4-oxo- N- (1,1,1-trifluoro-2-methylpropan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

[0330]

[0331] To a solution of 250 mg (705 µmol) 7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, 127 mg (775 µmol) 1,1,1-trifluoro-2-methylpropane-2-amine hydrochloride and 490 µl (2.80 mmol) DIPEA in 7.0 ml ethyl acetate became 1.6 ml (2.80 mmol) 2,4,6-tripropyl-1,3,5 ,2,4,6-trioxatriphosphorinan-2,4,6-trioxide (T3P, 50% in ethyl acetate) added dropwise. Stirring was continued at 80°C for 30 minutes. The solvent was removed under reduced pressure and the reaction mixture was diluted with 50 ml of water. The resulting precipitate was filtered off, washed with water and dried. 297 mg (88% of theory, 97% purity) of the title compound were obtained. LC-MS (Method 3): R t = 2.34 min; MS (ESIpos): m / z = 464 [M+H] + 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.062 (0.91), -0.008 (0.99), 0.008 (1.16) , 1,653 (16.00), 7,597 (1.19), 7,618 (2.22), 7,641 (1.22), 7,767 (2.50), 7,788 (2.63), 8,746 (2.59), 8,767 (2.51), 9,080 (3.17), 10,101 (2.5 5) . Example 50A 7-[(3 R ,4 R )-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo- N -(1,1,1-trifluoro-2-methylpropan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

[0332]

[0333] According to AAV3, 297 mg (666 µmol) 7-chloro-4-oxo- N -(1,1,1-trifluoro-2-methylpropan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide with 102 mg ( 733 µmol) (3 R ,4 R)-Pyrrolidine-3,4-diol hydrochloride and 410 µl (2.30 mmol) DIPEA in 6.0 ml DMF were reacted. 20 ml of water and aqueous 1N hydrochloric acid were added to the reaction mixture. The resulting precipitate was filtered off, washed with water and dried. 272 mg (77% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.73 min; MS (ESIpos): m / z = 531 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.79), 0.008 (1.49), 1.634 (16.00) , 2.073 (5.68), 3.052 (0.77), 3.083 (1.03), 3.226 (0.66), 3.235 (0.76), 3.257 (0.63), 3.268 (0.68), 3.348 (1.35), 3.593 (0.56), 3.603 (0.65) , 3.621 (0.52), 3,630 (0.49), 3.923 (0.97), 4.046 (0.97), 6.759 (1.98), 6.782 (2.03), 7.545 (0.73), 7.567 (7.585 (0.74), 8.266) , 8,289 (2.10), 8,739 (3.50), 10,653 (2.89). Example 51A 7-chlorine N -[(1 S )-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

[0334]

[0335] To a solution of 4.00 g (11.3 mmol) 7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, 2.18 g (12.4 mmol) (1 S )-1-Cyclopropyl-2,2,2-trifluoroethanamine hydrochloride and 7.9 ml (45.0 mmol) of DIPEA in 110 ml of ethyl acetate became 26 ml (45.0 mmol) of 2,4,6-tripropyl-1,3,5,2,4 ,6-trioxatriphosphorinan-2,4,6-trioxide (T3P, 50% in ethyl acetate) was added dropwise. Stirring was continued at 80°C for 30 minutes. The solvent was removed under reduced pressure and the reaction mixture was diluted with 150 ml of water. The precipitate was filtered off, washed with water and dried. 5.30 g (95% of theory, 96% purity) of the title compound were obtained. LC-MS (Method 3): R t = 2.33 min; MS (ESIpos): m / z = 476 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.55), -0.062 (4.39), 0.008 (4.02 ). ). ). ). ). ). .75 ), 8,940 (0.46), 9,126 (16.00), 10,025 (6.55), 10,049 (6.26). Example 52A N -[(1 S )-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(3 R ,4 R )-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridin-3-carboxamide

[0336]

[0337] According to AAV3, 5.30 g (11.1 mmol) of 7-chlorine N -[(1 S )-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide with 1.87 g ( 13.4 mmol) (3 R ,4 R)-pyrrolidine-3,4-diol hydrochloride and 6.8 ml (39.0 mmol) of DIPEA in 50 ml of DMF were reacted. 400 ml of water and aqueous 1N hydrochloric acid were added to the reaction mixture. The precipitate was filtered off, washed with water and dried. 5.47 g (91% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.71 min; MS (ESIpos): m / z = 543 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.74), -0.061 (4.97), -0.008 ( 6.91), 0.008 (5.18), 0.146 (0.66), 0.324 (1.75), 0.334 (2.68), 0.346 (2.68), 0.358 (2.07), 0.370 (1.01), 0.510 (1.88), 0.522 (2.81), 0.535 ( 2.49), 0.547 (2.58), 0.556 (2.24), 0.567 (2.75), 0.578 (2.32), 0.588 (2.16), 0.598 (1.73), 0.612 (1.10), 0.626 (1.37), 0.636 (1.52), 0.647 ( 2.47), 0.657 (2.16), 0.662 (2.11), 0.670 (2.03), 0.682 (1.01), 0.691 (0.72), 0.944 (1.48), 1.165 (0.82), 1.177 (1.44), 1.186 (1.99), 1.198 ( 3.15), 1.206 (2.49), 1.218 (3.32), 1.231 (2.32), 1.238 (1.99), 1.263 (1.33), 1.398 (0.59), 2.328 (0.85), 2.367 (0.78), 2.524 (2.62), 2.670 ( 0.80), 2.711 (0.68), 2.731 (3.21), 2.891 (3.89), 3.056 (3.25), 3.088 (4.25), 3.230 (2.62), 3.239 (2.98), 3.261 (2.35), 3.272 (2.32), 3.353 ( 4.10), 3,600 (2.37), 3,609 (2.71), 3,627 (2.20), 3,637 (1.99), 3,927 (3.89), 4,050 (3.89), 4,356 (1.39), 4,377 (2.41), 4,398 (2.39), 4,418 ( 1.25), 5.145 (3.74), 5.233 (3.53), 6.772 (8.20), 6.794 (8.43), 7.543 (3.17), 7.566 (5.60), 7.583 (3.19), 7.953 (0.51), 8.271 (9.72), 8.293 ( 9.13), 8,798 (16.00), 10,558 (5.71), 10,582 (5.45). Example 53A 1,1,1,2,2-Pentafluoro-N-[(1S)-1-phenylethyl]pentane-3-imine

[0338]

[0339] 1,1,1,2,2-Pentafluoropentan-3-one (50.0 g, 284 mmol) was placed in 2 L of diethyl ether and cooled to 0 ° C. Then (1S)-1-phenylethanamine (34.4 g, 284 mmol) and triethylamine (79 ml, 570 mmol) were quickly added and titanium (IV) chloride (1 M in toluene, 140) was then slowly added at an internal temperature of 0 ° C ml, 140 mmol) added dropwise. The ice bath was then removed and the mixture was warmed to RT. The reaction mixture was then heated under reflux for 1 h and then stirred overnight at RT. The reaction mixture was mixed with kieselguhr, stirred for 1 h, then filtered through kieselguhr and washed well with diethyl ether. The filtrate was evaporated at a water bath temperature of 20°C. The raw product was used in the subsequent stage without further purification. 79 g (quantitative yield) of the title compound were obtained. Example 54A 1,1,1,2,2-Pentafluoro-N-[(1S)-1-phenylethyl]pentane-3-amine hydrochloride (enantiomerically pure)

[0340]

[0341] 1,1,1,2,2-Pentafluoro-N-[(1S)-1-phenylethyl]pentane-3-imine (79 g, 283 mmol) was placed in 640 ml of dichloromethane, then 130 ml of DMF and 3Å molecular sieve was added and the mixture was stirred at RT for 1 h. The reaction mixture was cooled to -50 ° C and trichlorosilane (86 ml, 850 mmol) was slowly added dropwise. After 30 minutes and at an internal temperature of -70 ° C to - 50 ° C, quenching was carried out first with saturated sodium hydrogen carbonate solution, then with solid sodium hydrogen carbonate until pH 7 was reached. Dichloromethane was added and the phases were separated. The organic phase was dried over sodium sulfate and then 200 ml of hydrogen chloride in diethyl ether (2 M solution) was added and the crude product was evaporated in vacuo. 48.6 g (54% of theory) of the title compound were obtained. 1< H NMR (400 MHz, DMSO-d6): δ [ppm] = 7.82 (br. s, 1H), 7.26 -7.60 (m, 5H), 4.13 (br. s, 1H), 3.20 (br. s , 1H), 1.40-1.77 (m, 5H), 0.80 (t, 3H). Example 55A 1,1,1,2,2-Pentafluoropentane-3-amine hydrochloride (enantiomerically pure)

[0342]

[0343] 48.6 g (153 mmol) of 1,1,1,2,2-pentafluoro-N-[(1S)-1-phenylethyl]pentane-3-amine hydrochloride (enantiomerically pure, from Example 54A) were dissolved in 250 ml of ethanol and 4.86 g of palladium(II) hydroxide (20% on carbon) were added and then hydrogenated overnight at RT and normal pressure. The precipitate was filtered off, washed well and the filtrate was carefully evaporated. 31.7 g (97% of theory) of the title compound were obtained. 1< H NMR (400 MHz, DMSO-d6): δ [ppm] = 9.16 (br. s, 3H), 4.12-4.28 (m, 1H), 3.47 (br. s, 1H), 1.69-1.96 (m , 2H), 1.06 (t, 3H). Example 56A 3,3,4,4,4-Pentafluoro-N-[(1S)-1-phenylethyl]butane-2-imine

[0344]

[0345] 3,3,4,4,4-Pentafluorobutan-2-one (200 g, 1.23 mol) was placed in 6.4 L of diethyl ether and cooled to -40 ° C. Then (1S)-1-phenylethanamine (160 ml, 1.2 mol) and triethylamine (340 ml, 2.5 mol) were quickly added and titanium (IV) chloride (1 M in toluene, 620) was then slowly added at an internal temperature of 0 ° C ml, 620 mmol) added dropwise. The ice bath was then removed and the mixture was warmed to RT. The reaction mixture was then heated under reflux for 1 h and then stirred at RT overnight. Celite was added to the reaction mixture, stirred for 1 h, then filtered through Celite and washed well with diethyl ether. The filtrate was evaporated at a water bath temperature of 25°C. The residue was mixed with cyclohexane and filtered again through Celite and washed with cyclohexane. The filtrate was evaporated at 25 ° C water bath temperature. The raw product was used in the subsequent stage without further purification. 289 g (88% of theory) of the title compound were obtained. Example 57A 3,3,4,4,4-Pentafluoro-N-[(1S)-1-phenylethyl]butane-2-amine hydrochloride (enantiomerically pure)

[0346]

[0347] 3,3,4,4,4-Pentafluoro-N-[(1S)-1-phenylethyl]butane-2-imine (239 g, 901 mmol) was placed in 1.9 L of dichloromethane, then 420 ml of DMF and 3Å molecular sieve were added and the mixture was stirred at RT for 1 h. The reaction mixture was then cooled to -50 ° C and trichlorosilane (270 ml, 2.7 mol) was slowly added dropwise. After 30 minutes and at an internal temperature of -70 ° C to - 50 ° C, the mixture was carefully quenched with half-concentrated sodium hydroxide solution until pH 7 was reached. Dichloromethane was added and the phases were separated. The organic phase was dried over sodium sulfate and then 2.2 l of hydrogen chloride in diethyl ether (2 M solution) were added and the crude product was evaporated in vacuo. 192 g (70% of theory) of the title compound were obtained. LC-MS (Method 1): R t = 1.22 min; MS (ESIpos): m / z = 268 [M-HCl+H] +< Example 58A 3,3,4,4,4-Pentafluorobutane-2-amine hydrochloride (enantiomerically pure)

[0348]

[0349] 192 g (632 mmol) of 3,3,4,4,4-pentafluoro-N-[(1S)-1-phenylethyl]butane-2-amine hydrochloride (enantiomerically pure, from Example 57A) were dissolved in 1.2 l of ethanol and mixed with 19.2 g of palladium(II) hydroxide (20% on carbon) and then hydrogenated overnight at RT and normal pressure. The precipitate was filtered off, washed well and the filtrate was carefully evaporated. 117 g (93% of theory) of the title compound were obtained. 1< H NMR (400 MHz, DMSO-d6): δ [ppm] = 9.29 (br. s, 3H), 4.22-4.44 (m, 1H), 1.42 (d, H). Example 59A 7-Chloro-6-fluoro-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro- 1,8-naphthyridine-3 -carboxamide (racemate)

[0350]

[0351] 7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (200 mg, 537 µmol) was dissolved in 1.3 ml Acetonitrile was introduced, 1,1,1,2,2-pentafluoropentane-3-amine hydrochloride (racemate, 138 mg, 644 µmol) and N,N-diisopropylethylamine (370 µl, 2.1 mmol) were added and then mixed with 380 µl (50% Purity, 640 µmol) T3P solution (propanephosphonic acid cycloanhydride, 50% in ethyl acetate). The reaction solution was stirred overnight and then added to water. The mixture was freed from acetonitrile and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. 282 mg of the target compound (97% of theory, purity 98%) were obtained. LC-MS (Method 3): R t = 2.53 min; MS (ESIpos): m / z = 532 [M+H] +< Example 60A 7-Chloro-6-fluoro-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro- 1,8-naphthyridine-3 -carboxamide (enantiomerically pure)

[0352]

[0353] 7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (5.00 g, 13.4 mmol) was dissolved in 33 ml Acetonitrile presented. 3.44 g, (16.1 mmol) of 1,1,1,2,2-pentafluoropentane-3-amine hydrochloride (enantiomerically pure, from Example 55A) and N,N-diisopropylethylamine (9.3 ml, 54 mmol) were added. T3P solution (propanephosphonic acid cycloanhydride, 50% in ethyl acetate, 9.5 ml, 50% purity, 16 mmol) was then added and the mixture was stirred at room temperature overnight. Water was added to the reaction solution. A viscous suspension was created. This was acidified with dilute hydrochloric acid and stirred at room temperature for 1 hour. The solid was filtered off, then washed with water and dried under high vacuum. 6.69 g of the compound (84% of theory, purity 90%) were obtained. LC-MS (Method 5): R t = 1.67 min; MS (ESIpos): m / z = 532 [M+H] +< Example 61A tert-Butyl-4-[3-fluoro-5-oxo-6-{[1,1,1,2,2-pentafluoropentan-3-yl]carbamoyl}-8-(2,4,6-trifluorophenyl)- 5,8-dihydro-1,8-naphthyridin-2-yl]-2-(hydroxymethyl)piperazine-1-carboxylate (mixture of diastereomers)

[0354]

[0355] 7-Chloro-6-fluoro-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro- 1,8-naphthyridine-3-carboxamide (enantiomerically pure from Example 60A, 200 mg, 90% purity, 338 µmol) was placed in 1.7 ml of DMF, with N,N-diisopropylethylamine (590 µl, 3.4 mmol) and tert-butyl- (2-(hydroxymethyl)piperazine-1-carboxylate (80.5 mg, 372 µmol) was added at room temperature. The reaction solution was stirred for 1 h at room temperature. Water was added to the reaction solution and extracted three times with ethyl acetate. The combined organic phases were added twice washed with water, dried over sodium sulfate, filtered and evaporated. The crude product was purified using silica gel chromatography (mobile phase: cyclohexane / ethyl acetate = 2 / 1). 204 mg of the target compound (85% of theory, purity 100%) were used as a mixture of diastereomers of two diastereomers. LC-MS (Method 5): R t = 1.62 min; MS (ESIpos): m / z = 712 [M+H] +< Example 62A

[0356] 7-Chloro-6-fluoro-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro- 1,8-naphthyridine-3-carboxamide (racemate)

[0357] 7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (200 mg, 537 µmol) was dissolved in 1.3 ml Acetonitrile presented. 1,1,1,2,2-Pentafluorobutane-3-amine hydrochloride (racemate, 129 mg, 644 µmol) and N,N-diisopropylethylamine (370 µl, 2.1 mmol) were added and then mixed with 380 µl (50% purity , 640 µmol) T3P solution (propanephosphonic acid cycloanhydride, 50% in ethyl acetate). The reaction solution was stirred overnight. The reaction solution was added to water and precipitated. The solid was filtered off and dried overnight in a high vacuum. 250 mg of the compound (76% of theory, purity 84%) were obtained. LC-MS (Method 3): R t = 2.45 min; MS (ESIpos): m / z = 518 [M+H] +< Example 63A 7-Chloro-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluoro-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1, 4-dihydro-1,8-naphthyridine-3-carboxamide

[0358]

[0359] 7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (1.50 g, 4.03 mmol) was dissolved in 38 ml Acetonitrile presented. 3,3,4,4,4-Pentafluoro-2-methylbutane-2-amine hydrochloride (1.12 g, 5.23 mmol) and N,N-diisopropylethylamine (3.5 ml, 20 mmol) were added and then 3.6 ml (50% Purity, 6.0 mmol) T3P solution (propanephosphonic acid cycloanhydride, 50% in ethyl acetate). The reaction solution was stirred at room temperature overnight. Water was then added to the reaction solution. The solution was almost completely freed of acetonitrile under vacuum; over time, a solid precipitated upon evaporation. The solid contained was washed with water. The solid was dried under high vacuum. 1.96 g of the target compound (91% of theory, 99% purity) were obtained. LC-MS (Method 3): R t = 2.50 min; MS (ESIpos): m / z = 532 [M+H] +< Example 64A Ethyl (2Z)-2-[(2,6-dichloro-5-fluoropyridin-3-yl)carbonyl]-3-ethoxyacrylate

[0360]

[0361] Ethyl 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxopropanoate (500 mg, 1.79 mmol) and (diethoxymethoxy)ethane (590 µl, 3.6 mmol) were dissolved in acetic anhydride (1.2 ml, 12 mmol) and stirred at 140 ° C overnight. The reaction solution was evaporated and reacted further in the subsequent stage without further purification. LC-MS (Method 1): R t = 1.01 min; MS (ESIpos): m / z = 336 [M+H] +< Example 65A Ethyl 7-chloro-6-fluoro-1-(4-fluoro-2,6-dimethylphenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

[0362]

[0363] Ethyl (2Z)-2-[(2,6-dichloro-5-fluoropyridin-3-yl)carbonyl]-3-ethoxyacrylate (9.36 g, 27.8 mmol) and 4-fluoro-2,6-dimethylaniline (4.65 g , 33.4 mmol) were placed in 47 ml of dichloromethane and N,N-diisopropylethylamine (34 ml, 194.9 mmol) was added at room temperature (exotherm). The reaction solution was stirred at room temperature for 4 h. Potassium carbonate (3.85 g, 27.84 mmol) was then added and the mixture was stirred under reflux overnight. The reaction mixture was then cooled, diluted with dichloromethane and washed with 1M hydrochloric acid until there was a color change. The organic phase was dried over sodium sulfate, filtered, evaporated and dried under high vacuum. The crude product was purified using silica gel chromatography (mobile phase: cyclohexane / ethyl acetate: 5 / 1 to cyclohexane / ethyl acetate: 3 / 1). 6.47 g of the target compound (58% of theory, purity 99%) were obtained. LC-MS (Method 3): R t = 2.00 min; MS (ESIpos): m / z = 393 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.95), 0.008 (0.78), 1.254 (2.75) , 1.271 (5.79), 1.289 (2.77), 1.975 (16.00), 2.523 (0.61), 4.205 (0.87), 4.222 (2.65), 4.240 (2.61), 4.258 (0.82), 5.754 (3.81), 7.188 (2.22 ) , 7,211 (2.23), 8,543 (1.72), 8,561 (5.10). Example 66A 7-Chloro-6-fluoro-1-(4-fluoro-2,6-dimethylphenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

[0364]

[0365] Ethyl 7-chloro-6-fluoro-1-(4-fluoro-2,6-dimethylphenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (6.47 g, 99% purity , 16.3 mmol) was suspended in 49 ml THF. 49 ml water and 49 ml concentrated. Hydrochloric acid was added and the mixture was allowed to stir at a bath temperature of 110 ° C for 4 hours. The THF was largely concentrated in vacuo. 100 ml of water were added to the aqueous phase while cooling with ice. A solid precipitated. This was filtered off and rinsed three times with water. 5.35 g of the target compound (89% of theory, purity 99%) were obtained. LC-MS (Method 1): R t = 1.03 min; MS (ESIpos): m / z = 365 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.957 (16.00), 1.975 (0.43), 7.195 (2.23), 7,218 (2.20), 8,775 (1.30), 8,794 (1.29), 8,871 (2.87). Example 67A 7-Chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-1-(4-fluoro-2,6-dimethylphenyl)-4-oxo-1,4- dihydro-1,8-naphthyridine-3-carboxamide

[0366]

[0367] 7-Chloro-6-fluoro-1-(4-fluoro-2,6-dimethylphenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (1.00 g, 2.74 mmol) was added 25.5 ml of acetonitrile were introduced, (1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (530 mg, 3.02 mmol) and N,N-diisopropylethylamine (1.9 ml, 11 mmol) were added, then 1.9 ml (3.29 mmol) T3P solution (propanephosphonic acid cycloanhydride, 50% in ethyl acetate) was added. The reaction solution was stirred at room temperature overnight. (1S)-1-Cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (144 mg, 823 μmol), 0.32 ml (1.1 mmol) of T3P solution (propanephosphonic acid cycloanhydride, 50% in ethyl acetate) and N,N -Diisopropylethylamine (0.48 ml, 2.74 mmol) was added. The reaction solution was stirred at room temperature over the weekend. The mixture was then freed from acetonitrile and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered off and dried under high vacuum. The residue was purified using column chromatography (silica gel, mobile phase: dichloromethane / cyclohexane = 7.5 / 1). 1.05 g (99% purity, 78% of theory) of the target compound were obtained. LC-MS (Method 1): R t = 1.28 min; MS (ESIpos): m / z = 486 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (1.25), 0.339 (0.87), 0.353 (0.89), 0.364 (0.51), 0.554 (0.81), 0.567 (1.37), 0.582 (1.20), 0.601 (0.63), 0.610 (0.52), 0.651 (0.46), 0.666 (0.81), 0.671 (0.70), 0.684 (0.55), 1.219 (0.47), 1.231 (0.87), 1.240 (0.65), 1.251 (0.75), 1.264 (0.44), 1.957 (16.00), 4.361 (0.43), 4.382 (0.73), 4.402 (0.73), 4.422 (0.40), 5,754 (3.95), 7,193 (3.42), 7,216 (3.43), 8,709 (7.53), 8,726 (2.88), 10,138 (1.51), 10,162 (1.49). Example 68A 7-Chloro-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluorobutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro- 1,8-naphthyridine-3 -carboxamide (enantiomerically pure)

[0368]

[0369] 7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (500 mg, 1.34 mmol) was dissolved in 5 ml Acetonitrile presented. 3,3,4,4,4-pentafluorobutane-2-amine hydrochloride (enantiomerically pure) (321 mg, 1.61 mmol) and N,N-diisopropylethylamine (930 µl, 5.4 mmol) were added. T3P solution (propanephosphonic acid anhydride solution 50% in ethyl acetate) (950 µl, 50% purity, 1.6 mmol) was then added and stirred overnight at room temperature. The reaction solution was added to water. The acetonitrile was evaporated and the residue was added three times extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and evaporated. This gave 785 mg (99% of theory, 88% purity) of the title compound. LC-MS (Method 5): R t = 1.60 min; MS (ESIpos): m / z = 518 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.04), -0.008 (8.48), 0.008 (8.27 ), 0.146 (1.00), 0.891 (0.71), 0.910 (0.58), 1.157 (2.01), 1.175 (4.01), 1.193 (2.59), 1.244 (2.51), 1,259 (2.92), 1.356 (0.67), 1.411 (14.66 ), 1,429 (14.62), 1.455 (0.92), 1.473 (0.84), 1.511 (2.26), 1,528 (2.21), 1.864 (0.50), 1,988 (6.56), 2.328 (2.367 (1.80), 2.671 (1.50 ). ). ), 7.604 (6.02), 7.626 (11.07), 7.648 (5.81), 8.412 (0.50), 8.574 (0.46), 8.687 (0.92), 8.702 (10.11), 8.721 (9.750 (0.50), 9.055 (1.21 ), 9.173 (16.00), 9.877 (0.46), 9.896 (0.50), 9.938 (5.89), 9.961 (5.68). Example 69A 1-tert-Butyl-2-ethyl-(2R,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate

[0370]

[0371] Ethyl (3S)-3-hydroxy-D-prolinate (1.13 g, 7.08 mmol) was placed in 50 ml of dichloromethane. Triethylamine (3.0 ml, 21 mmol) and di-tert-butyl dicarbonate (1.8 ml, 7.8 mmol) were added and the mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and evaporated. The residue was taken up in ethyl acetate and washed twice with 1M hydrochloric acid. The organic phase was dried over sodium sulfate, filtered and evaporated. 1.3 g (57% of theory, 80% purity) of the title compound were obtained. 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.152 (0.77), 1.170 (1.65), 1.178 (1.69), 1.188 (0.96), 1.195 (3.23), 1.213 (1.56), 1.321 ( 16.00), 1.383 (8.03), 1.988 (0.75), 3.266 (0.62), 3.294 (0.42), 3.404 (0.44), 3.409 (0.43), 3.423 (0.42), 4.019 (0.41), 4.037 (0.44), 4.046 (4.046 0.70), 4.064 (0.85), 4.082 (0.46), 4.111 (0.57), 4.129 (0.54), 4.150 (1.28), 4.156 (0.42), 4.167 (1.45), 4.433 (0.46), 4.449 (0.53), 5.398 ( 1.16), 5,410 (1.11). Example 70A tert-Butyl-(2S,3S)-3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[0372]

[0373] 1-tert-Butyl-2-ethyl-(2R,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate (1.30 g, 5.01 mmol) was placed in 20 ml of THF under argon and cooled to 0 ° C. Lithium borohydride (10 ml, 2.0 M, 20 mmol) was added at 0 ° C and the mixture was stirred overnight at room temperature. The reaction mixture was cooled down to 0 ° C and carefully added with saturated aqueous ammonium chloride solution. Dichloromethane was added and separated using an Extrelud cartridge. The organic phase was evaporated and the residue was dried under high vacuum. 506 mg (37% of theory, 80% purity) of the title compound were obtained. 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.391 (16.00), 1.409 (2.86), 1.860 (0.40), 3.601 (0.62), 3.608 (0.58), 3.615 (0.78), 3.629 ( 0.46), 3.633 (0.42). Example 71A (2S,3S)-2-(Hydroxymethyl)pyrrolidin-3-ol hydrochloride

[0374] 1-tert-Butyl-2-ethyl-(2R,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate (506 mg, 1.95 mmol) was placed in 20 ml of 4N aqueous hydrochloric acid in dioxane and stirred overnight at room temperature. The reaction mixture was evaporated and the residue was dried under high vacuum. 380 mg (127% of theory, 80% purity) of the title compound were obtained. 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.17), -0.008 (10.39), 0.008 (8.46), 0.146 (1.12), 0.912 (0.42), 1.130 (0.62), 1.180 (0.99), 1.235 (1.17), 1.259 (1.59), 1.276 (1.51), 1.292 (1.07), 1.308 (0.84), 1.356 (3.67), 1.596 (1.31), 1.847 (3.37), 1.857 (3.45), 1,862 (3.72), 1,872 (5.90), 1,876 (5.04), 1,881 (5.11), 1,884 (4.79), 1,891 (4.81), 1,895 (5.01), 1,900 (4.59), 1,954 (1.36), 1,974 (3.15), 1,985 (4.12), 1,998 (5.48), 2,008 (7.59), 2,032 (4.96), 2,042 (3.97), 2,055 (1.89), 2,067 (1.84), 2,073 (2.08), 2,090 (0.97), 2,104 (1.54), 2.115 (2.06), 2.139 (1.81), 2.148 (1.44), 2.182 (0.84), 2.328 (1.96), 2.367 (1.04), 2.524 (1.24), 2.666 (1.02), 2.670 (1.44), 2.675 (0.99), 2,711 (0.45), 3,150 (3.84), 3,161 (5.23), 3,174 (6.15), 3,187 (6.55), 3,201 (5.83), 3,212 (6.23), 3,236 (5.95), 3,241 (5.93), 3,260 (3.82), 3,306 (6.40), 3,322 (7.64), 3,343 (6.05), 3,364 (2.90), 3,450 (8.83), 3,462 (8.88), 3,474 (8.33), 3,490 (7.32), 3,502 (6.38), 3,609 (10.64), 3,631 (10.54), 3,638 (14.78), 3,660 (13.59), 3,680 (3.32), 3,699 (3.27), 3,708 (2.68), 3,712 (3.00), 3,733 (11.88), 3,746 (12.38), 3,762 (9. 30), 3,774 (9.13), 4,073 (4.22), 4,106 (5.66), 4,266 (4.34), 4,274 (4.49), 4,300 (16.00), 4,669 (2.95), 4,678 (4.94), 5,329 (0.72), 7,112 (1.49), 7,240 (1.56), 7,368 (1.41), 8,748 (2.90), 9,193 (1.39), 9,383 (1.81), 10,016 (0.45). Example 72A Ethyl 3-(2,6-dichloropyridin-3-yl)-3-oxopropanoate

[0375]

[0376] 1500 ml of THF were introduced under argon and 2,6-dichloronicotinic acid (200 g, 1.04 mol) was added. 4-Dimethylaminopyridine (63.6 g, 521 mmol) and 1,1'-carbonyldiimidazole (253 g, 1.56 mol) were added in portions (gas evolution). The mixture was stirred at room temperature for 24 hours. A precipitate fell out (suspension 1). Potassium 3-ethoxy-3-oxopropanoate (266 g, 1.56 mol) was placed in 1000 ml of THF in another flask and magnesium chloride (179 g, 1.87 mol) was added. The suspension was stirred at 50 ° C for 24 h (suspension 2). Suspension 2 was then added to suspension 1 and stirred at room temperature for 24 hours. The mixture was then stirred into 5 l of ice and approx. 20 l of water and adjusted to pH 4 with approx. 500 ml of hydrochloric acid / water (1:1). It was then extracted twice with ethyl acetate. The org. Phase was washed with 10% NaCl solution. The phases were separated, dried over magnesium sulfate, evaporated and dried under high vacuum. 255 g of the target compound (93.5% of theory) were obtained. LC-MS (Method 1): R t = 0.89 min; MS (ESIpos): m / z = 261 [M+H] +< Example 73A Ethyl (2Z)-2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-ethoxyacrylate

[0377]

[0378] Ethyl 3-(2,6-dichloropyridin-3-yl)-3-oxopropanoate (4 g, 15 mmol) and (diethoxymethoxy)ethane (5 ml, 30 mmol) were introduced and washed with acetic anhydride (11.7 ml, 99 mmol). offset. The reaction mixture was stirred at 140 ° C for 24 h and after cooling the mixture was evaporated. 5.3 g of the target compound (109% of theory) were obtained. Example 74A N-Benzyl-1,1-dicyclopropylmethanimine

[0379]

[0380] Dicyclopropylmethanone (13 ml, 110 mmol) was placed in 430 ml of diethyl ether and cooled to -40 ° C. Then 1-phenylmethanamine (12 ml, 110 mmol) and triethylamine (32 ml, 230 mmol) were quickly added and titanium (IV) chloride (57 ml, 57 mmol, 1M in toluene) was slowly added dropwise at an internal temperature of 0 ° C . The ice bath was then removed and the mixture was allowed to come to RT. The mixture was then stirred under reflux for 1 h. The mixture was stirred at room temperature for 3 hours. Celite was then added and stirred for 1 h. It was then filtered through Celite and washed several times with diethyl ether. The filtrate was carefully evaporated at a bath temperature of 30 ° C. 18.86 g of the target compound (73% of theory, purity 88%) were obtained. 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.542 (1.44), 0.550 (3.04), 0.558 (4.43), 0.562 (2.41), 0.565 (2.73), 0.571 (3.30), 0.578 ( 5.02), 0.585 (2.16), 0.664 (2.05), 0.671 (4.51), 0.678 (3.98), 0.683 (5.39), 0.690 (3.22), 0.700 (1.42), 0.830 (0.46), 0.839 (1.51), 0.843 ( 2.02), 0.851 (8.62), 0.855 (8.05), 0.863 (8.85), 0.868 (9.08), 0.877 (5.06), 0.881 (2.92), 0.887 (7.68), 0.894 (1.79), 0.901 (0.41), 0.907 ( 0.50), 0.922 (0.49), 0.956 (1.93), 0.966 (4.42), 0.971 (4.39), 0.979 (4.47), 0.984 (4.15), 0.996 (1.28), 1.186 (0.70), 1.198 (1.38), 1.206 ( 1.44), 1.218 (2.55), 1.230 (1.31), 1.238 (1.20), 1.250 (0.55), 1.929 (0.78), 1.942 (1.59), 1.949 (1.59), 1.954 (0.98), 1.963 (3.02), 1.971 ( 0.92), 1.975 (1.51), 1.984 (1.44), 1.997 (0.66), 2.104 (0.65), 2.115 (1.21), 2.122 (1.09), 2.128 (0.77), 2.134 (2.24), 2.142 (0.78), 2.147 ( 1.20), 2.153 (1.01), 2.166 (0.60), 2.299 (7.88), 3.217 (0.51), 3.313 (4.75), 4.582 (16.00), 7.142 (0.84), 7.162 (1.77), 7.174 (1.38), 7.180 ( 2.56), 7.191 (2.64), 7.202 (1.07), 7.208 (1.78), 7.212 (1.21), 7.230 (1.81), 7.235 (0.73), 7.249 (2.09), 7.255 (1.43), 7.260 (2.42), 7.268 ( 1.78), 7.276 (10.04), 7.282 (12.94), 7.289 (1.48), 7.299 (6.19), 7.303 (2.61), 7.315 (0.93), 7.318 (1.58). Example 75A N-Benzyl-1,1-dicyclopropyl-2,2,2-trifluoroethanamine hydrochloride

[0381]

[0382] N-Benzyl-1,1-dicyclopropylmethanimine (35.4 g, 89% purity, 158 mmol) was placed in a mixture of 320 ml of acetonitrile and 70 ml of DMF and cooled to 0 ° C. Potassium hydrogen difluoride (39.5 g, 506 mmol) was added at 0°C and TFA (22 ml, 280 mmol) was added at 0°C. Trimethyl(trifluoromethyl)silane (82 ml, 550 mmol) was then added dropwise. The reaction mixture was stirred at room temperature for 4 h. The reaction solution was cooled to 0°C and potassium hydrogen difluoride (9.26 g, 119 mmol) and trimethyl(trifluoromethyl)silane (18 ml, 120 mmol) were added. The reaction solution was further stirred overnight at room temperature. Potassium hydrogen difluoride (9.26 g, 119 mmol), trifluoroacetic acid (4.9 ml, 63 mmol) and trimethyl(trifluoromethyl)silane (12 ml, 79 mmol) were added and stirring was continued at room temperature for 3.5 h. Trimethyl(trifluoromethyl)silane (23 ml, 160 mmol) was then added and the mixture was stirred at 60° C. for 2.5 h. The mixture was added with saturated aqueous sodium carbonate solution and extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered. The filtrate was then mixed with 4 M HCl in dioxane (400 ml, 1.6 mol) and evaporated in a water bath at 30 ° C. The residue was purified using flash chromatography (cyclohexane / dichloromethane 20 / 1 to cyclohexane / dichloromethane 10 / 1). 10.64 g of the target compound (22% of theory, purity 99%) were obtained. LC-MS (Method 1): R t = 1.31 min; MS (ESIpos): m / z = 270 [M-HCl+H] +< 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: -0.008 (1.25), 0.008 (1.56), 0.591 (10.11) , 0.750 (13.34), 0.876 (1.90), 0.952 (1.06), 1.091 (6.01), 1.236 (1.18), 1.906 (0.42), 2.329 (0.82), 2.367 (0.46), 2.571 (0.49), 2.589 (0.63 ) , 2,671 (0.80), 2,711 (0.55), 3,615 (0.68), 4,212 (4.68), 5,107 (0.66), 7,358 (13.21), 7,375 (16.00), 7,502 (7.66). Example 76A 1,1-Dicyclopropyl-2,2,2-trifluoroethanamine hydrochloride

[0383]

[0384] N-Benzyl-1,1-dicyclopropyl-2,2,2-trifluoroethanamine hydrochloride (10.6 g, 34.8 mmol) was placed under argon in 200 ml of ethanol, with 1 M hydrochloric acid in ethanol (170 ml) and palladium on activated carbon (3.70 g, 10% purity). Hydrogenation was carried out for 60 minutes at normal pressure and room temperature. The mixture was filtered through Celite, 4 M hydrochloric acid in dioxane (87 ml, 350 mmol) was added and evaporated at a water bath temperature of 30 ° C. The residue was mixed with diethyl ether, stirred for 10 minutes and the solid contained was filtered off. 6.39 g of the target compound (84% of theory) were obtained and reacted further without further purification. LC-MS (Method 1): R t = 0.49 min; MS (ESIpos): m / z = 180 [M-HCl+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.489 (2.34), 0.502 (4.38), 0.512 (7.72 ), .524 (12.33), .535 (11.32), .546 (9.58), .557 (10.43), .569 (9.17), .581 (11.40), .591 (13.47), .603 (8.94), .614 (4.93), .626 (3 .21 ). .06 ), 0.899 (2.37), 1.056 (4.75), 1,070 (9.13), 1,078 (10.15), 1.091 (16.00), 1,099 (6.84), 1.105 (8.35), 1,113, 1.126 (3.14), 8.942 (2.96 ). Example 77A

[0385] N-Benzyl-1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropane-1-amine hydrochloride

[0386] N-Benzyl-1,1-dicyclopropylmethanimine (4.00 g, 20.1 mmol) was placed under argon in a mixture of 40 ml of acetonitrile and 8.9 ml of DMF and cooled to 0 ° C. Potassium hydrogen difluoride (5.02 g, 64.2 mmol) was added at 0°C and TFA (2.8 ml, 36 mmol) was added at 0°C. Trimethyl(pentafluoroethyl)silane (12 ml, 70 mmol) was then added dropwise. The reaction mixture was further stirred at room temperature for 3 days. The mixture was stirred at 60°C for 7.5 h. The mixture was mixed with 20 ml of acetonitrile and 4.5 ml of DMF and cooled to 0°C. At 0°C, potassium hydrogen difluoride (1.88 g, 24.1 mmol), TFA (770 µl, 10 mmol) and trimethyl(pentafluoroethyl)silane (5.3 ml, 30 mmol) were added and the mixture was stirred overnight at room temperature. The mixture was added with saturated aqueous sodium carbonate solution and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered. The filtrate was then mixed with 4 M HCl in dioxane (50 ml, 200 mmol) and evaporated. The residue was purified using silica gel chromatography (mobile phase: cyclohexane / dichloromethane: 20 / 1). The product fractions were combined, added with 4 M HCl in dioxane (50 ml, 200 mmol) and evaporated at 30 ° C water bath temperature. 2.14 g of the target compound (30% of theory, purity 99%) were obtained. LC-MS (Method 1): R t = 1.39 min; MS (ESIpos): m / z = 320 [M-HCl+H] +< 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 0.008 (1.21), 0.331 (1.50), 0.354 (4.75), 0.365 (5.92), 0.376 (5.94), 0.385 (4.06), 0.397 (2.65), 0.450 (2.43), 0.461 (3.95), 0.470 (6.34), 0.482 (6.37), 0.491 (5.64), 0.502 (3.07), 0.515 (2.14), 0.648 (6.10), 0.659 (6.45), 0.668 (6.49), 0.680 (7.00), 0.690 (6.84), 0.703 (4.80), 0.909 (2.14), 0.930 (4.98), 0.944 (7.05), 0.957 (4.27), 0.978 (1.50), 2,329 (0.40), 3.568 (11.42), 4.046 (14.52), 7.064 (0.43), 7.098 (0.47), 7.128 (0.48), 7.194 (2.29), 7.212 (5.53), 7,229 (4.28), 7,279 (6.89), 7,298 (16.00), 7,316 (12.69), 7,331 (13.22), 7,349 (5.73). Example 78A 1,1-Dicyclopropyl-2,2,3,3,3-pentafluoropropane-1 -amine hydrochloride

[0387]

[0388] N-Benzyl-1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropane-1-amine hydrochloride (3.22 g, 9.06 mmol) was prepared under argon with 90 ml ethanol, 45 ml 1M hydrochloric acid in ethanol and (964 mg, 10% purity) palladium added to activated carbon. Hydrogenation was carried out for 45 minutes at normal pressure and room temperature. The mixture was filtered through Celite, washed well with ethanol, mixed with 23 ml of 4M hydrochloric acid in dioxane and evaporated at a water bath temperature of 30 ° C. The residue was mixed with diethyl ether and stirred for 10 minutes and the solid contained was filtered off. The product was further implemented without cleaning. 1.64 g of the target compound (68% of theory) were obtained. 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (1.30), -0.008 (13.14), 0.008 (11.58), 0.146 (1.12), 0.540 (12.55), 0.550 (12.29), 0.572 (11.02), 0.605 (12.52), 0.791 (12.35), 0.875 (10.67), 1.060 (4.89), 1.080 (11.64), 1.094 (16.00), 1.128 (3.30), 2.328 (2.12), 2.366 (0 .80), 2,670 (2.12), 2,710 (0.65), 8,767 (1.97). Example 79A N-[(E)-Cyclopropylmethylene]-2-methylpropane-2-sulfinamide (enantiomer 1)

[0389]

[0390] (S)-2-Methylpropane-2-sulfinamide (8.65 g, 71.3 mmol) was placed in 430 ml of dichloromethane under argon and treated with cyclopropane carbaldehyde (11 ml, 140 mmol) and anhydrous copper(II) sulfate (34.2 g, 214 mmol). added at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite, washed with diethyl ether and the filtrate was evaporated and dried under high vacuum. 15.3 g of the target compound (99% of theory, purity approx. 80%) were obtained. LC-MS (Method 1): R t = 0.73 min; MS (ESIpos): m / z = 174 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.952 (0.47), 0.958 (0.76), 0.964 (0.55), 0.967 (0.45), 0.970 (0.53), 1.041 (0.67), 1.055 (1.45), 1.061 (0.80), 1.068 (0.56), 1.070 (0.52), 1.082 (1.02), 1.092 (16.00), 5.751 (1.54), 7,389 (0.82), 7,409 (0.82). Example 80A N-[1-Cyclopropyl-2,2,3,3,3-pentafluoropropyl]-2-methylpropane-2-sulfinamide (diastereomer 1)

[0391]

[0392] N-[(E)-Cyclopropylmethylene]-2-methylpropane-2-sulfinamide (enantiomer 1) (5.00 g, 28.9 mmol) was placed in a glovebox under argon together with tetramethylammonium fluoride (6.45 g, 69.3 mmol). The reaction vessel was removed from the glovebox after 14 h and 110 ml of THF were added to the mixture and a solution of trimethyl(pentafluoroethyl)silane (13 ml, 72 mmol), dissolved in 170 ml of THF, was slowly added at -55 ° C . After the addition was complete, the mixture was stirred for 30 minutes and then carefully added with 50 ml of saturated aqueous ammonium chloride solution and 165 ml of water at -30 ° C. The aqueous phase was extracted twice with tert-butyl methyl ether. The combined organic phases were washed once each with water and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and evaporated. The crude product was purified using silica gel (mobile phase: cyclohexane 100% after cyclohexane / ethyl acetate 2 / 1). 4.9 g of the target compound (58% of theory, de > 95%) were obtained. LC-MS (Method 1): R t = 0.92 min; MS (ESIpos): m / z = 294 [M+H] +< Example 81A 1-Cyclopropyl-2,2,3,3,3-pentafluoropropane-1-amine hydrochloride (enantiomer 1)

[0393]

[0394] N-[1-Cyclopropyl-2,2,3,3,3-pentafluoropropyl]-2-methylpropane-2-sulfinamide (diastereomer 1) (4.10 g, 14.0 mmol) was placed in 130 ml of diethyl ether and 25 ml of methanol. 2N hydrochloric acid in diethyl ether (130 ml, 250 mmol) was then added dropwise at room temperature and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was largely evaporated at a water bath temperature of 30 ° C. The residue was stirred with 10 ml of acetonitrile, filtered off and washed with a few drops of acetonitrile. 2.1 g of the target compound (65% of theory, purity 98%) were obtained. LC-MS (Method 1): R t = 0.31 min; MS (ESIpos): m / z = 190 [M-HCl+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.543 (2.57), 0.556 (4.32), 0.569 (5.47 ), 0.584 (3.62), 0.604 (0.54), 0.669 (0.44), 0.685 (1.59), 0.699 (3.25), 0.718 (8.78), 0.733 (16.00), 0.748 (15.55), 0.759 (0.767 (3.55 ), 1,019 (0.99), 1.038 (2.50), 1,045 (5.40), 1,050 (3.89), 1.064 (3.077 (3.57), 1.103 (14.10), 1,270 (0.53), 2.330 (0.40), 2.363 (0.83 ), 3,167 (10.46), 3.671 (6.50), 3,685 (5.12), 3,697 (4.27), 3.712 (3.56), 3.723 (7.42), 3.739 (2.98), 3.751 (2.86), 3.47), 4.059 (0.82 ), 9.207 (10.25). Example 82A N-[(E)-Cyclopropylmethylene]-2-methylpropane-2-sulfinamide (enantiomer 2)

[0395]

[0396] (R)-2-Methylpropane-2-sulfinamide (13.0 g, 107 mmol) was placed in 640 ml of dichloromethane under argon and treated with cyclopropane carbaldehyde (15.0 g, 214 mmol) and anhydrous copper(II) sulfate (51.2 g, 321 mmol). added at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite, washed with diethyl ether and the filtrate was evaporated and dried under high vacuum. 18.9 g of the target compound (100% of theory, purity approx. 98%) were obtained. LC-MS (Method 1): R t = 0.72 min; MS (ESIpos): m / z = 174 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.952 (0.48), 0.958 (0.77), 0.964 (0.57), 0.967 (0.47), 0.969 (0.54), 1.055 (0.76), 1.061 (0.80), 1.068 (0.57), 1.070 (0.53), 1.081 (1.07), 1.092 (16.00), 7.389 (0.83), 7.409 (0.82). Example 83A N-[1-Cyclopropyl-2,2,3,3,3-pentafluoropropyl]-2-methylpropane-2-sulfinamide (diastereomer 2)

[0397]

[0398] N-[(E)-Cyclopropylmethylene]-2-methylpropane-2-sulfinamide (enantiomer 2) (5.10 g, 98% purity, 28.8 mmol) was placed in a glovebox under argon together with tetramethylammonium fluoride (6.45 g, 69.2 mmol). The reaction vessel was removed from the glovebox after 14 h and 110 ml of THF were added to the mixture and a solution of trimethyl(pentafluoroethyl)silane (13 ml, 72 mmol), dissolved in 170 ml of THF, was slowly added at -55 ° C . After the addition was complete, the mixture was stirred for 30 minutes and then carefully added with 50 ml of saturated aqueous ammonium chloride solution and 165 ml of water at -30 ° C. The aqueous phase was extracted twice with tert-butyl methyl ether. The combined organic phases were washed once each with water and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and evaporated. The crude product was purified using silica gel (mobile phase: cyclohexane 100% after cyclohexane / ethyl acetate 2 / 1). 5.8 g of the target compound (69% of theory, de>95%) were obtained. LC-MS (Method 1): R t = 0.92 min; MS (ESIpos): m / z = 294 [M+H] +< Example 84A 1-Cyclopropyl-2,2,3,3,3-pentafluoropropane-1-amine hydrochloride (enantiomer 2)

[0399]

[0400] N-[1-Cyclopropyl-2,2,3,3,3-pentafluoropropyl]-2-methylpropane-2-sulfinamide (diastereomer 2) (5.00 g, 17.0 mmol) was placed in 150 ml of diethyl ether and 31 ml of methanol. 2N hydrochloric acid in diethyl ether (150 ml, 2.0 M, 300 mmol) was then added dropwise at room temperature and stirred at room temperature for 2.5 h. The reaction solution was largely evaporated at a water bath temperature of 30 ° C. The residue was stirred with 10 ml of acetonitrile, filtered off and washed with a few drops of acetonitrile. 2.5 g of the target compound (64% of theory, purity 98%) were obtained. LC-MS (Method 1): R t = 0.33 min; MS (ESIpos): m / z = 190 [M-HCl+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.70), 0.008 (1.55), 0.549 ( 4.38), 0.565 (4.26), 0.574 (3.54), 0.586 (2.02), 0.688 (2.56), 0.706 (9.75), 0.723 (16.00), 0.743 (10.93), 0.765 (2.53), 0.783 (0.70), 1.014 ( 0.92), 1.029 (1.97), 1.046 (3.89), 1.058 (3.39), 1.072 (2.94), 1.086 (1.64), 1.103 (0.66), 2.329 (0.53), 2.671 (0.54), 3.669 (2.36), 3.683 ( 2.43), 3.695 (2.47), 3.710 (2.40), 3.722 (2.51), 3.737 (2.41), 3.748 (2.39), 3.763 (2.17), 9.063 (5.76). Example 85A N-[(1E)-2,2-Dimethylpropylidene]-2-methylpropane-2-sulfinamide (enantiomer 1)

[0401]

[0402] (S)-2-Methylpropane-2-sulfinamide (15.0 g, 124 mmol) was placed in 650 ml of dichloromethane under argon and treated with pivalaldehyde (27 ml, 250 mmol) and anhydrous copper(II) sulfate (59.3 g, 371 mmol). added at room temperature. The mixture was stirred at room temperature for 4 days. The reaction mixture was filtered through Celite, washed with diethyl ether and the filtrate was evaporated and dried under high vacuum. 22.7 g of the target compound (97% of theory) were obtained. LC-MS (Method 1): R t = 0.93 min; MS (ESIpos): m / z = 190 [M+H] + 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.013 (0.56), 1.079 (2.03), 1.102 (15.53), 1.113 (1.97), 1,120 (16.00), 1,271 (1.00), 7,814 (1.55). Example 86A 2-Methyl-N-[1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl]propane-2-sulfinamide (diastereomer 1)

[0403]

[0404] N-[(1E)-2,2-dimethylpropylidene]-2-methylpropane-2-sulfinamide (enantiomer 1) (3.50 g, 18.5 mmol) was placed in a glovebox under argon together with tetramethylammonium fluoride (4.13 g, 44.4 mmol). The reaction vessel was removed from the glovebox after 14 h and 56 ml of THF were added to the mixture and a solution of trimethyl(pentafluoroethyl)silane (8.1 ml, 46 mmol), dissolved in 82 ml of THF, was slowly added at -78 ° C . The reaction mixture was stirred at -78°C for 3.5 h. Saturated aqueous ammonium chloride solution and water were added to the reaction solution at approximately -50°C. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once each with water and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and evaporated. The residue was purified using silica gel (mobile phase: cyclohexane, then cyclohexane / ethyl acetate: 5 / 1). 4.25 g of the target compound (73% of theory, purity 98%, de > 95%) were obtained. LC-MS (Method 4): R t = 3.30 min; MS (ESIpos): m / z = 310 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.33), 0.008 (0.58), 1.054 (0.45) , 1.058 (0.43), 1.104 (7.77), 1.106 (7.67), 1.178 (16.00), 1.201 (1.02), 2.519 (0.54), 2.524 (0.57), 5.114 (0.43), 5.137 (0.41). Example 87A 1,1,1,2,2-Pentafluoro-4,4-dimethylpentane-3-amine hydrochloride (enantiomer 1)

[0405]

[0406] 2-Methyl-N-[1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl]propane-2-sulfinamide (diastereomer 1) (4.14 g, 98% purity, 13.1 mmol). in 240 ml of diethyl ether and 48 ml of methanol. 2N hydrochloric acid in diethyl ether (240 ml, 480 mmol) was then added and the mixture was stirred at room temperature for 2.5 h. The reaction solution was largely evaporated at a water bath temperature of 35 ° C. The residue was stirred with approx. 5 ml of diethyl ether, filtered off and the residue was dried. This was mixed with 20 ml of 20% potassium hydroxide solution and extracted three times with dichloromethane. The combined organic phases were mixed with 2N hydrochloric acid in diethyl ether and evaporated at a bath temperature of 35° C. and dried in a high vacuum. 2.94 g of the target compound (89% of theory) were obtained and used in the subsequent stage without further purification. LC-MS (Method 1): R t = 0.81 min; MS (ESIpos): m / z = 206 [M-HCl+H] +< Example 88A N-[(1E)-2,2-Dimethylpropylidene]-2-methylpropane-2-sulfinamide (enantiomer 2)

[0407]

[0408] (R)-2-Methylpropane-2-sulfinamide (15.0 g, 124 mmol) was placed in 650 ml of dichloromethane under argon and treated with pivalaldehyde (27 ml, 250 mmol) and anhydrous copper(II) sulfate (59.3 g, 371 mmol). added at room temperature. The mixture was stirred at room temperature for 4 days. Copper sulfate (24.7 g, 155 mmol) was added again and stirring was continued overnight at room temperature. The reaction mixture was filtered through Celite, washed with diethyl ether and the filtrate was evaporated and dried under high vacuum. 20.15 g of the target compound (86% of theory) were obtained. LC-MS (Method 1): R t = 0.94 min; MS (ESIpos): m / z = 190 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.078 (14.51), 1.102 (16.00), 1.113 (1.88), 1,120 (15.93), 1,270 (1.08), 5,290 (0.56), 7,814 (1.44). Example 89A 2-Methyl-N-[1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl]propane-2-sulfinamide (diastereomer 2)

[0409]

[0410] Under Argon! The flask and the tetramethylammonium fluoride lay in a glove box to dry overnight! N-[(1E)-2,2-Dimethylpropylidene]-2-methylpropane-2-sulfinamide (enantiomer 2) (4.38 g, 80% purity, 18.5 mmol) was combined with tetramethylammonium fluoride (4.13 g, 44.4 mmol) in a glovebox submitted under argon. The reaction vessel was removed from the glovebox after 14 h and 56 ml of THF were added to the mixture and a solution of trimethyl(pentafluoroethyl)silane (8.1 ml, 46 mmol), dissolved in 82 ml of THF, was slowly added at -78 ° C . The reaction mixture was stirred at -70° C. for 3 h and then slowly thawed and stirred overnight at room temperature. Saturated aqueous ammonium chloride solution and water were carefully added to the reaction solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once each with water and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and evaporated. The residue was purified using silica gel (mobile phase: 100% cyclohexane, then cyclohexane / ethyl acetate: 2 / 1). 3.81 g of the target compound (65% of theory, purity 98%, de > 90%) were obtained. LC-MS (Method 4): R t = 3.30 min; MS (ESIpos): m / z = 310 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.054 (0.40), 1.059 (0.42), 1.104 (7.59), 1,106 (7.75), 1,178 (16.00), 1,201 (1.05), 5,113 (0.42). Example 90A 1,1,1,2,2-Pentafluoro-4,4-dimethylpentane-3-amine hydrochloride (enantiomer 2)

[0411]

[0412] 2-Methyl-N-[1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl]propane-2-sulfinamide (diastereomer 2) (3.73 g, 12.0 mmol) was dissolved in 220 ml of diethyl ether and 44 ml of methanol. 2N hydrochloric acid in diethyl ether (220 ml, 440 mmol) was then added and the mixture was stirred at room temperature for 2.5 h. The reaction solution was largely evaporated at a water bath temperature of 35 ° C. The residue was stirred with diethyl ether and dried under high vacuum. 2.48 g of the target compound (81% of theory, purity 95%) were obtained. LC-MS (Method 1): R t = 0.80 min; MS (ESIpos): m / z = 206 [M-HCl+H] +< Example 91A 7-Chloro-N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro- 1,8-naphthyridine-3-carboxamide (enantiomer 1)

[0413]

[0414] 7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (300 mg, 805 µmol) was dissolved in 7.5 ml Acetonitrile presented. 1-Cyclopropyl-2,2,3,3,3-pentafluoropropane-1-amine hydrochloride (enantiomer 1) (204 mg, 98% purity, 886 µmol) and N,N-diisopropylethylamine (560 µl, 3.2 mmol) were added . T3P solution (propanephosphonic acid cycloanhydride, 50% in ethyl acetate; 570 µl, 970 µmol) was then added to the mixture. The reaction solution was stirred at room temperature overnight. Water was added to the mixture and the precipitated solid was filtered off, washed with water and dried under high vacuum. 439 mg of the target compound (99% of theory, purity 99%) were obtained. LC-MS (Method 3): R t = 2.53 min; MS (ESIpos): m / z = 544 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.22), -0.008 (9.36), 0.008 (8.14 ). ). ). ), 4.466 (1.63), 4.488 (2.00), 4.507 (2.03), 4.530 (1.63), 4.554 (0.64), 7.602 (5.39), 7.624 (10.27), 7.646 (5.42), 8.719 (9.63), 8.738 (9.63 ), 9,167 (16.00), 10,048 (5.32), 10,072 (5.32). Example 92A 7-Chloro-N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro- 1,8-naphthyridine-3-carboxamide (enantiomer 2)

[0415]

[0416] 7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (300 mg, 805 µmol) was dissolved in 7.5 ml Acetonitrile presented. 1-Cyclopropyl-2,2,3,3,3-pentafluoropropane-1-amine hydrochloride (enantiomer 2) (204 mg, 98% purity, 886 µmol) and N,N-diisopropylethylamine (560 µl, 3.2 mmol) were added. T3P solution (propanephosphonic acid cycloanhydride, 50% in ethyl acetate; 570 µl, 970 µmol) was then added to the mixture. The reaction solution was stirred at room temperature overnight. Water was added to the mixture and the precipitated solid was filtered off, washed with water and dried under high vacuum. 422 mg of the target compound (96% of theory, purity 100%) were obtained. LC-MS (Method 3): R t = 2.52 min; MS (ESIpos): m / z = 544 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.93), -0.008 (7.99), 0.008 (6.97 ), .146 (.89), .316 (.84), .328 (2.12), .338 (3.25), .351 (3.23), .363 (2.48), .374 (1.19), .530 (.88), .542 (2.44), .553 (3.54 ). ). ). ), 4.466 (1.97), 4.488 (2.26), 4.508 (2.30), 4.530 (1.93), 4.554 (0.71), 7.601 (5.75), 7.623 (11.11), 7.646 (5.82), 8.719 (9.38), 8.738 (9.40 ), 9,167 (16.00), 10,048 (6.22), 10,072 (6.09). Example 93A 7-Chloro-N-(1,1-dicyclopropyl-2,2,2-trifluoroethyl)-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1, 8-naphthyridine-3-carboxamide

[0417]

[0418] 7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (100 mg, 268 µmol), 1.1 -Dicyclopropyl-2,2,2-trifluoroethanamine hydrochloride (63.7 mg, 295 µmol) and N,N-diisopropylethylamine (160 µl, 940 µmol) were placed in 2.4 ml of ethyl acetate. T3P solution (propanephosphonic acid cycloanhydride, 50% in ethyl acetate; 630 µl, 1.1 mmol) was added and the mixture was stirred at 80 ° C for 2 h. Water was added to the mixture and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue was purified using preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were re-extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and evaporated. 101 mg of the target compound (70% of theory, purity 99%) were obtained. LC-MS (Method 1): R t = 1.33 min; MS (ESIpos): m / z = 534 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.44), -0.008 (11.48), 0.008 (10.40 ). ). ). ). ), 7,621 (10.64), 7,643 (5.84), 8,754 (10.37), 8,773 (10.40), 9,117 (16.00), 9,409 (12.46). Example 94A 7-Chloro-N-(1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropyl)-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4- dihydro-1,8-naphthyridine-3-carboxamide

[0419]

[0420] 7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (140 mg, 376 µmol), 1.1 -Dicyclopropyl-2,2,3,3,3-pentafluoropropane-1-amine hydrochloride (110 mg, 413 µmol) and N,N-diisopropylethylamine (230 µl, 1.3 mmol) were placed in ethyl acetate. T3P solution (propanephosphonic acid cycloanhydride, 50% in ethyl acetate; 890 µl, 1.5 mmol) was added and the mixture was stirred at 80 ° C for 2 h. Water was added to the mixture and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue was purified using preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA). The combined product fractions were evaporated. The residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were re-extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and evaporated. 88 mg of the target compound (40% of theory, purity 99%) were obtained. LC-MS (Method 1): R t = 1.44 min; MS (ESIpos): m / z = 584 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.61), -0.008 (4.76), 0.008 (4.40 ). ). ). ), 1,660 (1.40), 2.328 (0.83), 2,367 (0.48), 2.671 (0.90), 2,710 (0.50), 5.755 (0.47), 7.597 (5.68), 7.619 (10.97), 7.641 (5.82), 8.759 (9.67 ), 8,778 (9.61), 9,126 (16.00), 9,386 (11.83). Example 95A 7-Chloro-6-fluoro-4-oxo-N-[1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl]-1-(2,4,6-trifluorophenyl)- 1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 1)

[0421]

[0422] 7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (300 mg, 805 µmol) was dissolved in 7.5 ml Acetonitrile presented. 1,1,1,2,2-Pentafluoro-4,4-dimethylpentane-3-amine hydrochloride (enantiomer 1) (214 mg, 100% purity, 886 µmol) and N,N-diisopropylethylamine (560 µl, 3.2 mmol) were added. A T3P solution (propanephosphonic acid cycloanhydride, 50% in ethyl acetate; 570 µl, 970 µmol) was added. The reaction solution was stirred at room temperature overnight. 1,1,1,2,2-pentafluoro-4,4-dimethylpentane-3-amine hydrochloride (enantiomer 1) (97 mg, 403 µmol) was again added to the reaction solution and stirred at room temperature for two days. 1,1,1,2,2-pentafluoro-4,4-dimethylpentane-3-amine hydrochloride (enantiomer 1) (97 mg, 403 µmol), N,N-diisopropylethylamine (280 µl, 1.6 mmol) and a T3P solution (propanephosphonic acid cycloanhydride, 50% in ethyl acetate; 285 µl, 480 µmol) was added to the reaction solution and stirred for 2 days at room temperature. The reaction solution was diluted with dichloromethane and washed twice with water. The combined aqueous phases were re-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The residue was purified using silica gel (mobile phase: cyclohexane / ethyl acetate gradient: ethyl acetate 4% to 32%). 318 mg of the target compound (71% of theory, purity 100%) were obtained. LC-MS (Method 5): R t = 1.72 min; MS (ESIpos): m / z = 560 [M+H] +< Example 96A 7-Chloro-6-fluoro-4-oxo-N-[1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl]-1-(2,4,6-trifluorophenyl)- 1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomer 2)

[0423]

[0424] 7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (300 mg, 805 µmol) was dissolved in 7.5 ml Acetonitrile presented. 1,1,1,2,2-Pentafluoro-4,4-dimethylpentane-3-amine hydrochloride (enantiomer 2) (214 mg, 100% purity, 886 µmol) and N,N-diisopropylethylamine (560 µl, 3.2 mmol) were added. A T3P solution (propanephosphonic acid cycloanhydride, 50% in ethyl acetate; 570 µl, 970 µmol) was added. The reaction solution was stirred at room temperature overnight. 1,1,1,2,2-pentafluoro-4,4-dimethylpentane-3-amine hydrochloride (enantiomer 2) (97 mg, 403 µmol) was again added to the reaction solution and stirred at room temperature for two days. 1,1,1,2,2-pentafluoro-4,4-dimethylpentane-3-amine hydrochloride (enantiomer 2) (97 mg, 403 µmol), N,N-diisopropylethylamine (280 µl, 1.6 mmol) and a T3P solution (propanephosphonic acid cycloanhydride, 50% in ethyl acetate; 285 µl, 480 µmol) was added to the reaction solution and stirred at room temperature for 2 days. The reaction solution was diluted with dichloromethane and washed twice with water. The combined aqueous phases were re-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The residue was purified using silica gel (mobile phase: cyclohexane / ethyl acetate gradient: ethyl acetate 4% to 32%). 373 mg of the target compound (82% of theory, purity 99%) were obtained. LC-MS (Method 5): R t = 1.73 min; MS (ESIpos): m / z = 560 [M+H] +< Example 97A 7-Chloro-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8- naphthyridine-3 -carboxamide (enantiomerically pure)

[0425]

[0426] To a solution of 2.50 g (7.05 mmol) 7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, 1.55 g (7.75 mmol) 3,3,4,4,4-pentafluorobutane-2-amine hydrochloride (enantiomerically pure) and 3.7 ml (21.1 mmol) of DIPEA in 70 ml of ethyl acetate became 16.5 ml (28.2 mmol) of 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide (T3P, 50% in ethyl acetate) added dropwise. Stirring was continued overnight at 80°C. The reaction mixture was evaporated and poured onto water. The precipitate was filtered off, dissolved in DCM, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The raw product was used in the subsequent stage without further purification. 3.35 g (95% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 3): R t = 2.34 min; MS (ESIpos): m / z = 500 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.92), 0.146 (0.85), 0.928 (1.24) , 0.943 (1.22), 1.175 (0.71), 1.244 (1.98), 1.259 (2.16), 1.274 (1.27), 1.409 (15.77), 1.426 (16.00), 1.488 (0.94), 1.988 (1.17), 2.328 (1.6 8) , 2,367 (1.01), 2,670 (1.82), 2.711 (1.04), 4.998 (0.81), 5.020 (1.36), 5.043, 5.062 (1.73), 5.086 (1.43), 5.107 (0.78), 7.595 (5.78) , 7,618 (11.30), 7,640 (5.82), 7,773 (10.54), 7,794 (11.10), 8,741 (11.23), 8,761 (10.77), 9,142 (15.95), 9,986 (6.05), 10,010 (5.92). Example 98A 7-[(3S)-3-Hydroxypyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl )-1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomerically pure)

[0427]

[0428] According to AAV3, 5.00 g (10.0 mmol) of 7-chloro-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1 ,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomerically pure) with 1.36 g (11.0 mmol) (3S)-pyrrolidin-3-ol hydrochloride and 7.0 ml (40.0 mmol) N,N-diisopropylethylamine in 37 ml Dimethylformamide reacted. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were once with sat. Washed sodium chloride solution, dried over sodium sulfate and evaporated. The crude product was purified using normal phase chromatography (cyclohexane-ethyl acetate gradient). 4.99 g (88% of theory, 97% purity) of the title compound were obtained. LC-MS (Method 1): R t = 1.04 min; MS (ESIpos): m / z = 551 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.51), 0.147 (0.51), 1.157 (0.52) , 1.175 (1.05), 1.193 (0.49), 1.385 (14.87), 1.402 (14.89), 1.788 (0.91), 1.921 (1.77), 1.989 (2.75), 2.329 (0.83), 2.367 (0.42), 2.671 (0.7 9) , 2,711 (0.44), 3.051 (1.08), 3.083 (1.84), 3.163, 3.185 (2.68), 3.518 (2.49), 3.534 (2.97), 4.021 (0.47), 4.039 (0.47), 4.270 (1.69) , 4,387 (1.43), 4.961 (2.74), 4.984 (1.50), 5.007 (1.64), 5.052 (3.17), 6.744 (1.70), 6.773 (2,76), 6.798 (2.07), 7.55 (7.553 (6.61) , 7,575 (3.83), 8,265 (3.13), 8,286 (2.86), 8,805 (16.00), 10,551 (6.33), 10,575 (6.15). EXAMPLES OF EMBODIMENTS: example 1 1-(2,6-Difluorophenyl)-7-[(3 R ,4 R )-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo- N -(4,4,4-trifluoro-2-methylbutan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

[0429]

[0430] According to AAV1, 99.9 mg (237 µmol) 1-(2,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 40.1 mg (284 µmol) 4,4,4-trifluoro-2-methylbutane-2-amine in the presence of 108 mg (284 µmol) HATU and 103 µl (593 µmol ) DIPEA reacted in 2.4 ml DMF. The reaction mixture was analyzed directly using preparative HPLC [at UV max: 265nm, column: Chromatorex C18, 10 µm, 125x30 mm, solvent: acetonitrile / 0.05% formic acid gradient; (0 to 3 min. 10% acetonitrile to 15 min. 90% acetonitrile and another 3 min. 90% acetonitrile)]. The product fractions were combined, freed from solvent and lyophilized. 107 mg (82% of theory, 99% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.76 min; MS (ESIpos): m / z = 545 [M+H] +< . 1< H NMR (400 MHz, DMSO-d6): δ [ppm] = 10.10 (s, 1H), 8.67 (s, 1H), 8.00 (d, 1H), 7.77-7.66 (m, 1H), 7.47- 7.36 (m, 2H), 5.18 (br. s, 2H), 4.09-3.51 (br. m, 4H), 3.27-2.86 (br. s, 4H). Example 2 N -[(1 S )-1-Cyclopropyl-2,2,2-trifluoroethyl]-1-(2,6-difluorophenyl)-7-[(3 R ,4 R )-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide

[0431]

[0432] According to AAV1, 99.9 mg (237 µmol) 1-(2,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 49.9 mg (284 µmοl) (1 S )-1-Cyclopropyl-2,2,2-trifluoroethanamine hydrochloride was reacted in the presence of 108 mg (284 µmol) HATU and 103 µl (593 µmol) DIPEA in 2.4 ml DMF. The reaction mixture was then directly analyzed using preparative HPLC [at UV max: 265nm, column: Chromatorex C18, 10 µm, 125x30 mm, solvent: acetonitrile / 0.05% formic acid gradient; (0 to 3 min. 10% acetonitrile to 15 min. 90% acetonitrile and another 3 min. 90% acetonitrile)]. The product fractions were combined, freed from solvent and lyophilized. 100 mg (77% of theory, 99% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.77 min; MS (ESIpos): m / z = 543 [M+H] +< . 1< H NMR (400 MHz, DMSO-d6): δ [ppm] = 10.49 (d, 1H), 8.78 (s, 1H), 8.02 (d, 1H), 7.76-7.67 (m, 1H), 7.46- 7.38 (m, 2H), 5.19 (br. s, 2H), 4.45-4.32 (m. 1H), 4.11-3.53 (br. m, 4H), 3.27-2.89 (m. 2H), 1.27-1.16 (m , 1H), 0.70-0.49 (m, 3H), 0.38-0.28 (m, 1H). Example 3 1-(2,6-Difluorophenyl)-7-[(3 R ,4 R )-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo- N -[(2 S )-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

[0433]

[0434] According to AAV1, 100 mg (237 μmol) 1-(2,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 46.6 mg (285 µmοl) (2 S )-1,1,1-trifluorobutane-2-amine hydrochloride was reacted in the presence of 108 mg (285 µmol) HATU and 103 µl (593 µmol) DIPEA in 2.4 ml DMF. The reaction mixture was then diluted with 2 ml of aqueous hydrochloric acid and analyzed using preparative HPLC [at UV max: 265nm, column: Chromatorex C18, 10 µm, 125x30 mm, solvent: acetonitrile / 0.05% formic acid gradient; (0 to 3 min. 10% acetonitrile to 15 min. 90% acetonitrile and another 3 min. 90% acetonitrile)]. The product fractions were combined, freed from solvent and lyophilized. 32.7 mg (26% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 1): R t = 0.92 min; MS (ESIpos): m / z = 531 [M+H] +< . 1< H NMR (400 MHz, DMSO-d6): δ [ppm] = 10.36 (d, 1H), 8.79 (s, 1H), 8.02 (d, 1H), 7.77-7.67 (m, 1H), 7.47- 7.38 (m, 2H), 5.19 (br. s, 2H), 4.81-4.67 (m. 1H), 4.10-3.56 (br. m, 4H), 3.27-2.90 (br. s, 2H), 1.94-1.82 (m , 1H), 1.71-1.58 (m, 1H), 0.97 (t, 1H). Example 4 1-(2,6-Difluorophenyl)-6-fluoro-7-[(2-hydroxyethyl)(methyl)amino]-4-oxo- N -[(2 S )-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide

[0435]

[0436] According to AAV3, 50.0 mg (108 µmol) 7-chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo- N -[(2 S )-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide with 8.91 mg (119 µmol) 2-(methylamino)ethanol in the presence of 66 µl (0.38 mmol) DIPEA reacted in 0.5 ml DMF. It was then diluted with acetonitrile, water and 0.2 ml of aqueous hydrochloric acid and the crude solution was purified using preparative HPLC (acetonitrile-water with formic acid, C18 RP-HPLC). The product fractions were purified, concentrated in vacuo and lyophilized from acetonitrile / water overnight. 37.9 mg (70% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.97 min; MS (ESIpos): m / z = 503 [M+H] +< . 1< H NMR (400 MHz, DMSO-d6): δ [ppm] = 10.33 (d, 1H), 8.81 (s, 1H), 8.01 (d, 1H), 7.75-7.65 (m, 1H), 7.45- 7.37 (m, 2H), 4.80-4.67 (m, 2H), 3.51-3.35 (m, 4H), 3.05 (s, 3H), 1.94-1.82 (m, 1H), 1.71-1.58 (m, 1H), 0.97 (t, 3H). Example 5 N -(Bicyclo[1.1.1]pent-1-yl)-1-(2,6-difluorophenyl)-7-[(3 R ,4 R )-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3 -carboxamide

[0437]

[0438] According to AAV1, 100 mg (237 μmol) 1-(2,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4 -dihydro-1,8-naphthyridine-3-carboxylic acid with 34.1 mg (285 µmol) bicyclo[1.1.1]pentane-1-amine hydrochloride in the presence of 108 mg (285 µmol) HATU and 103 µl (593 µmol) DIPEA in 2.4 ml of DMF reacted. The reaction mixture was then diluted with 2 ml of aqueous hydrochloric acid and analyzed twice using preparative HPLC [at UV max: 265nm, column: Chromatorex C18, 10 µm, 125x30 mm, solvent: acetonitrile / 0.05% formic acid gradient; (0 to 3 min. 10% acetonitrile to 15 min. 90% acetonitrile and another 3 min. 90% acetonitrile)]. The product fractions were combined, freed from solvent and lyophilized. 3 mg (2% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.65 min; MS (ESIpos): m / z = 487 [M+H] +< . Example 6 7-[(3 R ,4 R )-3,4-Dihydroxypyrrolidin-l-yl]-6-fluoro-4-oxo- N -[(2 S )-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

[0439]

[0440] According to AAV3, 417 mg (717 µmol) of 6-fluoro-4-oxo-7-(1-[1,2,3]triazole[4,5- b ]pyridin-1-yloxy)- N- [(2 S )-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide with 120 mg (861 µmol) ( 3 R ,4 R)-pyrrolidine-3,4-diol hydrochloride was reacted in the presence of 437 µl (2.51 mmol) of DIPEA in 7.25 ml of DMF. The reaction solution was then added to 80 ml of water, acidified with 2 ml of 1M aqueous hydrochloric acid, the precipitate was filtered off with suction and washed with water. The residue was taken up in 6 ml of acetonitrile and purified using preparative HPLC (acetonitrile-water with formic acid, C18 RP-HPLC). The product fractions were combined, concentrated in vacuo and the residue was lyophilized from acetonitrile / water overnight. 296 mg (74% of theory, 99% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.78 min; MS (ESIpos): m / z = 549 [M+H] +< . 1< H NMR (400 MHz, DMSO-d6): δ [ppm] = 10.34 (d, 1H), 8.84 (s, 1H), 8.02 (d, 1H), 7.62-7.53 (m, 2H), 5.20 ( br , 1H), 0.97 (t, 1H). Example 7 N -[(1 S )-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(3 R ,4 R )-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

[0441]

[0442] According to AAV1, 1.00 g (2.28 mmol) of 7-[(3 R ,4 R )-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with 480 mg (2.73 mmol) (1 S )-1-Cyclopropyl-2,2,2-trifluoroethanamine hydrochloride was reacted in the presence of 1.04 g (2.73 mmol) HATU and 991 µl (5.69 mmol) DIPEA in 23 ml DMF. It was then acidified with 1M aqueous hydrochloric acid and diluted with 200 ml of water and 100 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted twice with 60 ml of ethyl acetate. The combined organic phases were washed with 50 ml of buffer pH 7 and with 50 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified using normal phase chromatography (cyclohexane-ethyl acetate), the fractions were purified, concentrated in vacuo and lyophilized overnight from acetonitrile / water. 1.05 g (83% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.81 min; MS (ESIpos): m / z = 561 [M+H] +< . 1< H NMR (400 MHz, DMSO-d6): δ [ppm] = 10.48 (d, 1H), 8.83 (s, 1H), 8.02 (d, 1H), 7.62-7.52 (m, 2H), 5.20 ( br , 3H), 0.38-0.28 (m, 1H). Example 8 7-[(3 R ,4 R )-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo- N -[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereomers)

[0443]

[0444] According to AAV1, 2.77 g (6.31 mmol) of 7-[(3 R ,4 R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with 1.51 g (7.57 mmol) of 3,3,4,4,4-pentafluorobutane-2-amine hydrochloride (racemate) was reacted in the presence of 2.88 g (7.57 mmol) of HATU and 3.84 ml (22.1 mmol) of DIPEA in 30 ml of DMF. The reaction solution was then dripped into a mixture of 3 ml of aqueous 1M hydrochloric acid and 300 ml of ice water. The resulting precipitate was filtered off, dried and purified using normal phase chromatography (cyclohexane ethyl acetate). 2.40 g (65% of theory, 100% purity) of the title compound were obtained. LC-MS (Method 3): R t = 1.84 min; MS (ESIpos): m / z = 585 [M+H] +< . 2.40 g of the title compound (diastereomer mixture) was separated into the diastereomers by chiral SFC (preparative SFC: column Daicel Chiralpak AD, 5 µm, 250x30 mm; eluent: 85% carbon dioxide, 15% iso-propanol; temperature: 38 ° C; flow: 130 ml / min; pressure: 140 bar; UV detection: 210 nm.) This gave (in the order of elution from the column) 1.15 g of diastereomer 1 from Example 9 (99% de) R t = 3.23 min, 1.09 g Diastereomer 2 from Example 10 (94% de) R t = 4.79 min. [Analytical SFC: column Daicel Chiralpak AD-3, 3 µm, 100x4.6 mm; Eluent: 90% carbon dioxide, 10% iso-propanol; Temperature: 60°C; Flow: 3.0 ml / min; Pressure: 130 bar; UV detection: 220nm]. Diastereomer 1 was purified using normal phase chromatography (cyclohexane ethyl acetate). 903 mg (24% of theory, 99% purity) of the compound from Example 9 were obtained. Diastereomer 2 was purified using normal phase chromatography (cyclohexane ethyl acetate). 912 mg (25% of theory, 99% purity) of the compound from Example 10 were obtained. Example 9 7-[(3 R ,4 R )-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo- N -[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer 1)

[0445] LC-MS (Method 3): R t = 1.84 min; MS (ESIpos): m / z = 585 [M+H] +< . 1< H NMR (400 MHz, DMSO-d6): δ [ppm] = 10.46 (d, 1H), 8.84 (s, 1H), 8.01 (d, 1H), 7.62-7.53 (m, 2H), 5.20 ( br. Example 10 7-[(3 R ,4 R )-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo- N -[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer 2)

[0446] LC-MS (Method 3): R t = 1.84 min; MS (ESIpos): m / z = 585 [M+H] +< . 1< H NMR (400 MHz, DMSO-d6): δ [ppm] = 10.47 (d, 1H), 8.84 (s, 1H), 8.01 (d, 1H), 7.62-7.54 (m, 2H), 5.20 ( br.

[0447] The following exemplary embodiments were produced analogously to Example 8 according to AAV1: Example IUPAC name structure LC-MS (method): retention time; detected mass 1< H NMR amine used (yield, purity) 11 7-[(3 R ,4 R )-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2S)-1,1,1-trifluoro-4-methylpentan-2-yl]-1-(2, 4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide LC-MS (Method 1): R t = 1.07 min; MS (ESIpos): m / z = 577 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (1.63), 0.882 (15.82), 0.898 (15.97), 0.940 (15.69), 0.956 (16.00), 1.527 (0.65), 1.562 ( 2.61), 1.590 (2.10), 1.640 (2.07), 1.650 (3.07), 1.676 (3.98), 1.703 (1.66), 2.328 (0.72), 2.366 (0.49), 2.524 (2.17), 2.670 (0.75), 2.710 ( 0.47), 3.070 (0.79), 3.696 (0.83), 3.904 (1.68), 4.017 (1.18), 4.815 (1.32), 4.838 (1.35), 4.857 (0.78), 5.201 (2.98), 7.554 (2.23), 7.558 ( 2.44), 7.575 (4.26), 7.580 (4.31), 7.597 (2.46), 7.993 (6.91), 8.025 (6.83), 8.847 (12.23), 10.316 (4.89), 10.340 (4.71). (2S)-1,1,1-Trifluoro-4-methylpentane-2-amine hydrochloride (75% of theory, 99% purity) 12 N-(Bicyclo[1.1.1]pent-1-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4 ,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide LC-MS (Method 1): R t = 0.91 min; MS (ESIpos): m / z = 505 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (0.98), 2.094 (16.00), 2.477 (2.52), 2.519 (0.42), 5.188 (0.90), 7.557 (0.60), 7.579 ( 1.03), 7,599 (0.60), 7,949 (1.39), 7,981 (1.36), 8,696 (2.25), 10,195 (1.71). Bicyclo[1.1.1]pentane-1-amine hydrochloride (69% of theory, 100% purity) 13 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1- (2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide LC-MS (Method 3): R t = 1.8 min; MS (ESIpos): m / z = 563 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.480 (16.00), 2.902 (0.72), 2.932 (2.07), 2.963 (2.01), 2.992 (0.69), 3.908 (0.59), 5.192 ( 1.67), 7,552 (1.20), 7,573 (2.17), 7,595 (1.21), 7,980 (2.69), 8,012 (2.63), 8,724 (4.96), 10,086 (3.27). 4,4,4-Trifluoro-2-methylbutane-2-amine hydrochloride (92% of theory, 100% purity) 14 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2R)-1,1,1-trifluoro-4-methylpentan-2-yl ]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide LC-MS (Method 1): R t = 1.07 min; MS (ESIpos): m / z = 577 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.52), 0.008 (2.37), 0.882 (15.72), 0.898 (15.79), 0.940 (15.66), 0.956 (16.00), 1.528 (0.63), 1.534 (0.59), 1.555 (1.28), 1.563 (2.58), 1.571 (1.29), 1.591 (2.06), 1.640 (1.99), 1.650 (2.98), 1.676 (3.84), 1.704 (1.62), 1.713 (1.08), 2.329 (0.42), 2.524 (1.33), 2.671 (0.45), 3.070 (0.76), 3.694 (0.77), 3.912 (1.65), 4.018 (1.13), 4.816 (1.26), 4.839 (1.29), 4.858 (0.73), 5.201 (4.77), 7.556 (3.83), 7.578 (6.91), 7.599 (3.80), 7.994 (7.11), 8.026 (6.94), 8.848 (12.19), 10.318 (4.80), 10.342 (4.57). (2R)-1,1,1-Trifluoro-4-methylpentane-2-amine hydrochloride (73% of theory, 97% purity) 15 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-[(2R)-3-methylbutan-2-yl]-4-oxo-1-(2,4 ,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide LC-MS (Method 3): R t = 1.67 min; MS (ESIpos): m / z = 509 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.45), 0.008 (1.92), 0.900 (14.25), 0.918 (16.00), 0.924 (14.85), 0.941 (14.39), 1.098 (14.84), 1.115 (14.90), 1,731 (0.46), 1.747 (1.23), 1.764 (1.75), 1,778 (1.69), 1.795 (1.13), 1.811 (0.41), 2.328 (0.43), 2.519 (1.74), 2.524 (1.27), 2.671 (0.43), 3.070 (0.46), 3.269 (0.67), 3.276 (0.53), 3.680 (0.48), 3.887 (2.02), 3.903 (2.66), 3.908 (2.44), 3.921 (2.64), 3.938 (2.04), 3.954 (1.12), 5.191 (3.01), 7.550 (2.38), 7.571 (4.17), 7.592 (2.37), 7.992 (5.69), 8.024 (5.64), 8.711 (9.43), 9.868 (3.38), 9.890 (3.30). (2R)-3-Methylbutane-2-amine (75% of theory, 99% purity) 16 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-[(2S)-3-methylbutan-2-yl]-4-oxo-1-(2,4 ,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide LC-MS (Method 3): R t = 1.67 min; MS (ESIpos): m / z = 509 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (1.40), 0.901 (14.31), 0.918 (16.00), 0.925 (14.98), 0.942 (14.43), 1.099 (14.84), 1.116 ( 14.86), 1.731 (0.49), 1.748 (1.30), 1.765 (1.85), 1,778 (1.73), 1,795 (1.14), 3.063 (0.51), 3,680 (0.53), 3.888 (2.11), 3.904 (2.84), 3.922 ( 2.79), 3,939 (2.15), 5.194 (4.39), 7.550 (2.81), 7.572 (4.99), 7.593 (2.71), 7.994 (6.12), 8.026 (6.00), 8.713 (11.30), 9.870 (3.57), 9.892 ( 3.45). (2S)-3-Methylbutane-2-amine (77% of theory, 100% purity) 17 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-[(2S)-1-methoxy-3-methylbutan-2-yl]-4-oxo-1- (2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide LC-MS (Method 3): R t = 1.58 min; MS (ESIpos): m / z = 539 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.71), 0.008 (1.47), 0.912 (10.53), 0.929 (10.84), 1.903 (0.49), 1.920 (0.75), 1.936 (0.74), 1.953 (0.46), 3.269 (16.00), 3.352 (0.72), 3.365 (0.83), 3.377 (1.17), 3.390 (1.12), 3.439 (1.10), 3.464 (0.76), 3.477 (0.70), 3.919 (0.46), 3.965 (0.52), 3.980 (0.91), 3.994 (0.99), 4.002 (1.00), 4.017 (0.87), 5.192 (1.07), 7.553 (0.86), 7.573 (1.56), 7.594 (0.86), 8,000 (2.37), 8,031 (2.31), 8,723 (4.24), 9,926 (1.34), 9,949 (1.29). (2S)-1-Methoxy-3-methylbutane-2-amine hydrochloride (87% of theory, 99% purity) 18 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-N-[(2S)-1,1 ,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide LC-MS (Method 1): R t = 0.89 min; MS (ESIpos): m / z = 535 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.40), 1.366 (15.93), 1.383 (16.00), 2.328 (0.75), 2.367 (0.46), 2.670 (0.72), 2.710 (0.46), 3.065 (0.82), 3.692 (0.82), 3.906 (1.71), 4.011 (1.21), 4.842 (0.45), 4.861 (1.18), 4.882 (1.82), 4.902 (1.87), 4.920 (1.20), 5.199 (4.80), 7,555 (2.86), 7,577 (5.42), 7,598 (2.83), 7,990 (8.04), 8,022 (7.89), 8,837 (14.74), 10,383 (5.19), 10,406 (4.90). (2S)-1,1,1-Trifluoropropane-2-amine (77% of theory, 99% purity) 19 N-[(1R)-1-Cyclopropylethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl )-1,4-dihydro-1,8-naphthyridine-3-carboxamide LC-MS (Method 3): R t = 1.63 min; MS (ESIpos): m / z = 507 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.68), -0.008 (6.67), 0.008 (5.02), 0.146 (0.68), 0.218 (1.10), 0.229 (1.68), 0.241 (2.46), 0.249 (2.36), 0.261 (1.43), 0.266 (1.39), 0.278 (2.30), 0.287 (2.75), 0.299 (1.94), 0.310 (1.26), 0.322 (0.55), 0.394 (0.65), 0.402 (0.65), 0.414 (1.85), 0.425 (2.27), 0.435 (2.59), 0.447 (3.11), 0.461 (2.75), 0.469 (2.01), 0.482 (1.59), 0.491 (0.62), 0.940 (0.45), 0.952 (0.87), 0.960 (1.30), 0.972 (2.27), 0.980 (1.46), 0.992 (2.14), 1.004 (1.10), 1.012 (0.74), 1.215 (15.87), 1.231 (16.00), 2.327 (1.13), 2,366 (1.00), 2,523 (3.85), 2,670 (1.23), 2,710 (1.10), 3,064 (0.55), 3,482 (0.42), 3,498 (1.39), 3,518 (2.56), 3,535 (2.49), 3,553 (1.33), 3,571 (0.49), 3,679 (0.62), 3,917 (1.39), 5,189 (4.15), 7,546 (3.17), 7,568 (5.73), 7,589 (3.21), 7,975 (6.25), 8,007 (6.19), 8,708 (10.85), 9,864 (4.05), 9,884 (3.92). (1R)-1-Cyclopropylethanamine (76% of theory, 100% purity) 20 N-[(1S)-1-Cyclopropylethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl )-1,4-dihydro-1,8-naphthyridine-3-carboxamide LC-MS (Method 3): R t = 1.62 min; MS (ESIpos): m / z = 507 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.42), -0.008 (4.00), 0.008 (2.96), 0.146 (0.42), 0.207 (0.46), 0.218 (1.12), 0.229 (1.67), 0.241 (2.46), 0.249 (2.39), 0.261 (1.42), 0.266 (1.39), 0.278 (2.32), 0.287 (2.75), 0.299 (1.93), 0.310 (1.19), 0.321 (0.56), 0.394 (0.60), 0.402 (0.67), 0.414 (1.84), 0.425 (2.23), 0.435 (2.56), 0.448 (3.05), 0.456 (1.96), 0.461 (2.72), 0.470 (1.98), 0.482 (1.60), 0.491 (0.60), 0.502 (0.44), 0.940 (0.44), 0.952 (0.88), 0.960 (1.26), 0.972 (2.25), 0.980 (1.44), 0.984 (1.40), 0.992 (2.16), 1.005 (1.09), 1.012 (0.74), 1.215 (15.91), 1.232 (16.00), 2,328 (0.61), 2,367 (0.60), 2.524 (2.23), 2,670 (0.65), 2,710 (3.073 (0.54), 3.484 (0.40), 3,501 (1.35), 3,520 (2.49), 3,537 (2.46), 3,556 (1.30), 3,573 (0.44), 3,673 (0.56), 3,909 (1.32), 5,190 (4.47), 7,547 (2.51), 7,568 (4.49), 7,589 (2.51), 7,976 (6.25), 8,008 (6.18), 8,709 (10.70), 9,864 (4.05), 9,884 (3.89). (1S)-1-Cyclopropylethanamine (77% of theory, 100% purity) 21 N-(Dicyclopropylmethyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4- dihydro-1,8-naphthyridine-3-carboxamide LC-MS (Method 1): R t = 0.94 min; MS (ESIpos): m / z = 533 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.11), -0.008 (9.56), 0.008 (7.59), 0.146 (1.11), 0.299 (15.57), 0.311 (15.27), 0.322 (4.14), 0.370 (2.56), 0.393 (6.91), 0.415 (5.85), 0.452 (4.99), 0.472 (6.31), 0.498 (1.92), 1.016 (2.82), 1.029 (5.25), 1.036 (3.41), 1,049 (4.99), 1,061 (2.60), 2,328 (2.22), 2,367 (1.11), 2,670 (2.13), 2,710 (1.07), 3,221 (2.22), 3,239 (4.44), 3,261 (4.74), 3,280 (2.86), 3,903 (1.79), 5,189 (5.16), 7,545 (3.50), 7,568 (6.27), 7,588 (3.58), 7,988 (9.09), 8,020 (8.75), 8,709 (16.00), 9,892 (5.03), 9,914 (4.82). 1,1-Dicyclopropylmethanamine (61% of theory, 99% purity) 22 N-(1,1-Difluoro-2-methylpropan-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2 ,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide LC-MS (Method 1): R t = 0.93 min; MS (ESIpos): m / z = 531 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.57), 0.008 (1.50), 1.434 (16.00), 2.073 (0.74), 2.328 (0.48), 2.670 (0.52), 3.910 (0.55), 5.192 (1.49), 6.277 (0.88), 6.420 (1.62), 6.562 (0.73), 7.554 (1.10), 7.577 (1.94), 7.597 (1.10), 7.987 (2.44), 8.019 (2.41), 8.750 (4.28), 10,232 (3.14). 1,1-Difluoro-2-methylpropane-2-amine hydrochloride (57% of theory, 100% purity) 23 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-1- (2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide LC-MS (Method 3): R t = 1.77 min; MS (ESIpos): m / z = 549 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.89), 0.008 (0.56), 1.633 (16.00), 2.520 (0.82), 2.524 (0.74), 3.908 (0.50), 5.194 (1.18), 7.557 (0.97), 7.579 (1.58), 7.600 (0.89), 8.008 (2.21), 8.040 (2.14), 8.775 (3.54), 10.561 (2.95). 1,1,1-Trifluoro-2-methylpropane-2-amine hydrochloride (63% of theory, 100% purity) 24 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-N-(2,4-dimethylpentan-3-yl)-6-fluoro-4-oxo-1-(2,4,6 -trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide LC-MS (Method 3): R t = 1.87 min; MS (ESIpos): m / z = 537 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.92), 0.008 (0.71), 0.865 (13.39), 0.877 (15.46), 0.881 (16.00), 0.893 (13.11), 1.810 (0.43), 1.827 (1.26), 1.844 (2.06), 1.860 (2.00), 1.877 (1.16), 2.524 (0.55), 3.640 (0.71), 3.656 (1.27), 3.666 (0.90), 3.672 (0.89), 3.681 (1.31), 3.697 (0.75), 3.911 (0.57), 5.198 (1.63), 7.550 (1.24), 7.572 (2.16), 7.592 (1.23), 8.013 (3.06), 8.045 (2.98), 8.727 (5.38), 9.761 (1.66), 9,786 (1.59). 2,4-Dimethylpentane-3-amine (57% of theory, 100% purity) 25 N-(2-Cyclopropylpropan-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl )-1,4-dihydro-1,8-naphthyridine-3-carboxamide LC-MS (Method 3): R t = 1.79 min; MS (ESIpos): m / z = 521 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.397 (5.62), 0.414 (4.00), 1.290 (0.69), 1.311 (16.00), 1.325 (0.79), 5.187 (1.10), 7.550 ( 0.76), 7.572 (1.33), 7.593 (0.73), 7.993 (1.77), 8.024 (1.73), 8.680 (3.16), 9.863 (2.07). 2-Cyclopropylpropane-2-amine (95% of theory, 100% purity) 26 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2)-1-(trifluoromethoxy)butan-2-yl]-1-( 2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereomers) LC-MS (Method 3): R t = 1.78 min; MS (ESIpos): m / z = 579 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.02), 0.008 (1.73), 0.922 (6.79), 0.941 (16.00), 0.959 (7.44), 1.550 (0.56), 1.568 (0.97), 1.585 (1.26), 1.603 (1.40), 1.622 (0.89), 1.633 (0.55), 1.651 (1.04), 1.663 (1.19), 1.669 (1.15), 1.682 (1.27), 1.698 (0.74), 1.716 (0.46), 2.074 (1.63), 2.328 (0.45), 2.524 (1.32), 2.671 (0.43), 3.069 (0.51), 3.685 (0.52), 3.911 (1.21), 4.148 (2.09), 4.162 (2.31), 4.176 (3.98), 4.183 (4.11), 4.194 (4.10), 4.211 (2.53), 5.193 (3.51), 7.552 (2.57), 7.574 (4.50), 7.595 (2.53), 7.995 (6.24), 8.026 (6.06), 8.762 (10.71), 9.985 (2.62), 10.005 (2.44). 1-(Trifluoromethoxy)butane-2-amine hydrochloride (racemate) (54% of theory, 100% purity) 27 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(3)-1,1,1,2,2-pentafluoropentan-3-yl ]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer mixture) LC-MS (Method 3): R t = 1.93 min; MS (ESIpos): m / z = 599 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.944 (7.18), 0.962 (16.00), 0.981 (7.74), 1.619 (0.90), 1.638 (1.31), 1.654 (1.50), 1.663 ( 1.39), 1.673 (1.34), 1.681 (1.41), 1.699 (1.00), 1.922 (1.31), 2.329 (0.58), 2.672 (0.66), 3.079 (0.81), 3.693 (0.86), 3.905 (1.75), 4.012 ( 1.22), 4,852 (1.12), 4,879 (1.06), 5,208 (3.80), 7,557 (3.27), 7,579 (5.89), 7,599 (3.25), 8,005 (7.21), 8,037 (7.04), 8,850 (14.56), 10,377 ( 4.69), 10,402 (4.39). 1,1,1,2,2-Pentafluoropentane-3-amine hydrochloride (racemate) (85% of theory, 99% purity) 28 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-(2-methylpentan-3-yl)-4-oxo-1-(2,4,6-trifluorophenyl )-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereomers) - LC-MS (Method 3): R t = 1.80 min; MS (ESIpos): m / z = 523 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (1.53), 0.851 (4.76), 0.869 (11.65), 0.878 (11.15), 0.888 (7.46), 0.896 (16.00), 0.915 ( 10.32), 1,380 (0.55), 1.397 (0.79), 1.414 (1,00), 1.436 (1.06), 1.454 (0.71), 1.538 (0.78), 1,550 (0.92), 1.568 (1.584 (0.72), 1.602 ( 0.49), 1.794 (0.89), 1.810 (1.24), 1.824 (1.23), 1.840 (0.80), 2.328 (0.45), 3.680 (0.42), 3.764 (0.53), 3.777 (0.93), 3.788 (1.29), 3.799 ( 1.63), 3.811 (1.29), 3.822 (0.87), 3.834 (0.59), 3.907 (0.94), 5.199 (2.67), 7.551 (2.01), 7.573 (3.53), 7.594 (1.96), 7.999 (4.29), 8.031 ( 4.21), 8,716 (8.19), 9,768 (2.51), 9,792 (2.39). 2-Methylpentane-3-amine hydrochloride (racemate) (31% of theory, 100% purity) Example 29 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-(2-methylpentan-3-yl)-4-oxo-1-(2,4,6-trifluorophenyl )-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer 1)

[0448] 37 mg 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-(2-methylpentan-3-yl)-4-oxo-1-(2,4,6 -trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer mixture) was separated into the diastereomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak OX-H, 5 µm, 250 x 20 mm; Eluent: 80% n-heptane / 20% isopropanol; flow 15 ml / min; temperature: 35°C, detection: 265 nm). Diastereomer 1: 13 mg (>99% de) R t = 6.27 min [analytical HPLC: column Daicel® Chiralpak OX-H, 1ml / min; 5µm, 250 x 4.6mm; Eluent: 75% iso-hexane / 25% isopropanol + 0.2% DEA; Detection: 265 nm]. LC-MS (Method 3): R t = 1.80 min; MS (ESIpos): m / z = 523 [M+H] +< Example 30 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-(2-methylpentan-3-yl)-4-oxo-1-(2,4,6-trifluorophenyl )-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer 2)

[0449] 37 mg 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-(2-methylpentan-3-yl)-4-oxo-1-(2,4,6 -trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer mixture) was separated into the diastereomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak OX-H, 5 µm, 250 x 20 mm; Eluent: 80% n-heptane / 20% isopropanol; flow 15 ml / min; temperature: 35°C, detection: 265 nm). Diastereomer 2: 13 mg (>99% de) R t = 7.35 min [analytical HPLC: column Daicel® Chiralpak OX-H, 1ml / min; 5µm, 250 x 4.6mm; Eluent: 75% iso-hexane / 25% isopropanol + 0.2% DEA; Detection: 265 nm]. LC-MS (Method 3): R t = 1.80 min; MS (ESIpos): m / z = 523 [M+H] +< Example 31 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2)-1-(trifluoromethoxy)butan-2-yl]-1-( 2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer 1)

[0450] 218 mg 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2)-1-(trifluoromethoxy)butan-2-yl]-1 -(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer mixture) was separated into the diastereomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak ID, 5 µm, 250 x 20 mm; eluent: 85% n-heptane / 15% isopropanol; flow 15 ml / min; temperature: 30°C, detection: 220 nm). Diastereomer 1: 63.7 mg (99% de) R t = 5.50 min [analytical HPLC: column Daicel® Chiralpak ID, 1ml / min; 5µm, 250 x 4.6mm; Eluent: 80% iso-hexane / 20% propanol; Detection: 220 nm]. LC-MS (Method 3): R t = 1.78 min; MS (ESIpos): m / z = 579 [M+H] +< Example 32 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2)-1-(trifluoromethoxy)butan-2-yl]-1-( 2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer 2)

[0451] 218 mg 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2)-1-(trifluoromethoxy)butan-2-yl]-1 -(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer mixture) was separated into the diastereomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak ID, 5 µm, 250 x 20 mm; eluent: 85% n-heptane / 15% isopropanol; flow 15 ml / min; temperature: 30°C, detection: 220 nm). Diastereomer 2: 64.2 mg (97.6% de) R t = 6.23 min [analytical HPLC: column Daicel® Chiralpak ID, 1ml / min; 5µm, 250 x 4.6mm; Eluent: 80% iso-hexane / 20% propanol; Detection: 220 nm]. LC-MS (Method 3): R t = 1.78 min; MS (ESIpos): m / z = 579 [M+H] +< Example 33 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(3)-1,1,1,2,2-pentafluoropentan-3-yl ]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer 1) 292 mg 7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(3)-1,1,1,2,2-pentafluoropentane-3 -yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereomers)

[0452] was separated into the diastereomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak IA, 5 µm, 250 x 20 mm; eluent: 85% n-heptane / 15% isopropanol; flow 15 ml / min; temperature: 30 ° C, Detection: 220 nm). Diastereomer 1: 111.6 mg (>99% de) R t = 6.10 min [analytical HPLC: column Daicel® Chiralpak IA, 1ml / min; 5µm, 250 x 4.6mm; Eluent: 80% iso-hexane / 20% isopropanol; Detection: 265 nm]. LC-MS (Method 3): R t = 1.93 min; MS (ESIpos): m / z = 599 [M+H] +< Example 34 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(3)-1,1,1,2,2-pentafluoropentan-3-yl ]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer 2) 292 mg 7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(3)-1,1,1,2,2-pentafluoropentane-3 -yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (mixture of diastereomers)

[0453] was separated into the diastereomers by chiral HPLC (preparative HPLC: column Daicel® Chiralpak IA, 5 µm, 250 x 20 mm; eluent: 85% n-heptane / 15% isopropanol; flow 15 ml / min; temperature: 30°C, Detection: 220 nm). Diastereomer 2: 110.1 mg 99.5% de) R t = 6.76 min [analytical HPLC: column Daicel® Chiralpak IA, 1ml / min; 5µm, 250 x 4.6mm; Eluent: 80% iso-hexane / 20% isopropanol; Detection: 265 nm]. LC-MS (Method 3): R t = 1.93 min; MS (ESIpos): m / z = 599 [M+H] +< Example 35 (3R,4R)-1-[3-Fluoro-5-oxo-6-{[(2S)-1,1,1-trifluorobutan-2-yl]carbamoyl}-8-(2,4,6-trifluorophenyl )-5,8-dihydro-1,8-naphthyridin-2-yl]-4-hydroxypyrrolidin-3-yl acetate

[0454]

[0455] (7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1 -(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (60.0 mg, 109 µmol) was dissolved in dichloromethane (1.0 ml) and treated with dimethylaminopyridine (1.34 mg, 10.9 µmol ). Acetyl chloride (5.4 µl, 77 µmol) was added dropwise at 0°C and stirred at RT for 3 h. The reaction mixture was concentrated and the residue was taken up in acetonitrile and analyzed using preparative HPLC (acetonitrile-water with formic acid, C18 RP- HPLC). The product fractions were combined, concentrated and lyophilized overnight from acetonitrile / water. 25.9 mg (39% of theory, 99% purity) of the title compound were obtained. LC-MS (Method 3): R t = 2.07 min; MS (ESIpos): m / z = 591 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.90), -0.008 (7.72), 0.008 (6.90), 0.146 (0.88), 0.952 (2.34), 0.971 (5.26), 0.989 (2.57), 1.625 (0.47), 1.642 (0.53), 1.651 (0.53), 1.661 (0.51), 1.668 (0.53), 1.685 (0.41), 1.852 (0.41), 1.871 (0.49), 1.881 (0.58), 1.897 (0.45), 1.990 (16.00), 2.328 (0.68), 2.523 (1.81), 2.670 (0.68), 2.710 (0.41), 4.139 (0.45), 4.738 (0.51), 4.951 (0.41), 5.607 (0.94), 7.555 (1.38), 7.577 (2.51), 7.599 (1.40), 8.036 (2.20), 8.067 (2.20), 8.858 (5.18), 10,300 (1.75), 10,324 (1.68).

[0456] The following reactions were prepared analogously to Example 1 according to AAV1: Example IUPAC name structure LC-MS (method): retention time; detected mass 1< H NMR amine used (yield, purity) 36 7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1- (2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide LC-MS (Method 3): R t = 1.78 min; MS (ESIpos): m / z = 549 [M+H] + 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.60), -0.008 (5.32), 0.008 (4.91) , 0.147 (0.57), 0.950 (7.28), 0.969 (16.00), 0.987 (7.85), 1.604...

Claims

1. Compound of the formula (I) in which X represents halogen, R1 represents hydrogen, or represents -NR4R5, in which R4 represents hydrogen, methyl, (C2-C4) -alkyl or (C3-C6)-cycloalkyl, where (C2-C4)-alkyl may be substituted by hydroxyl or up to trisubstituted by fluorine and R5 represents (C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered saturated heterocyclyl or (C1-C4)-alkylsulfonyl, where (C1-C6) -alkyl, (C3-C6) -cycloalkyl and 3-to 6-membered saturated heterocyclyl may be up to trisubstituted, identically or differently, by methyl, difluoromethyl, trifluoromethyl, hydroxyl, hydroxycarbonyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy and cyano, and additionally up to tetrasubstituted by fluorine, or R4 and R5 together with the nitrogen atom to which they are bonded form a saturated or partially unsaturated, 3- to 6-membered monocyclic or 6- to 10-membered bicyclic heterocycle which may contain one or two further, identical or different heteroatoms from the group of N, O, S, SO and / or SO2 as ring members, where the 3- to 6-membered monocyclic and the 6-to 10-membered bicyclic heterocycle may each be substituted by 1 to 5 substituents independently selected from the group of (C1-C4)-alkyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxycarbonyl, oxo, (C1-C3)-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, (C1-C3)-alkoxycarbonyl, aminocarbonyl, mono-(C1-C3)-alkylaminocarbonyloxy,-NHC(=O)R14A, -CH2NHC(=O)R14B, -OC(=O)R15, and additionally up to tetrasubstituted by fluorine, in which (C1-C4)-alkyl may be mono- or disubstituted, identically or differently, by hydroxyl and (C1-C3)-alkoxy, and up to tetrasubstituted by fluorine, R14A and R14B independently of one another represent (C1-C3)-alkyl or cyclopropyl, and in which R15 represents (C1-C4)-alkyl, R2 represents a group of the formula in which * marks the point of attachment to the nitrogen atom of the amide moiety, R6A represents hydrogen or (C1-C4)-alkyl, R6B represents hydrogen, (C1-C4)-alkyl, cyclopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl or trifluoromethoxymethyl, R7 represents (C1-C6) -alkyl or (C3-C5) -cycloalkyl which is up to tetrasubstituted by fluorine, where (C1-C6)-alkyl may be substituted by amino, hydroxy, (C1-C6) -alkoxy and up to pentasubstituted by fluorine, where (C1-C6)-alkoxy may be up to pentasubstituted by fluorine, L1 represents a bond or a group of the formula -C(R8AR8B)-(C(R9AR9B))m-, in which m represents 0 or 1, R8A represents hydrogen or methyl, R8B represents hydrogen, methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl, R9A and R9B each independently of one another represent hydrogen or methyl, Ar2 represents phenyl, where phenyl may be mono- to trisubstituted, identically or differently, by fluorine, chlorine, (C1-C3) -alkyl, difluoromethoxymethyl, trifluoromethoxymethyl and / or trifluoromethyl, or represents a 5- to 10-membered monocyclic, bicyclic or tricyclic carbocycle or heterocycle which may contain one or two further identical or different heteroatoms from the group consisting of N and / or O as ring members, where the 5- to 10-membered monocyclic, bicyclic or tricyclic carbocycle or heterocycle may be up to trisubstituted by identical or different substituents from the group consisting of (C1-C3) -alkyl, trifluoromethyl and (C1-C4)-alkoxycarbonyl and furthermore up to tetrasubstituted by fluorine, Ar1 represents a group of the formula in which *** marks the point of attachment to the nitrogen atom, R3A represents fluorine, chlorine, trifluoromethyl or methyl, R3B represents hydrogen or fluorine and R3C represents hydrogen, fluorine, chlorine or methyl, or represents a pyridine ring which is attached via a ring carbon atom, where the pyridine ring may be mono- or disubstituted by fluorine, chlorine, cyano, methyl or trifluoromethyl, and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof.

2. Compound of the formula (I) according to Claim 1, in which X represents fluorine, chlorine or bromine, R1 represents hydrogen, or represents NR4R5, in which R4 represents hydrogen, methyl or ethyl, and R5 represents (C1-C3) -alkyl which is up to tetrasubstituted by fluorine, where (C1-C3)-alkyl may be substituted by hydroxy, or R4 and R5 together with the nitrogen atom to which they are attached form a saturated 4- to 6-membered monocyclic or 6- to 9-membered bicyclic heterocycle which may contain one or two further identical or different heteroatoms from the group consisting of N and O as ring members, where the 4- to 6-membered monocyclic and the 6-to 9-membered bicyclic heterocycle may each be substituted by 1 to 4 substituents independently of one another selected from the group consisting of (C1-C4)-alkyl, difluoromethyl, trifluoromethyl, hydroxy, oxo, (C1-C3) -alkoxy, difluoromethoxy, trifluoromethoxy, (C1-C3)-alkoxycarbonyl, (C1-C3) -alkylaminocarbonyloxy and -OC(=O)R15 and furthermore up to tetrasubstituted by fluorine, where (C1-C4)-alkyl may be mono- or disubstituted by identical or different substituents from the group consisting of hydroxy and (C1-C3) -alkoxy, and up to tetrasubstituted by fluorine, and where R15 represents (C1-C4)-alkyl, R2 represents a group of the formula in which * marks the point of attachment to the nitrogen atom of the amide moiety, R6A represents hydrogen or (C1-C4)-alkyl, R6B represents methyl, ethyl, isopropyl, cyclopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl, and R7 represents (C1-C4)-alkyl which is up to pentasubstituted by fluorine, (C3-C5) - cycloalkyl which is up to tetrasubstituted by fluorine, methoxymethyl or trifluoromethoxymethyl, L1 represents a bond or a group of the formula -CR8AR8B-, in which R8A represents hydrogen, R8B represents hydrogen, methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl, Ar2 represents phenyl, where phenyl may be mono- to trisubstituted by identical or different substituents from the group consisting of fluorine and chlorine, or represents a 5- to 7-membered bicyclic carbocycle or 5- or 6-membered monocyclic heterocycle which contains one nitrogen atom as ring member, where the 5- to 7-membered bicyclic carbocycle or the 5- or 6-membered monocyclic heterocycle may in each case be substituted by (C1-C4)-alkoxycarbonyl and additionally up to tetrasubstituted by fluorine, Ar1 represents a group of the formula in which *** marks the point of attachment to the nitrogen atom, R3A represents fluorine, chlorine, trifluoromethyl or methyl, R3B represents hydrogen or fluorine and R3C represents hydrogen, fluorine, chlorine or methyl, or represents a pyridine ring which is attached via a ring carbon atom, where the pyridine ring may be mono- or disubstituted by fluorine, chlorine or cyano, and the salts, solvates and solvates of the salts thereof.

3. Compound of the formula (I) according to Claim 1 or 2, in which X represents fluorine, chlorine or bromine, R1 represents NR4R5, in which R4 represents methyl or ethyl, and R5 represents methyl, 2-hydroxyethyl or 2-hydroxypropyl, or represents a heterocycle, attached via a nitrogen atom, of the formula in which **marks the point of attachment to the remainder of the molecule, R10 represents fluorine, methyl, hydroxy, hydroxymethyl, methoxycarbonyl or acetyloxy, p represents the number 0, 1 or 2, where, in the case that the substituents R10 occur more than once, their meanings may in each case be identical or different, Y1 represents -NH-, -N(CH3)- or -O-, R2 represents a group of the formula in which * marks the point of attachment to the nitrogen atom of the amide moiety, R6A represents hydrogen, methyl or ethyl, R6B represents methyl, ethyl, trifluoromethyl, isopropyl or cyclopropyl, and R7 represents methyl, ethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, isopropyl, isobutyl, methoxymethyl, trifluoromethoxymethyl or cyclopropyl, R11 represents hydrogen, R12 represents methoxycarbonyl, R13 represents hydrogen or tert-butoxycarbonyl, L1 represents a bond or a group of the formula -CR8AR8B-, in which R8A represents hydrogen, R8B represents hydrogen, methyl or trifluoromethyl, Ar2 represents phenyl, where phenyl may be mono- to disubstituted by identical or different substituents from the group consisting of fluorine and chlorine, Ar1 represents a group of the formula in which *** marks the point of attachment to the nitrogen atom, R3A represents fluorine or chlorine, and R3C represents hydrogen or fluorine, and the salts, solvates and solvates of the salts thereof.

4. Compound of the formula (I) according to any of Claims 1 to 3, in which X represents fluorine, R1 represents a heterocycle, attached via a nitrogen atom, of the formula in which **marks the point of attachment to the remainder of the molecule, R2 represents a group of the formula in which * marks the point of attachment to the nitrogen atom of the amide moiety, Ar1 represents a group of the formula in which *** marks the point of attachment to the nitrogen atom, and the salts, solvates and solvates of the salts thereof.

5. Compound of the formula (I) according to Claim 1 or 2, in which X represents fluorine, R1 represents a heterocycle, attached via a nitrogen atom, of the formula or in which ** marks the point of attachment to the remainder of the molecule, R2 represents a group of the formula in which * marks the point of attachment to the nitrogen atom of the amide moiety, Ar1 represents a group of the formula in which *** marks the point of attachment to the nitrogen atom, and the salts, solvates and solvates of the salts thereof.

6. Compound of the formula (I) according to Claim 1 or 2, in which X represents fluorine, R1 represents a heterocycle, attached via a nitrogen atom, of the formula in which ** marks the point of attachment to the remainder of the molecule, R2 represents a group of the formula in which * marks the point of attachment to the nitrogen atom of the amide moiety, Ar1 represents a group of the formula in which *** marks the point of attachment to the nitrogen atom, and the salts, solvates and solvates of the salts thereof.

7. Compound of the formula (I) according to any of Claims 1 to 3, in which R1 represents a heterocycle, attached via a nitrogen atom, of the formula in which ** marks the point of attachment to the remainder of the molecule.

8. Compound according to Claim 1, in which the compound of the formula (I) has the structure below 9. Compound according to Claim 1, in which the compound of the formula (I) has the structure below 10. Compound according to Claim 1, in which the compound of the formula (I) has the structure below 11. Compound according to Claim 1, in which the compound of the formula (I) has the structure below 12. Compound according to Claim 1, in which the compound of the formula (I) has the structure below 13. Compound according to Claim 1, in which the compound of the formula (I) has the structure below 14. Compound according to Claim 1, in which the compound of the formula (I) has the structure below 15. Compound according to Claim 1, in which the compound of the formula (I) has the structure below 16. Compound according to Claim 1, in which the compound of the formula (I) has the structure below 17. Compound according to Claim 10, which is the diastereomer 1 which is obtainable by preparative SFC on Daicel Chiralpak AD, 5 µm, 250 × 30 mm with the mobile phase 85% carbon dioxide / 15% isopropanol at a temperature of 38°C and a flow rate of 130 ml / min at a pressure of 140 bar from the racemate and, under these conditions, elutes after 3.23 min.

18. Compound according to Claim 10, which is the diastereomer 2 which is obtainable by preparative SFC on Daicel Chiralpak AD, 5 µm, 250 × 30 mm with the mobile phase 85% carbon dioxide / 15% isopropanol at a temperature of 38°C and a flow rate of 130 ml / min at a pressure of 140 bar from the racemate and, under these conditions, elutes after 4.79 min.

19. Compound according to Claim 16, which is the diastereomer 1 which is obtainable by preparative HPLC on Daicel Chiralcel OX-H, 5 µm, 250 × 30 mm with the mobile phase 80% n-heptane / 20% ethanol at a temperature of 25°C and a flow rate of 40 ml / min from the racemate and, under these conditions, elutes after 6.40 min.

20. Compound according to Claim 16, which is the diastereomer 2 which is obtainable by preparative HPLC on Daicel Chiralcel OX-H, 5 µm, 250 × 30 mm with the mobile phase 80% n-heptane / 20% ethanol at a temperature of 25°C and a flow rate of 40 ml / min from the racemate and, under these conditions, elutes after 8.57 min.

21. Process for preparing compounds of the formula (I) as defined in any of Claims 1 to 20, characterized in that [A] a compound of the formula (II) in which X, R2 and Ar1 have the meanings given in Claims 1 to 20 for compounds of the formula (I) and Hal represents fluorine, chlorine, bromine or iodine, is reacted with a compound of the formula (III)         R1-H     (III), in which R1 has the meaning given in Claims 1 to 20 for compounds of the formula (I) and where R1 does not represent hydrogen, to give the carboxamide of the formula (I-A) in which X, R1, R2 and Ar1 have the meanings given in Claims 1 to 20 for compounds of the formula (I) and where R1 does not represent hydrogen, or [B] a compound of the formula (IV) in which X, R1 and Ar1 have the meanings given in Claims 1 to 20 for compounds of the formula (I) is reacted with a compound of the formula (V)         R2-NH2     (V), in which R2 has the meaning given in Claims 1 to 20 for compounds of the formula (I), to give the carboxamide of the formula (I) in which R1, R2 and Ar1 have the meanings given in Claims 1 to 20 for compounds of the formula (I), and the resulting compounds of the formula (I) are optionally separated into their enantiomers and / or diastereomers and / or converted with the appropriate (i) solvents and / or (ii) bases or acids into their solvates, salts and / or solvates of the salts.

22. Compound of the formula (II) in which X, R2 and Ar1 have the meanings given in Claims 1 to 20 for compounds of the formula (I), and Hal represents fluorine, chlorine, bromine or iodine.

23. Compound, as defined in any of Claims 1 to 20, for use in the treatment and / or prophylaxis of diseases.

24. Compound of the formula (I), as defined in any of Claims 1 to 20, for use in a method of treatment and / or prophylaxis of heart failure, coronary heart disease, atrial and ventricular arrhythmias, renal failure and nephropathies.

25. Medicament, comprising a compound as defined in any of Claims 1 to 20 in combination with one or more further active ingredients selected from the group consisting of active hypotensive ingredients, active antiarrhythmic ingredients, vasopressin receptor antagonists, PDE 5 inhibitors, platelet aggregation inhibitors, sGC activators and sGC stimulators.

26. Medicament, comprising a compound as defined in any of Claims 1 to 20 in combination with an inert, nontoxic, pharmaceutically suitable auxiliary.

27. Medicament according to Claim 25 or 26 for use in the treatment and / or prophylaxis of heart failure, coronary heart disease, atrial and ventricular arrhythmias, renal failure and nephropathies.

28. Positive allosteric modulator of the muscarinergic M2 receptor of the formula (I) according to any of Claims 1 to 20.