EP3271332A1

EP3271332A1 - Oxo-pyridine-derivatives as factor xia inhibitors for the treatment of thrombosis

Info

Publication number: EP3271332A1
Application number: EP16709921.7A
Authority: EP
Inventors: Susanne Röhrig; Henrik Teller; Stefan Heitmeier; Karl-Heinz Schlemmer; Jan Stampfuss; Alexander Hillisch; Adrian Tersteegen; Eloisa JIMENEZ NUNEZ
Original assignee: Bayer Pharma AG
Current assignee: Bayer Pharma AG
Priority date: 2015-03-19
Filing date: 2016-03-15
Publication date: 2018-01-24
Also published as: CA2979937A1; WO2016146606A1; HK1247615A1; CN107428689A; JP2018509426A; US20190119213A1

Abstract

The invention relates to substituted oxo-pyridine derivatives and methods for the production thereof, as well as to the use thereof in the production of medicaments for treating and/or preventing diseases, especially diseases of the cardiovascular system, preferably thrombotic or thromboembolic diseases, as well as oedemas, and also ophthalmological diseases.

Description

OXOPYRIDINE DERIVATIVES AS FACTOR XIA INHIBITORS FOR THE TREATMENT OF THROMBOSE

The invention relates to substituted oxopyridine derivatives and processes for their preparation and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular cardiovascular diseases, preferably of thrombotic or thromboembolic diseases and of edema, as well as of ophthalmological diseases.

Blood clotting is a protective mechanism of the organism that can rapidly and reliably "seal" defects in the blood vessel wall, thus preventing or minimizing blood loss, and hemostasis following vascular injury is essentially through the coagulation system, where an enzymatic cascade becomes more complex It involves numerous clotting factors, each of which, once activated, converts the next inactive precursor to its active form, transforming the soluble fibrinogen into the insoluble fibrin at the end of the cascade Traditionally, one differentiates between the intrinsic and the extrinsic system in blood coagulation, which culminate in a final common pathway, where factors Xa and IIa (thrombin) play key roles: Factor Xa bundles the signals of the two ger because it is produced both by Factor VIIa / Tissue Factor (extrinsic pathway) and the Tenase complex (intrinsic pathway) by reaction of Factor X. The activated serine protease Xa cleaves prothrombin to thrombin, which transmits the cascade impulses to the coagulation status of the blood via a series of reactions.

In recent years, the traditional theory of the two separate regions of the coagulation cascade (extrinsic or intrinsic pathway) has been modified based on new findings: in these models, coagulation is initiated by binding of activated factor VIIa to tissue factor (TF). The resulting complex activates factor X, which in turn leads to thrombin generation with subsequent production of fibrin and platelet activation (via PAR-1) as hemorrhagic end-products of hemostasis. In comparison to the subsequent amplification / propagation phase, the rate of thrombin production in this first phase is small and limited by the occurrence of TFPI as an inhibitor of the TF-FVIIa-FX complex.

A key component of the transition from initiation to amplification and propagation of coagulation is Factor XIa: Thrombin activates in positive feedback loops in addition to Factor V and Factor VIII, Factor XI to Factor XIa, Factor IXa converts Factor IXa, and Factor IXa so generated / Factor VIIIa complex the factor X activation and thus in turn, strongly stimulates thrombin generation, leading to severe thrombus growth and stabilizing the thrombus.

In addition, attention has been drawn to the fact that, in addition to the stimulation via tissue factor, activation of the coagulation system can take place on, in particular, negatively charged surfaces, which include not only surface structures of foreign cells (for example bacteria) but also artificial surfaces such as vascular prostheses, stents and extracorporeal circuits. Activation of factor ΧΠ (FXII) to factor Xüa first activates on the surface, activating cellI factor XI to factor XIa. This leads, as described above, to further activation of the coagulation cascade. In addition, factor Xlla also activates bound plasma pro-kallikrein to plasma kallikrein (PK) which, on the one hand, leads to further factor XII activation in a potentiation loop, resulting in an overall increase in the initiation of the coagulation cascade. In addition, PK is an important bradikinin-releasing protease, which among other things leads to an increase in endothelial permeability. Other substrates described include prorenin and prourokinase, whose activation may affect the regulatory processes of the renin-angiotensin system and fibrinolysis. Thus, the activation of PK is an important link between coagulative and inflammatory processes.

An uncontrolled activation of the coagulation system or a defective inhibition of the activation processes can cause the formation of local thromboses or embolisms in vessels (arteries, veins, lymphatics) or cardiac cavities. In addition, systemic hypercoagulability can lead to system-wide thrombus formation and eventually to consumption coagulopathy in the context of disseminated intravascular coagulation. Thromboembolic complications may also be found in extracorporeal blood circuits such. B. during hemodialysis, as well as in vascular or heart valve prostheses and stents occur.

In the course of many cardiovascular and metabolic diseases systemic factors, such as hyperlipidemia, diabetes or smoking, due to blood flow changes with stasis, such as in atrial fibrillation, or due to pathological vascular wall changes, eg endothelial dysfunction or atherosclerosis, lead to an increased tendency of coagulation and platelet activation. This undesirable and excessive activation of coagulation can lead to thromboembolic diseases and thrombotic complications with life-threatening conditions by formation of fibrin and platelet-rich thrombi. In this case, inflammatory processes may be involved. Thromboembolic diseases therefore remain among the most common causes of morbidity and mortality in most industrialized countries Countries.

The anticoagulants known in the art, i. Substances for inhibiting or preventing blood clotting have various disadvantages. An efficient treatment method or prophylaxis of thrombotic / thromboembolic diseases therefore proves to be very difficult and unsatisfactory in practice.

In the therapy and prophylaxis of thromboembolic diseases, on the one hand heparin is used, which is administered parenterally or subcutaneously. Due to more favorable pharmacokinetic properties, although increasingly low molecular weight heparin is nowadays increasingly preferred; However, this also the known disadvantages described below can not be avoided, which consist in the therapy with heparin. Thus, heparin is orally ineffective and has only a comparatively low half-life. In addition, there is a high risk of bleeding, in particular cerebral hemorrhage and bleeding may occur in the gastrointestinal tract, and it can lead to thrombocytopenia, alopecia medicomentosa or osteoporosis. Although low molecular weight heparins have a lower probability of developing heparin-induced thrombocytopenia, they can only be administered subcutaneously. This also applies to fondaparinux, a synthetically produced, selective factor Xa inhibitor with a long half-life.

A second class of anticoagulants are the vitamin K antagonists. These include, for example, 1,3-indandiones, but especially compounds such as warfarin, phenprocoumon, dicumarol and other coumarin derivatives, which are unsuitable for the synthesis of various products of certain vitamin K-dependent coagulation factors in the liver. Due to the mechanism of action, the effect is only very slow (latency until the onset of action 36 to 48 hours). Although the compounds can be administered orally, because of the high risk of bleeding and the narrow therapeutic index but a complex individual attitude and observation of the patient is necessary. In addition, other side effects such as gastrointestinal disturbances, hair loss and skin necrosis are described.

More recent approaches to oral anticoagulants are at various stages of clinical trials and clinical trials, and have demonstrated efficacy in several studies. However, bleeding complications may occur even with the use of these drugs, especially in predisposed patients. Therefore, in the case of antithrombotic drugs, the therapeutic range is of central importance: The distance between the therapeutically effective dose for anticoagulation and the dose at which bleeding can occur should be as large as possible so that maximum therapeutic efficacy is achieved with minimal risk profile. In various in vitro and in vivo models with, for example, antibodies as factor XIa inhibitors, but also in factor XIa knockout models, the anti-thrombotic effect was demonstrated with little prolongation of bleeding time or increase in blood volume. In clinical studies, increased factor XIa levels were associated with an increased event rate. In contrast, factor XI deficiency (hemophilia C) did not lead to spontaneous bleeding and was only noticeable during surgery and trauma, but showed protection against certain thromboembolic events.

In addition, plasma kallikrein (PK) is associated with other diseases associated with increased vascular permeability or chronic inflammatory diseases, e.g. in diabetic retinopathy, macular edema and hereditary angioedema or inflammatory bowel disease. The diabetic retinopathy is based primarily on a microvascular weakness, resulting in a basal membrane thickening of the vessels and the loss of vascular sheathing pericytes, later vascular occlusion with retinal ischemia, which due to the induced retinal hypoxia to increased vascular permeability with subsequent training of a Macular edema and, due to all the processes involved, may lead to blindness of the patient. In hereditary angioedema (HAE), reduced formation of the physiological kallikrein inhibitor Cl-esterase inhibitor leads to uncontrolled plasma kallikrein activation and thus inflammation with fulminant edema formation and severe pain. From animal experiments there is evidence that the inhibition of plasma kallikrein inhibits the increased vascular permeability and thus can prevent the formation of macular edema or diabetic retinopathy or improve the acute symptoms of HAE. Oral plasma kallikrein inhibitors could also be used to prevent HAE. In the progression of chronic inflammatory bowel disease (IBD), the kinakines generated by plasma kallikrein play a major role. Their pro-inflammatory effect via activation of bradykinin receptors induces and potentiates the disease process. Studies in Crohn's disease patients show a correlation between the kallikrein concentration in the intestinal epithelium and the degree of intestinal inflammation. Activation of the kallikrein-kinin system has also been observed in animal studies. An inhibition of bradykinin synthesis by kallikrein inhibitors could therefore also be used for the prophylaxis and / or treatment of inflammatory bowel disease.

Furthermore, the combination of antithrombotic and antiinflammoric principles may be particularly attractive for many diseases to increase the mutual amplification of To prevent coagulation and inflammation.

An object of the present invention is therefore to provide novel compounds for the treatment of cardiovascular diseases, in particular thrombotic or thromboembolic diseases, and / or edematous diseases, and / or ophthalmological diseases, in particular diabetic retinopathy or macular edema, in humans and Animals that have a broad therapeutic range.

WO 2006/030032 describes inter alia substituted pyridinones as allosteric modulators of the mGluR2 receptor and WO 2008/079787 describes substituted pyridin-2-ones and their use as glucokinase activators. WO 2014/154794, WO 2014/160592, WO 2015/011087 and WO 2015/063093 describe substituted oxopyridine derivatives as factor XIa inhibitors for the treatment of thromboses.

The invention relates to compounds of the formula

in which

R is a group of the formula

where * is the point of attachment to the oxopyridine ring,

R ^{6 is} chlorine, cyano, difluoromethyl or difluoromethoxy,

R 'is hydrogen or fluorine,

R ^{2 is} chlorine or methoxy, is ethyl, wherein ethyl is substituted with a substituent selected from the group consisting of tert-butoxy, iso-propoxy, C3-C6 cycloalkyloxy and 4- to 6-membered oxo-heterocyclyloxy, wherein tert-butoxy and iso-propoxy substituted may be substituted with 1 to 3 fluorine substituents, and wherein cycloalkyloxy and oxo-heterocyclyloxy may be substituted with 1 to 2 substituents independently selected from the group consisting of fluorine and methyl, represents hydrogen, represents a group of formula

where # is the point of attachment to the nitrogen atom,

R ^{9 is} hydroxycarbonyl, R ^{10 is} hydrogen or fluorine, and their salts, their solvates and the solvates of their salts.

Compounds of the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, as well as those of formula (I), hereinafter referred to as embodiment (e) and their salts, solvates and solvates of the salts, as far as the compounds of formula (I) mentioned below are not already salts, solvates and solvates of the salts.

Depending on their structure, the compounds according to the invention can exist in different stereoisomeric forms, ie in the form of configuration isomers or given also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers). The present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.

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

The present invention also includes all suitable isotopic variants of the compounds according to the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound of 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 0, ¹⁸ 0, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic variants of a compound of the invention, such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with ³ H or ¹⁴ C isotopes are particularly suitable for this purpose. In addition, the incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as an increase in half-life in the body or a reduction in the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by the methods known to the person skilled in the art, for example by the methods described below and the rules reproduced in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.

Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. But are also included salts that are not suitable for pharmaceutical applications but for example for the isolation or purification of the Compounds according to the invention can be used.

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

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms. Atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, -methylmorpholine, arginine, lysine, ethylenediamine, -methylpiperidine and choline. Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water.

In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" includes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically).

For the purposes of the present invention, the term "treatment" or "treating" includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the course or progression of such conditions and / or the symptoms of such conditions. The term "therapy" is understood to be synonymous with the term "treatment".

The terms "prevention", "prophylaxis" or "prevention" are used interchangeably in the context of the present invention and denote the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or the symptoms of such conditions get to know, to suffer or to have.

The treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.

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

Cycloalkyl represents a monocyclic cycloalkyl group having 3 to 6 carbon atoms, by way of example and preferably cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Cycloalkyloxy is a monocyclic cycloalkyl group which is bonded via an oxygen atom having 3 to 6 carbon atoms, by way of example and preferably cycloalkyloxy may be mentioned cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.

4- to 6-membered oxo-heterocyclyloxy in the definition of the radical R ³ is a saturated monocyclic radical having 4 to 6 ring atoms, in which a ring atom is an oxygen atom and which is bonded via an oxygen atom, by way of example and preferably for oxetanyloxy, tetrahydrofuranyloxy and tetrahydro-2H-pyranyloxy.

In the formulas of the group which can stand for R ¹ , the end point of the line next to each one * does not represent a carbon atom or a CEh group but is part of the bond to the atom to which R ^{1 is} attached ,

In the formulas of the group which can stand for R ⁵ , the end point of the line next to each of which represents a is not a carbon atom or a CEL group but is part of the bond to the atom to which R ^{5 is} bonded ,

Preference is given to compounds of the formula (I) in which

R ^{1 is} a group of the formula

where * is the point of attachment to the oxopyridine ring, is chlorine, cyano or difluoromethoxy,

R 'is hydrogen, is methoxy, ethyl, wherein ethyl is substituted with a substituent selected from the group consisting of tert-butoxy, iso-propoxy and cyclobutyloxy, wherein cyclobutyloxy may be substituted by a methyl substituent, is hydrogen , for a group of the formula

where # is the point of attachment to the nitrogen atom, is hydroxycarbonyl,

R 10 is hydrogen, and their salts, their solvates and the solvates of their salts.

Preference is also given to compounds of the formula (I) in which

R is a group of the formula

stands, where * is the point of attachment to the oxopyridine ring, R ^{6 is} chlorine, R ^{7 is} cyano or difluoromethoxy, R ^{8 is} hydrogen, R ^{2 is} methoxy, R ^{3 is} ethyl, wherein ethyl is substituted with a substituent selected from the group consisting of tert-butoxy, iso-propoxy and cyclobutyloxy,

R ^{4 is} hydrogen, R ^{5 is} a group of the formula

where # is the point of attachment to the nitrogen atom,

R ^{9 is} hydroxycarbonyl,

R ^{10 is} hydrogen, and their salts, their solvates and the solvates of their salts. Preference is also given to compounds of the formula (I) in which R ^{1 is} a group of the formula

stands, where * is the point of attachment to the oxopyridine ring,

R ^{6 is} chlorine,

R ^{7 is} cyano,

R ^{8 is} hydrogen. Preference is also given to compounds of the formula (I) in which R ^{3 is} ethyl, where ethyl is substituted by one substituent tert-butoxy.

Preference is also given to compounds of the formula (I) in which R ^{3 is} ethyl, where ethyl is substituted by one substituent cyclobutyloxy.

Preference is also given to compounds of the formula (I) in which R ^{3 is} ethyl, where ethyl is substituted by a substituent cyclobutyloxy, in which cyclobutyloxy may be substituted by a substituent methyl.

Preference is also given to compounds of the formula (I) in which R ^{3 is} ethyl, where ethyl is substituted by a substituent 1-methylcyclobutyloxy.

Preference is also given to compounds which have the formula (Ia)

wherein R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined above.

The invention further provides a process for the preparation of the compounds of the formula (I), or their salts, their solvates or the solvates of their salts, wherein

[A] the compounds of the formula

(Ha), in which

R ¹ , R ² , R ³ , R ⁴ and R ^{10 have} the abovementioned meaning, and

R ^{14 is} tert-butyl,

with an acid to compounds of the formula

in which

R ^L , R ² , R ³ , R ⁴ and R ¹⁰ are as defined above and R ^{9 is} hydroxycarbonyl,

to be implemented

or

[B] the compounds of the formula

in which

R ¹ , R ² , R ³ , R ⁴ and R ^{10 have} the abovementioned meaning, and

R ^{14 is} methyl or ethyl,

with a base to compounds of the formula in which

R ¹ , R ² , R ³ , R ⁴ and R ¹⁰ are as defined above, and R ^{9 is} hydroxycarbonyl, are reacted.

The compounds of the formulas (IIa) and (Hb) together form the amount of the compounds of the formula (II).

The reaction according to process [A] is generally carried out in inert solvents, preferably in a temperature range from room temperature to 60 ° C at atmospheric pressure. Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, or ethers such as tetrahydrofuran or dioxane, preferably dichloromethane.

Acids are for example trifluoroacetic acid or hydrogen chloride in dioxane, preferred is trifluoroacetic acid. The reaction according to process [B] is generally carried out in inert solvents, preferably in a temperature range from room temperature to reflux of the solvent under normal pressure.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, alcohols such as methanol or ethanol, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dimethylformamide , Dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents, or mixtures of solvent with water, preferred is a mixture of tetrahydrofuran and water or a mixture of methanol and water. Bases are, for example, alkali metal hydroxides such as sodium, lithium or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or alcoholates such as potassium or sodium tert-butoxide, preferably lithium hydroxide or cesium carbonate.

The compounds of the formula (II) are known or can be prepared by reacting compounds of the formula

in which

R ¹ , R ² and R ^{3 have} the abovementioned meaning, with compounds of the formula

in which

R ⁴ and R ^{10 have} the abovementioned meaning, and

R ^{14 is} methyl, ethyl or tert-butyl, are reacted in the presence of a dehydrating reagent. The reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to room temperature at atmospheric pressure.

Examples of suitable dehydrating reagents include carbodiimides such as Ν, Ν'-diethyl, / V, / V'-dipropyl, / V, / V'-diisopropyl, A ^ 'dicyclohexylcarbodiimide, / V- (3-dimethylamino - isopropyl) - / V'-ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), cyclohexylcarbodiimide '-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2- Oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline , or propanophosphonic anhydride, or isobutyl chloroformate, or bis (2-oxo-3-oxazolidinyl) -phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or 0- (benzotriazole-yl) -NNN N4-tetra-methyluronium hexafluorophosphate ( HBTU), 2- (2-oxo-l- (2H) -pyridyl) -1,3,3-tetramethyluronium tetrafluoroborate (TPTU), (benzotriazol-1-ylxy) bis-dimethylamino-methylium-fluoroborate (TBTU) or (^ - ( T-azabenzotriazole-1'- / V'- / V'-tetramethyl-uronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP ), or mixtures thereof, with bases Preferably, the condensation is carried out with HATU.

Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines, e.g. Triethylamine, -methylmorpholine, / V-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine. Preferably, the condensation is carried out with diisopropylethylamine. Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane or trichloromethane, hydrocarbons, such as benzene, or other solvents, such as nitromethane, dioxane, dimethylformamide, dimethyl sulfoxide or acetonitrile. It is likewise possible to use mixtures of the solvents. Particularly preferred is dimethylformamide.

The compounds of formula (IV) are known or can be synthesized by known methods from the corresponding starting compounds.

The compounds of formula (III) are known or can be prepared by

[C] Compounds of the formula

in which

R ¹ , R ² and R ^{3 have} the abovementioned meaning, and

R 15 is tert-butyl, reacted with an acid, or

[D] Compounds of the formula

in which R ¹ , R ² and R ^{3 have} the abovementioned meaning, and

R 15 is methyl, ethyl or benzyl, are reacted with a base.

The compounds of formulas (Va) and (Vb) together form the amount of compounds of formula (V).

The reaction according to method [C] is carried out as described for method [A].

The reaction according to process [D] is carried out as described for process [B].

The compounds of the formula (V) are known or can be prepared by reacting compounds of the formula

in which

R ¹ and R ^{2 have} the meaning given above, and

R 15 is methyl, ethyl, benzyl or tert-butyl, with compounds of the formula

R ^' (VII), in which

R ^{3 has} the meaning given above, and

X is chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy or para-toluenesulfonyloxy.

The reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from -78 ° C. to room temperature at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, alcohols such as methanol or ethanol, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dimethylformamide , Dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents, or mixtures of solvent with water, preferred is tetrahydrofuran. Examples of bases are potassium or sodium tert-butylate, sodium hydride, n-butyl lithium or bis (trimethylsilyl) lithium amide; bis (trimethylsilyl) lithium amide is preferred.

The compounds of the formula (VII) are known, can be synthesized by known processes from the corresponding starting compounds or can be prepared analogously to the processes described in the Examples section. The compounds of the formula (VI) are known or can be prepared by reacting compounds of the formula

in which

R ¹ and R ^{2 have} the abovementioned meaning, with compounds of the formula in which

R 15 is methyl, ethyl, benzyl or tert-butyl, and

X ^{2 is} chloro, bromo, iodo, methanesulphonyloxy or trifluoromethanesulphonyloxy.

The reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from room temperature to reflux of the solvents under atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, alcohols such as methanol or ethanol, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dimethylformamide , Dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents, or mixtures of solvent with water, preferred is dimethylformamide. Bases are, for example, alkali metal hydroxides such as sodium, lithium or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or potassium or sodium tert-butoxide, sodium hydride or a mixture of these bases or a mixture of sodium hydride and lithium bromide, is preferred Potassium carbonate or sodium hydride.

The compounds of formula (IX) are known or can be synthesized by known methods from the corresponding starting compounds.

The compounds of the formula (VIII) are known or can be prepared by reacting compounds of the formula

in which R ¹ and R ^{2 have} the abovementioned meaning, be reacted with pyridinium hydrochloride or pyridinium hydrobromide.

The reaction is generally carried out in inert solvents, preferably in a temperature range from 80 ° C to 120 ° C at atmospheric pressure.

Inert solvents are, for example, hydrocarbons, such as benzene, or other solvents, such as nitromethane, dioxane, dimethylformamide, dimethyl sulfoxide or acetonitrile. It is likewise possible to use mixtures of the solvents. Particularly preferred is dimethylformamide.

The compounds of the formula (X) are known or can be prepared by reacting compounds of the formula

in which

R ^{2 has} the meaning given above, and

Q ^{1 is} -B (OH) ₂ , a boronic acid ester, preferably boronic acid pinacol ester, or -BF ₃ ^~ K ⁺ , with compounds of the formula

R-X ³ (XII), in which

R ^{1 has} the meaning given above, and

X ^{3 is} chlorine, bromine or iodine, are reacted under Suzuki coupling conditions.

The reaction is generally carried out in inert solvents, in the presence of a catalyst, optionally in the presence of an additional reagent, optionally in a microwave, preferably in a temperature range from room temperature to 150 ° C at atmospheric pressure to 3 bar. Catalysts are for example customary for Suzuki reaction conditions palladium catalysts, preference is given to catalysts such as dichlorobis (triphenylphosphine) palladium, tetrakistriphenylphosphinepalladium (O), palladium (II) acetate / triscyclohexylphosphine, tris (dibenzylideneacetone) dipalladium, bis (diphenylphosphanferrocenyl) palladium - (II) chloride, l, 3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene (1,4-naphthoquinone) palladium dimer, allyl (chloro) - (1,3-dimesityl-l, 3-dihydro -2H-imidazol-2-ylidene) palladium, palladium (II) acetate / dicyclohexyl- (2 ', 4', 6'-triisopropyl-biphenyl-2-yl) -phosphine, [1, 1-bis (diphenylphosphino) ferrocene] - palladium (II) chloride monodichloromethane adduct or XPhos precatalyst [(2'-aminobiphenyl-2-yl) (chloro) palladium dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (1: 1)], preferably tetrakistriphenylphosphine palladium (O), [l, l-bis (diphenylphosphino) ferrocene] - palladium (II) chloride monodichloromethane adduct or XPhos precatalyst [(2'-aminobiphene) yl-2-yl) (chloro) palladium-dicyclohexyl (2 ', 4', 6'-triisopropyl-biphenyl-2-yl) -phosphine (1: 1)].

Additional reagents are for example potassium acetate, cesium, potassium or sodium carbonate, potassium tert-butoxide, cesium fluoride or potassium phosphate, which may be present in aqueous solution, preference is given to additional reagents such as potassium carbonate or aqueous potassium phosphate solution.

Inert solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons, such as benzene, xylene or toluene, or carboxamides, such as dimethylformamide or dimethylacetamide, alkylsulfoxides, such as dimethylsulfoxide, or N-methylpyrrolidone or acetonitrile, or mixtures of the solvents with alcohols, such as methanol or ethanol and / or water, preferred is tetrahydrofuran, dioxane or acetonitrile.

The compounds of formulas (XI) and (ΧΠ) are known or can be synthesized by known methods from the corresponding starting compounds.

The preparation of the starting compounds and the compounds of the formula (I) can be illustrated by the following synthesis scheme.

The compounds of the invention show an unpredictable, valuable pharmacological activity spectrum and a good pharmacokinetic behavior. These are compounds which influence the proteolytic activity of the serine protease factor XIa (FXIa) and / or the serine protease plasma kallikrein (PK). The compounds of the present invention inhibit FXIa and / or PK catalyzed enzymatic cleavage of substrates that play important roles in activating blood clotting, platelet aggregation via reduction of thrombin required for PAR-1 activation of platelets, and in inflammatory processes in particular, including an increase in vascular permeability.

They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.

Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular cardiovascular diseases, preferably thrombotic or thromboembolic diseases and / or thrombotic or thromboembolic complications, and / or ophthalmological diseases, in particular of diabetic retinopathy or macular edema, and / or inflammatory diseases, especially those associated with excessive plasma kallikrein activity, such as hereditary angioedema (HAE) or chronic inflammatory diseases, especially of the intestine, such. Crohn's disease.

Factor XIa (FXIa) is an important coagulation enzyme that can be activated by both thrombin and factor XIIa (FXIIa), and is thus involved in two major processes of coagulation: it is a central component of the transition from initiation to coagulation Amplification and propagation of coagulation: Thrombin activated in positive feedback loops in addition to Factor V and Factor VIII and Factor XI to Factor XIa, the factor ΓΧ to Factor Ka converts and the thus generated factor Ka / Factor VIIIa complex the Factor X activation and thus in turn, strongly stimulates thrombin generation, leading to severe thrombus growth and stabilizing the thrombus.

In addition, factor XIa is an important component of the intrinsic initiation of coagulation: In addition to stimulation via tissue factor (TF), the activation of the coagulation system can also be carried out on particularly negatively charged surfaces, which include not only surface structures of foreign cells (eg bacteria) but also artificial surfaces such as vascular prostheses, stents and extracorporeal circuits. On the surface, activation of factor ΧΠ (FXII) to factor XIIa (FXIIa) first occurs, which subsequently activates cell surface-bound FXI to FXIa. This leads, as described above, to further activation of the coagulation cascade.

In contrast, thrombin generation in the initiation phase via TF / factor VIIa and factor X activation and ultimately thrombin formation, the physiological response to vascular injury, remains unaffected. This may explain why no bleeding time extensions were found in FXIa knockout mice, as well as in rabbits and other species on FXIa inhibitor administration. This low bleed tendency caused by the substance is of great advantage for human use, especially in patients with an increased risk of bleeding.

In addition, factor XIIa also activates plasma pro-kallikrein into plasma kallikrein (PK) as part of intrinsic activation, which among other things leads to further factor ΧΠ activation in the context of a potentiation loop, resulting in an overall increase in the initiation of the coagulation cascade on surfaces. A PK-inhibiting activity of a compound according to the invention will therefore reduce the coagulation via surface activation and thus act anticoagulatory. An advantage could be the combination of factor XIa and PK inhibitory activity, which allows a balanced antithrombotic effect. The compounds according to the invention are therefore suitable for the treatment and / or prophylaxis of diseases or complications which may arise due to clot formation.

For the purposes of the present invention, "thrombotic or thromboembolic diseases" include diseases which occur both in the arterial and in the venous vascular bed and can be treated with the compounds according to the invention, in particular diseases in the coronary arteries of the heart, such as acute coronary syndrome (ACS). , Heart attack with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusions and restenosis after coronary interventions such as angioplasty, stent implantation or aortocoronary bypass, but also thrombotic or thromboembolic Diseases in other vessels leading to peripheral arterial occlusive diseases, pulmonary embolism, venous thromboembolism, venous thrombosis, especially in deep leg veins and renal veins, transient ischemic attacks as well as thrombotic stroke and thromboembolic stroke Stimulation of the coagulation system can be caused by various causes or comorbidities. Among other things, in the context of surgical interventions, immobility, bed-rest, infections, inflammation or cancer or cancer therapy, the coagulation system can be greatly stimulated and there are thrombotic complications, especially venous thrombosis come. The compounds according to the invention are therefore suitable for thrombosis prophylaxis in the context of surgical interventions in patients who have a cancer. The compounds according to the invention are therefore also suitable for thrombosis prophylaxis in patients with an activated coagulation system, for example under the stimulation situations described.

The compounds of the invention are therefore also useful in the prevention and treatment of cardiogenic thromboembolisms, such as brain ischemia, stroke and systemic thromboembolism and ischaemia, in patients with acute, intermittent or persistent cardiac arrhythmias, such as atrial fibrillation, and in patients undergoing cardioversion patients with valvular heart disease or with artificial heart valves. In addition, the compounds according to the invention are suitable for the treatment and prevention of disseminated intravascular coagulation (DIC), which occur, inter alia, in the context of sepsis, but also as a result of operations, tumor diseases, burns or other injuries and can lead to severe organ damage through microthromboses. Thromboembolic complications also occur in microangiopathic hemolytic anemias and by contact of the blood with extraneous surfaces within extracorporeal blood circuits, such as hemodialysis, extracorporeal membrane oxygenation (ECMO), left ventricular assist device (LVAD), and similar procedures. AV fistulas, vascular and heart valve prostheses.

In addition, the compounds according to the invention are suitable for the treatment and / or prophylaxis of diseases in which micro clots or fibrin deposits occur in brain vessels, which can lead to dementia diseases such as, for example, vascular dementia or Alzheimer's disease. In this case, the clot can contribute to the disease both via occlusions and via the binding of further disease-relevant factors.

In addition, the compounds according to the invention are particularly suitable for the treatment and / or prophylaxis of diseases in which not only the procoagulant but also the proinflammatory component plays an essential role. In particular, the mutual reinforcement of coagulation and inflammation can be prevented by the compounds according to the invention and therefore the probability of a thrombotic complication can be decisively reduced. Both the factor XIa-inhibitory component (via inhibition of thrombin production) and the PK-inhibitory component can contribute to the anticoagulant and anti-inflammatory action (for example via bradikinin). Therefore, inter alia, the treatment and / or prophylaxis in the context of atherosclerotic vascular diseases, inflammation in the context of rheumatic diseases of the musculoskeletal system, inflammatory diseases of the lung, such as pulmonary fibrosis, inflammatory diseases of the kidney, such as glomerulonephritis, inflammatory diseases of the intestine, such as Crohn's disease or ulcerative colitis, or diseases that may be present as part of a diabetic underlying disease, such as diabetic retinopathy or nephropathy into consideration.

In the progression of chronic inflammatory bowel disease (IBD), kinins generated by plasma kallikrein, among others, play a major role. Their pro-inflammatory effect via activation of bradykinin receptors induces and potentiates the disease process. Studies in Crohn's disease patients show a correlation between the kallikrein concentration in the intestinal epithelium and the degree of intestinal inflammation. Activation of the kallikrein-kinin system has also been observed in animal studies. An inhibition of bradykinin synthesis by kallikrein inhibitors could therefore also be used for the prophylaxis and / or treatment of inflammatory bowel disease. In addition, the compounds of the invention can be used to inhibit tumor growth and metastasis, and to prevent and / or treat thromboembolic complications such as venous thromboembolism in tumor patients, especially those undergoing major surgery or chemo- or radiotherapy.

In addition, the compounds according to the invention are also suitable for the prophylaxis and / or treatment of pulmonary hypertension.

The term "pulmonary hypertension" in the context of the present invention includes pulmonary arterial hypertension, pulmonary hypertension in diseases of the left heart, pulmonary hypertension in lung disease and / or hypoxia and pulmonary hypertension due to chronic thromboembolism (CTEPH).

"Pulmonary Arterial Hypertension" includes Idiopathic Pulmonary Arterial Hypertension (IPAH, formerly referred to as Primary Pulmonary Hypertension), Familial Pulmonary Arterial Hypertension (FPAH), and Associated Pulmonary Arterial Hypertension (AP AH), which is associated with collagenosis , congenital systemic pulmonary shunt veins, portal hypertension, HIV infections, the use of certain drugs and medications, with other diseases (thyroid disorders, glycogen storage diseases, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy), with diseases with a significant venous capillary involvement such as pulmonary veno-occlusive disease and pulmonary-capillary hemangiomatosis, as well as persistent pulmonary hypertension of newborns.

Pulmonary hypertension in left heart disease includes left atrial or ventricular disease and mitral or aortic valve failure.

Pulmonary hypertension in lung disease and / or hypoxia includes chronic obstructive pulmonary disease, interstitial lung disease, sleep apnea syndrome, alveolar hypoventilation, chronic altitude sickness, and plant-related malformations.

Pulmonary hypertension due to chronic thromboembolism (CTEPH) includes thromboembolic occlusion of proximal pulmonary arteries, thromboembolic occlusion of distal pulmonary arteries, and non-thrombotic pulmonary embolisms (tumor, parasites, foreign bodies). Another object of the present invention is the use of the compounds of the invention for the preparation of medicaments for the treatment and / or prophylaxis of pulmonary hypertension in sarcoidosis, histiocytosis X and Lymphangiomatosis.

In addition, the substances according to the invention are also suitable for the treatment of pulmonary and hepatic fibroses.

In addition, the compounds according to the invention also come for the treatment and / or prophylaxis of disseminated intravascular coagulation in the context of infectious disease and / or systemic inflammatory syndrome (SIRS), septic organ dysfunction, septic organ failure and multi-organ failure, acute respiratory distress syndrome (ARDS), acute lung Injury (ALI), septic shock and / or septic organ failure.

In the course of an infection, there may be generalized activation of the coagulation system ("Disseminated Intravascular Coagulation", or "Consumption Coagulopathy", hereinafter referred to as "DIC") with microthrombosis in various organs and secondary bleeding complications. In addition, endothelial damage can result in increased vascular permeability and leakage of fluid and proteins into the extravasal space. Subsequently, organ failure (e.g., renal failure, liver failure, respiratory failure, CNS deficits and cardiovascular failure) or multiple organ failure may occur.

DIC causes massive activation of the coagulation system on the surface of damaged endothelial cells, foreign body surfaces or cross-linked extravascular tissue. As a result, coagulation occurs in small vessels of various organs with hypoxia and subsequent organ dysfunction. Secondarily, coagulation factors (eg Factor X, prothrombin and fibrinogen) and platelets are consumed, reducing the blood's ability to coagulate and causing severe bleeding. Compounds of the invention which inhibit plasma kallikrein alone or in combination with factor XIa are additionally contemplated for the treatment and / or prophylaxis of diseases in the course of which plasma kallikrein is involved. In addition to anticoagulant activity, plasma kallikrein is an important bradikinin-releasing protease, thus leading inter alia to an increase in endothelial permeability. The compounds can thus be used for the treatment and / or prophylaxis of diseases associated with edema formation, such as, for example, ophthalmological diseases, in particular diabetic retinopathy or macular edema, or hereditary angioedema. For the purposes of the present invention, "ophthalmological diseases" include in particular diseases such as diabetic retinopathy, diabetic macular edema (DME), macular edema, macular edema associated with retinal venous occlusion, age-related macular degeneration (AMD), choroidal neovascularization (CNV), choroidal neovascular membranes (CNVM), cystoid macular edema (cystoid macula edema, CME), epiretinal membranes (ERM) and macular perforations, myopia-associated choroidal neovascularization, angioid or vascular streaks, retinal detachment, atrophic Changes in the retinal pigment epithelium, hypertrophic changes in the retinal pigment epithelium, retinal venous occlusion, choroidal retinal venous occlusion, retinitis pigmentosa, Stargardt's disease, prematurity retinopathy, glaucoma, inflammatory diseases of the eye such as uveitis, scleritis or endophthalmitis Cataract, refractive anomalies such as myopia, hyperopia or astigmatism and keratoconus, diseases of the anterior eye such as corneal angiogenesis as a result of eg keratitis, corneal transplantation or keratoplasty, corneal angiogenesis as a result of hypoxia (eg by prolonged wearing of contact lenses), Pterygium conjunctivae, subcorneal edema and intracorneal edema.

Furthermore, the compounds of the invention for primary prophylaxis of thrombotic or thromboembolic diseases and / or inflammatory diseases and / or diseases with increased vascular permeability in patients in question in which gene mutations lead to increased activity of the enzymes or increased levels of zymogens and these by appropriate tests / measurements of the Enzyme activity or zymogen concentrations are detected.

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

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

Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using a therapeutically effective amount of a compound of the invention.

Another object of the present invention are the compounds of the invention for use in a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using a therapeutically effective amount of a compound of the invention.

Another object of the present invention are pharmaceutical compositions containing a compound of the invention and one or more other active ingredients. In addition, the compounds of the invention may also be used to prevent coagulation ex vivo, e.g. to protect organs to be transplanted from organ damage caused by clot formation and to protect the organ recipient from thromboemboli from the transplanted organ, to preserve blood and plasma products, to clean / pretreat catheters and other medical devices and devices, to coat artificial surfaces of medical devices and equipment used in vivo or ex vivo, or biological samples that might contain factor XIa or plasma kallikrein.

Another object of the present invention is a method for the prevention of blood coagulation in vitro, in particular in blood or biological samples containing factor XIa or plasma kallikrein or both enzymes, which is characterized in that an anticoagulatory effective amount of the compound of the invention is added.

Another object of the present invention are pharmaceutical compositions containing a compound of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases. As suitable combination active ingredients may be mentioned by way of example and preferably:

Lipid-lowering drugs, in particular HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors such as lovastatin (Mevacor), simvastatin (Zocor), pravastatin (pravachol), fluvastatin (Lescol) and atorvastatin (Lipitor) ;

Coronary / vasodilators, in particular ACE (angiotensin converting enzyme) inhibitors such as captopril, lisinopril, enalapril, ramipril, cilazapril,

Benazepril, fosinopril, quinapril and perindopril, or AII (angiotensin II) receptor antagonists such as embusartan, losartan, valsartan, irbesartan, candesartan, eprosartan and temisarta, or beta-adrenoceptor antagonists such as carvedilol, alprenolol, bisoprolol, acebutolol , Atenolol, betaxolol, carteolol, metoprolol, nadolol, penbutolol, pindolol, propranolol and timolol, or alpha 1-adrenoceptor antagonists such as prazosin, bunazosin, doxazosin and terazosin, or diuretics such as hydrochlorothiazide, furosemide, bumetanide, piretanide, torasemide , Amiloride and dihydralazine, or calcium channel blockers such as verapamil and diltiazem, or dihydropyridine derivatives such as nifedipine (adalate) and nitrendipine (bayotensin), or nitro preparations such as isosorbide-5-mononitrate, isosorbide dinitrate and glycerol trinitrate, or substances containing a Increase cyclic guanosine monophosphate (cGMP), such as, for example, stimulators of soluble guanylate cyclase, such as riociguat;

Plasminogen activators (thrombolytics / fibrinolytics) and thrombolysis / fibrinolysis-enhancing compounds such as inhibitors of plasminogen activator inhibitor (PAI inhibitors) or inhibitors of thrombin-activated fibrinolysis inhibitor (TAFI inhibitors) such as tissue plasminogen activator ( t-PA, such as Actilyse ^®), streptokinase, reteplase and urokinase or plasminogen modulating substances that lead to increased plasmin formation; anticoagulant substances (anticoagulants) such as heparin (UFH), low molecular weight heparin (LMWH) such as tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE 5026), adomiparin (Ml 18) and EP-42675 / ORG42675; direct thrombin inhibitors (DTI) such as Pradaxa (Dabigatran), Atecegatran (AZD-0837), DP-4088, SSR-182289A, argatroban, bivalirudin, and Tanogitran (BIBT-986 and prodrug BITT-1011), hirudin; direct factor Xa inhibitors such as rivaroxaban, apixaban, edoxaban (DU-176b), betrixaban (PRT-54021), R-1663, darexaban (YM-150), otamixaban (FXV-673 / RPR-130673), letaxaban (TAK -442), razaxaban (DPC-906), DX-9065a, LY-517717, tanogitran (BIBT-986, prodrug: BITT-1011), idraparinux and fondaparinux, platelet aggregation inhibiting agents (platelet aggregation inhibitors), such as aspirin ), P2Y12 antagonists such as ticlopidine (ticlid), clopidogrel (Plavix), prasugrel, ticagrelor, cangrelor, elinogrel, PAR-1 antagonists such as vorapaxar, PAR-4 antagonists, EP3 antagonists such as DG041;

Platelet adhesion inhibitors such as GPVI and / or GPIb antagonists such as Revacept or Caplacizumab;

Fibrinogen receptor antagonists (glycoprotein-iib / IHa antagonists) such as abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban and fradafiban; Recombinant human activated protein C such as xigris or recombinant thrombomodulin;

• as well as antiarrhythmics;

Inhibitors of VEGF and / or PDGF signaling pathways such as aflibercept, ranibizumab, bevacizumab, KH-902, pegaptanib, ramucirumab, squalamine, or

Bevasiranib, apatinib, axitinib, brivanib, cediranib, dovitinib, lenvatinib, linifanib, motesanib, pazopanib, regorafenib, sorafenib, sunitinib, tivozanib, vandetanib, vatalanib, vargatef and E-10030;

Inhibitors of Angiopoietin-Tie signaling pathways such as AMG386; · Inhibitors of Tie2 receptor tyrosine kinase;

Inhibitors of integrin signaling pathways such as volociximab, cilengitide, and ALG1001;

Inhibitors of PI3K Akt-mTor signaling pathways such as XL-147, perifosine, MK2206, sirolimus, temsirolimus and everolimus;

Corticosteroid such as anecortave, betamethasone, dexamethasone, triamcinolone, fluocinolone and fluocinolone acetonide;

• inhibitors of the ALKl-Smadl / 5 signaling pathway, such as ACE041;

Cyclooxygenase inhibitors such as bromfenac and nepafenac;

Inhibitors of the kallikrein kinin system such as safotibant and ecallantide;

Inhibitors of sphingosine-1-phosphate signaling pathways such as sonepcizumab; · Inhibitors of the complement C5a receptor such as eculizumab;

Inhibitors of the 5HTla receptor, such as tandospirone;

• inhibitors of the Ras-Raf-Mek-Erk signaling pathway; Inhibitor of MAPK signaling pathways; Inhibitors of FGF signaling pathways; Inhibitor of endothelial cell proliferation; Apoptosis-inducing agents;

Photodynamic therapy consisting of an active substance and the action of light, the active substance being, for example, verteporfin. "Combinations" in the sense of the invention not only pharmaceutical forms containing all components (so-called. Fixed combinations) and combination packs containing the components separated from each other understood, but also simultaneously or temporally staggered applied components, if they are for prophylaxis and / or It is also possible to combine two or more active substances with each other, that is to say two or more combinations in each case.

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

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

For the oral administration are according to the prior art functioning rapidly and / or modified compounds of the invention donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules ), Dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the extraocular (topical) application are according to the prior art functioning fast and / or modified or controlled release the drug application forms containing the active ingredient in crystalline and / or amorphized and / or dissolved form, such as eye drops, sprays and lotions (eg solutions, suspensions, vesicular / colloidal systems, emulsions, aerosols), powder for eye drops, sprays and lotions (eg milled active ingredient, mixtures, lyophilisates, precipitated active substance), semi-solid eye preparations (eg hydrogels, in-situ hydrogels, creams and ointments), eyeliners (solid and semi-solid preparations, eg bioadhesives, films / wasters, tablets, contact lenses).

The intraocular administration comprises e.g. intravitreal subretinal, subscleral, intrachoroidal, subconjunctival, retrobulbar and subtenal administration. For the intraocular administration are according to the state of the art functioning fast and / or modified or controlled drug-releasing application forms containing the active ingredient in crystalline and / or amorphized and / or dissolved form, such. Injections and concentrates for injections (eg solutions, suspensions, vesicular colloidal systems, emulsions, powders for injections (eg milled active ingredient, mixtures, lyophilisates, precipitated active substance), gels for injections (semi-solid preparations, eg hydrogels, in-situ hydrogels) and implants (solid preparations, eg biodegradable and non-biodegradable implants, implantable pumps).

Oral application or, in the case of ophthalmological diseases, extraocular and intraocular administration is preferred. For the other routes of administration are suitable, for example Inhalation medicines (including powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, Pastes, foams, scattering powders, implants or stents.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitol oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (For example, albumin), stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous. Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, preferably together with one or more inert non-toxic, pharmaceutically suitable excipient, as well as their use for the purposes mentioned above. In general, it has been found to be beneficial to administer amounts of about 5 to 250 mg per 24 hours when administered parenterally to achieve effective results. When administered orally, the amount is about 5 to 500 mg per 24 hours.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out.

The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume. The term "w / v" means "weight / volume". Thus, for example, "10% w / v" means: 100 ml of solution or suspension contains 10 g of substance.

A) Examples

Abbreviations:

Boc tert. butyloxycarbonyl

about circa

d day (s), doublet (by NMR)

TLC thin layer chromatography

DCM dichloromethane

DCI direct chemical ionization (in MS)

dd double doublet (by NMR)

DIEA -diisopropylethylamine

DMF N, -dimethylformamide

DMSO dimethyl sulfoxide

d. Th. Of theory (at yield)

eq. Equivalent (s)

ESI electrospray ionization (in MS)

h hour (s)

HATU 0- (7-azabenzotriazol-1-yl) - / V, / V, / V ', / V'-tetramethyluronium hexafluorophosphate

HPLC high pressure, high performance liquid chromatography

HV high vacuum

LC-MS liquid chromatography-coupled mass spectrometry

m multiplet (by NMR)

min minute (s)

MS mass spectroscopy

NMR nuclear magnetic resonance spectroscopy

Oxime Hydroxyiminocyanoacetic acid ethyl ester

q Quartet or Quadruple «(by NMR)

quant. quantitatively

quin quintet (by NMR)

RP reverse phase (on HPLC)

RT room temperature

Retention time (on HPLC)

s singlet (by NMR)

sxt sextet (by NMR)

SFC supercritical liquid chromatography (with supercritical Carbon dioxide as mobile phase)

t triplet (by NMR)

THF tetrahydrofuran

TFA trifluoroacetic acid

T3P 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide

HPLC. LC / MS and GC methods:

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

Method 2: Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ 50 mm x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 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 3: Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 μ 50 mm x 1 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 97% A-> 0.5 min 97% A -> 3.2 min 5% A -> 4.0 min 5% A; Oven: 50 ° C; Flow: 0.3 ml / min; UV detection: 210 nm. Method 4: Instrument MS: Waters (Micromass) Quattro Micro; Instrument HPLC: Agilent 1100 series; Column: YMC-Triart C18 3μ 50 mm x 3 mm; Eluent A: 1 l of water + 0.01 mol of ammonium carbonate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 100% A-> 2.75 min 5% A-> 4.5 min 5% A; Oven: 40 ° C; Flow: 1.25 ml / min; UV detection: 210 nm.

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

Method 6: Instrument MS: Waters (Micromass) ZQ; Instrument HPLC: Agilent 1100 series; Column: Agient ZORBAX Extend-C18 3.0mm x 50mm 3.5-micron; Eluent A: 1 l of water + 0.01 mol of ammonium carbonate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 98% A-> 0.2 min 98% A-> 3.0 min 5% A ^ 4.5 min 5% A; Oven: 40 ° C; Flow: 1.75 ml / min; UV detection: 210 nm. Method 7: Instrument: Thermo DFS, Trace GC Ultra; Column: Restek RTX-35, 15 mx 200 μιη x 0.33 μιη; constant flow with helium: 1.20 ml / min; Oven: 60 ° C; Met: 220 ° C; Gradient: 60 ° C, 30 ° C / min -> 300 ° C (hold for 3.33 min).

Method 8: Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8 μ 50 mm x 2.1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A-> 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 9: Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra; Column: Restek RTX-35MS, 15 m x 200 μιη x 0.33 μιη; 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).

Method 10: Device Type MS: Thermo Scientific FT-MS; Device type UHPLC +: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 mm x 75 mm, C18 1.8 μηι; Eluent A: 1 liter of water + 0.01% of formic acid; Eluent B: 1 liter 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.

Microwave: The microwave reactor used was an Emrys ™ Optimizer single mode device.

When purifying compounds of the invention by preparative HPLC by the methods described above, in which the eluants contain additives such as trifluoroacetic acid, formic acid or ammonia, the compounds of the invention may be in salt form, for example as trifluoroacetate, formate or ammonium salt, if the Compounds according to the invention contain a sufficiently basic or acidic functionality. Such a salt can be converted into the corresponding free base or acid by various methods known to those skilled in the art.

When a compound in the form of a salt of the corresponding base or acid is listed in the below-described synthesis intermediates and embodiments of the invention, the exact stoichiometric composition of such a salt as obtained by the respective preparation and / or purification process was not known, as a rule. Therefore, unless otherwise specified, name and structural formula additives such as "hydrochloride", "trifluoroacetate", "sodium salt" or "x HCl", "x CF 3 COOH", "x Na ⁺ " are not stoichiometric for such salts but solely descriptive of the contained salt-forming components. The same applies mutatis mutandis to the case where synthesis intermediates or embodiments or salts thereof according to the described preparation and / or purification processes in the form of solvates, such as hydrates, were obtained, the stoichiometric composition (if defined type) is not known.

starting compounds

General Method 1A: Preparation of Boronic Acid

A solution of the corresponding pyridine derivative in tetrahydrofuran (about 3 ml / mmol) was treated at -78 ° C with lithium diisopropylamide (2M in tetrahydrofuran / heptane / ethylbenzene), stirred for 2 to 4 h and then treated quickly with triisopropyl borate. The reaction mixture was kept at -78 ° C for a further 2 to 3 h and then thawed slowly to RT overnight. After addition of water, the tetrahydrofuran was removed in vacuo and the aqueous phase extracted twice with ethyl acetate. The aqueous phase was acidified with aqueous hydrochloric acid (2M), usually precipitating, which was filtered, washed with water and dried. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried (sodium or magnesium sulfate), filtered and concentrated in vacuo.

General Method 2A: Suzuki coupling

In a heated argon purged flask, 1.0 eq. the corresponding boronic acids, 1.0 eq. of aryl bromide or aryl iodide, 3.0 eq. Potassium carbonate and 0.1 eq. [1,1-bis (diphenylphosphino) ferrocene] palladium (II) chloride monodichloromethane adduct or tetrakis (triphenylphosphine) palladium (0) submitted. The flask was then evacuated three times and aerated with argon again and again. The reaction mixture was treated with dioxane (about 6 ml / mmol) and stirred at 110 ° C for several hours until substantially complete reaction. The reaction mixture was then filtered through Celite, the filtrate concentrated in vacuo. The residue was mixed with water. After adding Ethyl acetate and phase separation, the organic phase was washed once with water and once with saturated aqueous sodium chloride solution, dried (sodium or magnesium sulfate), filtered and concentrated in vacuo. The crude product was then purified either by normal phase chromatography (cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative RP-HPLC (water-acetonitrile gradient or water-methanol gradient).

General Method 3A: Methoxypyridine Cleavage

A solution of the corresponding methoxypyridine in dimethylformamide (10-12.5 ml / mmol) was treated with 20 eq. Pyridinium hydrochloride or pyridinium hydrobromide and stirred at 100 ° C for several hours to days, possibly mixed with further pyridinium hydrochloride or pyridinium hydrobromide, until almost complete reaction. Subsequently, the reaction solution was concentrated in vacuo and the residue was stirred with water. The resulting precipitate was filtered, washed with water and dried in vacuo.

General Method 4A: N-alkylation of 2-pyridinone derivatives with the corresponding 2-bromo or 2-chloropropanoic ester derivatives in the presence of potassium carbonate

A solution of 1.0 eq. of the corresponding 2-pyridinone derivative in dimethylformamide (5-10 ml / mmol) under argon at RT with 1.2 eq. of the corresponding 2-bromo or 2-chloropropanoic ester derivative and 1.5 eq. Added potassium carbonate and stirred at 100 ° C. After removal of the dimethylformamide and addition of water / ethyl acetate and phase separation, the organic phase was washed with water and with saturated aqueous sodium chloride solution, dried (sodium or magnesium sulfate), filtered and concentrated in vacuo. The crude product was then purified either by normal phase chromatography (cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative RP-HPLC (water-acetonitrile gradient or water-methanol gradient).

General Method 5A: Amide coupling with T3P / pyridine

A solution of the corresponding carboxylic acid (1 eq.) And the corresponding amine (1.1-1.5 eq.) In pyridine (ca 0.1M) was heated to 60-80 ° C and added dropwise with T3P (50% in ethyl acetate, 4 eq .). Alternatively, T3P was added at RT and then stirred at RT or heated to 60-90 ° C. After 1-20 h, the reaction mixture was cooled to RT and treated with water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous buffer solution (pH = 5), with saturated aqueous sodium bicarbonate solution and washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was then optionally purified either by normal phase chromatography (eluent: cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative RP-HPLC (water-acetonitrile gradient or water-methanol gradient).

General Method 5B: Amide coupling with HATU / DIEA

A solution of the corresponding carboxylic acid (1.0 eq.) In dimethylformamide (7-15 ml / mmol) was added under argon at RT with the amine (I. leq.), With / V, / V-diisopropylethylamine (2.2 eq.) And a Solution of HATU (1.2 eq.) Put into some DMF. The reaction mixture was stirred at RT. After addition of water / ethyl acetate and phase separation, the organic phase was washed with water and with saturated aqueous sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was then purified either by flash chromatography (silica gel-60, eluent: cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative HPLC (Reprosil C18, water-acetonitrile gradient or water-methanol gradient).

General Method 6A: Saponification of a tert. Butyl ester or a Boc-protected amine by TFA

A solution of 1.0 eq. of the corresponding ieri.-Butylesterderivates in dichloromethane (about 5-10 ml / mmol) was at RT with 20 eq. TFA and stirred at RT for 1 to 8 h. The reaction mixture was then concentrated in vacuo, the residue coevaporated several times with dichloromethane and toluene and dried in vacuo. The crude product was then optionally purified either by normal phase chromatography (cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative RP-HPLC (water-acetonitrile gradient or water-methanol gradient).

General Method 6B: Saponification of a methyl / ethyl or benzyl ester with lithium hydroxide

A solution of 1.0 eq. of the corresponding methyl or ethyl ester in tetrahydrofuran / water (3: 1, ca. 7-15 ml / mmol), lithium hydroxide (2-4 eq.) was added at RT. The reaction mixture was stirred at RT to 60 ° C and then adjusted to pH 1 with aqueous hydrochloric acid (IN). After addition of water / ethyl acetate and phase separation, the aqueous phase was extracted three times with ethyl acetate. The combined, organic phases were dried (sodium sulfate or magnesium sulfate), filtered and concentrated in vacuo. The crude product was then purified either by normal phase chromatography (cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative RP-HPLC (water-acetonitrile gradient or water-methanol gradient). General Method 6C: Saponification of a tert. Butyl ester with lithium hydroxide

A solution of 1.0 eq. the corresponding tert. Butyl ester in tetrahydrofuran / ethanol (1: 2, 15- 50 ml / mmol) was added at RT with lithium hydroxide (2-5 eq.). The reaction mixture was stirred at RT to 60 ° C, then treated with saturated aqueous ammonium chloride solution and adjusted to pH 1 with aqueous hydrochloric acid (IN). After addition of water / ethyl acetate and phase separation, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried (sodium sulfate or magnesium sulfate), filtered and concentrated in vacuo. The crude product was then purified either by normal phase chromatography (cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative RP-HPLC (water-acetonitrile gradient or water-methanol gradient).

Common Method 7A: Representation of Triflates

A solution of the corresponding alcohol (1 eq.) Was initially charged in dichloromethane (0.1-1M) and at -20 ° C to 0 ° C successively with lutidine (1.1-1.5 eq.) Or triethylamine (1.1-1.5 eq.) Or N , N-diisopropylethylamine (1.1-1.5 eq.) And trifluoromethanesulfonic anhydride (1.05-1.5 eq.). The reaction mixture was stirred for 1 h at -20 ° C to 0 ° C and then diluted with three times the amount (based on the reaction volume) methyl ieri.-butyl ether. The organic phase was washed three times with a 3: 1 mixture of saturated aqueous sodium chloride solution / 1N hydrochloric acid and finally with saturated aqueous sodium bicarbonate solution, dried (sodium or magnesium sulfate), filtered and the solvent removed under reduced pressure. The crude product was used in the next step without further purification.

General Method 8A: Alkylation of acetic acid esters with triflates

A solution of the corresponding acetic acid ester (1 eq.) In tetrahydrofuran (0.1-0.2M) was added dropwise under argon at -78 ° C with bis (trimethylsilyl) -lithium amide (1.0M in THF, 1.1-1.3 eq.) And 15 stirred for a few minutes. Subsequently, the corresponding alkyl triflate (1.5-2.0 eq.) Was added as a pure substance or solution in THF. The resulting reaction mixture was stirred for 15 minutes at -78 ° C. and for 1 h at RT. The reaction mixture was washed with saturated, aqueous ammonium chloride solution. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (sodium sulfate or magnesium sulfate), filtered and concentrated under reduced pressure. The crude product was then purified either by normal phase chromatography (cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative RP-HPLC (water-acetonitrile gradient or water-methanol gradient).

Example 1.1A

2,5-dimethoxy-pyridin-4-ylboronic acid

Following the general method 1A, 11.53 g (82.9 mmol) of 2,5-dimethoxypyridine were reacted. After acidification of the aqueous phase, the desired product precipitated as precipitate. Yield: 9.53 g (61% of theory)

LC / MS [Method 1]: R _t = 0.47 min; MS (ESIpos): m / z = 184 (M + H) ⁺ . Example 1.1B 4-Chloro-2- (2,5-dimethoxypyridin-4-yl) benzonitrile

According to General Method 2A, 7.87 g (95% pure, 40.86 mmol) of 2,5-dimethoxypyridin-4-ylboronic acid with 8.85 g (40.86 mmol) of 2-bromo-4-chlorobenzonitrile in the presence of [1,1- bis- ( diphenylphosphino) ferrocene] palladium (II) chloride dichloromethane monoadduct. Yield: 6.23 g (92% purity, 51% of theory)

LC / MS [Method 1]: R _t = 1.08 min; MS (ESIpos): m / z = 275 (M + H) ⁺ . Example 1.1C

4-chloro-2- (5-methoxy-2-oxo-l, 2-dihydropyridin-4-yl) benzonitrile

According to general method 3A, 7.23 g (92% purity, 24.21 mmol) of 4-chloro-2- (2,5-dimethoxypyridin-4-yl) benzonitrile were reacted with pyridinium hydrochloride. Yield: 6.66 g (91% purity, 96% of theory)

LC / MS [Method 1]: R _t = 0.76 min; MS (ESIpos): m / z = 261 (M + H) ⁺ ,

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 11.45 (br, s, 1H), 7.98 (d, 1H), 7.75-7.67 (m, 2H), 7.29 (br, s, 1H ), 6.43 (s, 1H), 3.64 (s, 3H).

Example 1.1D

[4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-l (2 /) -yl-2-thioacetate] butyl ester

According to the general method 4A 516 mg (91% purity, 1.8 mmol) of 4-chloro-2- (5-methoxy-2-oxo-l, 2-dihydropyridin-4-yl) benzonitrile with 1.2 eq. Bromoacetate ieri. butyl ester reacted at 100 ° C. Yield: 464 mg (68% of theory)

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

Example 1.2A

2-bromo-4-chlorophenyl-difluoromethyl ether

A solution of 3.5 g (16.9 mmol) of 2-bromo-4-chlorophenol in 36 ml of acetonitrile was treated with 36 ml of aqueous potassium hydroxide solution (6M), cooled in an ice bath and treated dropwise with vigorous stirring with 6.5 ml (26.9 mmol, 1.6 eq .) Difluoromethyl trifluoromethanesulfonate [Angew. Chem. Int. Ed. 2013, 52, 1-5; Journal of Fluorine Chemistry 2009, 130, 667-670]. The reaction mixture was stirred for 5 minutes and diluted with 200 ml of water. The aqueous phase was extracted twice with 150 ml of diethyl ether. The combined organic phases were dried (sodium sulfate), filtered, concentrated in vacuo and dried. The aqueous phase was extracted again with diethyl ether. The organic phase was dried (sodium sulfate), filtered, concentrated in vacuo and dried. Yield of both combined residues: 3.4 g (80% of theory)

LC / MS [Method 9]: R _t = 3.51 min; MS (ESIpos): m / z = 256 (M + H) ⁺ ,

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.91 (d, 1H), 7.55 (dd, 1H), 7.37 (d, 1H), 7.30 (t, 1H). Example 1.2B 4- [5-Chloro-2- (difluoromethoxy) phenyl] -2,5-dimethoxypyridine

According to general method 2A, 417 mg (2.19 mmol, 1.2 eq.) Of 2,5-dimethoxypyridin-4-ylboronic acid with 494 mg (1.82 mmol) of 2-bromo-4-chlorophenyl-difluoromethyl ether in the presence of [1,1-bis - (diphenylphosphino) ferrocene] -palladium (II) chloride-dichloromethane monoadduct reacted. The crude product was purified by flash chromatography (KP-SIL, petroleum ether / ethyl acetate 15-20%). Yield: 170 mg (90% purity, 27% of theory) LC / MS [Method 1]: R _t = 1.16 min; MS (ESIpos): m / z = 316 (M + H) ⁺ ,

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

Example 1.2C 4- [5-Chloro-2- (difluoromethoxy) phenyl] -5-methoxypyridine-2 (1 /) -one

According to general method 3A, 170 mg (90% purity, 0.49 mmol) of 4- [5-chloro-2- (difluoromethoxy) phenyl] -2,5-dimethoxypyridine were reacted with pyridinium hydrobromide. Yield: 127 mg (87% of theory) LC / MS [Method 1]: R _t = 0.84 min; MS (ESIpos): m / z = 302 (M + H) ⁺ .

Example 1.2D

{4- [5-Chloro-2- (difluoromethoxy) phenyl] -5-methoxy-2-oxopyridinol (2 //) -yl} -acetic acid. - butyl ester

According to general method 4A, 5.43 g (80% purity, 14.4 mmol) of 4- [5-chloro-2- (difluoromethoxy) phenyl] -5-methoxypyridin-2 (III) -one with 1.2 eq. Bromoacetate ieri. butyl ester in the presence of 1.5 eq. Potassium carbonate reacted at 100 ° C. Yield: 3.64 g (61% of theory)

LC / MS [Method 1]: R _t = 1.05 min; MS (ESIpos): m / z = 416 (M + H) ⁺ , Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 7.57 (dd, 1H), 7.45 (d, 1H), 7.43 (s, 1H), 7.30 (d, 1H), 7.13 (t, 1H ), 6.35 (s, 1H), 4.58 (s, 2H), 3.56 (s, 3H), 1.44 (s, 9H).

Example 2.1A

2-isopropoxyethyl-trifluormefhansulfonat

Following the general method 7A, 500 mg (4.8 mmol) of 2-isopropoxyethanol were reacted at 0 ° C. with 1.2 ml (7.2 mmol, 1.5 eq.) Of trifluoromethanesulfonic anhydride in the presence of 0.84 ml (7.2 mmol, 1.5 eq.) Of 2,6-dimethylpyridine , The crude product was reacted without further purification in the next step.

'H-NMR (400 MHz, CDC1 _3): δ [ppm] = 4.60 (t, 2H), 3.73 (t, 2H), 3.69-3.59 (m, 1H), 1.18 (d, 6H).

Example 2.2A

2- (cyclobutyloxy) ethyl trifluoromethanesulfonate

According to general method 7A, 500 mg (4.3 mmol) of 2- (cyclobutyloxy) ethanol were added at 0 ° C. to 1.1 ml (6.5 mmol, 1.5 eq.) Of trifluoromethanesulfonic anhydride in the presence of 1.1 ml (6.5 mmol, 1.5 eq.) / V, / V-diisopropylethylamine implemented. The crude product was reacted without further purification in the next step.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 4.60 (t, 2H), 4.01-3.93 (m, 1H), 3.65 (t, 2H), 2.26-2.16 (m, 2H), 2.00- 1.90 (m, 2H), 1.77-1.67 (m, 2H). Example 2.3A

2-tert-Butoxyethyl trifluoromefansulfonate

According to the general method 7A, 500 mg (4.2 mmol) of 2-ieri.-butoxyethanol at 0 ° C. with 1.1 ml (6.3 mmol, 1.5 eq.) Of trifluoromethanesulfonic anhydride in the presence of 0.74 ml (6.3 mmol, 1.5 eq.) 2.6 Implemented dimethylpyridine. The crude product was reacted without further purification in the next step.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 4.58 (t, 2H), 3.67 (t, 2H), 1.21 (s, 9H). Example 2.4A 2 - [(1-methylcyclobutyl) oxy] ethanol

A solution of 500 mg (3.47 mmol) of [(1-methylcyclobutyl) oxy] acetic acid in 20 ml of tetrahydrofuran under argon and ice cooling with 10.4 ml (10.4 mmol, 3 eq.) Lithiumaluminiumhydrid solution (IM in tetrahydrofuran) and 45 min stirred at RT. The reaction mixture was added dropwise under ice-cooling with 0.4 ml of water, 0.4 ml of 20% aqueous sodium hydroxide solution and three times with 0.4 ml of water. The resulting precipitate was filtered over Celite ^® and washed with tetrahydrofuran. The combined filtrates were concentrated in vacuo. The crude product was purified by flash chromatography (cyclohexane-ethyl acetate mixture). Yield: 411 mg (91% of theory) H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 4.50 (t, 1H), 3.44 (q, 2H), 3.25 (t, 2H) , 2.10-1.98 (m, 2H), 1.81-1.71 (m, 2H), 1.69-1.47 (m, 2H), 1.26 (s, 3H). Example 2.4B

2 - [(l-methylcyclobutyl) oxy] ethyl trifluoromethanesulfonate

According to general method 7A, 411 mg (3.16 mmol) of 2 - [(1-methylcyclobutyl) oxy] ethanol were added at -78 ° C. to 0.59 ml (3.47 mmol, 1.1 eq.) Of trifluoromethanesulfonic anhydride in the presence of 0.48 ml (3.47 mmol). 1.1 eq.) Triethylamine implemented. Yield: 711 mg, the crude product was reacted without further purification in the next step.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 4.45-4.37 (m, 2H), 3.56-3.49 (m, 2H), 2.16-2.04 (m, 2H), 1.87-1.77 (m , 2H), 1.73-1.53 (m, 2H), 1.32 (s, 3H). Example 3.1A

2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-l (2 /) -yl] -4-isopropoxybutanoic acid, tert-butyl ester (racemate)

According to general method 8A, 1.00 g (2.67 mmol) of ethyl 4- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-l (2-ethylbenzoyl) -butyl ester, 1.13 g ( 4.80 mmol, 1.8 eq.) Of 2-isopropoxyethyl trifluoromethanesulfonate and 3.47 ml (3.47 mmol, 1.3 eq.) Of bis (trimethylsilyl) lithium amide (IM in THF) in 27 ml of THF. After aqueous workup the crude product was purified by flash chromatography (50 g silica cartridge, flow: 50 ml / min, cyclohexane-ethyl acetate mixture). Yield: 784 mg (64% of theory)

LC / MS [Method 1]: R _t = 1.11 min; MS (ESIpos): m / z = 461 (M + H) ⁺ ,

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.99 (d, IH), 7.75-7.69 (m, 2H), 7.36 (s, IH), 6.48 (s, IH), 5.13 ( dd, IH), 3.63 (s, 3H), 3.48-3.39 (m, 2H), 3.20-3.11 (m, IH), 2.41-2.23 (m, 2H), 1.41 (s, 9H), 1.05 (d, 3H), 1.03 (d, 3H).

Example 3.1B

2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 /) -yl] -4-isopropoxybutanoic acid

(Racemate)

According to general method 6C, 784 mg (1.70 mmol) of 2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2-yl) -yl] -hexisopropoxybutanoic acid were added. butyl ester (racemate) in 50 ml of ethanol and 25 ml of tetrahydrofuran in the presence of 204 mg (8.50 mmol, 5.0 eq.) Lithium hydroxide. Yield: 681 mg (99% of Th.)

LC / MS [Method 1]: R _t = 0.85 min; MS (ESIpos): m / z = 405 (M + H) ⁺ .

Example 3.1C

Ethyl 4- ({2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 //) -yl] -4-isopropoxybutanoyl} -amino) benzoate (racemate)

According to general method 5A, 250 mg (0.62 mmol) of 2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2 //) -yl] -4-isopropoxybutanoic acid (racemate) were obtained. and 153 mg (0.93 mmol, 1.5 eq.) of 4-aminobenzoic acid ethyl ester in 7 ml of pyridine at 80 ° C with 1.44 ml (2.47 mmol, 4.0 eq.) Propylphosphonsäureanhydrid (T3P, 50% in ethyl acetate). The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm × 30 mm, eluent: water / 0.1% formic acid gradient (0 to 3 minutes 10% acetonitrile, to 35 minutes 90% acetonitrile and a further 3 minutes 90 % Acetonitrile)]. Yield: 278 mg (82% of theory)

LC / MS [Method 1]: R _t = 1.16 min; MS (ESIpos): m / z = 552 (M + H) ⁺ , Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 10.76 (s, 1H), 7.99 (d, 1H), 7.93 (d, 2H), 7.80 (d, 2H), 7.76-7.70 (m, 2H), 7.50 (s, 1H), 6.52 (s, 1H), 5.78 (dd, 1H), 4.29 (q, 2H), 3.69 (s, 3H), 3.51-3.38 (m, 2H), 3.3-3.25 (m, 1H), 2.45-2.35 (m, 2H), 1.31 (t, 3H), 1.02 (d, 3H), 0.98 ( d, 3H).

Example 4.1A

2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 /) -yl] -4- (cyclobutyloxy) butanoic acid, tert.-butyl ester (racemate)

According to general Method 8A, 500 mg (1.33 mmol) of [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 //) -yl] -acetic acid-ieri-butyl ester, 405 mg (90% purity, 1.47 mmol, 1.1 eq.) Of 2- (cyclobutyloxy) ethyl trifluoromethanesulfonate and 1.60 ml (1.60 mmol, 1.2 eq.) Of bis (trimethylsilyl) -lithium amide (IM in THF) in 25 ml of THF , After aqueous work-up, the crude product was purified by flash chromatography (50 g silica cartridge, flow: 50 ml / min, cyclohexane-ethyl acetate mixture). Yield: 493 mg (77% of theory)

LC / MS [Method 1]: R _t = 1.22 min; MS (ESIpos): m / z = 473 (M + H) ⁺ ,

^X H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.99 (d, IH), 7.75-7.69 (m, 2H), 7.38 (s, IH), 6.49 (s, IH), 5.14 (dd, IH), 3.86-3.77 (m, IH), 3.64 (s, 3H), 3.36-3.28 (m, IH, next to DMSO), 3.15-3.08 (m, IH), 2.39-2.27 (m, 2H ), 2.14-2.02 (m, 2H), 1.86-1.70 (m, 2H), 1.63-1.55 (m, IH), 1.48-1.4 (m, IH), 1.41 (s, 9H).

Example 4.1B

2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 /) -yl] -4- (cyclobutyloxy) butanoic acid (racemate)

According to general Method 6C, 491 mg (1.04 mmol) of 2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 //) -yl] -4- (cyclobutyloxy) butanoic acid butyl ester (racemate) in 28 ml of ethanol and 14 ml of tetrahydrofuran in the presence of 124 mg (5.19 mmol, 5.0 eq.) of lithium hydroxide. Yield: 510 mg (quantitative)

LC / MS [Method 1]: R _t = 0.99 min; MS (ESIpos): m / z = 417 (M + H) ⁺ . Example 4.1C

Ethyl 4- ({2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 /) -yl] -4- (cyclobutyloxy) butanoyl} -amino) benzoate (racemate)

According to general Method 5A, 387 mg (0.93 mmol) of 2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2 //) -yl] -4- (cyclobutyloxy) butanoic acid (Racemat) and 230 mg (1.39 mmol, 1.5 eq.) 4-Aminobenzoesäureethylester in 14 ml of pyridine at 80 ° C with 2.17 ml (3.71 mmol, 4.0 eq.) Propylphosphonsäureanhydrid (T3P, 50% in ethyl acetate). The crude product was purified by flash chromatography (50 g silica cartridge, flow: 50 ml / min, cyclohexane-ethyl acetate mixture). Yield: 403 mg (77% of theory)

LC / MS [Method 1]: R _t = 1.18 min; MS (ESIpos): m / z = 564 (M + H) ⁺ .

Example 5.1A

4-ieri. Butoxy-2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-l (2 /) -yl-1-butyric acid] -butyl ester (racemate)

According to general Method 8A, 953 mg (2.54 mmol) of [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 //) -yl] -acetic acid-ieri-butyl ester, 1.06 g (4.22 mmol, 1.7 eq.) Of 2-tert-butoxyethyl trifluoromethanesulfonate and 3.31 ml (3.31 mmol, 1.3 eq.) Of bis (trimethylsilyl) lithium amide (IM in THF) in 25 ml of THF. After aqueous work-up, the crude product was purified by flash chromatography (50 g silica cartridge, flow: 50 ml / min, cyclohexane-ethyl acetate mixture). Yield: 900 mg (75% of theory)

LC / MS [Method 1]: R _t = 1.15 min; MS (ESIpos): m / z = 475 (M + H) ⁺ ,

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.98 (d, 1H), 7.75-7.68 (m, 2H), 7.37 (s, 1H), 6.48 (s, 1H), 5.15 ( d, 1H), 3.64 (s, 3H), 3.41-3.33 (m, 1H), 3.19-3.10 (m, 1H), 2.42-2.31 (m, 1H), 2.31-2.20 (m, 1H), 1.41 ( s, 9H), 1.08 (s, 9H).

Example 5.1B

4-ieri. Butoxy-2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 /) -yl] butanoic acid (racemate)

According to general Method 6C, 900 mg (1.90 mmol) of 4-yl-butoxy-2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2 /) -yl] butanoic acid -butyl (racemate) in 50 ml of ethanol and 25 ml of tetrahydrofuran in the presence of 227 mg (9.47 mmol, 5.0 eq.) Lithium hydroxide reacted. Yield: 609 mg (74% of Th.)

LC / MS [Method 1]: R _t = 0.90 min; MS (ESIpos): m / z = 419 (M + H) ⁺ . Example 5.1C

4 - ({4-Ethoxy-2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-l (2 /) -yl] butanoyl} -amino) -benzoic acid ethyl ester (racemate )

According to general method 5A, 210 mg (0.49 mmol) of 4-tert-butoxy-2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 //) -yl] butanoic acid (racemate) and 120 mg (0.73 mmol, 1.5 eq.) 4-Aminobenzoesäureethylester in 10 ml of pyridine at 80 ° C with 1.13 ml (1.95 mmol, 4.0 eq.) Propylphosphonsäureanhydrid (T3P, 50% in ethyl acetate). The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm × 30 mm, eluent: water / 0.1% formic acid gradient (0 to 3 minutes 10% acetonitrile, to 35 minutes 90% acetonitrile and a further 3 minutes 90 % Acetonitrile)]. Yield: 215 mg (78% of theory)

LC / MS [Method 1]: R _t = 1.16 min; MS (ESIpos): m / z = 566 (M + H) ⁺ , Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 10.77 (s, 1H), 7.99 (d, 1H), 7.93 (d, 2H), 7.80 (d, 2H), 7.76-7.67 (m, 2H), 7.49 (s, 1H), 6.52 (s, 1H), 5.79 (t, 1H), 4.29 (q, 2H), 3.69 (s, 3H), 3.44-3.36 (m, 1H), 3.3-3.24 (m, 1H), 2.43-2.35 (m, 2H), 1.31 (t, 3H), 1.04 (s, 9H).

Example 6.1A

4-Ethyl-butoxy-2- {4- [5-chloro-2- (difluoromethoxy) -phenyl] -5-methoxy-2-oxopyridine-1 (2 /) -yl} -butanoic acid-tert.-butyl ester (racemate)

According to general Method 8A, 500 mg (1.20 mmol) of {4- [5-chloro-2- (difluoromethoxy) -phenyl] -5-methoxy-2-oxopyridine-l (2 /) -yl} -acetic acid-tert-butyl ester , 1.05 g (4.21 mmol, 3.5 eq.) 2-eggs. -Butoxyethyl trifluoromethanesulfonate and 3.31 ml (3.31 mmol, 1.3 eq.) Of bis (trimethylsilyl) - lithium amide (IM in THF) in 20 ml of THF to the reaction. After aqueous work-up, the crude product was purified by flash chromatography (50 g silica cartridge, flow: 50 ml / min, cyclohexane-ethyl acetate mixture). Yield: 309 mg (50% of theory)

LC / MS [Method 1]: R _t = 1.24 min; MS (ESIpos): m / z = 516 (M + H) ⁺ ,

^X H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.57 (dd, IH), 7.44 (d, IH), 7.29 (d, IH), 7.25 (s, IH), 7.10 (t , IH), 6.33 (s, IH), 5.12 (dd, IH), 3.69 (s, 3H), 3.39-3.33 (m, IH), 3.18-3.10 (m, IH), 2.40-2.30 (m, IH ), 2.29-2.18 (m, IH), 1.41 (s, 9H), 1.07 (s, 9H).

Example 6.1B

4-Ethyl-butoxy-2- {4- [5-chloro-2- (difluoromethoxy) -phenyl] -5-methoxy-2-oxopyridine-1 (2 /) -ylbutanoic acid (racemate)

According to general Method 6C, 307 mg (0.60 mmol) of 4-ethyl-butoxy-2- {4- [5-chloro-2- (difluoromethoxy) phenyl] -5-methoxy-2-oxopyridine-1 (2ii) -yl } butanoic acid-tert.-butyl ester (racemate) in 7 ml of ethanol and 3.5 ml of tetrahydrofuran in the presence of 71 mg (2.98 mmol, 5.0 eq.) Lithium hydroxide reacted. Yield: 227 mg (83% of th.)

LC / MS [Method 1]: R _t = 1.01 min; MS (ESIpos): m / z = 460 (M + H) ⁺ .

Example 6. IC

A - [(A-tert-Butoxy-2- {4- [5-chloro-2- (difluoromethoxy) phenyl] -5-methoxy-2-oxopyridine-1 (2 //) -yl} butanoyl) amino] ethyl benzoate (racemate)

According to general method 5A, 126 mg (0.27 mmol) of 4-ethyl-butoxy-2- {4- [5-chloro-2- (difluoromethoxy) phenyl] -5-methoxy-2-oxopyridine-1 (2 //) -yl} butanoic acid (racemate) and 68 mg (0.41 mmol, 1.5 eq.) of ethyl 4-aminobenzoate in 3 ml of pyridine at 80 ° C. with 0.64 ml (1.10 mmol, 4.0 eq.) Propylphosphonsäureanhydrid (T3P, 50% in ethyl acetate). The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm × 30 mm, eluent: water / 0.1% formic acid gradient (0 to 3 minutes 10% acetonitrile, up to 35 minutes 90% acetonitrile and a further 3 minutes 90 % Acetonitrile)]. Yield: 132 mg (79% of theory)

LC / MS [Method 1]: R _t = 1.27 min; MS (ESIpos): m / z = 607 (M + H) ⁺ ,

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 10.75 (s, IH), 7.93 (d, 2H), 7.80 (d, 2H), 7.57 (dd, IH), 7.44 (d, IH), 7.39 (s, IH), 7.29 (d, IH), 7.13 (t, IH), 6.37 (s, IH), 5.76 (t, IH), 4.29 (q, 2H), 3.63 (s, 3H ), 3.43-3.35 (m, IH), 3.3-3.25 (m, IH), 2.41-2.32 (m, 2H), 1.31 (t, 3H), 1.03 (s, 9H). Example 7.1A

2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 /) -yl] -4 - [(1-methylcyclobutyl) oxy] butanoic acid. butyl ester (racemate)

According to general Method 8A, 759 mg (2.03 mmol) of [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2 /) -yl] acetic acid were obtained. butyl ester, 664 mg (2.53 mmol, 1.25 eq.) of 2 - [(1-methylcyclobutyl) oxy] ethyl trifluoromethanesulfonate and 2.43 ml (2.43 mmol, 1.2 eq.) of bis (trimethylsilyl) -lithium amide (IM in THF) in 10 ml of THF reacted. After aqueous workup, the crude product was purified by flash chromatography (cyclohexane-ethyl acetate mixture). Yield: 743 mg (75% of theory)

LC / MS [Method 10]: R _t = 2.29 min; MS (ESIpos): m / z = 487 (M + H) ⁺ ,

H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.99 (d, IH), 7.73 (dd, IH), 7.70 (d, IH), 7.39 (s, IH), 6.49 (s, IH), 5.17 (dd, IH), 3.64 (s, 3H), 3.36-3.3 (m, IH), 3.13-3.04 (m, IH), 2.44-2.24 (m, 2H), 2.03 (q, IH) , 1.94 (q, IH), 1.76-1.64 (m, 2H), 1.64-1.46 (m, 2H), 1.41 (s, 9H), 1.22 (s, 3H). Example 7.1B

2- [4- (5-Chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 /) -yl] -4 - [(1-methylcyclobutyl) oxy] butanoic acid (racemate)

According to general Method 6C, 690 mg (1.42 mmol) of 2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 /) -yl] -4- [(1-methylcyclobutyl ) oxy] butyric acid feri. butyl ester (racemate) in 28 ml of ethanol and 14 ml of tetrahydrofuran in the presence of 170 mg (7.08 mmol, 5.0 eq.) Lithium hydroxide. Yield: 744 mg, the crude product was reacted without further purification in the next step. LC / MS [Method 10]: R _t = 1.78 min; MS (ESIpos): m / z = 431 (M + H) ⁺ .

Example 7.1C

4 - ({2- [4- (5-Chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 /) -yl] -4 - [(1-methylcyclobutyl) -oxy] -butanoyl} -amino ) ethyl benzoate (racemate)

According to general method 5B, 795 mg (80% purity assumed corresponding to 100% yield of th. In the precursor, 1.48 mmol) 2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine 1 (2 /) - yl] -4 - [(1-methylcyclobutyl) oxy] butanoic acid (racemate) and 268 mg (1.62 mmol, 1.1 eq.) of ethyl 4-aminobenzoate were reacted. After aqueous workup, the crude product was purified by flash chromatography (cyclohexane-ethyl acetate mixture). Yield: 449 mg (51% of theory)

LC / MS [Method 1]: R _t = 1.20 min; MS (ESIpos): m / z = 578 (M + H) ⁺ . Example 8.1A

2- {4- [5-Chloro-2- (difluoromethoxy) phenyl] -5-methoxy-2-oxopyridine-1 (2H) -methylcyclobutyl) oxy] butanoic acid. butyl ester (racemate)

According to general Method 8A, 700 mg (1.68 mmol) of {4- [5-chloro-2- (difluoromethoxy) phenyl] -5-methoxy-2-oxopyridine-1 (2 /) -yl} -acetic acid-ferric. -butyl ester, 618 mg (2.36 mmol, 1.4 eq.) of 2 - [(1-methylcyclobutyl) oxy] ethyl trifluoromethanesulfonate and 2.02 ml (2.02 mmol, 1.2 eq.) of bis (trimethylsilyl) -lithium amide (IM in THF) in 10 ml of THF reacted. After aqueous workup, the crude product was purified by flash chromatography (cyclohexane-ethyl acetate mixture). Yield: 753 mg (83% of theory)

LC / MS [Method 10]: R _t = 2.39 min; MS (ESIpos): m / z = 528 (M + H) ⁺ .

Example 8.1B 2- {4- [5-Chloro-2- (difluoromethoxy) phenyl] -5-methoxy-2-oxopyridine-1 (2 /) -yl} -4- [(1-methylcyclobutyl) oxy] butanoic acid ( racemate)

According to general method 6C, 753 mg (1.40 mmol) of 2- {4- [5-chloro-2- (difluoromethoxy) phenyl] -5-methoxy-2-oxopyridin-1 (2 /) -yl} -4 - [( 1-methylcyclobutyl) oxy] - butanoic acid-tert.-butyl ester (racemate) in 27 ml of ethanol and 13.5 ml of tetrahydrofuran in the presence of 167 mg (6.99 mmol, 5.0 eq.) Lithium hydroxide reacted. Yield: 643 mg (93% of th.)

LC / MS [Method 10]: R _t = 1.92 min; MS (ESIpos): m / z = 472 (M + H) ⁺ .

Example 8.1C

4 - [(2- {4- [5-Chloro-2- (difluoromethoxy) phenyl] -5-methoxy-2-oxopyridine-1 (2 /) -yl} -4- [(1-methylcyclobutyl) oxy] butanoyl ) amino] benzoic acid ethyl ester (racemate)

According to General Method 5B, 643 mg (1.29 mmol) of 2- {4- [5-chloro-2- (difluoromethoxy) phenyl] -5-methoxy-2-oxopyridine-1 (2 /) -yl} -4 - [( 1-methylcyclobutyl) oxy] butanoic acid (racemate) and 235 mg (1.42 mmol, 1.1 eq.) of ethyl 4-aminobenzoate were reacted. After aqueous workup, the crude product was purified by flash chromatography (cyclohexane-ethyl acetate mixture). Yield: 679 mg (94% purity, 80% of theory)

LC / MS [Method 10]: R _t = 2.40 min; MS (ESIpos): m / z = 619 (M + H) ⁺ .

Exemplary embodiments Example 1

4- ({2- [4- (5-Chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 /) -yl] -4-isopropoxybutanoyl} -amino) -benzoic acid (racemate)

A solution of 278 mg (0.50 mmol) of 4 - ({2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-l (2 //) -yl] -4-isopropoxybutanoyl} amino) benzoic acid (racemate) in 10 ml of methanol and 2.5 ml of water was mixed with 328 mg (1.01 mmol, 2 eq.) Cesium carbonate and stirred overnight at 60 ° C. Methanol was removed in vacuo. The aqueous residue was diluted with 10 ml of water, adjusted to pH 3 with aqueous hydrochloric acid solution (IN) and extracted three times with ethyl acetate. The combined organic phases were dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm × 30 mm, eluent: water / 0.05% formic acid gradient (0 to 3 minutes 10% acetonitrile, up to 35 minutes 90% acetonitrile and a further 3 minutes 90 % Acetonitrile)]. Yield: 154 mg (58% of theory)

LC / MS [Method 1]: R _t = 0.94 min; MS (ESIpos): m / z = 524 (M + H) ⁺ ,

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.74 (br.s, 1H), 10.73 (s, 1H), 7.99 (d, 1H), 7.90 (d, 2H), 7.77 ( d, 2H), 7.75-7.69 (m, 2H), 7.50 (s, 1H), 6.53 (s, 1H), 5.79 (dd, 1H), 3.69 (s, 3H), 3.51-3.39 (m, 2H) , 2.46-2.34 (m, 2H), 1.02 (d, 3H), 0.98 (d, 3H). Example 2

4 - ({(2 ^ -2- [4- (5-Chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 /) -yl] -4-isopropoxybutanoyl} -amino) benzoic acid (enantiomer 2)

Enantiomer separation of 125 mg of the racemate from Example 1 gave 55 mg of enantiomer 1 (chiral HPLC: R _t = 2.70 min, 99% ee) 51 mg of the title compound Example 2 (enantiomer 2): Chiral HPLC: R _t = 3.29 min; 99% ee.

Separation method (SFC): Column: AZ-H 250 mm x 30 mm; Eluent: 75% carbon dioxide / 25% ethanol; Temperature: 40 ° C; Flow: 80 ml / min; Pressure: 100 bar; UV detection: 210 nm. Analysis (SFC): Column: AZ-3 250 mm x 4.6 mm; Eluent: carbon dioxide / ethanol in the gradient 5% -> 60%; Temperature: 40 ° C; Flow: 3 ml / min; UV detection: 220 nm.

Further purification by means of preparative HPLC [column: chromate orex C18, 10 μm, 125 mm × 30 mm, eluent: water / 0.05% formic acid gradient (0 to 3 minutes 10% acetonitrile, up to 35 minutes 90% acetonitrile and a further 3 minutes 90% acetonitrile)] gave 32 mg of the title compound Example 3. LC / MS [Method 1]: R _t = 0.99 min; MS (ESIpos): m / z = 524 (M + H) ⁺ ,

H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.74 (br.s, 1H), 10.73 (s, 1H), 7.99 (d, 1H), 7.90 (d, 2H), 7.77 ( d, 2H), 7.75-7.69 (m, 2H), 7.50 (s, 1H), 6.53 (s, 1H), 5.79 (dd, 1H), 3.69 (s, 3H), 3.51-3.39 (m, 2H) , 2.46-2.34 (m, 2H), 1.02 (d, 3H), 0.98 (d, 3H). Example 3

4- ({2- [4- (5-Chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 /) -yl] -4- (cyclobutyloxy) -butanoyl} -amino) -benzoic acid (racemate)

A solution of 402 mg (0.71 mmol) 4 - ({2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2 //) -yl] -4- (cyclobutyloxy ) Butanoyl} amino) benzoic acid (racemate) in 14 ml of methanol and 3.5 ml of water was treated with 464 mg (1.43 mmol, 2 eq.) Cesium carbonate and stirred overnight at 60 ° C. Methanol was removed in vacuo. The aqueous residue was diluted with 10 ml of water, adjusted to pH 3 with aqueous hydrochloric acid solution (IN) and extracted three times with ethyl acetate. The combined organic phases were dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by preparative HPLC [column: chromate orex C 18, 10 μm, 125 mm × 30 mm, eluent: water / 0.1% formic acid gradient (0 to 3 minutes 10% acetonitrile, up to 35 minutes 90% acetonitrile and further 3 min 90% acetonitrile)]. Yield: 258 mg (67% of theory) LC / MS [Method 1]: R _t = 1.02 min; MS (ESIpos): m / z = 536 (M + H) ⁺ ,

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.74 (br.s, 1H), 10.76 (s, 1H), 8.00 (d, 1H), 7.90 (d, 2H), 7.77 ( d, 2H), 7.75-7.69 (m, 2H), 7.51 (s, 1H), 6.54 (s, 1H), 5.79 (t, 1H), 3.82 (m, 1H), 3.69 (s, 3H), 3.40 -3.3 (m, 1H), 3.27-3.18 (m, 1H), 2.46-2.35 (m, 2H), 2.12-1.97 (m, 2H), 1.82-1.64 (m, 2H), 1.61-1.50 (m, 1H), 1.46-1.32 (m, 1H). Example 4

4- {[(2 ^ -2- [4- (5-Chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 /) -yl] -4- (cyclobutyloxybutanoyl) amino} benzoic acid ( Enantiomer 2)

Enantiomer separation of 250 mg of the racemate from Example 3 gave, in addition to 109 mg of enantiomer 1 (chiral HPLC: R _t = 4.88 min, 99% ee) 112 mg of the title compound Example 4 (Enantiomer 2): Chiral HPLC: R _t = 9.71 min; 99% ee.

Separation method (SFC): Column: AZ-H 250 mm x 20 mm; Eluent: 70% carbon dioxide / 30% ethanol; Temperature: 40 ° C; Flow: 100 ml / min; Pressure: 100 bar; UV detection: 210 nm. Analysis (SFC): Column: AZ-3 250 mm x 4.6 mm; Eluent: 70% carbon dioxide / 30% ethanol; Temperature: 40 ° C; Flow: 3 ml / min; UV detection: 220 nm.

LC / MS [Method 1]: R _t = 0.98 min; MS (ESIpos): m / z = 536 (M + H) ⁺ ,

^X H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.74 (br.s, IH), 10.75 (s, IH), 7.99 (d, IH), 7.90 (d, 2H), 7.77 (d, 2H), 7.75-7.69 (m, 2H), 7.50 (s, IH), 6.54 (s, IH), 5.79 (t, IH), 3.82 (m, IH), 3.69 (s, 3H), 3.39-3.3 (m, IH), 3.27-3.18 (m, IH), 2.45-2.35 (m, 2H), 2.12-1.97 (m, 2H), 1.82-1.64 (m, 2H), 1.61-1.50 (m , IH), 1.46-1.32 (m, IH). Example 5

4 - ({4-yn-butoxy-2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-l (2 /) -yl] butanoyl} -amino) -benzoic acid (racemate)

A solution of 215 mg (0.38 mmol) of 4 - ({4-yl-butoxy-2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 //) - yl] butanoyl} amino) benzoic acid ethyl ester (racemate) in 10 ml of methanol and 2.5 ml of water was treated with 248 mg (0.76 mmol, 2 eq.) of cesium carbonate and stirred at 60 ° C. overnight. Methanol was removed in vacuo. The aqueous residue was diluted with 10 ml of water, adjusted to pH 3 with aqueous hydrochloric acid solution (IN) and extracted three times with ethyl acetate. The combined organic phases were dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm × 30 mm, eluent: water / 0.05% formic acid gradient (0 to 3 minutes 10% acetonitrile, up to 35 minutes 90% acetonitrile and a further 3 minutes 90 % Acetonitrile)]. Yield: 141 mg (68% of theory) LC / MS [Method 1]: R _t = 0.99 min; MS (ESIpos): m / z = 538 (M + H) ⁺ ,

^X H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.74 (br.s, 1H), 10.73 (s, 1H), 7.99 (d, 1H), 7.90 (d, 2H), 7.77 (d, 2H), 7.73 (dd, 1H), 7.70 (d, 1H), 7.50 (s, 1H), 6.52 (s, 1H), 5.79 (t, 1H), 3.69 (s, 3H), 3.43- 3.37 (m, 1H), 3.3-3.25 (m, 1H), 2.43-2.34 (m, 2H), 1.04 (s, 9H). Example 6

4- ({(2S) -A-tert-Butoxy-2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2H) -butanoyl} amino) benzoic acid (enantiomer 2)

Enantiomer separation of 110 mg of the racemate from Example 5 gave, in addition to 40 mg of enantiomer 1 (chiral HPLC: R _t = 2.64 min, 99% ee) 49 mg of the title compound Example 6 (enantiomer 2): Chiral HPLC: R _t = 3.35 min; 99% ee.

Separation method (SFC): Column: AZ-H 250 mm x 20 mm; Eluent: 75% carbon dioxide / 25% ethanol; Temperature: 40 ° C; Flow: 80 ml / min; Pressure: 100 bar; UV detection: 210 nm. Analysis (SFC): Column: AZ-3 250 mm x 4.6 mm; Eluent: carbon dioxide / ethanol in the gradient 5% -> 60%; Temperature: 40 ° C; Flow: 3 ml / min; UV detection: 220 nm.

Further purification by means of preparative HPLC [column: chromate orex C18, 10 μm, 125 mm × 30 mm, eluent: water / 0.05% formic acid gradient (0 to 3 minutes 10% acetonitrile, up to 35 minutes 90% acetonitrile and a further 3 minutes 90% acetonitrile)] gave 33 mg of the title compound. EXAMPLE 9 LC / MS [Method 2]: R _t = 3.19 min; MS (ESIpos): m / z = 538 (M + H) ⁺ ,

H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.7 (br.s, 1H), 10.73 (s, 1H), 7.99 (d, 1H), 7.90 (d, 2H), 7.77 ( d, 2H), 7.73 (dd, 1H), 7.70 (d, 1H), 7.49 (s, 1H), 6.52 (s, 1H), 5.79 (t, 1H), 3.69 (s, 3H), 3.45-3.3 (m, 1H), 2.43-2.34 (m, 2H), 1.04 (s, 9H). Example 7

4 - [(4-tert-Butoxy-2- {4- [5-chloro-2- (difluoromethoxy) phenyl] -5-methoxy-2-oxopyridine-1 (2 //) -yl} butanoyl) amino] benzoic acid (racemate)

A solution of 132 mg (0.22 mmol) of 4 - [(4-yl-butoxy-2- {4- [5-chloro-2- (difluoromethoxy) phenyl] -5-methoxy-2-oxopyridine-1 (2 / /) - yl} butanoyl) amino] benzoic acid ethyl ester (racemate) in 4 ml of methanol and 1 ml of water was combined with 142 mg (0.44 mmol, 2 eq.) Cesium carbonate and stirred overnight at 60 ° C. Methanol was removed in vacuo. The aqueous residue was diluted with 10 ml of water, adjusted to pH 3 with aqueous hydrochloric acid solution (IN) and extracted three times with ethyl acetate. The combined organic phases were concentrated in vacuo. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm × 30 mm, eluent: water / 0.1% formic acid gradient (0 to 3 minutes 10% acetonitrile, up to 35 minutes 90% acetonitrile and a further 3 minutes 90 % Acetonitrile)]. Yield: 34 mg (27% of theory)

LC / MS [Method 1]: R _t = 1.08 min; MS (ESIpos): m / z = 579 (M + H) ⁺ ,

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.74 (br.s, 1H), 10.72 (s, 1H), 7.90 (d, 2H), 7.77 (d, 2H), 7.57 ( d, 1H), 7.44 (d, 1H), 7.39 (s, 1H), 7.30 (d, 1H), 7.13 (t, 1H), 6.38 (s, 1H), 5.77 (t, 1H), 3.63 (s , 3H), 3.42-3.25 (m, 2H), 2.40-2.31 (m, 2H), 1.03 (s, 9H). Example 8

4- {[(2S) -4-tert. Butoxy-2- {4- [5-chloro-2- (difluoromethoxy) phenyl] -5-methoxy-2-oxopyridine-1 (2H) -yl} butanoyl] -amino} -benzoic Acid (Enantiomer 2)

Enantiomer separation of 30 mg of the racemate from Example 7 gave, in addition to 13 mg of enantiomer 1 (chiral HPLC: R _t = 3.89 min), 12 mg of the title compound. Example 8 (Enantiomer 2): Chiral HPLC: R _t = 6.25 min; 99% ee.

Separation method: column: Chiralpak IA 5 μιη, 250 mm x 20 mm; Eluent: 60% iso-hexane / 40% ethanol plus 0.2% trifluoroacetic acid; Temperature: 25 ° C; Flow: 15 ml / min; UV detection: 220 nm. Analysis: Column: Chiralpak IA 5 μιη, 250 mm x 4.6 mm; Eluent: 60% iso-hexane / 40% ethanol plus 0.2% trifluoroacetic acid and 1% water; Temperature: 30 ° C; Flow: 1.0 ml / min; UV detection: 220 nm.

LC / MS [Method 1]: R _t = 1.05 min; MS (ESIpos): m / z = 579 (M + H) ⁺ ,

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.7 (br.s, 1H), 10.71 (s, 1H), 7.90 (d, 2H), 7.77 (d, 2H), 7.57 ( d, 1H), 7.44 (d, 1H), 7.39 (s, 1H), 7.29 (d, 1H), 7.13 (t, 1H), 6.38 (s, 1H), 5.77 (t, 1H), 3.63 (s , 3H), 3.43-3.35 (m, 1H), 3.33-3.25 (m, 1H), 2.40-2.31 (m, 2H), 1.03 (s, 9H). Example 9

4- ({2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 //) - yl] -4- [(1-methylcyclobutyl) -oxy] butanoyl} amino) bericic acid (racemate)

A solution of 449 mg (0.75 mmol) of 4 - ({2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridin-1 (2 /) -yl] -4 - [(l -methylcyclobutyl) oxy] butanoyl} amino) benzoic acid ethyl ester (racemate) in 10 ml of methanol and 2.5 ml of water was stirred in the presence of 491 mg (1.51 mmol, 2 eq.) of cesium carbonate at 80 ° C for 3 h. Methanol was removed in vacuo. The aqueous residue was diluted with 30 ml of water, adjusted to pH 2-3 with aqueous hydrochloric acid solution (IN) and extracted twice with ethyl acetate. The combined organic phases were dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (cyclohexane-ethyl acetate mixture). Yield: 298 mg (72% of theory)

LC / MS [Method 1]: R _t = 1.03 min; MS (ESIpos): m / z = 550 (M + H) ⁺ , Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.73 (br.s, IH), 10.76 (s, IH) , 7.99 (d, IH), 7.90 (d, 2H), 7.77 (d, 2H), 7.73 (dd, IH), 7.70 (d, IH), 7.51 (s, IH), 6.54 (s, IH), 5.82 (dd, IH), 3.69 (s, 3H), 3.39-3.3 (m, IH), 3.23-3.14 (m, IH), 2.45-2.35 (m, 2H), 2.03-1.84 (m, 2H), 1.73-1.61 (m, 2H), 1.60-1.42 (m, 2H), 1.18 (s, 3H). Example 10

4 - ({(2, S ^, ) -2- [4- (5-chloro-2-cyanophenyl) -5-methoxy-2-oxopyridine-1 (2 /) -yl] -4 - [(1-methylcyclobutyl ) oxy] butanoyl} amino) benzoic acid (enantiomer 2)

Enantiomer separation of 298 mg of the racemate from Example 9 gave 114 mg of enantiomer 1 (chiral HPLC: R _t = 1.01 min) 112 mg of the title compound. Example 10 (enantiomer 2): chiral HPLC: R _t = 2.08 min; 99% ee.

Separation method (SFC): column: Daicel Chiralpak AZ-H 5 μιη, 250 mm x 20 mm; Eluent: 70% carbon dioxide / 30% ethanol; Temperature: 40 ° C; Flow: 100 ml / min; UV detection: 210 nm. Analysis (SFC): Column: Chiralpak AZ-H 5 μιη, 250 mm x 4.6 mm; Eluent: 60% carbon dioxide / 40% ethanol; Flow: 3.0 ml / min; UV detection: 210 nm.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.74 (br.s, 1H), 10.76 (s, 1H), 7.99 (d, 1H), 7.90 (d, 2H), 7.77 ( d, 2H), 7.73 (dd, 1H), 7.70 (d, 1H), 7.51 (s, 1H), 6.54 (s, 1H), 5.82 (dd, 1H), 3.69 (s, 3H), 3.38-3.3 (m, 1H), 3.23-3.14 (m, 1H), 2.45-2.35 (m, 2H), 2.03-1.84 (m, 2H), 1.73-1.61 (m, 2H), 1.60-1.42 (m, 2H) , 1.18 (s, 3H).

Example 11

4 - [(2- {4- [5-Chloro-2- (difluoromethoxy) phenyl] -5-methoxy-2-oxopyridine-1 (2 /) -methylcyclobutyl) oxy] butanoyl) amino] benzoic acid (racemate)

A solution of 679 mg (94% purity, 1.03 mmol) 4 - [(2- {4- [5-chloro-2- (difluorophenoxy) phenyl] -5-methoxy-2-oxopyridine-1 (2 /) - yl} -4 - [(1-methylcyclobutyl) oxy] butanoyl) amino] benzoic acid ethyl ester (racemate) in 10 ml of methanol and 3 ml of water in the presence of 672 mg (2.06 mmol, 2 eq.) of cesium carbonate for 3 h at 80 ° C stirred. Methanol was removed in vacuo. The aqueous residue was diluted with 30 ml of water and adjusted to pH 2-3 with aqueous hydrochloric acid solution (IN). The precipitate was filtered and dried in vacuo. The combined filtrates were extracted twice with ethyl acetate. The combined organic phases were dried (sodium sulfate), filtered and concentrated in vacuo. The precipitate and the residue from the filtrates were combined together by flash chromatography (cyclohexane-ethyl acetate mixture). Yield: 485 mg (78% of theory)

LC / MS [Method 1]: R _t = 1.08 min; MS (ESIpos): m / z = 591 (M + H) ⁺ ,

^X H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.72 (br.s, IH), 10.74 (s, IH), 7.90 (d, 2H), 7.77 (d, 2H), 7.58 (dd, IH), 7.45 (d, IH), 7.40 (s, IH), 7.30 (d, IH), 7.13 (t, IH), 6.39 (s, IH), 5.80 (t, IH), 3.63 ( s, 3H), 3.37-3.3 (m, IH), 3.23-3.14 (m, IH), 2.44-2.34 (m, 2H), 2.02-1.83 (m, 2H), 1.72-1.61 (m, 2H), 1.59-1.42 (m, 2H), 1.18 (s, 3H). Example 12

4- ({(25) -2- {4- [5-Chloro-2- (difluoromethoxy) phenyl] -5-methoxy-2-oxopyridine-1 (2) -methylcyclobutyl) oxy] butanoyl} amino) benzoic acid (enantiomer 2)

Enantiomer separation of 485 mg of the racemate from Example 11 gave, in addition to 216 mg of enantiomer 1 (chiral HPLC: R _t = 0.96 min), 195 mg of the title compound. Example 12 (enantiomer 2): chiral HPLC: R _t = 2.34 min; 96% ee.

Separation method (SFC): column: Daicel Chiralpak AZ-H 5 μιη, 250 mm x 20 mm; Eluent: 0-2.99 min: 65% carbon dioxide / 35% ethanol -> 3-4.99 min: 60% carbon dioxide / 40% ethanol -> 5-6 min: 65% carbon dioxide / 35% ethanol; Temperature: 30 ° C; Flow: 80 ml / min; UV detection: 210 nm.

Analysis (SFC): Column: Chiralpak AZ-H 5 μιη, 250 mm x 4.6 mm; Eluent: 60% carbon dioxide / 40% ethanol; Flow: 3.0 ml / min; UV detection: 210 nm.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.73 (br.s, 1H), 10.74 (s, 1H), 7.90 (d, 2H), 7.77 (d, 2H), 7.57 ( d, 1H), 7.45 (d, 1H), 7.40 (s, 1H), 7.30 (d, 1H), 7.13 (t, 1H), 6.39 (s, 1H), 5.80 (t, 1H), 3.63 (s , 3H), 3.37-3.3 (m, 1H), 3.23-3.14 (m, 1H), 2.44-2.34 (m, 2H), 2.02-1.83 (m, 2H), 1.72-1.61 (m, 2H), 1.59 -1.42 (m, 2H), 1.18 (s, 3H). B) Assessment of physiological efficacy

The suitability of the compounds according to the invention for the treatment of thromboembolic disorders can be demonstrated in the following assay systems: a) Test descriptions (in vitro) a.l) Measurement of FXIa inhibition

To determine the factor XIa inhibition of the substances according to the invention, a biochemical test system is used in which the reaction of a peptide factor Xla substrate is used to determine the enzymatic activity of human factor XIa. Factor XIa from the peptic factor XIa substrate cleaves the C-terminal aminomethylcoumarin (AMC) whose fluorescence is measured. The determinations are carried out in microtiter plates.

Test substances are dissolved in dimethyl sulfoxide and serially diluted in dimethylsulfoxide (3000 μΜ to 0.0078 μΜ, resulting final concentrations in the test: 50 μΜ to 0.00013 μΜ). 1 μΐ each of the diluted substance solutions are placed in the wells of white microtiter plates from Greiner (384 wells). Subsequently, 20 μl of assay buffer (50 mM Tris / HCl pH 7.4, 100 mM sodium chloride, 5 mM calcium chloride, 0.1% bovine serum albumin) and 20 μΐ factor XIa from Kordia (0.45 nM in assay buffer) are added successively. After incubation for 15 minutes, the enzyme reaction is started by adding 20 μl of the factor XIa substrate Boc-Glu (OBzl) -Ala-Arg-AMC (10 μl in assay buffer) dissolved in assay buffer, for 30 min at room temperature (22 ° C) and then a fluorescence measurement carried out (excitation: 360 nM, emission: 460 nM). The measured emissions of the test mixtures with test substance are compared with those of control preparations without test substance (excluding dimethyl sulfoxide instead of test substance in dimethylsulfoxide) and calculated from the concentration-effect relationships IC 50 values. Action data from this test are listed in Table A below:

Table A

Example No., ICso [nM] Example No., ICse [nM]

1 1.2 2 0.9

3 0.6 4 0.4

5 0.7 6 0.3 Example No., ICso [n] Example No., ICso [nM]

7 2.9 8 1.5

9 1.0 10 0.4

11 2.2 12 1.5

a.2) Determination of selectivity

To demonstrate the selectivity of the substances with respect to FXIa inhibition, the test substances are tested for their inhibition of other human serine proteases, such as factor Xa, trypsin and plasmin. To determine the enzymatic activity of factor Xa (1.3 nmol / l of Kordia), trypsin (83 mU / ml of Sigma) and plasmin (0.1 ug / ml of Kordia), these enzymes are dissolved (50 mmol / l Tris buffer [C , C, C-tris (hydroxymethyl) -aminomethane], 100 mmol / l NaCl, 0.1% BSA [bovine serum albumin], 5 mmol / l calcium chloride, pH 7.4) and for 15 min with test substance in various concentrations in dimethyl sulfoxide and with dimethyl sulfoxide incubated without test substance. The enzymatic reaction is then started by addition of the appropriate substrates (5 μιηοΐ / ΐ Boc-Ile-Glu-Gly-Arg-AMC from Bachem for factor Xa and trypsin, 50 μιηοΐ / ΐ MeOSuc-Ala-Phe-Lys-AMC from Bachem for plasmin). After an incubation period of 30 min at 22 ° C, the fluorescence is measured (excitation: 360 nm, emission: 460 nm). The measured emissions of the test batch with test substance are compared with the control batches without test substance (excluding dimethyl sulfoxide instead of test substance in dimethylsulfoxide) and IC 50 values are calculated from the concentration-effect relationships. a.3) thrombin generation assay (thrombogram)

The effect of the test substances on the Thrombogram (thrombin generation assay according to Hemker) is determined in vitro in human plasma (Octaplas® from Octapharma).

In Hemker thrombin generation assay, the activity of thrombin in clotting plasma is determined by measuring the fluorescent cleavage products of substrate 1-1140 (Z-Gly-Gly-Arg-AMC, Bachem). The reactions are carried out in the presence of varying concentrations of test substance or the corresponding solvent. Reagents from the company Thrombinoscope are used to start the reaction (30 pM or 0.1 pM recombinant tissue factor, 24 μM phosphohpids in HEPES). In addition, a Thrombin Calibrator from the company Thrombinoscope is used, whose amidolytic activity is required for calculating the thrombin activity in a sample with an unknown amount of thrombin. The test is carried out according to manufacturer's instructions (Thrombionocpe BV): 4 μΐ of test substance or solvent, 76 μΐ plasma and 20 μΐ PPP reagent or thrombin calibrator are incubated for 5 min at 37 ° C. After addition of 20 μM 2.5 mM thrombin substrate in 20 mM Hepes, 60 mg / ml BSA, 102 mM calcium chloride, the thrombin generation is measured every 20 seconds for 120 min. The measurement is carried out with a fluorometer (Fluoroskan Ascent) from Thermo Electron, equipped with a 390/460 nm filter pair and a dispenser.

By using the "thrombinoscope software", the thrombogram is calculated and graphically displayed and the following parameters are calculated: lag time, time to peak, peak, ETP (endogenous thrombin potential) and start tail a.4) Determination of the anticoagulant effect

The anticoagulant effect of the test substances is determined in vitro in human and rat plasma. For this purpose, blood is removed using a 0.11 molar sodium citrate solution as a template in a mixing ratio of sodium citrate / blood 1/9. The blood is mixed well immediately after collection and centrifuged for 15 minutes at approximately 4000 g. The supernatant is pipetted off.

The prothrombin time (PT, synonyms: thromboplastin time, quick test) is determined in the presence of varying concentrations of test substance or the corresponding solvent with a commercially available test kit (Neoplastin® from Boehringer Mannheim or Hemoliance® RecombiPlastin from Instrumentation Laboratory). The test compounds are incubated for 3 minutes at 37 ° C with the plasma. Subsequently, coagulation is triggered by the addition of thromboplastin and the time of coagulation is determined. The concentration of test substance is determined which causes a doubling of the prothrombin time.

The activated partial thromboplastin time (APTT) is determined in the presence of varying concentrations of test substance or the corresponding solvent with a commercially available test kit (PTT Reagent from Roche). The test compounds are incubated for 3 minutes at 37 ° C with the plasma and the PTT reagent (cephalin, kaolin). Subsequently, coagulation is triggered by the addition of 25 mM calcium chloride and the time of coagulation is determined. The concentration of test substance is determined which causes a 50% prolongation or a doubling of the APTT. a.5) Determination of plasma kallikrein activity

To determine the plasma kallikrein inhibition of the substances according to the invention is a biochemical test system, in which the reaction of a peptidic plasma kallikrein substrate is used to determine the enzymatic activity of human plasma kallikrein. Plasma kallikrein separates from the peptic plasma kallikrein substrate the C-terminal aminomethyl coumarin (AMC) whose fluorescence is measured. The determinations are carried out in microtiter plates.

Test substances are dissolved in dimethyl sulfoxide and serially diluted in dimethylsulfoxide (3000 μΜ to 0.0078 μΜ, resulting final concentrations in the test: 50 μΜ to 0.00013 μΜ). 1 μΐ each of the diluted substance solutions are placed in the wells of white microtiter plates from Greiner (384 wells). Subsequently, 20 μl of assay buffer (50 mM Tris / HCl pH 7.4, 100 mM sodium chloride solution, 5 mM calcium chloride solution, 0.1% bovine serum albumin) and 20 μM plasma kallikrein from Kordia (0.6 nM in assay buffer) are added in succession , After incubation for 15 min, the enzyme reaction is started by addition of 20 .mu.l of the substrate dissolved in assay buffer H-Pro-Phe-Arg-AMC (10 .mu.in in assay buffer) from Bachem, incubated for 30 min at room temperature (22 ° C.) and then a fluorescence measurement carried out (excitation: 360 nm, emission: 460 nm). The measured emissions of the test mixtures with test substance are compared with those of control samples without test substance (exclusively dimethyl sulfoxide instead of test substance in dimethyl sulfoxide) and IC 50 values calculated from the concentration-effect relationships. Action data from this test are listed in Table B below: Table B

a.6) Determination of endothelial integrity

The activity of the compounds according to the invention are characterized by means of an in vitro permeability assay on "human umbilical venous cells" (HUVEC) (EC IS: Electric Cell-substrate Impedance Sensing; Applied Biophysics, Inc., Troy, NY), differences in transendothelial electrical resistance (TEER) across an endothelial cell monolayer plated over gold electrodes can be continuously measured. HUVECs are sown on a 96-well sensor electrode plate (96W1E, Ibidi GmbH, Martinsried). Hyperpermeability of the resulting confluent cell monolayer is induced by stimulation with kininogen, prekallikrein and factor ΧΠ (per 100 nM). The compounds according to the invention are added before the addition of the substances indicated above. The usual concentrations of the compounds are 1 x 10 ^"10 to 1 x ^{10" 6} M. a.7) Determination of in vitro permeability of endothelial cells In another Hyperpermeabilitäts model, the activity of the substances is determined in the modulation of the macromolecular permeability. HUVECs are seeded on a fibronectin-coated Transwell filter membrane (24-well plates, 6.5 mm insert with 0.4 μΜ polycarbonate membrane, Costar # 3413). The filter membrane separates the upper from the lower cell culture space with the confluent endothelial cell layer at the bottom of the upper cell culture space. 250 g / ml 40 kDa FITC-Dextan (Invitrogen, D1 844) is added to the medium of the upper room. The hyperpermeability of the monolayer layer is induced by stimulation with kininogen, prekallikrein and factor XII (100 nM each). Medium samples are taken every 30 minutes from the lower chamber and the relative fluorescence, as a parameter for the changes of the macromolecular permeability as a function of time, determined with a fluorimeter. The compounds according to the invention are added before the addition of the substances indicated above. The usual Konzentationen the compounds are 1 x 10 ^"10 to 1 x ^{10" 6} M. b) Determination of the antithrombotic effect (in vivo) b. l) Arterial thrombosis model (iron (II) chloride-induced thrombosis) in combination with rabbit ear bleeding time

The antithrombotic activity of FXIa inhibitors is tested in an arterial thrombosis model. The thrombus formation is triggered by chemical damage to a portion of the carotid artery in the rabbit. Simultaneously, the ear bleeding time is determined.

Male rabbits (Crl: KBL (NZW) BR, Charles River) under a diet of 2.2-2.5 kg body weight are administered by intramuscular administration of xylazine and ketamine (Rompun, Bayer, 5 mg kg and Ketavet, Pharmacia & Upjohn GmbH, 40 mg kg Body weight) anesthetized. Anesthesia is further assisted by intravenous administration of the same preparations (bolus: continuous infusion) via the right ear vein.

After free preparation of the right carotid artery, the vascular damage is produced by wrapping a piece of filter paper (10 mm x 10 mm) on a Parafilm® (25 mm x 12 mm) strip around the carotid artery without affecting the blood flow. The filter paper containing 100 μΐ _^ of a 13% solution of iron (II) chloride (Sigma) in water. After 5 minutes, the filter paper is removed and the vessel rinsed twice with aqueous 0.9% sodium chloride solution. 30 minutes after the injury, the carotid artery is dissected out in the area of the damage and any thrombotic material is removed and weighed. The test substances are either administered intravenously via the femoral vein anesthetized or orally by gavage to the awake animals each 5 min or 2 h before damage.

The ear bleeding time is determined 2 minutes after the injury to the carotid artery. For this purpose, the left ear is shaved and a defined section of 3 mm in length (blade Art.No. 10-150-10, Martin, Tuttlingen, Germany) is set parallel to the longitudinal axis of the ear. Care is taken not to injure any visible vessel. Any escaping blood is collected at 15-second intervals with accurately weighed pieces of filter paper without touching the wound directly. The bleeding time is calculated as the time from placement of the incision to the time when no more blood is detectable on the filter paper. The leaked blood volume is calculated after weighing the pieces of filter paper. c) Determination of the effect on extravasation / edema formation and / or neovascularization in the eye (in vivo) cl) Testing of the efficacy of substances in the laser-induced choroidal neovascularization model This study aims to evaluate the efficacy of a test substance on the reduction of extravasation / Edema formation and / or choroidal neovascularization in the rat model of laser-induced choroidal neovascularization.

For this purpose, pigmented rats of the Brown-Norway strain, which show no signs of ophthalmological diseases, are selected and randomly assigned to treatment groups. On day 0, the animals are anesthetized by intraperitoneal injection (15 mg / kg xylazine and 80 mg / kg ketamine). After instillation of a drop of a 0.5% tropicamide solution for dilation of the pupils, the choroidal Neovascularization triggered by a 532 nm argon laser photocoagulator at six defined points around the optic nerve (50-75 μm diameter, 150 mW intensity, 100 ms duration). The test substance and the corresponding vehicle (eg PBS, isotonic saline) are either systemically administered orally or intraperitoneally or administered locally to the eye by repeated administration as eye drops or intravitreal injection. The body weight of all animals is determined before the start of the study, and then daily during the study.

On day 21 angiography is performed by means of a fluorescence fundus chamber (eg Kowe, HRA). Under narcosis and after pupil dilation, a 10% sodium fluorescein dye is injected subcutaneously (sc). 2-10 minutes later, images of the fundus are taken. The extent of extravasation / edema, represented by the leakage of fluorescein, is assessed by two to three allied observers, grading from severities 0 (no extravasation) to 3 (strong staining beyond the actual lesion). After killing the animals on day 23, the eyes are removed and fixed in 4% paraformaldehyde solution for one hour at room temperature. After a wash, the retina is gently peeled out and the sclera-choroid complex is stained with a FITC-isolectin B4 antibody and then placed flat on an objet carrier. The preparations thus obtained are evaluated by means of a fluorescence microscope (Apotom, Zeiss) at an excitation wavelength of 488 nm. The area or volume of the choroidal neovascularization (in μιη ² or μιη ³ ) is calculated by morphometric analysis using Axiovision 4.6 software. c.2) Testing the efficacy of substances in the oxygen-induced retinopathy model

It has been shown that oxygen-induced retinopathy is a valuable animal model for the study of pathological retinal angiogenesis. This model is based on the observation that hyperoxia during early postnatal development in the retina leads to the arrest or slow down of the growth of normal retinal blood vessels. Once the animals return to normoxic room air after a 7-day hyperoxic phase, this is equivalent to relative hypoxia as the retina lacks the normal vessels required to ensure adequate supply of neural tissue under normoxic conditions. The resulting ischemic situation leads to abnormal neovascularization, which bears some resemblance to pathophysiological neovascularization in ocular diseases such as wet AMD. In addition, the evoked neovascularization is very reproducible, quantifiable and important Parameters for the study of disease mechanisms and possible treatments for various forms of retinal diseases.

The aim of this study is to investigate the efficacy of daily systemically administered doses of the test compound on the growth of retinal vessels in the oxygen-induced retinopathy model. Newborns of C57B1 / 6 mice and their mothers are exposed to hyperoxia (70% oxygen) on postnatal day 7 (PD7) for 5 days. As of PD12, the mice are kept under normoxic conditions (room air, 21% oxygen) until PD17. From day 12 to day 17, the mice are treated daily with the test substance or the appropriate vehicle. On day 17, all mice are anesthetized with isoflurane and then killed by cervical dislocation. The eyes are removed and fixed in 4% formalin. After washing in phosphate buffered saline, the retina is dissected, flattened and then stained with Isolectin B4 antibody. Quantification of the newly grown vessels is performed using a Zeiss ApoTome. d) Determination of pharmacokinetic parameters after intravenous administration

To study the pharmacokinetic properties of a test substance, animals are injected with the respective test substances as bolus (in rats) or infusion (in dogs or monkeys). The preferred formulation of the test substances in rats is plasma / dimethyl sulfoxide in the ratio 99: 1. The infusion solution of the test substance in dogs and monkeys consists of polyethylene glycol / ethanol / water in the ratio 50/10/40. The application volume in rats is 2-10 ml / kg, 0.5-2 ml / kg in dogs and monkeys.

Test animals will be sampled with blood in sodium EDTA-containing tubes at the following times: at bolus dose 0.033, 0.083, 0.167, 0.25, 0.283, 0.333, 0.5, 0.75, 1, 2, 3, 5, 7, 24 hours after administration of the test substance and in infusions 0.083, 0.167, 0.25, 0.283, 0.333, 0.5, 0.75, 1, 2, 3, 5, 7, 24 hours after administration of the test substance.

The blood samples are centrifuged for 10 minutes at 1280 g after taking off. The supernatant (plasma) is removed and either further processed directly or frozen for later sample preparation. For sample preparation, mix 50 μΐ plasma with 250 μΐ acetonitrile (the precipitating reagent acetonitrile also contains the internal standard ISTD for subsequent analytical determination) and then allow to stand at room temperature for 5 minutes. Thereafter, the mixture is centrifuged for 3 minutes at 16000 g. The supernatant is removed and mixed with 500 .mu.ΐ of a matched to the run medium buffer. The samples are then analyzed by LC-MS / MS analysis (eg liquid chromatography with a gemini 5 μΜ C18 110A 50 mm x 3 mm (or 150 mm x 3 mm) column of Phenomenex; Mass spectrometry with an API 5500 or API 6500; SCIEX, Canada) to determine the concentration of the test substance in each sample.

Apart from the plasma concentrations, the concentration ratio of whole blood to plasma is also determined for a respective test substance. For this purpose, the test substance is incubated with a specific concentration for 20 minutes in whole blood. Subsequently, the preparation of the samples as described above to determine the concentration of the test substance in the plasma. The set concentration divided by the measured concentration in the plasma gives the parameter Cb / Cp. The pharmacokinetic parameters are calculated by non-compartmental analysis (NCA). The algorithms for calculating the parameters are defined in an internal process description and are based on rules published in general pharmacokinetic textbooks.

The primary pharmacokinetic parameters clearance (CL) and volume of distribution (Vss) are calculated as follows:

Parameter formula

Plasma (plasma clearance) CLplasma = area under the curve (AUC)

CLblood (blood clearance) CLblood = CLplasma / (Cb / Cp)

Vss Vss = CLplasma * MRViv

MRIive MRIv = AUMC / AUC

AUMC AUMC = AUMC (O-tlast) + tlast * Clast, cakulatedA «+ Clast.calculated / λ _ζ ² λ _ζ Rate constant for the terminal phase; is calculated from the logarithmic linear regression of unweighted data from the terminal phase with data points above the detection limit C) Exemplary embodiments of pharmaceutical compositions

The substances according to the invention can be converted into pharmaceutical preparations as follows:

Tablet: composition:

100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch, 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Germany) and 2 mg of magnesium stearate.

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

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

Oral suspension: Composition:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of rhodigel (xanthan gum) (FMC, USA) and 99 g of water.

A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension. production:

The rhodigel is suspended in ethanol, the compound of Example 1 is added to the suspension. While stirring, the addition of water. Until the swelling of the Rhodigels swirling is about 6 h stirred.

Solution or suspension for topical use on the eye (eye drops): A sterile pharmaceutical preparation for topical application to the eye can be prepared by reconstitution of a lyophilizate of the compound of the invention in sterile saline solution. As a preservative for such a solution or suspension For example, benzalkonium chloride, thiomersal or phenylmercuric nitrate in a concentration range of 0.001 to 1 weight percent are suitable.

Solution or suspension for topical use on the eye (eye drops):

A sterile pharmaceutical preparation for topical application to the eye can be prepared by reconstitution of a lyophilizate of the compound of the invention in sterile saline. As a preservative for such a solution or suspension, for example, benzalkonium chloride, thiomersal or phenylmercuric nitrate in a concentration range of 0.001 to 1% by weight is suitable.

Claims

claims

1. Compound of the formula

where * is the point of attachment to the oxopyridine ring, R ^{6 is} chlorine,

R ^{7 is} cyano, difluoromethyl or difluoromethoxy, R ^{8 is} hydrogen or fluorine,

R is chlorine or methoxy,

R ^{3 is} ethyl, wherein ethyl is substituted with a substituent selected from the group consisting of tert-butoxy, iso -propoxy, C ₃ -C 6 cycloalkyloxy and 4- to 6-membered oxo-heterocyclyloxy, wherein tert-butoxy and iso -Propoxy may be substituted with 1 to 3 substituents fluorine, and wherein cycloalkyloxy and oxo-heterocyclyloxy may be substituted with 1 to 2 substituents independently selected from the group consisting of fluorine and methyl, representing hydrogen, for a group of the formula

where # is the point of attachment to the nitrogen atom, R ^{9 is} hydroxycarbonyl, R ^{10 is} hydrogen or fluorine, or one of its salts, its solvates or the solvates of its salts.

2. A compound according to claim 1, characterized in that R ^{1 is} a group of the formula

where * is the point of attachment to the oxopyridine ring,

R ^{6 is} chlorine,

R ^{7 is} cyano or difluoromethoxy,

R ^{8 is} hydrogen, R ^{2 is} methoxy, R ^{3 is} ethyl, wherein ethyl is substituted with a substituent selected from the group consisting of tert-butoxy, iso-propoxy and cyclobutyloxy, wherein cyclobutyloxy may be substituted with a substituent methyl,

R ^{4 is} hydrogen,

R ^{5 is} a group of the formula

where # is the point of attachment to the nitrogen atom,

R ^{9 is} hydroxycarbonyl,

R ^{10 is} hydrogen, or one of its salts, its solvates or the solvates of their salts.

3. A compound according to any one of claims 1 or 2, characterized in that it has the formula

in which R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined in claim 1 or 2, or one of their salts, their solvates or the solvates of their salts.

Process for the preparation of a compound of formula (I) or one of its salts, its solvates or the solvates of its salts according to claim 1, characterized in that either in which

R ¹ , R ² , R ³ , R ⁴ and R ¹⁰ are as defined in claim 1, and R ^{14 is} tert-butyl,

with an acid to a compound of the formula

in which

R ¹ , R ² , R ³ , R ⁴ and R ¹⁰ are as defined in claim 1, and R ^{9 is} hydroxycarbonyl,

is implemented,

or

[B] a compound of the formula

in which R ¹ , R ² , R ³ , R ⁴ and R ^{10 have} the meaning given in claim 1, and

R 14 is methyl or ethyl, with a base to give a compound of the formula

in which

R ¹ , R ² , R ³ , R ⁴ and R ^{10 have} the meaning given in claim 1, and is hydroxycarbonyl, is reacted.

A compound according to any one of claims 1 to 3 for the treatment and / or prophylaxis of diseases.

A compound according to any one of claims 1 to 3 for use in a method for the treatment and / or prophylaxis of thrombotic or thromboembolic diseases.

Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prophylaxis of diseases.

Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prophylaxis of thrombotic or thromboembolic disorders.

Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prophylaxis of ophthalmological diseases.

Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prophylaxis of hereditary angioedema or inflammatory diseases of the intestine, such as Crohn's disease or ulcerative colitis. A medicament containing a compound according to any one of claims 1 to 3 in combination with an inert, non-toxic, pharmaceutically suitable excipient.

Medicament according to claim 11 for the treatment and / or prophylaxis of thrombotic or thromboembolic disorders.

Medicament according to claim 11 for the treatment and / or prophylaxis of ophthalmological diseases.

Medicament according to claim 11 for the treatment and / or prophylaxis of hereditary angioedema or inflammatory diseases of the intestine, such as Crohn's disease or ulcerative colitis.

A method for controlling thrombotic or thromboembolic disorders or ophthalmic diseases or hereditary angioedema or inflammatory diseases of the intestine, such as Crohn's disease or ulcerative colitis, in humans and animals by administering a therapeutically effective amount of at least one compound according to any one of claims 1 to 3, of a drug according to claim 11 or a medicament obtained according to claim 7, 8, 9 or 10.