WO2018184976A1 - Substituted imidazo[1,2-a]pyridinecarboxamides and use of same - Google Patents

Abstract

The invention relates to new substituted imidazo[1,2-a]pyridinecarboxamides, to methods for the production of same, the use of same alone or in combination for the treatment and/or prophylaxis of diseases, and the use of same for producing drugs for the treatment and/or prophylaxis of diseases, particularly for the treatment and/or prophylaxis of cardiovascular diseases.

Description

 Substituted imidazo [l, 2-alpyridinecarboxamide and their use

The present application relates to novel substituted imidazo [l, 2-a] pyridinecarboxamides, processes for their preparation, their use alone or in combinations for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases , in particular for the treatment and / or prophylaxis of cardiovascular diseases.

One of the most important cellular transmission systems in mammalian cells is cyclic guanosine monophosphate (cGMP). Together with nitric oxide (NO), which is released from the endothelium and transmits hormonal and mechanical signals, it forms the NO / cGMP system. The guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP). The previously known members of this family can be divided into two groups according to both structural features and the nature of the ligands: the particulate guanylate cyclases stimulable by natriuretic peptides and the soluble guanylate cyclases stimulable by NO. The soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer that is part of the regulatory center. This is central to the activation mechanism. NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme. On the other hand, heme-free preparations can not be stimulated by NO. Also, carbon monoxide (CO) is able to bind to the central iron atom of the heme, with stimulation by CO being significantly less than by NO.

Through the formation of cGMP and the resulting regulation of phosphodiesterases, ion channels and protein kinases, guanylate cyclase plays a crucial role in various physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion, neuronal signaling and diseases based on a disturbance of the above operations. Under pathophysiological conditions, the NO / cGMP system may be suppressed, leading, for example, to hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual dysfunction.

An NO-independent treatment option for such diseases aimed at influencing the cGMP signaling pathway in organisms is a promising approach on account of the expected high efficiency and low side effects.

For therapeutic stimulation of soluble guanylate cyclase, only compounds such as organic nitrates have been used, whose action is based on NO. This is formed by bioconversion and activates the soluble guanylate cyclase by attack on the central iron atom of the Heme. In addition to the side effects, tolerance development is one of the decisive disadvantages of this treatment.

In recent years, some substances have been described which directly release the soluble guanylate cyclase, i. without stimulating NO, such as 3- (5'-hydroxymethyl-2'-furyl) -l-benzylindazole [YC-1; Wu et al., Blood 84 (1994), 4226; Mülsch et al., Brit. J. Pharmacol. 120 (1997), 681], fatty acids [Goldberg et al., J. Biol. Chem. 252 (1977), 1279], diphenyliodonium hexafluorophosphate [Pettibone et al., Eur. J. Pharmacol. 116 (1985), 307], isoliquiritigenin [Yu et al., Brit. J. Pharmacol. 114 (1995), 1587] and various substituted pyrazole derivatives (WO 98/16223).

Inter alia in EP 0 266 890-A1, WO 89/03833-A1, JP 01258674-A [cf. Chem. Abstr. 112: 178986], WO 96/34866-A1, EP 1 277 754-A1, WO 2001/096335, WO 2006/015737-A1, WO 2006/135667, WO 2008/008539-A2, WO 2008/082490-A2, WO 2008/134553-A1, WO 2010/030538-A2, WO 2011/113606-A1 and WO 2012/165399-A1, WO 2014/068099, WO 2014/068104, WO 2014/068095, WO 2014/195333, WO 2015 WO2015 / 124544, WO 2015/140199, WO 2015/140254, WO 2015/165933, WO 2015/165970, WO 2015/165930, WO 2015/165931, WO2016 / 087343 are various imidazo [1,2-a] pyridine Derivatives which can be used to treat diseases.

The object of the present invention was to provide novel substances which act as stimulators of soluble guanylate cyclase, and as such are suitable for the treatment and / or prophylaxis of diseases and have the same or improved therapeutic profile compared to the compounds known from the prior art, such as for example, in terms of their in vivo properties, such as their pharmacokinetic and pharmacodynamic behavior, their solubility and / or their metabolism profile and / or their dose-response relationship.

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

in which

A is CH ₂ , CD ₂ or CH (CH ₃ ), R ^{1 is} phenyl, wherein phenyl having 1 to 4 substituents independently of one another selected from the group halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl and (Ci-C i) alkyl may be substituted, R ^{2 is} hydrogen, (Ci-C i) -alkyl, cyclopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl, a group of the formula

 stands, where

* represents the point of attachment to the carbonyl group,

L ^{1 is} a bond, -C (R ^U R ¹² ) -, oxygen, sulfur or nitrogen,

R ^{7 is} hydrogen, (Ci-C i) -alkyl or amino, wherein (Ci-C i) -alkyl may be substituted with 1 to 3 substituents independently selected from the group fluorine, difluoromethyl, trifluoromethyl, hydroxy and amino,

R ^{8 is} hydrogen or (C 1 -C ₄ ) -alkyl, or

R ⁷ and R ⁸ together with the carbon atom to which they are attached form a 3- to 5-membered carbocycle in which the 3- to 5-membered carbocycle may be substituted up to two times by fluorine,

R ^{9 is} hydrogen, (C ₁ -C ₆ ) -alkyl, -NR ¹³ R ¹⁴ , -NO ₂ NR ¹⁵ R ¹⁶ , (C ₃ -C ₇ ) -cycloalkyl, (C ₄ -C ₇ ) -heterocyclyl, or 6-membered heteroaryl or phenyl, in which (C 1 -C 6) -alkyl having 1 to 3 substituents independently of one another is selected from the group consisting of fluorine, trifluoromethyl, difluoromethoxy, hydroxy, (C 1 -C 4) -alkoxy, (C 3 -C 7) - Cycloalkyl, (C ₄ -C ₄ ) -heterocyclyl and 5- or 6-membered heteroaryl may be substituted, wherein R is hydrogen, (Ci-C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl, wherein (C3 -Cv) -cycloalkyl having 1 or 2 substituents independently of one another can be substituted from the group fluorine or methyl, in which R is hydrogen or (Ci-C i) -alkyl, wherein R 15 is hydrogen or (Ci-C i) -Alkyl, and wherein R is hydrogen or (Ci-C i) -alkyl, wherein phenyl having 1 to 3 substituents independently selected from the group halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl and (C 1 -C 4) -alkyl may be substituted, wherein 5- or 6-membered heteroaryl may be substituted with 1 or 2 substituents independently selected from the group halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl and (Ci-C ₄ ) alkyl, wherein (C3-Cv ) -Cycloalkyl having 1 or 2 substituents independently selected from the group e is fluorine or methyl, in which (C ₄ -C ₄ ) -heterocyclyl may be substituted by 1 or 2 substituents independently of one another selected from the group of fluorine or methyl,

R ^{11 is} hydrogen, (C 1 -C ₄ ) -alkyl or amino, in which (C 1 -C ₄ ) -alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, hydroxy and amino,

R ^{12 is} hydrogen or (Ci-C ₄ ) -alkyl, or R ^u and R ¹² together with the carbon atom to which they are attached form a 3- to 5-membered carbocycle, wherein the 3- to 5-membered carbocycle may be substituted up to two times by fluorine, or

R ⁷ and R ¹¹ together with the carbon atoms to which they are attached form a 3- to 5-membered carbocycle, wherein the 3- to 5-membered carbocycle may be substituted up to two times by fluorine, or

R ^{3 is} a group of the formula

 stands, where

* is the point of attachment to the carbonyl group, L ^{2 is} a bond or -C = C-,

R ^{10 is} 5- or 6-membered heteroaryl or (C 5 -C 4) -heterocyclyl, in which 5- or 6-membered heteroaryl having 1 to 3 substituents independently of one another selected from the group halogen, trifluoromethyl or (Ci-C i) - Alkyl and in which 5-membered heteroaryl may be fused with (C5-Cv) -cycloalkyl, wherein (C5-Cv) -cycloalkyl having 1 or 2 substituents independently selected from the group halogen or (Ci-C i) Alkyl, or

R ^{3 is} a group of the formula

 stands, where

R ^{17 is} (C 1 -C ₈ ) -alkyl, wherein (C 1 -C ₈ ) -alkyl may be substituted by phenyl or 5- or 6-membered heteroaryl, wherein phenyl having 1 to 3 substituents independently selected from the group consisting of halogen or (Ci-C i) -alkyl may be substituted, wherein 5- or 6-membered heteroaryl may be substituted with 1 to 3 substituents independently selected from the group halogen or (Ci-C i) -alkyl,

R ^{4 is} hydrogen,

R ^{5 represents} hydrogen, chlorine, fluorine, difluoromethyl, trifluoromethyl or (C 1 -C 4) -alkyl, R ^{6 represents} hydrogen or chlorine, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides Oxides and salts.

Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.

Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.

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

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, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine. 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. As solvates, hydrates are preferred in the context of the present invention.

The compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atrop isomers). 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 of the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 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 manufacturing and detectability are suitable for this purpose, in particular compounds labeled with ³ H or ¹⁴ C isotopes. In addition, incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the instructions given in the exemplary embodiments by using corresponding isotopic modifications of the respective reagents and / or starting compounds.

In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically). Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:

In the formulas of the group which R ^{1 can} stand for, the end point of the line on which a symbol * stands does not stand for a carbon atom or a CH 2 group, but is part of the bond to the respectively designated atom to which R ¹ is attached ^{1 are} bound. For the purposes of the present invention, the term "treatment" or "treating" includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the course or progression of such conditions and / or the symptoms of such conditions. The term "therapy" is understood to be synonymous with the term "treatment".

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

The treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete. Preferred in the context of the present invention are compounds of the formula (I) in which

A is CH ₂ ,

R ^{1 is} phenyl, where phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group of fluorine, chlorine or methyl,

R ^{2 is} methyl,

R ^{3 is} a group of the formula

 stands, where

* represents the point of attachment to the carbonyl group,

L ^{1 is} a bond, -C (R ^U R ¹² ) -, oxygen or sulfur,

R ^{7 is} hydrogen, (Ci-C i) -alkyl or amino, wherein (Ci-C i) -alkyl may be substituted with amino, R ^{8 is} hydrogen, or

R ^{9 is} hydrogen, (C ₁ -C ₄ ) -alkyl, -NR ¹³ R ¹⁴ , -NO ₂ NR ¹⁵ R ¹⁶ , (C ₃ -C ₆ ) -cycloalkyl, (C ₄ -C ₆ ) -heterocyclyl, or 6-membered heteroaryl or phenyl, in which (C 1 -C 12) -alkyl may be substituted by fluorine, difluoromethyl, trifluoromethyl or methoxy, in which R ^{13 is} hydrogen, methyl, ethyl or (C 3 -C ₆ ) -cycloalkyl, wherein (C 3 -C 6) -cycloalkyl may be substituted up to two times by fluorine, in which R is hydrogen or methyl, in which R 15 is hydrogen or methyl, and wherein R ^{16 is} hydrogen or methyl, wherein phenyl may be substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, chloro, cyano, trifluoromethyl and methyl, wherein 5 or 6 membered heteroaryl having 1 or 2 substituents independently may be substituted from the group fluorine, chlorine, cyano, trifluoromethyl and methyl, wherein (C3-C6) -cycloalkyl having 1 or 2 substituents independently of one another may be substituted from the group fluorine or methyl, wherein (C3-C6) Heterocyclyl having 1 or 2 substituents selected independently of one another from the group fluorine or methyl,

R ^{11 is} hydrogen, (Ci-C i) -alkyl or amino, wherein (Ci-C i) -alkyl may be substituted with amino,

R ^{12 is} hydrogen, or

R ⁷ and R ¹¹ together with the carbon atoms to which they are attached form a 3- to 5-membered carbocycle,

for a group of the formula

J O stands, where

* is the point of attachment to the carbonyl group, L ^{2 is} a bond or -C = C-,

R ^{10 is} 5- or 6-membered heteroaryl or (C 5 -C 4) -heterocyclyl, wherein 5- or 6-membered heteroaryl may be substituted with 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl or methyl, and wherein 5-membered heteroaryl may be fused with (C5-C6) -cycloalkyl, wherein (C5- C6) cycloalkyl having 1 or 2 substituents independently selected from the group fluorine or methyl, or

R ^{3 is} a group of the formula

 H

 •% 17 stands, where

R ^{17 is} (C 1 -C ₈ ) -alkyl, in which (C 1 -C 6) -alkyl may be substituted by phenyl, in which phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine or methyl,

R ^{4 is} hydrogen,

R ^{5 is} hydrogen or methyl,

R ^{6 is} hydrogen, and the salts, solvates and solvates of the salts of these compounds.

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

A is CH ₂ , R ^{1 is} phenyl, where phenyl may be substituted by 1 or 2 substituents fluorine, R ^{2 is} methyl, for a group of the formula

stands, where

* represents the point of attachment to the carbonyl group,

L ^{1 is} a bond, -C (R ^U R ¹² ) -, oxygen or sulfur,

R ^{7 is} hydrogen, methyl or amino,

R ^{8 is} hydrogen, or

R ^{9 is} hydrogen, (GC ₄ ) alkyl, -NR ¹³ R ¹⁴ , -NO ₂ NR ¹⁵ R ¹⁶ , (C ₃ -C ₆ ) -cycloalkyl, (C ₄ -C ₆ ) -heterocyclyl, pyrazolyl, pydridyl or Phenyl, wherein (Ci-C i) -alkyl may be substituted with trifluoromethyl, wherein R ^{13 is} hydrogen, methyl, cyclopentyl or cyclohexyl, wherein R ^{14 is} hydrogen or methyl, wherein R ^{15 is} methyl, and wherein R ^{16 is} hydrogen, methyl, in which phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine or chlorine,

R ^{1 1} is hydrogen or amino,

R ^{12 is} hydrogen, or

R ⁷ and R ^u together with the carbon atoms to which they are attached form a 3- to 5-membered carbocycle, R ^{4 is} hydrogen,

R ^{5 is} hydrogen or methyl,

R ^{6 is} hydrogen,

and the salts, solvates and solvates of the salts of these compounds.

Also preferred in the context of the present invention are compounds of the formula (I) in which A is CH ₂ ,

and the salts, solvates and solvates of the salts of these compounds.

Also preferred in the context of the present invention are compounds of the formula (I) in which R ^{1 is} phenyl,

 wherein phenyl may be substituted by 1 or 2 substituents fluorine,

and the salts, solvates and solvates of the salts of these compounds.

Also preferred in the context of the present invention are compounds of the formula (I) in which R ^{2 is} methyl,

and the salts, solvates and solvates of the salts of these compounds.

Also preferred in the context of the present invention are compounds of the formula (I) in which R ^{3 is} a group of the formula

 stands, where

 * represents the point of attachment to the carbonyl group,

L ^{1 is} a bond, -C (R ¹ 'R ¹² ) -, oxygen or sulfur,

R ^{7 is} hydrogen, methyl or amino,

R ^{8 is} hydrogen, or

R ^{9 is} hydrogen, (C ₁ -C ₄ ) -alkyl, -NR ¹³ R ¹⁴ , -NO ₂ NR ¹⁵ R ¹⁶ , (C ₃ -C ₆ ) -cycloalkyl, (C ₄ -C ₆ ) -heterocyclyl, pyrazolyl, Pyridyl or phenyl wherein (Ci-C i) -alkyl may be substituted with trifluoromethyl, wherein R ^{13 is} hydrogen, methyl, cyclopentyl or cyclohexyl, wherein R ^{14 is} hydrogen or methyl, wherein R ^{15 is} methyl, and wherein R ^{16 is} hydrogen, methyl, in which phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine or chlorine,

R ^{11 is} hydrogen or amino,

R ^{12 is} hydrogen, or

R ⁷ and R ^u together with the carbon atoms to which they are attached form a 3- to 5-membered carbocycle, and the salts, solvates and solvates of the salts of these compounds.

Also preferred in the context of the present invention are compounds of the formula (I) in which R ^{4 is} hydrogen, and the salts, solvates and solvates of the salts of these compounds.

Also preferred in the context of the present invention are compounds of the formula (I) in which R ^{5 is} hydrogen or methyl, and the salts, solvates and solvates of the salts of these compounds.

Also preferred in the context of the present invention are compounds of the formula (I) in which R ^{6 is} hydrogen, and the salts, solvates and solvates of the salts of these compounds.

The definitions of radicals mentioned as preferred apply both to the compounds of the formula (I) and, correspondingly, to all intermediates.

The invention further provides a process for the preparation of the compounds of the formula (I) according to the invention which comprises reacting a compound of the formula (II)

in which A, R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ each have the meanings given above,

 [A] in an inert solvent under amide coupling conditions with a carboxylic acid of

Formula (III)

 (ΠΙ)

in which R ^{3 has} the meanings given above,

 implements,

 optionally cleaving off any protecting groups present, and converting the resulting compounds of formula (I) optionally with the appropriate (i) solvents and / or (ii) acids or bases in their solvates, salts and / or solvates of the salts, or

[B] in an inert solvent, if appropriate in the presence of a suitable base, with a compound of the formula (IV)

in which T ^{1 is} phenyl or para-nitrophenyl,

 to a compound of formula (V)

(V) in which A, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and T ¹ each have the meanings given above, and these in an inert solvent, optionally in the presence of a suitable base, optionally in a microwave with a compound of formula (VI),

H

 17

 NO

 H

 (VI)

in which R ^{17 has} the meanings given above,

 then optionally splits off any protecting groups present, and the resulting

Compounds of formula (I) optionally with the corresponding (i) solvents and / or (ii) acids or bases in their solvates, salts and / or solvates of the salts.

The described preparation process can be exemplified by the following synthesis schemes (Scheme 1 and Scheme 2):

Scheme 1:

 [a): phenyl chloroformate, sodium carbonate, THF, RT; b): amine; THF / pyridine, 100 ° C, microwave].

The compounds of the formulas (III), (IV) and (VI) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature.

Inert solvents for process steps (II) + (III) - ^> (I) are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons, such as Dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichlorethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N, N-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (ΝΜΡ). It is also possible to use mixtures of the solvents mentioned. Preference is given to dichloromethane, tetrahydrofuran, dimethylformamide or mixtures of these solvents. Suitable condensing agents for amide formation in process steps (II) + (III) -> (I) and are, for example, carbodiimides such as NN'-diethyl, NN'-dipropyl, NN'-diisopropyl, NN'-dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as NN'-carbonyldiimidazole (CDI), 1, 2-oxazolium compounds such as 2-ethyl-5-phenyl-1, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or isobutylchloroformate, propanephosphonic anhydride (T3P) , 1-chloro-NN, 2-trimethylpropl-en-1-amine, diethyl cyanophosphonate, bis (2-oxo-3-oxazolidinyl) -phosphoryl chloride, benzotriazole-1-ynyloxy-tris (dimethylamino) phosphonium hexafluorophosphate , Benzotriazole 1-ylxy-tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), 0- (benzotriazol-1-yl) -NNN ', N'-tetramethyluronium tetrafluoroborate (TBTU), 0- (benzotriazol-1-yl) -NNN ', N'-tetramethyl uronium hexafluorophosphate (HBTU), 2- (2-oxo-l- (2H) -pyridyl) -1,3,3-tetra-methyluronium tetrafluoroborate (TPTU), 0- (7-azabenzotriazole-1-yl ) -N, N, N'N'-tetramethyluronium hexafluorophosphate (HATU) or O- (1H-6-chlorobenzotriazol-1-yl) -l, 1,3,3-tetramethyluronium tetrafluoroborate (TCTU), optionally in combination with other auxiliaries such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and as bases alkali carbonates, for example sodium or potassium carbonate or bicarbonate, or organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N -Methylpiperidine or NN-diisopropylethylamine. Preferably, TBTU is used in conjunction with N-methylmorpholine, HATU in conjunction with N, N-diisopropylethylamine or 1-chloro-N, 2-trimethylprop-1-ene-1-amine. The condensations (II) + (III) -> (I) and is generally carried out in a temperature range from -20 ° C to + 100 ° C, preferably at 0 ° C to + 60 ° C. The reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.

Alternatively, the carboxylic acid of the formula (III) can also first be converted into the corresponding carboxylic acid chloride and this can then be reacted directly or in a separate reaction with an amine of the formula (II) to give the compounds according to the invention. The formation of carboxylic acid chlorides from carboxylic acids is carried out by the methods known in the art, for example by treatment with thionyl chloride, sulfuryl chloride or oxalyl chloride in the presence of a suitable base, for example in the presence of pyridine, and optionally with the addition of dimethylformamide, optionally in a suitable inert solvent.

Inert solvents for process steps (V) + (VI) - ^{> ■} (I) are, for example, diethyl ether, tetrahydrofuran, dioxane, dichloromethane, acetonitrile, DMF, NMP, DMSO and mixtures thereof. Preference is given to using tetrahydrofuran. Suitable bases for process step (V) + (VI) -> (I) are pyridine, DMAP, trialkylamines, eg triethylamine, N-methylmorpholine, N-methylpiperidine or N, N-diisopropylethylamine and DBU. Preferably, pyridine is used.

The reaction is generally carried out in a temperature range from 0 ° C to + 150 ° C, preferably at + 20 ° C to + 120 ° C in a microwave. The reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar).

The compounds of the formula (II) are known from the literature or can be prepared by [A] being a compound of the formula (VII)

in which R ⁴ , R ⁵ and R ⁶ each have the meanings given above,

 in an inert solvent in the presence of a suitable base with a compound of

Formula (VIII)

R ¹

 I

^X (VIII),

in which A and R ¹ each have the meanings given above and

X ^{1 is} a suitable leaving group, in particular chlorine, bromine, iodine, mesylate, triflate or tosylate, to give a compound of the formula (IX)

in which A, R ¹ , R ⁴ , R ⁵ and R ⁶ each have the meanings given above,

is reacted, and this then in an inert solvent with a compound of formula (X)

in which X ^{2 is} chlorine or bromine and in which R ^{2 has} the abovementioned meaning, to give a compound of the formula (XI)

in which A, R ¹ , R ² , R ⁴ , R ⁵ and R ^{6 in} each case have the abovementioned meanings, is reacted, then converted by reaction with 3-methylbutyl nitrite in a suitable inert solvent, first into a compound of the formula (XII) is transferred

in which A, R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ each have the meanings given above, and then reacting them in an inert solvent in the presence of zinc and acetic acid, and then optionally cleaving off any protecting groups present, or

[B] a compound of the formula (XIII)

in which A, R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ each have the meanings given above, in an inert solvent with diphenyl phophorazidate in the presence of tert-butanol and a suitable base, to give a compound of the formula (XIV)

(XIV)

in which A, R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ each have the meanings given above, is reacted and then the protective group is split off under methods known to those skilled in the art.

The procedures described are exemplified by the following schemes (Scheme 3 and Scheme 4): Scheme 3:

[a): i) NaOMe, MeOH, RT; ii) DMSO, RT; b): EtOH, Rf; c): 3-methylbutyl nitrite, dioxane, 100 ° C; d): Zn, acetic acid, H2O, RT].

Scheme 4:

[a): diphenylphosphorazidate, triethylamine, toluene, tert-butanol, 75 ° C; b): hydrochloric acid, MeOH, RT].

The synthesis of the compounds of the formula (XIII) is described in WO2016 / 087343 (compound III).

Inert solvents for process step (VII) + (VIII) - ^> (IX) are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, Toluene, xylene, hexane, cyclohexane or petroleum fractions, alcohols such as methanol, ethanol, tert-butanol, or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝΜΡ ) or pyridine. It is likewise possible to use mixtures of the solvents mentioned. Preferably, methanol, dimethylformamide or dimethyl sulfoxide is used.

Suitable bases for process step (VII) + (VIII) -> (IX) are the customary inorganic or organic bases. These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, optionally with the addition of an alkali iodide such as sodium iodide or potassium iodide, alkali alcoholates such as sodium or potassium, Sodium or potassium ethoxide or sodium or potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as sodium amide, lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N Methyl piperidine, N, N-diisopropylethylamine, pyridine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,4 - diazabicyclo [2.2.2] octane (DABCO ^®). Preferably, potassium carbonate, cesium carbonate or sodium methoxide is used.

The reaction is generally carried out in a temperature range from 0 ° C to + 120 ° C, preferably at + 20 ° C to + 80 ° C, optionally in a microwave. The reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar).

Inert solvents for ring closure (IX) + (X) -> (XI) are the common organic solvents. These include preferably alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, dichloromethane, 1,2-dichloroethane, acetonitrile, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned. Preferably, ethanol is used.

The ring closure is generally carried out in a temperature range from + 50 ° C to + 150 ° C, preferably at + 50 ° C to + 100 ° C, optionally in a microwave. The ring closure (IX) + (X) -> (XI) is optionally carried out in the presence of water-withdrawing reaction additives, for example in the presence of molecular sieve (4Ä pore size) or by means of water. The reaction (IX) + (X) -> (XI) is carried out using an excess of the reagent of formula (X), for example with 1 to 10 equivalents of the reagent (X), optionally with the addition of bases (such as sodium bicarbonate) the addition of this reagent can be done once or in several portions.

Inert solvents for process step (XI) + 3-methylbutylnitrile-> (XII) are, for example, dioxane, THF, DMF or NMP. It is likewise possible to use mixtures of the solvents mentioned. Preferably, dioxane is used. The reaction is generally carried out in a temperature range from 25 ° C to + 150 ° C, preferably at + 60 ° C to + 120 ° C, optionally in a microwave. The reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar).

Inert solvents for process step (XII) + zinc + acetic ^»■ (II) are, for example, water, methanol or ethanol. It is likewise possible to use mixtures of the solvents mentioned. Preferably, water is used.

The reaction is generally carried out in a temperature range from 0 ° C to + 150 ° C, preferably at + 0 ° C to + 80 ° C, optionally in a microwave. The reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar).

Inert solvents for process step (XIII) + diphenylphosphorazidate-> (XIV) are, for example, benzene, xylene, toluene or chlorobenzene. It is likewise possible to use mixtures of the solvents mentioned. Preferably, toluene is used.

The reaction is generally carried out in a temperature range from 0 ° C to + 150 ° C, preferably at + 25 ° C to + 120 ° C, optionally in a microwave. The reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Inert solvents for process step (XIV) - ^{> ■} (II) are, for example, diethyl ether, dioxane, THF, methanol, ethanol or water. It is likewise possible to use mixtures of the solvents mentioned. Preferably, methanol is used

The reaction is generally carried out in a temperature range from 0 ° C to + 150 ° C, preferably at + 0 ° C to + 60 ° C, optionally in a microwave. The reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Other compounds of the invention may optionally also be prepared by conversions of functional groups of individual substituents, in particular the compounds listed under R ³ , starting from the compounds of formula (I) obtained by the above method. These transformations are carried out by conventional methods known to those skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, elimination, alkylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of carbonamides, and introduction and removal of temporary protection groups.

The compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals. The compounds according to the invention open up a further treatment alternative and thus represent an enrichment of pharmacy.

The compounds of the invention act as potent stimulators of soluble guanylate cyclase, have valuable pharmacological properties, and have an improved therapeutic profile, such as in their in vivo properties and / or their pharmacokinetic behavior and / or metabolic profile. It is therefore suitable for the treatment and / or prophylaxis of diseases in humans and animals.

The compounds of the invention cause vasorelaxation and inhibition of platelet aggregation and lead to a reduction in blood pressure and to an increase in coronary blood flow. These effects are mediated via direct stimulation of soluble guanylate cyclase and intracellular cGMP increase. In addition, the compound of the invention enhances the action of cGMP level enhancing substances such as endothelium-derived relaxing factor (EDRF), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

The compounds according to the invention are suitable for the treatment and / or prophylaxis of cardiovascular, pulmonary, thromboembolic and fibrotic disorders.

The compounds according to the invention can therefore be used in medicaments for the treatment and / or prophylaxis of cardiovascular diseases such as hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, atrial arrhythmias and ventricular dysfunction such as atrio-ventricular blockades grade I-III (Till-Till), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular tachyarrhythmia, torsades de pointes tachycardia, atrial and ventricular extrasystoles, AV -junctional extrasystoles, sick sinus syndrome, syncope, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute Coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), shock such as cardiogenic shock, septic shock and anaphylactic shock, aneurysms, premature ventricular contraction (PVC), for the treatment and / or prophylaxis of thromboembolic Diseases and ischaemias such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transitory and ischemic attacks, pre-eclampsia, inflammatory cardiovascular diseases, spasms of the coronary arteries and peripheral arteries, edema formation such as pulmonary edema, cerebral edema, renal edema or cardiac insufficiency-related edema, peripheral Circulatory disorders, reperfusion damage, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, for the prevention of restenosis such as after thrombolytic therapy, percutaneous transluminal angioplasties (PTA), transluminal coronary angiogenesis Plastics (PTCA), heart transplants and bypass operations, as well as micro- and macrovascular damage (vasculitis), increased levels of fibrinogen and low-density LDL and elevated levels of plasminogen activator inhibitor 1 (PAI-1), as well as for treatment and / or Prophylaxis of erectile dysfunction and female sexual dysfunction are used. For the purposes of the present invention, the term cardiac failure includes both acute and chronic manifestations of cardiac insufficiency, as well as more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects. heart failure heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic regurgitation, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve, combined heart valve defects, heart muscle inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic cardiac insufficiency, alcohol-toxic cardiomyopathy, cardiac storage diseases, diastolic cardiac insufficiency and systolic Heart failure and acute phases of Worsening of an existing chronic heart failure.

In addition, the compound according to the invention can also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemias, dyslipidemias,

Hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, abetelipoproteinemia, sitosterolemia, xanthomatosis, Tangier's disease, obesity, obesity and combined hyperlipidaemias and the metabolic syndrome.

In addition, the compounds of the invention may be used for the treatment and / or prophylaxis of primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic Ulcers on the extremities, gangrene, CREST syndrome, erythematosis, onychomycosis, rheumatic diseases and to promote wound healing.

Furthermore, the compounds according to the invention are suitable for the treatment of urological diseases such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS, including Feiine's urological syndrome ( FUS)), diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as mixed, urge, stress, or overflow incontinence (MUI, UUI, SUI, OUI), Pelvic pain, benign and malignant diseases of the organs of the male and female urogenital system. Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of kidney diseases, in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure. For the purposes of the present invention, the term renal insufficiency includes both acute and chronic manifestations of renal insufficiency, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulo-interstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as renal transplant rejection, immune complex-induced kidney disease, nephropathy induced by toxic substances, contrast agent-induced nephropathy, diabetic and nondiabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome abnormally decreased creatinine and / or water excretion, abnormally elevated blood levels of urine nitrogen, potassium and / or creatinine, altered activity of renal enzymes, e.g. Glutamyl synthetase, altered urinary or urinary output, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilation, hyperphosphatemia, and / or the need for dialysis. The present invention also encompasses the use of the compounds of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte imbalances (e.g., hyperkalemia, hyponatremia), and disorders in bone and carbohydrate metabolism.

Furthermore, the compounds according to the invention are also suitable for the treatment and / or prophylaxis of asthmatic diseases, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including left heart disease, HIV, sickle cell anemia, thromboembolism (CTEPH), sarcoidosis, COPD or Pulmonary fibrosis associated pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute respiratory syndrome (ARDS), the acute Lung damage (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (eg, cigarette smoke-induced emphysema) and cystic fibrosis (CF).

The compounds described in the present invention are also agents for controlling central nervous system diseases characterized by disorders of the NO / cGMP system. In particular, they are suitable for improving the perception, concentration performance, learning performance or memory performance after cognitive disorders such as occur in situations / diseases / syndromes such as mild cognitive impairment, age-associated learning and memory disorders, age-associated memory loss, vascular dementia, cranial brain -Trauma, stroke, post-stroke dementia, post-traumatic traumatic brain injury, generalized concentration disorder, difficulty concentrating in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies Dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis. They are also suitable for the treatment and / or prophylaxis of diseases of the central nervous system such as states of anxiety, tension and depression, central nervous system-related sexual dysiunctions and sleep disorders and for the regulation of pathological disorders of food, consumption and addiction absorption. Furthermore, the compounds according to the invention are also suitable for regulating cerebral blood flow and are effective agents for combating migraine. They are also suitable for the prophylaxis and control of the consequences of cerebral infarct events (Apoplexia cerebri) such as stroke, cerebral ischaemias and craniocerebral trauma , Likewise, the compounds of the invention can be used to combat pain and tinnitus. In addition, the compounds of the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for the treatment and / or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic inflammatory bowel disease (IBD, Crohn's Disease, UC), pancreatitis , Peritonitis, rheumatoid diseases, inflammatory skin diseases as well as inflammatory eye diseases. Furthermore, the compounds of the invention can also be used for the treatment and / or prophylaxis of autoimmune diseases.

Furthermore, the compounds according to the invention are for the treatment and / or prophylaxis of fibrotic disorders of the internal organs such as, for example, the lung, the heart, the kidney, the bone marrow and in particular the liver, as well as dermatological fibroses and fibrotic Illnesses of the eye, suitable. For the purposes of the present invention, the term fibrotic disorders includes in particular the following terms: liver fibrosis, cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also after surgical interventions), nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis).

Furthermore, the compounds of the invention are useful for controlling postoperative scarring, e.g. as a result of glaucoma surgery.

The compounds according to the invention can likewise be used cosmetically for aging and keratinizing skin.

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

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.

The present invention further relates to the use of the compounds according to the invention for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders, atherosclerosis, dementia disorders and erectile dysfunction.

The present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and atherosclerosis.

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 the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemia, vascular disease, renal insufficiency, thromboembolic diseases, fibrotic diseases, arteriosclerosis, dementia and erectile dysfunction.

Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.

The present invention further provides a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and atherosclerosis, using an effective amount of at least one of the compounds according to the invention ,

The compounds of the invention may be used alone or as needed in combination with other agents. Another object of the present invention are pharmaceutical compositions containing at least one of the compounds 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:

• organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;

Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP), for example inhibitors of phosphodiesterases (PDE) 1, 2 and / or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil and tadalafil;

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

Anti-hypertensives, by way of example and by way of example and by way of preference from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, NEP inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-

Receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors and diuretics; and or

Lipid metabolism-modifying agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP

Inhibitors, PPAR-alpha, PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists.

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

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

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab. In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a factor Xa inhibitor such as, for example and preferably, rivaroxaban (BAY 59-7939), edoxaban (DU-176b), apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin. Among the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and diuretics.

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

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

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

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan, avosentan, macitentan, atrasentan or sitaxsentan. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.

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

In a preferred embodiment of the invention, the compounds of the invention are used in combination with a loop diuretic, such as furosemide, torasemide, bumetanide and piretanide, with potassium-sparing diuretics such as amiloride and triamterene, with aldosterone antagonists, such as spironolactone, potassium canrenoate and eplerenone, and thiazide diuretics, such as Hydrochlorothiazide, chlorthalidone, xipamide, and indapamide. Among the lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and lipoproteins antagonists understood.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as by way of example and preferably torcetrapib (CP-529 414), anacetrapib, JJT-705 or CETP vaccine (Avant). In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thyroid receptor agonist, such as by way of example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

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

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

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

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

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

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.

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

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

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

For oral administration are according to the prior art functioning, the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as tablets (uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention), tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatine capsules), dragees, granules, rapidly disintegrating in the oral cavity Pellets, powders, emulsions, suspensions, aerosols or solutions. The parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral administration, suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

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

Preference is given to oral or parenteral administration, in particular oral administration.

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

In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight, in order to achieve effective results. When administered orally, the dosage is about 0.001 to 2 mg / kg, preferably about 0.001 to 1 mg / kg of body weight.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The following embodiments illustrate the invention. The 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.

A. Examples

Abbreviations:

Section. absolutely (= dried)

aq. aqueous solution

calculated

 Boc teri-butyloxycarbonyl

br. Broadened signal (NMR coupling pattern)

 CAS-No. Chemical Abstracts Service Number

 Cbz benzyloxycarbonyl

δ shift in the NMR spectrum (in ppm)

d doublet (NMR coupling pattern)

 TLC thin layer chromatography

 DCI direct chemical ionization (in MS)

 DMAP 4-N, N-dimethylaminopyridine

 DMF dimethylformamide

 DMSO dimethyl sulfoxide

 EDCI N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide

d. Th. Of theory (at yield)

ent enantiomerenrein

eq. Equivalent (s)

 ESI electrospray ionization (in MS)

 Et ethyl

gef. found

h hour (s)

 HATU N - [(dimethylamino) (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylene] -N-methylmethanaminium hexafluorophosphate

 HOBT 1H-benzotriazole-1-ol

 HPLC high pressure, high performance liquid chromatography

 HRMS high-resolution mass spectrometry

 ID inner diameter

conc. concentrated LC-MS liquid chromatography-coupled mass spectrometry

 LiHMDS lithium hexamethyldisilazide

m multiplet

 Me methyl

min minute (s)

 MS mass spectrometry

 NMR nuclear magnetic resonance spectrometry

 PDA photodiode array detector

 Pd2dba3 tris (dibenzylideneacetone) dipalladium

 Ph phenyl

q quartet (NMR coupling pattern)

quint. Quintet (NMR coupling pattern)

rac racemic

Rel relative stereochemistry

 RF retention factor (in thin-layer chromatography)

 RT room temperature

R _t retention time (by HPLC)

s singlet (NMR coupling pattern)

t triplet (NMR coupling pattern)

 THF tetrahydrofuran

 TBTU (benzotriazole-1-yloxy) bis-dimethylaminomethylium fluoroborate

 UPLC-MS Ultrafast Liquid Chromatography Coupled Mass Spectrometry

 UV ultraviolet spectrometry

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

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. Data on coupling patterns in NMR spectra are descriptive in nature, coupling patterns of higher order are not described as such. LC-MS and HPLC methods:

Method 1 (LC-MS):

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

Method 2 (LC-MS):

Instrament: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ 50 x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A Furnace: 50 ° C; Flow: 0.40 ml / min; UV detection: 210 - 400 nm.

Method 3 (LC-MS):

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

Method 4 (preparative HPLC):

Chromatorex C18 10μ 250x20mm Gradient: A = water + 0.5% formic acid, B = acetonitrile, 0 min = 5% B, 3min = 5% B pre-rinse without substance, then injection, 5 min = 5% B, 25min = 30% B, 38 min = 30% B, 38.1 min = 95% B, 43 min = 95% B, 43.01 min = 5% B, 48.0 min = 5% B Flow rate 20 ml / min, wavelength 210 nm.

Method 5 (preparative HPLC):

Chromatorex C18 10μ 250x20 mm Gradient: A = water + 0.5% formic acid, B = acetonitrile, 0 min = 5% B, 3 min = 5% B rinse without substance, then injection, 5 min = 5% B, 25min = 50% B, 38 min = 50% B, 38.1 min = 95% B, 43 min = 95% B, 43.01 min = 5% B, 48.0 min = 5% B Flow rate 20 ml / min, wavelength 210 nm. Method 6 (preparative HPLC):

XBridge Prep. C18 5μ 50x19 mm gradient: A = water + 0.5% ammonium hydroxide, B = acetonitrile, 0min = 5% B, 3 min = 5% B pre-rinse without substance, then injection, 5 min = 5% B, 25 min = 50%> B, 38 min = 50% B, 38.1 min = 95% B, 43 min = 95% B, 43.01 min = 5% B, 48.0 min = 5% B Flow rate 15 ml / min, wavelength 210 nm

Method 7 (LC-MS):

Instrument MS: Waters (Micromass) QM; Instrument HPLC: Agilent 1100 series; Column: Agient ZORBAX Extend-C18 3.0x50mm 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 8 (LC-MS):

Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ 30 x 2 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A Furnace: 50 ° C; Flow: 0.60 ml / min; UV detection: 208-400 nm.

Method 9 (preparative HPLC):

Instrument MS: Waters, instrument HPLC: Waters (column Waters X-Bridge C18, 18 mm x 50 mm, 5 μιη, eluent A: water + 0.05% triethylamine, eluent B: acetonitrile (ULC) + 0.05% triethylamine, with gradient; Flow: 40 ml / min; UV detection: DAD: 210-400 nm). respectively.:

Instrument MS: Waters, Instrument HPLC: Waters (column Phenomenex Luna 5μ C18 (2) 100A, AXIA Tech 50 x 21.2 mm, eluent A: water + 0.05% formic acid, eluent B: acetonitrile (ULC) + 0.05% formic acid, with Gradient: flow: 40 ml / min; UV detection: DAD: 210-400 nm).

Method 10 (LC-MS): Instrument MS: Waters SQD; Instrument HPLC: Waters UPLC; Column: Zorbax SB-Aq (Agilent), 50 mm x 2.1 mm, 1.8 μιη; Eluent A: water + 0.025%) formic acid, eluent B: acetonitrile (ULC) + 0.025%) formic acid; Gradient: 0.0 min 98% A - 0.9 min 25% A - 1.0 min 5% A - 1.4 min 5% A - 1.41 min 98% A - 1.5 min 98% A; Oven: 40 ° C; Flow: 0.600 ml / min; UV detection: DAD; 210 nm.

Method 11 (MS): Instrament: Waters ZQ 2000; Electrospray ionization; 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; 25% A, 75% B; Flow: 0.25 ml / min.

Method 12 (DCI-MS):

Instrument: Thermo Fisher-Scientific DSQ; chemical ionization; Reactant gas ammonia; Source temperature: 200 ° C; Ionization energy 70eV.

Method 13 (LC-MS): Instrument MS: Waters (Micromass) Quattro Micro; Instrument HPLC: Agilent 1100 series; Column: YMC-Triart C18 3 μ 50 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 14 (GC-MS):

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 15 (LC-MS, Analytical): Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8 μ 50 x 2.1 mm; Eluent A: 1: 1 water + 0.25 ml 99% formic acid, eluent B: 1: 1 acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 90% A -> 0.3 min 90% A -> 1.7 min 5% A -> 3.0 min 5% A Furnace: 50 ° C; Flow: 1.20 ml / min; UV detection: 205-305 nm.

Method 16 (LC-MS Analytical): Instrument MS: Waters (Micromass) Quattro Micro; Instrument Waters UPLC Acquity; Column: Waters BEH C18 1.7 μ 50 x 2.1 mm; Eluent A: 1 l of water + 0.01 mol of ammonium formate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 95% A -> 0.1 min 95% A -> 2.0 min 15% A -> 2.5 min 15% A ^ 2.51 min 10% A -> 3.0 min 10% A; Oven: 40 ° C; Flow: 0.5 ml / min; UV detection: 210 nm. Method 17 (LC-MS):

Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ 50 x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% strength formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% strength 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 18 (LC-MS):

Device Type MS: Waters ZQ; Device Type HPLC: Agilent 1100 Series; UV DAD; Column: Thermo Hypersil GOLD 3 μ 20 mm x 4 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 100% A-> 3.0 min 10% A-> 4.0 min 10% A, oven: 55 ° C; Flow 2ml / min; UV detection: 210 nm.

More information:

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 of the invention contain sufficiently basic or acidic functionalities. Such a salt can be converted into the corresponding free base or acid by various methods known to those skilled in the art.

 Thus, the trifluoroacetate, formate or ammonium salts can be converted into the salt-free form by shaking out an organic solution or suspension with saturated, aqueous sodium bicarbonate solution. Furthermore, amidines may be present as free compounds or proportionally (depending on the preparation in the presence of acetic acid) as acetate salts or acetate solvates.

When a compound in the form of a salt of the corresponding base or acid is listed in the synthesis intermediates and embodiments of the invention described below, the exact stoichiometric composition of such a salt, as according to the respective preparation and / or purification process was received, usually unknown. 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. Furthermore, the secondary amides according to the invention can be present as rotational isomers / isomer mixtures, in particular in NMR investigations. Purity specifications generally refer to corresponding peak integrations in the LC / MS chromatogram, but may additionally have been determined with the aid of the 'H-NMR spectrum. If no purity is specified, it is usually a 100% purity according to automatic peak integration in the LC / MS chromatogram, or purity was not explicitly determined.

 Data on yields in% d. Th. Are purity-corrected as a rule, provided that a purity of <100% is specified. For solvent-containing or contaminated batches, the yield may be formally "> 100%"; in these cases, the yield is not solvent or purity corrected.

All data in 'H NMR spectra indicate the chemical shifts δ in ppm.

 The multiplicities of proton signals in 'H-NMR spectra given in the following paragraphs represent the respective observed signal shape and do not take into account higher-order signal phenomena. As a rule, the indication of the chemical shift refers to the center of the relevant signal. For wide multiplets, an interval is specified. Solvent or water concealed signals were either tentatively assigned or are not listed. Strongly broadened signals - e.g. caused by rapid rotation of moieties or due to exchanging protons - have also been tentatively assigned (often referred to as broad multiplet or broad singlet) or are not listed.

 The methyl group of the chemical system "2-methylimidazo [1,2-a] pyrazine" appears as singlet in 'H-NMR spectra (often in DMSO-d6 and in the range of 2.40 - 2.60 ppm) and is perhaps as clear as such is apparent, is superimposed on the solvent signals or is completely below the signals of the solvent.

Melting points and melting ranges, where indicated, are not corrected.

For all reactants or reagents, the preparation of which is not explicitly described below, it is true that they were obtained commercially from generally available sources. For all other reactants or reagents, the preparation of which is also not described below and which were not commercially available or obtained from sources that are not generally available, reference is made to the published literature describing their preparation. Starting compounds and intermediates:

Example 1A tert -Butyl {8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbamate

12.0 g (36.1 mmol) of 8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid (described in WO 2014068104, Example 24A) were dissolved in 1093 ml of toluene initially charged, with 328 ml of tert-butanol, 6.19 ml (44.4 mmol) of triethylamine and 8.56 ml (39.7 mmol) of diphenylphosphorazidate and stirred overnight at an internal temperature of 70 ° - 75 ° C. The reaction mixture was then concentrated and the residue was purified by silica gel chromatography (eluent: dichloromethane / methanol: 100/0, 100/1). There were obtained 3.32 g (20% of theory, purity 88%), 1.32 g (5% of theory, purity 55%) and 6.80 g (16% of theory, purity 25%) of the title compound.

LC-MS (Method 2): R _t = 0.72 min

MS (ESpos): m / z = 404 (M + H) ⁺

Example 2A 8 - [(2,6-Difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-amine

3.32 g (7.24 mmol, purity 88%) of tert-butyl {8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [l, 2-a] pyridin-3-yl} carbamate from Example 1A were placed in 38.4 ml of methanol and treated with 38.4 ml (461 mmol) of 37% aqueous hydrochloric acid. Subsequently, the reaction mixture was stirred for 3 hours at room temperature. The reaction solution was added with 90 ml of water and washed three times with dichloromethane. The aqueous phase was adjusted to pH 12 with sodium hydroxide solution and then extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 2.27 g (98% of theory, purity 95%) of the title compound were obtained.

LC-MS (Method 15): R _t = 0.79 min MS (ESpos): m / z = 304 (M + H) ⁺

Ή NMR (400 MHz, DMSO-d ₆ ) 5 [ppm]: 2175 (16.00), 2242 (2.20), 2256 (11.09), 2258 (11.14), 4.489 (4.84), 5.235 (6.07), 6.473 (3.06 ), 7.186 (0.29), 7.196 (1.91), 7.207 (0.59), 7.216 (3.26), 7.225 (0.70), 7.236 (2.27), 7.245 (0.53), 7.509 (2.97), 7.531 (0.42), 7.542 (0.46 ), 7.548 (0.90), 7.552 (0.77), 7.569 (1.47), 7.586 (0.75), 7.590 (0.79), 7.607 (0.35). Example 3A rac-Benzyl- [1- ({8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} amino) -1-oxopropane-2 yl] carbamate

13.4 mg (0.06 mmol) of rac-N - [(benzyloxy) carbonyl] alanine were treated with 19.3 mg (0.06 mmol) of bis (dimethylamino) (3-oxido-lH-benzotriazol-1-yl) methylium tetrafluoroborate and 30 μΐ (0.274 mmol). 4-Methylmorpholin presented in 0.46 ml of DMF and stirred for 10 min at room temperature. Subsequently, 20 mg (0.055 mmol, purity 83%) of 8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [l, 2-a] pyridin-3-amine from Example 2A were added to the reaction solution and stirred overnight at room temperature. A further 30.5 mg (0.137 mmol) of raoN - [(benzyloxy) carbonyl] alanine were dissolved in 0.2 ml of DMF, with 43.9 mg (0.137 mmol) of bis (dimethylamino) (3-oxido-1H-benzotriazole-1 - yl) methylium tetrafluoroborate and 18 μΐ (0.164 mmol) of 4-methylmorpholine and stirred for 10 min at room temperature. Subsequently, the solution was added to the first reaction solution and stirred overnight at room temperature.

In a renewed reaction, 24 mg (0.109 mmol) raoN - [(benzyloxy) carbonyl] alanine in 0.46 ml of DMF were charged, with 41.6 mg (0.109 mmol) of HATU and 48 .mu.ΐ (0.274 mmol) of N, N-diisopropylethylamine and for 10 Stirred at room temperature for min. Subsequently, 20 mg (0.055 mmol, purity 83%) of 8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [l, 2-a] pyridin-3-amine from Example 2A were added to the reaction solution and Stirred at room temperature overnight.

Both reaction mixtures were combined and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1%> TFA). 41 mg of the target compound (58% of theory, purity 79%) were obtained.

LC-MS (Method 2): R _t = 0.78 min

MS (ESPOS): m / z = 509 (M + H) ⁺

Example 4A rac-tert-butyl- [1- (4-chloro-ethyl) -2- ({8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethyl-imidazo [1,2-a] pyridine 3-yl} amino) -2-oxoethyl] carbamate trifluoroacetate

89 mg (0.31 mmol) of rac - [(tert-butoxycarbonyl) amino] (4-chlorophenyl) acetic acid were initially charged in 0.5 ml of DMF, admixed with 119 mg (0.31 mmol) of HATU and 136 μΐ (0.78 mmol) of Ν, Ν-diisopropylethylamine and stirred for 10 min at room temperature. Subsequently, 50 mg (0.16 mmol, purity 95%) 8- [(2,6-Difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-amine from Example 2A was added to the reaction solution and stirred overnight at room temperature. The reaction mixture was admixed with acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA). 45 mg of the target compound (42% of theory) were obtained.

LC-MS (Method 2): R _t = 0.94 min

MS (ESpos): m / z = 571 (M-TFA + H) ⁺

Example 5A rac-tert-butyl [2- (4-chlorobenzyl) -3- ({8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3- yl} amino) -3-oxopropyl] carbamate trifluoroacetate

138 mg (0.44 mmol) of rac-3 - [(tert-butoxycarbonyl) amino] -2- (4-chlorobenzyl) propanoic acid were initially charged in 1.0 ml of DMF, with 167 mg (0.44 mmol) HATU and 273 μΐ (1.57 mmol) N , N-diisopropylethylamine and stirred for 10 min at room temperature. Subsequently, 100 mg (0.31 mmol, purity 95%) of 8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [l, 2-a] pyridin-3-amine from Example 2A were added to the reaction solution and for Stirred for 4 hours at room temperature. A further 29 mg (0.09 mmol) of rac-3 - [(tert-butoxycarbonyl) amino] -2- (4-chlorobenzyl) propanoic acid in 0.2 ml of DMF were initially charged with 36 mg (0.09 mmol) of HATU and 27 μΐ (0.16 mmol ) Ν, Ν-diisopropylethylamine and stirred for 10 minutes at room temperature. Subsequently, the solution was added to the first reaction solution and stirred overnight at room temperature. The reaction mixture was admixed with acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, eluent: Acetonitrile / water gradient with the addition of 0.1% TFA). 142 mg of the target compound (63% of theory, purity 99%) were obtained.

LC-MS (Method 2): R _t = 0.94 min

MS (ESpos): m / z = 599 (M-TFA + H) ⁺ Example 6A rac-tert-butyl [2- ({8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [ l, 2-a] pyridin-3-yl} amino) -1- (4-fluorophenyl) -2-oxoethyl] carbamate trifluoroacetate

 84 mg (0.31 mmol) of rac - [(tert-butoxycarbonyl) amino] (4-fluorophenyl) acetic acid were initially charged in 0.5 ml of DMF, admixed with 119 mg (0.31 mmol) of HATU and 136 μΐ (0.78 mmol) of Ν, Ν-diisopropylethylamine and stirred for 10 min at room temperature. Subsequently, 50 mg (0.16 mmol, purity 95%) of 8- [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [l, 2-a] pyridin-3-amine from Example 2A were added to the reaction solution and over Stirred at room temperature overnight. The reaction mixture was admixed with acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA). 77 mg of the target compound (63% of theory, purity 85%) were obtained.

LC-MS (Method 2): R _t = 0.89 min

MS (ESpos): m / z = 555 (M-TFA + H) Example 7A rac -N-alpha - [(benzyloxy) carbonyl] -4-chloro-N- {8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3 -yl} phenylalanine amide trifluoroacetate

105 mg (0.31 mmol) of rac-N - [(benzyloxy) carbonyl] -4-chlorophenylalanine were initially charged in 0.5 ml of DMF, treated with 119 mg (0.31 mmol) of HATU and 136 μΐ (0.78 mmol) of Ν, Ν-diisopropylethylamine and 10 Stirred at room temperature for min. Subsequently, 50 mg (0.16 mmol, purity 95%) of 8- [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [l, 2-a] pyridin-3-amine from Example 2A were added to the reaction solution and over Stirred at room temperature overnight. The reaction mixture was admixed with acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA). 84 mg of the target compound (71% of theory, purity 98%) were obtained.

LC-MS (Method 2): R _t = 0.96 min

MS (ESpos): m / z = 619 (M-TFA + H) ⁺ Example 8A rac-tert-butyl [2- (4-chloro-1-yl) -3- ({8 - [(2,6-difluorobenzyl ) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} amino) -3-oxopropyl] carbamate trifluoroacetate

 131 mg (0.44 mmol) of rac-3 - [(tert-butoxycarbonyl) amino] -2- (4-chlorophenyl) propanoic acid were initially charged in 1.0 ml of DMF, with 167 mg (0.44 mmol) of HATU and 273 μΐ (1.57 mmol) of N , N-diisopropylethylamine and stirred for 10 min at room temperature. Subsequently, 100 mg (0.31 mmol, purity 95%) of 8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [l, 2-a] pyridin-3-amine from Example 2A were added to the reaction solution and over Stirred at room temperature overnight. A further 56 mg (0.19 mmol) of rac-3 - [(tert-butoxycarbonyl) amino] -2- (4-chlorophenyl) propanoic acid in 0.2 ml of DMF were initially charged with 71 mg (0.19 mmol) of HATU and 55 μΐ (0.31 mmol ) Ν, Ν-diisopropylethylamine and stirred for 20 minutes at room temperature. Subsequently, the solution was added to the first reaction solution and stirred overnight at room temperature. The reaction mixture was admixed with acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1%> TFA). The clean product fractions were combined and concentrated. 110 mg of the target compound (50% of theory, purity 100%) were obtained. The less clean product fractions were also combined, concentrated and purified again by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1%) TFA). A further 36 mg (15% of theory, purity 91%) of the target compound were obtained.

LC-MS (Method 17): R _t = 2.92 min

MS (ESpos): m / z = 585 (M-TFA + H) ⁺

Example 9A rac-tert-butyl [1- (4-chloro-1-yl) -3- ({8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethyl-imidazo [1,2-a] pyridine 3-yl} amino) -3-oxopropyl] carbamate trifluoroacetate

 131 mg (0.44 mmol) of rac-3 - [(tert-butoxycarbonyl) amino] -3- (4-chlorophenyl) propanoic acid were initially charged in 1.0 ml of DMF, with 167 mg (0.44 mmol) of HATU and 273 μΐ (1.57 mmol) of N , N-diisopropylethylamine and stirred for 10 min at room temperature. Subsequently, 100 mg (0.31 mmol, purity 95%) of 8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [l, 2-a] pyridin-3-amine from Example 2A were added to the reaction solution and for Stirred for 4 hours at room temperature. A further 28 mg (0.09 mmol) of rac-3 - [(tert-butoxycarbonyl) amino] -3- (4-chlorophenyl) propanoic acid in 0.2 ml of DMF were initially charged with 36 mg (0.09 mmol) of HATU and 27 μΐ (0.16 mmol ) Ν, Ν-diisopropylethylamine and stirred for 10 minutes at room temperature. Subsequently, the solution was added to the first reaction solution and stirred overnight at room temperature. The reaction mixture was admixed with acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA). 158 mg (71% of theory, purity 99%) of the target compound were obtained.

LC-MS (Method 2): R _t = 0.93 min MS (ESpos): m / z = 585 (M-TFA + H) ⁺

Example 10A

3 - [(2,6-difluorobenzyl) oxy] pyridin-2-amine

 51 g of sodium methoxide (953 mmol, 1.05 equivalents) were initially charged in 1000 ml of methanol at RT, admixed with 100 g of 2-amino-3-hydroxypyridine (908 mmol, 1 equivalent) and stirred at RT for 15 min. The reaction mixture was concentrated under reduced pressure, the residue was taken up in 2500 ml of DMSO and admixed with 197 g of 2,6-difluorobenzylbromide (953 mmol, 1.05 equivalents). After 4 h at RT, the reaction mixture was poured onto 20 L of water, stirred for 15 min and the solid was filtered off. The solid was washed with 1 l of water and 100 ml of isopropanol and 500 ml of petroleum ether and dried under high vacuum. 171 g of the title compound (78% of theory) were obtained.

LC-MS (Method 1): R _t = 0.67 min MS (ESpos): m / z = 237 (M + H) ⁺ Example IIA

8 - [(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-ajpyridine

12.0 g (50.8 mmol) of 3 - [(2,6-difluorobenzyl) oxy] pyridin-2-amine from Example 10A and 6.93 ml (86.4 mmol) of 1-chloroacetone were admixed with 90 ml of ethanol and stirred under reflux overnight. Subsequently, the reaction mixture was concentrated together with silica gel. The residue was purified by silica gel chromatography (eluent: dichloromethane / ethanol 50: 1 dichloromethane / methanol / diethylamine 50: 1: 0.1 → 40: 1: 0.5 → 30: 1: 0.5). There was obtained 6.26 g (45% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.58 min MS (ESpos): m / z = 275 (M + H) ⁺

^! H-NMR (400 MHz, DMSO-de) delta [ppm]: 2.268 (16.00), 5.265 (7.33), 6.714 (1.11), 6.733 (2.66), 6.749 (2.85), 6.761 (3.08), 6.764 (3.15) , 6,780 (1.27), 7,195 (0.33), 7,204 (2.15), 7,225 (3.82), 7,245 (2.49), 7,254 (0.36), 7,539 (0.44), 7,556 (0.99), 7,561 (0.84), 7,577 (1.63) , 7.594 (0.83), 7.599 (0.84), 7.616 (0.38), 7.644 (4.05), 8.079 (2.28), 8.081 (2.18), 8.095 (2.28), 8.097 (2.09).

Example 12A

8 - [(2,6-Difluorobenzyl) oxy] -2-methyl-3-nitrosoimidazo [1,2-a] pyridine

 800 mg (2.92 mmol) of 8 - [(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine from Example IA were dissolved in 15 ml of dioxane, with 943 μM (7.00 mmol) of 3 Methylbutylnitrit added and stirred for 30 minutes at 100 ° C in the microwave. The reaction solution was concentrated and the residue was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate 2: 1). There was obtained 621 mg (70% of theory) of the title compound.

LC-MS (Method 18): R _t = 1.95 min MS (ESpos): m / z = 304 (M + H)

Example 13A

8 - [(2,6-difluorobenzyl) oxy] -2-methylimidazo [l, 2-a] pyridin-3-amine

 620 mg (2.04 mmol) of 8 - [(2,6-difluorobenzyl) oxy] -2-methyl-3-nitrosoimidazo [1,2-a] pyridine from Example 12A were initially charged in 7.16 ml (125 mmol) of acetic acid, with 3.6 ml of water and 641 mg (9.81 mmol) of zinc and stirred for 75 minutes at room temperature. The reaction mixture was filtered through Celite, washed with dichloromethane and the filtrate was freed from dichloromethane. The aqueous residue was purified by preparative HPLC (RP18 column, eluent: methanol / water gradient with the addition of 0.1% TFA). The product fractions were combined and the organic solvent was distilled off. The residue was treated with saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated and dried under high vacuum. There were obtained 327 mg (55% of theory) of the title compound.

LC-MS (Method 18): R _t = 1.16 min

MS (ESpos): m / z = 290 (M + H) ⁺ Example 14A

Phenyl {8 - [(2,6-difluorobenzyl) oxy] -2-methylimidazo [l, 2-a] pyridin-3-yl} carbamate

2.20 g (7.61 mmol) of 8 - [(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-amine from Example 13A were dissolved in 100 ml of THF and mixed with 0.806 g (7.61 mmol ) Sodium carbonate. 2.86 ml (22.82 mmol) of phenyl chloroformate were added dropwise and the mixture was stirred at RT for 5 h. The mixture was filtered off, evaporated and then purified by silica gel chromatography (eluent: dichloromethane / dichloromethane / methanol = 80:20). 1.62 g (32% of theory, purity 62%) of the title compound were obtained.

LC-MS (Method 2): R _t = 0.77 min

MS (ESpos): m / z = 410 (M + H) ⁺

Exemplary embodiments Example 1

2- (4-Chlo ^ henyl) -N- {8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [l, 2-a] pyridin-3-yl} acetamide

53 mg (0.31 mmol) of (4-chlorophenyl) acetic acid were initially charged in 0.5 ml of DMF, treated with 119 mg (0.31 mmol) of HATU and 136 μΐ (0.78 mmol) of Ν, Ν-diisopropylethylamine and stirred at room temperature for 10 min. Subsequently, 50 mg (0.16 mmol, purity 95%) of 8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [l, 2-a] pyridin-3-amine from Example 2A were added to the reaction solution and for Stirred for 3 days at room temperature. A further 53 mg (0.31 mmol) of (4-chlorophenyl) acetic acid in 0.5 ml of DMF were initially charged, admixed with 119 mg (0.31 mmol) of HATU and 68 μΐ (0.39 mmol) of Ν, Ν-diisopropylethylamine and stirred for 10 minutes at room temperature. Subsequently, the solution was added to the first reaction solution and stirred for 3 hours at room temperature. The reaction mixture was admixed with acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition from 0.1% TFA). The product fractions were combined, concentrated and the residue was purified again by preparative HPLC (column XBridge C18, 5 μιη, 75 x 30 mm, eluent: Milli-Q water, acetonitrile, 1% TFA in water). The product fractions were combined and concentrated. The residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 7 mg of the target compound (10% of theory, purity 97%) were obtained.

LC-MS (Method 2): R _t = 0.78 min

MS (ESpos): m / z = 456 (M + H) ⁺ Ή-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 2,100 (16:00), 2,248 (11:55), 3,760 (9.49), 5,261 ( 6.20), 6,721 (3.52), 7,201 (0.41), 7,209 (2.08), 7,225 (3.60), 7,241 (2.57), 7,247 (0.59), 7,290 (3.40), 7,403 (1.16), 7,409 (0.77), 7,415 ( 1.34), 7.421 (10.50), 7.426 (11.55), 7.431 (1.23), 7.438 (0.77), 7.443 (1.11), 7.549 (0.36), 7.562 (0.90), 7.565 (0.85), 7.579 (1.49), 7.592 ( 0.82), 7.596 (0.82), 7.609 (0.39), 9.915 (3.32).

Example 2

-N- {8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethlimidazo [1,2-a] pyridin-3-yl} alaninamide

41 mg (0.064 mmol, purity 79%) of rac-benzyl- [1- ({8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} amino) -l-oxopropan-2-yl] carbamate from Example 3A were dissolved in 2.0 ml of ethanol, treated with 24 μΐ TFA and 6.8 mg of palladium on activated carbon (10%) and hydrogenated for 2 hours at normal pressure. The reaction solution was filtered through a Millipore filter and the filtrate was concentrated. The residue was purified by thick layer chromatography (eluent: dichloromethane / methanol = 10/1). The isolated product fraction was lyophilized and again purified by thick layer chromatography (eluent: dichloromethane / 2N ammonia in methanol = 20 / 1.5). The product fraction was stirred with dichloromethane / 2N ammonia in methanol, the solution mixed with a little dry ice and concentrated. 9.7 mg (38% of theory, purity 94%) of the target compound were obtained.

LC-MS (Method 2): R _t = 0.43 min

MS (ESpos): m / z = 375 (M + H) ^{+ 1} H-NMR (400 MHz, DMSO-d ₆ ) 8 [ppm]: 1.294 (8.12), 1.312 (8.19), 2.123 (16.00), 2.279 (11.36), 3.530 (0.63), 3.547 (2.07), 3.564 (2.03), 3.581 (0.60), 5.270 (6.43), 6.722 (3.65), 7.202 (0.37), 7.212 (1.99), 7.232 (3.56), 7.252 (2.32), 7.261 (0.36), 7.381 (3.28), 7.547 (0.37), 7.564 (0.88), 7.568 (0.81), 7.585 (1.44), 7.602 (0.77), 7.606 (0.78), 7.623 (0.33).

Example 3 rac-2-amino-2- (4-chloro-1-yl) -N- {8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3 yljacetamid

 56 mg (0.082 mmol) of rac-tert-butyl [1- (4-chlorophenyl) -2- ({8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} amino) -2-oxoethyl] carbamate trifluoroacetate from Example 4A were treated with 0.5 ml of dichloromethane and 0.5 ml of trifluoroacetic acid and stirred for 2.5 hours at room temperature. The reaction solution was concentrated and the residue was purified by means of thick layer chromatography (mobile phase: dichloromethane: methanol = 10/1). The product was isolated and again purified by thick layer chromatography (eluent: dichloromethane / 2N ammonia in methanol = 10/1). 25 mg (65% of theory, purity 98%) of the title compound were obtained.

LC-MS (Method 2): R _t = 0.56 min

MS (ESpos): m / z = 471 (M + H) + Ή-NMR (400 MHz, DMSO-de) δ [ppm]: 2.038 (16.00), 2.203 (11.94), 4.665 (3.76), 5.254 (6.45), 6.706 (3.79), 7.072 (3.51), 7.192 (0.40) , 7,201 (2,10), 7,221 (3.83), 7,241 (2.52), 7,250 (0.64), 7,458 (3.93), 7,480 (5.81), 7,539 (0.48), 7,567 (5.85), 7,588 (4.21), 7,613 (0.50) ,

Example 4 rac-3-amino-2- (4-chlorobenzyl) -N- {8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl-propanamide

142 mg (0.197 mmol, purity 99%) of rac-tert-butyl [2- (4-chlorobenzyl) -3- ({8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [l, 2-a] pyridin-3-yl} amino) -3-oxopropyl] carbamate trifluoroacetate from Example 5A were treated with 1.2 ml of dichloromethane and 1.2 ml of trifluoroacetic acid and stirred for 2.5 hours at room temperature. The reaction solution was concentrated and the residue was purified by means of thick-layer chromatography (mobile phase: dichloromethane / methanol = 10/1). The product was isolated and again purified by thick layer chromatography (eluent: dichloromethane / 2N ammonia in methanol = 10/1). There was obtained 62 mg (62% of theory) of the title compound. LC-MS (Method 2): R _t = 0.62 min

MS (ESpos): m / z = 499 (M + H)

Ή NMR (400 MHz, DMSO-de) δ [ppm]: 0.000 (16.00), 1.995 (6.63), 2.210 (5.78), 2.812 (0.64), 2.842 (2.82), 2.869 (0.53), 5.249 (2.93) , 6,681 (1.81), 6,925 (1.50), 7,190 (0.24), 7,200 (0.97), 7,220 (1.78), 7,240 (1.09), 7,252 (0.23), 7,284 (1.59), 7,305 (2.34), 7,379 (2.56) , 7.400 (1.68), 7.538 (0.19), 7.557 (0.45), 7.575 (0.67), 7.596 (0.40), 7.615 (0.15).

Example 5 rac-2-amino-N- {8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} -2- (4-fluorophenyl) acetamide

77 mg (0.098 mmol, purity 85%) of rac-tert-butyl [2 - ({8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-. yl} amino) -1- (4-fluorophenyl) -2-oxoethyl] carbamate trifluoroacetate from Example 6A were treated with 0.5 ml of dichloromethane and 0.5 ml of trifluoroacetic acid and stirred for 2.5 hours at room temperature. The reaction solution was concentrated and the residue was purified by means of thick-layer chromatography (mobile phase: dichloromethane / methanol = 10/1). The product was isolated and again purified by thick layer chromatography (eluent: dichloromethane / 2N ammonia in methanol = 10/1). 31 mg (68% of theory, purity 98%) of the title compound were obtained. LC-MS (Method 2): R _t = 0.52 min

MS (ESpos): m / z = 455 (M + H) ⁺

^! H-NMR (500 MHz, DMSO-de) δ [ppm]: 2,035 (16:00), 2,201 (10:53), 4,665 (4.03), 5,254 (5:65), 6,705 (3.34), 7,076 (3.12), 7,197 (0.33) , 7,205 (1.90), 7,215 (2.72), 7,220 (3.67), 7,232 (4.78), 7,236 (3.19), 7,246 (1.09), 7,250 (2.38), 7,256 (0.35), 7,545 (0.32), 7,558 (0.78) , 7.562 (0.75), 7.576 (3.31), 7.587 (2.88), 7.593 (2.87), 7.600 (1.01), 7.604 (2.19).

Example 6 rac-4-chloro-N- {8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridm-3-yl} phenylalanine amide

 60 mg (0.08 mmol, purity 98%) rac-N-alpha - [(benzyloxy) carbonyl] -4-chloro-N- {8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [l , 2-a] pyridin-3-yl} phenylalaninamide trifluoroacetate from Example 7A were treated with 1.2 ml of trifluoroacetic acid and stirred for 7 days at room temperature. The reaction mixture was mixed with acetonitrile and water and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1%> TFA). The product fractions were combined and concentrated. The residue was taken up in dichloromethane and a little methanol and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 33 mg of the target compound (84% of theory, purity 98%) were obtained.

LC-MS (Method 2): R _t = 0.60 min

MS (ESpos): m / z = 485 (M + H) ⁺

^! H-NMR (400 MHz, DMSO-de) δ [ppm]: 2,045 (16:00), 2,250 (12:41), 2,840 (0.74), 2,858 (0.82), 2,874 (1.32), 2,892 (1.31), 2,958 (1.30) , 2,974 (1.37), 2,991 (0.79), 3,007 (0.82), 3,689 (1:00), 3,706 (1.92), 3,723 (0.91), 5,258 (6.62), 6,705 (3.99), 7,077 (3.43), 7,198 (0.35) , 7,208 (2:00), 7,228 (3.73), 7,247 (2.36), 7,257 (0.42), 7,309 (3.04), 7,330 (6:00), 7,369 (6.25), 7,390 (3,10), 7,544 (0.38), 7,561 (0.89) , 7.582 (1.43), 7.602 (0.80), 7.619 (0.31).

Example 7 rac-3-Amino-2- (4-chloro-1-yl) -N- {8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3 yljpropanamid

143 mg (0.205 mmol) of rac-tert-butyl [2- (4-chlorophenyl) -3- ({8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} amino) -3-oxopropyl] carbamate trifluoroacetate from Example 8A were admixed with 0.75 ml of dichloromethane and 0.75 ml of trifluoroacetic acid and stirred for 40 minutes at room temperature. The reaction solution was concentrated and the residue was purified by means of thick-layer chromatography (mobile phase: dichloromethane / methanol = 10/1). The product was isolated and again purified by thick layer chromatography (eluent: dichloromethane / 2N ammonia in methanol = 10/1). 57 mg (54% of theory, purity 94%) of the title compound were obtained. LC-MS (Method 2): R _t = 0.58 min

MS (ESpos): m / z = 485 (M + H) ⁺

^! H-NMR (400 MHz, DMSO-de) δ [ppm]: 2,048 (16:00), 2,217 (10.74), 2,865 (0.91), 2,879 (1.03), 2,896 (1.16), 2,910 (1.07), 3,178 (1.04) , 3,201 (1.24), 3,209 (1:00), 3,231 (0.96), 3,801 (1.02), 3,815 (1.16), 3,824 (1.13), 3,838 (0.91), 5,258 (5.80), 6,713 (3.45), 7,192 (3.34) , 7,203 (2:09), 7,223 (3.53), 7,243 (2.41), 7,410 (1.71), 7,415 (0.86), 7,431 (7.45), 7,445 (7.86), 7,461 (0.85), 7,466 (1.78), 7,540 (0.36) , 7,557 (0.86), 7,561 (0.78), 7,578 (1.43), 7,595 (0.76), 7,599 (0.79), and 7,616 (0.36).

Example 8 rac-3-amino-3- (4-chloro-1-yl) -N- {8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3 yljpropanamid

158 mg (0.224 mmol, purity 99%) of rac-tert-butyl [1- (4-chlorophenyl) -3- ({8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [l, 2-a] pyridin-3-yl} amino) -3-oxopropyl] carbamate trifluoroacetate from Example 9A were mixed with 1.4 ml of dichloromethane and 1.4 ml of trifluoroacetic acid and stirred for 2.5 hours at room temperature. The reaction solution was concentrated and the residue was purified by means of thick-layer chromatography (mobile phase: dichloromethane / methanol = 10/1). The product was isolated and again purified by thick layer chromatography (eluent: dichloromethane / 2N ammonia in methanol = 10/1). 63 mg (57% of theory, purity 98%) of the title compound were obtained. LC-MS (Method 17): R _t = 1.48 min MS (ESpos): m / z = 485 (M + H) ⁺

^! H-NMR (400 MHz, DMSO-de) δ [ppm]: 2,058 (16:00), 2,231 (13.36), 2,654 (0.33), 2,671 (0.58), 2,689 (2.36), 2,695 (2.50), 2,706 (2.38) , 2,714 (2.13), 2,730 (0.30), 2,749 (0.28), 4,306 (1.08), 4,324 (2.04), 4,342 (1:00), 5,255 (6.72), 6,695 (4.11), 7,079 (3.56), 7,193 (0.56) , 7,203 (2.30), 7,223 (4.14), 7,242 (2.63), 7,251 (0.59), 7,402 (3.22), 7,423 (6.39), 7,460 (6.23), 7,482 (3.05), 7,541 (0.48), 7,558 (0.98) , 7,578 (1.55), 7,598 (0.89), 7,616 (0.36).

Example 9

2- (4-chlorophenyl) -N- {8 - [(2,6-difluorobenzyl) oxy] -2-methylimidazo [l, 2-a] pyridin-3-yl} acetamide

 18.6 mg (0.11 mmol) of (4-chlorophenyl) acetic acid were charged with 35 mg (0.11 mmol) of bis (dimethylamino) (3-oxo-1H-benzotriazol-1-yl) methylium tetrafluoroborate and 55 .mu.l of 4-methylmorpholine in 1 ml of dichloromethane and Stirred for 10 minutes at room temperature. Subsequently, 29 mg (0.10 mmol, purity 80%) of 8 - [(2,6-difluorobenzyl) oxy] -2-methylimidazo [l, 2-a] pyridin-3-amine from Example 13A were added to the reaction solution and 2 days Room temperature stirred. The reaction mixture was concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: methanol / water gradient with the addition of 0.1% TFA). The product fractions were concentrated, the residue dissolved in ethyl acetate, washed once with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered, concentrated and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1%) TFA). The product fractions were concentrated, the residue dissolved in ethyl acetate, washed once with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. 20 mg (46% of theory) of the target compound were obtained.

LC-MS (Method 2): R _t = 0.89 min

MS (ESPOS): m / z = 442 (M + H) ⁺

Ή NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2,135 (15.36), 3,769 (9.28), 5,279 (6.27), 6,781 (0.90), 6,800 (2.37), 6,820 (2.88), 6,822 (3.07 ), 6.839 (0.90), 7.189 (0.38), 7.204 (2.05), 7.224 (3.58), 7.244 (2.37), 7.253 (0.45), 7.392 (0.64), 7.401 (0.51), 7.417 (16.00), 7.432 (0.45 ), 7.439 (0.58), 7.506 (1.86), 7.510 (1.92), 7.522 (1.86), 7.525 (1.79), 7.540 (0.45), 7.556 (0.90), 7.560 (0.83), 7.578 (1.54), 7.594 (0.77 ), 7,599 (0.77), 7,615 (0.38), 10,019 (2.88). Example 10

N- {8 - [(2,6-difluorobenzyl) oxy] -2-m th H ^

 138 mg (1.04 mmol) of aluminum trichloride were suspended in 8.0 ml of 1,2-dichloroethane, admixed with 198 mg (1.04 mmol) of (3,4-difluorophenyl) acetyl chloride and stirred at room temperature for 20 minutes. Then, 200 mg (0.69 mmol) of 8 - [(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-amine, Example 13A, were added and stirred under reflux overnight. The reaction mixture was concentrated, the residue taken up in ethyl acetate and poured onto ice-water. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (eluent: dichloromethane / methanol = 100/1). The product fractions were combined, concentrated, dissolved in ethyl acetate and washed three times with saturated aqueous sodium bicarbonate solution. Then washed once more with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered, the filtrate was concentrated and dried under high vacuum. There were obtained 106 mg (35% of theory) of the target compound.

LC-MS (Method 2): R _t = 0.83 min

MS (ESpos): m / z = 444 (M + H) ⁺ Ή-NMR (400 MHz, DMSO-de) δ [ppm]: 2.143 (16.00), 3.792 (8.37), 5.282 (6.54), 6.787 (0.81 ), 6,806 (2.43), 6,822 (4.18), 6,827 (3.32), 6,843 (0.86), 7,195 (0.43), 7,205 (2.54), 7,225 (4.54), 7,245 (3.10), 7,255 (0.52), 7,383 (0.83 ), 7.404 (1.54), 7.410 (0.97), 7.425 (1.45), 7.431 (2.08), 7.445 (0.82), 7.453 (1.48), 7.459 (0.80), 7.474 (0.74), 7.479 (0.71), 7.544 (2.04 ), 7,547 (2.02), 7,559 (2.59), 7,562 (2.54), 7,578 (1.62), 7,595 (0.86), 7,599 (0.94), 7,616 (0.36), 9,983 (3.38).

Example 11 N- {8 - [(2,6-difluorobenzyl) oxy] -2,6-dimethylim ^

yl) acetamide

 28.6 mg (200 .mu.mol) of (2-oxopyrrolidin-1-yl) acetic acid were placed on a MTP (microtiter plate). 76 mg (200 μιηοΐ) of [0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate] were dissolved in 400 μΐ Ν, Ν-dimethylformamide and added to the carboxylic acid. The MTP was shaken for 10 minutes at room temperature. Subsequently, 30.3 mg (100 μmol) of 8- [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-amine were dissolved in 400 μl of N, N-dimethylformamide and added to the reaction solution followed by 50 μΐ (455 μιηοΐ) of 4-methylmorpholine. The reaction solution was shaken overnight at room temperature, filtered off and separated by LC / MS. 8.4 mg (18% of theory, purity 90%) of the target compound were obtained.

LC-MS (Method 10): R _t = 0.69 min

MS (ESpos): m / z = 429 (M + H) ⁺

The following examples were prepared in analogy to Example 11:

IUPAC name

 structure

 example

 yield

 Analytical data

 (6% of the time)

LC-MS (Method 10): R _t = 0.83 min; m / z = 402 [M + H] ⁺ .

(2E) - N - {8 - [(2,6-Difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} -3- (pyridin-4-yl) acrylamide

C H 3Q

18

CH ₃

 (25% of the time)

LC-MS (Method 10): R _t = 0.70 min; m / z = 435 [M + H] ⁺ .

N- {8 - [(2,6-Difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} -5-methyl-1H-pyrazole-3-carboxamide

19

CH ₃

 (42% of the time)

LC-MS (Method 10): R _t = 0.74 min; m / z = 412 [M + H] ⁺ .

20 N - {8 - [(2,6-Difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} -N ² , N ² -dimethylglycine amide

IUPAC name

 structure

 example

 yield

 Analytical data

 (46% of theory)

LC-MS (Method 10): R _t = 0.78 min; m / z = 388 [M + H] ⁺ .

Example 31 rac-1 - {8 - [(2,6-Difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} -3- [1- (3,4-difluorophenyl) ethyl ]urea

150 mg (0.37 mmol) of phenyl {8 - [(2,6-difluorobenzyl) oxy] -2-methylimidazo [l, 2-a] pyridin-3-yl} carbamate from Example 14A were dissolved in 5 ml of THF and washed with Add 1.19 ml of pyridine and 58 mg (0.37 mmol) of rac-1 - (3,4-difluorophenyl) ethanamine. The mixture was stirred in the microwave at 100 ° C for 1 h. The reaction mixture was then evaporated and purified by preparative HPLC (RP18 Column, eluent: acetonitrile / water gradient). 97 mg (55% of theory) of the title compound were obtained.

LC-MS (Method 8): R _t = 0.76 min MS (ESpos): m / z = 473 (M + H) ⁺ Example 32 l- {8 - [(2,6-Difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} -3 - [(2S) -hexan-2-yl] urea

 150 mg (0.37 mmol) of phenyl {8 - [(2,6-difluorobenzyl) oxy] -2-methylimidazo [l, 2-a] pyridin-3-yl} carbamate from Example 14A were dissolved in 5 ml of THF and washed with 1.19 ml of pyridine and 37 mg (0.37 mmol) of (2S) -hexan-2-amine were added. The mixture was stirred in the microwave at 100 ° C for 1 h. The reaction mixture was then evaporated and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient). 73 mg (48% of theory) of the title compound were obtained.

LC-MS (Method 2): R _t = 0.83 min

MS (ESpos): m / z = 417 (M + H)

B. Evaluation of Pharmacological Activity

The following abbreviations are used:

ATP adenosine triphosphate

 Brij35 polyoxyethylene (23) lauryl ether

BSA bovine serum albumin

 DTT dithiothreitol

TEA triethanolamine

The pharmacological activity of the compounds according to the invention can be demonstrated in the following assays:

B-l. Measurement of sGC enzyme activity by PPi detection

Soluble guanylyl cyclase (sGC) converts GTP to cGMP and pyrophosphate (PPi) upon stimulation. PPi is detected by the method described in WO 2008/061626. The signal generated in the test increases as the reaction progresses and serves as a measure of the sGC enzyme activity. By means of a PPi reference curve, the enzyme can be characterized in a known manner, e.g. in terms of turnover rate, stimulability or Michaelis constant.

Execution of the test

To perform the assay, 29 μM enzyme solution (0-10 nM soluble guanylyl cyclase (prepared according to Hönicka et al., Journal of Molecular Medicine 77 (1999) 14-23) was dissolved in 50 mM TEA, 2 mM magnesium chloride, 0.1% BSA (fraction V ), 0.005% Brij 35, pH 7.5) in the microplate and 1 μΕ of the stimulator solution (0-10 μΜ 3-Morpholinosydnonimine, SIN-1, Merck in DMSO) added. It was incubated at RT for 10 min. Subsequently, 20 μM detection mix (1.2 nM firefly luciferase {Photinus pyralis luciferase, Promega), 29 μM dehydro-luciferin (prepared according to Bitler & McElroy, Arch. Biochem., Biophys., 72 (1957) 358), 122 μ l luciferin (Promega ), 153 μM ATP (Sigma) and 0.4 mM DTT (Sigma) in 50 mM TEA, 2 mM magnesium chloride, 0.1% BSA (fraction V), 0.005% Brij 35, pH 7.5). The enzyme reaction was started by addition of 20 .mu.ΐ substrate solution (1.25 mM guanosine 5'-triphosphate (Sigma) in 50 mM TEA, 2 mM magnesium chloride, 0.1%> BSA (fraction V), 0.005%) Brij 35, pH 7.5) and measured continuously luminometrically. B-2. Effect on recombinant guanylate cyclase reporter cell line

The cellular activity of the compounds of the invention is measured on a recombinant guanylate cyclase reporter cell line as described in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005). Representative MEC values (MEC = minimum effective concentration) for the compounds according to the invention are given in the table below (in part as mean values from individual determinations):

Table A:

Example MEC [μΜ] Example MEC [μΜ]

1 0.3 15 10.0

2 10.0 16 10.0

3 3.0 17 1.0

4 10.0 18 3.0

5 3.0 19 10.0

6 10 20 3.0

7 3.0 21 3.0

8 3.0 22 3.0

9 1.0 23 10.0

10 1.0 24 3.0

11 3.0 25 10.0

12 0.3 26 3.0

13 0.3 27 3.0

14 3.0 28 1.0 Example MEC [μΜ] Example MEC [μΜ]

29 3.0 31 3.0

30 3.0 32 10.0

B-3. Vaso-relaxant effect in vitro

Rabbits are stunned and bled by a stroke of the neck. The aorta is harvested, detached from adherent tissue, divided into 1.5 mm wide rings and placed individually under bias in 5 ml organ baths with 37 ° C warm, carbogen-fumed Krebs-Henseleit solution of the following composition (in each case mM): Sodium chloride: 119; Potassium chloride: 4.8; Calcium chloride dihydrate: 1; Magnesium sulfate heptahydrate: 1.4; Potassium dihydrogen phosphate: 1.2; Sodium hydrogencarbonate: 25; Glucose: 10. The force of contraction is detected with Statham UC2 cells, amplified and digitized via A / D converter (DAS-1802 HC, Keithley Instruments Munich) and registered in parallel on a chart recorder. To create a contraction, phenylephrine is added cumulatively to the bath in increasing concentration. After several control cycles, the substance to be examined is added in each subsequent course in increasing dosages and the height of the contraction is compared with the height of the contraction achieved in the last predistortion. This is used to calculate the concentration required to reduce the level of the control value by 50% (IC ₅ o value). The standard application volume is 5 μΐ, the DMSO content in the bath solution corresponds to 0.1%>.

B-4. Blood pressure measurement on anesthetized rats

Male Wistar rats weighing 300-350 g are anesthetized with thiopental (100 mg / kg i.p.). After tracheostomy, a catheter is inserted into the femoral artery to measure blood pressure. The substances to be tested are administered as solutions either orally by gavage or by the femoral vein (Stasch et al., Br. J. Pharmacol., 2002; 135: 344-355).

B-fifth Radiotelemetric blood pressure measurement on awake, spontaneously hypertensive rats

 A commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA is used for the blood pressure measurement on awake rats described below. The system consists of 3 main components:

Implantable transmitters (Physiotel® telemetry transmitters) Receivers (Physiotel® receivers) connected to a data acquisition computer through a multiplexer (DSI Data Exchange Matrix).

The telemetry system allows a continuous recording of blood pressure heart rate and body movement on awake animals in their habitual habitat. animal material

The investigations are carried out on adult female spontaneously hypertensive rats (SHR Okamoto) with a body weight of> 200 g. SHR / NCrl from Okamoto Kyoto School of Medicine, 1963 were crossed out of male Wistar Kyoto rats with high blood pressure and female with slightly elevated blood pressure, and in Fl 3 with U.S. Patent No. 4,806,014. National Institutes of Health.

The experimental animals are kept individually in macroion cages type 3 after transmitter implantation. You have free access to standard food and water.

The day - night rhythm in the experimental laboratory is changed by room lighting at 6:00 in the morning and at 19:00 in the evening. transmitter implantation

The TAI 1 PA - C40 telemetry transmitters are surgically implanted into the experimental animals under aseptic conditions at least 14 days before the first trial. The animals so instrumented are repeatedly used after healing of the wound and ingrowth of the implant. For implantation, the fasting animals are anesthetized with pentobabital (Nembutal, Sanofi: 50 mg / kg i.p.) and shaved and disinfected on the ventral side. After opening the abdominal cavity along the alba line, the system's fluid-filled measuring catheter above the bifurcation is inserted cranially into the descending aorta and secured with tissue adhesive (VetBonD ™, 3M). The transmitter housing is fixed intraperitoneally to the abdominal wall musculature and the wound is closed in layers.

Postoperatively, an antibiotic is administered for infection prophylaxis (Tardomyocel COMP Bayer lml / kg s.c.)

Substances and solutions

Unless otherwise described, the substances to be tested are each administered orally to a group of animals (n = 6) by gavage. Corresponding to an application volume of 5 ml / kg body weight, the test substances are dissolved in suitable solvent mixtures or suspended in 0.5% Tylose.

A solvent-treated group of animals is used as a control. Experimental procedure The existing telemetry measuring device is configured for 24 animals. Each trial is registered under a trial number (VYear month day).

The instrumented rats living in the plant each have their own receiving antenna (1010 receivers, DSI).

The implanted transmitters can be activated externally via a built-in magnetic switch. They will be put on the air during the trial run. The emitted signals can be recorded online by a data acquisition system (Dataquest ™ A.R.T. for Windows, DSI) and processed accordingly. The storage of the data takes place in each case in a folder opened for this purpose which carries the test number.

Systolic blood pressure (SBP) Diastolic blood pressure (DBP) Arterial mean pressure (MAP) Heart rate (HR) Activity (ACT) The measured value acquisition is repeated computer-controlled at 5-minute intervals. The absolute value of the source data is corrected in the diagram with the currently measured barometric pressure (Ambient Pressure Reference Monitor, APR-1) and stored in individual data. Further technical details can be found in the extensive documentation of the manufacturer (DSI).

Unless otherwise stated, the administration of the test substances will take place on the day of the experiment at 9.00. Following the application, the parameters described above are measured for 24 hours.

evaluation

After the end of the test, the collected individual data are sorted with the analysis software (DATAQUEST TM ART TM ANALYSIS). Blank values are assumed 2 hours before application, so that the selected record covers the period from 7:00 am on the trial day to 9:00 am the following day.

The data is smoothed over a presettable time by averaging (15 minutes average) and transferred as a text file to a disk. The presorted and compressed measured values are transferred to Excel templates and displayed in tabular form. The filing of the collected data takes place per experiment day in a separate folder that bears the test number. Results and test reports are sorted in folders and sorted by paper.

Literature:

Klaus Witte, Kai Hu, Johanna Swiatek, Claudia Müssig, Georg Ertl and Björn Lemmer: Experimental heart failure in rats: effects on cardiovascular circadian rhythms and on myocardial beta-adrenergic signaling. Cardiovasc Res 47 (2): 203-405, 2000; Kozo Okamoto: Spontaneous hypertension in rats. Int Rev. Exp Pathol 7: 227-270, 1969; Maarten van den Buuse: Circadian Rhythms of Blood Pressure, Heart Rate, and Locomotor Activity in Spontaneously Hypertensive Rats as Measured with Radio Telemetry. Physiology & Behavior 55 (4): 783-787, 1994. B-6. Determination of pharmacokinetic parameters after intravenous and oral administration

The pharmacokinetic parameters of the compounds of the invention are determined in male CD-1 mice, male Wistar rats and female beagle dogs. Intravenous administration is in mice and rats using a species-specific plasma / DMSO formulation and in dogs using a water / PEG400 / ethanol formulation. Oral administration of the solute by gavage is performed in all species based on a water / PEG400 / ethanol formulation. Rats are placed in the right external jugular vein for ease of blood sampling prior to drug administration. The operation is carried out at least one day before the experiment under isoflurane anesthesia and with the administration of an analgesic (atropine / rimadyl (3/1) 0.1 mL s.c.). The blood collection (usually more than 10 times) takes place in a time window, which includes terminal times of at least 24 to a maximum of 72 hours after substance administration. The blood is transferred to heparinized tubes at collection. So then the blood plasma is recovered by centrifugation and optionally stored at -20 ° C until further processing.

An internal standard is added to the samples of the compounds according to the invention, calibration samples and qualifiers (this may also be a chemically unrelated substance) and protein precipitation by means of acetonitrile follows in excess. After addition of a buffer solution adapted to the LC conditions and subsequent vortexing, it is centrifuged at 1000 g. The supernatant is analyzed by LC-MS / MS using C18 reversed-phase columns and variable eluent Measure mixtures. The quantification of the substances is based on the peak heights or areas of extracted ion chromatograms of specific selected ion monitoring experiments.

The pharmacokinetic parameters such as AUC, Cmax, ti 2 (terminal half-life), F (bioavailability), MRI (Mean Residence Time) and CL (clearance) are calculated from the plasma concentration-time profiles determined by means of a validated pharmacokinetic calculation program.

Since the substance quantification is carried out in plasma, the blood / plasma distribution of the substance must be determined in order to adjust the pharmacokinetic parameters accordingly. For this purpose, a defined amount of substance is incubated in heparinized whole blood of the corresponding species for 20 min in a tumble roll mixer. After centrifugation at 1000 g, the concentration in the plasma is measured (by means of LC-MS / MS, see _above ) and determined by quotient formation of the CBiut / Cpi _aS ma value.

B. 7 Metabolism investigation

To determine the metabolism profile of the compounds according to the invention, they are incubated with recombinant human cytochrome P450 (CYP) enzymes, liver microsomes or with primary fresh hepatocytes of various animal species (eg rat, dog) as well as of human origin in order to obtain information on as complete hepatic phase I as possible and phase Ii metabolism as well as the enzymes involved in the metabolism and to compare.

The compounds of the invention were incubated at a concentration of about 0.1 -10 μΜ. For this purpose, stock solutions of the compounds according to the invention with a concentration of 0.01-1 mM in acetonitrile were prepared, and then pipetted with a 1: 100 dilution into the incubation mixture. The liver microsomes and recombinant enzymes were incubated in 50 mM potassium phosphate buffer pH 7.4 with and without NADPH-generating system consisting of 1 mM NADP ⁺ , 10 mM glucose-6-phosphate and 1 unit glucose-6-phosphate dehydrogenase at 37 ° C. Primary hepatocytes were also incubated in suspension in Williams E medium also at 37 ° C. After an incubation period of 0-4 h, the incubation mixtures were stopped with acetonitrile (final concentration about 30%) and the protein was centrifuged off at about 15,000 × g. The samples thus stopped were either analyzed directly or stored at -20 ° C until analysis.

The analysis is carried out by means of high performance liquid chromatography with ultraviolet and mass spectrometric detection (HPLC-UV-MS / MS). For this, the supernatants of the incubation samples are chromatographed with suitable C18-reversed-phase columns and variable eluent mixtures of acetonitrile and 10 mM aqueous ammonium formate solution or 0.05% formic acid. The UV chromatograms in combination with mass spectrometry data are used for identification, Structure clarification and quantitative estimation of the metabolites, and the quantitative metabolic decrease of the compound according to the invention in the incubation mixtures.

B-eighth Caco-2 permeability test

The permeability of a test substance was determined using the Caco-2 cell line, an established in vitro model for permeability predictions at the gastrointestinal barrier (Artursson, P. and Karlsson, J. (1991) Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells, Biochem., Biophys. 175 (3), 880-885). The Caco-2 cells (ACC No. 169, DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany) were seeded in 24-well plates and cultured for 14 to 16 days. For the permeability studies, the test substance was dissolved in DMSO and diluted to the final test concentration with transport buffer (Hanks Buffered Salt Solution, Gibco / Invitrogen, with 19.9 mM glucose and 9.8 mM HEPES). To determine the permeability from apical to basolateral (P _app AB) of the test substance, the solution containing the test substance was added to the apical side of the Caco-2 cell monolayer and transport buffer to the basolateral side. To determine the permeability from basolateral to apical (P _app BA) of the test substance, the solution containing the test substance was added to the basolateral side of the Caco-2 cell monolayer and transport buffer to the apical side. At the beginning of the experiment, samples were taken from the respective donor compartment to ensure mass balance. After incubation for two hours at 37 ° C, samples were taken from both compartments. The samples were analyzed by LC-MS / MS and the apparent permeability coefficients (P _apP ) were calculated. The permeability of Lucifer Yellow was determined for each cell monolayer to ensure the integrity of the cell layer. The permeability of atenolol (low permeability marker) and sulfasalazine (active excretion marker) was determined in each run as a quality control.

B. 9 hERG potassium current assay

The so-called hERG (human ether-a-go-go related gene) potassium current contributes significantly to the repolarization of the human cardiac action potential (Scheel et al., 2011). Inhibition of this current by drugs may, in rare cases, result in potentially lethal cardiac arrhythmias, and therefore, be investigated early during drug development.

The functional hERG assay used here is based on a recombinant HEK293 cell line stably expressing the KCNH2 (HERG) gene (Zhou et al., 1998). These cells are assayed by the whole-cell voltage-clamp technique (Hamill et al., 1981) in an automated system (Patchliner ™, Nanion, Munich, D) which controls membrane voltage and hERG potassium current at room temperature measures. The PatchControlHT ™ software (Nanion) controls patchliner system, data acquisition and data analysis. The voltage is controlled by 2 EPC-10 quadro amplifiers under the control of the PatchMasterPro ™ software (both: HEKA Elektronik, Lambrecht, D). NPC-16 medium resistance chips (~ 2 Ω, Nanion) serve as a planar substrate for the voltage-clamp experiments.

 NPC-16 chips are filled with intra- and extracellular solution (see Himmel, 2007) as well as with cell suspension. After forming a giga-ohm seal and preparing the whole-cell mode (including several automated quality control steps), the cell membrane is clamped to the holding potential -80 mV. The following voltage clamping protocol changes the command voltage to +20 mV (duration 1000 ms), -120 mV (duration 500 ms), and back to the holding potential -80 mV; this is repeated every 12 seconds. After an initial stabilization phase (about 5-6 minutes), the test substance solution is pipetted in ascending concentrations (for example 0.1, 1 and 10 μιηοΙ / L) (exposure for about 5-6 minutes per concentration), followed by several wash-out steps.

The amplitude of the inward tail current generated by a potential change from +20 mV to -120 mV serves to quantify the hERG potassium current and is represented as a function of time (IgorPro ™ software). The current amplitude at the end of different time periods (e.g., test substance stabilization phase, first / second / third test substance concentration) is used to generate a concentration-response curve from which the half-maximal inhibitory concentration IC50 of the test substance is calculated.

Hamill OP, Marty A, Neher E, Sakman B, Sigworth FJ. Improved patch-clamp techniques for high-resolution current recording from cell and cell-free membrane patches. Pfluegers Arch 1981; 391: 85-100.

 Heaven HM. Suitability of commonly used excipients for electrophysiological in vitro safety pharmacology assessment of effects on hERG potassium current and on rabbit Purkinje fiber action potential. J Pharmacol Toxicol Methods 2007; 56: 145-158.

Scheel O, Himmel H, Rascher-Eggstein G, Knott T. Introduction of a modular automated voltage-clamp platform and its correlation with manual human-a-go-go related gene voltage-clamp data. Assay Drag Dev Technol 2011; 9: 600-607.

Zhou ZF, Gong Q, Ye B, Fan Z, Makielski JC, Robertson GA, January CT. Properties of hERG

Channels stably expressed in HEK293 cells studied at physiological temperature. Biophys J

1998; 74: 230-241.

Claims

 claims

1. Compound of formula (I)

 in which

A is CH ₂ , CD ₂ or CH (CH ₃ ), R ^{1 is} phenyl, where phenyl having 1 to 4 substituents independently of one another selected from the group halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl and (C 1 -C 4) - Alkyl may be substituted,

R ^{2 is} hydrogen, (C 1 -C 4) -alkyl, cyclopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl, R ^{3 is} a group of the formula

 stands, where

* represents the point of attachment to the carbonyl group,

L ^{1 is} a bond, -C (R ^U R ¹² ) -, oxygen, sulfur or nitrogen,

R ^{7 is} hydrogen, (C 1 -C ₄ ) -alkyl or amino, in which (C 1 -C ₄ ) -alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, hydroxy and amino, R ^{8 is} hydrogen or (C 1 -C ₄ ) -alkyl, or

R ⁷ and R ⁸ together with the carbon atom to which they are attached form a 3- to 5-membered carbocycle in which the 3- to 5-membered carbocycle may be substituted up to two times by fluorine,

R ^{9 is} hydrogen, (C ₁ -C ₆ ) -alkyl, -NR ¹³ R ¹⁴ , -NO ₂ NR ¹⁵ R ¹⁶ , (C ₃ -C ₇ ) -cycloalkyl, (C ₄ -Cv) -heterocyclyl, 5- or 6-membered heteroaryl or phenyl, in which (C 1 -C 6) -alkyl having 1 to 3 substituents independently of one another selected from the group of fluorine, trifluoromethyl, difluoromethoxy, hydroxy, (C 1 -C 4) -alkoxy, (C 3 -C 4) - Cycloalkyl, (C4-Cv) -heterocyclyl and 5- or 6-membered heteroaryl may be substituted, wherein R ^{13 is} hydrogen, (Ci-C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl, wherein (C3 -Cv) -cycloalkyl having 1 or 2 substituents independently selected from the group fluorine or methyl may be substituted, wherein R ^{14 is} hydrogen or (Ci-C i) -alkyl, wherein R ^{15 is} hydrogen or (Ci-C i ) Alkyl, and wherein R ^{16 is} hydrogen or (Ci-C i) -alkyl, wherein phenyl having 1 to 3 substituents independently selected from the group halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl and (Ci- C i ) alk yl may be substituted, wherein 5- or 6-membered heteroaryl may be substituted with 1 or 2 substituents independently selected from the group halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl and (Ci-C i) alkyl, wherein (C3- Cv) -cycloalkyl having 1 or 2 substituents independently of one another can be substituted from the group fluorine or methyl, wherein (C 4 -C 4) -heterocyclyl may be substituted by 1 or 2 substituents independently of one another selected from the group fluorine or methyl,

R ^{11 is} hydrogen, (C 1 -C 4) -alkyl or amino, in which (C 1 -C 4) -alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, hydroxy and amino,

R ^{12 is} hydrogen or (Ci-C ₄ ) -alkyl, or

R ¹¹ and R ¹² together with the carbon atom to which they are attached form a 3- to 5-membered carbocycle wherein the 3- to 5-membered carbocycle may be substituted up to two times by fluorine, or

R ⁷ and R ¹¹ together with the carbon atoms to which they are attached form a 3- to 5-membered carbocycle, wherein the 3- to 5-membered carbocycle may be substituted up to two times by fluorine, or

R ^{3 is} a group of the formula

 stands, where

* is the point of attachment to the carbonyl group, L ^{2 is} a bond or -C = C-,

R ^{10 is} 5- or 6-membered heteroaryl or (C 5 -C 4) -heterocyclyl, in which 5- or 6-membered heteroaryl having 1 to 3 substituents independently of one another are selected from the group halogen, trifluoromethyl or (C 1 -C 4) -alkyl may be substituted and wherein 5-membered heteroaryl may be annealed with (C5-Cv) -cycloalkyl, wherein (C5-Cv) -cycloalkyl may be substituted with 1 or 2 substituents independently selected from the group consisting of halogen or (Ci-C i) -alkyl , or

R ^{3 is} a group of the formula

stands, where

R ^{17 is} (C 1 -C ₈ ) -alkyl, wherein (C 1 -C ₈ ) -alkyl may be substituted by phenyl or 5- or 6-membered heteroaryl, wherein phenyl having 1 to 3 substituents independently selected from the group consisting of halogen or (Ci-C i) -alkyl may be substituted, wherein 5- or 6-membered heteroaryl may be substituted with 1 to 3 substituents independently selected from the group halogen or (Ci-C i) -alkyl,

R ^{4 is} hydrogen,

R ^{5 is} hydrogen, chlorine, fluorine, difluoromethyl, trifluoromethyl or (Ci-C i) alkyl, R ^{6 is} hydrogen or chlorine, and their N-oxides, salts, solvates, salts of N-oxides and solvates of the N Oxides and salts. 2. A compound of the formula (I) according to claim 1, in which A is CH ₂ , R ^{1 is} phenyl, where phenyl having 1 or 2 substituents independently of one another can be substituted by fluorine, chlorine or methyl,

R ^{2 is} methyl, a group of the formula

 stands, where

* represents the point of attachment to the carbonyl group,

L ^{1 is} a bond, -C (R ^U R ¹² ) -, oxygen or sulfur,

R ^{7 is} hydrogen, (Ci-C i) -alkyl or amino, wherein (Ci-C i) -alkyl may be substituted with amino, R ^{8 is} hydrogen, or

R ^{9 is} hydrogen, (C ₁ -C ₄ ) -alkyl, -NR ¹³ R ¹⁴ , -NSO ₂ NR ¹⁵ R ¹⁶ , (C ₃ -C ₆ ) -cycloalkyl, (C ₄ -C ₆ ) -heterocyclyl, 5-or 6-membered heteroaryl or phenyl, in which (C 1 -C 12) -alkyl may be substituted by fluorine, difluoromethyl, trifluoromethyl or methoxy, in which R ^{13 is} hydrogen, methyl, ethyl or (C 3 -C 6) -cycloalkyl, in which ( C3-C6) cycloalkyl can be substituted up to two times with fluorine, wherein R ¹⁴ is hydrogen or methyl, wherein R ¹⁵ is hydrogen or methyl, and wherein R ¹⁶ is hydrogen or methyl, wherein the phenyl by 1 or 2 substituents independently of one another may be substituted from the group fluorine, chlorine, cyano, trifluoromethyl and methyl, wherein 5 or 6-membered heteroaryl may be substituted with 1 or 2 substituents independently selected from the group of fluorine, chlorine, cyano, trifluoromethyl and methyl, wherein (C3-C6) -cycloalkyl having 1 or 2 substituents independently selected from In which (C 3 -C 6) -heterocyclyl may be substituted by 1 or 2 substituents independently of one another selected from the group of fluorine or methyl,

R ^{11 is} hydrogen, (Ci-C i) -alkyl or amino, wherein (Ci-C i) -alkyl may be substituted with amino,

R ^{12 is} hydrogen, or

R ⁷ and R ¹¹ together with the carbon atoms to which they are attached have a 3- to

 Form 5-membered carbocycle, or

R ^{3 is} a group of the formula

 stands, where

* is the point of attachment to the carbonyl group, L ^{2 is} a bond or -C = C-,

R ^{10 is} 5- or 6-membered heteroaryl or (C 5 -C 4) -heterocyclyl, wherein 5- or 6-membered heteroaryl may be substituted with 1 or 2 substituents independently selected from the group consisting of fluorine, trifluoromethyl or methyl, and wherein 5-membered heteroaryl can be fused with (C5-C6) -cycloalkyl, wherein (C 5 -C 6) -cycloalkyl having 1 or 2 substituents independently selected from the group of fluorine or methyl may be substituted, or a group of the formula

 stands, where

R ^{17 is} (C 1 -C ₈ ) -alkyl, in which (C 1 -C 5 -j-alkyl may be substituted by phenyl, in which phenyl having 1 to 3 substituents independently of one another may be substituted from the group of fluorine, chlorine or methyl,

R ^{4 is} hydrogen,

R ^{5 is} hydrogen or methyl,

R ^{6 is} hydrogen, and the salts, solvates and solvates of the salts of these compounds. 3. A compound according to claim 1 or 2, wherein A is CH ₂ , R ^{1 is} phenyl, wherein phenyl may be substituted by 1 or 2 substituents fluorine, R ^{2 is} methyl, R ^{3 is} a group of the formula

 stands, where

* represents the point of attachment to the carbonyl group, L ^{1 is} a bond, -C (R ^U R ¹² ) -, oxygen or sulfur, R ^{7 is} hydrogen, methyl or amino, R ^{8 is} hydrogen, or

R ^{9 is} hydrogen, (C ₁ -C ₄ ) -alkyl, -NR ¹³ R ¹⁴ , -NO ₂ NR ¹⁵ R ¹⁶ , (C ₃ -C ₆ ) -cycloalkyl, (C ₄ -C ₆ ) -heterocyclyl, pyrazolyl, pydridyl or phenyl, wherein (Ci-C i) alkyl may be substituted with trifluoromethyl, wherein R ^{13 is} hydrogen, methyl, cyclopentyl or cyclohexyl, wherein R ^{14 is} hydrogen or methyl, wherein R ^{15 is} methyl, and wherein R ^{16 is} hydrogen, in which phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine or chlorine,

R ^{11 is} hydrogen or amino,

R ^{12 is} hydrogen, or

R ⁷ and R ¹¹ together with the carbon atoms to which they are attached have a 3- to

 Form a 5-membered carbocycle,

R ^{4 is} hydrogen,

R ^{5 is} hydrogen or methyl,

R ^{6 is} hydrogen, and the salts, solvates and solvates of the salts of these compounds.

4. Process for the preparation of compounds of the formula (I) as defined in claims 1 to 3, characterized in that a compound of the formula (II)

in which A, R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ each have the meanings given above,

 [A] in an inert solvent under amide coupling conditions with a carboxylic acid of the formula (III)

O HO

 (ΠΙ)

in which R ^{3 has} the meanings given above,

 implements,

 optionally cleaving off any protecting groups present, and converting the resulting compounds of formula (I) optionally with the appropriate (i) solvents and / or (ii) acids or bases in their solvates, salts and / or solvates of the salts, or

[B] in an inert solvent, if appropriate in the presence of a suitable base, with a compound of the formula (IV)

°

 (IV),

in which T ^{1 is} phenyl or para-nitrophenyl,

to a compound of formula (V)

(V) in which A, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and T ¹ each have the meanings given above, and these in an inert solvent, optionally in the presence of a suitable base, optionally in a microwave with a compound of formula (VI),

in which R ^{17 has} the meanings given above,

 subsequently optionally splits off existing protective groups, and the resulting compounds of formula (I) optionally with the corresponding (i) solvents and / or (ii) acids or bases in their solvates, salts and / or solvates of the salts.

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

Use of a compound of formula (I) as defined in claims 1 to 3 for the manufacture of a medicament for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders , Atherosclerosis, dementia and erectile dysfunction.

A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 3 in combination with one or more inert non-toxic pharmaceutically acceptable excipients.

A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 3, in combination with another active ingredient selected from the group consisting of organic Nitrates, NO donors, cGMP-PDE inhibitors, antithrombotic agents, antihypertensive agents and lipid metabolising agents.

9. Medicament according to claim 7 or 8 for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic diseases, fibrotic diseases, arteriosclerosis, dementia and erectile dysfunction.

10. A method for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic disorders, atherosclerosis, dementia and erectile dysfunction in humans and animals using an effective amount of at least one compound of formula ( I) as defined in claims 1 to 3 or a pharmaceutical composition as defined in any one of claims 7 to 9.