WO2013144191A1 - Substituted 2-amino-3-cyanopyridines as inhibitors of sodium-calcium exchange and use thereof for cardiovascular diseases - Google Patents

Description

 SUBSTITUTED 2 -AMINO-3-CYANOPYRIDINES AS INHIBITORS OF SODIUM CALCIUM REPLACEMENT AND THEIR USE IN CARDIOVASCULAR

DISEASES

 The present application relates to novel substituted 2-amino-3-cyanopyridines, processes for their preparation, their use for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of cardiovascular disease.

Chronic heart failure is one of the most common medical conditions whose incidence and prevalence increase with age [Redfield MM, N Engl J Med 347: 1442-1444; 2002]. Despite improved pharmacological therapy, especially in the ΝΥΗΑ III-TV stadiums, the mortality of heart failure patients is very high at up to 50% per year [Hoppe UC & Erdmann E, Z Kardiol 90: 218-237; 2001]. In the forefront of complex myocardial changes in heart failure are functional and structural remodeling processes, initially triggered by, for example, a myocardial infarction, a chronic pressure or volume burden and / or inflammatory processes. The activation of compensatory mechanisms (including stimulation of the sympathoadrenergic system and activation of the renin-aldosterone system), which initially maintain sufficient cardiac output and thus organ perfusion, lead in the long term to a worsening of cardiac contractility and relaxation as a result of progressive functional (especially impaired intracellular calcium balance). and structural (notably cardiomyocytic hypertrophy and myocardial fibrosis) alterations [Cohn JN et al., JACC 35: 569-582, 2000]. In addition to increasing deterioration in cardiac output, these changes favor the predisposition of heart failure patients to malignant cardiac arrhythmias, especially atrial and ventricular fibrillation [Knollmann BC & Roden DM, Nature 451: 929-936, 2008].

Mammalian sarcolemmal sodium-calcium exchangers (Na ⁺ / Ca ²⁺ exchangers, NCX) are encoded by a family of three genes (NCX1, NCX2, and NCX3). NCX1 (SLC8A1 gene on chromosome 2p22.1) is expressed primarily in heart, brain, skeletal muscle, vascular smooth muscle cells and kidney, while NCX2 and NCX3, which have only 68-75% sequence homology with NCX1 [Schulze DH et al., Ann NY Acad Sci 976: 187-196, 2002], are restricted to nerve cells and skeletal muscle cells [Lytton J, Biochem J 406: 365-382, 2007]. To date, 16 isoforms have been described for NCX1 (alternative splicing of the six exons A, B, C, D, E, and F), with NCX 1.1 (exons ACDEF) dominating the myocardial tissue.

NCX are transmembrane proteins which transport Na ⁺ and Ca ²⁺ ions in the opposite direction (antiport) across the membrane in a stoichiometric ratio of 3: 1. Depending on the intracellular sodium concentration, which is actively regulated by the Na ⁺ / K ⁺ -ATPase, the antiport occurs in forward mode (Ca ²⁺ - outward transport) or in reverse mode (Ca ²⁺ inward transport). Mechanically based, the myocardial NCX1 thus influences the membrane potential (depolarization), the intracellular Ca ²⁺ equilibrium (contraction / relaxation) and the Ca ²⁺ signaling in cardiomyocytes [Levi AJ et al., Am J Physiol 266: H1422-H1433 , 1994]. NCX1 thus plays an essential role in the electromechanical Coupling, ie NCXl affects the electrical excitability (action potential) and its conversion into mechanical work (contraction / relaxation) in the heart.

The mechanism of electromechanical coupling in the heart is based on temporally and spatially limited oscillations of the intracellular calcium concentration. Through depolarization of the cell membrane, calcium flows via the voltage-dependent L-type calcium channels into the cell interior during the action potential. This transmembrane calcium influx activates the spatially proximate ryanodine receptors and induces calcium release from the sarcoplasmic reticulum into the cytosol. This increase in the intracellular calcium concentration stimulates the contractile proteins and induces systolic strength development in the heart. By decreasing the intracellular calcium concentration in diastole, the stimulability of the contractile proteins diminishes until complete relaxation of the heart muscle cell. The removal of calcium from the cytosol occurs mainly via the SERCA (sarcoplasmic reticulum Ca ²⁺ - ATPase) back into the sarcoplasmic reticulum and via the sarcolemmal NCXl into the extracellular space.

At the center of heart failure research, various changes in intracellular calcium homeostasis, and thus the electromechanical coupling: reduction of the expression and activity of SERCA, increasing occurrence of spontaneous Ca ²⁺ release (Ca ²⁺ sparks) from the sarcoplasmic reticulum and increased transsarkolemmale calcium -Elimination via the NCXl, whose expression and activity are increased. The above processes lead to an overall depletion of calcium in the sarcoplasmic reticulum, to temporally and spatially uncoordinated Ca ²⁺ oscillations and, due to the increased transport of Ca ²⁺ via NCXl, to an increase in the intracellular sodium concentration with displacement of the resting membrane potential more positive values. While the first processes are counted among the major causes of impaired systolic and diastolic function of the deficient heart [Morgan JP et al., Circulation 81: 21-23, 1990; Beuckelmann DJ et al., Circulation 85: 1046-1055, 1992], the latter leads to an electrical instability of the cardiomyocytes and is therefore among other things causally involved in the development of malignant arrhythmias (in particular the development of postdepolarizations) [Knollmann BC & Roden DM, Nature 451: 929-936, 2008].

The central role of myocardial NCX1 in the above-mentioned processes could be demonstrated in mouse models with cardiac-specific NCX1 overexpression or knockout. Thus, NCX1 overexpression led to a disturbed electromechanical coupling with progressive cardiac hypertrophy and finally to impaired heart failure (cause of death) [Reuter et al., J Physiol 554.3: 779-789, 2003]. Furthermore, in mice with cardiac-specific NCX1 overexpression [Pott C et al., Ann NYA 1099: 310-314, 2007] or knockout [Henderson SA et al., Circ. Res. 95: 604-61 1, 2004], that there is a direct dependency between the repolarization time and the expression level of the NCX1, and that mice with an NCX1 overexpression have a predisposition to post-depolarizations and ventricular arrhythmias. Conversely, it was shown that a selective 80% blockade of the NCX1 in Langendorff-perfused rabbit hearts leads to a shortening of the action potential duration, suppresses early post-depolarizations and prevents the development of polymorphic ventricular tachycardia [Milberg P et al., Heart Rhythm 5: 1444-1452, 2008]. Similarly, partial inhibition (23% and 27%, respectively) of NCX1 by XIP (20 amino acid exchange inhibitory peptides, 10 and 30 μΜ) in isolated cardiomyocytes from hearts of dogs with tachypacing-induced heart failure led to an improvement in contractile force by a normalization of intracellular calcium homeostasis [Hobai et al., Circ. Res. 95: 292-299, 2004].

In addition, it was shown that inhibition of NCX with KB-R7943 has a cardioprotective effect in rats (reduced ischemia / reperfusion-related myocardial damage to the heart) and that a single dose of 10 mg / kg KB-R7943 prior to induction of myocardial ischemia (transient Coronary artery ligation) reduced the experimental incidence of ventricular arrhythmias to cardiac death [Nagasawa Y et al. Eur J Pharmacol 506: 249-255, 2005]. In pretreated guinea pigs with 1 and 3 mg / kg KB-R7943 it was shown that digitalis intoxication-induced extrasystoles, ventricular tachycardias and fibrillation up to cardiac arrest occurred less frequently [Watano T et al., Br J Pharmacol 127: 1846- 1850, 1999]. However, these effects were not observed in a therapeutic trial with intravenous administration of 5 mg / kg up to 10 mg / kg KB-R77943 (administration after induction of ischemia / reperfusion injury or after digitalis intoxication) [Miyamoto S et al., Jpn J Pharmacol 90: 229-235, 2002].

In contrast to KB-R7943, in therapeutic regimens (0.3 and 1.0 mg / kg post-coronary artery ligation) of SEA0400 it was shown that the incidence of ventricular fibrillation and cardiac arrest was reduced [ Takahashi K et al. Eur J Pharmacol 458: 155-162, 2003]. However, this therapeutic effect of SEA0400 was not found in dogs at i.V. 3 mg / kg after transient coronary artery ligation [Nagasawa Y et al., Eur J Pharmacol 506: 249-255].

Benzyloxyphenyl derivatives with different affinity and selectivity to NCX1 and other ion channels are known, e.g. KB-R7943 and SEA0400. KB-R7943 is a nonspecific NCX inhibitor (NCX3 »NCX1> NCX2), which has a 20-fold higher affinity for reverse mode (IC ₅ o 0.3 μΜ) than for forward mode (IC50 17 μΜ) of NCX, and, in addition, it influences the intracellular Na ⁺ and Ca ²⁺ oscillations unselectively in relation to other ion channels [Amran MS et al., Cardiovasc Drug Rev 21: 255-276, 2003]. Inhibition of NCX with KB-R7943 has been demonstrated to be cardioprotective in rats (reduced ischemia / reperfusion myocardial damage to the heart) [Nagasawa Y et al., Eur J Pharmacol 506: 249-255, 2005]. In guinea pigs pretreated with KB-R7943, it has been shown that digitalis intoxication-induced extrasystoles, ventricular tachycardias, and fibrillation to cardiac arrest were less common [Watano T et al., BrJ Pharmacol 127: 1846-1850, 1999].

SEA0400 blocks NCX with an affinity sequence of NCX1 >> NCX2 NCX3 and a higher preference for forward mode [Lee C et al., J Pharmacol Exp Ther 311: 748-757, 2004]. In membrane preparations from In dogs and rats, SEA0400 blocked the NCX1 with an IC50 of 90 and 92 nM, while for KB-R7943 the IC50 values were 7 μΜ and 9.5 μΜ, respectively. However, both compounds are considered to have a high molecular weight due to their physicochemical and pharmacodynamic properties [Amran MS et al., Cardiovasc Drug Rev 21: 255-276, 2003; Lee C & Hryshko LV, Cardiovascular Drug Rev 4: 334-347, 2004] are not suitable for chronic oral therapy of heart failure patients with / without malignant arrhythmias.

In WO 96/18616 substituted 2-aminopyridines are claimed as NO synthase inhibitors. WO 01/62233 describes substituted cyanopyridines and -pyrimidines as adenosine receptor modulators for the treatment of, for example, Alzheimer's and Parkinson's disease. EP-A 1302463 claims dicyanopyridines as potassium channel opener for the treatment of incontinence. WO 2004/055015 discloses aminocyanopyridines as MAP kinase inhibitors for the treatment of cancers. Variously substituted pyridines for the treatment of cancers are described in WO 2008/008059, US 2008/0280891 and US 2009/0093479. DE-A 102008053024 discloses substituted pyridines for controlling insects and mites.

The object of the present invention was to provide novel compounds which act as selective inhibitors of the cellular sodium-calcium exchanger and are suitable as such, in particular for the treatment and / or prevention of cardiovascular diseases.

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

für Phenyl oder 5- oder 6-gliedriges Heteroaryl steht,

represents phenyl or 5- or 6-membered heteroaryl,

wherein phenyl and 5- or 6-membered heteroaryl having 1 to 4 substituents independently selected from the group halogen, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -R ⁴ , -OR ⁴ , - (C = 0) -OR ⁶ , -C (= O) -NR ⁴ R ⁵ , -NR ⁴ - (C = O) _n -R ⁵ , -NR ⁴ -SO ₂ -R ⁵ , -SO ₂ NR ⁴ R ⁵ and -S (0) _p -R ⁴ can be substituted,

 wherein

 n is the number 0 or 1,

 p is the number 0, 1 or 2,

R ⁴ and R ⁵ independently of one another each represent hydrogen, (G-C 6) -alkyl or (C 3 -C 9) -cycloalkyl,

in which (C 1 -C 6) -alkyl in turn has 1 to 3 substituents selected independently from the group of fluorine, cyano, trifluoromethyl, (C 3 -C 9) -cycloalkyl, hydroxy, (C 1 -C 6) -alkoxy, trifluoromethoxy, (C 1 -C 4) -alkoxycarbonyl, amino, mono- (C 1 -C 4) -alkylamino, di- (C 1 -C 4) -alkylamino, 4 to 8-membered heterocyclyl and or 6-membered heteroaryl and a group of the formula

s substitution ^c t ^# se ¹ in can,

 wherein the 4- to 8-membered heterocycle in turn may be substituted with 1 or 2 substituents independently selected from the group trifluoromethyl, (Ci-C6) alkyl, hydroxy, oxo and (Ci-C6) alkoxy, and wherein

C # ^{l represents} a carbon atom of (C ¹ -C 6) -alkyl,

 Q is a 3- to 6-membered carbocycle or a 4- to 7-membered heterocycle,

 or

R ⁴ and R ⁵ together with the atom (s) to which they are attached form a 4- to 8-membered heterocycle,

 in which the 4- to 8-membered heterocycle in turn contains 1 or 2 substituents independently of one another selected from the group consisting of cyano, trifluoromethyl, (C 1 -C 6) -alkyl, hydroxy, oxo, (C 1 -C 6) -alkoxy, trifluoromethoxy, C4) -alkoxycarbonyl, amino, mono- (C 1 -C 4) -alkylamino and di (C 1 -C 4) -alkylamino may be substituted,

R ^{6 is} (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₈ ) -cycloalkyl,

 or

wherein two substituents bonded to adjacent carbon atoms of a phenyl ring together form a group of the formula -O- (CH ₂ ) _q -O-, -O-CHF-O-, -O-CF ₂ -O- or -O-CF ₂ -CF ₂ -O - form,

 wherein

 q is a number 1, 2 or 3,

R ^{2 is} halogen, cyano, methyl or hydroxymethyl,

R ^{3 is} phenyl,

 where phenyl having 1 or 2 substituents independently of one another can be substituted from the group halogen, cyano, difluoromethyl, trifluoromethyl, (C 1 -C 4) -alkyl, trifluoromethoxy, (C 1 -C 4) -alkoxy and pentafluorosulfanyl,

and their N-oxides, salts, solvates and solvates of N-oxides and salts.

Compounds according to the invention are the compounds of the formula (I) and their N-oxides, salts, solvates and solvates of N-oxides and salts, the compounds of the formulas below and their N-oxides, salts, solvates and compounds encompassed by formula (I) Solvates of N-oxides and salts as well as those of formula (I), hereinafter referred to as exemplary compounds and their N-oxides, salts, solvates and Solvates of N-oxides and salts, as far as the compounds of formula (I) below are not already N-oxides, salts, solvates and solvates of N-oxides and 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 of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.

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 atropisomers). The present invention therefore encompasses 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 hereby used as a compound understood in which at least one atom is exchanged within the inventive compound for another atom of the same atomic number, but with a different atomic mass than the usual or predominantly occurring in nature atomic mass. 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, to study the mechanism of action or distribution of drug in the body; Due to the comparatively easy production and detectability, compounds labeled with ³ H or ¹⁴ C isotopes in particular are suitable for this purpose. Moreover, the incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.

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

In the context of the present invention, unless specified otherwise, the substituents have the following meaning: In the context of the invention, alkyl is a linear or branched alkyl radical having 1 to 6 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2 Methylbutyl, 3-methylbutyl, n -hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,4-dimethylpentyl and 4,4 -Dimethylpentyl. Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 6 or 1 to 4 or 2 to 4 carbon atoms. Preference is given to a linear or branched alkoxy radical having 1 to 4 or 2 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isoproperoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy. Alkoxycarbonyl in the context of the invention are a linear or branched alkoxy radical having 1 to 4 carbon atoms and an oxygen-bonded carbonyl group. Preferred is a linear or branched alkoxycarbonyl radical having 1 to 4 carbon atoms in the alkoxy group. By way of example and preferably mention may be made of: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

Mono-alkylamino in the context of the invention represents an amino group having a linear or branched alkyl substituent which has 1 to 4 carbon atoms. Examples which may be mentioned by way of example include methylamino, ethylamino, propylamino, isopropylamino and tert-butylamino.

Di-alkylamino in the context of the invention represents an amino group having two identical or different linear or branched alkyl substituents, each having 1 to 4 carbon atoms. Examples which may be mentioned are: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino and N-tert-butyl-N-methylamino.

Cycloalkyl or carbocycle in the context of the invention is a monocyclic, saturated alkyl radical having 3 to 8 or 3 to 6 carbon atoms. Examples which may be mentioned by way of example are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Preference is given to a monocyclic, saturated alkyl radical having 3 to 6 carbon atoms.

Heterocycle or heterocyclyl in the context of the invention is a saturated heterocycle having a total of 4 to 8 ring atoms which contains one or two ring heteroatoms from the series N, O and / or S and via a ring carbon atom or optionally a ring nitrogen atom is linked. Examples which may be mentioned are: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl. Preferred are azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and morpholinyl.

Heteroaryl is in the context of the invention for a monocyclic aromatic heterocycle (heteroaromatics) having a total of 5 or 6 ring atoms, which contains up to three identical or different ring heteroatoms from the series N, O and / or S and via a ring carbon atom or optionally linked via a ring nitrogen atom. Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl. Preference is given to furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiadiazolyl, pyridyl. Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine and fluorine.

An oxo group in the context of the invention is an oxygen atom which is bonded via a double bond to a carbon atom. In the formulas of the groups for which R ¹ , R ³ and R ^{4 may} stand, the end point of the line where the symbol *, # ² or # ¹ stands does not stand for a carbon atom or a CFb group, respectively is part of the bond to the respective designated atom to which R ¹ , R ³ or R ^{4 are} bonded.

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.

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

In the context of the present invention, preference is given to compounds of the formula (I) in which

R ^{1 is} phenyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl or pyridyl,

where phenyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl or pyridyl having 1 to 3 substituents independently of one another are selected from the group of fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -R ⁴ , -OR ⁴ , - (C = O) -OR ⁶ , -C (= O) -NR ⁴ R ⁵ , -NR ⁴ - (C = O) "- R ⁵ , -NR ⁴ -SO ₂ -R ⁵ , -SO ₂ NR ⁴ R ⁵ and -S (O) _p -R ⁴ may be substituted,

 wherein

 n is the number 0 or 1,

 p is the number 2,

R ⁴ and R ⁵ independently of one another each represent hydrogen, (C 1 -C 6) -alkyl or (C 3 -C 5) -cycloalkyl,

wherein (C 1 -C 6) -alkyl, in turn, having 1 to 3 substituents independently selected from the group fluorine, cyano, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxy, (Ci-C i) alkoxy, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, amino, methyl - mino, ethylamino, dimethylamino, N-methyl-N-ethylamino, diethylamino, azetidinyl,

Pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and pyridyl and a group of

 may be substituted

 wherein azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl may in turn be substituted by 1 substituent selected from the group consisting of methyl, ethyl, hydroxy, oxo and methoxy,

 and in which

C # ^{l represents} a carbon atom of (C ¹ -C 6) -alkyl,

 Q is a cyclopropyl, cyclobutyl or cyclopentyl ring, or

R ⁴ and R ⁵ together with the atom (s) to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl ring,

wherein the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl ring may in turn be substituted with 1 or 2 substituents independently selected from the group trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy and ethoxy, R ^{6 is} methyl or Ethyl stands,

or

wherein two substituents bonded to adjacent carbon atoms of a phenyl ring together form a group of the formula -O- (CH ₂ ) _q -O-, -O-CHF-O-, -O-CF ₂ -O-, or -O-CF 2 -CF 2 - O form,

 wherein

 q is a number 1, 2 or 3,

represents chlorine, cyano, methyl or hydroxymethyl,

for one

 * * *

stands, where

 * stands for the point of attachment to the 2-amino-3-cyanopyridine

and where

R ^{7 is} chlorine, cyano, trifluoromethyl, (C 1 -C 4) -alkyl or trifluoromethoxy,

R ^{8 is} hydrogen, fluorine, chlorine or trifluoromethyl, R ^{9 is} chlorine,

R ^{10 is} hydrogen or chlorine,

R ^{11 represents} chlorine, cyano, trifluoromethyl, (C 1 -C 4) -alkyl or trifluoromethoxy,

R ^{12 is} chlorine or methyl,

and their salts, solvates and solvates of the salts.

In the context of the present invention, particular preference is given to compounds of the formula (I) in which R ^{1 represents 1}

 stands, where

# ^{2 represents} the point of attachment to the 2-amino-3-cyanopyridine,

R ^{4 is} hydrogen or (C ₁ -C ₆ ) -alkyl,

wherein (C 1 -C 6) -alkyl having 1 or 2 substituents independently of one another can be substituted from the group cyano, trifluoromethyl, hydroxy, (C ¹ -C 4) -alkoxy, trifluoromethoxy and a group of the formula c # ¹ ,

in which C # ^{1 represents} a carbon atom of (C ¹ -C 6) -alkyl,

 stands for cyano,

 for a l

steht, wobei

stands, where

 * for the point of attachment to the 2-amino-3-cyanopyridine

 and where

R ^{7 is} trifluoromethyl,

R ^{8 is} hydrogen, fluorine or chlorine,

 their salts, solvates and solvates of salts.

In the context of the present invention, particular preference is also given to compounds of the formula (I) in which R ^{1 is} pyridyl,

wherein pyridyl may be substituted with 1 to 3 substituents independently of one another selected from the group fluorine, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -R ⁴ and -OR ⁴ ,

 wherein

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

 in which (C 1 -C 4) -alkyl in turn may be substituted by 1 to 3 substituents independently of one another selected from the group cyano, trifluoromethyl, hydroxy, methoxy, ethoxy and trifluoromethoxy,

R ^{2 is} cyano,

R ^{3 is} a group of the formula

steht, wobei

stands, where

 * stands for the point of attachment to the 2-amino-3-cyanopyridine

 and where

R ^{7 is} trifluoromethyl,

R ^{8 is} hydrogen, fluorine or chlorine,

and their salts, solvates and solvates of the salts.

In the context of the present invention, particular preference is also given to compounds of the formula (I) in which R ^{1 is} e for e

 stands, where

# ^{2 represents} the point of attachment to the 2-amino-3-cyanopyridine,

oder Methylsulfonyl steht, R ^{13 is} fluorine, methyl, hydroxymethyl, methoxy, ethoxy, isopropoxy, dimethylamino, diethylamino, dimethylaminocarbonyl, diethylaminocarbonyl, morpholin-4-yl,

or methylsulfonyl,

R ^{14 is} hydrogen, fluorine or methoxy,

R ^{15 is} hydrogen, fluorine or methoxy, R '2 stands for cyano,

 *

 stands, where

 * stands for the point of attachment to the 2-amino-3-cyanopyridine

 and where

R ^{7 is} trifluoromethyl,

R ^{8 is} hydrogen, fluorine or chlorine,

and their salts, solvates and solvates of the salts.

In the context of the present invention, preference is also given to compounds of the formula (I) in which R ^{2 is} cyano,

and their salts, solvates and solvates of the salts.

In the context of the present invention, preference is also given to compounds of the formula (I) in which R ^{3 is} an I

 *

 stands, where

 * stands for the point of attachment to the 2-amino-3-cyanopyridine

 and where

R ^{7 is} trifluoromethyl,

R ^{8 is} hydrogen or chlorine,

and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which

R ^{2 is} cyano,

R ^{3 is} a group of the formula

 *

 stands, where

 * stands for the point of attachment to the 2-amino-3-cyanopyridine

 and where

R ^{7 is} trifluoromethyl,

R ^{8 is} hydrogen, fluorine or chlorine,

and their salts, solvates and solvates of the salts.

In the context of the present invention, preference is also given to compounds of the formula (I) in which R ^{1 is} a group of the formula

 stands, where

# ^{2 represents} the point of attachment to the 2-amino-3-cyanopyridine,

R ^{16 is} cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -R ⁴ , -OR ⁴ , - (C = O) -OR ⁶ , -C (= O) -NR ⁴ R ⁵ , -NR ⁴ - (C = 0) _n -R ⁵ , -NR ⁴ -SO ₂ -R ⁵ , -S0 ₂ NR ⁴ R ⁵ and -S (0) _p -R ⁴ where

 n is the number 0 or 1,

 p is the number 0, 1 or 2,

R ⁴ and R ⁵ independently of one another each represent hydrogen, (C 1 -C 6) -alkyl or (C 3 -C 6) -cycloalkyl,

in which (C 1 -C 6) -alkyl, in turn, having 1 to 3 substituents selected independently from the group fluorine, cyano, trifluoromethyl, (C3-Cg) -cycloalkyl, hydroxy, (Ci-C6) -alkoxy, trifluoromethoxy, (Ci-C4 ) Alkoxycarbonyl, amino, mono (Ci-C i) - alkylamino, di (Ci-C4) -alkylamino, 4- to 8-membered heterocyclyl and 5- or 6 eroaryl and a group of the formula

may be substituted wherein the 4- to 8-membered heterocycle in turn may be substituted with 1 or 2 substituents independently selected from the group trifluoromethyl, (Ci-C6) alkyl, hydroxy, oxo and (Ci-C6) alkoxy, and wherein

C # ^{l represents} a carbon atom of (C ¹ -C 6) -alkyl,

 Q is a 3- to 6-membered carbocycle or a 4- to 7-membered heterocycle,

 or

R ⁴ and R ⁵ together with the atom (s) to which they are attached form a 4- to 8-membered heterocycle,

 in which the 4- to 8-membered heterocycle in turn contains 1 or 2 substituents independently of one another selected from the group consisting of cyano, trifluoromethyl, (C 1 -C 6) -alkyl, hydroxy, oxo, (C 1 -C 6) -alkoxy, trifluoromethoxy, C4) -alkoxycarbonyl, amino, mono- (C 1 -C 4) -alkylamino and di (C 1 -C 4) -alkylamino may be substituted,

R ^{6 is} (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₈ ) -cycloalkyl,

and their salts, solvates and solvates of the salts.

In the context of the present invention, preference is also given to compounds of the formula (I) in which R ^{1 is} a group of the formula

 stands, where

# ^{2 represents} the point of attachment to the 2-amino-3-cyanopyridine,

R ^{16 is} (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy or aminosulfonyl,

 wherein (Ci-C6) alkyl and (Ci-C6) alkoxy can be substituted with 1 or 2 substituents independently selected from the group hydroxy, methoxy and ethoxy, as well as their salts, solvates and solvates of the salts.

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

Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.

Another object of the invention is a process for the preparation of the compounds of formula (I) according to the invention, characterized in that a V

 in which R and R each have the meanings given above,

 in a suitable solvent with a compound of the formula (III-A) or (III-B)

OT ¹

 1B

R ¹ -B or R -H

 O-T '

(III-A) (III-B)

 in which

 R is phenyl or C-linked 5- or 6-membered heteroaryl,

 where phenyl and C-linked 5- or 6-membered heteroaryl may be substituted in the scope of meaning given above,

 R is pyrazol-1-yl, pyrrol-1-yl, imidazol-1-yl or triazol-1-yl,

 where pyrazol-1-yl, pyrrol-1-yl, imidazol-1-yl and triazol-1-yl can be substituted in the scope of meaning given above,

 and

T ^{1 is} hydrogen or (Ci-C ₄ ) -alkyl or

the two radicals T ¹ together form a -C (CH 3) 2 -C (CH 3) 2 bridge,

 to e

 (I-A) (I-B)

in which R ^1A , R ^1B , R ² and R ³ each have the meanings given above,

 implements, or

[B] a compound of the formula (IV)

in which R ² and R ³ each have the meanings given above,

in an inert solvent with a compound of the formula (III-B) to give a compound of the formula (I-B)

implements,

a compound of formula (IV) in an inert solvent with hydrazine hydrate in a compound

,

.

² (V),

in which R ² and R ³ each have the meanings given above,

and then these in an inert solvent in the presence of a suitable acid with a compound of formula (VI)

in which

R ^{16 is} cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -R ⁴ , -OR ⁴ , - (C = O) -OR ⁶ , -C (= O) -NR ⁴ R ⁵ , -NR ⁴ - (C = 0) _n -R ⁵ , -NR ⁴ -SO ₂ -R ⁵ , -S0 ₂ NR ⁴ R ⁵ and -S (0) _p -R ⁴ where

 n is the number 0 or 1,

 p is the number 0, 1 or 2,

R ⁴ and R ⁵ independently of one another each represent hydrogen, (C 1 -C 6) -alkyl or (C 3 -C 8) -cycloalkyl,

wherein (C 1 -C 6) -alkyl, in turn, having 1 to 3 substituents independently selected from the group fluorine, cyano, trifluoromethyl, (C3-Cg) -cycloalkyl, hydroxy, (Ci-Ce) -alkoxy, trifluoromethoxy, (Ci-C4 ) Alkoxycarbonyl, amino, mono (Ci-C4) - alkylamino, di- (Ci-C4) -alkylamino, 4- to 8-membered heterocyclyl and 5- or 6-eroaryl and a group of the formula

 may be substituted

 wherein the 4- to 8-membered heterocycle in turn may be substituted with 1 or 2 substituents independently selected from the group trifluoromethyl, (Ci-C6) alkyl, hydroxy, oxo and (Ci-C6) alkoxy, and wherein

C # ^{l represents} a carbon atom of (C ¹ -C 6) -alkyl,

 Q is a 3- to 6-membered carbocycle or a 4- to 7-membered heterocycle,

 or

II ⁴ and R ⁵ together with the atom (s) to which they are attached form a 4- to 8-membered heterocycle,

 in which the 4- to 8-membered heterocycle in turn contains 1 or 2 substituents independently of one another selected from the group consisting of cyano, trifluoromethyl, (C 1 -C 6) -alkyl, hydroxy, oxo, (C 1 -C 6) -alkoxy, trifluoromethoxy, C4) -alkoxycarbonyl, amino, mono- (C 1 -C 4) -alkylamino and di (C 1 -C 4) -alkylamino may be substituted,

R ^{6 is} (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₈ ) -cycloalkyl,

 and

T ^{2 is} (C 1 -C ₄ ) -alkyl,

 to e

 (I-c),

in which R ² , R ³ and R ¹⁶ each have the meanings given above, or a compound of the formula (VII)

 (VII)

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

 in an inert solvent in the presence of a suitable base with a compound of formula (VIII)

in which R ^{1A has} the abovementioned meaning,

 to a compound of the formula (I-D)

in which R ^1A , R ² and R ³ each have the meanings given above,

or a compound of formula (VII) in an inert solvent in the presence of ammonium acetate with a compound of formula (ΓΧ-Α) or (ΓΧ-Β)

 (IX-A) (IX-B)

in which R ^{1A has} the abovementioned meaning,

R ^{2A is} chlorine,

 and

R ^{2B is} (C 1 -C ₄ ) -alkyl,

to a compound of the formula (I-El) or (I-E2)

(I-E1) (I-E2)

in which R ^1A , R ^2A , R ^2B and R ³ each have the meanings given above,

 optionally, the resulting compounds of the formulas (IA), (IB), (IC), (ID), (I-El) and (I-E2) separates into their enantiomers and / or diastereomers according to methods known in the art and / / or optionally with the corresponding (i) solvents and / or (ii) bases or acids to their solvates, salts and / or solvates of the salts.

The preparation of the compounds according to the invention can be exemplified by the following synthesis schemes (Schemes 1 to 5):

[a): Cs ₂ C0 ₃ , DMSO, RT, b): NaHCO ₃ , Pd (dppf) ₂ x CH ₂ Cl ₂ , dimethoxyethane, H ₂ O, 80 ° C]. Scheme 2

[a): Cs ₂ C0 ₃ , DMSO, RT].

Scheme 3

 [a): ethanol, RT; b): acetic acid, 140 ° C, microwave].

 Scheme 4

[a): DBU, EtOH, 80 ° C].

[a): NH ₄ OAc, n-butanol, 160 ° C, microwave; b: NH ₄ OAc, xylene, 120 ° C].

Suitable solvents for process step (II) + (III-A) -> (IA) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, Glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethoxyethane (DME), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝΜΡ ), Pyridine, acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to a mixture of dimethoxyethane and water or dioxane and water.

Suitable bases for process step (II) + (III-A) -> (I-A) are customary inorganic bases. These include in particular alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali metal bicarbonates such as sodium or potassium bicarbonate, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, or alkali metal hydrogen phosphates such as disodium or dipotassium hydrogen phosphate. Preferably, sodium bicarbonate or sodium carbonate is used.

As palladium catalyst for the process step (II) + (III-A) -> (IA) ["Suzuki coupling"], for example, palladium on activated carbon, palladium (II) acetate, tetrakis (triphenylphosphine) palladium ( 0), bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (II) chloride and [1,1'-

Bis (diphenylphosphino) ferrocene] dichloφalladium (II) -dichloromethane complex suitable [see. e.g. Hassan J. et al., Chem. Rev. 102, 1359-1469 (2002)].

The reaction (II) + (III-A) -> (I-A) are generally carried out in a temperature range of + 20 ° C to + 150 ° C, preferably at + 50 ° C to + 100 ° C.

Inert solvents for process steps (II) + (III-B) or (IV) + (III-B) -> (IB) are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or di ethylene glycol dimethyl ethers, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylformamide (DMF), Dimethylsulfoxide (DMSO), NN'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝΜΡ) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferably, DMSO is used.

Suitable bases for the process steps (II) + (III-B) and (IV) + (III-B) -> (I-B) are customary inorganic see or organic bases. These preferably include alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal alcoholates such as sodium or potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as lithium or potassium bis (trimethylsilyl) amide, or organic amines such as triethylamine, Af-methylmorpholine, V-methylpiperidine, A ^ -diisopropylethylamine, pyridine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,4-diazabicyclo [2.2.2] octane (DABCO). Cesium carbonate is preferably used.

The process steps (II) + (III-B) or (IV) + (III-B) -> (IB) are generally carried out in a temperature range from 0 ° C to + 150 ° C, in particular from + 20 ° C to + 50 ° C.

The reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, one works at normal pressure.

Inert solvents for process step (IV) → (V) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-dimethylpropyl urea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferred is ethanol. Suitable bases for process step (IV) -> (V) are alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali hydrogen carbonates such as sodium or potassium bicarbonate, alkali metal such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1 , 5-diazabicyclo [4.3.0] -ηοη-5-ene (DBN). Preferred is triethylamine.

The reaction (IV) -> (V) is generally carried out in a temperature range from 0 ° C to + 60 ° C, preferably from + 10 ° C to + 30 ° C. The reaction may be carried out at normal or elevated pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.

The reaction (V) + (VI) -> (I-C) can be carried out in an inert solvent or else without solvent. The reaction preferably takes place without solvent.

Inert solvents for this process step are, for example, ethers, such as diethyl ether, methyl tert-butyl 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, 1,2 Dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned.

Suitable acids for the reaction (V) + (VI) -> (I-C) are organic and inorganic acids such as formic acid, acetic acid, trifluoroacetic acid, para-toluenesulfonic acid, methanesulfonic acid or hydrochloric acid / hydrochloric acid, sulfuric acid or phosphoric acid. Preferably, acetic acid is used.

The reaction (V) + (VI) -> (I-C) is generally carried out in a temperature range of + 50 ° C to + 180 ° C, optionally in a microwave. The said reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar).

Inert solvents for process step (VII) + (VIII) -> (ID) are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols, such as methanol, ethanol, n-propanol, Isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), NN'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝΜΡ) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferably, ethanol is used. Suitable bases for the process step (VII) + (VIII) -> (ID) are 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, alkali alcoholates such as sodium or potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as lithium or potassium bis (trimethylsilyl) amide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, triethylamine, pyridine, 1,5-diazabicyclo [4.3.0 ] non-5-ene (DBN), l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1, 4-diazabicyclo [2.2.2] octane (DABCO). DBU is preferably used.

The process step (VII) + (VIII) -> (I-D) is generally carried out in a temperature range from + 20 ° C to + 150 ° C, preferably at + 50 ° C to +100 ° C, optionally in a microwave.

The reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, one works at normal pressure.

The process steps (VII) + (IX-B) (I-E2) and (VII) + (IX-A) (I-El) can be carried out with and without solvent. Inert solvents for this process step are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert. Butanol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using n-butanol or xylene.

The process step (VII) + (IX-B) -> (I-E2) is generally carried out in a temperature range from + 50 ° C to + 200 ° C, preferably at + 120 ° C to + 180 ° C, optionally in a microwave. The reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar).

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

The compounds of the formula (II) in which R ^{2 is} cyano can be prepared by reacting a compound of the formula (X)

 (X)

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

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

_(χι)?

_(χι)?

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

and then these in an inert solvent with hydrochloric acid to give a compound of formula (II-A)

in which R has the meaning given above,

implements.

Inert solvents for the reaction (X) -> (XI) are, for example, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylformamide (DMF ), Dimethyl sulfoxide (DMSO), NN'-dimethyl propylene urea (DMPU), N-methylpyrrolidone (ΝΜΡ) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferably, ethanol is used.

Suitable bases for process step (X) -> (XI) are customary inorganic or organic bases. These include preferably alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali alcoholates such as sodium methoxide, sodium ethylate, sodium or potassium hydroxide. tert.-butylate or alkali metal hydrides such as sodium or potassium hydride, amides such as lithium or potassium bis (trimethylsilyl) amide. Preference is given to using sodium methylate. The process step (X) -> (XI) is generally carried out in a temperature range from -20 ° C to + 50 ° C, preferably at 0 ° C to + 10 ° C. The reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar).

Inert solvents for the reaction (XI) → (II-A) are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols, such as methanol, ethanol, n-propanol, isopropanol , n-butanol or tert-butanol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or others Solvents such as acetone, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), NN'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝΜΡ) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferably, acetone is used.

The process step (XI) -> (II-A) is generally carried out in a temperature range of + 20 ° C to + 100 ° C. The reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). The compounds of the formula (VII) can be prepared by reacting malononitrile in an inert solution with a compound of the formula (XII)

in which R has the meaning given above,

implements. Inert solvents for process step (XII) -> (VII) are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols, such as methanol, ethanol, n-propanol, isopropanol , n-butanol or tert-butanol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), NN'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝΜΡ) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Isopropanol is preferably used.

Suitable bases for process step (XU) -> (VII) are customary inorganic or organic bases. These include preferably alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal alcoholates such as sodium or potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as lithium or potassium bis (trimethylsilyl) amide, or organic amines such as triethylamine, N-methylmorpholine, V-methylpiperidine, NN- Diisopropylethylamine, piperdine, pyridine, l, 5-diazabicyclo [4.3.0] non-5-ene (DBN), l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 4-diazabicyclo [ 2.2.2] octane (DABCO). Preference is given to using piperidine.

The process step (XII) -> (VII) is generally carried out in a temperature range from + 20 ° C to + 150 ° C, preferably at + 50 ° C to + 100 ° C, optionally in a microwave.

The compounds of the formulas (X) and (XII) are commercially available, known from the literature or can be prepared in analogy to those known from the literature:

The preparation processes described above are exemplified by the following synthesis schemes (Schemes 6 and 7):

 [a): NaOMe, ethanol, 0 ° C; b): conc. HCl, acetone, reflux].

Scheme 7

 [a): piperdine, isopropanol, reflux].

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 are potent and selective inhibitors of the cellular Na ⁺ / Ca ²⁺ exchanger and are therefore suitable for the treatment and / or prevention of cardiovascular diseases.

The compounds according to the invention can be used as medicaments for the treatment and / or prophylaxis of cardiovascular diseases such as acute and chronic heart failure, arterial hypertension, essential hypertension, therapy-resistant hypertension, coronary heart disease, acute coronary syndrome, acute coronary syndrome with ST elevation, acute coronary syndrome without ST Elevation, stable and unstable angina pectoris, Prinzmetal angina, persistent ischemic dysfunction (hibernating myocardium), transient post-ischemic dysfunction (stunned myocardium), tachycardia, atrial tachycardia, atrial fibrillation with normal left ventricular function, atrial fibrillation with impaired left ventricular function, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, rhythm disorders of the atria and ventricles, ventricular and supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, Chamber flutter, torsade 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, cardiomyopathies), cardiogenic shock, boxer cardiomyopathy (premature ventricular contraction (PVC)), for the treatment and / or prophylaxis of myocardial ischemia, myocardial infarction, cardiac hypertrophy, inflammatory cardiovascular disease, reperfusion injury, myocardial insufficiency, as well as for the reduction of Myocardial area affected by an infarct, as well as for the prevention of secondary infarcts.

For the purposes of the present invention, the term cardiac failure includes both acute and chronic manifestations of heart failure, as well as more specific or related forms of disease such as acute congestive heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, heart failure in heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valvular insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure and systolic heart failure and acute ph the worsening heart failure worsening of existing chronic heart failure.

Furthermore, the compounds according to the invention are suitable for the reduction of the infarcted myocardium area and for the prevention of secondary infarcts, reperfusion damage after ischemia. Ischemias such as myocardial infarction, cardioprotection in coronary artery bypass graft surgery (CABG), primary PTCAs, PTCAs after thrombolysis, rescue PTCA, heart transplants, and open heart surgery. and organ protection in transplantation, bypass surgery, cardiac catheterization and other surgical procedures.

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

The present invention furthermore relates to the use of the compounds according to the invention for the treatment and / or prevention of myocardial infarction, cardioprotection in coronary artery bypass grafting (CABG), percutaneous transluminal angioplasties (PTAs) and primary percutaneous transluminal coronary angioplasties (PTCAs), acute and chronic heart failure , acute and chronic renal diseases as well as acute and chronic inflammatory diseases.

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

The present invention furthermore relates to the use of the compounds according to the invention for the manufacture of a medicament for the treatment and / or prevention of myocardial infarction, cardioprotection in coronary artery bypass grafting (CABG), percutaneous transluminal angioplasties (PTAs) and primary percutaneous transluminal coronary angioplasties (PTCAs), acute and chronic heart failure, acute and chronic renal diseases and acute and chronic inflammatory diseases.

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

The present invention further relates to a method for the treatment and / or prevention of myocardial infarction, cardioprotection in coronary artery bypass grafting (CABG), percutaneous transluminal angioplasties (PTAs) and primary percutaneous transluminal coronary angioplasties (PTCAs), acute and chronic heart failure, acute and chronic heart failure Chronic kidney disease and acute and chronic inflammatory diseases using an effective amount of at least one of the compounds of the invention.

Another object of the present invention are the compounds of the invention for use in a method for the treatment and / or prophylaxis of cardiovascular diseases.

The present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prophylaxis of myocardial infarction, cardioprotection in coronary artery bypass operations (CABG), percutaneous transluminal angioplasties (PTAs) and primary percutaneous transluminal coronary angioplasties (PTCAs), acute and chronic heart failure, acute and chronic renal diseases, and acute and chronic inflammatory diseases.

The present invention further relates to medicaments comprising at least one of the compounds according to the invention and one or more further active compounds, in particular for the treatment and / or prevention of myocardial infarction, cardioprotection in coronary artery bypass surgery (CABG), percutaneous transluminal angioplasties (PTAs) and primary percutaneous -transluminal coronary angioplasties (PTCAs), acute and chronic heart failure, acute and chronic renal diseases, and acute and chronic inflammatory diseases.

The compounds of the invention may be used alone or as needed in combination with other agents. Another object of the present invention are therefore 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.

Examples of suitable combination active ingredients are lipid metabolism-altering active substances, antidiabetics, hypotensives, circulation-promoting and / or antithrombotic agents, antioxidants, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists. Anorectics, PAF-AH inhibitors, anti-inflammatory drugs (COX inhibitors, LTB i receptor antagonists), analgesics such as aspirin, anti-depressants and other psychotropic drugs.

Another object of the present invention are combinations of at least one of the compounds of the invention with one or more active ingredients independently selected from:

Active substances which alter lipid metabolism, such as by way of example and preferably from the group of HMG-CoA reductase inhibitors, inhibitors of HMG-CoA reductase expression, squalene synthesis inhibitors, ACAT inhibitors, LDL receptor inducers, cholesterol Absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, MTP inhibitors, lipase inhibitors, LpL activators, fibrates, niacin, CETP inhibitors, PPAR-a, PPAR-γ and / or PPAR-8 agonists, RXR Modulators, FXR modulators, LXR modulators, thyroid hormones and / or thyroid mimetics, ATP citrate lyase inhibitors, Lp (a) antagonists, cannabinoid receptor 1 antagonists, leptin receptor agonists, bombesin receptor Agonists, histamine receptor agonists and the antioxidants / radical scavengers,

• Antidiabetics listed in the Red List 2004/11, Chapter 12, and by way of example and preferably those from the group of sulfonylureas, biguanides, meglitinide derivatives, glucosidase inhibitors, inhibitors of dipeptidyl peptidase TV (DPP-TV inhibitors ), Oxadiazolidinones, thiazolidinediones, GLP1 receptor agonists, glucagon antagonists, insulin sensitizers, CCK1 receptor agonists, leptin receptor agonists, inhibitors of liver enzymes that are involved in the stimulation of glucose metabolism. and glucose glycogenolysis, glucose uptake modulators, and potassium channel openers, such as those disclosed in WO 97/26265 and WO 99/03861,

Hypotensive agents, by way of example and with preference from the group of calcium antagonists, angiotensin II ATI receptor antagonists, ACE inhibitors, renin inhibitors, beta-receptor blockers, alpha-receptor blockers, aldosterone antagonists, mineralocorticoid Receptor antagonists, ECE inhibitors, ACE / NEP inhibitors and also the vasopeptidase inhibitors, antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances, factor Xa inhibitors or vitamin K antagonists,

 Cyclooxygenase inhibitors (COX inhibitors), such as, for example, meloxicam, rofecoxib and celecoxib

 Anti-inflammatory agents, by way of example and preferably from the group of glucocorticosteroids, non-steroidal anti-inflammatory drugs or non-steroidal anti-inflammatory drugs (NSAIDs), beta-receptor blockers

 Diuretics, such as by way of example and preferably loop diuretics, thiazides, potassium-sparing diuretics, or carbonic anhydrase inhibitors,

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

Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, such as sildenafil, vardenafil, tadalafil and milrinone positive inotropic agents such as digitoxin, digoxin, epinephrine, norepinephrine, dobutamine and dopamine,

antiproliferative agents, such as multikinase inhibitors and preferably sorafenib, imatinib, gefitinib and erlotinib

 Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil and tadalafil and PDE 3 inhibitors such as milrinone;

natriuretic peptides, e.g. atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, Nesiritide), C-type natriuretic peptide (CNP) and urodilatin; Agonists of the prostacyclin receptor (IP receptor), such as iloprost, beraprost, cicaprost; Inhibitors of the If (funny channel) channel, such as Ivabradine;

Calcium sensitizers, such as by way of example and preferably levosimendan;

Potassium supplements; NO-independent, but heme-dependent guanylate cyclase stimulators, such as in particular the compounds described in WO 00/06568, WO 00/06569, WO 02/42301, WO 03/095451 and WO 2011/147809;

 Guanylate cyclase NO- and heme-independent activators, in particular those described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510

Links;

 • inhibitors of human neutrophil elastase (HNE), such as Sivelestat and DX-890 (relrans);

 The signal transduction cascade inhibiting compounds, such as tyrosine kinase inhibitors, especially sorafenib, imatinib, gefitinib and erlotinib; and or

 Anti-inflammatory agents, by way of example and with preference from the group of glucocorticoids, in particular prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone;

 Vasopressin receptor antagonists such as, and preferably, conivaptan, tolvaptan, lipivaptan, mozavaptan, satavaptan, SR-121463, RWJ 676070 or BAY 86-8050;

 • the energy metabolism of the heart affecting compounds such as etomoxir, dichloroacetate, ranolazines and trimetazidines

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapol, torcetrapib, JTT-705 or CETP vaccine (CETi-1).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

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

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, RPR 107393 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, lecimibid, CP-113818 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, CP-346086, AEGR-733, LAB678 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 by way of preference, pioglitazone, ciglitazone 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, pamaqueside or colesevelam.

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 according to the invention are administered in combination with a polymeric bile acid adsorbent, such as, by way of example and by way of preference, cholestyramine, colobrepol, 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 according to 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.

In a preferred embodiment of the invention, the compounds according to the invention are combined with a calcium antagonist, such as by way of example and preferably nifedipine, amlodipine, nitrendipine, felodipine, lercanidipine, nimodipine, nicardipine, lacidipine, israpidine, nisoldipine, nilvadipine, manidipine, verapamil or Diltiazem administered.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, by way of example and preferably prazosin, terazosin, dopazosin, trimazosin, and the non-selective blockers of the first generation phentolamine and phenoxybenzamine , 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, acebutolol, betaxolol, pindolol, levibunolol or bucindolol.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin AT-1 receptor antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan, irbesartan, eprosartan, olmesartan or embursatan.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor, by way of example and preferably enalapril, captopril, lisinopril, spirapril, 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, attresentan, ambrisentan or sitaxsentan. In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600, SPP-800, SPP-1148, VTP-27999 or MK-8141.

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

In a preferred embodiment of the invention, the compounds of the invention are used in combination with a loop diuretic, such as by way of example and preferably bumetanide, ethacrynic acid, toresemide or furosemide; in combination with thiazides, such as, by way of example and by way of illustration, chlorothiazide, chlorthalidone, hydrochlorothiazide, hydroflumethiazide, indapamide, metyclothiazide, metolazone or polythiazide; in combination with potassium-sparing diuretics, such as and preferably amiloride, eplerenone, spironolactone or triamterene, and / or in combination with carbonic anhydrase inhibitors such as, and preferably, acetazolamide, dichlophenamide or mathazolamide.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vasopressin receptor antagonist, such as by way of example and preferably Tolvaptan. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as by way of example and preferably aspirin, clopidogrel, ticlopidine, prasugrel, tirofiban 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, argatroban, bivalirudin, hirudin, lepirudin, desirudin 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 preferably tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban, DU-176b, apixaban, otamixaban, fidexaban, razaxaban, edoxaban, enoxaparin, otamixaban, fondaparinux, idraparinux, PMD-31 12, 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 by way of preference, warfarin, coumarin, acenocoumarol, phenprocoumone or dicumarol.

Particularly preferred in the context of the present invention are combinations containing at least one of the compounds according to the invention and one or more further active compounds selected from the group consisting of the energy metabolism of the heart affecting compounds, diuretics, beta-receptor blocker, organic nitrates and NO donors, blockers of the renin-angiotensin-aldosterone system, platelet aggregation inhibitors, anticoagulants, vasopressin receptor antagonists, glucocorticoids, NSAIDs and COX inhibitors, and their use for the treatment and / or prevention of the aforementioned disorders.

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.

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 can be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent. For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For the oral administration are according to the prior art functioning, 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. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates, capsules (e.g. Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by bypassing a Κεβθφΐίοηββοΐιπΐΐεβ (e.g., intravenously, intraarterially, intracardially, intraspinally, or intralumbarally) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the 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 plasters), milk, pastes, foams, powdered powders, implants or stents.

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

The compounds of the invention can be converted into the mentioned application forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include, but are not limited to, excipients (e.g., microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitanoleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g. Albumin), stabilizers (eg antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxides) and flavor and / or odoriferous agents. 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 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 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 invention is not limited to the examples.

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 and acronyms:

 Eq. Equivalent (s)

br. s broad singlet (NMR)

 Ex. example

d doublet (NMR)

 DBU l, 8-diazabicyclo [5.4.0] undec-7-ene

 DCM dichloromethane

 DHP 3, 4-dihydro-2 / pyran

 DIPEA N, N-diisopropylethylamine

 DME 1, 2-dimethoxyethane

 DMF N, N-dimethylformamide

 DMSO dimethyl sulfoxide

d. Th. Of theory

 EE ethyl acetate (ethyl acetate)

 EI electron impact ionization (in MS)

 ESI electrospray ionization (in MS)

 Et ethyl

 GC gas chromatography

h hour (s)

 HATU 0- (7-azabenzotriazol-1-yl) -NNN ', N'-tetramethyluronium hexafluorophosphate

 HPLC high pressure, high performance liquid chromatography

conc. concentrated p. boiling point

crystalline. crystallized crystalline /

 LAH lithium aluminum hydride

 LC-MS liquid chromatography-coupled mass spectrometry

LDA lithium N, N-diisopropylamide

 LiHMDS Lithium N, N-Bistrimethylsilylamide

 Literature (position)

 Solution. Solution

m meta; Multiple «(NMR)

 Me methyl

 MW molecular weight

minute Minute (s)

 MS mass spectroscopy

 MTBE methyl tert-butyl ether

 NMR nuclear magnetic resonance spectroscopy

o ortho

p para

 PPTS pyridinium p-toluenesulfonate

 Pr Propyl

q Quartet (NMR)

quint. Quintet (NMR)

 RF reflux

 RP reverse phase (on HPLC)

 RT room temperature

R _t retention time (by HPLC)

 SEM 2- (trimethylsilyl) ethoxymethyl

t triplet (NMR)

 TFA trifluoroacetic acid

 TFAA trifluoroacetic anhydride

 THF tetrahydrofuran

 Ts p-toluenesulfonyl (tosyl)

 TsOH p-toluenesulfonic acid

dil. diluted

see. compare

 Vol. Volume

GC / MS and LC / MS methods: Method 1 (GC / MS:

 Instrument: Micromass GCT, GC6890; Column: Restek RTX-35, 15 m x 200 μπι x 0.33 μηι; constant flow with helium: 0.88 ml / min; Oven: 70 ° C; Inlet: 250 ° C; Gradient: 70 ° C, 30 ° C / min 310 ° C (hold for 3 min).

Method 2 (LC / MS:

Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ 30 x 2 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 ^ 1.2 min 5% A 2.0 min 5% A; Oven: 50 ° C; Flow: 0.60 ml / min; UV detection: 208-400 nm.

Method 3 (LC / MS:

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

Method 4 (LC / MS:

Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 μ 50 x 1 mm; Eluant 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 5 (LC / MS:

Instrument MS: Waters ZQ 2000; Instrument HPLC: Agilent 1100, 2-column circuit, Autosampler: HTC PAL; Column: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 μπι; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 100% A 0.2 min 95% A 1.8 min 25% A 1.9 min 10% A 2.0 min 5% A 3.2 min 5% A 3.21 min 100% A 3.35 min 100% A; Oven: 40 ° C; Flow: 3.0 ml / min; UV detection: 210 nm. Method 6 (LC / MS:

Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ 50 x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A ^ 1.2 min 5% A 2.0 min 5% A; Oven: 50 ° C; Flow: 0.40 ml / min; UV detection: 210-400 nm. In the case of purification of compounds according to the invention by preparative HPLC according to the methods described above, in which the eluents contain additives such as, for example, trifluoroacetic acid, formic acid or ammonia, the compounds according to the invention can be prepared in salt form, for example as triflate. luoracetat incurred, formate or ammonium salt, provided that the compounds of the invention a sufficient basic or acidic functionality. Such a salt can be converted into the corresponding free base or acid by various methods known to those skilled in the art.

General working methods

 General Method 1:

To a mixture of the corresponding chloropyridine (1 eq.) And pyrazole (1.2 eq.) In DMSO (1 ml / 100 mg chloropyridine) is added cesium carbonate (1.2 eq to 2.0 eq.). The reaction mixture is stirred at RT until complete conversion of the chloropyridine. For workup, the reaction mixture is treated with water and extracted with ethyl acetate. The combined organic phases are washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC.

General Method 2:

 The corresponding arylboronic acid (1.0 eq.) Is presented on an MTP. Then a solution of the corresponding 2-chloropyridine (1.0 eq.) In dioxane (6.0 ml / mmol), tetrakis (triphenylphosphine) palladium (0.05 eq.) And a solution of sodium carbonate (1.5 eq.) In water (2.0 ml / mmol). The reaction mixture is shaken overnight at 85 ° C. The reaction mixture is filtered, and the corresponding crude product is dissolved in DMSO, filtered and purified by HPLC.

General Method 3:

 A mixture of the corresponding 2-chloropyridine in dimethoxyethane / water (3.12 ml / 0.93 ml / mmol) under argon at RT with [l, Γ-bis (diphenylphosphine) ferrocene] dichloφalladium (II) -dichloromethane complex (0.05 eq.). with the corresponding arylboronic acid or the arylboron ester (1.5 eq.) And sodium hydrogen carbonate (3.0 eq.) Is added. The reaction mixture is stirred overnight at 80.degree. The reaction mixture is filtered through Celite. After addition of dichloromethane and water and phase separation, the organic phase is washed once with water and once with saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel-60, eluent: dichloromethane-methanol mixtures) or preparative HPLC.

Starting compounds and intermediates:

 Example 1A

[4- (trifluoromethyl) benzylidene] malononitrile

 47.3 g (272 mmol) of 4- (trifluoromethyl) benzaldehyde were dissolved in 250 ml of ethanol. 18.8 g (285 mmol) of malononitrile and 231 mg (2.72 mmol) of piperidine were added and the mixture was heated to reflux for 1 h. It was allowed to cool to RT, the precipitate was filtered off with suction and washed with a little cold ethanol and petroleum ether. The title compound was obtained as a solid. Yield: 50.0 g (83% of theory).

GC-MS (Method 1): R _t = 4.27 min; MS (EIpos): m / z = 222 [M] ⁺ .

'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.69 (s, 1H), 8.11 (d, 2H), 8.02 (d, 2H).

Example 2A

 [3-fluoro-4- (trifluoromethyl) benzylidene] malononitrile

 3.00 g (15.6 mmol) of 3-fluoro-4- (trifluoromethyl) benzaldehyde [US Pat. No. 6,331,649] were initially charged in 15 ml of ethanol. 1.08 g (16.4 mmol) of malononitrile and 13 mg (0.16 mmol) of piperidine were added and the mixture was heated to reflux for 1 h. The reaction mixture was cooled with an ice bath, precipitating. It was sucked off and washed with a little ethanol. The mother liquor was concentrated and the residue was purified by chromatography on silica gel (eluent: cycohexane / ethyl acetate 1: 1) and then stirred with MTBE / pentane and filtered with suction. The product fractions were pooled. Yield: 2.81 g (75% of theory).

GC-MS (Method 1): R _t = 4.29 min; MS (EIpos): m / z = 240 [M] ⁺ .

'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.66 (s, 1H), 8.10 (t, 1H), 8.00-7.91 (m, 2H). Example 3A

 3-chloro-4- (tri

10.5 g (49.9 mmol) of 3-chloro-4- (trifluoromethyl) benzyl alcohol in 158 ml of trichloromethane were added and 8.67 g (99.7 mmol) of manganese dioxide were added. The reaction mixture was heated to reflux overnight, then filtered with suction through kieselguhr and the filtrate was concentrated. The residue was taken up in 150 ml of trichloromethane, treated with 2.60 g (29.9 mmol) of manganese dioxide and again heated to reflux overnight. It was again sucked on silica gel and after concentration in vacuo, the desired aldehyde was obtained as a yellowish oil. The aldehyde was reacted further without purification. Yield: 9.40 g (90% of theory). GC-MS (Method 1): R _t = 2.71 min; MS (EIpos): m / z = 208 [M] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 10.09 (s, 1H), 8.21 (s, 1H), 8.12 (d, 1H), 8:06 (d, 1H).

Example 4A

 [3-Chloro-4 - (trifluoromethyl) benzylidene] malononitrile

 75.0 g (360 mmol) of 3-chloro-4- (trifluoromethyl) benzaldehyde from Example 3A and 29.6 g (448 mmol) of malononitrile in 150 ml of 2-propanol were added dropwise and 367 mg (4.32 mmol) of piperidine slowly added dropwise. It was then heated to reflux for 7 h. It was allowed to stir overnight and come to RT. It was then cooled to 10 ° C, stirred for 1 h at this temperature and sucked off. It was washed with 2-propanol and the residue was dried in air. Yield: 77.0 g (83% of theory).

GC-MS (Method 1): R _t = 5.08 min; MS (EIpos): m / z = 256 [M] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8.65 (s, 1H), 8.18 (s, 1H), 8.15 (d, 1H), 8:06 (d, 1H). Example 5A

4-ethoxy-1-pyrazole

 500 mg (5.95 mmol) of 1-pyrazol-4-ol and 1.23 g (8.92 mmol) of potassium carbonate in 5.0 ml of DMF were added, and 974 mg (6.24 mmol) of iodoethane were added. The reaction mixture was allowed to stir at RT overnight. Then it was diluted with MTBE and washed with water. The aqueous phase was extracted four times with MTBE. The combined organic phases were shaken with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 2: 1 gradient to 1: 1) to give the title compound. Yield: 432 mg (64% of t.l.).

LC-MS (Method 6): R _t = 0.40 min; MS (EIpos): m / z = 113 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ώ): δ [ppm] = 12.30 (br, s, 1H), 7.41 (br, s, 1H), 7.21 (br, s, 1H), 3.87 (q, 2H), 1.26 (t, 3H).

Example 6A

Ethyl 1 - (tol-4-carboxylate

 A mixture of 3.0 g (21.41 mmol) of ethyl 1-pyrazole-4-carboxylate, 3.60 g (42.81 mmol) of 3,4-dihydro-2-pyran, 0.37 g (2.14 mmol) of 7-toluenesulfonic acid in 82 ml Ethyl acetate and 83 ml of DMF were stirred at RT overnight. The reaction mixture was admixed with a saturated aqueous sodium bicarbonate solution and extracted with MTBE. The combined organic phases were washed with a saturated aqueous sodium chloride solution and with saturated aqueous ammonium chloride solution, dried over magnesium sulfate and concentrated. Yield: 5.36 g (100% of theory).

LC-MS (Method 4): R _t = 1.81 min; MS (EIpos): m / z = 225 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8:44 (s, 1H), 7.89 (s, 1H), 5:46 (dd, 1H), 4.21 (q, 2H), 3.95-3.90 ( m, 1H), 3.68-3.59 (m, 1H), 2.17-2.05 (m, 1H), 1.98-1.84 (m, 2H), 1.72-1.60 (m, 1H), 1.59-1.48 (m, 2H), 1.26 (t, 3H). Example 7A

 [1 - (Tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl] methanol

 To a solution of 2.0 g (8.03 mmol) of ethyl 1 - (tetrahydro-2-pyran-2-yl) -l-pyrazole-4-carboxylate from Example 6A in 16 ml of THF under argon was added 11.24 ml of 11.24 mmol) of an IM lithium aluminum hydride solution in THF. After 10 minutes at RT, water was added and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with water and with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. Yield: 1.31 g (90% of theory).

LC-MS (Method 4): R _t = 1.21 min; MS (EIpos): m / z = 183 [M + H] ⁺ .

Example 8A

 4- (M -pyran-2-yl) -1 / pyrazole

To a solution of 140 mg (0.77 mmol) of 4- (methoxymethyl) -1- (tetrahydro-2 / pyran-2-yl) -1 / pyrazole from Example 7A in 2 ml of DMF at 0 ° C., 52 mg of 1.31 mmol) of sodium hydride (60% dispersion in mineral oil) was added. After 45 minutes at 0 ° C, 0.14 ml (2.31 mmol) of iodomethane was added. The reaction mixture was stirred at RT overnight. The mixture was added with water and extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated. Yield: 103 mg (50% of theory) in 73% strength (LC-MS), which was reacted without further purification. LC-MS (Method 4): R _t = 0.61 min; MS (EIpos): m / z = 197 [M + H] ⁺ .

Example 9A

4- (methoxymethyl) -1 / pyrazole

 To a solution of 103 mg (0.38 mmol) of [1- (tetrahydro-2-pyran-2-yl) -l-pyrazol-4-yl] methanol in 0.4 ml of dichloromethane was added 1.9 ml (7.66 mmol) of a 4M solution of hydrogen chloride in dioxane added. After stirring at RT for 3 h, the mixture was evaporated. The residue was taken up in dichloromethane, evaporated again and dried under high vacuum. Yield: 39 mg (68% of theory).

LC-MS (Method 6): R _t = 0.65 min; MS (EIpos): m / z = 113 [M + H] ⁺ .

Example 10A

 2,2-dichloro-1 - (3-methoxyphenyl) ethanone

To a solution of 1.00 g (5.35 mmol) of 3-bromoanisole in 10 ml of THF was slowly added dropwise at -78 ° C 3.2 ml (8.0 mmol) of a 2.5M solution of "-butyllithium in hexane. The mixture was stirred for 2 h at this temperature and then added dropwise 1.09 g (6.95 mmol) of ethyldichloroacetate as a solution in 10 ml of THF. The mixture was stirred for a further 2 h at -78 ° C, then sat a mixture of 0.5 ml of conc. Hydrochloric acid and 1 ml of methanol and heated to 0 ° C. It was then diluted with MTBE, washed with water and the organic phase dried over sodium sulfate. The mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10: 1). The title compound was obtained as a yellowish oil. Yield: 91 mg (7% of theory).

GC-MS (Method 1): R _t = 5.05 min; MS (EIpos): m / z = 218 [M] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 7.93 (s, 1H), 7.67 (d, 1H), 7:58 to 7:56 (m, 1H), 7:53 (t, 1H), 7:32 ( dd, 1H), 3.84 (s, 3H)

Example IIA

 2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 / pyrazol-1-yl] ethanol

500 mg (2.58 mmol) 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-l//-pyrazol und 250 mg (2.83 mmol) l,3-Dioxolan-2-on wurden in 2.5 ml DMF vorgelegt. Man setzte 10 mg (0.26 mmol) Natriumhydroxid hinzu und erhitzte 2 h zum Rückfluss. Man ließ auf RT kommen, setzte Kieselgur hinzu, saugte ab und wusch mit DMF nach. Das Filtrat wurde im Vakuum eingeengt und ohne Aufreinigung weiter umgesetzt. Ausbeute: 707 mg.

500 mg (2.58 mmol) of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -l-pyrazole and 250 mg (2.83 mmol) of 1,3-dioxolane 2-on were presented in 2.5 ml of DMF. 10 mg (0.26 mmol) of sodium hydroxide were added and the mixture was heated to reflux for 2 h. It was allowed to come to RT, added diatomaceous earth, sucked off and washed with DMF. The filtrate was concentrated in vacuo and reacted further without purification. Yield: 707 mg.

LC-MS (Method 3): R _t = 0.79 min; MS (EIpos): m / z = 239 [M + H] ⁺ . Example 12A

 2-Methyl-1 - [4- (4,4,5,5-tetramethyl-1,3,3-dioxaborolan-2-yl) -1-pyrazol-1-yl] propan-2-ol

 500 mg (2.5 mmole) of 4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -1 / pyrazole and 3.72 g of 2,2-dimethyloxirane (51.5 mmole) were in the microwave with 840 mg (2.58 mmol) cesium carbonate for 30 min. heated to 120 ° C. The reaction solution was taken up in water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and the solvent removed in vacuo. The product was reacted further without purification. Yield: 268 mg (39% of theory).

LC-MS (Method 6): R _t = 0.81 min; MS (EIpos): m / z = 267 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 7.84 (s, 1H), 7:56 (s, 1H), 4.69 (s, 1H), 4:02 (s, 2H), 1.25 (s, 12H), 1.03 (s, 6H).

Example 13A

 (25) - 1,1,1-trifluorobenzolan-2-yl) -1-pyrazole-1-yl] propan-2-ol

 100 mg (0.52 mmol) of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -l / pyrazole were dissolved in 0.50 ml (5.8 mmol) (2S) -2- (Trifluoromethyl) oxirane heated at 100 ° C for 4 h. The title compound was obtained after chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10: 3). Yield: 138 mg (82% of theory).

GC-MS (Method 4): R _t = 1.97 min; MS (EIpos): m / z = 307 [M + H] ⁺ . 'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 7.96 (s, 1H), 7.63 (s, 1H), 6.64 (s, 1H), 4:42 to 4:36 (m, 2H), 4.27 ( dd, 1H), 1.25 (s, 12H).

Example 14A

 1-Methoxy-3 - [4- (4,4,5,5-tetramethyl-1,3,3-dioxaborolan-2-yl) -1-pyrazol-1-yl] propan-2-ol

 100 mg (0.52 mmol) of 4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -l-pyrazole were dissolved in 0.50 ml (5.6 mmol) of 2- (methoxymethyl) oxirane heated at 100 ° C for 10 h. The reaction mixture was then concentrated in vacuo and the residue (purity 50%) was further reacted without purification step.

GC-MS (Method 1): R _t = 6.13 min; MS (EIpos): m / z = 281 [M] ⁺ . Example 15A

1- (2-M-aborolan-2-yl) -1 / pyrazole

₃

₃

200 mg (1.03 mmol) of 4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -1 / pyrazole and 158 mg (1.13 mmol) of 2-bromoethylmethyl ether were dissolved in 2.0 ml DMF submitted. 504 mg (1.55 mmol) of cesium carbonate were added and the mixture was heated at 90 ° C. overnight. It was allowed to come to RT, watered and extracted with MTBE. The organic phase was dried over sodium sulfate and the solvent removed in vacuo. The crude product was reacted further without further purification. Yield: 158 mg (57% of theory). LC-MS (Method 6): R _t = 0.85 min; MS (EIpos): m / z = 253 [M + H] ⁺ .

Example 16A

Ethyl 3- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 / pyrazol-1-yl] propanoate

 2.00 g (10.3 mmol) of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-pyrazole were initially charged in 15 ml of acetonitrile. 1.45 ml (13.4 mmol) of ethyl acrylate and 157 mg (1.03 mmol) of cesium fluoride were added and the mixture was heated at 80 ° C. overnight. Thereafter, the reaction solution was concentrated in vacuo, mixed with water and extracted with MTBE. The organic phase was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed in vacuo. The crude product was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 2: 1). The title compound was obtained. Yield: 1.89 g (60% of theory).

LC-MS (Method 6): R _t = 0.96 min; MS (EIpos): m / z = 295 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 7.91 (s, 1H), 7:57 (s, 1H), 4:35 (t, 2H), 4:04 (q, 2H), 2.85 (t, 2H), 1.24 (s, 12H), 1.14 (t, 3H).

Example 17A

 2-Arnino-6- (phenylsulfanyl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

61.6 g (277 mmol) of [4- (trifluoromethyl) benzylidene] malononitrile from Example 1A were initially charged in 450 ml of 2-propanol. 18.3 g (277 mmol) of malononitrile, 28.5 ml (277 mmol) of thiophenol and 1.16 ml (8.3 mmol) of triethylamine were added and the mixture was heated to reflux for 6 h. Thereafter, it was stirred overnight at RT. 300 ml of 2-propanol were distilled off. It was then filtered with suction through a frit and slurried three times with 30 ml of 2-propanol and sucked off again. It was dried in vacuo and the title compound was obtained. Yield: 34.1 g (29% of theory at 7.8%> isopropanol residual content).

LC-MS (Method 6): Rt = 1.21 min; MS (EIpos): m / z = 397 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 7.99 (d, 2H), 7.92, 7.82 (d, 2H), 7.65-7.58 (m, 2H), (br s, 2H.). , 7.55-7.47 (m, 3H). Example 18A

 2-Anuno-6-hydrazino-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

 2.00 g (5.05 mmol) of 2-amino-6- (phenylsulfanyl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 17A and 1.96 ml (40.4 mmol) of hydrazine hydrate were dissolved in 43.5 ml Ethanol stirred over the weekend at RT. The reaction mixture was filtered and the filter cake washed with ethanol. The solid formed in the filtrate were also filtered off with suction. Yield 1.45 g (86% of theory).

LC-MS (Method 6): R _t = 0.85 min; MS (EIpos): m / z = 319 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 9.00 (br, s, 1H), 7.93 (d, 2H), 7.71 (d, 2H), 7.52 (br. , 2H), 4.63 (br. S., 2H)

Example 19A

 2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- (phenylsulfanyl) pyridine-3, 5-dicarbonitrile

 To a mixture of 150.0 g (0.72 mol) of 3-chloro-4- (trifluoromethyl) benzaldehyde from Example 3A, 95.0 g (1.44 mol) of malononitrile and 79.2 g (0.72 mol) of thiophenol was added 7.11 ml (71.92 mmol) of piperidine. The reaction mixture was stirred at 50 ° C overnight. The undissolved solid was filtered off, washed twice with ethanol and dried in vacuo. Yield: 80 g (25% of theory).

LC-MS (Method 3): R _t = 1.35 min; MS (EIpos): m / z = 434 [M + H] ⁺ .

Example 20A

2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6-hydroxypyridine-3, 5-dicarbonitrile

 10.6 g (24.7 mmol) of 2-amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- (phenylsulfanyl) pyridine-3,5-dicarbonitrile from Example 19A were initially charged in 110 ml of DMSO. 49.4 ml (49.4 mmol) of IM sodium hydroxide solution were added and the mixture was heated at 80 ° C. for 2 h. It was allowed to cool to RT, added water and washed three times with MTBE. The organic phases were discarded. The aqueous phase was acidified to pH3 with 1N hydrochloric acid. The precipitate was sucked off, washed with water and MTBE and dried the residue in the air. Yield: 7.3 g (87% of theory).

LC-MS (Method 2): R _t = 0.87 min; MS (EIpos): m / z = 338 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 12.22-11.87 (m, 1H), 8:08 (d, 1H), 7.97 (s, 1H), 7.95 (br s, 2H. ), 7.71 (d, 1H).

Example 21A

 [4- (trifluoromethyl) benzoyl] malononitrile

 A solution of 1.84 g (27.9 mmol) of malononitrile in 4 ml of THF was slowly added dropwise under argon at 0 ° C. to a suspension of 0.74 g (18.6 mmol) of sodium hydride (60% dispersion in mineral oil) in 8 ml of THF. After 30 minutes, 2.00 g (9.30 mmol) of 4- (trifluoromethyl) benzoyl chloride was added slowly. The reaction mixture was allowed to come to RT. For work-up, the mixture was adjusted to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. Yield: 2.90 g (100% of theory) in 87% strength (LC-MS), which was reacted without further purification operations.

LC-MS (Method 6): R _t = 0.75 min; MS (Elneg): m / z = 237 [MH] \ Example 22A

 {Chloro [4-ethylene} malononitrile

 A solution of 77.2 g (240 mmol) of [4- (trifluoromethyl) benzoyl] malononitrile from Example 21A in 1.0 l of dichloromethane was cooled to approximately 5 ° C. 74.9 g (360 mmol) of phosphorus pentachloride were added slowly. The reaction mixture was stirred for 4.5 h at reflux temperature. Then, the ice-cooled reaction solution was carefully mixed with water. The organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product was then purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10: 1). The product was stirred with pentane and filtered with suction. This gave colorless crystals. Yield: 26.2 g (43% of theory).

GC-MS (Method 1): R _t = 4.38 min; MS (EIpos): m / z = 256, 258.

Example 23A

 2- [4-, 1,3,3-tetracarbonitrile

To a solution of 0.46 g (6.69 mmol) of sodium methylate in 8 ml of ethanol was added 0.23 g (3.44 mmol) of malononitrile. The mixture was stirred for 5 minutes. Subsequently, 1.10 g (about 3.34 mmol) of {chloro [4- (trifluoromethyl) phenyl] methylene} malononitrile from Example 22A were added at 0 ° C. After 1.5 h, the reaction mixture was concentrated by rotary evaporation, the residue was admixed with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. Yield: 1.36 g (99% of theory) in 70% purity (LC-MS), which was reacted without further purification operations. LC-MS (Method 3): R _t = 1.28 min; MS (Elneg): m / z = 285 [MH] \ Example 24A

 2-amino-6-] pyridine-3,5-dicarbonitrile

 To a solution of 1.30 g (about 4.54 mmol) 2- [4- (trifluoromethyl) phenyl] prop-1-en-l, l, 3,3-tetracarbonitrile from Example 23 A in 18 ml of acetone, 4.17 ml (49.96 mmol) conc. Hydrochloric acid, and the reaction mixture was stirred overnight at reflux temperature. The reaction mixture was concentrated under reduced pressure, the residue was admixed with water and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC. Yield: 900 mg (55% of theory).

LC-MS (Method 6): R _t = 0.99 min; MS (Elneg): m / z = 321 [MH] ^" .

'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.23 (br, s, 2H), 8.00 (d, 2H), 7.83 (d, 2H).

Example 25A

 3-Chloro-4-enoyl chloride

 A mixture of 3.30 g (14.7 mmol) of 3-chloro-4- (trifluoromethyl) benzoic acid and 2.68 ml (36.7 mmol) of thionyl chloride was stirred at 70 ° C. overnight. The reaction mixture was concentrated in vacuo, treated with dichloromethane and concentrated again. The residue was reacted without further purification. Yield: 4.20 g (100% of theory).

Example 26A

[3-chloro-4- (trifluoromethyl) benzoyl] malononitrile

A solution of 10.4 g (0.16 mol) of malononitrile in 10 ml of THF was slowly added dropwise under argon at 0 ° C. to a suspension of 4.19 g (0.10 mol) of sodium hydride (60% dispersion in mineral oil) in 50 ml of THF. After 30 minutes, 14.0 g (52.4 mmol) of 3-chloro-4- (trifluoromethyl) benzoyl chloride from Example 25A were slowly added. The reaction mixture was warmed to RT. For work-up, the mixture was adjusted to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The crude product was then purified by flash chromatography (Kieselgel-60, eluent: cyclohexane-ethyl acetate mixtures). Yield: 11.7 g (82% of theory).

LC-MS (Method 6): R _t = 0.78 min; MS (Elneg): m / z = 271 [MH] \

Example 27A

 {Chloro [3-chloro-4 - (trifluoromethyl) phenyl] methylene} malononitrile

To a solution of 11.7 g (42.9 mmol) of 3-chloro-4- (trifluoromethyl) benzoylmalononitrile from Example 26A in 155 ml of dichloromethane were added 13.4 g (64.3 mmol) of phosphorus pentachloride. The reaction mixture was stirred at reflux temperature overnight. The reaction solution was evaporated. The residue was then purified by flash chromatography (silica gel 60, eluent: cyclohexane / ethyl acetate 1: 1). Yield: 12.4 g (90% of theory).

LC-MS (Method 3): R _t = 1.57 min; MS (EIpos): m / z = 291 [M + H] ⁺ . Example 28A

 2- [3-Chloro-4- (trifluoromethyl) phenyl] prop-1-ene-1,1,3,3-tetracarbonitrile

 To a solution of 5.29 g (77.8 mmol) of sodium methylate in 100 ml of ethanol was added 2.65 g (40.1 mmol) of malononitrile. The mixture was stirred for 5 minutes at RT. Subsequently, 12.4 g (about 38.9 mmol) of {chloro [3-chloro-4- (trifluoromethyl) phenyl] methylene} malononitrile from example 27A were added at 0 ° C. The reaction mixture was further stirred at 0 ° C. After 1.5 h, the mixture was concentrated in vacuo and the corresponding residue was added with water. It was extracted with ethyl acetate and the organic phase dried over sodium sulfate and concentrated. The crude product was then purified by flash chromatography (Kieselgel-60, eluent: cyclohexane-ethyl acetate). Yield: 2.2 g (17% of theory).

LC-MS (Method 3): R _t = 1.40 min; MS (Elneg): m / z = 319 [MH] \ Example 29A

 2-amino-6-chloro-4- [3-chloro-4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

To a solution of 1.65 g (5.15 mmol) of 2- [3-chloro-4- (trifluoromethyl) phenyl] prop-1-en-1, 1,3,3-tetracarbonitrile in 20 ml of acetone 4.77 ml (154 mmol) of conc. Hydrochloric acid added. The reaction mixture was stirred at 50 ° C overnight. The reaction solution was evaporated and the residue was added with water and extracted with ethyl acetate. The organic phase was washed with water and with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate. dried and concentrated. Yield: 1.92 g (94% of theory), in 90% purity (LC-MS), which was reacted without further purification.

LC-MS (Method 3): Rt = 1.31 min; MS (EIpos): m / z = 358 [M + H] ⁺ . Alternative synthesis:

7.00 g (20.7 mmol) of 2-amino-4- [3-chloro-4- (nifluoromethyl) phenyl] -6-hydroxypyridine-3,5-dicarbonitrile from Example 20A and 14.1 g (62.0 mmol) of benzyltriethylammonium chloride were dissolved in 70 ml ( 750 mmol) of phosphoryl chloride are refluxed for 2 h. The reaction mixture was concentrated in vacuo and then treated with toluene twice and concentrated again. The residue was taken up in ethyl acetate / water. The organic phase was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and the solvent removed in vacuo. The crude product was purified by chromatography on silica gel (eluant: ethyl acetate / cyclohexane 1: 1). The product was stirred with pentane, filtered off with suction and dried. Yield: 3.33 g (45% of theory).

LC-MS (Method 6): R _t = 1.06 min; MS (Elneg): m / z = 355, 357 [MH] \

 'H NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.84 (br, s, 1H), 8.35 (br, s, 1H), 8.14 (d, 1H), 8.08 (s , 1H), 7.81 (d, 1H).

Example 30A

 3-amino-3 - (2-furyl) acrylonitrile

 An LDA solution was prepared by dropwise addition of 83 ml (133 mmol) of a 1.6N solution of n-butyllithium in hexane to 13.1 g (130 mmol) of diisopropylamine in 100 ml of THF at -78 ° C. and stirring for 30 min. Subsequently, 4.70 g (1 14 mmol) of acetonitrile were added dropwise as a solution in 70 ml of THF and 30 min. further stirred. Then 7.09 g (76.2 mmol) of 2-furanonitrile were added as a solution in 100 ml of THF. After 20 min. was warmed to RT and stirred overnight at this temperature. 20 ml of water were added, then diluted with ethyl acetate and washed twice with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 2: 1). After concentrating the product fractions, the title compound was obtained. Yield: 9.89 g (97% of theory).

LC-MS (Method 6): R _t = 0.62 min; MS (EIpos): m / z = 135 [M + H] ⁺ .

The proton NMR spectrum shows E (= major component, maj.) And Z isomer (= minor component, min.). 'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 7.87, 7.79 (maj, d, 1H.), 7.17 (min, d, (min, d, 1H.). 1H), 7.13 (maj., D, 1H), 6.75 (maj., Br. S, 2H), 6.69 (min., Br. S, 2H), 6.68 (min., Dd, 1H), 6.62 (m. maj., dd, 1H), 4.37 (maj, s, 1H), 4.24 (min, s, 1H).

Example 31A

 3-amino-3 - [3 - (methylsulfonyl) phenyl] acrylonitrile

 To a solution of 4.79 g (46.91 mmol) of diisopropylamine in 34 ml of THF under argon at -70 ° C, 29.3 ml (46.9 mmol) of a "-Butyllithium- solution (1.6 M in hexane) was slowly added dropwise. After 10 minutes, a solution of 2.18 ml (41.39 mmol) of anhydrous acetonitrile in 32 ml of THF was added slowly. The reaction mixture was stirred at -60 ° C for 30 minutes. Then, 5.0 g (27.59 mmol) of 4- (methylsulfonyl) benzonitrile in 32 ml of THF was added at -60 ° C. The mixture was warmed to RT and stirred overnight. For workup, the mixture was mixed with water and extracted with dichloromethane. The organic phases were dried over magnesium sulfate, concentrated and dried in vacuo. The crude product was purified by flash chromatography (Kieselgel-60, eluent: cyclohexane-ethyl acetate). Yield: 2.68 g (35% of theory), in 80% purity (LC-MS).

LC-MS (Method 6): R _t = 0.61 min; MS (EIpos): m / z = 223 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8.07 (d, 1H), 8:00 (d, 1H), 7.90 (d, 1H), 7.71 (t, 1H), 7:03 ( br., 2H), 4.33 (s, 1H), 3.26 (s, 3H).

Example 32A

 3-amino-3 - (4

To a solution of 2.54 g (24.84 mmol) of diisopropylamine in 17 ml of THF under argon at -70 ° C were slowly added dropwise 15.5 ml (24.8 mmol) of a -Butyllithium solution (1.6M in hexane). After 10 minutes, a solution of 1.15 ml (21.9 mmol) of anhydrous acetonitrile in 17 ml of THF was added slowly. The reaction mixture was stirred at -60 ° C for 30 minutes. Subsequently, 2.00 g (14.61 mmol) of 4-methoxypyridine-2-carbonitrile in 16 ml of THF at -60 ° C were added. The mixture was warmed to RT, and stirred at RT overnight. For workup, the mixture was mixed with water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, concentrated and concentrated in vacuo. dries. The crude product was purified by flash chromatography (Kieselgel-60, eluent: cyclohexane-ethyl acetate). Yield: 1.46 g (53% of theory).

LC-MS (Method 6): R _t = 0.57 min; MS (EIpos): m / z = 176 [M + H] ⁺ .

 'H NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.44 (d, 1H), 7.47 (d, 1H), 7.07 (dd, 1H), 6.90 (br, s, 2H) , 4.91 (s, 1H), 3.88 (s, 3H).

Example 33A

 3-amino-3 - (6-methylpyridin-2-yl) acrylonitrile

 To a solution of 5.25 g (51.4 mmol) of diisopropylamine in 40 ml of THF under argon at -70 ° C 32.1 ml (51.4 mmol) of a "-Butyllithium solution (1.6M in hexane) was slowly added dropwise. After 10 minutes, a solution of 2.39 ml (45.3 mmol) of anhydrous acetonitrile in 30 ml of THF was added slowly.

The reaction mixture was stirred at -60 ° C for 30 minutes. Subsequently, 3.57 g (30.2 mmol) of 6

Methylpyridine-2-carbonitrile in 30 ml THF at -60 ° C added. The mixture was warmed to RT and stirred overnight. For workup, the mixture was mixed with water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, concentrated and dried in vacuo.

The crude product was purified by flash chromatography (silica gel 60, eluent: cyclohexane).

Ethyl acetate). Yield: 3.40 g (70% of theory).

LC-MS (Method 6): R _t = 0.68 min; MS (EIpos): mz = 160 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 7.80 (t, 1H), 7.73 (d, 1H), 7:36 (d, 1H), 6.88 (br s, 2H.). , 4.85 (s, 1H), 2.54 (s, 3H).

Example 34A

 3-amino-3 - (5-chloropyridin-2-yl) acrylonitrile

To a solution of 6.27 g (61.4 mmol) of diisopropylamine in 50 ml of THF under argon at -70 ° C were slowly added dropwise 24.5 ml (61.4 mmol) of a -Butyllithium solution (2.5M in hexane). After 10 minutes, a solution of 2.85 ml (54.1 mmol) of anhydrous acetonitrile in 50 ml of THF was added slowly. The reaction mixture was stirred at -60 ° C for 30 minutes. Subsequently, 5.0 g (36.09 mmol) 5 The reaction mixture was heated to RT and stirred overnight, and water was added to the mixture and extracted with dichloromethane, and the organic phase was dried over magnesium sulfate , concentrated and dried in vacuo The crude product was purified by flash chromatography (silica gel-60, eluent: cyclohexane-ethyl acetate mixtures) Yield: 3.37 g (50% of theory).

LC-MS (Method 6): R _t = 0.74 min; MS (EIpos): m / z = 180 [M + H] ⁺ .

 'H NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.69 (d, 1H), 8.07 (dd, 1H), 7.95 (d, 1H), 6.93 (br, s, 2H) , 4.88 (s, 1H).

Example 35A

1-methyl-1 / -

 5.00 g (53.7 mmol) of 1-pyrazole-4-carbonitrile and 14.8 g (107 mmol) of potassium carbonate were initially charged in 40 ml of acetonitrile. It was cooled with an ice bath and added dropwise 4.01 ml (64.5 mmol) of iodomethane. Then let it slowly come to RT. After 3 h, the reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. It was dried over sodium sulfate and the solvent was removed in vacuo. The residue was stirred with pentane / MTBE and filtered with suction. Yield: 4.62 g (80% of theory).

GC-MS (Method 1): R _t = 3.17 min; MS (EIpos): m / z = 107 [M] ⁺ .

'H-NMR (400 MHz, CDC1 _3): δ [ppm] = 7.80 (s, 1H), 7.79 (s, 1H), 3.97 (s, 3H). Example 36A

 3-amino-3 - (1-methyl-1 / pyrazol-4-yl) acrylonitrile

53.2 ml (85.1 mmol) of a 1.6N solution of n-butyllithium in hexane in 125 ml of THF were added at -78 ° C., and 4.48 ml (85.1 mmol) of acetonitrile were added dropwise. It was left for 15 min. stirred at -78 ° C and then added dropwise 4.56 g (42.5 mmol) of 1-methyl-l / -pyrazole-4-carbonitrile from Example 35A as a solution in 125 ml of THF. After 30 min. let one come to RT. The reaction solution was then added to saturated aqueous ammonium chloride solution. It was extracted with ethyl acetate and the organic phase was washed with water, dried over sodium sulfate and the solvent was removed in vacuo. The residue was stirred with MTBE and filtered with suction. The title compound was obtained. Yield: 5.20 g (81% of theory). LC-MS (Method 2): R _t = 0.43 min; MS (EIpos): m / z = 149 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-i / e): δ [ppm] = 8.11 (s, 1H), 7.82 (s, 1H), 6.62 (br. S., 2H), 4.19 (s, 1H) , 3.82 (s, 3H).

Example 37A

1- (tetrahydro-pyran-2-yl) -1 / pyrazole-4-carbonitrile

 44.0 g (473 mmol) of 1-pyrazole-4-carbonitrile [M. Jachak, U. Kriessmann, M. Mittelbach, H. Junek, Monatsh. Chem. 1993, 124, 199-208.], 79.5 g (945 mmol) of 3,4-dihydro-2 / pyran and 8.14 g (47.3 mmol) of p-toluenesulfonic acid were dissolved in a mixture of 2.2 l of ethyl acetate and 2.2 l of N , N-dimethylformamide stirred for 20 h at RT. The reaction mixture was poured onto 5 l of MTBE and extracted with 5 l of saturated aqueous sodium carbonate solution. The aqueous phase was extracted once with MTBE. Then the combined organic phases were washed three times with saturated aqueous sodium chloride solution and once with saturated aqueous ammonium chloride solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was stirred with petroleum ether, filtered off with suction and washed with petroleum ether. Yield: 71.2 g (85% of theory).

LC-MS (Method 4): R _t = 1.52 min; MS (EIpos): m / z = 178 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.76 (s, 1H), 8.1 1 (s, 1H), 5.50 (dd, 1H), 3.96-3.89 (m, 1H) , 3.69-3.61 (m, 1H), 2.09-1.98 (m, 1H), 1.97-1.86 (m, 2H), 1.73-1.60 (m, 1H), 1.58-1.44 (m, 2H).

Example 38A

3-amino-3 - [1- (tetrahydro-2 / pyran-2-yl) -1 / pyrazol-4-yl] acrylonitrile

An LDA solution was first prepared by adding 19.4 g (192 mmol) of diisopropylamine in 400 ml of THF at -70 ° C and dropping 65.5 ml (164 mmol) of a 2.5M solution of n-butyllithium in hexane and dropping for 10 min. allowed to stir. Then, 6.95 g (169 mmol) of acetonitrile was added as a solution in 50 ml of THF. The mixture was stirred for 30 min, resulting in a thick suspension. 20.0 g (113 mmol) of 1- (tetrahydro-2 / pyran-2-yl) -1 / pyrazole-4-carbonitrile from Example 37A was added dropwise as a solution in 60 ml of THF. After 20 min. allowed to come to RT and stir for 2 h. The reaction solution was then poured onto 1.5 l of MTBE and 1.5 l of saturated aqueous sodium chloride solution. The organic phase was separated and extracted twice with saturated aqueous sodium chloride solution and once with saturated aqueous ammonium chloride solution. The organic phase was dried over sodium sulfate and concentrated in vacuo. The mixture was mixed with a little MTBE, sucked off and washed with MTBE. Yield: 21.5 g (87% of theory).

LC-MS (Method 2): R _t = 0.65 min; MS (EIpos): m / z = 219 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.37 (s, 1H), 7.89 (s, 1H), 6.65 (s, 2H), 5.39 (dd, 1H), 4.29 ( s, 1H), 3.94-3.87 (m, 1H), 3.67-3.59 (m, 1H), 2.05-1.87 (m, 3H), 1.74-1.60 (m, 1H), 1.58-1.47 (m, 2H).

Example 39A

 4-Amino-2- [3-fluoro-4- (trifluoromethyl) phenyl] -4- [1- (tetrahydro-2 / pyran-2-yl) -1 / pyrazol-4-yl] but-3 - 1, 1, 3 -tricarbonitrile

1.45 g (6.66 mmol) of 3-amino-3- [1- (tetrahydro-2 / pyran-2-yl) -1 / pyrazol-4-yl] acrylonitrile from Example 38A and 1.60 g (6.66 mmol) [3 Fluoro-4- (trifluoromethyl) benzylidene] malononitrile from Example 2A were initially charged in 12 ml sulfolane and stirred at RT overnight. It was then diluted with MTBE, washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was stirred with methanol and filtered with suction. The title compound was obtained. Yield: 2.25 g (74% of theory).

LC-MS (Method 6): R _t = 1.00 min; MS (EIpos): m / z = 459 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8.29 (s, 1H), 7.93 (t, 1H), 7.87 (s, 1H), 7.65 (d, 1H), 7:53 (d, 1H), 7.23 (br.s, 2H), 5.77 (d, 1H), 5.46 (d, 1H), 5.06 (d, 1H), 3.95-3.89 (m, 1H), 3.68-3.59 (m, 1H) , 2.10-1.96 (m, 1H), 1.96-1.86 (m, 2H), 1.73-1.59 (m, 1H), 1.58-1.45 (m, 2H).

Example 40A

2-Amino-4- [3-fluoro-4- (trifluoromethyl) phenyl] -6- [1- (tetrahydro-2 / pyran-2-yl) -1 / pyrazol-4-yl] pyridine-3, 5-dicarbonitrile

 640 mg (7.36 mmol) of manganese dioxide in 20 ml of acetic acid were initially introduced at RT, and a solution of 2.25 g (4.91 mmol) of 4-amino-2- [3-fluoro-4- (trifluoromethyl) phenyl] -4- [ 1 - (tetrahydro-2 / pyran-2-yl) -1-pyrazol-4-yl] but-3-en-1, 1,3-tricarbonitrile from Example 39A. It was allowed to stir overnight at RT, then added diatomaceous earth and sucked on diatomaceous earth. It was washed with DMF. The filtrate was added to ice-water and made weakly basic with potassium carbonate. It was extracted with MTBE, dried over sodium sulfate and the solvent removed in vacuo. The residue was crystallized with a little methanol, stirred and filtered with suction. The title compound was obtained. Yield: 1.64 g (73% of theory).

LC-MS (Method 2): R _t = 1.15 min; MS (EIpos): m / z = 457 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8:56 to 8:52 (m, 1H), 8:21 to 8:17 (m, 1H), 8.16-7.97 (m, 3H), 7.93 (d , 1H), 7.68 (d, 1H), 5.58 (dd, 1H), 3.98-3.92 (m, 1H), 3.72-3.64 (m, 1H), 2.09-1.89 (m, 3H), 1.75-1.60 (m , 1H), 1.59-1.51 (m, 2H).

Example 41A

 4-Amino-2- [3-chloro-4- (trifluoromethyl) phenyl] -4- [1- (tetrahydro-2 / pyran-2-yl) -1 / pyrazol-4-yl] but-3 - 1, 1, 3 -tricarbonitrile

1.56 g (7.14 mmol) of 3-amino-3- [1- (tetrahydro-2 / pyran-2-yl) -1 / pyrazol-4-yl] acrylonitrile from Example 38A and 1.83 g (7.14 mmol) [3 Chloro-4- (trifluoromethyl) benzylidene] malononitrile from Example 4A were dissolved in 12.5 ml Submitted to sulfolane and stirred for 3 h at RT. It was then diluted with MTBE, washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was stirred with methanol and filtered with suction. The title compound was obtained. Yield: 2.51 g (74% of theory).

LC-MS (Method 2): R _t = 1.08 min; MS (EIpos): m / z = 475 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ώ): δ [ppm] = 8.30 (s, 1H), 8.00 (d, 1H), 7.87 (s, 1H), 7.86 (br, s, 1H), 7.66 ( d, 1H), 7.23 (br.s, 2H), 5.81 (d, 1H), 5.46 (dd, 1H), 5.03 (d, 1H), 3.95-3.89 (m, 1H), 3.68-3.60 (m, 1H), 2.08-1.96 (m, 1H), 1.91 (d, 2H), 1.66 (s, 1H), 1.57-1.49 (m, 2H).

Example 42A

 2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- [1- (tetrahydro-2 / pyran-2-yl) -1 / pyrazol-4-yl] pyridine-3, 5-dicarbonitrile

 275 mg (3.16 mmol) of manganese dioxide in 10 ml of acetic acid were initially introduced at RT, and a solution of 1.00 g (2.11 mmol) of 4-amino-2- [3-chloro-4- (trifluoromethyl) phenyl] -4- [ l- (tetrahydro-2 / pyran-2-yl) -1 / pyrazol-4-yl] but-3-en-1, l, 3-tricarbonitrile from Example 41A. The mixture was stirred overnight at RT, then Celery was added and the mixture was filtered through kieselguhr. It was washed with DMF. The filtrate was added to ice-water and made weakly basic with potassium carbonate. It was extracted with MTBE, dried over sodium sulfate and the solvent removed in vacuo. The residue was crystallized with a little methanol, stirred and filtered with suction. The title compound was obtained. Yield: 745 mg (75% of theory).

LC-MS (Method 6): R _t = 1.19 min; MS (EIpos): mz = 473 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ώ): δ [ppm] = 8.54 (s, 1H), 8.19 (s, 1H), 8.13 (d, 1H), 8.10 (s, 1H), 8.06 (br. s, 2H), 7.82 (dd, 1H), 5.58 (dd, 1H), 3.98-3.92 (m, 1H), 3.72-3.64 (m, 1H), 2.09-1.89 (m, 3H), 1.74-1.61 ( m, 1H), 1.59-1.52 (m, 2H).

Example 43A

2-Amino-4- (3,4-dichlorophenyl) -6- [1- (tetrahydro-2 / pyran-2-yl) -1 / pyrazol-4-yl] pyridine-3, 5-dicarbonitrile

 300 mg (1.38 mmol) of 3-amino-3- [1- (tetrahydro-2 / pyran-2-yl) -1 / pyrazol-4-yl] acrylonitrile from Example 38A and 460 mg (2.06 mmol) (3 , 4-dichlorobenzylidene) malononitrile were placed in 3.2 ml of ethanol. 21 mg (0.14 mmol) of DBU were added and the mixture was heated for 50 min. in a preheated oil bath at 80 ° C. It was then allowed to cool to rt and stirred for 2 h in an open flask. The precipitate formed was filtered off with suction and washed with ethanol cooled to -10.degree. The crude product was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 4: 1 gradient to 1: 1). Yield: 89 mg (15% of theory).

LC-MS (Method 2): R _t = 1.17 min; MS (EIpos): m / z = 439 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8:54 (s, IH), 8.18 (s, IH), 8.01 7.98 (d, IH), (br s, 2H). 7.90 (d, IH), 7.62 (ddd, IH), 5.57 (dd, IH), 3.98-3.92 (m, IH), 3.72-3.64 (m, IH), 2.09-1.88 (m, 3H), 1.74- 1.62 (m, IH), 1.59-1.52 (m, 2H)

Example 44A

 N '- {4- [3-Chloro-4- (trifluoromethyl) phenyl] -3,5-dicyan-6- (1-pyrazol-4-yl) pyridin-2-yl} -N, N-dimethylimidoformamide

7 0 mg (0.1 mmol) of 2-amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- (1-pyrazol-4-yl) pyridine-3,5-dicarbonitrile from Example 86 were presented in 1.0 ml of toluene. 21 mg (0.18 mmol) of dimethylformamide dimethylacetal were added and the mixture was stirred for 2 h at reflux. The reaction mixture was subsequently in Concentrated vacuum and the residue stirred with MTBE / pentane. It was sucked off and received yellowish crystals. Yield: 66 mg (82% of t.l.).

LC-MS (Method 6): R _t = 1.07 min; MS (EIpos): m / z = 444 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ώ): δ [ppm] = 13.52 (br, s, 1H), 9.05 (s, 1H), 8.69 (br, s, 1H), 8.44 (br, s, 1H), 8.14-8.11 (m, 2H), 7.83 (d, 1H), 3.31 (s, 3H), 3.17 (s, 3H).

Example 45A

 N '- {4- [3-Chloro-4- (trifluoromethyl) phenyl] -3,5-dicyan-6- (1-methyl-1 / pyrazol-4-yl) pyridin-2-yl} -NN- dimethylimidoformamid

63 mg (0.14 mmol) of N '- {4- [3-chloro-4- (trifluoromethyl) phenyl] -3,5-dicyan-6- (1-pyrazol-4-yl) pyridine-2 were added -yl} -N, N-dimethylimidoformamide from Example 44A and 139 mg (0.43 mmol) of cesium carbonate in 1.1 ml of acetonitrile with ice cooling and 21 mg (0.15 mmol) of iodomethane added. It was allowed to come slowly to RT. After 2 h, a further 7 mg (0.05 mmol) of iodomethane were added and stirring was again carried out at RT for 2 h. For work-up, the reaction mixture was taken up in ethyl acetate and washed with water. The organic phase was dried over sodium sulfate and the solvent removed in vacuo. A yellowish oil was obtained which was reacted further without purification. Yield: 70 mg (quant). LC-MS (Method 6): R _t = 1.19 min; MS (EIpos): m / z = 458 [M + H] ⁺ .

Example 46A

tert -Butyl- (4- {6-arnino-3,5-dicyano-4- [4- (trifluoromethyl) phenyl] pyridin-2-yl} phenyl) carbamate

 According to General Method 3, 2.50 g (7.75 mmol) of the compound from Example 24A and 2.84 g (11.62 mmol) of {4- [(tert.-butoxycarbonyl) amino] phenyl} boronic acid were reacted. Yield: 3.55 g (82% of theory) in 86% of purity (LC-MS). The product was further reacted without purification operations.

LC-MS (Method 6): R _t = 1.21 min; MS (EIpos): m / z = 480 [M + H] ⁺ .

Example 47A

 3- {6-Amino-3,5-dicyano-4- [4- (trifluoromethyl) phenyl] pyridin-2-yl} benzoic acid

 According to General Method 3, 1.00 g (3.10 mmol) of the compound from Example 24A and 0.77 g (4.65 mmol) of 3- (dihydroxyboryl) benzoic acid were reacted. Yield: 0.89 g (70% of theory).

LC-MS (Method 6): R _t = 0.95 min; MS (EIpos): m / z = 409 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 13:26 (s, 1H), 8:41 to 8:42 (m, 1H), 8:13 to 8:08 (m, 2H), 8:00 (d, 2H), 7.90 (d, 2H), 7.69 (t, 1H).

Example 48A

ter /.- butyl (3- {6-amino-3,5-dicyano-4- [4- (trifluorm

 According to General Method 3, 2.20 g (6.82 mmol) of the compound from Example 24A and 2.42 g (10.23 mmol) of {3 - [(tert-butoxycarbonyl) amino] phenyl} boronic acid were reacted. Yield: 3.99 g (73% of theory) in 60% purity (LC-MS), which were reacted without further purification.

LC-MS (Method 2): R _t = 1.22 min; MS (EIpos): m / z = 480 [M + H] ⁺ .

Example 49A

 2-Amino-4- [4-1,3-oxazol-5-yl] pyridine-3,5-dicarbonitrile

100 mg (0.31 mmol) of 2-amino-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 218 mg (0.62 mmol) of 5- (4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2- (triisopropylsilyl) -1,3-oxazole [N. Primas, A. Bouillon, J.-C. Lancelot, S. Rault, Tetrahedron 2009, 65, 6348-6353.], 104 mg (1.24 mmol) of sodium bicarbonate and 13 mg (0.016 mmol) of [l, -Bis (diphenylphosphine) ferrocene] dichloroalladium (II) dichloromethane. Complex was treated with a degassed mixture of 0.9 ml of 1,2-dimethoxyethane and 0.3 ml of water and heated to 80 ° C for 6 h. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The crude product (159 mg) according to LC-MS proportionately already desilylated end compound and was further reacted without purification step. LC-MS (Method 4): R _t = 3.12 min; MS (EIpos): m / z = 512 [M + H] ⁺ (37% share). Desilylated compound: R _t = 2.12 min; MS (EIpos): m / z = 355 [M + H] ⁺ (20% share).

Example 50A

 Methyl (2Z) -2- (3-methoxybenzoyl) -3 - [4- (trifluoromethyl) phenyl] acrylate

 25.0 g (144 mmol) of 4- (trifluoromethyl) benzaldehyde and 29.9 g (144 mmol) of methyl 3- (3-methoxyphenyl) -3-oxopropanoate were initially charged in 25 ml of ethanol. 1.22 g (14.6 mol) of piperidine and 3 drops of acetic acid were added and the reaction mixture was allowed to stir at RT overnight. The precipitated product was filtered off with suction and recrystallized from ethanol. Yield 36.7 g (70% of theory).

LC-MS (Method 6): R _t = 1.23 min; MS (EIpos): mz = 365 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8.06 (s, 1H), 7.72 (d, 1H), 7:57 (d, 1H), 7:46 to 7:43 (m, 2H), 7.41- 7.39 (m, 1H), 7.28-7.23 (m, 1H), 3.80 (s, 3H), 3.74 (s, 3H)

Example 51A

 Methyl 6-amino-5-cyano-2- (3-methoxyphenyl) -4- [4- (trifluoromethyl) phenyl] -4 / pyran-3-carboxylate

72.4 g (199 mmol) of methyl (2Z) -2- (3-methoxybenzoyl) -3- [4- (trifluoromethyl) phenyl] acrylate from Example 50A and 13.1 g (199 mmol) of malononitrile were dissolved in 500 ml of ethanol. 423 mg (4.97 mmol) of piperidine were added and the mixture was heated to 60 ° C. with stirring for 3 h. It was then allowed to come to RT and sucked off the precipitate. The mother liquor was concentrated in vacuo. The residue was combined with the crystals and then recrystallized from MTBE / pentane. It was sucked off and dried the crystals in vacuo. The title compound was obtained. Yield: 82.1 g (96% of theory). LC-MS (Method 6): R _t = 1.10 min; MS (EIpos): m / z = 431 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-i / e): δ [ppm] = 7.74 (d, 2H), 7.49 (d, 2H), 7.36 (t, 1H), 7.16 (s, 2H), 7.08- 6.99 (m, 3H), 4.56 (s, 1H), 3.79 (s, 3H), 3.32 (s, 3H)

Example 52A

 Methyl-6-amino-5-cyano-2- (3-methoxyphenyl) -4- [4- (trifluoromethyl) phenyl] nicotinate

 82.1 g (191 mmol) of methyl 6-amino-5-cyano-2- (3-methoxyphenyl) -4- [4- (trifluoromethyl) phenyl] -4 / -pyran-3-carboxylate from Example 51A and 176 g ( 2.29 mol) of ammonium acetate were heated in 500 ml of glacial acetic acid for 3 h to reflux. It was then allowed to come to RT and concentrated in a vacuum. The residue was taken up in ethyl acetate, washed with 1N sodium hydroxide solution and saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 3: 1). The product was then stirred with a little methanol and filtered with suction. The title compound was obtained. Yield: 13.2 g (16% of theory).

LC-MS (Method 2): R _t = 1.17 min; MS (EIpos): m / z = 428 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 7.89 (d, 2H), 7.62 (d, 2H), 7.61-7.54 (m, 2H), 7.41-7.35 (m, 1H ), 7.07-7.03 (m, 3H), 3.78 (s, 3H), 3.25 (s, 3H).

Example 53A

6-amino-5-cyano-2- (3-methoxyphenyl) -4- [4- (trifluoromethyl) phenyl] nicotinic acid

13.1 g (30.7 mmol) of methyl 6-amino-5-cyano-2- (3-methoxyphenyl) -4- [4- (trifluoromethyl) phenyl] nicotinate from Example 52A were mixed with 21.3 g (153 mmol) of lithium iodide in 655 ml Pyridine heated to reflux for 20 h. The solvent was then removed in vacuo. It was taken up in water and acidified to pH 2 with hydrochloric acid. It was then extracted with ethyl acetate. The organic phase was concentrated in vacuo, the residue was stirred with MTBE, filtered off with suction and washed with pentane. Yield: 14.7 g (98% of theory) LC-MS (Method 6): R _t = 0.97 min; MS (EIpos): m / z = 414 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 12.93 (br.s, 1H), 7.89 (d, 2H), 7.65 (d, 2H), 7.43 (br. S, 2H ), 7.37 (t, 1H), 7.18-7.12 (m, 2H), 7.04 (dd, 1H), 3.77 (s, 3H). Example 54A

 [3-chloro-4- (trifluoromethoxy) benzylidene] malononitrile

 3.00 g (13.4 mmol) of 3-chloro-4- (trifluoromethoxy) benzaldehyde were dissolved in 3.5 ml of ethanol. 918 mg (13.9 mmol) of malononitrile and 114 mg (1.34 mmol) of piperidine were added and the mixture was heated at reflux for 1 h. It was allowed to cool to RT, the precipitate was filtered off with suction and washed with a little cold ethanol and petroleum ether. The title compound was obtained. Yield: 1.40 g (38% of theory).

GC-MS (Method 1): R _t = 4.88 min. MS (EI): m / z = 272 [M] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8:58 (s, 1H), 8.20 (d, 1H), 8:05 (dd, 1H), 7.88 (d, 1H). Example 55A

 (3-chloro-4-

 1.00 g (6.47 mmol) of 3-chloro-4-methylbenzaldehyde was dissolved in 5 ml of ethanol. 444 mg (6.73 mmol) of malononitrile and 6 mg (0.07 mmol) of piperidine were added and the mixture was heated under reflux for 1 h. It was allowed to cool, the precipitate was filtered off with suction and washed with a little ethanol. One received the titles connection. Yield: 940 mg (72% of theory).

GC-MS (Method 1): R _t = 5.72 min. MS (EI): m / z = 202 [M] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.50 (s, 1H), 7.98 (d, 1H), 7.85 (dd, 1H), 7.63 (d, 1H), 2.43 ( s, 3H).

Example 56A

 [4-Chloro-3 - (trifluoromethyl) benzylidene] malononitrile

 4.50 g (21.6 mmol) of 4-chloro-3- (trifluoromethyl) benzaldehyde were dissolved in 20 ml of ethanol. 1.50 g (22.7 mmol) of malononitrile and 18 mg (0.22 mmol) of piperidine were added and the mixture was heated under reflux for 1 h. It was then cooled with an ice bath, sucked the precipitate and washed with a little ethanol. The title compound was obtained. Yield: 3.12 g (56% of theory).

GC-MS (Method 1): R _t = 5.14 min. MS (EI): m / z = 256 [M] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8.64 (s, 1H), 8:39 (d, 1H), 8.23 (dd, 1H), 8:04 (d, 1H). Example 57A

4- (pentafluoro ^ ^6- sulfanyl) benzylidene] malononitrile

1.00 g (4.31 mmol) of 4- (pentafluoro ^ ^6- sulfanyl) benzaldehyde was dissolved in 10 ml of ethanol. 296 mg (4.48 mmol) of malononitrile and 4 mg (0.04 mmol) of piperidine were added and the mixture was heated under reflux for 1 h. It was allowed to cool, the precipitate was filtered off with suction and washed with a little ethanol. The title compound was obtained. Yield: 509 mg (42% of theory).

GC-MS (Method 1): R _t = 5.11 min. MS (EI): m / z = 280 [M] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.69 (s, 1H), 8.20 (d, 2H), 8.10 (d, 2H).

Example 58A

 [2-Chloro-4 - (trifluoromethyl) benzylidene] malononitrile

950 mg (4.08 mmol) of 2-chloro-4- (trifluoromethyl) benzaldehyde were dissolved in 3.1 ml of ethanol. 280 mg (4.24 mmol) of malononitrile and 3 mg (0.03 mmol) of piperidine were added and the mixture was heated under reflux for 1 h. It was allowed to cool, the precipitate was filtered off with suction and washed with a little ethanol. The title compound was obtained. Yield: 702 mg (67% of theory). GC-MS (Method 1): R _t = 4.29 min. MS (EI): m / z = 256 [M] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8.79 (s, 1H), 8.16 (s, 2H), 8.03-7.99 (m, 1H). Example 59A

 (4-tert-butylbenzylidene) malononitrile

 2.00 g (12.3 mmol) -tert. Butylbenzaldehyde was dissolved in 4 ml of ethanol. 847 mg (12.8 mmol) of malononitrile and 10 mg (0.12 mmol) of piperidine were added and the mixture was heated under reflux for 1 h. It was allowed to cool, concentrated in vacuo and the crude product purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10: 1). The product was stirred with a little pentane and filtered with suction. The title compound was obtained. Yield: 840 mg (32% of theory).

GC-MS (Method 1): R = 5.76 min. MS (EI): m / z = 210 [M] ⁺ .

'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.51 (s, 1H), 7.91 (d, 2H), 7.67 (d, 2H), 1.31 (s, 9H).

Example 60A

 2- [(1-trityl-1 / -azol-4-yl) oxy] ethanol

 500 mg (1.53 mmol) of 1-trityl-l / -pyrazol-4-ol [US Pat. No. 6,232,337, preparation 7] was mixed with 148 mg (1.69 mmol) of 1,3-dioxolan-2-one and 6 mg (0.15 mmol) of sodium hydroxide heated in 2.0 ml of DMF for 3 h under reflux. The reaction solution was then taken up with MTBE, washed with water and the organic phase was dried over sodium sulfate. The solvent was removed in vacuo and the residue was crystallized with pentane / MTBE. The title compound was obtained. Yield: 493 mg (87% of theory).

LC-MS (Method 6): R = 1.14 min. MS (EI): m / z = 243 [CPh ₃ ] ⁺ .

'H-NMR (400MHz, _DMSO-ö): δ [ppm]

(t, 1H), 3.79 (t, 2H), 3.59 (q, 2H).

Example 61A

2- (1-pyrazol-4-yloxy) ethanol H

 413 mg (1.12 mmol) of 2 - [(1-trityl-1-pyrazol-4-yl) oxy] ethanol from example 60A in 83 ml of ethanol were added and 25 mg of 10% palladium on activated carbon were added. It was then hydrogenated for 3 h at RT and normal pressure in a hydrogen atmosphere. It was sucked on kieselguhr, washed with ethanol and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: ethyl acetate) to give the title compound. Yield: 123 mg (84% of theory).

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 12.33 7:43, 7:23 (br s, 1H..), 4.82 ((br s, 1H.). (Br s, 1H.). t, 1H), 3.84 (t, 2H), 3.63 (q, 2H).

Example 62A

2-Methyl-1 - [(1-tritol-1-pyrazol-4-yl) oxy] propan-2-ol

 500 mg (1.53 mmol) of 1-trityl-l / -pyrazol-4-ol [US Pat. No. 6,232,337, preparation 7] was incubated with 499 mg (1.53 mmol) of cesium carbonate in 3.0 ml of 2,2-dimethyloxirane in the microwave for a mere 30 minutes. heated to 120 ° C and then for 1 h at 140 ° C. The reaction solution was then taken up in water, extracted with ethyl acetate and the organic phase was dried over sodium sulfate. The solvent was removed in vacuo and the residue was stirred with pentane / MTBE and filtered with suction. The title compound was obtained. Yield: 473 mg (73% of theory).

Th.).

LC-MS (method 2): R _t = 1.27 min. MS (EI): m / z = 399 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 7.42 (s, 1H), 7:34 (s, 9H), 7:09 to 7:04 (m, 6H) 7.00 (s, 1H), 4.54 (s, 1H), 3.52 (s, 2H), 1.11 (s, 6H).

Example 63A

2-methyl-1 - (1-pyrazol-4-yloxy) propan-2-ol

450 mg (1.13 mmol) of 2-methyl-1 - [(1-trityl-l / -pyrazol-4-yl) oxy] -propan-2-ol from Example 62A in 5 ml of dichloromethane were added and 5 ml of trifluoroacetic acid added , The mixture was stirred for 2 h at RT, then slowly added to saturated aqueous sodium carbonate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and the solvent removed in vacuo. Purification by chromatography on silica gel (eluent: ethyl acetate / cyclohexane gradient 2: 1 to 1: 0) gave the title compound. Yield: 104 mg (59% of theory).

LC-MS (Method 6): R _t = 0.30 min. MS (EI): m / z = 157 [M + H] ⁺ .

'H NMR (400 MHz, DMSO-ώ): δ [ppm] = 12.31 (br, s, 1H), 7.42 (br, s, 1H), 7.23 (br, s, 1H), 4.58 (s , 1H), 3.58 (s, 2H), 1.15 (s, 6H).

Example 64

2- (1 / pyrazol-4-yl) propan-2-ol

300 mg (2.04 mmol) of 4-bromo-1 / pyrazole were initially charged in 3.0 ml of THF at -78 ° C. 3.1 ml (4.9 mmol) of a 1.6N solution of n-butyllithium in hexane were added dropwise, and the mixture was allowed to come to RT, after which stirring was continued for 1.5 h at this temperature. It was then cooled again to -78 ° C, was set to 150 μΐ (2.04 mmol) of acetone and allowed to come to RT overnight. A little saturated ammonium chloride solution was added, diluted with ethyl acetate and dried over sodium sulfate. Solvents were removed in vacuo. The residue was purified by chromatography on silica gel (eluent: ethyl acetate) to give the title compound. Yield: 58 mg (23% of theory).

LC-MS (Method 6): R _t = 0.23 min; MS (EIpos): m / z = 127 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 12.49 (br, s, 1H), 7.51 (br, s, 1H), 7.38 (br, s, 1H), 4.72 (s, 1H), 1.39 (s, 6H). Example 65A

 2-Methyl-1- (1-trit-1-pyrazol-4-yl) -propan-2-ol

500 mg (1.28 mmol) 4-bromo-1-trityl-l / -pyrazole [R. Hüttel, W. Schwarz, J. Miller, F. Wunsch, Chem. Ber. 1962, 95, 222-227.] Were initially charged at -78 ° C. in 5.0 ml of THF. 2.25 ml (3.6 mmol) of a 1.6N solution of n-butyllithium in hexane were added dropwise, followed by 30 min. -78 ° C was stirred. Then, 463 mg (6.42 mmol) of 2,2-dimethyloxirane was added as a solution in 5.0 ml of THF. The reaction mixture was allowed to stir at -78 ° C for 3 hours. A little saturated ammonium chloride solution was added, diluted with ethyl acetate and the organic phase was washed with water. Then it was dried over sodium sulphate and the solution removed. in a vacuum. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 3: 1) to give the title compound. Yield: 283 mg (58% of theory). LC-MS (Method 6): R _t = 1.25 min; MS (EIpos): m / z = 383 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ώ): δ [ppm] = 7.43 (s, 1H), 7.38-7.30 (m, 9H), 7.14 (s, 1H), 7.07-7.02 (m, 6H), 4.22 (s, 1H), 2.44 (s, 2H), 1.00 (s, 6H).

Example 66A

 2-methyl-1 - (1-pyrazol-4-yl) propan-2-ol

280 mg (0.73 mmol) of 2-methyl-1- (1-trityl-l / -pyrazol-4-yl) -propan-2-ol from Example 65A in 30 ml of ethanol were initially added and 14 mg of 10% palladium were added Activated carbon added. It was then hydrogenated overnight at RT and normal pressure in a hydrogen-Ateno sphere. It was sucked on kieselguhr, washed with ethanol and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: ethyl acetate) to give the title compound. Yield: 79 mg (77% of theory). LC-MS (Method 6): R _t = 0.30 min; MS (EIpos): m / z = 141 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 12.48 7:37, 4:22 (s, 1H), 2:47 (s, 2H (br s, 1H.). (Br s, 2H.). ), 1.02 (s, 6H).

Example 67A

 2-amino-4-hydroxy-6- (3-methoxyphenyl) pyridine-3,5-dicarboniteil

827 mg (7.65 mmol) of 1,2-oxazol-5-ylacetoniteil [WO 2009/33581, p. 85] were initially charged in 8.0 ml of methanol at RT. 1.50 g (7.65 mmol) of methyl N-cyano-3-methoxybenzenecarboximidoate [P. Yin, W.-B. Ma, Y. Chen, W.-C. Huang, Y. Deng, L. He, Org. Lett. 2009, 11, 5482-5485.] And then slowly added dropwise 5.7 ml (31 mmol) of a 4N sodium methoxide solution in methanol. The reaction mixture was stirred at RT for 3 h and then allowed to stand at RT overnight. For workup was acidified with 4N hydrochloric acid and the precipitate was filtered off with suction. The residue was stirred successively with methanol, hot acetone and pentane / MTBE and in each case filtered with suction. The title compound was obtained. Yield: 1.76 g (86% of theory). LC-MS (Method 2): R _t = 0.55 min. MS (EI): m / z = 267 [M + H] ⁺ . 'H-NMR (400 MHz, OMSO-d ₆ ): δ [ppm] = 1 1.78 (br.s, 1H), 7.54 (t, 1H), 7.28 (s, 4H), 7.23 (dd, 1H), 3.83 (s, 3H).

Example 68A

 2-Amino-4-chloro-6- (3-methoxyphenyl) pyridine-3,5-dicarbonitrile

 2.92 g (19.0 mmol) of phosphoryl chloride were initially charged in 10 ml of sulfolane. 1.93 g (19.0 mmol) of triethylamine were slowly added dropwise to the solution and then 1.69 g (6.35 mmol) of 2-amino-4-hydroxy-6- (3-methoxyphenyl) -pyridine-3,5-dicarbonitrile from Example 67A were added to. Thereafter, it was heated to 70 ° C for 3 h. The mixture was then allowed to cool to RT and the reaction mixture was stirred carefully into hot water and then for 30 min. stir. With sodium carbonate was then neutralized, the precipitate was filtered off and washed with water. The residue was triturated with ethyl acetate, the crystals were filtered off with suction and dried in vacuo. The title compound was obtained. Yield: 1.12 g (59% of theory).

LC-MS (Method 2): R _t = 0.98 min. MS (EI): m / z = 285 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.36 (br.s, 2H), 7.47 (t, 1H), 7.37-7.32 (m, 2H), 7.16 (dd, 1H ), 3.81 (s, 3H).

Example 69A

 3-amino-3 - (3-methoxyphenyl) acrylonitrile

An LDA solution was prepared by dropwise addition of 109 ml (272 mmol) of a 2.5N solution of n-butyllithium in hexane to 32.3 g (319 mmol) of diisopropylamine in 400 ml of THF at -70 ° C. and stirring for 10 min. Subsequently, 1.6 g (282 mmol) of acetonitrile were added dropwise as a solution in 50 ml of THF and stirring was continued for 30 min. Then, 25.0 g (188 mmol) of 3-methoxybenzonitrile was added as a solution in 100 ml of THF. After 20 min. was warmed to RT and stirred overnight at this temperature. It was then poured onto 500 ml of MTBE and 150 ml of saturated aqueous sodium chloride solution, the phases were separated and the aqueous phase extracted twice with MTBE. The combined organic phases were then concentrated under reduced pressure and the residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate gradient 4: 1 to 2: 1). cleans. The product was stirred with a little petroleum ether, filtered off with suction and dried in vacuo. Yield: 30.0 g (92% of theory).

LC-MS (Method 6): R _t = 0.81 min. MS (EI): m / z = 175 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ώ): δ [ppm] = 7.33 (t, 1H), 7.16-7.12 (m, 1H), 7.11 (t, 1H), 7.03 (dd, 1H), 6.81 ( br., 2H), 4.20 (s, 1H), 3.79 (s, 3H).

Example 70A

 ( 1 -

 500 mg (4.90 mmol) of 1- (hydroxymethyl) cyclobutanol were introduced into 50 ml of dichloromethane and cooled with an ice bath. 1.49 g (14.7 mmol) of triethylamine, 60 mg (0.49 mmol) of 4-dimethylaminopyridine (DMAP) and 1.03 g (5.39 mmol) of 7-toluenesulfonyl chloride were added, and then slowly allowed to come to RT and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium carbonate solution, the organic phase was dried over sodium sulfate and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 2: 1) to give the title compound. Yield: 615 mg (49% of theory).

LC-MS (Method 6): R _t = 0.84 min. MS (EI): m / z = 257 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ώ): δ [ppm] = 7.81 (d, 2H), 7.49 (d, 2H), 5.31 (br, s, 1H), 3.92 (s, 2H), 2.43 ( s, 3H), 1.93-1.86 (m, 4H), 1.58 (d, 1H), 1.43-1.29 (m, 1H).

Example 71A

1- (2-hydroxyethyl) cyclobutanol

 13.3 ml (13.3 mmol) of an IN solution of lithium alanate in THF were initially charged and cooled with an ice bath. Then, 2.10 g (13.3 mmol) of ethyl (1-hydroxycyclobutyl) acetate [K. L. Erickson, J. Markstein, K. Kim, J. Org. Chem. 1971, 36, 1024-1030.] As a solution in 10 ml THF slowly added dropwise. The mixture was stirred for 2 h at RT, then sat sat saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo. The aqueous phase was also concentrated and the residue was triturated with ethyl acetate. The solvent was removed in vacuo to give a total of 1.25 g (80% of theory).

GC-MS (Method 1): R _t = 2.56 min. MS (DCI): m / z = 134 [M + NH ₄ ] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 4.87 (s, 1H), 4:32 (t, 1H), 3:52 (td, 2H), 1.99-1.86 (m, 4H), 1.69 ( t, 2H), 1.64-1.53 (m, 1H), 1.49-1.36 (m, 1H). Example 72A

 2- (1-hydro

 1.30 g (11.2 mmol) of 1- (2-hydroxyethyl) cyclobutanol from Example 71A were initially charged in 100 ml of dichloromethane and cooled with an ice bath. 3.40 g (33.6 mmol) of triethylamine, 137 mg (1.12 mmol) of 4-dimethylaminopyridine (DMAP) and 2.35 g (12.3 mmol) of 7-toluenesulfonyl chloride were added, and then slowly allowed to come to RT and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium carbonate solution, the organic phase was dried over sodium sulfate and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (eluents: cyclohexane / ethyl acetate 2: 1) to give the title compound as a pale yellowish oil. Yield: 1.89 g (63% of t.l.).

LC-MS (Method 6): R _t = 0.90 min. MS (EI): m / z = 271 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 7.79 (d, 2H), 7.49 (d, 2H), 5.06 (s, 1H), 4.08 (t, 2H), 2.43 ( s, 3H), 1.92-1.80 (m, 6H), 1.63-1.50 (m, 1H), 1.47-1.34 (m, 1H). Example 73A

 2-Methyl-4- [- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 / pyrazol-1-yl] butan-2-ol

 100 mg (0.387 mmol) of 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate [Y. Qiu, J. Gao, F. Guo, Y. Qiao, D. Li, Bioorg. Med. Chem. Lett. 2007, 17, 6164-6168.] Were initially charged in 2.0 ml of acetonitrile. 75.1 mg (0.387 mmol) of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 / pyrazole and 143 mg (0.387 mmol) of tetrabutylammonium iodide were added and heated to 50 ° C for 3 h. Thereafter, the reaction mixture was taken up in ethyl acetate and washed with water. The organic phase was dried over sodium sulfate and the solvent removed in vacuo. Purification by chromatography on silica gel (eluent: ethyl acetate / cyclohexane 1: 1). Yield: 70 mg (53% of theory).

LC-MS (Method 2): R _t = 0.84 min. MS (EI): m / z = 281 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 7.92 (s, 1H), 7:55 (s, 1H), 4:43 (s, 1H), 4:20 to 4:15 (m, 2H), 1.89- 1.83 (m, 2H), 1.24 (s, 12H), 1.10 (s, 6H). Analogously to the synthesis of Example 39A, 3-amino-3- (1-methyl-1 / pyrazol-4-yl) acrylonitrile from Example 36A with the respective benzylidenemalononitrile in the molar ratio 1: 1 in sulfolane as solvent (2 ml / mmol 36A ) were reacted at RT and the addition products listed in Table 1 were isolated.

Table 1 :

MS 1H), 1H),

MS 1H), s, 2H),

MS

MS 1H),

ei, Z.-M. Zong, Synth. Commun. 2005, 35, 1915-1920. 1H),

egg, Z.-M. Zong, Synth. Commun. 2005, 35, 1915-1920.

 * 2) (3,5-dichlorobenzylidene) malononitrile: BCH May, JA Zorn, J. Witkop, J. Sherrill, AC Wallace, G. Legname, SB Prusiner, FE Cohen, J. Med. Chem. 2007, 50, 65 -73.

* 3) (2,4-dichlorobenzylidene) malononitrile: see * 1)

* 4) (4-chlorobenzylidene) malononitrile: see * 1)

embodiments

example 1

 2-Amino-6- (1-imidazol-1-yl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

 According to General Method 1, 100 mg (0.31 mmol) of the compound from Example 24A and 21 mg (0.31 mmol) of imidazole hydrochloride were reacted. Yield: 13 mg (12% of theory).

LC-MS (Method 2): R _t = 0.90 min; MS (EIpos): m / z = 355 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8:45 (s, 1H), 8:03 (d, 2H), 7.88 (d, 2H), 7.84 (s, 1H), 7.24 ( s, 1H).

Example 2

2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- [4- (hydroxymethyl) -1 / -imidazol-1-yl] pyridine-3, 5-dicarbonitrile

 1 0 0 mg (0.231 mmol) 2-Anuno-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- (phenylsulfanyl) pyridine-3,5-dicarbonitrile from Example 19A and 182 mg ( 1.86 mmol) of 1H-iridazol-4-ylmethanol were heated to 120 ° C. in 2 ml of DMSO for 1 h. It was then diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and the organic phase was concentrated in vacuo. Purification by preparative HPLC (eluent: methanol / water 65:35). Yield: 36 mg (37% of theory).

LC-MS (Method 6): R _t = 0.86 min; MS (EIpos): m / z = 419 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ώ): δ [ppm] = 8.82-8.19 (m, 2H), 8.35 (d, 1H), 8.17 (d, 1H), 8.12 (s, 1H), 7.85 ( d, 1H), 7.67 (d, 1H), 5.44-4.80 (m, 1H), 4.44 (s, 2H).

Example 3

 2-Amino-6- (4-methyl-1 / pyrazol-1-yl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

100 mg (0.314 mmol) of 2-amino-6-hydrazino-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 18A and 36 mg (0.31 mmol) of 3-ethoxy-2-methylacrylaldehyde were dissolved in Dissolve 0.3 ml of acetic acid and microwave in the oven for 15 min. heated to 140 ° C. It was then concentrated in vacuo, the residue was taken up in ethyl acetate and the organic phase was washed with 1N sodium hydroxide solution. The organic phase was then dried over sodium sulfate and concentrated in vacuo. Purification by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 2: 1 gradient to 0: 1, then ethyl acetate / ethanol 100: 1 gradient to 50: 1). Yield: 50 mg (43% of theory). LC-MS (Method 6): R _t = 1.02 min; MS (EIpos): m / z = 369 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8.26 (s, 1H), 8.21, 7.98 (d, 2H), 7.83-7.79 (m, 3H (br s, 2H). ). Example 4

 2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- [4- (hydroxymethyl) -1 / pyrazole-1-yl] pyridine-3, 5-dicarbonitrile

 According to General Method 1, 100 mg (0.23 mmol) of the compound from Example 19A and 27 mg (0.28 mmol) of 1H-pyrazol-4-ylmethanol [WO200674925, p. 48] were reacted. Yield: 16 mg (17% of theory).

LC-MS (Method 4): R _t = 2.15 min; MS (EIpos): m / z = 419 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8:36 (s, 1H), 8.12 (d, 1H), 8:07 (s, 1H), 7.89 (s, 1H), 7.79 ( d, 1H), 5.19 (t, 1H), 4.48 (d, 2H).

Example 5

 2-Amino-6- [4- (methoxymethyl) -1 / pyrazol-1-yl] -4- [4- (trifluoromethyl) phenyl] pyridine-3, 5-dicarbonitrile

 According to General Method 1, 30.0 mg (0.092 mmol) of the compound from Example 24A and 24 mg (0.1 mmol) of 4- (methoxymethyl) -1 / pyrazole from Example 9A were reacted. Yield: 2 mg (5% of theory).

LC-MS (Method 6): R _t = 1.03 min; MS (EIpos): m / z = 399 [M + H] ⁺ . 'H-NMR (400 MHz, _DMSO-ö): δ [ppm] 8:44 (s, 1H), 8.24, 7.99 (d, 2H), 7.94 (s, 1H), 7.81 ((br s, 2H.). d, 2H), 4.41 (s, 2H), 3.29 (s, 3H).

Example 6

 2-Amino-6- [4- (hydroxyethyl) -1-pyrazol-1-yl] -4- [4- (trifluoromethyl) phenyl] pyridine-3, 5-dicarbonitrile

 According to General Method 1, 50 mg (0.15 mmol) of the compound from Example 24A and 18 mg (0.16 mmol) of 2- (1H-pyrazol-4-yl) ethanol [R. Jones, M.J. Mann, J. Am. Chem. Soc. 1953, 75, 4048-4052.] Implemented. Yield: 2 mg (3% of theory).

LC-MS (Method 6): R _t = 0.95 min; MS (EIpos): m / z = 399 [M + H] ⁺ .

'H NMR (400 MHz, DMSO-ώ): δ [ppm] = 8.32 (s, 1H), 8.20 (br., S, 2H), 7.98 (d, 2H), 7.84 (s, 1H), 7.80 (d, 2H), 4.76 (t, 1H), 3.60 (dd, 2H), 2.67-2.64 (m, 2H).

Example 7

 2-amino-6- (4-thyl) phenyl] pyridine-3,5-dicarbonitrile

According to General Method 1, 131 mg (0.41 mmol) of the compound from Example 24A and 41 mg (0.49 mmol) 1 / pyrazol-4-ol were reacted. Yield: 3 mg (2% of theory).

LC-MS (Method 6): R _t = 0.91 min; MS (EIpos): m / z = 371 [M + H] ⁺ . 'H-NMR (400 MHz, _DMSO-ö): δ [ppm] 9:58 = (s, 1H), 8.17 7.97 (d, 2H), 7.91 (s, 1H), 7.78 (br s, 2H.). (d, 2H), 7.66 (s, 1H).

Example 8

 2-Anuno-6- (4-methoxy-1-pyrazol-1-yl) -4- [4- (ta

 150 mg (0.470 mmol) of 2-anuno-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A in 1.5 ml of DMSO were added, giving 55 mg (0.56 mmol) of 4 -Methoxypyrazole and 182 mg (0.56 mmol) of cesium carbonate and allowed to stir for 1 h at RT. It was then diluted with MTBE, washed with water and the organic phase dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 1). The product was stirred with pentane / methanol and filtered with suction. The title compound was obtained. Yield: 90 mg (49% of theory).

LC-MS (Method 4): R _t = 2.26 min; MS (EIpos): m / z = 385 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8.20, 8.12 (s, 1H), 7.98 (d, 2H), 7.87 (s, 1H), 7.80 ((br s, 2H). d, 2H), 3.81 (s, 3H).

Example 9

 2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- (4-methoxy-1 / pyrazol-1-yl) pyridine-3, 5-dicarbonitrile

300 mg (0.700 mmol) 2-Anuno-4-[3-chlor-4-(trifluormethyl)phenyl]-6-(phenylsulfanyl)pyridin-3,5- dicarbonitril aus Beispiel 19A und 82 mg (0.84 mmol) 4-Methoxy- l -pyrazol wurden mit 272 mg (0.84 mmol) Cäsiumcarbonat in 3 ml DMSO über Nacht bei RT gerührt. Man verdünnte dann mit MTBE, wusch mit Wasser und trocknete die organische Phase über Natriumsulfat. Das Lösungsmittel wurde im Vakuum entfernt und das Rohprodukt mittels präparativer HPLC (Eluens: Acetonitril/Wasser Gradient) zweimal aufgereinigt. Das Produkt wurde mit Methanol/Pentan verrührt und abgesaugt. Man erhielt die Titelverbindung. Ausbeute: 60.4 mg (21% d. Th.).

300 mg (0.700 mmol) of 2-anuno-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- (phenylsulfanyl) pyridine-3,5-dicarbonitrile from Example 19A and 82 mg (0.84 mmol) of 4-methoxy - l -pyrazole were stirred with 272 mg (0.84 mmol) of cesium carbonate in 3 ml of DMSO overnight at RT. It was then diluted with MTBE, washed with water and the organic phase was dried over sodium sulfate. The solvent was removed in vacuo and the crude product purified by preparative HPLC (eluent: acetonitrile / water gradient) twice. The product was stirred with methanol / pentane and filtered with suction. The title compound was obtained. Yield: 60.4 mg (21% of theory).

LC-MS (Method 6): R _t = 1.07 min; MS (EIpos): m / z = 419 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8.26, 8.12 (s, 1H), 8.12 (d, 1H), 8:06 (s, 1H), 7.88 ((br s, 2H). s, 1H), 7.78 (d, 1H), 3.81 (s, 3H).

Example 10

 2-Amino-6- (4-ethoxy-1-pyrazol-1-yl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

 150 mg (0.47 mmol) of 2-amino-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A and 63 mg (0.56 mmol) of 4-ethoxy-1-pyrazole from Example 5A were stirred together with 182 mg (0.56 mmol) of cesium carbonate in 1.5 ml of DMSO for 3 h. It was then diluted with MTBE, washed with water and the organic phase was dried over sodium sulfate. The solvent was removed in vacuo and the product purified by preparative HPLC (acetonitrile / 0.05% formic acid gradient). The title compound was obtained. Yield: 33.4 mg (18% of theory).

LC-MS (Method 6): R = 1.11 min; MS (EIpos): m / z = 399 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8.19 (br s., 2H), 8.10 (d, 1H), 7.98 (d, 2H), 7.86 (d, 1H), 7.80 ( d, 2H), 4.03 (q, 2H), 1.34 (t, 3H).

Example 11

2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- (4-ethoxy-1 / pyrazol-1-yl) pyridine-3, 5-dicarbonitrile

 645 mg (1.81 mmol) of 2-amino-6-chloro-4- [3-chloro-4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 29A, and 243 mg (2.17 mmol) of 4-ethoxy 1 / pyrazole from Example 5A was stirred together with 706 mg (2.17 mmol) cesium carbonate overnight in 5.0 ml DMSO. It was then diluted with MTBE, washed with water and the organic phase was dried over sodium sulfate. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 2: 1). Preparative HPLC (acetonitrile / 0.05% formic acid gradient) was followed by final purification. The title compound was obtained. Yield: 168 mg (22% of theory).

LC-MS (Method 2): R _t = 1.16 min.MS (EIpos): m / z = 433 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8.25, 8.12 (d, 1H), 8:09 (d, 1H), 8:06 (s, 1H), (br s, 2H). 7.87 (d, 1H), 7.78 (d, 1H), 4.03 (q, 2H), 1.34 (t, 3H)

Example 12

 2-Amino-6- (4-isopropoxy-1-pyrazol-1-yl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

According to General Method 1, 100 mg (0.31 mmol) of the compound from Example 24A and 47 mg (0.37 mmol) of 4-isopropoxy-l / -pyrazole [H. Plümpe, E. Schegk, Arch. Pharm. 1967, 300, 704-708.]. Yield: 47 mg (37% of theory).

LC-MS (Method 2): R _t = 1.15 min; MS (EIpos): m / z = 413 [M + H] ⁺ . 'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8.19, 8:08 (s, 1H), 7.97 (d, 2H), 7.85 (s, 1H), 7.79 (br s, 2H.). (d, 2H), 4.39-4.34 (m, 1H), 1.30 (d, 6H).

Example 13

 2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- (4-isopropoxy-1 / pyrazol-1-yl) pyridine-3, 5-dicarbonitrile

 According to General Method 1, 100 mg (0.23 mmol) of the compound from Example 19A and 35 mg (0.28 mmol) of 4-isopropoxy-l / -pyrazole [H. Plümpe, E. Schegk, Arch. Pharm. 1967, 300, 704-708.] Implemented. Yield: 10 mg (9% of theory).

LC-MS (Method 6): R _t = 1.17 min; MS (EIpos): m / z = 447 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8.25, 8.11 (d, 1H), 8:08 (s, 1H), 8:07 (d, 1H) (br s, 2H.). , 7.86 (s, 1H), 7.77 (d, 1H), 4.40-4.34 (m, 1H), 1.30 (d, 6H).

Example 14

 2-Amino-6- [4- (2-methoxyethoxy) -1-pyrazole-1-yl] -4- [4- (trifluoromethyl) phenyl] pyridine-3, 5-dicarbonitrile

100 mg (0.314 mmol) of 2-amino-6-hydrazino-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 18A and 54 mg (0.31 mmol) of 3- (dimethylamino ) -2- (2-methoxyethoxy) acrylic aldehyde dissolved in 0.3 ml of acetic acid and in the microwave for 15 min. heated to 140 ° C. The reaction mixture was then concentrated in vacuo, the residue was taken up in ethyl acetate and the organic phase was washed with saturated aqueous sodium carbonate solution. It was dried with sodium umsulfat and concentrated in a vacuum. The residue was stirred with methanol and filtered with suction. It was then purified by preparative HPLC. Yield: 15.5 mg (4.5% of theory).

LC-MS (Method 6): R _t = 1.00 min; MS (EIpos): m / z = 429 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.18 (br, s, 2H), 8.12 (d, 1H), 7.98 (d, 2H), 7.88 (d, 1H) , 7.80 (d, 2H), 4.13-4.09 (m, 2H), 3.67-3.63 (m, 2H).

Example 15

 2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- (4-cyano-1-pyrazol-1-yl) pyridine-3, 5-dicarbonitrile

 According to General Method 1, 100 mg (0.23 mmol) of the compound from Example 19A and 36 mg (0.28 mmol) of 1 / pyrazole-4-carbonitrile hydrochloride were reacted. Yield: 5 mg (5% of theory).

LC-MS (Method 6): R _t = 1.09 min; MS (EIpos): m / z = 414 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 9.19 (s, 1H), 8:55 (s, 1H), 8.50, 8.14 (d, 1H), 8:09 (br s, 2H.). (s, 1H), 7.81 (d, 1H).

Example 16

2-Amino-6- [3 - (methylsulfonyl) phenyl] -4- [4- (trifluoromethyl) phenyl] pyridine-3, 5-dicarbonitrile

To a mixture of 1 19 (0.53 mmol) of [4- (trifluoromethyl) benzylidene] malononitrile from Example 1A and 90 mg (0.36 mmol) of 3-amino-3- [3- (methylsulfonyl) phenyl] acrylonitrile from Example 31A in 0.9 ml Ethanol were 0.03 ml (0.18 mmol) of DBU was added. The reaction mixture was stirred at 80 ° C for 30 minutes. The undissolved solid was filtered off, washed with ethanol and diethyl ether and dried in vacuo. Yield: 66 mg (27% of theory).

LC-MS (Method 6): R _t = 1.02 min; MS (Elneg): m / z = 441 [MH] \

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8:36 (s, 1H), 8.20 (d, 1H), 8.14 (d, 1H), 8:01 (d, 2H), 7.90 ( d, 2H), 7.85 (t, 1H), 3.28 (s, 3H).

Example 17

 2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- [3 - (methylsulfonyl) phenyl] pyridine-3, 5-dicarbonitrile

To a mixture of 137 mg (0.53 mmol) of [3-chloro-4- (trifluoromethyl) benzylidene] malononitrile from Example 4A and 90 mg (0.36 mmol) of 3-amino-3- [3- (methylsulfonyl) phenyl] acrylonitrile from Example 31A in 1.0 ml of ethanol was added 0.03 ml (0.18 mmol) of DBU. The reaction mixture was stirred at 80 ° C for 30 minutes. The undissolved solid was filtered off, washed with ethanol and diethyl ether and dried in vacuo. The mother liquor was concentrated by rotary evaporation and the corresponding residue was separated by preparative HPLC. Yield: 45 mg (17% of theory).

LC-MS (Method 6): R _t = 1.08 min; MS (Elneg): m / z = 475 [MH] \

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8:36 (s, 1H), 8.20 (d, 1H), 8:16 to 8:14 (d, 3H), 7.88 (s, 1H), 7.76 (d, 1H), 3.28 (s, 3H).

Example 18

2-Arnino-6- (4-aminophenyl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

 To a solution of 3.55 g (7.40 mmol) of the compound of Example 46A in 35 ml of dichloromethane was added 28.5 ml (0.37 mol) of trifluoroacetic acid. The reaction mixture was stirred at RT for 1.5 h. For workup, the solvent was evaporated and the residue taken up in ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Yield: 1.74 g (61% of theory).

LC-MS (Method 6): R _t = 0.97 min; MS (EIpos): m / z = 380 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 7.97 (d, 2H), 7.90 (br s., 2H.), 7.84 (d, 2H), 7.69 (d, 2H), 6.63 (d, 2H), 5.86 (s, 2H).

Example 19

 2-Amino-6- (3-aminophenyl) -4- [4- (trifluoimethyl) phenyl] pyridine-3,5-dicarbonitrile

 To a solution of 3.99 g (8.32 mmol) of the compound from Example 48A in 300 ml of dichloromethane was added 32.1 ml (0.42 mol) of trifluoroacetic acid. The reaction mixture was stirred at RT for 1.5 h. For workup, the solvent was evaporated and the residue taken up in ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Yield: 2.74 g (85% of theory).

LC-MS (Method 4): R _t = 2.22 min; MS (EIpos): m / z = 380 [M + H] ⁺ . 'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8:09, 8:00 (d, 2H), 7.87 (d, 2H), 7.16 (t, 1H), 6.98 (br s, 2H.). - 6.92 (m, 2H), 6.73 (dd, 1H), 5.34 (s, 2H).

Example 20

 3- {6-Amino-3,5-dicyano-4- [4- (trifluoromethyl) phenyl] pyridin-2-yl} -N, N-dimethylbenzami

 A mixture of 80 mg (0.20 mmol) of compound 47A, 11 mg (0.26 mmol) of dimethylamine, 89 mg (0.24 mmol) of HATU and 0.11 ml (0.69 mmol) of diisopropylethylamine in 1.3 ml of DMF was stirred at RT overnight. The reaction mixture was mixed with water, the resulting solid was filtered off and dried under high vacuum. Yield: 74 mg (86% of theory).

LC-MS (Method 6): R _t = 1.02 min; MS (EIpos): m / z = 436 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8.20, from 8.00 (d, 2H), 7.89 (d, 3H), 7.84 (s, 1H) (br s, 2H.). , 7.65-7.59 (m, 2H), 3.00 (s, 3H), 2.94 (s, 3H).

Example 21

N- (3- {6-Amino-3,5-dicyano-4- [4- (trifluoromethyl) phenyl] pyridin-2-yl} phenyl) -N ² , N ² -dimethylglycine amide

A mixture of 80 mg (0.20 mmol) of the compound of Example 19, 40 mg (0.25 mmol) of N, N-dimethylglycyl chloride and 0.15 ml (0.95 mmol) of diisopropylethylamine in 2.0 ml of dichloromethane was stirred at RT for two days. The reaction mixture was added with water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was separated by flash chromatography (silica gel-60, eluent: dichloromethane-methanol) and purified by preparative HPLC. Yield: 9 mg (9% of theory).

LC-MS (Method 6): R _t = 0.85 min; MS (EIpos): m / z = 465 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 9.81 (s, 1H), 8.20, 8:06 (s, 1H), 8:00 (d, 2H), 7.87 (br s, 2H.). (d, 2H), 7.77-7.76 (m, 1H), 7.56-7.52 (m, 2H), 4.15 (s, 2H), 2.87 (s, 6H).

Example 22

 N- (3- {6-Amino-3,5-dicyano-4- [4- (trifluoromethyl) phenyl] pyridin-2-yl} phenyl) cyclobutanecarboxamide

A mixture of 80 mg (0.21 mmol) of the compound from Example 19, 30 mg (0.25 mmol) of cyclobutane chloride and 0.13 ml (0.74 mmol) of diisopropylethylamine in 2 ml of dichloromethane was stirred at RT overnight. The reaction mixture was added with water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The final product was crystallized in dichloromethane. Yield: 29 mg (28% of theory).

LC-MS (Method 6): R _t = 1.11 min; MS (EIpos): m / z = 462 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8.20, 8.12 (s, 1H), 7.99 (d, 2H), 7.87 (d, 2H), 7.74 (br s, 2H.). - 7.71 (m, 1H), 7.47-7.42 (m, 2H), 3.25 (q, 1H), 2.27-2.18 (m, 2H), 2.16-2.08 (m, 2H), 2.00-1.89 (m, 1H) , 1.83-1.77 (m, 1H).

In analogy to Example 22, the examples listed in Table 2 were prepared from the corresponding starting materials. Table 2:

MS (s, (t,

MS (d, 7.14

(d, 7.11 5H),

MS (d, 1H) (d, (dd, 0.98

MS (d, 1H)

MS

MS (d, 3.89

BeiVorstufe/ Struktur Analytische Daten spiel Allg. Methode MS (d, 7.51-

BeiVorstufe / Struktur Analytical data spielGeneral method

 56 24A / Allg. Yield: 18 mg (19% of theory).

 Method 2

LC-MS (Method 5): R = 2.25 min; MS (EIpos): m / z = 413 [M + H] ⁺ .

57 24A / Allg. Yield: 8 mg (19% of theory).

 Method 2

LC-MS (Method 5): R = 2.25 min; MS (EIpos): m / z = 436 [M + H] ⁺ .

 58 24A / Allg. Yield: 12 mg (26% of theory).

 Method 2

LC-MS (Method 5): R = 1.52 min; MS (EIpos): m / z = 436 [M + H] ⁺ .

 59 24A / Allg. Yield: 13 mg (30% of theory).

 Method 2

LC-MS (Method 5): R = 2.27 min; MS (EIpos): m / z = 379 [M + H] ⁺ .

At precursor / structure Analytical data

Game Gen. method

 60 24A / Allg. Yield: 6 mg (15% of t.l.).

 Method 2

LC-MS (Method 5): R _t = 2.13 min; MS (EIpos): m / z = 402 [M + H] ⁺ .

61 24A / Allg. Yield: 15 mg (38% of theory).

 Method 2

LC-MS (Method 5): R _t = 2.04 min; MS (EIpos): m / z = 407 [M + H] ⁺ .

62 29A / Allg. Yield: 5 mg (5% of t.l.).

 Method 3

LC-MS (Method 3): R _t = 1.42 min; MS (EIpos): m / z = 430 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8.23, 8.12 (d, 1H), 8:09 (s, 2H), 7.96 (dd, 1H), 7.80 (br s, 2H.). (d, 1H), 7.78 (d, 1H), 7.05 (d, 1H), 3.96 (s, 3H).

 63 24A / Allg. Yield: 4 mg (6% of t.l.).

 Method 3

LC-MS (Method 2): R _t = 1.04 min; MS (EIpos): mz = 424 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 9.25 (d, 1H), 9.24 (d, 1H), 8.73 (dd, 1H), 8.30 (br s., 2H.) 8.02 (d, 2H), 7.90 (d,

, CH, 2H), 3.94 (s, 3H). BeiVorstufe / Struktur Analytical data spielGeneral method

 64 24A / Allg. Yield: 14 mg (27% of theory).

 Method 2

LC-MS (Method 5): R _t = 2.07 min; MS (EIpos): m / z = 462 [M + H] ⁺ .

65 24A / Allg. Yield: 13 mg (32% of theory).

 Method 2

LC-MS (Method 5): R _t = 1.90 min; MS (EIpos): m / z = 380 [M + H] ⁺ .

66 24A / Allg. Yield: 3 mg (8% of theory).

 Method 2

LC-MS (Method 5): Rt = 1.91 min; MS (EIpos): m / z = 366 [M + H] ⁺ .

 67 24A / Allg. Yield: 4 mg (1 1% of theory).

 Method 2

LC-MS (Method 5): R _t = 1.73 min; MS (EIpos): m / z = 380 [M + H] ⁺ .

BeiVorstufe/ Struktur Analytische Daten

At precursor / structure Analytical data

 Game Gen. method

 72 24A / Allg. Yield: 2 mg (6% of theory).

 Method 2

LC-MS (method 5): R _t = 1.88 min; MS (EIpos): m / z = 366 [M + H] ⁺ .

Example 73

 6-Anuno-5'-] -2,2'-bipyridine-3,5-dicarbonitrile

 To a mixture of 200 mg (0.78 mmol) of [3-CMor-4- (trifluoromethyl) benzylidene] malononitrile from Example 4A and 96 mg (0.52 mmol) of 3-amino-3- (5-chloropyridin-2-yl) acrylonitrile Example 34A in 4.0 ml of ethanol was added 0.23 ml (1.56 mmol) of DBU. The reaction mixture was stirred at 80 ° C for 20 minutes. For workup, the reaction mixture was concentrated in vacuo, treated with water and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC. Yield: 31 mg (9% of theory).

LC-MS (Method 3): R _t = 1.48 min; MS (EIpos): m / z = 435 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ώ): δ [ppm] = 8.80 (d, 1H), 8.30 (br, s, 2H), 8.20 (dd, 1H), 8.13-8.09 (m, 2H) , 7.81 (d, 1H).

Example 74

6-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6'-methyl-2,2'-bipyridine-3, 5-dicarbonitrile

 To a mixture of 200 mg (0.78 mmol) of [3-CWor-4- (trifluoromethyl) benzylidene] malononitrile from Example 4A and 83 mg (0.52 mmol) of 3-amino-3- (6-methylpyridin-2-yl) acrylonitrile Example 33A in 4.0 ml of ethanol was added 0.23 ml (1.56 mmol) of DBU. The reaction mixture was stirred at 80 ° C for 10 minutes. For workup, the reaction mixture was concentrated in vacuo, treated with water and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC. Yield: 29 mg (9% of theory).

LC-MS (Method 6): R _t = 1.08 min; MS (EIpos): m / z = 414 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.20 (br.s .., 2H), 8.12 (d, 1H), 8.10 (s, 1H), 7.93 (dd, 1H) , 7.86 (d, 1H), 7.82 (s, 1H), 7.46 (d, 1H), 3.31 (s, 3H).

Example 75

 6-amino-4- (3,4-dichloφhenyl) -6'-methyl-2,2'-bipyridine-3,5-dicarbonitrile

To a mixture of 200 mg (0.90 mmol) of [3-chloro-4-chlorobenzylidene] malononitrile and 144 mg (0.90 mmol) of 3-amino-3- (6-methylpyridin-2-yl) acrylonitrile from Example 33A in 1.0 ml of ethanol four drops of triethylamine were added. The reaction mixture was stirred at 80 ° C for 1 h. For workup, the reaction mixture was treated with water and extracted with ethyl acetate. The combined organic Phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by Bio Isolation Isolera, and the final product was crystallized in methanol. Yield: 18 mg (5% of theory).

LC-MS (Method 6): R _t = 1.09 min; MS (EIpos): m / z = 382 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8.15 (br s., 2H.), 7.98 (d, 1H), 7.92 (dd, 1H), 7.89 (d, 1H), 7.84 (d, 1H), 7.61 (dd, 1H), 7.45 (d, 1H), 3.3 1 (s, 3H).

Example 76

 6-Amino-4'-methoxy-4- [4- (trifluoimethyl) phenyl] -2,2'-bipyridine-3,5-dicarbonitrile

To a mixture of 200 mg (0.89 mmol) of [4- (trifluoromethyl) benzylidene] malononitrile from Example 1A and 1 13 mg (0.59 mmol) of 3-amino-3- (4-methoxypyridin-2-yl) acrylonitrile from Example 32A in 1.5 ml of ethanol was added to 0.04 ml (0.30 mmol) of DBU. The reaction mixture was stirred at 80 ° C for 30 minutes. For workup, the reaction mixture was concentrated under reduced pressure, combined with water and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC. Yield: 29 mg (8% of theory).

LC-MS (Method 3): Rt = 1.41 min; MS (EIpos): m / z = 396 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8:54 (d, 1H), 8. 19 (br s., 2H.), 7.98 (d, 1H), 7.83 (d, 1H) , 7.59 (d, 1H), 7.18 (dd, 1H), 3.92 (s, 3H). Example 77

6-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -4'-methoxy-2,2'-bipyridine-3, 5-dicarbonitrile

 To a mixture of 200 mg (0.78 mmol) of [3-chloro-4- (trifluoromethyl) benzylidene] malononitrile from Example 4A and 98 mg (0.52 mmol) of 3-amino-3- (4-methoxypyridin-2-yl) acrylonitrile Example 32A in 1.5 ml ethanol was added 0.04 ml (0.26 mmol) DBU. The reaction mixture was stirred for 30 minutes at 80.degree. For workup, the reaction mixture was concentrated in vacuo, mixed with water and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by HPLC flash chromatography (silica gel-60, eluent: cyclohexane-ethyl acetate mixtures). Yield: 43 mg (13% of theory).

LC-MS (Method 6): R _t = 1.03 min; MS (EIpos): m / z = 430 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8:54 (d, 1H), 8.23, 8.12 (d, 1H), 8:09 (s, 1H), 7.81 (br s, 2H.). (d, 1H), 7.59 (d, 1H), 7.19 (dd, 1H), 3.92 (s, 3H).

Example 78

 6-amino-4- (3,4-dichloφhenyl) -4'-methoxy-2,2'-bipyridine-3,5-dicarbonitrile

To a mixture of 200 mg (0.90 mmol) of (3,4-dichlorobenzylidene) malononitrile and 113 mg (0.60 mmol) of 3-amino-3- (4-methoxypyridin-2-yl) acrylonitrile from Example 32A in 1.5 ml of ethanol 0.04 ml (0.30 mmol) DBU was added. The reaction mixture was stirred at 80 ° C for 30 minutes. The undissolved solid was filtered off, washed with ethanol and diethyl ether and dried in vacuo. Yield: 102 mg (27% of theory).

LC-MS (Method 6): R _t = 1.04 min; MS (EIpos): m / z = 396 [M + H] ⁺ . 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.53 (d, 1H), 8.15 (br, s, 2H), 7.97 (d, 1H), 7.89 (d, 1H) , 7.60 (dd, 1H), 7.58 (d, 1H), 7.18 (dd, 1H), 3.91 (s, 3H).

Example 79

 2-Anuno-6- (3-methoxyphenyl) -5-methyl-4- [4- (trifluoromethyl) phenyl] nicotinonita

 650 mg (2.93 mmol) of [4- (trifluoromethyl) benzylidene] malononitrile from Example 1A, 706 mg (68%, 2.93 mmol) of 1- (3-methoxyphenyl) propane-1-one [T. GC Bird, P. Bruneau, GC Crawley, MP Edwards, SJ Foster, J. Med. Chem. 1991, 34, 2176-2186.] And 338 mg (4.39 mmol) of ammonium acetate were dissolved in 8.7 ml of 1-butanol in the microwave 30 minute heated to 160 ° C. First, a pre-purification by preparative HPLC was carried out. The material obtained was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10: 1 gradient to 2: 1). The product was stirred with MTBE and filtered with suction. Yield: 113 mg (10% of t.l.).

LC-MS (Method 6): R _t = 1.25 min; MS (EIpos): m / z = 484 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 7.92 (d, 2H), 7.66 (d, 2H), 7.38 (t, 1H), 7.08-7.03 (m, 2H), 7.01 (dd, 1H), 6.86 (br s, 2H), 3.79 (s, 3H), 1.81 (s, 3H).

Example 80

 2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- (3-methoxyphenyl) -5-methylnicotinonitrile

650 mg (2.53 mmol) [3-Chlor-4-(trifluormethyl)benzyliden]malononitril aus Beispiel 4A, 612 mg (68%ig, 2.53 mmol) l-(3-Methoxyphenyl)propan-l-on [T. G. C. Bird, P. Bruneau, G. C. Crawley, M. P. Edwards, S. J. Foster, J. Med. Chem.1991, 34, 2176-2186.] und 293 mg (3.80 mmol) Ammoniumacetat wurden in 7.5 ml 1- Butanol in der Mikrowelle 30 min. auf 160 °C erhitzt. Man nahm in Essigsäureethylester auf und extrahierte mit gesättigter wässriger Natriumhydrogencarbonat-Lösung. Die organische Phase wurde über Natriumsulfat getrocknet und das Lösungsmittel im Vakuum entfernt. Dann wurde durch Chromatographie an Kieselgel (Ehlens: Cyclohexan/Essigsäureethylester 10: 1 Gradient bis 2: 1) gereinigt. Ausbeute: 150 mg (13% d. Th.). LC-MS (Methode 6): R_t = 1.27 min; MS (EIpos): m/z = 418 [M+H]⁺.

650 mg (2.53 mmol) of [3-chloro-4- (trifluoromethyl) benzylidene] malononitrile from Example 4A, 612 mg (68%, 2.53 mmol) of 1- (3-methoxyphenyl) propan-1-one [TGC Bird, P Bruneau, GC Crawley, MP Edwards, SJ Foster, J.Med.Chem.1991, 34, 2176-2186.] And 293 mg (3.80 mmol) of ammonium acetate were dissolved in 7.5 ml of 1-butanol in the microwave for 30 min. heated to 160 ° C. It was taken up in ethyl acetate and extracted with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate and the solvent removed in vacuo. It was then purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10: 1 gradient to 2: 1). Yield: 150 mg (13% of theory). LC-MS (Method 6): R _t = 1.27 min; MS (EIpos): m / z = 418 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.05 (d, 1H), 7.91 (s, 1H), 7.64 (d, 1H), 7.39 (t, 1H), 7.08- 6.99 (m, 3H), 6.91 (br, s, 2H), 3.79 (s, 3H), 1.83 (s, 3H).

Example 81

 2 - Aimno- 5 - (hydroxymethyl) - 6 - (3-methoxyphenyl) -4 ^

 100 mg (0.210 mmol) of 6-amino-5-cyano-2- (3-methoxyphenyl) -4- [4- (trifluoromethyl) phenyl] nicotinic acid from Example 53 A were initially charged in 6 ml of THF at RT. 41 mg (0.31 mmol) of 1-chloro-N, 2-trimethylprop-1-en-1-amine were added and the mixture was left for 30 min. stir at RT. Then a solution of 11.7 mg (0.31 mmol) of sodium borohydride in 3 ml of water was added and stirring was continued overnight. The reaction mixture was poured onto saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and the crude product was purified by preparative HPLC. The product was then dissolved in dichloromethane, precipitated with diethyl ether / w-pentane and filtered with suction. The title compound was obtained. Yield: 21 mg (23% of theory).

LC-MS (Method 6): R _t = 1.00 min; MS (EIpos): m / z = 400 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 7.90 (d, 2H), 7.73 (d, 2H), 7.41-7.33 (m, 2H), 7.32-7.28 (m, 1H ), 7.08 (s, 2H), 7.03 (dd, 1H), 4.89-4.84 (m, 1H), 3.91 (br, s, 2H), 3.79 (s, 3H). Example 82

2-amino-5-chloro-6- (3-methoxyphenyl) -4- [4- (trifluoimethyl) phenyl] nicotinonitrile

 92 mg (0.41 mmol) of [4- (trifluoromethyl) benzylidene] malononitrile from Example 1A and 91 mg (0.41 mmol) of 2,2-dichloro-1- (3-methoxyphenyl) ethanone from Example 10A were mixed with 191 mg (2.48 mmol). Ammonium acetate in 1 ml of xylene for 6 h at 120 ° C heated. The reaction mixture was then taken up in ethyl acetate, washed with water and dried over sodium sulfate. The solvent was removed in vacuo. Purification by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 3: 1) gave the title compound. Yield: 6.1 mg (4% of theory).

LC-MS (Method 6): R _t = 1.26 min; MS (EIpos): m / z = 404 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 7.94 (d, 2H), 7.74 (d, 2H), 7:40 (t, 1H), 7:32 (br s, 2H.), 7.19 (d, 1H), 7.17-7.14 (m, 1H), 7.05 (dd, 1H), 3.79 (s, 3H).

Example 83

 2-Amino-5-br-6- (3-methoxyphenyl) -4- [4- (trifluoromethyl) phenyl] nicotinonitrile

Mn 3 0 0 mg (8 5%, 6 1 7 mmol) of 6-amino-5-cyano-2- (3-methoxyphenyl) -4- [4- (trifluoromethyl) phenyl] nicotinic acid from Example 53 A together with 317 mg (3.08 mmol) of sodium bromide and 65 mg (0.62 mmol) of sodium carbonate in a mixture of 6 ml of water and 6 ml of methanol. Subsequently the reaction mixture at RT was added 266 mg (0.432 mmol) Oxone ^® was added and 20 minutes under exclusion of light stirred. One then sucked off and washed with water. The dried solid was purified by chromatography. on silica gel (eluent: cyclohexane / ethyl acetate 10: 1 gradient to 5: 1). Yield 186 mg (66% of theory).

LC-MS (Method 2): R _t = 1.29 min; MS (EIpos): m / z = 448/450 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö) δ [ppm] = 7.93 (d, 2H), 7.69 (d, 2H), 7:39 (t, 1H), 7.33 7.14 7.11 (br s, 2H). (m, 1H), 7.10-7.08 (m, 1H), 7.03 (dd, 1H), 3.79 (s, 3H).

Example 84

 2-Amino-6- (2-furyl) -5-methyl-4- [4- (trifluoromethyl) phenyl] nicotinonitri

300 mg (2.93 mmol) of [4- (trifluoromethyl) benzylidene] malononitrile from Example 1A, 147 mg (1.13 mmol) of 1- (2-furyl) propane-1-one and 520 mg (6.75 mmol) of ammonium acetate were dissolved in 2.1 ml of acetic acid in the microwave 10 min. heated to 110 ° C. It was diluted with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate solution. The organic phase was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10: 1 gradient to 2: 1). Yield: 199 mg (51% of theory).

LC-MS (method 2): R _t = 1.20 min; MS (EIpos): m / z = 344 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 7.95-7.90 (m, 3H), 7.62 (d, 2H), 7.10 (d, 1H), 6.84 (br s, 2H.), 6.70 (dd, 1H), 2.05 (s, 3H).

Example 85

2-Arnino-6- (2-furyl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

 16.3 g (73.4 mmol) of [4- (trifluoromethyl) benzylidene] malononitrile from Example 1A and 9.85 g (73.4 mmol) of 3-amino-3- (2-furyl) acrylonitrile from Example 30A were initially charged in 250 ml of methanol and 14.3 ml ( 77.1 mmol) of a 5.4M solution of sodium methylate in methanol. The reaction mixture was heated to 65 ° C overnight with stirring. Thereafter, the reaction mixture was allowed to come to RT and added to water. It was extracted with ethyl acetate and the organic phase dried over sodium sulfate. It was concentrated in vacuo and the residue was stirred with MTBE and sucked off. The resulting crude product was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 3: 2). This gave a product fraction and 4.1 g of a fraction consisting mainly of dihydropyridine. The latter was dissolved in 27 ml of DMF and added to 1.50 g (17.3 mmol) of manganese dioxide in 20 ml of acetic acid. This mixture was 30 min. heated to 130 ° C, then treated with diatomaceous earth, filtered off with suction and washed with ethyl acetate. The filtrate was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified along with the first product fraction by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 3: 2). Yield: 3.06 g (11% of theory).

LC-MS (Method 6): R _t = 1.06 min; MS (EIpos): m / z = 355 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.09 (br.s, 2H), 8.08-8.06 (m, 1H), 7.99 (d, 2H), 7.83 (d, 2H ), 7.46 (d, 1H), 6.81-6.79 (m, 1H).

Example 86

2-Amino-6- (1-pyrrol-3-yl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

 100 mg (0.3-10 mmol) of 2-anuno-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 91 mg (0.34 mmol) of 1- (triisopropylsilyl) -1 / -pyrrol-3-yl] boronic acid, 104 mg (1.24 mmol) sodium hydrogen carbonate and 12.7 mg (0.015 mmol) of [l, -Bis (diphenylphosphine) ferrocene] dichloroalladium (II) dichloromethane complex were treated with a degassed mixture of 0.9 ml of 1,2-dimethoxyethane and 0.2 ml of water and heated to 80 ° C for 6 h. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 2: 1). Yield: 32.6 mg (28% of theory).

LC-MS (Method 6): R _t = 0.97 min; MS (EIpos): m / z = 354 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 1 1:48 (.. Br s, 1H), 7.97 (d, 2H), 7.81 (d, 2H), 7.81-7.73 (m , 3H), 6.93-6.90 (m, 1H), 6.89-6.86 (m, 1H).

Example 87

 2-Amino-6- (1-pyrazol-3-yl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

 125 mg (0.387 mmol) of 2-amino-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 92 mg (0.773 mmol) of 3- (4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -l / pyrazole, 130 mg (1.55 mmol) of sodium bicarbonate and 15.8 mg (0.019 mmol) of [1,1 '-].

Bis (diphenylphosphine) ferrocene] -dichloropalladium (II) -dichloromethane complex was treated with a degassed mi from 1.5 ml of 1, 2-dimethoxyethane and 0.5 ml of water and heated to 80 ° C for 20 h. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 1 gradient to 1: 4) and by preparative HPLC. Yield: 21 mg (15% of theory).

LC-MS (Method 2): R _t = 1.02 min; MS (EIpos): m / z = 355 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8:48 (d, 1H), 8.27 (br s., 2H), 7.99 (d, 2H), 7.98-7.96 (m, 1H), 7.82 (d, 2H), 6.71-6.69 (m, 1H).

Example 88

 2-Amino-6- (1-methyl-1-pyrazol-5-yl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

 100 mg (0.3-10 mmol) of 2-amino-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 71 mg (0.34 mmol) of 1-methyl-5- (4 , 4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -1 / pyrazole, 104 mg (1.24 mmol) of sodium bicarbonate and 1: 2. 7 mg (0. 0 1 5 mmol) of [1,1'-bis (diphenylphosphine) ferrocene] -dichloropalladium (II) -dichloromethane complex were treated with a degassed mixture of 0.9 ml of 1,2-dimethoxyethane and 0.3 ml of water, and 6 h heated to 80 ° C. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was pre-purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 1) and then finally purified by preparative HPLC (eluent: acetonitrile / water). The title compound was obtained. Yield: 21.5 mg (18% of theory).

LC-MS (Method 2): Rt = 1.01 min; MS (EIpos): m / z = 369 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8.25 (br s, 2H.), From 8.00 (d, 2H), 7.86 (d, 2H), 7:58 (d, 1H), 6.93 ( d, 1H), 4.07 (s, 3H).

Example 89

2-Amino-6- (3-furyl) -4- [4- (trifluoromethyl) phenyl] pyridine-3, 5-dicarbonitrile

 150 mg (0.465 mmol) of 2-anuno-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 135 mg (0.697 mmol) of 2- (3-furyl) -4 , 4,5,5-tetramethyl-l, 3,2-dioxaborolane, 156 mg (1.86 mmol) sodium bicarbonate and 19.0 mg (0.023 mmol) of [l, -Bis (diphenylphosphine) ferrocene] dichloroalladium (II) dichloromethane. Complex was treated with a degassed mixture of 1.8 ml of 1,2-dimethoxyethane and 0.6 ml of water and heated to 80 ° C for 12 h. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10: 1 gradient to 2: 1). Yield: 137 mg (83% of theory).

LC-MS (Method 6): R _t = 1.07 min; MS (EIpos): m / z = 355 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8:47 to 8:46 (m, 1H), 8:07 (br s., 2H), 7.99 (d, 2H), 7.90-7.89 (m , 1H), 7.84 (d, 2H), 7.09-7.07 (m, 1H).

Example 90

 2-Arnino-6- (3-thienyl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

100 mg (0.3-10 mmol) of 2-amino-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 44 mg (0.34 mmol) of 3-thienylboronic acid, 104 mg (1.24 mmol) of sodium bicarbonate and 12.7 mg (0.015 mmol) of [l, Γ-bis (diphenylphosphine) ferrocene] dichloφalladium (II) -dichloromethane complex were treated with a degassed mixture of 0.9 ml of 1,2-dimethoxyethane and 0.3 ml of water and 6 h at 80 ° C hitzt. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 2: 1). The title compound was obtained. Yield: 63 mg (55% of theory).

LC-MS (Method 6): R _t = 1.09 min; MS (EIpos): m / z = 371 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8:35 to 8:32 (m, 1H), 8.10 (br s, 2H.), From 8.00 (d, 2H), 7.86 (d, 2H), 7.74-7.71 (m, 1H), 7.71-7.68 (m, 1H)

Example 91

 100 mg (0.3-10 mmol) of 2-amino-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 192 mg (0.620 mmol) of 4 - {[4- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-thienyl] methyl} -monochholin, 104 mg (1.24 mmol) of sodium bicarbonate and 12.7 mg (0.015 mmol) of [l, l '-]. Bis (diphenylphosphine) -ferrocene] -dichloropalladium (II) -dichloromethane complex was treated with a degassed mixture of 1.2 ml of 1,2-dimethoxyethane and 0.4 ml of water and heated at 80 ° C overnight. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was chromatographed on silica gel (eluent: cyclohexane / ethyl acetate 1: 1). The title compound was obtained. Yield: 86 mg (59%> D. Th.).

LC-MS (Method 6): R _t = 0.79 min; MS (EIpos): m / z = 470 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8.26 (d, 1H), 8:07 (br s., 2H), 7.99 (d, 2H), 7.85 (d, 2H), 7:53 ( d, 1H), 3.72 (s, 2H), 3.61-3.56 (m, 4H), 2.46-2.40 (m, 4H).

Example 92

2-Aniino-6- (l, 3-oxazol-5-yl) -4- [4- (nifluormethyl) phenyl] pyridine-3,5-dicarbonitrile

 159 mg (0.31 mmol) of 2-anuno-4- [4- (trifluoromethyl) phenyl] -6- [2- (triisopropylsilyl) -1,3-oxazol-5-yl] pyridine-3,5-dicarbonitrile as a crude product Example 49A was initially charged in 2.0 ml of THF at -10 ° C., and 620 μl of an IM solution of tetra-n-butylammonium fluoride in THF were added. It was left for 15 min. Stir at -10 ° C and then added saturated aqueous ammonium chloride solution. It was diluted with water and extracted with ethyl acetate, the organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 1). The product was stirred with a little methanol and filtered with suction. The title compound was obtained. Yield: 60 mg (54% of theory).

LC-MS (Method 6): R _t = 0.93 min; MS (EIpos): m / z = 356 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8.78 (s, 1H), 8:26, 8:03 (s, 1H), 8:01 (d, 2H), (br s, 2H). 7.85 (d, 2H).

Example 93

 2-Arnino-6- (1-pyrazol-4-yl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

100 mg (0.3-10 mmol) of 2-amino-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 120 mg (0.620 mmol) of 4- (4,4,5 , 5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -l / pyrazole, 104 mg (1.24 mmol) sodium bicarbonate and 12.7 mg (0.015 mmol) of [1,1'-bis (diphenylphosphine) ferrocene] dichloroalladium (II) dichloromethane complex was treated with a degassed mi mixture of 1.2 ml of 1,2-dimethoxyethane and 0.4 ml of water and heated to 80 ° C overnight. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was pre-purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 1) and then isolated by preparative HPLC (eluant: acetonitrile / water gradient). The title compound was obtained. Yield: 34 mg (31% of theory).

LC-MS (Method 6): R _t = 0.89 min; MS (EIpos): m / z = 355 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 13:46, 8:52 to 8:13 (m, 2H), 7.99 (d, 2H), 7.96 (br s, 2H (br s, 1H.). ), 7.84 (d, 2H). Example 94

 2-Amino-4- [3-fluoro-4- (trifluoromethyl) phenyl] -6- (1-pyrazol-4-yl) pyridine-3, 5-dicarbonitrile

 1.64 g (3.59 mmol) of 2-amino-4- [3-fluoro-4- (trifluoromethyl) phenyl] -6- [1- (tetrahydro-2 / pyran-2-yl) -1-pyrazole-4 were added -yl] pyridine-3,5-dicarbonitrile from Example 40A in a mixture of 5.0 ml of methanol and 10 ml of dioxane and added 3.6 ml of a 4M solution of hydrogen chloride in dioxane. The mixture was stirred at RT overnight, then diluted with ethyl acetate and washed twice with saturated aqueous sodium carbonate solution. The organic phase was dried over sodium sulfate and concentrated in vacuo. The title compound was obtained. Yield: 1.29 g (90% of theory at 93% purity).

LC-MS (Method 4): R _t = 2.13 min; MS (EIpos): m / z = 373 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 13:48, 8:46 (s, 1H), 8.19 (s, 1H), 8:07 (t, 1H), 8:03 (br s, 1H.). (br.s, 2H), 7.93 (d, 1H), 7.68 (d, 1H).

Example 95

2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- (1-pyrazol-4-yl) pyridine-3, 5-dicarbonitrile

 855 mg (1.81 mmol) of 2-amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- [1- (tetrahydro-2 / pyran-2-yl) -l-pyrazole were added -4-yl] pyridine-3,5-dicarbonitrile from Example 42A in a mixture of 14.3 ml of methanol and 28.5 ml of dioxane before and added 0.9 ml of a 4M solution of hydrogen chloride in dioxane. After 4 h and 6 h reaction time, an additional 0.3 ml and then 0.6 ml of the hydrogen chloride solution were added. The mixture was stirred at RT overnight, then diluted with ethyl acetate and washed three times with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was stirred with dichloromethane, filtered off with suction and washed with -30 ° C. cold dichloromethane. The title compound was obtained. Yield: 656 mg (93% of theory).

LC-MS (Method 6): R _t = 0.95 min; MS (EIpos): m / z = 389 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 13:48, 8:46 (s, 1H), 8.19 (s, 1H), 8.12 (d, 1H) (br s, 1H.). , 8.10 (s, 1H), 8.02 (brs s, 2H), 7.82 (d, 1H).

Example 96

 2-Amino-4- (3,4-dichloro-phenyl) -6- (1-pyrazol-4-yl) -pyridine-3,5-dicarbonitrile

89 mg (0.20 mmol) of 2-amino-4- (3,4-dichloro-phenyl) -6- [1- (tetrahydro-2 / -pyran-2-yl) -l / -pyrazol-4-yl] pyridine-3 , 5-dicarbonitrile from Example 43A were presented in a mixture of 3.2 ml of dioxane and 1.6 ml of methanol. 0.1 ml of a 4M solution of hydrogen chloride in dioxane was added and the mixture was stirred at RT for 4 h. The reaction mixture was poured into ethyl acetate / saturated aqueous sodium bicarbonate solution, the phases were separated and the organic phase was washed twice with saturated aqueous sodium bicarbonate. washed carbonate solution. It was dried over sodium sulfate and concentrated in vacuo. Yield: 69 mg (94% of theory).

LC-MS (Method 6): R _t = 0.96 min; MS (EIpos): m / z = 355 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 13:47 8.45 (s, 1H), 8.18 (s, 1H), 7.98 (d, 1H), 7.96 (br s, 1H.). (br.s, 2H), 7.89 (d, 1H), 7.62 (dd, 1H).

Example 97

 2-Amino-6- (1-methyl-1-pyrazol-4-yl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

 100 mg (0.3-10 mmol) of 2-amino-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 129 mg (0.620 mmol) of 1-methyl-4- (4 , 4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -1 / pyrazole, 104 mg (1.24 mmol) of sodium bicarbonate and 12.7 mg (0.015 mmol) of [1,1'-bis (diphenylphosphine ) Ferrocen] di- chloφalladium (II) -Dichlormethan- complex were treated with a degassed mixture of 1.2 ml of 1,2-dimethoxyethane and 0.4 ml of water and heated to 80 ° C overnight. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was stirred with methanol, filtered off with suction and dried. The title compound was obtained as a solid. Yield: 108 mg (95% of theory).

LC-MS (Method 6): R _t = 1.00 min; MS (EIpos): m / z = 369 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8:42 (s, 1H), 8.14 (s, 1H), 7.99 (d, 2H), 7.95, 7.83 ((br s, 2H). d, 1H), 3.95 (s, 3H). Example 98

2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- (1-methyl-1 / pyrazol-4-yl) pyridine-3,5-dicarbonitrile

 A solution of 100 mg (0.25 mmol) of the compound from Example 29A in 1,2-dimethoxyethane / water (0.83 ml / 0.24 ml) was added under argon at RT with 10 mg (0.01 mmol) of 1,1'-bis (diphenylphosphine ) ferrocene] dichloro-palladium (II), 78 mg (0.38 mmol) of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 / pyrazole and 13 mg (0.76 mmol) of sodium bicarbonate. The reaction mixture was stirred at 80 ° C overnight. After addition of dichloromethane and water, the organic phase was dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The final product was crystallized in dichloromethane. Yield: 23 mg (22% of theory).

LC-MS (Method 3): R _t = 1.25 min; MS (EIpos): m / z = 403 [M + H] ⁺ . Alternative method:

 70 mg (0.15 mmol) of N '- {4- [3-chloro-4- (trifluoromethyl) phenyl] -3,5-dicyan-6- (1-methyl-1 / pyrazol-4-yl ) pyridin-2-yl} -N, N-dimethylimidoformamide from Example 45A was dissolved in 1.0 ml of methanol and 1.0 ml of a 4M solution of hydrogen chloride in dioxane was added. The mixture was stirred at RT overnight, then taken up in ethyl acetate and washed with saturated aqueous sodium carbonate solution. The organic phase was dried over sodium sulfate and the solvent was removed in vacuo. The residue was stirred with MTBE / pentane and filtered with suction. The title compound was obtained as white crystals. Yield: 44.6 mg (71% of theory).

LC-MS (Method 6): R _t = 1.06 min; MS (EIpos): m / z = 403 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8:42 (s, 1H), 8.13 (s, 1H), 8.12 (d, 1H), 8:08 (s, 1H), 7.98 (br. s., 2H), 7.81 (d, 1H), 3.95 (s, 3H).

Example 99

2-Amino-6- (1-ethyl-1 / pyrazol-4-yl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

 100 mg (0.3-10 mmol) of 2-amino-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 75 mg (0.34 mmol) of 1-isopropyl-4- (4 , 4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -l / pyrazole, 104 mg (1.24 mmol) sodium bicarbonate and 12.7 mg (0.015 mmol) of [1,1'-bis (diphenylphosphine ) Ferrocen] dichloφalladium (II) -dichloromethane complex were treated with a degassed mixture of 1.2 ml of 1,2-dimethoxyethane and 0.4 ml of water and heated to 80 ° C for 6 h. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 1). It was mixed with methanol and sucked off. The title compound was isolated. Yield: 28 mg (24% of theory).

LC-MS (Method 6): R _t = 0.85 min; MS (EIpos): m / z = 383 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8:45 (s, 1H), 8.16 (s, 1H), 7.99 (d, 2H), 7.97 (br s, 2H). 7.83 (d, 2H), 4.26 (q, 2H), 1.40 (t, 3H).

Example 100

2-Arnino-6- (1-isopropyl-1-pyrazol-4-yl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

100 mg (0.3-10 mmol) of 2-amino-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 80 mg (0.32 mmol) of 1-isopropyl-4- (4 , 4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -l / pyrazole, 104 mg (1.24 mmol) of sodium bicarbonate and 12.7 mg (0.015 mmol) of [1,1 '-] Bis (diphenylphosphine) ferrocene] di ^ were treated with a degassed mixture of 1.2 ml of 1, 2-dimethoxyethane and 0.4 ml of water and heated to 80 ° C for 6 h. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 1) and the title compound was isolated. Yield: 96 mg (78% of theory).

LC-MS (Method 6): R _t = 1.06 min; MS (EIpos): m / z = 397 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8:44 (s, 1H), 8.18 (s, 1H), 7.99 (d, 2H), 7.96 (br s, 2H). 7.83 (d, 2H), 4.65 (spt, 1H), 1.45 (d, 6H). Example 101

 2-Amino-6- (1-isobutyl-1 / pyrazol-4-yl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

 150 mg (0.47 mmol) of 2-amino-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 130 mg (0.51 mmol) of 1-isobutyl-4- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -l / pyrazole, 156 mg (1.86 mmol) sodium bicarbonate, and 19 mg (0.023 mmol) of [1,1'-bis (diphenylphosphine). ferrocene] dichloro-palladium (II) -dichloromethane complex were treated with a degassed mixture of 1.7 ml of 1,2-dimethoxyethane and 0.8 ml of water and heated to 80 ° C for 6 h. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 2: 1). Yield: 92 mg (48% of theory).

LC-MS (Method 6): R _t = 1.15 min; MS (EIpos): mz = 411 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8:42 (s, 1H), 8.16 (s, 1H), 7.99 (d, 2H), 7.96 (br s, 2H). 7.83 (d, 2H), 4.05 (d, 2H), 2.13 (spt, 1H), 1.12-1.09 (m, 1H), 0.85 (d, 6H).

Example 102

2-Amino-6- [1- (2-hydroxyethyl) -1-pyrazol-4-yl] -4- [4- (trifluoromethyl) phenyl] pyridine-3, 5-dicarbonitrile

 125 mg (0.387 mmol) of 2-anuno-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 147 mg (0.580 mmol) 2- [4- (4.4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -l / -pyrazol-1-yl] ethanol from example I IA, 130 mg (1.55 mmol) of sodium bicarbonate and 15.8 mg (0.019 mmol) [ 1,1'-Bis (diphenylphosphine) ferrocene] -dichloropalladium (II) -dichloromethane complex was treated with a degassed mixture of 1.5 ml of 1,2-dimethoxyethane and 0.5 ml of water and heated to 80 ° C. for 6 hours. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 1 gradient to 1: 4). The product was stirred with a little dichloromethane / MTBE, filtered off with suction and washed with MTBE and pentane. Yield: 45 mg (29% of theory).

LC-MS (Method 6): R _t = 0.87 min; MS (EIpos): m / z = 399 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8:44 (s, 1H), 8.19 (s, 1H), 7.99 (d, 2H), 7.96 (br s, 2H). 7.83 (d, 2H), 4.98 (t, 1H), 4.26 (t, 2H), 3.75 (q, 2H).

Example 103

 2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- [1- (2-hydroxyethyl) -1 / pyrazol-4-yl] pyridine-3, 5-dicarbonitrile

150 mg (0.42 mmol) 2-Anuno-6-chlor-4-[3-chlor-4-(nifluormethyl)phenyl]pyridin-3,5-dicarbonitril aus Beispiel 29A, 236 mg (63%ig, 0.63 mmol) 2-[4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-l /-pyrazol-l- yl]ethanol aus Beispiel I IA, 141 mg (1.68 mmol) Natriumhydrogencarbonat und 24 mg (0.029 mmol) [1,1 '- Bis(diphenylphosphin)ferrocen]dichloφalladium(II) Dichlormethan-Komplex wurden mit einer entgasten Mischung aus 2.0 ml 1,2-Dimethoxyethan und 1.0 ml Wasser versetzt und 2 h auf 80 °C erhitzt. Man verdünnte dann mit Essigsäureethylester, wusch die organische Phase mit gesättigter wässriger Natriumcarbonat-Lösung, trocknete über Natriumsulfat und entfernte das Lösungsmittel im Vakuum. Der Rückstand wurde durch Chromatographie an Kieselgel (Eluens: Essigsäureethylester) gereinigt. Man erhielt die Titelverbindung als orangefarbene Kristalle. Ausbeute: 104 mg (57% d. Th.).

150 mg (0.42 mmol) of 2-anuno-6-chloro-4- [3-chloro-4- (nifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 29A, 236 mg (63%, 0.63 mmol) of 2 - [4- (4,4,5,5-Tetramethyl-l, 3,2-dioxaborolan-2-yl) -l / -pyrazol-1-yl] ethanol from Example I IA, 141 mg (1.68 mmol) of sodium bicarbonate and 24 mg (0.029 mmol) of [1,1'-bis (diphenylphosphine) ferrocene] dichloroalladium (II) dichloromethane complex were added with a degassed mixture of 2.0 ml of 1,2-dimethoxyethane and 1.0 ml of water and heated to 80 ° for 2 hours C heated. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluant: ethyl acetate). The title compound was obtained as orange crystals. Yield: 104 mg (57% of theory).

LC-MS (Method 4): R _t = 2.20 min; MS (EIpos): m / z = 433 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8:44 (s, 1H), 8.18 (s, 1H), 8.12 (d, 1H), 8.10 (s, 1H) 8.02 (br. s., 2H), 7.81 (d, 1H), 4.99 (t, 1H), 4.26 (t, 2H), 3.75 (q, 2H).

Example 104

 2-Amino-6- [1- (2-hydroxy-2-methylpropyl) -1 / pyrazol-4-yl] -4- [4- (trifluoromethyl) phenyl] pyridine-3, 5-dicarbonitrile

 53 mg (0.17 mmol) of 2-amino-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 48 mg (0.18 mmol) of 2-methyl-1- [4- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -l / -pyrazol-1-yl] propan-2-ol from Example 12A, 56 mg (0.66 mmol) of sodium bicarbonate and 6.8 mg (0.008 mmol) of [Ι, - bis (diphenylphosphine) ferrocene] dichloroalladium (II) -dichloromethane complex were admixed with a degassed mixture of 0.6 ml of 1,2-dimethoxyethane and 0.3 ml of water and heated at 80 ° C. for 6 hours , It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 1). The title compound was obtained. Yield: 19.6 mg (28% of theory).

LC-MS (Method 4): R _t = 2.17 min; MS (EIPOS): m / z = 427 [M + H] ^+.

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8:46 (s, 1H), 8.16 (s, 1H), 7.99 (d, 2H), 7.98, 7.83 ((br s, 2H). d, 2H), 4.81 (s, 1H), 4.13 (s, 2H), 1.08 (s, 6H). Example 105

 2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- [1- (2-hydroxy-2-methylpropyl) -1-pyrazol-4-yl] pyridine-3, 5 dicarbonitrile

220 mg (0.620 mmol) 2-amino-6-chloro-4- [3-chloro-4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 29A, 180 mg (0.680 mmol) 2-methyl-1 - [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl] propan-2-ol from Example 12A, 207 mg (2.46 mmol ) Sodium bicarbonate and 25.1 mg (0.031 mmol) of [l, Γ-bis (diphenylphosphine) ferrocene] dichloφalladium (II) -Dichlormethan- complex were treated with a degassed mixture of 3.0 ml of 1,2-dimethoxyethane and 1.0 ml of water and for 3 h Heated to 80 ° C. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 1). The title compound was obtained. Yield: 148 mg (51% of theory).

LC-MS (Method 6): R _t = 1.05 min; MS (EIPOS): m / z = 461 [M + H] ^+.

'H-NMR (400 MHz, DMSO-ώ): δ [ppm] = 8.46 (s, 1H), 8.15 (s, 1H), 8.12 (d, 1H), 8.10 (s, 1H), 8.02 (br. s., 2H), 7.81 (d, 1H), 4.81 (s, 1H), 4.13 (s, 2H), 1.08 (s, 6H).

Example 106

2-Amino-6- {1 - [(2S) -3,3,3-trifluoro-2-hydroxypropyl] -1 / pyrazol-4-yl} -4- [4- (trifluoromethyl) phenyl] pyridine-3 , 5-dicarbonitrile

 129 mg (0.40 mmol) of 2-amino-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 135 mg (0.44 mmol) of (2S), 1,1-trifluoro -3- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 / pyrazol-1-yl] propan-2-ol from Example 13A, 134 mg (1.35 mmol) of sodium bicarbonate and 16 mg (0.020 mmol) of [l, Γ-bis (diphenylphosphine) ferrocene] dichloφalladium (II) -dichloromethane complex were treated with a degassed mixture of 1.5 ml of 1,2-dimethoxyethane and 0.5 ml of water and Heated to 80 ° C for 6 h. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by preparative HPL (eluent: acetonitrile, 0.05% formic acid). The title compound was obtained. Yield: 49 mg (26% of theory).

LC-MS (Method 6): R _t = 1.03 min; MS (EIpos): m / z = 467 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8:52 (s, 1H), 8.22 (s, 1H), 8.07-7.91 (m, 4H), 7.84 (d, 2H), 6.78 (d, 1H), 4.54-4.41 (m, 3H).

Example 107

2-Amino-6- [1- (2-hydroxy-3-methoxypropyl) -1 / pyrazol-4-yl] -4- [4- (trifluoromethyl) phenyl] pyridine-3, 5-dicarbonitrile

104 mg (0.32 mmol) of 2-amino-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 200 mg (0.35 mmol, 50% purity) of 1-methoxy -3- [4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 / pyrazol-1-yl] propan-2-ol from Example 14A, 108 mg (1.29 mmol) of sodium bicarbonate and 13 mg (0.016 mmol) of [l, Γ-bis (diphenylphosphine) ferrocene] dichloroalladium (II) -dichloromethane complex were washed with a degassed mixture of 1.2 ml of 1,2-dimethoxyethane and 0.4 ml of water and heated to 80 ° C for 6 h. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluant: ethyl acetate). The title compound was obtained. Yield: 65 mg (46% of theory).

LC-MS (Method 2): R _t = 0.95 min; MS (EIpos): m / z = 443 [M + H] ⁺ .

 'H NMR (400 MHz, DMSO-ώ): δ [ppm] = 8.42 (s, 1H), 8.18 (s, 1H), 7.99 (d, 2H), 7.96 (br, s, 2H), 7.83 ( d, 2H), 5.25 (d, 1H), 4.28 (dd, 1H), 4.15 (dd, 1H), 4.00-3.91 (m, 1H), 3.29-3.26 (m, 5H).

Example 108

 2-Amino-6- [1- (2-methoxyethyl) -1-pyrazol-4-yl] -4- [4- (trifluoromethyl) phenyl] pyridine-3, 5-dicarbonitrile

 124 mg (0.387 mmol) of 2-amino-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 156 mg (0.580 mmol) of 1- (2-methoxyethyl) -4 - (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -l / -pyrazole from example 15A, 130 mg (1.55 mmol) sodium bicarbonate and 15.8 mg (0.019 mmol) [1, 1 '- Bis (diphenylphosphine) ferrocene] dichloroalladium (II) -dichloromethane complex was treated with a degassed mixture of 1.5 ml of 1,2-dimethoxyethane and 0.5 ml of water and heated at 80 ° C overnight. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 1). The title compound was obtained. Yield: 53 mg (33% of theory).

LC-MS (Method 6): R _t = 0.98 min; MS (EIpos): m / z = 413 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8:44 (s, 1H), 8.18 (s, 1H), 7.99 (d, 2H), 7.97, 7.83 ((br s, 2H). d, 2H), 4.39 (t, 2H), 3.71 (t, 2H), 3.23 (s, 3H).

Example 109 2-Amino-6- {1- [2- (4-methyl-4-yl) ethyl] -1-pyrazol-4-yl} -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

 100 mg (0.3-10 mmol) 2-anuno-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from example 24A, 152 mg (0.465 mmol) 4- {2- [4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl] ethyl} morpholine, 104 mg (1.24 mmol) sodium bicarbonate, and 12.7 mg (0.015 mmol). [1,1'-Bis (diphenylphosphine) ferrocene] -dichloropalladium (II) -dichloromethane complex was treated with a degassed mixture of 1.2 ml of 1,2-dimethoxyethane and 0.4 ml of water and heated to 80 ° C for 6 hours. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / ethanol 100: 0 gradient to 100: 1) and then stirred with MTBE and filtered with suction. Yield: 89 mg (61% of theory).

LC-MS (Method 6): R _t = 0.83 min; MS (EIpos): m / z = 468 [M + H] ⁺ .

 'H NMR (400 MHz, DMSO-ώ): δ [ppm] = 8.56 (s, 1H), 8.14 (s, 1H), 7.99 (d, 2H), 7.95 (br, s, 2H), 7.83 ( d, 2H), 4.34 (t, 2H), 3.55-3.52 (m, 4H), 2.71 (t, 2H), 2.43-2.38 (m, 4H).

Example 110

 Ethyl 3- (4- {6-amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -3,5-dicyanopyridin-2-yl} -1 / pyrazol-1-yl) propanoate

200 mg (0.56 mmol) 2-Anuno-6-chlor-4-[3-chlor-4-(trifluormethyl)phenyl]pyridin-3,5-dicarbonitril aus Beispiel 29A, 258 mg (0.84 mmol) Ethyl-3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yljpropanoat aus Beispiel 16A, 188 mg (2.24 mmol) Natriumhydrogencarbonat und 22.9 mg (0.028 mmol) [l,Γ-Bis(diphenylphosphin)ferrocen]dichloφalladium(II)-Dichlormethan-Komplex wurden mit einer entgas- ten Mischung aus 2.25 ml 1,2-Dimethoxyethan und 0.75 ml Wasser versetzt und 3 h auf 80 °C erhitzt. Man verdünnte dann mit Essigsäureethylester, wusch die organische Phase mit gesättigter wässriger Natriumcarbo- nat-Lösung, trocknete über Natriumsulfat und entfernte das Lösungsmittel im Vakuum. Der Rückstand wurde durch Chromatographie an Kieselgel (Eluens: Cyclohexan/Essigsäureethylester 1 :3) gereinigt. Das Produkt wurde mit Methanol verrührt und abgesaugt. Man erhielt die Titelverbindung. Ausbeute: 171 mg (62% d. Th.). LC-MS (Methode 6): R_t = 1.15 min; MS (EIpos): m/z = 489 [M+H]⁺.

200 mg (0.56 mmol) of 2-anuno-6-chloro-4- [3-chloro-4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 29A, 258 mg (0.84 mmol) of ethyl 3- [ 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl-propanoate from Example 16A, 188 mg (2.24 mmol) of sodium bicarbonate and 22.9 mg (0.028 mmol ) [l, Γ-bis (diphenylphosphine) ferrocene] dichloφalladium (II) -dichloromethane complex was treated with a degassed mixture of 2.25 ml of 1,2-dimethoxyethane and 0.75 ml of water and heated to 80 ° C for 3 h. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 3). The product was stirred with methanol and filtered with suction. The title compound was obtained. Yield: 171 mg (62% of theory). LC-MS (Method 6): R _t = 1.15 min; MS (EIpos): m / z = 489 [M + H] ⁺ .

 'H NMR (400 MHz, DMSO-ώ): δ [ppm] = 8.45 (s, 1H), 8.16 (s, 1H), 8.12 (d, 1H), 8.09 (s, 1H), 8.02 (br. s., 2H), 7.81 (d, 1H), 4.47 (t, 2H), 4.05 (q, 2H), 2.91 (t, 2H), 1.15 (t, 3H).

Example 111

 2-Amino-6- (3-methoxyphenyl) -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

 957 mg (4.31 mmol) of [4- (trifluoromethyl) benzylidene] malononitrile from Example 1A and 500 mg (2.87 mmol) of 3-amino-3- (3-methoxyphenyl) acrylonitrile [T. de Paulis, K. Hemstapat, Y. Chen, Y. Zhang, S. Saleh, D. Alagille, RM Baldwin, GD Tamagnan, PJ Conn, J. Med. Chem. 2006, 49, 3332-3344.] were published in 5.0 ml of ethanol submitted. 87 mg (0.57 mmol) of DBU were added and the mixture was heated for 30 min. to 80 ° C, whereby a precipitate failed. It was aspirated and washed with a little ethanol and pentane and the title compound was obtained. Yield: 320 mg (28% of theory).

LC-MS (Method 6): R _t = 1.09 min; MS (EIpos): m / z = 395 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.17 (br.s, 2H), 8.00 (d, 2H), 7.88 (d, 2H), 7.47 (t, 1H), 7.41-7.36 (m, 2H), 7.14 (ddd, 1H), 3.82 (s, 3H). Example 112

2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- (3-methoxyphenyl) pyridine-3, 5-dicarbonitrile

 A mixture of 800 mg (3.12 mmol) of [3-chloro-4- (trifluoromethyl) benzylidene] malononitrile from Example 4A and 543 mg (3.12 mmol) of 3-amino-3- (3-methoxyphenyl) acrylonitrile [T. de Paulis, K. Hemstapat, Y. Chen, Y. Zhang, S. Saleh, D. Alagille, RM Baldwin, GD Tamagnan, PJ Conn, J. Med. Chem. 2006, 49, 3332-3344 Drops of triethylamine are added and 10 min. heated to 120 ° C. The reaction mixture was then taken up in ethyl acetate and shaken with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate and the solvent removed in vacuo. Purification by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 8: 1 Grandient to 2: 1). It was mixed with diethyl ether and filtered off with suction. The title compound was obtained. Yield: 230 mg (17% of theory).

LC-MS (Method 3): R _t = 1.46 min; MS (EIpos): m / z = 429 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8.21, 8.16-8.1 1 (m, 2H), 7.86 (d, 1H), 7:48 (t, (br s, 2H). 1H), 7.42-7.36 (m, 2H), 7.15 (ddd, 1H), 3.82 (s, 3H).

Example 113

2-amino-6- (3) pyridine-3,5-dicarbonitrile

100 mg (0.3-10 mmol) of 2-amino-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 84 mg (0.47 mmol) of (3-isopropoxyphenyl) boronic acid, 104 mg (1.24 mmol) of sodium bicarbonate and 12.7 mg (0.015 mmol) of [l, Γ-bis (diphenylphosphine) ferrocene] dichloroalladium (II) -dichloromethane complex were added with a degassed mixture of 1.5 ml of 1,2-dimethoxyethane and 0.5 ml of water and heated to 80 ° C overnight. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 2: 1). Yield: 68 mg (52% of theory).

LC-MS (Method 6): R _t = 1.20 min; MS (EIpos): m / z = 423 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.15 (br.s, 2H), 8.00 (d, 2H), 7.89 (d, 2H), 7.46-7.41 (m, 1H ), 7.37-7.33 (m, 2H), 7.11 (ddd, 1H), 4.66 (spt, 1H), 1.30 (d, 6H).

Example 114

2-Arnino-4- (3,4-dichloφhenyl) -6- (3,4-dimethoxyphenyl) pyridine-3,5-dicarbonitrile

 200 mg (0.897 mmol) of (3,4-dichlorobenzylidene) malononitrile [X.-S. Wang, Z.S. Zeng, Y.-L. Li, D.-Q. Shi, S.-J. Tu, X.-Y. Wei, Z.-M. Zong, Synth. Commun. 2005, 35, 1915-1920.] And 183 mg (0.897 mmol) of 3-amino-3- (3,4-dimethoxyphenyl) acrylonitrile [A. B. Ridley, W.C. Taylor, Aust. J. Chem. 1987, 40, 631-634.] Were initially charged in 5.0 ml of methanol. 0.17 ml (0.94 mmol) of a 5M sodium methoxide solution in methanol was added and the mixture was heated in the microwave for 10 min. to 120 ° C. Then you sucked the precipitate and washed with MTBE. The crude product was purified by preparative HPLC. Yield: 42 mg (11% of theory).

LC-MS (Method 3): R _t = 1.36 min; MS (EIpos): m / z = 425/427 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8:08 (br s., 2H) 8.02 (d, 1H), 7.90 (d, 1H), 7.65 (dd, 1H), 7.50 ( d, 1H), 7.47 (d, 1H), 7.13 (d, 1H), 3.84 (s, 3H), 3.81 (s, 3H).

Example 115

2-Amino-6- [3-fluoro-4- (hydroxymethyl) -5-methoxyphenyl] -4- [4- (trifluoromethyl) phenyl] pyridine-3, 5-dicarbonitrile

 100 mg (0.3-10 mmol) of 2-anuno-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 131 mg (0.47 mmol) of [2-fluoro-6-methoxy -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -phenyl] -methanol, 104 mg (1.24 mmol) sodium bicarbonate and 12.7 mg (0.015 mmol) of [1,1 '-] Bis (diphenylphosphine) ferrocene] -dichloropalladium (II) -dichloromethane complex was treated with a degassed mixture of 1.5 ml of 1,2-dimethoxyethane and 0.5 ml of water and heated at 80 ° C overnight. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 1). Yield: 51 mg (40% of theory).

LC-MS (Method 6): R _t = 0.99 min; MS (EIPOS): m / z = 443 [M + H] ^+.

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8.22 8:01 (d, 2H), 7.89 (d, 2H), 7:32 (s, 1H), (br s, 2H). 7.24 (d, 1H), 4.99 (t, 1H), 4.52 (d, 2H), 3.88 (s, 3H).

Example 116

2-Amino-6- [3 - (pyrrolidin-1-ylmethyl) phenyl] -4- [4- (trifluoromethyl) phenyl] pyridine-3, 5-dicarbonitrile

100 mg (0.310 mmol) 2-Anuno-6-chlor-4-[4-(trifluormethyl)phenyl]pyridin-3,5-dicarbonitril aus Beispiel 24A, 142 mg (0.47 mmol) l-[3-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl]pyrrolidin, 104 mg (1.24 mmol) Natriumhydrogencarbonat und 12.7 mg (0.015 mmol) [l,Γ-Bis(diphenylphosphin)ferrocen]dichloφal- ladium(II)-Dichlormethan- Komplex wurden mit einer entgasten Mischung aus 1.2 ml 1,2-Dimethoxyethan und 0.4 ml Wasser versetzt und 6 h auf 80 °C erhitzt. Man verdünnte dann mit Essigsäureethylester, wusch die organische Phase mit gesättigter wässriger Natriumcarbonat-Lösung, trocknete über Natriumsulfat und entfernte das Lösungsmittel im Vakuum. Der Rückstand wurde durch Chromatographie an Kieselgel (Eluens: Essigsäu- reethylester/Ethanol 1 :0 Gradient bis 100: 1) gereinigt, dann mit MBTE verrührt und abgesaugt. Ausbeute: 60 mg (41% d. Th.).

100 mg (0.310 mmol) of 2-anuno-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 142 mg (0.47 mmol) of 1- [3- (4.4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl] pyrrolidine, 104 mg (1.24 mmol) of sodium bicarbonate and 12.7 mg (0.015 mmol) of [l, Γ-bis (diphenylphosphine) ferrocene] dichloφal- Ladium (II) -Dichlormethan- complex were treated with a degassed mixture of 1.2 ml of 1,2-dimethoxyethane and 0.4 ml of water and heated to 80 ° C for 6 h. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluant: ethyl acetate / ethanol 1: 0 gradient to 100: 1), then stirred with MBTE and filtered with suction. Yield: 60 mg (41% of theory).

LC-MS (Method 6): R _t = 0.75 min; MS (EIpos): m / z = 448 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8.16, from 8.00 (d, 2H), 7.89 (d, 2H), 7.78 (s, 1H) (br s, 2H.). , 7.73-7.67 (m, 1H), 7.52-7.45 (m, 2H), 3.64 (s, 2H), 2.47-2.40 (m, 4H), 1.75-1.63 (m, 4H).

Example 117

 2-Amino-6- [3 - (4-methylphenyl) phenyl] -4- [4- (trifluoromethyl) phenyl] pyridine-3, 5-dicarbonitrile

 100 mg (0.310 mmol) of 2-amino-6-c-Mor-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 150 mg (0.47 mmol) of 4- [3- (4.4 , 5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) benzyl] -monomerhine, 104 mg (1.24 mmol) of sodium bicarbonate and 12.7 mg (0.015 mmol) of [l, -Bis (diphenylphosphine) ferrocene] dic-morphine (II ) - Dichloromethane complex was added to a degassed mixture of 1.2 ml of 1,2-dimethoxyethane and 0.4 ml of water and heated to 80 ° C for 6 h. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluant: ethyl acetate / ethanol 1: 0 gradient to 20: 1), then stirred with MBTE and filtered with suction. Yield: 89 mg (61% of theory).

LC-MS (Method 2): R _t = 0.74 min; MS (EIpos): mz = 464 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8.16, from 8.00 (d, 2H), 7.89 (d, 2H), 7.78 (s, 1H), (br s, 2H). 7.74-7.68 (m, 1H), 7.53-7.48 (m, 2H), 3.59-3.55 (m, 4H), 3.54 (s, 2H), 2.41-2.35 (m, 4H).

Example 118 2-Amino-6- {3 - [(4-methylpiperazin-1-yl) methyl] phenyl} -4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile

 100 mg (0.3-10 mmol) of 2-anuno-6-chloro-4- [4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 24A, 147 mg (0.47 mmol) of 1-methyl-4- [3 (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) benzyl] -piperazine, 104 mg (1.24 mmol) of sodium bicarbonate and 12.7 mg (0.015 mmol) of [l, l '-Bis ( diphenylphosphine) ferrocene] - dichloφalladium (II) -dichloromethane complex were treated with a degassed mixture of 1.2 ml of 1, 2-dimethoxyethane and 0.3 ml of water and heated to 80 ° C for 6 h. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluant: ethyl acetate / ethanol 2: 1 gradient to 1: 1), then stirred with MBTE and filtered with suction. Subsequent purification by preparative HPLC gave the title compound. Yield: 53 mg (34% of theory).

LC-MS (Method 2): R _t = 0.75 min; MS (EIpos): m / z = 477 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8.15, 7.99 (d, 2H), 7.88 (d, 2H), 7.75 (s, 1H), (br s, 2H). 7.72-7.69 (m, 1H), 7.52-7.47 (m, 2H), 3.53 (s, 2H), 2.45-2.20 (m, 8H), 2.13 (s, 3H).

Example 119

2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- [4- (2-hydroxyethoxy) -1 / pyrazole-1-yl] pyridine-3, 5-dicarbonitrile

 332 mg (0.93 mmol) of 2-amino-6-chloro-4- [3-chloro-4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 29A in 3.0 ml of DMSO were initially added and 19 mg was added (0.93 mmol) of 2- (1 // pyrazol-4-yloxy) ethanol from Example 61A and 454 mg (1.39 mmol) of cesium carbonate and allowed to stir at RT overnight. Then the reaction mixture was taken up in ethyl acetate, washed with water and the organic phase dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by preparative HPLC (eluant: acetonitrile / 0.05% aqueous formic acid). The product was mixed with pentane / MTBE and sucked off. Further purification was carried out by chromatography on silica gel (eluent: dichloromethane / methanol 20: 1) to give the title compound. Yield: 27 mg (6% of theory).

LC-MS (Method 2): R _t = 0.98 min. MS (EI): m / z = 449 [M + H] ^+.

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8.26, 8:14 to 8:10 (m, 2H), 8:07 to 8:05 (m, 1H), 7.89 (d (br s, 2H). , 1H), 7.78 (d, 1H), 4.96 (t, 1H), 4.00 (t, 2H), 3.71 (q, 2H).

Example 120

2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- [4- (2-hydroxy-2-methylpropoxy) -1 / pyrazole-1-yl] pyridine-3,5-dicarbonitrile

236 mg (0.66 mmol) of 2-amino-6-chloro-4- [3-chloro-4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 29A in 2.0 ml of DMSO were added and 103 mg of 0.66 mmol) 2-methyl-1- (1-pyrazol-4-yloxy) propane 2-ol from Example 63A and 322 mg (0.99 mmol) cesium carbonate and allowed to stir at RT overnight. Then the reaction mixture was taken up in ethyl acetate, washed with water and the organic phase dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by preparative HPLC (eluant: acetonitrile / 0.05% aqueous formic acid). The product was mixed with pentane / MTBE and sucked to give the title compound. Yield: 67 mg (21% of theory). LC-MS (Method 6): R _t = 1.07 min. MS (EI): m / z = 477 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ώ): δ [ppm] = 8.24 (br, s, 2H), 8.12 (t, 2H), 8.06 (s, 1H), 7.89 (d, 1H), 7.78 (d, 1H), 4.72 (s, 1H), 3.73 (s, 2H), 1.19 (s, 6H).

Example 121

 2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- [4- (2-hydroxypropan-2-yl) -1 / pyrazole-1-yl] pyridine-3, 5-dicarbonitrile

 150 mg (0.42 mmol) of 2-amino-6-chloro-4- [3-chloro-4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 29A in 2.0 ml of DMSO were added and 53 mg of 0.42 mmol) of 2- (1-pyrazol-4-yl) propan-2-ol from Example 64A and 205 mg (0.63 mmol) of cesium carbonate and allowed to stir at RT overnight. Then the reaction mixture was taken up in MTBE, washed with water and the organic phase dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by preparative HPLC (eluent: gradient acetonitrile / 0.05% aqueous formic acid). The product was mixed with pentane / MTBE and sucked to give the title compound. Yield: 97 mg (52% of theory).

LC-MS (Method 6): R _t = 1.00 min. MS (EI): m / z = 447 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8.31 (s, 1H), 8.30 8.12 (d, 1H), 8:07 (s, 1H), 7.93 ((br s, 2H). s, 1H), 7.79 (d, 1H), 5.18 (s, 1H), 1.46 (s, 6H).

Example 122

2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- [4- (2-hydroxy-2-methylpropyl) -1 / pyrazole-1-yl] pyridine-3, 5-dicarbonitrile

 191 mg (0.54 mmol) of 2-amino-6-chloro-4- [3-chloro-4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 29A in 2.0 ml of DMSO were added and 75 mg of 0.54 mmol) of 2-methyl-1- (1-pyrazol-4-yl) propan-2-ol from Example 66A and 261 mg (0.80 mmol) cesium carbonate and allowed to stir at RT overnight. Then the reaction mixture was taken up in MTBE, washed with water and the organic phase dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by preparative HPLC (eluent: gradient acetonitrile / 0.05% aqueous formic acid). The product was mixed with pentane / MTBE and sucked to give the title compound. Yield: 43 mg (17% of theory).

LC-MS (Method 6): R _t = 1.06 min. MS (EI): m / z = 461 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.31 (s, 1H), 8.12 (d, 1H), 8.28 (br.s, 2H), 8.06 (s, 1H), 7.82-7.76 (m, 2H), 4.46 (s, 1H), 2.59 (s, 2H), 1.10 (s, 6H).

Example 123

 2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- [4- (pyridin-3-yl) -1 / pyrazole-1-yl] pyridine-3, 5-dicarbonitrile

200 mg (0.56 mmol) of 2-amino-6-chloro-4- [3-chloro-4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 29A in 2.5 ml of DMSO were initially added and 81 mg of 0.56 mmol) of 3- (1-pyrazol-4-yl) pyridine [N. Kudo, M. Perseghini, GC Fu, Angew. Chem. Int. Ed. 2006, 45, 1282-1284.] And 274 mg (0.84 mmol) of cesium carbonate and allowed to stir at RT for 4 h. Then the reaction mixture was taken up in MTBE / ethyl acetate, washed with water and the organic phase dried over sodium sulfate. You removed that Solvent in vacuo and the residue was purified by preparative HPLC (eluent: gradient acetonitrile / 0.05% aqueous formic acid). The product was mixed with pentane / MTBE and sucked to give the title compound. Yield: 55 mg (87% purity, 18% of theory).

LC-MS (Method 6): R _t = 1.01 min. MS (EI): mz = 466 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 9.02 (d, 1H), 8.99 (s, 1H), 8.59 (s, 1H), 8.53 (dd, 1H), 8.35 ( br. s, 2H), 8.18-8.09 (m, 3H), 7.83 (d, 1H), 7.49 (dd, 1H).

Example 124

1- {6-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -3,5-dicyanopyridin-2-yl} -1 / pyrazole-4-sulfonoar

150 mg (0.42 mmol) of 2-amino-6-chloro-4- [3-chloro-4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 29A in 2.0 ml of DMSO were added and 62 mg of 0.42 mmol) of 1 // pyrazole-4-sulfonamide and 205 mg (0.63 mmol) of cesium carbonate and allowed to stir at RT overnight. Then the reaction mixture was taken up in ethyl acetate, washed with water and the organic phase dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by preparative HPLC (eluant: acetonitrile / 0.05% aqueous formic acid) and then by chromatography on silica gel (eluant: ethyl acetate / cyclohexane 2: 1). The title compound was obtained. Yield: 46 mg (22% of theory). LC-MS (Method 2): R _t = 0.97 min. MS (EI): m / z = 468, 470 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8.77 (s, 1H), 8.73-8.25 (m, 2H), 8.22 (s, 1H), 8.15 (d, 1H), 8:08 ( s, 1H), 7.81 (d, 1H), 7.66 (s, 2H).

Example 125

2-Amino-6- (3-methoxyphenyl) -4- (4-methylphenyl) pyridine-3,5-dicarbonitrile

 100 mg (0.30 mmol) of 2-amino-4-chloro-6- (3-methoxyphenyl) pyridine-3,5-dicarbonitrile from Example 68A, 81 mg (0.60 mmol) of (4-methylphenyl) boronic acid, 100 mg (1.19 mmol Sodium hydrogen carbonate and 12 mg (0.015 mmol) of [l, Γ-bis (diphenylphosphine) ferrocene] dichloroalladium (II) dichloromethane complex were treated with a degassed mixture of 1.5 ml of 1,2-dimethoxyethane and 0.5 ml of water and brought to 80 overnight ° C heated. It was then diluted with ethyl acetate, the organic phase was washed with saturated sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by preparative HPLC (eluant: acetonitrile / water gradient). The product was obtained. Yield: 59 mg (58% of theory).

LC-MS (Method 6): R _t = 1.05 min. MS (EI): m / z = 341 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): (br. S, 2H) δ [ppm] = 8.04 7:51 (d, 2H), 7:45 (t, 1H), 7:42 to 7:35 (m, 4H ), 7.13 (dd, 1H), 3.81 (s, 3H), 2.41 (s, 3H).

Analogously to the synthesis of Example 16, the respective benzylidenemalononitrile (1.5 eq.) Was reacted with amino-3- (3-methoxyphenyl) acrylonitrile from Example 69A (1.0 eq.) And DBU (0.1 eq.) In ethanol (2.5 ml / mmol 69A). heated to reflux. After purification, the products listed in Table 3 were isolated.

Table 3:

 * 1) (4-cyanobenzylidene) malononitrile: A. Cornelis, S. Lambert, P. Laszlo, J. Org. Chem. 1977, 42, 381-382.

* 2) (4-chloro-2-methylbenzylidene) malononitrile: WO2006 / 78676, p. 44.

* 3) (4-Isopropylbenzylidene) malononitrile: FR1517178 (1967). * 4) (3-chlorobenzylidene) malononitrile: X.-S. Wang, Z.S. Zeng, Y.-L. Li, D.-Q. Shi, S.-J. Tu, X.-Y. Wei, Z.-M. Zong, Synth. Commun. 2005, 35, 1915-1920.

Example 132

 2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- {1 - [(1-hydroxycyclobutyl) methyl] -1-pyrazol-4-yl} pyridine-3,5-dicarbonitrile

 200 mg (0.45 mmol) of N '- {4- [3-chloro-4- (trifluoromethyl) phenyl] -3,5-dicyano ^

 N, N-dimethylimidoformamide from Example 44A was initially charged in 2.0 ml of acetonitrile. 116 mg (0.45 mmol) of (1-hydroxycyclobutyl) methyl 4-methylbenzenesulfonate from Example 70A, 166 mg (0.45 mmol) of tetrabutylammonium iodide and 176 mg (0.54 mmol) of cesium carbonate were added and the reaction mixture was heated to 50 ° C. for 3 h , Then 4.0 ml of THF were added and stirring was continued overnight at 50.degree. The mixture was then taken up in ethyl acetate, the organic phase was washed with water, dried over sodium sulfate and the solvent was removed in vacuo. Then 3.0 ml of methanol were added and 3.0 ml (12 mmol) of 4N hydrogen chloride solution in dioxane. The mixture was heated at 40 ° C. for 4 h, then diluted with ethyl acetate, washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica gel (eluent: dichloromethane / methanol 20: 1), then stirred with a little pentane and MTBE and filtered off with suction. The product was obtained. Yield: 135 mg (92%, 58% of theory).

LC-MS (method 6): R _t = 1:09 min. MS (EI): m / z = 473 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8:46 (s, 1H), 8.16 (s, 1H), 8.12 (d, 1H), 8:09 (s, 1H) 8.02 ( br. s, 2H), 7.81 (d, 1H), 5.51 (s, 1H), 4.28 (s, 2H), 2.1-2.02 (m, 2H), 2.00-1.89 (m, 2H), 1.70-1.59 (m, 1H), 1.59- 1.46 (m, 1H).

Example 133

2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- {1- [2- (1-hydroxycyclobutyl) ethyl] -1 / pyrazol-4-yl} pyridine-3,5- dicarbonitrile

 200 mg (0.45 mmol) of N '- {4- [3-chloro-4- (trifluoromethyl) phenyl] -3,5-dicyano ^

 N, N-dimethylimidoformamide from Example 44A was initially charged in 4.0 ml of THF. 122 mg (0.45 mmol) of 2- (1-hydroxycyclobutyl) ethyl 4-methylbenzenesulfonate from Example 72A, 166 mg (0.45 mmol) of tetrabutylammonium iodide and 176 mg (0.54 mmol) of cesium carbonate were added and the reaction mixture was heated for 3 h 50 ° C and then overnight at 80 ° C. The mixture was then taken up in ethyl acetate, the organic phase was washed with water, dried over sodium sulfate and the solvent was removed in vacuo. The intermediate was purified by chromatography on silica gel (eluent: ethyl acetate / cyclohexane 2: 1), then taken up in 2.2 ml of methanol and 2.2 ml (9 mmol) of 4N hydrogen chloride solution in dioxane. After stirring overnight at RT, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica gel (eluent: dichloromethane / methanol 20: 1), then stirred with a little pentane and MTBE and filtered with suction. The product was obtained as colorless crystals. Yield: 69 mg (31% of theory).

LC-MS (Method 6): R _t = 1.07 min. MS (EI): m / z = 487 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-i / _o): δ [ppm] = 8:46 (s, 1H), 8.16 (s, 1H), 8.12 (d, 1H), 8:09 (s, 1H), 8:01 ( br. s, 2H), 7.81 (d, 1H), 5.15 (s, 1H), 4.27 (dd, 2H), 2.05 (dd, 2H), 2.00-1.81 (m, 4H), 1.66-1.54 (m, 1H), 1.52- 1.39 (m, 1H).

Example 134

2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- [1- (3-hydroxy-3-methylbutyl) -1 / pyrazol-4-yl] pyridine-3, 5-dicarbonitrile

 1 07 mg (0.30 mmol) 2-anuno-6-chloro-4- [3-chloro-4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 29A, 68 mg (0.20 mmol) 2-methyl- 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl] butan-2-ol from Example 73A, 67 mg (0.80 mmol) of sodium bicarbonate and 8.1 mg (0.01 mmol) of [1,1'-bis (diphenylphosphine) ferrocene] -dichloropalladium (II) -dichloromethane complex were treated with a degassed mixture of 1.5 ml of 1,2-dimethoxyethane and 0.5 ml of water and 3 h heated to 80 ° C. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / cyclohexane 2: 1). Yield: 47 mg (50% of theory).

LC-MS (Method 6): R _t = 1.03 min. MS (EI): m / z = 475 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.46 (s, 1H), 8.15 (s, 1H), 8.12 (d, 1H), 8.10-8.08 (m, 1H), 8.01 (br.s, 2H), 7.81 (d, 1H), 4.49 (s, 1H), 4.33-4.26 (m, 2H), 1.95-1.89 (m, 2H), 1.12 (s, 6H).

Example 135

 Methyl 2- (4- {6-amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -3,5-dicyanopyridin-2-yl} -1-pyrazol-1-yl) -2- methylpropanoate

200 mg (0.56 mmol) of 2-amino-6-chloro-4- [3-chloro-4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 29A, 354 mg (1.12 mmol) of methyl 2-methyl -2- [4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 / pyrazol-1-yl] propanoate [WO 2006/21881, p. 69], 188 mg (2.24 mmol) of sodium bicarbonate and 23 mg (0.03 mmol) of [l, Γ-bis (diphenylphosphine) ferrocene] dichloroalladium (II) dichloromethane. Complex was treated with a degassed mixture of 2.7 ml of 1,2-dimethoxyethane and 0.9 ml of water and heated to 80 ° C for 1.5 h. It was then diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1.5: 1). The product was triturated with a little methanol and filtered with suction. Yield: 149 mg (54% of theory).

LC-MS (Method 6): R _t = 1.14 min. MS (EI): m / z = 489 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8:54 (s, 1H), 8.21 (s, 1H), 8.13 (d, 1H), 8.10 (s, 1H), 8:06 (br. s, 2H), 7.82 (d, 1H), 3.65 (s, 3H), 1.83 (s, 6H).

Analogously to the synthesis of Example 40A, the respective dihydropyridine was oxidized in acetic acid / DMF as solvent with manganese (IV) oxide at RT to 60 ° C and the addition products listed in Table 4 were isolated.

Table 4:

MS s, 3.95

MSs, 3.95

MS s, (dd,

MS 1H),

MS, 3.95

BeiDihydro- Struktur Analytische Daten MS s,

For dihydro structure Analytical data

 play pyridine

 144 82A F Yield: 241 mg (82% of TL).

LC-MS (Method 2): R _t = 1.04 min; MS fl (EIpos): m / z = 427 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.42 (s, 1H), 8.17 (d, 2H), 8.13 (s, 1H), 7.99 (br. S, 2H), 7.85 (d, 2H), 3.95 (s, 3H).

H ₂ NN ' ⁱⁱⁱ N-CH ₃

Example 145

 2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- [4- (2-hydroxyethyl) -1 / pyrazole-1-yl] pyridine-3, 5-dicarbonitrile

 3,18 mg (0.8 mmol) of 2-amino-6-chloro-4- [3-chloro-4- (trifluoromethyl) phenyl] pyridine-3,5-dicarbonitrile from Example 29A in 4.0 ml DMSO and gave 100 mg (0.892 mmol) of 2- (1H-pyrazol-4-yl) ethanol [R. Jones, M.J. Mann, J. Am. Chem. Soc. 1953, 75, 4048-4052.] And 436 mg (1.34 mmol) of cesium carbonate and allowed to stir at RT overnight. Then the reaction mixture was taken up in MTBE, washed with water and the organic phase dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by preparative HPLC (eluent: gradient acetonitrile / 0.05% aqueous formic acid). The product was mixed with pentane / MTBE and sucked off. The obtained fraction was again subjected to the same purification procedure. The title compound was obtained. Yield: 57 mg (14% of theory).

LC-MS (Method 2): R _t = 0.99 min. MS (EI): m / z = 433 [M + H] ⁺ .

'H-NMR (400 MHz, _DMSO-ö): δ [ppm] = 8:32 (s, 1H), 8.28, 8.12 (d, 1H), 8:06 (s, 1H), 7.85 ((br s, 2H). s, 1H), 7.79 (d, 1H), 4.76 (t, 1H), 3.61 (q, 2H), 2.66 (t, 2H).

Example 146 2-Amno-6- {3 - [(3-hydroxyazetidin-1-yl) carbo

dicarbonitrile

 A mixture of 80 mg (0.20 mmol) of compound 47A, 27 mg (0.26 mmol) of 3-hydroxyacetidine hydrochloride, 89 mg (0.24 mmol) of HATU and 0.15 ml (0.88 mmol) of diisopropylethylamine in 1.3 ml of DMF was stirred at RT overnight. The reaction mixture was added with water. The resulting solid was filtered off with suction and dried under high vacuum. Yield: 23 mg (25% of theory).

LC-MS (Method 6): R _t = 0.94 min; MS (EIpos): m / z = 464 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.20 (br, s, 2H), 8.06 (s, 1H), 8.01 (d, 1H), 7.96 (d, 1H) , 7.90 (d, 1H), 7.81 (d, 1H), 7.64 (dd, 1H), 5.78 (d, 1H), 4.59-4.41 (m, 2H), 4.42-4.33 (m, 1H), 4.15-4.04 (m, 1H), 3.98-3.74 (m, 1H).

Example 147

 2-Amino-6- [3 - (morpholin-4-ylcarbonyl) phenyl] -4- [4- (trifluoromethyl) phenyl] pyridine-3, 5-dicarbonitrile

A mixture of 80 mg (0.20 mmol) of compound 47A, 22 mg (0.26 mmol) of morpholine, 89 mg (0.24 mmol) of HATU and 0.12 ml (0.88 mmol) of diisopropylethylamine in 1.3 ml of DMF was stirred at RT overnight. The reaction mixture was mixed with water, the resulting solid was filtered off and dried under high vacuum. Yield: 78 mg (83% of theory). LC-MS (Method 6): R _t = 1.01 min; MS (EIpos): m / z = 478 [M + H] ⁺ .

 'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.22 (br, s, 2H), 8.01 (d, 1H), 7.92-7.91 (m, 3H), 7.85 (s, 7.66-7.60 (m, 1H), 3.70-3.50 (m, 6H).

Example 148

 2-Amino-4- [3-chloro-4- (trifluoromethyl) phenyl] -6- [3 - (trifluoromethoxy) phenyl] pyridine-3, 5-dicarbonitrile

 According to General Method 3, 80 mg (0.20 mmol) of the compound from Example 29A and 62 mg (0.30 mmol) of [3- (trifluoromethoxy) phenyl] boronic acid were reacted. Yield: 35 mg (36% of theory).

LC-MS (Method 6): R _t = 1.29 min; MS (Elneg): m / z = 481 [MH] \

'H-NMR (400 MHz, DMSO-ί / β): δ [ppm] = 8.29 (br, s, 2H), 8.18-8.12 (m, 2H), 7.90-7.84 (m, 2H), 7.80 ( s, 1H), 7.72 (dd, 1H), 7.61 (d, 1H).

B. Evaluation of Pharmacological Activity

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

Abbreviations:

 EDTA ethylenediaminetetraacetic acid

 DMEM Dulbecco's Modified Eagle Medium

 FCS fetal calf serum

 HEPES 4- (2-hydroxyethyl) -1-piperazinethanesulfonic acid

 Pluronic F-127 nonionic surfactant polyol, MW 12,500

 Probenecid 4- (dipropylsulfamoyl) benzoic acid

 SmGM Smooth Muscle Cell Growth Media

 Tris-HCl 2-amino-2- (hydroxymethyl) -1,3-propanediol hydrochloride

 UtSMC Uterine Smooth Muscle Cells

Bl. Cellular assay for IC50 determination on human NCX1 The test is performed using a Chinese hamster ovary cell line (CHO) stably transfected with a pcDNA3 (Invitrogen, # V790-20) human NCX1 expression construct. Activation of NCX1 in this cell line occurs by reducing the extracellular sodium ion (Na ⁺ ) concentration, with the NCX1 then being active in 'reverse mode', the calcium ion (Ca ²⁺ ) in-flow mode. The change in the intracellular Ca ²⁺ concentration is monitored by means of the fluorescent Ca ²⁺ indicator Fluo-4 (Invitrogen, #M 14206).

To perform the assay, cells are seeded to 4000 cells per well of a 384 well plate (clear black 384 MTP, # 781092, greiner bio-one) in 30 μM medium (DMEM (# 31885-023, Life Technologies-Invitrogen) / 10% ( v / v) FBS (# 10270-106, GIBCO) seeded 48 hours prior to testing and incubated at 37 ° C and 5% carbon dioxide After 48 hours of incubation, the supernatant is discarded and cells are washed with 35 μM CAFTY Buffer (130 mM sodium chloride, 5 mM potassium chloride, 20 mM HEPES, 1 mM gastric acid chloride, 5 mM sodium hydrogenphosphate, pH 7.4) to subsequently be loaded with Fluo-4 in a CAFTY buffer of the following composition: The loading buffer contains 1 mM Brilliant Black (# 152633, MP Biomedicals), 2.5mM Probenecid (# P8761, SIGMA), 9mM calcium chloride, and 2.2μΜ Fluo-4 AM The Fluo-4 AM is prepared from a 500μΜ DMSO stock solution containing 10% Pluronic F-127 (v After 1 hour of loading, the compounds according to the invention are added n in loading buffer and incubated for 15 minutes at 37 ° C and 5%> carbon dioxide. Subsequently, the measurement is carried out, wherein the NCX1, reverse mode ', resulting in Ca ²⁺ influx, by adding an equal volume of Na ⁺ - reduced buffer (260 mM sucrose, 5 mM potassium chloride, 20 mM HEPES, 1 mM magnesium chloride , 5 mM sodium hydrogenphosphate, pH 7.4). The final concentration of Na ⁺ over the cells is then 65 mM. Measurement of the intracellular Ca ²⁺ concentration takes place in a measuring device by means of excitation at 475 nM and measurement of the emission at 545 nM, the increase in fluorescence based on the NCXI-mediated Ca ²⁺ influx is inhibited by NCX1 inhibitors in proportion to the potency. The determination of the increase of the intracellular Ca ²⁺ concentration is based on the slope of the Ca ²⁺ kinetics between second 1 and 17 after addition of the Na ⁺ -free buffer.

Representative IC50 values *) of the compounds according to the invention are given in Table 5:

Table 5:

 Example IC50 [nmol / 1] Example IC50 [nmol / 1] Example IC50 [nmol 1]

 1 610 51 435 101 197

 2 431 52 270 102 260

 3 560 53 495 103 37

 4 285 54 175 104 39.8

 5 460 55 250 105 22.6

 6,388,556,106,537

7 560 57 165 107 165 Example ICso [nmol / 1] Example ICso [nmol1] Example ICso [nmol / 1]

8 223 58 260 108 220

9 89.5 59 65 109 752

10 153 60 455 110 420

11 37.5 61 425 111 16.7

12 99.5 62 458 112 14.1

13 27.2 63 710 113 185

14 115 64 880 114 596

15 800 65 550 115 593

16 125 66 405 116 205

17 202 67 185 117 35

18 420 68 120 118 220

19 93 69 175 119 47.5

20 215 70 345 120 77.4

21 410 71 300 121 88.2

22 400 72 185 122 12.8

23 430 73 770 123 1080

24 99 74 67 124 197

25 815 75 173 125 325

26 595 76 343 126 104

27 148 77 126 127 250

28 418 78 210 128 238

29 330 79 110 129 417

30 336 80 186 130 412

31 206 81 195 131 334

32 243 82 235 132 55.3

33 420 83 508 133 67.5

34 335 84 145 134 91.6

35 305 85 355 135 120

36 430 86 135 136 114

37 135 87 950 137 78.8

38 152 88 980 138 235

39 115 89 62.5 139 180

40 48.7 90 110 140 364

41 123 91 49.5 141 341

42 175 92 415 142 975

43 215 93 212 143 720

44 245 94 116 144 381

45 330 95 58.4 145 28.8 Example ICso [nmol / 1] Example ICso [nmol / 1] Example ICso [nmol / 1]

 46 185 96 170 146 690

 47 500 97 1 10 147 625

 48 650 98 22.4 148 1030

 49 455 99 48.5

 50 250 100 203

 ) The IC50 values given in the table are average values of several measurements.

B-2. Determination of adenosine A1 receptor modulation by NCX1 inhibitors via gene expression

For the determination of antagonistic or agonistic activity of the NCX1 inhibitors on the adenosine receptor subtype AI, CHO (Chinese Hamster Ovary) Kl cells are incubated with a Ca ²⁺ -sensitive reporter construct (NFAT-TA-Luc, Clontech) and an Al Gal6 fusion construct stably transfected. This receptor chimera is coupled to phospholipase C in contrast to the native AI receptor (Gai coupling). The reporter gene luciferase is thus expressed as a function of the cytosolic Ca ²⁺ concentration.

The permanent cell lines are cultured in DMEM F12 (Cat. No BE04-687Q; BioWhittaker) with 10% FCS (Fetal Calf Serum) and various additives (20 ml liter of IM HEPES (Cat. No 15630; Gibco), 20 ml / liter GlutaMAX (Cat. No. 35050-038, Gibco), 14 ml of liter of MEM sodium pyruvate (Cat. No. 11360-039; Gibco), 10 ml of PenStrep (Cat. No 15070-063, Gibco) at 37 ° C below 5 % Carbon dioxide cultured and split twice a week.

For testing in 384- or 96-well plate format, the cells are seeded at 2000 or 5000 cells / well in 25 or 50 μΙ / well seed medium and cultured until the substance is tested at 37 ° C under 5% carbon dioxide. The Al-Gal6 cells are seeded 48 hours before substance testing in OptiMEM with 2.5% charcoal-purified FCS and additives. The substances are added to a final concentration of 1 x 10 ^"5 M to 1 x ^{10" 9} M to the test cultures, the DMSO content does not exceed 0.5% on the cells o. For the study of antagonistic activity at the Al receptor of Al-Gal6 cells, 25 nM CPA (N6-cyclopentyl-adenosine) is used as agonist, while the study for possible agonistic activity is performed separately without the addition of CPA. After the substance has been added, the cell plates are incubated for 3-4 h at 37 ° C. under 5% carbon dioxide. The cells are then immediately before the measurement with 25 μΐ a solution consisting of 50% o from lysis reagent (30 mM disodium hydrogen phosphate, 10% glycerol, 3%> Triton X-100, 25 mM TrisHCl, 2 mM dithiothreitol (DTT) , pH 7.8) and 50% of luciferase substrate solution (2.5 mM ATP, 0.5 mM luciferin, 0.1 mM coenzyme A, 10 mM tricine, 1.35 mM magnesium sulfate, 15 mM DTT, pH 7.8). The luciferase activity is detected with a luminescence reader. In the case of the antagonistic study, the IC50 values, ie the concentration at which the luciferase response, caused by the added agonist CPA, is inhibited to 50% o. The reference antagonist used for the Al-Gal6 cells is DPCPX (1,3-dipropyl-8-cyclopentylxanthine). In the event of In the agonistic study the EC50 values are calculated. The calculation of the IC50 / EC50 values is carried out with the help of the computer program GraphPad PRISM (Version 3.02).

B-3. Effect of NCX1 inhibitors on the function of the isolated and perfused rat heart according to Langendorff ex-vivo

Male Wistar rats (strain: HsdCpb: WU, Harlan- Winkelmann) weighing 200-250 g are anesthetized with Narcoren (100 mg / kg). After opening the thorax, the heart is dissected free, excised and connected by cannulation of the aorta to a Langendorff apparatus. The heart is retrograded with a Krebs-Henseleit buffer solution (gassed with 95% oxygen and 5% carbon dioxide, pH 7.4, 35 ° C) with the following composition in mmol / l: sodium chloride 118; Potassium chloride 3; Sodium bicarbonate 22; Potassium dihydrogen phosphate 1.2; Magnesium sulfate 1.2; Calcium chloride 1.8; Glucose 10; Sodium pyruvate 2, perfused with constant flow rate of 9 ml / min. To record the frequency and contraction force of the heart, a balloon made of thin plastic film attached to a PE tube and filled with water is inserted into the left ventricle through an opening in the left atrial appendage. The balloon is connected to a pressure absorber. The end-diastolic pressure is adjusted to 5-10 mmHg over the balloon volume. The data is amplified by a bridge amplifier and registered by a computer.

B-4. Effect of NCX1 inhibitors on Quabain-induced ventricular arrhythmias in isolated guinea-pig strip of the guinea pig ex vivo

 Male guinea pigs (HsdPoc: DH, Harlan-Winkelmann, 200-250 g) are anesthetized with 5% isoflurane (500 ml / min compressed air, 300 ml / min oxygen) and killed by thoracotomy and heart removal. The heart is warmed to 37 ° C and fumigated (95% oxygen and 5%> carbon dioxide, pH 7.4) Tyrode solution with the following composition in mmol / 1: sodium chloride 137; Potassium chloride 5.4; Sodium hydrogen phosphate 22.6; Sodium dihydrogen phosphate 0.42; Magnesium chloride 1.05; Calcium chloride 1.8; Glucose 5.5; Ascorbic acid 0.28 transferred. The trabeculae preparations (1mm x 1mm) isolated from the right ventricle are incubated for 80 min at a bias voltage of 5 mN (pacing frequency 1 Hz / 60 bpm, pulse width 5 ms, 1.5-fold the threshold) and, if necessary, re-tensioned. Ventricular arrhythmias can be induced by a single dose of 1.3 μΜ ouabain octahydrate (Sigma). The resulting arrhythmias develop qualitatively within three hours from the sinus rhythm (stage 1), via extrasystoles (stage 2), to tachycardia (stage 3), ventricular flutter (stage 4-6) to ventricular fibrillation (stage 7 and 8) and are recorded and evaluated using the Powerlab system (AD Instruments, ADI-PWLB-4SP) and Chart7 software (SN 425-0586). The test substance or the solvent (50 μM DMSO) is added 30 min before administration of ouabain.

B-fifth Effect of NCX1 inhibitors on aconitine-induced ventricular arrhythmias in the rat in vivo

Male Wistar rats (HsdCpb: WU, Harlan-Winkelmann, 250-300 g) are anesthetized with 5% isoflurane (500 ml / min compressed air, 300 ml / min oxygen). The anesthetized rats are examined during the instruc- spontaneously breathing and maintaining a 2% isoflurane maintenance dose on a thermal mat at a constant body temperature of 37-38 ° C. For the application of the test substances and the aconitine intravenous accesses are placed in the tail vein and the jugular vein. The pressure catheter (Miliar SPR-320 2F) is inserted through the carotid artery and positioned in the left ventricle, and the occurrence of ventricular arrhythmias by ECG measurement using the Powerlab system (AD Instruments, ADI-PWLB-4SP) and Chart7 Software (SN 425-0586) recorded and evaluated. Ventricular arrhythmias are induced by iv administration of aconitine (30-40 μg / kg body weight). Only rats with manifest ventricular arrhythmias for at least 10 min were given a single intravenous administration of the test substance or solvent (60 g glycerol, 100 g water, 969 g PEG-400) via the tail vein. The effect of the test substances / of the solvent on the aconitine-induced ventricular arrhythmias is measured and evaluated over a period of 30 min. At the end of the experiment a blood sample is taken for the determination of the plasma concentration of the test substance with subsequent killing of the animals by potassium chloride administration (1 ml saturated solution, iv).

B-sixth Effect of NCX1 inhibitors on cardiac function in rats with ischemia-reperfusion damage due to acute myocardial infarction (aMI)

Male Wistar rats (Harlan-Winkelmann, 280-300 g) are anesthetized with Ketavet (100 mg / ml ketamine hydrochloride solution; Pfizer) / Rompun (2% xylazine hydrochloride solution; Bayer) in a ratio of 4: 1 to 1.25 ml / kg body weight, intubated, connected to a respiratory pump (Hugo basile 7025 rodent, 50 strokes per minute, 7 ml) and ventilated with a compressed air / oxygen mixture (1: 2). The body temperature is maintained at 37-38 ° C by a heat mat. The thorax is opened laterally between the third and fourth ribs and the heart is exposed. The coronary artery of the left ventricle (LAD) is punctured with a occlusion thread (PROLENE 1 metric 5-0 ETHICON1H) just below its origin (below the left atrium) and set for 30 min. The occurrence of myocardial infarction is monitored by ECG measurement (Cardioline, Remco (Italy)). After 30 minutes, the vessel is reopened. The thorax is closed again and the muscle layers are sutured with ETHIBOND excel 1 metric 5/0 6951H and the epidermis with ETHIBOND excel 3/0 6558H. As anesthetic antidotes, the rats receive 1.83 mg of antise- dan in 0.4 ml / kg body weight. 24 h after reperfusion, the animals are anaesthetized again (2% isofluoran / nitrous oxide / air) and a pressure catheter (Miliar SPR-320 2F) is introduced via the carotid artery into the left ventricle. There are heart rate, left ventricular pressure (LVP), left ventricular end-diastolic pressure (LVEDP), contractility (dp / dt) and relaxation rate (tau) and the electrocardiogram of animals using the Powerlab system (AD Instruments, ADI-PWLB-4SP) and Chart7 software (SN 425-0586). Subsequently, a blood sample is taken for the determination of the substance plasma levels and plasma biochemical markers via the abdominal aorta. The heart is cannulated by inserting a cannula into the aorta and removed. The heart is then rinsed retrograde with heparin and physiological saline. The thread around the LAD is tightened again and the heart is perfused retrograde for 10 min with 0.1% Evans Blue solution and thereby stained. After that, the heart is in 2 mm sliced wide and stained in 1% TTC (triphenyl tetrazolium chloride, Sigma) at 37 ° C for 20 min. The infarct size is evaluated by computer-aided planimetry of the non-ischemic, blood-perfused areas (blue), the ischemic areas (red) and the dead areas (white). The infarct size (white areas) is given as% of the so-called "area of risk" (red and white areas).

As a control, a "sham" group, in which only the surgical procedure, but not the LAD occlusion is performed, carried along.

The single oral application of the test substance or the solvent (60 g glycerol, 100 g water, 969 g PEG-400) takes place four hours before LAD occlusion.

B. 7 Effect of NCX1 inhibitors on cardiac function in rats with chronic myocardial infarction (cMD

Male Wistar rats (HsdCpb: WU, Harlan-Winkelmann, 280-300g) are anesthetized with 5% enflurane in the anesthesia cage, intubated, connected to a respiratory pump (Hugo basile 7025 rodent, 50 strokes per minute, 7 ml) and 3.5-4 % Enflurane / N20 / 02 ventilated. The body temperature is maintained at 37-38 ° C by a heat mat. The analgesic is 0.05 mg / kg sc Temgesic. The thorax is opened laterally between the third and fourth ribs and the heart is exposed. The coronary artery of the left ventricle (LAD) is punctured with a occlusion thread (PROLENE 1 metric 5-0 ETHICON1H) just below its origin (below the left atrium) and permanently ligated. The occurrence of a myocardial infarction is monitored by an electrocardiographic measurement (Cardioline, Remco (Italy)). The thorax is closed again and the muscle layers are sutured with ETHIBOND excel 1 metric 5/0 6951H and the epidermis with ETHIBOND excel 3/0 6558H. The operation seam is wetted with spray plaster (eg Nebacetin ^® N spray dressing, active ingredient: neomycin sulfate), and then discharged anesthesia.

As a control, a "sham" group, in which only the surgical procedure, but not the LAD occlusion is performed, carried along.

The therapy begins one week after surgery. The substance treatment takes place over 8 weeks by gavage once a day. The animals are weighed weekly and the water or feed consumption is determined every 14 days.

After 8 weeks of treatment, the animals are anaesthetized again (2% isoflurane / nitrous oxide / air) and a pressure catheter (Miliar SPR-320 2F) introduced via the carotid artery in the left ventricle. There are heart rate, left ventricular pressure (LVP), left ventricular enddiastolic pressure (LVEDP), contractility (dp / dt) and relaxation rate (tau) and the electrocardiogram of the animals using the Powerlab system (AD Instruments, ADI-PWLB-4SP) and the Chart7 software (SN 425-0586) recorded and evaluated. Subsequently, a blood sample is taken to determine the plasma levels of the substance and plasma biolabels. killed and the animals. Heart (ventricles, left ventricle plus septum, right ventricle), liver, lung and kidney are removed and weighed.

C. Embodiments of Pharmaceutical Compositions

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

Tablet:

 Composition:

 100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

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

production:

 The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

 Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water.

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

 The rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.

Orally administrable solution:

 Composition:

 500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound according to the invention correspond to 20 g of oral solution.

production:

The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention. iv solution:

 The compound of the invention is dissolved at a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, 5% glucose solution, and / or 30% PEG 400 solution). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

Claims

Patent claims (I),

in which R ¹ represents phenyl or 5- or 6-membered heteroaryl, where phenyl and 5- or 6-membered heteroaryl with 1 to 4 substituents are independently selected from the group of halogen, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -R ⁴ , -OR ⁴ , -(C=0)- OR ⁶ , -C(=0)-NR ⁴ R ⁵ , -NR ⁴ -(C=0) _n -R ⁵ , -NR ⁴ -S0 ₂ - R ⁵ , -S0 ₂ NR ⁴ R ⁵ and -S( 0) _p -R ⁴ can be substituted, wherein n means the number 0 or 1, p means the number 0, 1 or 2, R ⁴ and R ⁵ each independently represent hydrogen, (Ci-C6)-alkyl or (C3-Cs)-cycloalkyl, wherein (Ci-C6)-alkyl in turn has 1 to 3 substituents independently selected from the group of fluorine, cyano, trifluoromethyl, (C3-C8)-cycloalkyl, hydroxy, (Ci-C6)-alkoxy, trifluoromethoxy, (Ci-C i)-Alkoxycarbonyl, amino, mono-(Ci-C4)-alkylamino, di-(Ci-C4)-alkylamino, 4- to 8-membered heterocyclyl-membered heteroaryl and a group of the formula

can be substituted, wherein the 4- to 8-membered heterocycle can in turn be substituted with 1 or 2 substituents independently selected from the group trifluoromethyl, (Ci-C6)-alkyl, hydroxy, oxo and (Ci-C6)-alkoxy, and wherein C# ^l represents a carbon atom of (Ci-C6)-alkyl, Q represents a 3- to 6-membered carbocycle or a 4- to 7-membered heterocycle, Ld R ⁵ together with the atom(s) to which they are bonded form a 4- to 8-membered heterocycle, wherein the 4- to 8-membered heterocycle in turn has 1 or 2 substituents independently selected from the group cyano, trifluoromethyl, (Ci-Ce)-alkyl, hydroxy, oxo, (Ci-C6)-alkoxy, trifluoromethoxy, (Ci- C4)-alkoxy-carbonyl, amino, mono-(Ci-C4)-alkylamino and di-(Ci-C4)-alkylamino can be substituted, R ⁶ represents (Ci-C ₆ )-alkyl or (C ₃ -C ₈ )-cycloalkyl, or where two substituents bonded to adjacent carbon atoms of a phenyl ring together form a group of the formula -0-(CH2) _q -0-, -O-CHF-O-, -O-CF2-O- or -O-CF2-CF2-O- form, wherein q stands for a number 1, 2 or 3, R ² represents halogen, cyano, methyl or hydroxymethyl, R ³ represents phenyl, where phenyl can be substituted with 1 or 2 substituents independently selected from the group of halogen, cyano, difluoromethyl, trifluoromethyl, (Ci-C4)-alkyl, trifluoromethoxy, (C1-C4)-alkoxy and pentafluorosulfanyl, as well as their N-oxides, salts, solvates and solvates of N-oxides and salts. A compound of formula (I) according to claim 1, in which R ¹ represents phenyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl or pyridyl, where phenyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl or pyridyl with 1 to 3 substituents are independently selected from the group of fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -R ⁴ , -OR ⁴ , - (C=0)-OR ⁶ , -C(=0)- NR ⁴ R ⁵ , -NR ⁴ -(C=0)“-R ⁵ , -NR ⁴ -S0 ₂ -R ⁵ , -S0 ₂ NR ⁴ R ⁵ and -S(0) _p -R ⁴ may be substituted, wherein n means the number 0 or 1, p means the number 2, R ⁴ and R ⁵ each independently represent hydrogen, (Ci-C6)-alkyl or (C3-Cs)-cycloalkyl, wherein (Ci-C6)-alkyl in turn has 1 to 3 substituents independently selected from the group of fluorine, cyano, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxy, (Ci-C4)-alkoxy, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, Ethylamino, dimethylamino, N-methyl-N-ethylamino, diethylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and pyridyl and a group of the formula

can be substituted, wherein azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl can in turn be substituted with 1 substituent selected from the group methyl, ethyl, hydroxy, oxo and methoxy, and wherein C# ^l represents a carbon atom of (Ci-C6)-alkyl, Q represents a cyclopropyl, cyclobutyl or cyclopentyl ring, or R ⁴ and R ⁵ together with the atom(s) to which they are bonded form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl ring, wherein the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and Piperazinyl ring in turn with 1 or 2 substituents can be independently selected from the group trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy and ethoxy, R ⁶ represents methyl or ethyl, or where two substituents bonded to adjacent carbon atoms of a phenyl ring together form a group of the formula -0-(CH ₂ ) _q -0-, -0-CHF-O-, -O-CF2-O-, or -O-CF2-CF2- O- form, wherein q for a number 1, 2 or 3 stands, R ² represents chlorine, cyano, methyl or hydroxymethyl, ^R3

* * * stands, whereby * stands for the attachment point to the 2-amino-3-cyanopyridine and where R ⁷ represents chlorine, cyano, trifluoromethyl, (Ci-C4)-alkyl or trifluoromethoxy, R ⁸ represents hydrogen, fluorine, chlorine or trifluoromethyl, R ⁹ stands for chlorine, R ¹⁰ stands for hydrogen or chlorine, R ¹¹ represents chlorine, cyano, trifluoromethyl, (G-C4)-alkyl or trifluoromethoxy, R ¹² represents chlorine or methyl, as well as their salts, solvates and solvates of salts. 3. A compound of formula (I) according to claim 1 or 2, in which R r formula

stands, whereby # ² stands for the connection point to which 2-amino-3-cyanopyridine stands, represents hydrogen or (GC ₆ )-alkyl, in which (Ci-C6)-alkyl can be substituted with 1 or 2 substituents independently selected from the group of cyano, trifluoromethyl, hydroxy, (Ci-C4)-alkoxy, trifluoromethoxy and a group of the formula c # ¹ , wherein C# ^l represents a carbon atom of (Ci-C6)-alkyl, R ² stands for cyano, R ³ represents a group of the formula

stands, whereby * stands for the connection point to the 2-amino-3-cyanopyridine and where R ⁷ stands for trifluoromethyl, R ⁸ represents hydrogen, fluorine or chlorine, their salts, solvates and solvates of salts. 4. A compound of formula (I) according to claim 1 or 2, in which R ¹ formula

stands, whereby # ² stands for the connection point to which 2-amino-3-cyanopyridine stands, R ¹³ represents fluorine, methyl, hydroxymethyl, methoxy, ethoxy, isopropoxy, dimethylamino, diethylamino, dimethylaminocarbonyl, diethylaminocarbonyl, moφholin-4-yl, morpholin-4-ylmethyl or methylsulfonyl, R ¹⁴ represents hydrogen, fluorine or methoxy, R ¹⁵ represents hydrogen, fluorine or methoxy, R ² stands for cyano, R ³ of the formula

* stands, whereby * stands for the attachment point to the 2-amino-3-cyanopyridine and where R ⁷ stands for trifluoromethyl, R ⁸ represents hydrogen, fluorine or chlorine, as well as their salts, solvates and solvates of salts. 5. A compound of formula (I) according to claim 1 or 2, in which R ¹ represents pyridyl, where pyridyl can be substituted with 1 to 3 substituents independently selected from the group of fluorine, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -R ⁴ and -OR ⁴ , wherein R ⁴ represents hydrogen or (Ci-C ₄ )-alkyl, in which (Ci-C i)-alkyl can in turn be substituted with 1 to 3 substituents independently selected from the group cyano, trifluoromethyl, hydroxy, methoxy, ethoxy and trifluoromethoxy, R ² stands for cyano, R ³ of the formula

stands, whereby * stands for the attachment point to the 2-amino-3-cyanopyridine and where R ⁷ stands for trifluoromethyl, R ⁸ represents hydrogen, fluorine or chlorine, as well as their salts, solvates and solvates of salts. I. Process for the preparation of compounds of formula (I), as defined in claims 1 to 5, characterized in that [A] a compound of formula (II)

in which R ² and R ³ each have the meanings given in claims 1 to 5, in a suitable solvent with a compound of the formula (III-A) or (III-B) OT ¹ YES ^■ B or R ^1B — H x1 O—T (III-A) (III-B) in which R 1A represents phenyl or C-bonded 5- or 6-membered heteroaryl, where phenyl and C-bonded 5- or 6-membered heteroaryl in the above scope of meaning can be substituted, R 1B represents pyrazol-l-yl, pyrrol-l-yl, imidazol-l-yl or triazol-l-yl, where pyrazol-l-yl, pyrrol-l-yl, imidazol-l-yl and triazol-l-yl can be substituted in the scope of meaning given above, and T ¹ represents hydrogen or (Ci-C4)-alkyl or the two residues T ¹ together form a -C(CH3)2-C(CH3)2 bridge,

(I-A) (I-B) in which R ^1A , R ^1B , R ² and R ³ each have the meanings given above, implemented, or

in which R ² and R ³ each have the meanings given in claims 1 to 5, in an inert solvent with a compound of the formula (III-B) to give a compound of the formula (IB) implemented, or [C] a compound of formula (IV) in an inert solvent with hydrazine hydrate to a compound of formula (V)

in which R ² and R ³ each have the meanings given in claims 1 to 5, and these are then converted into an inert solvent in the presence of a suitable acid with a compound of the formula (VI)

in which R ¹⁶ for cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -R ⁴ , -OR ⁴ , - (C=0)-OR ⁶ , -C(=0)-NR ⁴ R ⁵ , -NR ⁴ -(C= 0) _n -R ⁵ , -NR ⁴ -S0 ₂ -R ⁵ , -S0 ₂ NR ⁴ R ⁵ and -S(0) _p -R ⁴ stands, where n means the number 0 or 1, p means the number 0, 1 or 2, R ⁴ and R ⁵ each independently represent hydrogen, (Ci-C6)-alkyl or (C3-Cs)-cycloalkyl, wherein (Ci-C6)-alkyl in turn has 1 to 3 substituents independently selected from the group of fluorine, cyano, trifluoromethyl, (C3-Cg)-cycloalkyl, hydroxy, (Ci-C6)-alkoxy, trifluoromethoxy, (Ci-C4 )-alkoxycarbonyl, amino, mono-(Ci-C4)-alkylamino, di-(Ci-C4)-alkylamino, 4- to 8-membered heterocyclyl-membered heteroaryl and a group of the formula

can be substituted, wherein the 4- to 8-membered heterocycle can in turn be substituted with 1 or 2 substituents independently selected from the group trifluoromethyl, (Ci-C6)-alkyl, hydroxy, oxo and (Ci-C6)-alkoxy, and wherein C# ^l represents a carbon atom of (Ci-C6)-alkyl, Q represents a 3- to 6-membered carbocycle or a 4- to 7-membered heterocycle, or R ⁴ and R ⁵ together with the atom(s) to which they are bonded form a 4- to 8-membered heterocycle, wherein the 4- to 8-membered heterocycle in turn has 1 or 2 substituents independently selected from the group cyano, trifluoromethyl, (Ci-Ce)-alkyl, hydroxy, oxo, (Ci-C6)-alkoxy, trifluoromethoxy, (Ci-C4)-alkoxy-carbonyl, amino, mono-(Ci-C4)-alkylamino and di-(Ci-C4)-alkylamino can be substituted, R ⁶ represents (Ci-C ₆ )-alkyl or (C ₃ -C ₈ )-cycloalkyl, and T ² represents (Ci-C ₄ )-alkyl, (I-C)

(i-c), in which R, R and R each have the meanings given above, or a compound of the formula (VII)

in which R ³ has the meaning given in claims 1 to 5, in an inert solvent in the presence of a suitable base with a compound of formula (VIII)

in which R ^1A has the meaning given above, to a compound of the formula (I-D)

in which R ^1A , R ² and R ³ each have the meanings given above, implemented, or a compound of the formula (VII) in an inert solvent in the presence of ammonium acetate with a compound of the formula (ΓΧ-Α) or (ΓΧ-Β)

(IX-A) (IX-B) in which R ^1A has the meaning given above, R ^2A stands for chlorine, and R ^2B stands for (Ci-C ₄ )-alkyl,

(I-El) (I-E2) in which R ^1A , R ^2A , R ^2B and R ³ each have the meanings given above, reacts, optionally the resulting compounds of the formulas (IA), (IB), (IC), (ID), (I-El) and (I-E2) is separated into its enantiomers and/or diastereomers by methods known to those skilled in the art and/or optionally reacted with the corresponding (i) solvents and/or (ii) bases or acids to form their solvates, salts and/or solvates of the salts . 7. Compound of formula (I), as defined in any one of claims 1 to 5, for the treatment and/or prevention of diseases. A compound of formula (I) as defined in any one of claims 1 to 5 for use in a method for the treatment and/or prevention of myocardial infarction, cardioprotection in coronary artery bypass grafting (CABG), percutaneous transluminal angioplasties (PTAs) and primary percu - tan transluminal coronary angioplasties (PTCAs), acute and chronic heart failure, acute and chronic kidney diseases and acute and chronic inflammatory diseases. Medicament containing a compound of formula (I) as defined in any one of claims 1 to 5, combination with an inert, non-toxic, pharmaceutically suitable excipient. 10. Medicaments containing a compound of formula (I), as defined in one of claims 1 to 5, in combination with one or more other active ingredients selected from the group consisting of compounds influencing the energy metabolism of the heart, diuretics, beta-receptor blockers , organic nitrates and NO donors, blockers of the renin-angiotensin-aldosterone system (renin inhibitors, ACE inhibitors, angiotensin receptor antagonists, aldosterone or mineralocorticoid receptor antagonists), platelet aggregation inhibitors, anticoagulants, vasopressin Receptor antagonists, glucocorticoids, NSAIDs and COX inhibitors. 11. Medicament according to claim 9 or 10 for the treatment and / or prevention of myocardial infarction, cardioprotection in coronary artery bypass operations (CABG), percutaneous transluminal angioplasties (PTAs) and primary percutaneous transluminal coronary angioplasties (PTCAs), acute and chronic heart failure, acute and chronic kidney diseases as well as acute and chronic inflammatory diseases.