WO2010020366A1 - Azabicyclic substituted 5-aminopyrazoles and the use thereof - Google Patents

Abstract

The present application relates to novel 4-azabicyclic substituted 5-aminopyrazoles, to a method for the production thereof, to the use thereof either alone or in combination for treating and/or preventing diseases, and to the use thereof for producing pharmaceuticals for the treatment and/or prevention of diseases.

Description

 - -

Azabicyclo-substituted 5-aminopyrazoles and their use

The present application relates to novel 4-azabicyclic-substituted 5-aminopyrazoles, processes for their preparation, their use alone or in combinations for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or prevention of diseases ,

Adenosine, a purine nucleoside, is present in all cells and is released from a variety of physiological and pathophysiological stimuli. Adenosine is produced by the degradation of adenosine 5'-monophosphate (AMP) and S-adenosyl homocysteine and can be released from the cell via transporters or after cell damage. Extracellular adenosine may also be produced by nuclothidase-catalyzed degradation of adenine nucleotides. Released adenosine then exerts functions as a hormone-like substance or neurotransmitter through binding to specific receptors. However, the concentration of extracellular adenosine varies considerably and is dependent on the organ and extent of stress on the particular tissue. Thus, the extracellular concentration of adenosine increases dramatically under ischemic or hypoxic conditions. Then, adenosine generally has cytoprotective functions, e.g. Increase of the supply of oxygen or reduction of the metabolism of the affected organ.

The action of adenosine is mediated by specific receptors, which are subdivided into the four previously known subtypes, Al, A2a, A2b and A3. These receptors belong to the family of G-protein coupled receptors characterized by seven transmembrane domains. While the Al and A3 receptors are coupled to Gi proteins that inhibit adenylate cyclase, resulting in a decrease in intracellular cAMP content, the A2a and A2b receptors activate adenylate cyclase via Gs proteins, resulting in an increase in intracellular cAMP. Adenosine receptors may also be coupled to other signal transmission systems, e.g. Phospholipase C. Thus, the activation of Al receptors may also lead to the stimulation of potassium channels or the inhibition of calcium channels.

According to the invention, "adenosine receptor-selective ligands" are those substances which bind selectively to one or more subtypes of adenosine receptors and either mimic the action of adenosine (adenosine agonists) or block its action (adenosine antagonists).

The aforementioned receptor selectivity can be determined by the effect of the substances on cell lines which after stable transfection with the corresponding cDNA, the respective - -

Expression of receptor subtypes (Olah ME, Ren H., Ostrowski J., Jacobson KA, and Stiles GL: Cloning, Expression, and Characterization of the Unique Bovine Al adenosine Receptor Studies on the ligand binding site by site-directed mutagenesis., J. Biol Chem. 1992, 267, 10764-10770, the disclosure of which is hereby incorporated by reference in its entirety).

The effect of the substances on such cell lines can be detected by biochemical measurement of the intracellular messenger cAMP (Klotz N., Hessling J., Hegler J., Owman C, KuIl B., Fredhohn BB and Lohse JM: Comparative pharmacology of human adenosine receptor subtypes characterization of stably transfected receptors in CHO cells., Naunyn Schmiedebergs Arch. Pharmacol., 1998, 357, 1-9, the disclosure of which is hereby incorporated by reference in its entirety).

Selective interaction with the adenosine receptor subtypes offers a broad spectrum of therapeutic potential, such as e.g. Regulation of heart rate, contraction force and blood pressure in the cardiovascular system, regulation of renal function and respiratory system, immune system and influence on some functions of the central nervous system and cell growth (Jacobson KA and Gao Z., Adenosine receptors as therapeutic targets., Nature Reviews Drug Discovery 2006 , 5, 247-264).

Adenosine A1 receptors are strongly expressed in the brain (e.g., cortex, hippocampus), but also in peripheral organs and tissues such as the heart, kidney, lung or adipocyte.

In the kidney, adenosine A1 receptors play a key role in controlling the fluid and electrolyte balance. Al receptors are used in the preglomerular microcirculation, in the

Glomerulus, expressed in juxtaglomerular apparatus, as well as in the collecting tube and the Henle loop. Activation of Al receptors in the kidney causes a decrease in glomerular

Filtration rate and renal blood flow. These effects are caused by the vasoconstriction of the afferent arterioles and by the suppression of the tubuloglomerular feedback mechanism (TGF), which is primarily responsible for the autoregulation of glomerular vascular resistance (Welch J.W., Current Opinion in Pharmacology 2002, 2, 165-170).

In various animal studies and clinical studies in humans, it has been shown that the inhibition of Al receptors by selective Al antagonists is uricosuric, natriuretic and potassium-sparing and diuretic. Moreover, the glomerular filtration rate was not affected by adenosine A1 receptor antagonists (Vallon V., Miracle C. and Thomson S., Adenosine and kidney function: potential implications in patients with heart failure., Eur. J. Heart Failure 2008, 10, 176 -187). The kidney-protective effect of Al antagonists by maintaining the glomerular filtration rate as well as the renal - -

Plasma flux has also been demonstrated in various animal models of acute and chronic renal failure (Welch JW, Current Opinion in Pharmacology 2002, 2, 165-170; Nagashima K., Kusaka H. and Karasawa A., Protective effects of KW-3902, on adenosine Al-receptor antagonist, against cisplatin-induced acute renal failure in rats, Jpn. J. Pharmacol., 1995, 67, 349-357, Kalk P., Eggert B., Relle K., Godes M., Heiden S., Sharkovska Y., Fischer Y., Ziegler D., Bielenberg GW and Hocher B .: The adenosine Al receptor antagonist SLV 320 reduces myocardial fibrosis in rats with 5/6 nephrectomy without affecting blood pressure., Brit. J. Pharmacol. 1025-1032).

The decrease in renal function is frequently observed in patients with heart failure. Treatment is with loop diuretics such as furosemide, however, which results in a decrease in the glomerular filtration rate, thereby resulting in undesirable complication of the condition of patients with heart failure. In addition, diuretic resistance is another indicator of a poor prognosis for heart failure patients.

Selective Al antagonists are thus suitable, inter alia, for the treatment of acutely decompensated heart failure and chronic heart failure. Furthermore, they may be used for kidney protection in nephropathy and other kidney diseases such as e.g. acute and chronic renal failure and chronic renal insufficiency.

WO 2004/050651, WO 2005/086656, WO 2005/112923 and WO 2007/027842 disclose variously substituted 5-aminopyrazoles for the treatment of diabetes. WO 93/19054 describes arylaminopyrazoles as fungicides. JP 07-285962 claims pyridyloxypyrazoles as herbicides. WO 2008/008286 discloses substituted pyrazoles as Grehlin receptor antagonists for the treatment of obesity.

The object of the present invention is to provide novel compounds which act as potent and selective antagonists of the adenosine A1 receptor and are suitable as such for the treatment and / or prophylaxis of diseases.

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

in which - -

Q is phenyl or pyridyl,

R ^{1 is} hydrogen, cyano, (C _r C ₃ ) -alkyl, trifluoromethyl, (C ₁ -C ₃ ) -alkoxy or trifluoromethoxy,

R ^{2 is} phenyl, naphthyl or 5- or 6-membered heteroaryl,

wherein phenyl, naphthyl and 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group halogen, cyano, _(Ci-C4) -alkyl, monofluoromethyl, difluoromethyl, trifluoromethyl, (C] _-C4) - Alkoxy, monofluoromethoxy, difluoromethoxy and trifluoromethoxy can be substituted,

R ^{3 is} hydroxycarbonyl, aminocarbonyl, cyanoaminocarbonyl, (C 1 -C ₄ ) -alkylsulfonylaminocarbonyl, oxadiazolonyl or tetrazol-5-yl,

where oxadiazolonyl may be substituted by a methyl substituent,

R ^{4 is} hydrogen, halogen, (C 1 -C ₄ ) -alkyl, monofluoromethyl, difluoromethyl, trifluoromethyl, (C 1 -C ₄ ) -alkoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy,

R ^{5 represents} hydrogen, halogen, (C 1 -C ₄ ) -alkyl, monofluoromethyl, difluoromethyl, trifluoromethyl, (C 1 -C ₄ ) -alkoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy,

R ^{6 is} a group of the formula

stands, where

* means the point of attachment to the pyrazole,

the ring U is phenyl, pyridyl, pyrimidinyl or pyrazinyl,

in which phenyl, pyridyl, pyrimidinyl and pyrazinyl having 1 to 3 substituents independently of one another selected from the group halogen, - -

Trifluoromethyl, (C _{r C4)} alkyl, hydroxy, (C, -C ₄₎ -alkoxy and trifluoromethoxy,

wherein (Ci-C ₄₎ -alkyl and (C ₁ -G _t) -alkoxy in turn with 1 or 2 Substiruenten independently selected from the group consisting of hydroxy and (C _r C ₄₎ -alkoxy,

ring V _{2 is} a 5- to 7-membered heterocycle fused to ring U and containing at least one nitrogen atom,

in which the heterocycle may be substituted by 1 to 5 substituents selected from the group consisting of halogen, oxo, thiooxo, (C 1 -C ₄ ) -alkyl, (C 1 -C ₄ ) -alkoxy and (C 1 -C ₄ ) -alkylthio,

and their salts, solvates and solvates of the salts.

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

Depending on their structure, the compounds of the formula (I) according to the invention can be used both in pure form and as mixtures of various possible isomeric forms, in particular of stereoisomers, such as E and Z, threo and erythro, as well as optical isomers, such as R and S isomers or atropisomers, but optionally also of tautomers. Both the E and the Z isomers, as well as the threo and erythro, and the optical isomers, any mixtures of these isomers, as well as the possible tautomeric forms claimed.

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

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 acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, trisethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

In the context of the invention, solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.

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

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

In the context of the invention, alkyl is a linear or branched alkyl radical having 1 to 4 or 1 to 3 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 4 or 1 to 3 carbon atoms. Examples which may be mentioned by way of example include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

Alkylthio in the context of the invention is a thio group having a linear or branched alkyl substituent which has 1 to 4 carbon atoms. Exemplary and preferred The following may be mentioned: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio and tert-butylthio.

Heterocycle is in the context of the invention for a fused to the ring U monocyclic, saturated or partially unsaturated heterocycle having a total of 5 to 7 ring atoms containing 1 to 3 ring nitrogen atoms and may contain another heteroatom from the series O or S. Examples include: pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,

Thiazolidinyl, isooxazolidinyl, isothiazolidinyl, tetrahydropyridinyl, piperidinyl,

Tetrahydropyridazinyl, piperazinyl, tetrahydropyrimidinyl, hexahydropyrimidinyl,

Tetrahydrotriazinyl, triazinanyl, oxazinanyl, monochlorinyl, thiomorpholinyl, thiadiazinanyl, diazepanyl, dihydrodiazepinyl and tetrahydrodiazepinyl. Preference is given to imidazolidinyl,

Tetrahydropyridazinyl, tetrahydropyrimidinyl, hexahydropyrimidinyl and tetrahydrotriazinyl.

Heteroaryl is in the context of the invention for a monocyclic aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms containing 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.

Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to fluorine or chlorine.

An oxo group in the context of the invention is an oxygen atom which is bonded via a double bond to a carbon atom.

A thiooxo group in the context of the invention represents a sulfur atom which is bonded via a double bond to a carbon atom.

In the formulas of the group for which R ² , R ⁶ or Q may stand, the end point of the line on which a symbol ##, * or # stands does not stand for a carbon atom or a CH ₂ group, but instead is part of the bond to the respectively designated atom to which R ² , R ⁶ or the amino group is bonded.

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 - - is. Substitution with one, two or three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.

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

Q is phenyl,

R ^{1 is} hydrogen, cyano, methyl, ethyl or trifluoromethyl,

R ^{2 is} phenyl,

where phenyl having 1 or 2 substituents independently of one another may be substituted from the group fluorine, chlorine, (C 1 -C ₄ ) -alkyl, trifluoromethyl, (C 1 -C ₄ ) -alkoxy and trifluoromethoxy,

R ^{3 is} hydroxycarbonyl or methylsulfonylaminocarbonyl,

R ^{4 is} hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy,

R ^{5 represents} hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy,

R ^{6 is} a group of the formula

or

- - stands, where

* means the point of attachment to the pyrazole,

K ^{1 is} CR ³³ or N, wherein R ^{33 is} hydrogen, fluorine, chlorine or methyl,

K ^{2 is} CR ³⁴ or N, in which

R ^{34 is} hydrogen, fluorine, chlorine or methyl, K ^{3 is} CR ^35A R ^35B , NR ³⁶ or O, wherein

R ^{35A is} hydrogen, fluorine or methyl,

R ^{35B is} hydrogen, fluorine or methyl, or

R ^35A and R ^35B together form an oxo or thiooxo group, R ^{36 is} hydrogen or methyl,

K ^{4 is} CR ^37A R ^37B or NR ³⁸ wherein

R ^{37A is} hydrogen, fluorine or methyl,

R ^{37B is} hydrogen, fluorine or methyl, or

R ^37A and R ^37B together form an oxo or thiooxo group,

R ^{38 is} hydrogen or methyl, K ^{5 is} CR ³⁹ or N, - - in which

R ^{39 is} hydrogen, fluorine, chlorine or methyl,

R ^{30 is} hydrogen, fluorine, chlorine or methyl,

R ³ 'is hydrogen or methyl,

R ^{32A is} hydrogen, fluorine or methyl,

R ^{32B is} hydrogen, fluorine or methyl,

or

R ^32A and R ^32B together form an oxo or thiooxo group,

and their salts, solvates and solvates of the salts.

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

Q for a group of the formula

stands, where

# means the point of attachment to the amino group,

R ^{3 is} hydroxycarbonyl,

R ^{4 is} hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy,

R ^{5 is} hydrogen or fluorine,

R ^{1 is} methyl,

R ^{2 is} phenyl, wherein phenyl may be substituted with 1 or 2 substituents independently of one another selected from the group fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy,

for a group of the formula

stands, where

the point of attachment to the pyrazole means

K ^{1 is} CR ³³ or N,

embedded image in which

R ^{33 is} hydrogen, fluorine, chlorine or methyl,

K ^{2 is} CR ³⁴ or N,

embedded image in which

R ^{34 is} hydrogen, fluorine, chlorine or methyl,

K ^{5 is} CR ^39A or N,

embedded image in which - -

R ^39A represents hydrogen, (C _{r C4)} alkyl or (C, -C ₄₎ alkoxy;

R ^{30 is} hydrogen, fluorine, chlorine or methyl,

R ³¹ is hydrogen or (C _r C ₄₎ alkyl,

R ³⁶ is hydrogen or (C _r C ₄₎ alkyl,

R ³⁸ is hydrogen or (C _r C ₄₎ alkyl,

R ³⁹ is hydrogen, (C _{r C4)} alkyl or (C _r C ₄₎ alkoxy,

and their salts, solvates and solvates of the salts.

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

Q for a group of the formula

stands, where

# means the point of attachment to the amino group,

R ^{3 is} hydroxycarbonyl,

R ^{4 is} hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl,

Methoxy, difluoromethoxy or trifluoromethoxy,

R ^{5 is} hydrogen or fluorine,

R ^{1 is} hydrogen or methyl,

R ^{2 is} phenyl,

wherein phenyl having 1 or 2 substituents independently selected from

Group fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy may be substituted, - -

R is a group of the formula

stands, where

* means the point of attachment to the pyrazole,

K ^{1 is} CR ³³ or N,

embedded image in which

R ^{33 is} hydrogen,

K ^{5 is} CR ³⁹ or N,

embedded image in which

R ^{39 is} hydrogen,

and their salts, solvates and solvates of the salts.

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

Q for a group of the formula

stands, where

# means the point of attachment to the amino group,

R ^{3 is} hydroxycarbonyl, - -

R ^{4 is} hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy,

R ^{5 is} hydrogen or fluorine,

R ^{1 is} methyl,

R ^{2 is} a group of the formula

stands, where

## is the point of attachment to the pyrazole,

R ^{40 represents} hydrogen, fluorine, chlorine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy,

R ^{6 is} a group of the formula

stands, where

the point of attachment to the pyrazole means - -

R ^{33 is} hydrogen, fluorine, chlorine or methyl,

K ^{5 is} CR ^39A or N,

wherein

R ^{39A is} hydrogen or methyl,

R ^{38 is} hydrogen or methyl,

and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which R ^{3 is} hydroxycarbonyl are also preferred.

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

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

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

R ^{2 is} a group of the formula

stands, where

## is the point of attachment to the pyrazole,

R ^{40 is} hydrogen, fluorine, chlorine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy.

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

R ^{2 is} phenyl, wherein phenyl may be substituted with 1 or 2 substituents independently selected from the group fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy.

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

R ^{6 is} a group of the formula

stands, where

the point of attachment to the pyrazole means

R ^{33 is} hydrogen, fluorine, chlorine or methyl,

K ^{5 is} CR ^39A or N,

embedded image in which

R> 3 ^j 9 ^y A ^{A is} hydrogen or methyl,

R ^{38 is} hydrogen or methyl.

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 compounds of the formula (I-1) according to the invention, in which R ^{3 is} hydroxycarbonyl, characterized in that

[A] a compound of the formula (II)

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

in an inert solvent with a halogenating agent in a compound of formula (EI-A)

in which R ¹ and R ² each have the meanings given above

and

X ^{1 is} halogen, in particular bromine or iodine,

these then in an inert solvent in the presence of a base and a suitable palladium catalyst with a compound of formula (FV)

in which R ^{6 has} the meaning given above

and - -

T ^{1 is} hydrogen or both radicals T ¹ together form a -C (CH ₃ ) ₂ -C (CH ₃ ) ₂ - or -CH ₂ C (CH ₃ ) ₂ CH ₂ bridge,

to a compound of formula (V-A)

(VA)

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

and these are subsequently reacted in an inert solvent in the presence of a suitable catalyst with a compound of the formula (VI-A)

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

and

T ^{2 is} (C 1 -C ₄ ) -alkyl,

X ^{2 is} halogen, preferably bromine or iodine,

to a compound of formula (VE)

in which Q, T r2, T R> 1, T R> 2, T Rj ₄ , TR) 5. and R> 6 j, in each case have the meanings given above, - 1 - implements,

or

[B] a compound of the formula (U) in an inert solvent in the presence of a suitable catalyst with a compound of the formula (VI-A) to give a compound of the formula (UI-B)

in which Q, T ² , R ¹ , R ² , R ⁴ and R ^{5 are} each as defined above,

reacted, and then in an inert solvent with a halogenating agent in a compound of formula (V-B)

in which Q, T, X, R, R, R and R are each as defined above,

überfuhrt and then this in an inert solvent in the presence of a base and a suitable palladium catalyst with a compound of formula (IV) to give a compound of formula (VII),

or

[C] a compound of the formula (VHI)

κ ^A (vm), in which R ^{6 has} the abovementioned meaning and

X ^{3 is} halogen, preferably bromine or iodine, in an inert solvent in the presence of a suitable palladium catalyst with trimethylsilylacetonitrile to give a compound of the formula (DC)

R ⁶ -

CN

(K),

in which R ^{6 has} the meaning given above,

and then this in an inert solvent in the presence of a suitable base with an ester of the formula (X)

in which R ^{1 has} the meaning given above and

T ^{3 is} (C 1 -C ₄ ) -alkyl,

to a compound of formula (XI)

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

Ak ^{+ represents} an alkali ion, preferably sodium,

and then reacted with a hydrazine of the formula (XII)

₂ HRN

^SNH * (XH), in which R ^{2 has} the meaning given above,

converted into a compound of the formula (V-A), and further converted into a compound of the formula (VII) by the process [A] described above,

and the respectively resulting compound of formula (VII) then by hydrolysis of the ester into a carboxylic acid of formula (I-1) - -

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

If necessary, these are reacted with the appropriate (i) solvents and / or (ii) bases or acids to give their solvates, salts and / or solvates of the salts.

Suitable halogenating agents in process steps (II) → (HI-A) or (HI-B) → (VB) are elemental bromine with acetic acid, 1,3-dibromo-5,5-dimethylhydantoin and in particular N-bromosuccinimide (ΝBS ), N-iodosuccinimide (ΝIS), optionally with the addition of α, α'-azobis (isobutyronitrile) (AIBΝ) as an initiator.

The halogenation in process steps (II) -> (III-A) or (DI-B) -> (VB) is in the use of ΝBS or ΝIS preferably in acetonitrile in a temperature range of 0 ⁰ C to +100 ⁰ C durchgeführtm and in the use of l, 3-dibromo-5,5-dimethylhydantoin preferably in dichloromethane in a temperature range of -20 ⁰ C to +30 ⁰ C.

Inert solvents for process steps (DI-A) + (IV) → (VA) and (VB) + (IV) → (VD) 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), dimethyl sulfoxide (DMSO), NN ' Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝMP), pyridine, acetonitrile or even water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to a mixture of dimethylformamide and water.

Suitable bases for the process steps (DI-A) + (IV) → (VA) and (VB) + (IV) → (VD) are customary inorganic bases. These include in particular alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali hydrogen carbonates such as sodium or potassium bicarbonate, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, or alkali hydrogen phosphates such as disodium or dipotassium hydrogencarbonate. phosphate. Preferably, sodium or potassium carbonate is used. - -

AIs palladium catalyst for the process steps (mA) + (IV) → (VA) and (VB) + (IV) → (VE) ["Suzuki coupling"] are, for example, palladium on activated carbon, palladium (II) acetate, Tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (π) chloride and [1,1 'bis (diphenylphosphino) ferrocene] dichloφalladium (II) - Dichloromethane complex suitable [cf. e.g. Hassan J. et al., Chem. Rev. 102, 1359-1469 (2002)].

The reactions (UI-A) + (IV) → (VA) and (VB) + (IV) → (VII) are generally in a temperature range from +20 ⁰ C to +150 ⁰ C, preferably at +50 ⁰ C. carried out to +100 ⁰ C.

Inert solvents for process steps (VA) + (VI-A) → (VII) and (II) + (VI-A) → (EI-B) are, for example, 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, dimethyl sulfoxide, N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝMP), pyridine, acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Preferably, toluene is used.

As transition metal catalysts for the coupling reactions (VA) + (VI-A) -> (VII) and (II) + (VI-A) - »(HI-B) are copper catalysts such as copper (I) iodide, and palladium catalysts such as palladium on activated charcoal, bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (O), tetrakis (triphenylphosphine) palladium (0), palladium (II) acetate, bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) -palladium (II) chloride or [1, l'-bis (diphenylphosphino) -ferrocene] -palladium (II) chloride, optionally in combination with additional phosphine ligands such as (2-biphenyl) di-ter / .-butylphosphine, dicyclohexyl [2 ', 4', 6'-tris-

(1-methylethyl) biphenyl-2-yl] phosphine (XPHOS), bis (2-phenylphosphinophenyl) ether (DPEphos) or 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (xanthphos) [see also, e.g. B., Hassan J. et al., Chem. Rev. JO2, 1359-1469 (2002); Farina V., Krishnamurthy V. and Scott W.J., in: The Silent Reaction, Wiley, New York, 1998].

The process steps (VA) + (VI-A) → (VII) and (EQ + (VI-A) → (UI-B) are generally in a temperature range of +20 ⁰ C to +200 ⁰ C, preferably + 80 ⁰ C to +180 ⁰ C, optionally carried out in a microwave. The reaction can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar). in general, one operates at atmospheric pressure.

The process step (VIII) → (LX) is carried out under the methods described in Hartwig JF et al, J. Am. Chem. Soc. 2005, 127, 15824-15832, conditions described. - -

In the reaction (DC) + (X) -> (XI) inert solvents are for example 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 or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using tetrahydrofuran.

Suitable bases for this reaction are the customary inorganic or organic bases. These include preferably alkali metal hydrides such as sodium hydride, alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal such as sodium or potassium, sodium or potassium or potassium tert-butoxide, amides such as sodium amide, lithium, sodium or potassium bis - (Trimethylsilyl) amide or lithium diisopropylamide or organometallic compounds such as butyl lithium or phenyllithium. Natrimhydrid is preferably used.

The process step (DX) + (X) - »(XI) is generally carried out in a temperature range from -78 ° C to + 100 ⁰ C, preferably from -20 ⁰ C to + 80 ⁰ C, optionally in a microwave performed. The reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.

The reaction (XI) + (Xu) -> (V-A) is carried out, for example, under the conditions described in Sorokin V.I. et al., Chem. Heterocycl. Comp. 2003, 39, 937-942.

The hydrolysis of the esters of the compounds (VIT) to compounds of formula (I-1) is carried out by conventional methods by treating the esters in inert solvents with acids or bases, the salts formed in the latter by treatment with acid in the free Carboxylic acids are transferred. In the case of the tert-butyl ester ester cleavage is preferably carried out with acids.

Suitable inert solvents for these reactions are water or the organic solvents customary for ester cleavage. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, dichloromethane, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned. In the case of a basic ester hydrolysis, preference is given to using mixtures of water with dioxane, tetrahydrofuran, methanol and / or ethanol, in the nitrile hydrolysis preferably water and / or n-propanol. In the case of the reaction with trifluoroacetic acid, preference is given to using dichloromethane and, in the case of the reaction with hydrogen chloride, preferably tetrahydrofuran, diethyl ether, dioxane or water. - -

As bases, the usual inorganic bases are suitable. These include preferably alkali or alkaline earth hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Particularly preferred are sodium or lithium hydroxide.

Suitable acids for the ester cleavage are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrobromic / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water. Hydrogen chloride or trifluoroacetic acid are preferred in the case of the tert-butyl esters and hydrochloric acid in the case of the methyl esters.

The Esterspaltung is generally carried out in a temperature range of 0 ⁰ C to +100 ⁰ C, preferably at +0 ⁰ C to +50 ⁰ 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.

The compounds of the formula (II) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature [cf. e.g. WO 2004/050651 p. 18-19; Sorokin V.I. et al., Chem. Heterocycl. Comp. 2003, 39, 937-942].

The compounds of the formulas (IV) and (VI-A) are commercially available, known from the literature or accessible by generally known processes.

The above-described processes for the preparation of the compounds according to the invention can be illustrated by the following synthesis schemes:

- -

Scheme 1

[a) for X ¹ = bromo, AcOH or N-bromosuccinimide, acetonitrile, RT to reflux temperature; for X ¹ = I: N-iodosuccinimide, acetonitrile, RT to reflux temperature; b) Pd (PPh ₃ ) ₄ , Na ₂ CO ₃ (aq), DMF, 110 ^° C; c) Pd (OAc) ₂ , K ₃ PO ₄ , (2-biphenyl) di-tert-butylphosphine, toluene, reflux temperature; d) NaOH (aq), dioxane / water, RT to reflux temperature].

Scheme 2

- -

[a): Pd (OAc) ₂ , K ₃ PO ₄ , (2-biphenyl) di-tert-butylphosphine, toluene, reflux temperature; b): for X ¹ = bromo, AcOH or N-bromosuccinimide, acetonitrile, RT to reflux temperature; for X ¹ = I: N-iodosuccinimide, acetonitrile, RT to reflux temperature; c) Pd (PPh ₃ ) ₄ , Na ₂ CO ₃ (aq), DMF, 110 ^° C; d) NaOH (aq), dioxane / water, RT to reflux temperature].

Scheme 3

[a) Tris (dibenzylideneacetone) dipalladium, Xantphos, zinc fluoride, DMF, ⁰ C 90 = [X ³ Br, I: see: Lingyun Wu, John F. Hartwig, J. Am. Chem. Soc. (2005), 127, 15824-15832.]; b) sodium hydride, THF, 0 ⁰ C → RT, then addition of the corresponding ester; RT> 60 ⁰ C; c) IN hydrochloric acid, reflux temperature].

Further compounds according to the invention of the formula (I) in which R ^{3 is} aminocarbonyl, cyanoaminocarbonyl or (C 1 -C ₄ ) -alkylsulfonylaminocarbonyl can be prepared by reacting the carboxylic acids of the formula (I-1) according to the invention using the methods known to the person skilled in the art implements, cf. eg Kwon CH., Synth. Commun. 1987, 17, 1677-1682; McDonald IM, J. Med. Chem. 2007, 50, 3101-3112.

The compounds of the formula (I) according to the invention in which R ^{3 is} 1, 3,4-oxadiazol-2 (3H) on-5-yl can be prepared by first reacting a compound of the formula (VII) in an inert Solvent with hydrazine in a compound of formula (XIH)

(XUT) in which Q, R, R 2, _D R 4, _D R 5 and R have the meanings given above,

and then reacted in an inert solvent with phosgene or a phosgene equivalent, such as N, N'-carbonyldiimidazole.

Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether are suitable as inert solvents for the first step of this reaction sequence. It is also possible to use mixtures of these solvents. Preferably, a mixture of methanol and tetrahydrofuran is used. The second reaction step is preferably carried out in an ether, in particular in tetrahydrofuran. The reactions are generally carried out in a temperature range of 0 ⁰ C to +70 ⁰ C under atmospheric pressure.

The compounds according to the invention of the formula (I) in which R ^{3 is} 1, 2,4-oxadiazol-5 (2H) on-3-yl can be prepared by reacting a compound of the formula (VI-B)

in which Q, X ² , R ⁴ and R ⁵ each have the meanings given above,

according to literature methods in a compound of formula (XIV)

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

this then provided with a suitable protective group PG ¹ and the resulting compound of formula (XV) - -

in which Q, X, R im R each have the meanings given above

and

PG ^{1 stands} for a protective group,

according to the above-described processes [A] or [B], further to a compound of the formula (XV)

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

then the protective group is cleaved off according to standard methods and the resulting compound of the formula (1-2)

in which Q, R, R, R, R and R each have the meanings given above, - - Where appropriate, with the corresponding (i) solvents and / or (ii) bases or acids to their solvates, salts and / or solvates of the salts.

The reaction (VI-B) → (XTV) is carried out according to the methods known to the person skilled in the art [cf. e.g. Iwao M., Kurashi T., J. Heterocycl. Chem. 1979, 16, 689-698].

Suitable protective groups PG ¹ in the reaction (XIV) -> (XV) are, for example, allyl, trityl, 2-nitrobenzyl, 2-trimethylsilylethoxymethyl (SEM), 2-cyanoethyl, methoxybenzyl, dimethoxybenzyl and trimethoxybenzyl [cf. eg Weller HN et al., Heterocycles 1993, 36, 1027-1038]. The cleavage of the protective groups in the reaction (XV) → (1-2) takes place according to the methods known to the skilled person [cf. Green TW, Wuts PGM, Protective Groups in Organic Synthesis, 3rd ed., John Wiley and Sons, 1999].

The compounds of the formula (I) according to the invention in which R ^{3 is} tetrazol-5-yl can be prepared by converting a compound of the formula (VI-B) into a compound of the formula (XVI) by methods known from the literature.

in which Q, X ² , R ⁴ and R ⁵ each have the meanings given above,

this then provided with a suitable protective group PG ² and the resulting compound of formula (XVH-A) or (XVH-B)

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

and

PG ^{2 stands} for a protective group,

according to the above-described processes [A] or [B], further to give a compound of the formula (XVm-A) or (XVm-B)

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

then the protective group is split off according to standard methods and the resulting compound of the formula (1-3)

(1-3)

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

optionally with the appropriate (i) solvents and / or (ii) bases or acids to their solvates, salts and / or solvates of the salts.

The reaction (VI-B) -> (XVI) takes place according to the methods known to the person skilled in the art [cf. eg Kivrakidou O., Bräse S., Hülshorst F., Griebenow N., Org. Lett. 2004, 6, 1143; Wittenberger SJ, Donner BG, J. Org. Chem. 1993, 58, 4139.]. Suitable protective groups PG ² in the reaction (XVI) → (XVII-A) or (XVII-B) are, for example, allyl, trityl, 2-nitrobenzyl, 2-trimethylsilylethoxymethyl (SEM), 2-cyanoethyl, methoxybenzyl, dimethoxybenzyl and trimethoxybenzyl [see. eg Kerdesky FAJ, Synth. Commun. 1996, 26, 1007-1013]. The cleavage of the protective groups in the reaction (XVDI-A) or (XVHI-B) - * (1-3) takes place according to the methods known to the person skilled in the art [cf. Green TW, Wuts PGM, Protective Groups in Organic Synthesis, 3rd ed., John Wiley and Sons, 1999].

The compounds of the formula (VI-B) are commercially available, known from the literature or accessible by generally known processes.

The compounds according to the invention have valuable pharmacological properties and can be used for the prevention and / or treatment of various diseases and disease-related conditions in humans and animals.

The compounds according to the invention are potent, selective adenosine A1 receptor antagonists which inhibit adenosine activity in vitro and in vivo.

In the context of the present invention, "adenosine A1 receptor selective ligands" refers to those adenosine receptor ligands in which, on the one hand, a marked effect on the Al adenosine receptor and, on the other hand, no or a significantly weaker effect (factor 10 or higher) on A2a , A2b and A3 adenosine receptor subtypes, with respect to the test methods for the selectivity of activity referred to in the section BI. described tests.

The compounds according to the invention are particularly suitable for the prophylaxis and / or treatment of cardiovascular diseases. In this context, the target indications are exemplified and preferably named: acute and chronic heart failure, acutely decompensated heart failure, arterial hypertension, coronary heart disease, stable and unstable angina pectoris, myocardial ischemia, myocardial infarction, shock, arteriosclerosis, atrial and ventricular arrhythmias, transient and ischemic attacks , Stroke, inflammatory cardiovascular diseases, peripheral and cardiovascular diseases, peripheral circulatory disorders, arterial pulmonary hypertension, spasms of the coronary arteries and peripheral arteries, thrombosis, thromboembolic disorders, edema formation such as pulmonary edema, cerebral edema, renal edema or congestive heart failure edema, and restenosis such as after thrombolytic therapies, percutaneous transluminal angioplasties (PTA), transluminal coronary angioplasties (PTCA), heart transplants and bypass operations.

For the purposes of the present invention, the term cardiac failure also encompasses more specific or related forms of disease such as right heart failure, left heart failure, global insufficiency. - - Ciency, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, valvular heart failure, valvular heart failure, mitral stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve 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.

Furthermore, the compounds of the invention are suitable for use as a diuretic for the treatment of edema and in electrolyte disorders, especially in the hypervolemic and euvolämischen hyponatremia.

The compounds according to the invention are also suitable for the prophylaxis and / or treatment of polycystic kidney disease (PCKD) and of the syndrome of inadequate ADH secretion (SIADH).

Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of kidney diseases, in particular renal insufficiency, as well as acute and chronic kidney failure. For the purposes of the present invention, the term renal insufficiency encompasses both acute and chronic manifestations of renal insufficiency, as well as underlying or related renal diseases such as renal hypoperfusion, obstructive uropathy, glomerulonephritis, acute glomerulonephritis, tubulo-interstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis toxic substances induced nephropathy, diabetic nephropathy, pyelonephritis, renal cysts and nephrosclerosis, which are diagnostically characterized by, for example, abnormally decreased creatinine and / or water excretion, abnormally increased blood concentrations of urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes such as glutamylsynthetase , altered urinary or urine output, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilatation, hyperphosphatemia, and / or d The need for dialysis can be characterized. The present invention also encompasses the use of the compounds of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism. - -

In addition, the compounds of the invention may be useful for the prophylaxis and / or treatment of cirrhosis of the liver, ascites, diabetes mellitus, and diabetic sequelae, e.g. Neuropathy can be used.

Furthermore, the compounds according to the invention are suitable for the prophylaxis and / or treatment of central nervous disorders such as anxiety and depression, glaucoma and cancer, in particular lung tumors.

In addition, the compounds of the invention for the prophylaxis and / or treatment of inflammatory diseases, asthmatic diseases, chronic obstructive pulmonary diseases (COPD), pain, prostatic hypertrophy, incontinence, bladder inflammation, hyperactive bladder, diseases of the adrenal glands such as pheochromocytoma and adrenal apoplexy , Disorders of the intestine such as Crohn's disease and diarrhea, or of menstrual disorders such as dysmenorrhea be used.

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

The present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prophylaxis of acutely decompensated and chronic heart failure, hypervolemic and euphermal hyponatremia, liver cirrhosis, ascites, edema, nephropathy, acute and chronic renal failure, renal insufficiency and the syndrome of inadequate ADH secretion (SIADH).

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

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

The compounds of the invention may be used alone or as needed in combination with other agents. Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more further active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases. Suitable combination active ingredients for this purpose are by way of example and preferably mentioned: - -

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

• Diuretics, especially loop diuretics and thiazides and thiazide-like diuretics;

Positive inotropic compounds such as cardiac glycosides (digoxin), beta adrenergic and dopaminergic agonists such as isoproterenol, epinephrine, norepinephrine, dopamine and dobutamine;

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 amrinone and milrinone;

Natriuretic peptides, e.g. atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, Nesiritide), C-type natriuretic peptide (CNP) and urodilatin;

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

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

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

Antagonists of vasopressin receptors such as Conivaptan, Tolvaptan, RWJ-676070 or RWJ-351647;

Inhibitors of human neutrophil elastase (HNE), such as Sivelestat or DX-890 (Reltran);

The signal transduction cascade inhibiting compounds, such as tyrosine kinase inhibitors, in particular sorafenib, imatinib, Gefϊtinib and erlotinib;

Compounds affecting the energy metabolism, such as, for example and preferably, etomoxir, perhexiline, dichloroacetate, ranolazine or trimetazidine; Antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;

Anti-hypertensive agents, by way of example and with preference from the group of calcium antagonists, angiotensin AH antagonists, ACE inhibitors, vasopeptidase inhibitors, inhibitors of neutral endopeptidase, endothelin antagonists, renin inhibitors, alpha-

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

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

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quineth- azon, acetazolamide, dichloφhenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

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

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

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPUb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab. - -

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a factor Xa inhibitor such as, by way of example and preferably, roxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD No. 3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.

Among the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AH antagonists, ACE inhibitors, vasopeptidase inhibitors, inhibitors of neutral endopeptidase, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta Receptor blockers, mineralocorticoid receptor antagonists, Rho kinase inhibitors, prostanoid IP receptor agonists and diuretics understood.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin Aü antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embusartan.

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vasopeptidase inhibitor or inhibitor of neutral endopeptidase (NEP), such as by way of example and preferably omapatrilate or AVE-7688.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan. - -

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.

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

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

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a rho-kinase inhibitor, such as, for example and preferably, Faslyil, Y-27632, SAR407899, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an agonist of the prostanoid IP receptor, such as, for example and preferably, iloprost, treprostinil, beraprost or NS-304.

Among the lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR alpha- , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as, for example and preferably, torcetrapib (CP-529 414), JJT-705, BAY 60-5521, BAY 78-7499 or CETP vaccine ( Avant). - -

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

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

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

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

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

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

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.

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

In a preferred embodiment of the invention, the compounds 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, colestipol, colesolvam, cholesta gel or colestimide. - -

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

In a preferred embodiment of the invention, the compounds 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.

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

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

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

For the oral administration are according to the prior art working, 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), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (e.g. Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

The parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For the parenteral administration, suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders. - -

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

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

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

In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 10 mg / kg, preferably about 0.01 to 1 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:

Ac acetyl

AcOH acetic acid aq. Aqueous

TLC thin layer chromatography

DCI direct chemical ionization (in MS)

DMF dimethylformamide

DMSO dimethyl sulfoxide d. Th. Of theory (in yield) eq. Equivalent (s)

ESI electrospray ionization (in MS) h hour (s)

Hal halogen

HPLC high pressure, high performance liquid chromatography

LC-MS liquid chromatography-coupled mass spectrometry min minute (s)

MPLC medium pressure chromatography

MS mass spectrometry mz multiple «, centered (by NMR)

NMR nuclear magnetic resonance spectrometry

Pd (PPh ₃ ) ₄ tetrakis (triphenylphosphine) palladium (0)

RP reverse phase (on HPLC)

RT room temperature

R. Retention time (by HPLC) sbr singlet, broad (by NMR) THF tetrahydrofuran

UV ultraviolet spectrometry v / v volume-to-volume ratio (of a mixture) - -

LC-MS. GC-MS and HPLC methods:

Method 1 (LC-MS):

Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Gemini 3μ 30 mm x 3.00 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min -> 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 5O ⁰ C; UV detection: 210 nm.

Method 2 (LC-MS):

Instrument: Micromass Quattro Micro MS with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3μ 20 x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A-> 3.0 min 10% A -> 4.0 min 10% A - »4:01 min 100% A (flow 2.5ml) -> 5:00 min 100% A furnace: 50 ⁰ C; Flow: 2 ml / min; UV detection: 210nm

Method 3 (LC-MS): Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2.5 μ MAX-RP 100A Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 0.1 min 90% A - »3.0 min 5% A -» 4.0 min 5% A -> 4.01 min 90% A; Flow: 2 ml / min ;; Oven: 50 ^° C .; UV detection: 210 nm.

Method 4 (LC-MS):

Instrument: Micromass QuattroPremier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD l, 9μ 50 x 1 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 0.1 min 90% A -> 1.5 min 10% A - »2.2 min 10% A Furnace: 50 ^° C; Flow: 0.33 ml / min; UV detection: 210 nm.

Method 5 (LC-MS):

Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3μ 20 x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A - »0.2 min 100% A -» 2.9 min 30% A -> 3.1 min 10% A -> 5.5 min 10% A; Oven: 50 ^° C .; Flow: 0.8 ml / min; UV detection: 210 nm. - -

Method 6 (GC-MSV

Instrument: Micromass GCT, GC6890; Column: Restek RTX-35, 15 m × 200 μm × 0.33 μm; constant flow with helium: 0.88 ml / min; Oven: 70 ^° C; Inlet: 250 ^° C; Gradient: 70 ⁰ C, 30 ° C / min -> 310 ⁰ C (hold for 3 min).

Method 7 (preparative HPLC):

Instrument: Abimed Gilson Pump 305/306, Manometric Module 806; Column: Grom-Sil 120 ODS-4HE 10 μm, 250 mm x 40 mm; Eluent: A = water, B = acetonitrile; Gradient: 0.0 min 10% B → 5 min 10% B → 27 min 98% B → 35 min 98% B → 35.01 min 10% B → 38 min 10% B; Flow: 50 ml / min; Column temperature: RT; UV detection: 210 nm.

Method 8 (preparative HPLC):

Instrument: Abimed Gilson Pump 305/306, Manometric Module 806; Column: Grom-Sil 120 ODS-4HE 10 μm, 250 mm x 40 mm; Eluent: A = water + 0.075% formic acid, B = acetonitrile; Gradient: 0.0 min 10% B → 5 min 10% B → 27 min 98% B → 35 min 98% B → 35.01 min 10% B → 38 min 10% B; Flow: 50 ml / min; Column temperature: RT; UV detection: 210 nm.

Method 9 (LC-MS):

Device Type MS: Waters ZQ; Device Type HPLC: Agilent 1100 Series; UV DAD; Column: Thermo Hypersil GOLD 3μ 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.1 min 100% flow: 2.5 ml / min, oven: 55 ° C; Flow 2 ml / min; UV detection: 210 nm.

Method 10 (LC-MSV

Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 l, 8μ 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. - -

Starting compounds and intermediates:

Example IA

5-bromo-l, 3-dihydro-2H-benzimidazol-2-one

100.0 g (0.535 mol) of 4-bromobenzene-l, 2-diamine were initially charged in 3 l of methanol / water (v / v = 2: 1) and admixed with 49.4 g (0.588 mol). 73.7 ml (92.1 g, 0.588 mol) of phenyl chlorocarbonate were added dropwise with stirring at room temperature to the suspension. After stirring for 3.5 h at room temperature, 598.8 ml of an IN sodium hydroxide solution were added and the mixture was stirred at room temperature for 16 h. The precipitate was filtered off, washed with water and dried in vacuo. There were obtained 71.5 g (63% of theory) of the target compound.

LC-MS (Method 5): R, = 2.72 min; MS (EIpos): m / z = 214 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 6.87 (d, IH), 7.05 (d, IH), 7.08 (dd, IH), 10.75 (sbr, 2H).

Example 2A

5- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl), 3-dihydro-2H-benzimidazol-2-one -l

Under an argon atmosphere, 516 mg (0.563 mmol) of tris (dibenzylideneacetone) dipalladium (0) and 379 mg (1.352 mmol) of tricyclohexylphosphine were dissolved in 50 ml of dioxane. There were 2622 mg (10.327 mmol) of 4,4,4 ', 4 ^l , 5,5,5', 5'-octamethyl-2,2'-bi-l, 3,2-dioxaborolan, 2000 mg (9388 mmol ) of the compound from Example IA and 1382 mg (14,082 mmol) of potassium acetate are added and the mixture is stirred at 80 ^° C. overnight. After cooling, the reaction mixture was treated with dioxane and filtered through Celite. The filtrate was stirred with tert-butyl methyl ether, the resulting precipitate was filtered off and dried in vacuo. It - - 1172 mg (48% of theory) of the target compound were obtained, which was reacted further without further purification.

LC-MS (method 1): R _t = 1.75 min; MS (EIpos): m / z = 261 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ [ppm] = 1.28 (s, 12H), 6.91 (d, IH), 7.18 (s, IH), 7.28 (d, IH), 10.82 ( sbr, 2H).

Example 3A

Methyl 5-methoxy-2 - {[3-methyl-1- (2-methylphenyl) -4- (2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -1H-pyrazole-5 -yl] amino} benzoate

Under an argon atmosphere, 350 mg (0.813 mmol) of methyl 2 - {[4-bromo-3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl] amino} -5-methoxybenzoate (described in WO 2005/112923, page 18) and 636 mg (2.444 mmol) of the compound from Example 2A dissolved in 8.7 ml of dimethylformamide and treated with 2033 ml of 2N aqueous sodium carbonate solution and 56 mg (0.049 mmol) of tetrakis (triphenylphosphine) palladium (0) , The mixture was stirred at 11O ⁰ C for 15 min. After cooling, water was added and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator under reduced pressure. The residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). 21 mg (5% of theory) of the target compound were obtained.

LC-MS (Method 4): R, = 1.13 min; MS (EIpos): m / z = 484 [M + H] ⁺ . - -

Example 4A

Methyl 5-methoxy-2- {[3-methyl-1- (2-methylphenyl) -4- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-6-one yl) - 1H-pyrazole-5-yl] amino} benzoate

Under an argon atmosphere, 257 mg (0.280 mmol) of tris (dibenzylideneacetone) dipalladium (O) and 189 mg (0.673 mmol) of tricyclohexylphosphine were dissolved in 30 ml of dioxane. There were 1305 mg (5,140 mmol) 4,4,4 ', 4 ^t , 5,5,5 ^! , 5'-Octamethyl-2,2'-bi-1,2,2-dioxaborolane, 1000 mg (4.672 mmol) 6-bromo-1,3-dihydro-2H-imidazo [4,5-b] pyridine-2 -on (described in WO 2004/035549, S.200) and 688 mg (7.008 mmol) of potassium acetate are added and the mixture is stirred overnight at 80 ⁰ C. After cooling, the reaction mixture was treated with dioxane and filtered through Celite. The filtrate was stirred with tert-butyl methyl ether, the resulting precipitate was filtered off and dried in vacuo. 2500 mg of crude product were obtained, which was reacted further without further purification.

1355 mg of the crude product and 350 mg (0.813 mmol) of methyl 2 - {[4-bromo-3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl] amino} -5-methoxybenzoate (described in US Pat WO 2005/112923, p.

18) were dissolved under argon atmosphere in 18 ml of dimethylformamide and with 2033 ml of aqueous

2N sodium carbonate solution and 56 mg (0.049 mmol) of tetrakis (triphenylphosphine) palladium (0). The mixture was stirred at 110 ^° C. for 15 min. After cooling, water was added and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a Roattions evaporator under reduced pressure. Of the

The residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ->

90:10). Thirteen mg (3% of theory) of the target compound were obtained.

LC-MS (Method 4): R, = 1.06 min; MS (EIpos): m / z = 485 [M + H] ⁺ . - -

Example 5A

6-iodo-3-methylquinazolin-4 (3H) -one

1.00 g (3.46 mmol) of 6-iodo-2H-3, 1-benzoxazine-2,4 (1H) -dione [Venuti MC et al., J. Med. Chem. 1988, 31, 2136-2145] and 0.326 g (3.46 mmol) methanamine solution (33% by weight in ethanol) was dissolved in 10 ml of ethanol. Then Ih was stirred at room temperature. Subsequently, the volatile components were separated on a rotary evaporator. 10 ml of formic acid were added, then it was stirred for ² h at 120 ⁰ C oil bath temperature. The formic acid was separated on a rotary evaporator. It was then taken up in 50 ml of half-concentrated sodium bicarbonate solution and extracted with ethyl acetate (3 × 50 ml). After drying with magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting product had a purity of> 95% (LC-MS) and was reacted without further purification steps. Thus, 890 mg (85% of theory) of the target compound was obtained.

LC-MS (Method 10): R, = 0.81 min; MS (EIpos): m / z = 287 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.49 (s, 3H), 7.47 (d, IH), 8.10 (dd, IH), 8.41 (s, IH), 8.42 (i.e. , IH).

Example 6A

3-methyl-6- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) quinazolin-4 (3H) -one

Under an argon atmosphere 850 mg (2.97 mmol) of Example 5A in 15 ml of abs. Dioxane solved. There were 525 mg (5.35 mmol) of potassium acetate, 194 mg (0.238 mmol) of l, r-bis (diphenylphosphino) ferrocenepalladium (π) chloride-dichloromethane complex and 830 mg (3.7 mmol) of 4,4,4 ', 4' , 5,5,5 ', 5'-octamethyl-2,2'-bi-l, 3 _> 2-dioxaborolane added. Then it was over - -

Night at 130 ⁰ C oil bath temperature stirred. The mixture was filtered through kieselguhr. After washing the silica with ethyl acetate, the filtrate was concentrated and the residue was purified by MPLC (Analogix 4OS: iso-hexane / ethyl acetate 1: 1 → 1: 4). 179 mg (21% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 0.95 min; MS (EIpos): m / z = 287 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.33 (s, 12H), 3.51 (s, 3H), 7.65 (d, IH), 8.02 (dd, IH), 8.42 (s, IH ), 8.49 (d, IH).

Example 7A

Methyl 5-methoxy-2 - {[3-methyl-4- (3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl) -1- (2-methylphenyl) -1H-pyrazole-5- yl] amino} benzoate

Under an argon atmosphere, 100 mg (0.233 mmol) of methyl 2 - {[4-bromo-3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl] amino} -5-methoxybenzoate (described in WO 2005/112923, p. 18) and 100 mg (0.349 mmol) of the compound from Example 6A in 3 ml of dimethylformamide and 0.233 ml (0.466 mmol) of 2N aqueous sodium carbonate solution and 24 mg (0.021 mmol) of tetrakis (triphenylphosphine) palladium (0) offset. The mixture was reacted at 110 ^° C. overnight. After cooling, it was poured onto water and extracted with ethyl acetate (3x). The combined organic phases were dried with magnesium sulfate. It was then concentrated on a rotary evaporator under reduced pressure. The residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 -> 90:10). 47 mg (39% of theory) of the target compound were obtained. LC-MS (Method 10): R, = 1.10 min; MS (EIpos): m / z = 510 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.14 (s, 3H), 2.40 (s, 3H), 3.47 (s, 3H), 3.57 (s, 3H), 3.79 (s , 3H), 6.41 (d, IH), 6.83 (dd, IH), 7.13 (d, IH), 7.23 (m, IH), 7.31 (s, 2H), 7.38 (d, IH), 7.61 (d, IH), 7.87 (dd, IH), 8.18 (d, IH), 8.32 (s, IH), 8.84 (s, IH).

Example 8A

Methyl 2- {[3-methyl-1- (2-methylphenyl) -1 H -pyrazol-5-yl] amino} benzoate

Under an argon atmosphere, 6.53 g (34.9 mmol) of 3-methyl-1- (2-methylphenyl) -H-pyrazole-5-amine (described in WO 2004/050650, p. 30) in 100 ml of abs. Toluene dissolved. It was purged with argon, with 261 mg (1.16 mmol) of palladium (II) acetate and with 1.25 g (2.33 mmol) of bis (2-diphenylphosphinophenyl) ether (DPEphos). Then, it was stirred at room temperature for 5 minutes. Subsequently, 5.00 g (23.3 mmol) of 2-bromobenzoate and 5.00 g (23.3 mmol) of cesium carbonate were added and then stirred at 95 ° C overnight. The reaction mixture was cooled and filtered through diatomaceous earth. It was washed with ethyl acetate. Then the combined organic phases were concentrated on a rotary evaporator and the residue was purified by column chromatography (silica gel: cyclohexane / ethyl acetate = 7/3). 7.37 g (98% of theory) of the target compound were obtained.

LC-MS (Method 4): R _t = 1.34 min; MS (EIpos): m / z = 322 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.03 (s, 3H), 2.24 (s, 3H), 3.72 (s, 3H), 6.21 (s, IH), 6.83 (t , IH), 7.24 (d, IH), 7.29-7.34 (m, 2H), 7.36-7.41 (m, 2H), 7.49 (mz, IH), 7.83 (dd, IH), 9.27 (s, IH).

Example 9A

Methyl 2- {[4-bromo-3-methyl-1- (2-methylphenyl) -1 H -pyrazol-5-yl] amino} benzoate - -

7.35 g (22.9 mmol) of the compound from Example 8A were dissolved in 150 ml of dichloromethane and, while cooling with ice, 3.27 g (11.5 mmol) of 1,3-dibromo-5,5-dimethylhydantoin were added. After a reaction time of 10 minutes, the mixture was diluted with 150 ml of dichloromethane and washed with 150 ml each of water, saturated sodium bicarbonate solution and 10% strength sodium thiosulfate solution. It was then dried with magnesium sulfate and the solvent was removed on a rotary evaporator. There were obtained 8.28 g (90% of theory) of the target compound.

LC-MS (Method 10): R, = 1.33 min; MS (EIpos): m / z = 400 [M] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.09 (s, 3H), 2.27 (s, 3H), 3.80 (s, 3H), 6.55 (d, IH), 6.79 (t , IH), 7.23 (m, IH), 7.28-7.36 (m, 3H), 7.39 (t, IH), 7.79 (dd, IH), 8.99 (s, IH).

Example IQA

Methyl 2- {[3-methyl-4- (3-methyl-4-oxo-3,4-dihydro-quinazolin-6-yl) -1- (2-methylphenyl) -1 H -pyrazol-5-yl] -amino } benzoate

Under an argon atmosphere, 100 mg (0.250 mmol) of the compound from Example 9A and 134 mg (0.375 mmol) of the compound from Example 6A were dissolved in 3 ml of dimethylformamide and treated with 0.250 ml (0.500 mmol) 2N aqueous sodium carbonate solution and 26 mg (0.022 mmol) - -

Tetrakis (triphenylphosphine) palladium (0). The mixture was reacted at 110 ^° C. overnight. After cooling, it was poured onto water and extracted with ethyl acetate (3x). The combined organic phases were dried with magnesium sulfate. It was then concentrated on a rotary evaporator under reduced pressure. The residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). There were obtained 110 mg (92% of theory) of the target compound.

LC-MS (Method 10): R, = 1.11 min; MS (EIpos): m / z = 480 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 2.16 (s, 3H), 2.41 (s, 3H), 3.46 (s, 3H), 3.79 (s, 3H), 6.43 (d, IH ), 6.60 (t, IH), 7.15 (d, IH), 7.23 (m, IH), 7.28-7.33 (m, 2H), 7.41 (d, IH), 7.61 (d, IH), 7.66 (dd, IH), 7.88 (dd, IH), 8.19 (d, IH), 8.32 (s, IH), 9.17 (s, IH).

Example IIA

2-Amino-5-iodo-N-methylbenzolcarboxamid

4.00 g (13.8 mmol) of 6-iodo-2H-3, 1-benzoxazine-2,4 (1H) -dione [Venuti MC et al., J. Med. Chem. 1988, 31, 2136-2145] and 1.30 g (13.8 mmol) methanamine solution (33% by weight in ethanol) was dissolved in 10 ml of ethanol. Then Ih was stirred at room temperature. Subsequently, the volatile components were separated on a rotary evaporator. Thus 3.80 g (99% of theory) of the target compound were obtained.

LC-MS (Method 2): R, = 1.55 min; MS (EIpos): m / z = 277 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ [ppm] = 2.70 (d, 3H), 6.50-6.60 (m, 3H), 7.37 (dd, IH), 7.73 (d, IH), 8.28 (d, IH).

Example 12A

6-iodo-3-methyl-l, 2,3-benzotriazin-4 (3H) -one

1.00 g (13.8 mmol) of the compound from Example IA were suspended in 10 ml of 10% hydrochloric acid. Subsequently, under ice-cooling, 274 mg (3.98 mmol) of sodium nitrite were added as a solution in 5 ml of water. After a reaction time of 30 minutes, 5 ml of ION sodium hydroxide solution were added basic under ice-cooling and then adjusted to pH 2 with concentrated hydrochloric acid. The product was filtered off and washed with a little water. Thus, 996 mg (96% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 0.90 min; MS (EIpos): m / z = 288 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.93 (d, 3H), 7.95 (d, IH), 8.39 (dd, IH), 8.53 (d, IH).

Example 13A

Methyl 2 - {[3-methyl-4- (3-methyl-4-oxo-3,4-dihydro-1,2,3-benzotriazin-6-yl) -1- (2-methylphenyl) -1H pyrazol-5-yl] amino} benzoate

Under an argon atmosphere, 980 mg (3.41 mmol) of the compound from Example 12A in 20 ml abs. Dioxane solved. There were added 603 mg (6.14 mmol) of potassium acetate, 223 mg (0.273 mmol) of l, r-bis (diphenylphosphino) ferrocenepalladium (II) chloride-dichloromethane complex and 953 mg (3.76 mmol) of 4,4,4 ', 4 ^l , 5,5,5 ', 5'-octamethyl-2,2'-bi-l, 3,2-dioxaborolane added. Then it was stirred overnight at 130 ° C oil bath temperature. Nearly complete conversion was detected, but partial hydrolysis of the boronic acid ester to boronic acid was observed - -

(LC-MS). The reaction was filtered through kieselguhr, then washed with ethyl acetate and the combined organic phases were concentrated on a rotary evaporator. The raw substance thus obtained was reacted without further workup, as described below. For the Suzuki coupling, a 50% purity of 3-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -l, 2,3- benzotriazine-4 (3H) -one.

253 mg (0.618 mmol, ca. 50%) of 3-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,3-benzotriazine -4 (3H) -one and 165 mg (0.412 mg) of the compound of Example 9A were dissolved in 5.5 ml of dimethylformamide. It was then purged with argon. 0.412 ml (0.824 mmol) of 2N sodium carbonate solution and 43 mg (0.037 mmol) of tetrakis (triphenylphosphine) palladium (O) were added. The mixture was reacted at 110 ^° C. overnight. After cooling, it was poured onto water and extracted with ethyl acetate (3x). The combined organic phases were washed with water and dried with magnesium sulfate. It was then concentrated on a rotary evaporator under reduced pressure. The residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). 43 mg (17% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 1.23 min; MS (EIpos): m / z = 481 [M + H] ⁺ .

Example 14A

7-bromo-2-methyl-4H-3, 1-benzoxazin-4-one

1500 mg (6.94 mmol) of 2-amino-4-bromobenzoic acid [Lawson W.B. et al., J. Am. Chem. Soc. 1960, 82, 5918-5923] and 10 ml (106 mmol) of acetic anhydride were stirred for 2 hours at reflux temperature. The batch was cooled to room temperature. After 2 h, the crystallized product was filtered off and dried under high vacuum. 1027 mg (62% of theory) of the target compound were obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.40 (s, 3H), 7.76 (dd, IH), 7.81 (d, IH), 8.00 (d, IH).

Example 15A

7-bromo-2-methylquinazolin-4 (3H) -one

500 mg (2:08 mmol) of the compound from Example 14A and 6 mL (40.5 mmol) of 26% aqueous ammonia solution were reacted in a closed pressure vessel at 80 ⁰ C for 2 h. After cooling, the resulting solid was filtered off and dried under high vacuum. 387 mg (78% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 1.23 min; MS (EIpos): m / z = 239 [M] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 2.35 (s, 3H), 7.61 (d, IH), 7.78 (s, IH), 7.98 (d, IH), 12.28 (s, IH ).

Example 16A

2-methyl-7- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) quinazolin-4 (3H) -one

Under an argon atmosphere, 387 mg (1.62 mmol) of the compound from Example 15A in 15 ml of abs. Dioxane solved. There were 286 mg (2.91 mmol) of potassium acetate, 106 mg (0.129 mmol) of l, r-bis (diphenylphosphino) ferrocenepalladium (II) chloride-dichloromethane complex and 452 mg (1.78 mmol) of 4,4,4 ', 4' , 5,5,5 ', 5'-octamethyl-2,2 ¹ -bi-l, 3,2-dioxaborolane added. Then it was stirred overnight at 130 ⁰ C oil bath temperature. The reaction was diluted with dichloromethane and filtered through a bed of diatomaceous earth and silica gel. It was then washed with ethyl acetate. The volatile components were dried under high vacuum. There was obtained 600 mg of raw material. The material thus obtained was used without further work-up steps. The following reactions were based on a 70% content of target compound.

LC-MS (Method 10): R, = 0.86 min; MS (EIpos): m / z = 287 [M + H] ⁺ - 5 -

Example 17A

Methyl 2 - {[3-methyl-4- (2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl) -1- (2-methylphenyl) -1H-pyrazol-5-yl] amino} benzoate

Under an argon atmosphere, 300 mg (0.749 mmol) of the compound from Example 9A and 459 mg (about 1.12 mmol, about 70% strength) of the compound from Example 16A were dissolved in 10 ml of dimethylformamide and treated with 0.749 ml (1.499 mmol) of 2N aqueous sodium carbonate solution and 78 mg (0.067 mmol) of tetrakis (triphenylphosphine) palladium (0). The mixture was reacted at 110 ^° C. overnight. After cooling, it was poured onto water and extracted with ethyl acetate (3x). The combined organic phases were washed with water (2x) and dried with magnesium sulfate. It was then concentrated on a rotary evaporator under reduced pressure. The residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). 139 mg (39% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 1.03 min; MS (EIpos): m / z = 480 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ [ppm] = 2.15 (s, 3H), 2.31 (s, 3H), 2.42 (s, 3H), 3.79 (s, 3H), 6.43 ( d, IH), 6.62 (t, IH), 7.17 (t, IH), 7.23 (m, IH), 7.26-7.33 (m, 2H), 7.39 (d, IH), 7.52 (dd, IH), 7.61 (d, IH), 7.67 (dd, IH), 7.97 (d, IH), 9.17 (s, IH), 12.12 (sbr, IH).

Example 18A

7-bromo-2,3-dimethylquinazolin-4 (3H) -one - -

500 mg (2.08 mmol) of the compound from Example 14A and 0.310 ml (2.50 mmol) of 33% methanamine solution in ethanol were reacted overnight in a closed pressure vessel at room temperature. The resulting solid was filtered off, washed with a little ethanol and dried under high vacuum. 365 mg (58% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 0.82 min; MS (EIpos): m / z = 253 [M] ⁺ .

¹ H-NMR (400 MHz, CDCl _3): δ [ppm] = 2.62 (s, 3H), 3.61 (s, 3H), 7:54 (d, IH), 7.79 (s, IH), 8.10 (d, IH ).

Example 19A

2,3-dimethyl-7- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) quinazolin-4 (3H) -one,

Under an argon atmosphere, 365 mg (1.44 mmol) of the compound from Example 18A in 15 ml of abs. Dioxane solved. There were 255 mg (2.60 mmol) of potassium acetate, 94 mg (0.115 mmol) l, r-bis (diphenylphosphino) -ferrocenpalladium (II) chloride-dichloromethane complex and 403 mg (1:59 mmol) of 4,4,4 ', 4 ^I , 5,5,5 ', 5'-octamethyl-2,2'-bi-l, 3,2-dioxaborolane added. Then it was stirred overnight at 130 ⁰ C oil bath temperature. The reaction was diluted with dichloromethane and filtered through a bed of diatomaceous earth and silica gel. It was then washed with ethyl acetate. The volatile components were dried under high vacuum. There was obtained 680 mg of raw material. The material thus obtained was used without further work-up steps. For the subsequent reactions, an 83% content of couplable starting material was assumed (consisting of the target compound and corresponding boronic acid, which was formed by partial saponification). - -

LC-MS (Method 10): R, = 0.96 min; MS (EIpos): m / z = 301 [M + H] ⁺ (destination connection).

LC-MS (Method 10): R, = 0.40 min; MS (EIpos): m / z = 219 [M + H] ⁺ (boronic acid).

Example 2OA

Methyl 2 - {[4- (2,3-dimethyl-4-oxo-3,4-dihydroquinazolin-7-yl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl] amino} benzoate

Under an argon atmosphere, 300 mg (0.749 mmol) of the compound from Example 9A and 482 mg (about 1.12 mmol, about 83% strength) of the mixture from Example 16A were dissolved in 10 ml of dimethylformamide and treated with 0.749 ml (1.499 mmol) of 2N aqueous sodium carbonate solution and 78 mg (0.067 mmol) of tetrakis (triphenylphosphine) palladium (0). The mixture was reacted at 110 ^° C. overnight. After cooling, it was poured onto water and extracted with ethyl acetate (3x). The combined organic phases were washed with water (2x) and dried with magnesium sulfate. It was then concentrated on a rotary evaporator under reduced pressure. The residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). 186 mg (50% of theory) of the target compound were obtained.

LC-MS (method 10): R, = 1.14 min; MS (EIpos): m / z = 494 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ [ppm] = 2.15 (s, 3H), 2.43 (s, 3H), 3.50 (s, 3H), 3.79 (s, 3H), 6.43 (i.e. , IH), 6.61 (t, IH), 7.16 (mz, IH), 7.23 (m, IH), 7.27-7.34 (m, 2H), 7.39 (d, IH), 7.54 (dd, IH), 7.62 ( d, IH), 7.67 (dd, IH), 7.99 (d, IH), 9.18 (s, IH).

Example 21A

Methyl 2 - benzoate [(3-methyl-l-phenyl-lH-pyrazol-5-yl) amino]

8000 g (46.184 mmol) of 5-amino-3-methyl-1-phenylpyrazole were dissolved in 130 ml of toluene under an argon atmosphere and treated with 0.346 g (1.539 mmol) of palladium (II) acetate and 1.658 g (3.079 mmol) of bis- [2 -diphenylphosphino) phenyl] ether. The mixture was stirred for 5 minutes at room temperature. Subsequently, 6,621 g (30,789 mmol) of 2-

Methyl bromobenzoate and 14.045 g (43.105 mmol) of cesium carbonate are added and the mixture is stirred overnight at 95.degree. After cooling, the mixture was filtered through silica gel, the filter cake was washed with ethyl acetate and the filtrate was concentrated. The residue was purified by preparative

HPLC (eluent: acetonitrile / water, gradient 20:80 → 90:10). 9.36 g (66% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 1.18 min; MS (EIpos): m / z = 308 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 2.25 (s, 3H), 3.80 (s, 3H), 6.23 (s, IH), 6.82 (t, IH), 6.94 (d, IH ), 7.33 (t, IH), 7.37-7.49 (m, 3H), 7.49-7.58 (m, 2H), 7.86 (d, IH), 9.38 (s, IH).

Example 22A

Methyl 2 - [(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl) amino] benzoate

9.370 g (30.486 mmol) of the compound from Example 21 A were dissolved in 160 ml of dichloromethane and treated portionwise with ice cooling with 4.358 g (15243 mmol) of l, 3-dibromo-5,5-dimethylhydantoin. Reaction control by means of HPLC showed complete conversion after 20 minutes. Dichloromethane was added and the organic phase with water, saturated aqueous sodium bicarbonate solution and 10% aqueous sodium thiosulfate solution washed. Subsequently, the organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. 11,441 g (96% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 1.32 min; MS (EIpos): m / z = 386 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d _ö ): δ [ppm] = 2.28 (s, 3H), 3.86 (s, 3H), 6.36 (d, IH), 6.79 (t, IH), 7.26-7.37 (m, 2H), 7.37-7.46 (m, 2H), 7.50-7.60 (m, 2H), 7.84 (d, IH), 9.14 (s, IH).

Example 23A

Methyl 2 - {[3-methyl-4- (3-oxo-3,4-dihydro-quinoxalin-6-yl) -l-phenyl-1H-pyrazol-5-yl] amino} benzoate

Under an argon atmosphere, 500 mg (2.22 mmol) of 7-bromoquinoxaline-2 (1H) -one [Lumma et al., J. Med. Chem. 1981, 24, 93] was dissolved in 30 ml of dioxane. Then, 654 mg (6.67 mmol) of potassium acetate, 145 mg (0.178 mmol) of l, r-bis (diphenylphosphino) ferrocenepalladium (II) chloride-dichloromethane complex and 620 mg (2.44 mmol) of 4,4,4 ', 4' were added. , 5,5,5 ', 5'-octamethyl-2,2'-bi-l, 3,2-dioxaborolane added. The reaction mixture was stirred overnight at 130 ⁰ C oil bath temperature. After cooling, the reaction mixture was treated with dioxane and filtered through kieselguhr. It was washed with ethyl acetate. The filtrate was concentrated on a rotary evaporator under reduced pressure and dried under high vacuum. Thus, 599 mg of 7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxalin-2 (1H) -one as crude product [ca. 75% (LC-MS)]. This was reacted below without further purification. 299 mg of the thus obtained 7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxaline-2 (1H) -one together with 283 mg (0.733 mmol) of Example 22A, 25 mg (0.088 mmol) of tricyclohexylphosphine, 34 mg (0.037 mmol) of tris (dibenzylideneacetone) dipalladium and 1.25 ml (1.25 mmol) of IM aqueous potassium phosphate solution were taken up in 5 ml of dioxane under an argon atmosphere. Then it was reacted overnight at 100 ⁰ C. After cooling, the - -

Filtered through kieselguhr, washed with ethyl acetate and the volatile components were separated on a rotary evaporator. The batch was concentrated and the residue was purified by HPLC (eluent: acetonitrile / water, gradient 20:80 → 90:10). 212 mg (64% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 1.07 min; MS (EIpos): m / z = 452 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d _ö ): δ [ppm] = 2.42 (s, 3H), 3.86 (s, 3H), 6.27 (d, IH), 6.63 (t, IH), 7.15 (t , IH), 7.29 (t, IH), 7.35-7.44 (m, 4H), 7.61 (d, 2H), 7.71 (d, IH), 7.74 (d, IH), 8.10 (s, IH), 9.34 ( sbr, IH).

Example 24A

Methyl 2- {[3 -methyl-1 - (2-methylphenyl) -4- (3-oxo-3,4-dihydroquinoxaline-6-yl) -1 H -pyrazol-5-yl] amino} benzoate

299 mg (about 0.825 mmol, about 75%) of 7- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) quinoxaline-2 (1H) -one (see example 23A) together with 293 mg (0.733 mmol) of Example 9A, 25 mg (0.088 mmol) of tricyclohexylphosphine, 34 mg (0.037 mmol) of tris (dibenzylideneacetone) dipalladium and 1.25 ml (1.25 mmol) of IM potassium phosphate solution under argon atmosphere in 5 ml of dioxane. Then it was reacted overnight at 100 ⁰ C. After cooling, the mixture was filtered through kieselguhr, washed with ethyl acetate and the volatile components were separated on a rotary evaporator. The batch was concentrated and the residue was purified by HPLC (eluent: acetonitrile / water, gradient 20:80 → 90:10). There were obtained 86 mg (25% of theory) of the target compound.

LC-MS (Method 10): R, = 1.08 min; MS (EIpos): m / z = 466 [M + H] ⁺ . - -

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 2.14 (s, 3H), 2.42 (s, 3H), 3.79 (s, 3H), 6.43 (d, IH), 6.63 (t, IH ), 7.17 (t, IH), 7.23 (mz, IH), 7.27-7.34 (m, 2H), 7.35-7.43 (m, 3H), 7.68 (d, IH), 7.70 (d, IH), 8.09 ( s, IH), 9.18 (s, IH), 12.40 (s, IH).

Example 25A

7-Bromo-1-methylquinoxaline-2 (1H) -one

600 mg (2.67 mmol) of 7-bromoquinoxaline-2 (1H) -one [Lumma et al., J. Med. Chem. 1981, 24, 93] and 1.73 ml (3.47 mmol) of trimethylsilyldiazomethane were dissolved in 5.25 ml of methanol / acetone. nitrile / dichloromethane (1/10/10). Then, 0.483 ml (3.47 mmol) of triethylamine was added and stirred at room temperature overnight. The batch was concentrated and the residue was purified by MPLC (Puriflash AnaLogix: 4OM: isohexane / ethyl acetate = 9/1 → isohexane / ethyl acetate = 3/1). In addition to 140 mg (22% of theory) of 7-bromo-2-methoxyquinoxaline, 110 mg (17% of theory) of the target compound were also obtained.

LC-MS (Method 10): R, = 0.80 min; MS (EIpos): m / z = 240 [M + H] ⁺ .

¹ H NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 3.59 (s, 3H), 7.56 (dd, IH), 7.76 (d, IH), 7.82 (d, IH), 8.26 (s, IH ).

Example 26A

Methyl 2- {[3-methyl-4- (4-methyl-3-oxo-3,4-dihydro-quinoxalin-6-yl) -1-phenyl-1H-pyrazol-5-yl] amino} benzoate

- -

Under an argon atmosphere, 110 mg (0.46 mmol) Example 25A was dissolved in 8 ml dioxane. Then, 135 mg (1.38 mmol) of potassium acetate, 30 mg (0.037 mmol) of 1,1-bis (diphenylphosphino) ferrocenepalladium (π) chloride-dichloromethane complex and 129 mg

(0.506 mmol) 4,4,4 ', 4 ^l , 5,5,5', 5'-octamethyl-2,2'-bi-l, 3,2-dioxaborolane added. The reaction mixture was stirred overnight at 130 ⁰ C oil bath temperature. After cooling, the reaction mixture was treated with dioxane and filtered through kieselguhr. It was washed with ethyl acetate. The filtrate was concentrated on a rotary evaporator under reduced pressure and dried under high vacuum. Thus, 129 mg of 1-methyl-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxalin-2 (1H) -one as crude product [ca. 90% (LC-MS)]. This was reacted below without further purification.

127 mg of the thus obtained l-methyl-7- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) quinoxaline-2 (1H) -one together with 118 mg (0.444 mmol ) Example 22A, 10 mg (0.036 mmol) tricyclohexylphosphine, 14 mg (0.015 mmol) tris (dibenzylideneacetone) dipalladium and 0.503 ml (0.503 mmol) IM potassium phosphate solution are taken up under argon atmosphere in 8 ml dioxane. Then it was reacted overnight at 100 ⁰ C. After cooling, the mixture was filtered through kieselguhr, washed with ethyl acetate and the volatile components were separated on a rotary evaporator. The batch was concentrated and the residue was purified by HPLC (eluent: acetonitrile / water, gradient 20:80 → 90:10). 20 mg (14% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 1.18 min; MS (EIpos): m / z = 480 [M + H] ⁺ .

Example 27A

Methyl 2- {[3-methyl-1- (2-methylphenyl) -4- (2-oxo-1,2-dihydroquinoxalin-6-yl) -1 H -pyrazol-5-yl] amino} benzoate

- -

Under an argon atmosphere, 500 mg (2.22 mmol) of 6-bromoquinoxaline-2 (1H) -one [Lumma et al., J. Med. Chem. 1981, 24, 93] was dissolved in 15 ml of dioxane. Then, 392 mg (4.00 mmol) of potassium acetate, 145 mg (0.178 mmol) of l, r-bis (diphenylphosphino) ferrocenepalladium (II) chloride-dichloromethane complex and 620 mg (2.444 mmol) of 4,4,4 ', 4' were added. , 5,5,5 ¹ , 5 ^1- octamethyl-2,2 ¹ -bi-l, 3,2-dioxaborolane added. The reaction mixture was stirred overnight at 110 ⁰ C oil bath temperature. After cooling, the reaction mixture was treated with dioxane and filtered through kieselguhr. It was washed with ethyl acetate. The filtrate was concentrated on a rotary evaporator under reduced pressure and dried under high vacuum. Thus, 1013 mg of 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxalin-2 (1H) -one as crude product [ca. 40% (LC-MS)]. This was reacted below without further purification.

621 mg of the thus obtained 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxaline-2 (1H) -one together with 300 mg (0.749 mmol) of Example 9A, 25 mg (0.090 mmol) of tricyclohexylphosphine, 34 mg (0.037 mmol) of tris (dibenzylideneacetone) dipalladium and 1274 ml (1.274 mmol) of IM potassium phosphate solution were taken up under an argon atmosphere in 10 ml of dioxane. Then was reacted at reflux temperature overnight. After cooling, the mixture was filtered through kieselguhr, washed with ethyl acetate and the volatile components were separated on a rotary evaporator. The batch was concentrated and the residue was purified by HPLC (eluent: acetonitrile / water, gradient 20:80 → 90:10). 63 mg (18% of theory, based on Example 9A) of the target compound were obtained.

LC-MS (Method 1): R _t = 2.26 min; MS (EIpos): m / z = 466 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 2.16 (s, 3H), 2.95 (s, 3H), 3.78 (s, 3H), 6.44 (d, IH), 6.61 (t, IH ), 7.14-7.35 (m, 5H), 7.39 (d, IH), 7.65 (t, 2H), 7.81 (s, IH), 8.13 (s, IH), 9.13 (s, IH), 12.40 (sbr, IH).

Example 28A

Methyl 2- {[4- (2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl) -3-methyl-1-phenyl-1H-pyrazol-5-yl] amino} benzoate

750 mg (3.11 mmol) of 6-bromoquinazoline-2,4- (1H, 3H) -dione [Feng et al., J. Med. Chem. 2007, 50, 2297] were dissolved in 10 ml of dioxane under an argon atmosphere. Then 550 mg (5.60 mmol) of potassium acetate, 102 mg (0.124 mmol) of 1, 1'-bis (diphenylphosphino) ferrocenepalladium (π) chloride-dichloromethane complex and 790 mg (3.11 mmol) of 4,4,4 ', 4 ', 5,5,5', 5'-octamethyl-2,2'-bi-l, 3,2-dioxaborolane added. The reaction mixture was stirred overnight at 130 ⁰ C oil bath temperature. After cooling, the reaction mixture was treated with dioxane and filtered through kieselguhr. It was washed with ethyl acetate. The filtrate was concentrated on a rotary evaporator under reduced pressure and dried under high vacuum. Thus, 740 mg of 6- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) quinazoline-2,4 (1H, 3H) -dione as crude product [ca. 30% (LC-MS)]. This was reacted below without further purification.

370 mg of the thus obtained 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxaline-2 (1H) -one together with 397 mg (1.03 mmol) of Example 22A, 35 mg (0.123 mmol) of tricyclohexylphosphine, 47 mg (0.051 mmol) of tris (dibenzylideneacetone) dipalladium and 1.75 ml (1.75 mmol) of IM potassium phosphate solution were taken up in 10 ml of dioxane under an argon atmosphere. Then was reacted at reflux temperature overnight. After cooling, the mixture was filtered through kieselguhr, washed with ethyl acetate and the volatile components were separated on a rotary evaporator. The batch was concentrated and the residue was purified by HPLC (eluent: acetonitrile / water, gradient 20:80 → 90:10). 18 mg (4% of theory, based on Example 22A) of the target compound were obtained.

LC-MS (Method 4): R, = 1.10 min; MS (EIpos): m / z = 468 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.36 (s, 3H), 3.85 (s, 3H), 6.24 (d, IH), 6.62 (t, IH), 7.06-7.18 (m, 2H), 7.27 (t, IH), 7.39 (t, 2H), 7.61 (d, 2H), 7.71 (d, 2H), 7.93 (s, IH), 9.28 (s, IH), II l (s, IH), 11.24 (s, IH). - -

Example 29A

Methyl 2- {[4- (2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl) -3-methyl-1- (2-methylphenyl) -1 H -pyrazol-5-yl ] amino} benzoate

750 mg (3.11 mmol) of 6-bromoquinazoline-2,4 (1H, 3H) -dione [Feng et al., J. Med. Chem. 2007, 50, 2297] were dissolved in 10 ml of dioxane under an argon atmosphere. Then, 550 mg (5.60 mmol) of potassium acetate, 102 mg (0.124 mmol) of 1,1'-bis (diphenylphosphino) -furfoenzene palladium (π) chloride-dichlorometlian complex and 790 mg (3.11 mmol) of 4,4,4 ', 4 ', 5,5,5', 5'-octamethyl-2,2'-bi-l, 3,2-dioxaborolane added. The reaction mixture was stirred overnight at 130 ⁰ C oil bath temperature. After cooling, the reaction mixture was treated with dioxane and filtered through kieselguhr. It was washed with ethyl acetate. The filtrate was concentrated on a rotary evaporator under reduced pressure and dried under high vacuum. Thus, 740 mg of 6- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) quinazoline-2,4 (1H, 3H) -dione as crude product [ca. 30% (LC-MS)]. This was reacted below without further purification.

370 mg of the thus obtained 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxaline-2 (1H) -one together with 411 mg (1.03 mmol) of Example 9A, 35 mg (0.123 mmol) of tricyclohexylphosphine, 47 mg (0.051 mmol) of tris (dibenzylideneacetone) dipalladium and 1.75 ml (1.75 mmol) of IM potassium phosphate solution were taken up in 10 ml of dioxane under an argon atmosphere. Then was reacted at reflux temperature overnight. After cooling, the mixture was filtered through kieselguhr, washed with ethyl acetate and the volatile components were separated on a rotary evaporator. The batch was concentrated and the residue was purified by HPLC (eluent: acetonitrile / water, gradient 20:80 → 90:10). 26 mg (5% of theory based on Example 9A) of the target compound were obtained. - -

LC-MS (Method 4): R, = 1.11 min; MS (EIpos): m / z = 482 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 2.15 (s, 3H), 2.36 (s, 3H), 3.79 (s, 3H), 6.40 (d, IH), 6.61 (t, IH ), 7.10 (d, IH), 7.17 (t, IH), 7.22 (m, IH), 7.29 (m, 2H), 7.38 (d, IH), 7.66 (d, IH), 7.70 (dd, IH) , 7.92 (d, IH), 9.11 (s, IH), 11.11 (s, IH), 11.24 (s, IH).

Example 3OA

6- (4,4,5,5-tetramethyl-1,3,3-dioxaborolan-2-yl) quinazolin-4 (1H) -one

Under an argon atmosphere, 232 mg (0.253 mmol) of tris (dibenzylideneacetone) dipalladium (O) and 170 mg (0.608 mmol) of tricyclohexylphosphine were dissolved in 25 ml of dioxane. There were 1.179 g (4.643 mmol) of 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi-l, 3,2-dioxaborolan, 1000 mg (4.221 mmol ) 6-Bromoquinazolin-4 (lH) -one and 621 mg (6.332 mmol) of potassium acetate are added and the mixture is stirred at 80 ⁰ C overnight. After cooling, the reaction mixture was treated with dioxane and filtered through Celite. The filtrate was concentrated on a rotary evaporator under reduced pressure and dried under high vacuum. There were 2.7676 mg of the crude product (purity 52% by GC-MS), which was reacted further without further purification.

GC-MS (Method 6): R, = 8.60 min; MS (EIpos): m / z = 272 [M] ⁺ .

Example 31A

Methyl 2 - {[3-methyl-1- (2-methylphenyl) -4- (4-oxo-1,4-dihydroquinazolin-6-yl) -1H-pyrazol-5-yl] amino} benzoate - -

1,530 g of the crude product from example 30A with 51 mg (0.056 mmol) of tris-

(Dibenzylidenaceton) dipalladium (O) and 37 mg (0.135 mmol) of tricyclohexylphosphine. It was evacuated 5 times and aerated with argon. Subsequently, 3 ml of dioxane 450 mg (1.124 mmol) of the compound from Example 9A and 1.50 ml of a 1.27 M potassium phosphate solution were added. It was stirred overnight at 100 ⁰ C. After cooling, water was added and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative

HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). 97.3 mg (19% of theory) of the target compound were obtained.

LC-MS (Method 10): R _t = 1.03 min; MS (EIpos): m / z = 466 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 2.16 (s, 3H), 2.41 (s, 3H), 3.80 (s, 3H), 6.44 (d, IH), 6.58-6.62 (m , IH), 7.13-7.17 (m, IH), 7.21-7.32 (m, 3H), 7.40 (d, IH), 7.60 (d, IH), 7.65 (dd, IH), 7.87 (dd, IH), 8.03 (d, IH), 8.15 (d, IH), 9.16 (s, IH), 12.18 (dbr, IH).

Example 32A

7- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) quinazolin-4 (lH) -one

- -

Under an argon atmosphere, 232 mg (0.253 mmol) of tris (dibenzylideneacetone) dipalladium (O) and 170 mg (0.608 mmol) of tricyclohexylphosphine were dissolved in 25 ml of dioxane. There were 1,179 g (4,643 mmol) of 4,4,4 ^l , 4 ^t , 5,5,5 ', 5'-octamethyl-2,2'-bi-l, 3,2-dioxaborolan, 1000 mg (4.221 mmol ) 7-Bromochmazolin-4 (lH) -one and 621 mg (6.332 mmol) added potassium acetate and the mixture was stirred at 80 ⁰ C overnight. After cooling, the reaction mixture was treated with dioxane and filtered through Celite. The filtrate was concentrated on a rotary evaporator under reduced pressure and dried under high vacuum. There were 2,370 mg of the crude product (purity 33% by GC-MS), which was reacted further without further purification.

GC-MS (Method 6): R, = 8.68 min; MS (EIpos): m / z = 272 [M] ⁺ .

Example 33A

Methyl 2- {[3 -methyl-1 - (2-methylphenyl) -4- (4-oxo-1,4-dihydroquinazolin-7-yl) -1 H -pyrazol-5-yl] amino} benzoate

2,370 g of the crude product from Example 32A were admixed with 66 mg (0.072 mmol) of tris (dibenzylideneacetone) dipalladium (O) and 48 mg (0.172 mmol) of tricyclohexylphosphine. It was evacuated 5 times and aerated with argon. Subsequently, 4 ml of dioxane 575 mg (1.437 mmol) of the compound from Example 69A and 1.92 ml of a 1.27 M potassium phosphate solution were added. It was stirred overnight at 100 ⁰ C. After cooling, water was added and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). 79 mg (12% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 1.04 min; MS (EIpos): m / z = 466 [M + H] ⁺ . - -

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.16 (s, 3H), 2.44 (s, 3H), 3.79 (s, 3H), 6.43 (d, IH), 6.62 (t , IH), 7.15-7.31 (m, 4H), 7.41 (d, IH), 7.61 (dd, IH), 7.67 (dd, IH), 7.69 (d, IH), 8.02-8.04 (m, 2H), 9.18 (s, IH), 12.16 (s br, IH).

Example 34A

2-amino-5-bromo-3-fluorobenzonitrile

360 mg (2.645 mmol) 2-amino-3-fluorobenzonitrile [representation see: P. A. Renhowe et al. J. Med. Chem., 2009, 52 (2), 278-292.] Were dissolved in 5 ml of DMF and incubated at a temperature between -34 ° C and -23 ° C with a solution of 1,3-dibromo-5 , 5-dimethylhydantoin in 5 ml of DMF added dropwise. The mixture was stirred for 2 h at room temperature, the reaction mixture was treated with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). 308 mg (54% of theory) of the target compound were obtained.

GC-MS (Method 6): R, = 4.66 min; MS (EIpos): m / z = 214 [M] ⁺ .

¹ H NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 6.41 (s br, 2H), 7.53 (s, IH), 7.61 (dd, IH).

Example 35A

6-Bromo-8-fluoroquinazolin-4 (1H) -one

There were 3 ml of formic acid and with 350 ul of water and 100 mg of conc. Sulfuric acid and heated to 110 ⁰ C. 308 mg (1.432 mmol) of the compound from Example 34A were added in portions within one hour. After cooling, ice water was added and the The resulting solid was filtered off, washed with water and dried under high vacuum. 297 mg (85% of theory) of the target compound were obtained.

GC-MS (Method 6): Rt = 7.42 min; MS (EIpos): m / z = 242 [M] +.

IH-NMR (400 MHz, DMSO-Cl ₆ ): δ [ppm] = 8.03-8.05 (m, 2H), 8.19 (d, IH), 12.64 (s br, IH).

Example 36A

8-fluoro-6- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) quinazolin-4 (lH) -one

Under an argon atmosphere, 60 mg (0.065 mmol) of tris (dibenzylideneacetone) dipalladium (0) and 44 mg (0.157 mmol) of tricyclohexylphosphine were dissolved in 7 ml of dioxane. There were 305 mg (1,199 mmol) of 4,4,4 ', 4', 5,5,5 ¹ , 5'-octamethyl-2,2'-bi-l, 3,2-dioxaborolan, 265 mg (1090 mmol ) of the compound from Example 153A and 160 mg (1.636 mmol) of potassium acetate are added and the mixture is stirred at 80 ^° C. overnight. After cooling, the reaction mixture was treated with dioxane and filtered through Celite. The filtrate was concentrated on a rotary evaporator under reduced pressure and dried under high vacuum. There were obtained 851 mg of the crude product (purity 23% by GC-MS), which was reacted further without further purification.

GC-MS (Method 6): R, = 8.88 min; MS (EIpos): m / z = 290 [M] ⁺ .

Example 37A

Methyl 2- {[4- (8-fluoro-4-oxo-1,4-dihydroquinazolin-6-yl) -3-methyl-1- (2-methylphenyl) -1 H -pyrazol-5-yl] -amino } benzoate - -

851 mg of the crude product from example 36A with 40 mg (0.044 mmol) of tris

(dibenzylideneacetone) dipalladium (O) and 29 mg (0.105 mmol) of tricyclohexylphosphine. It was evacuated 5 times and aerated with argon. Subsequently, 3 ml of dioxane 350 mg (0.874 mmol) of the compound from Example 9A and 1.17 ml of a 1.27 M potassium phosphate solution were added. It was stirred for 2 h at 100 ⁰ C. After cooling, water was added and with

Extracted ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (eluent:

Acetonitrile / water, gradient 10:90 → 90:10). 47 mg (11% of theory) of the target compound were obtained.

LC-MS (Method 2): R, = 2.18 min; MS (EIpos): m / z = 484 [M + H] ⁺ .

Example 38A

6- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -l, 2,3-benzotriazin-4 (3H) -one

Under an argon atmosphere, 243 mg (0.265 mmol) of tris (dibenzylideneacetone) dipalladium (O) and 179 mg (0.637 mmol) of tricyclohexylphosphine were dissolved in 27 ml of dioxane. There were 1,236 g of 4 (4.866 mmol) of 4,4,4 ^l, ', 5,5,5', 5 ^I -Octamethyl-2,2'-bi-l, 3,2-dioxaborolan, 1.000 g (4.424 mmol ) 6-Bromo-l, 2,3-benzotriazine-4 (3H) -one and 651 mg (6.636 mmol) of potassium acetate are added and the mixture is stirred overnight at 80 ⁰ C. After cooling, the reaction mixture was treated with dioxane and filtered through Celite. The filtrate was on - -

Rotary evaporator concentrated under reduced pressure and dried under high vacuum. There were 2,950 g of the crude product (purity 19% after LC-MS), which was reacted further without further purification.

LC-MS (method 2): R, = 1.97 min; MS (EIpos): m / z = 274 [M + H] ⁺ .

Example 39A

Methyl 2- {[3-methyl-1- (2-methylphenyl) -4- (4-oxo-3,4-dihydro-1,2,3-benzotriazin-6-yl) -1H-pyrazole-5 -yljamino} benzoate

2,950 g of the crude product from Example 38A were admixed with 81 mg (0.089 mmol) of tris (dibenzylideneacetone) dipalladium (O) and 60 mg (0.214 mmol) of tricyclohexylphosphine. It was evacuated 5 times and aerated with argon. Subsequently, 5 ml of dioxane 713 mg (1.782 mmol) of the compound from Example 69A and 2.39 ml of a 1.27 M potassium phosphate solution were added. It was stirred overnight at 100 ⁰ C. After cooling, water was added and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative

HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). There were 81 mg (10% d.

Th.) Of the target compound.

LC-MS (Method 10): R, = 1.10 min; MS (EIpos): m / z = 467 [M + H] ⁺ . - -

Embodiments;

example 1

5-Methoxy-2- {[3-methyl-1- (2-methylphenyl) -4- (2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -1H-pyrazole-5 - yl] amino} benzoic acid

20 mg (0.006 mmol) of the compound from Example 3A were dissolved in 1 ml dioxane / water (v / v = 3: 1) and admixed with 65 μl IN sodium hydroxide solution. It was stirred overnight at room temperature. The reaction mixture was acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum. 9 mg (46% of theory) of the target compound were obtained.

LC-MS (Method 1): R, = 1.93 min; MS (EIpos): m / z = 470 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.11 (s, 3H), 2.32 (s, 3H), 3.59 (s, 3H), 6.38 (d, IH), 6.82 (dd , IH), 6.87 (d, IH), 6.93 (s, IH), 6.97 (d, IH), 7.15 (d, IH), 7.17-7.22 (m, IH), 7.27-7.30 (m, 3H), 9.06 (sbr, IH), 10.53 (s, IH), 10.56 (s, IH), 13.05 (sbr, IH).

Example 2

5-Methoxy-2 - {[3-methyl-1- (2-methylphenyl) -4- (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-6-yl) - 1 H-pyrazol-5-yl] amino} benzoic acid - -

13 mg (0.006 mmol) of the compound from Example 4A were dissolved in 640 μl dioxane / water (v / v = 3: 1) and mixed with 40 μl IN sodium hydroxide solution. It was stirred overnight at room temperature. The reaction mixture was acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). 10 mg (79% of theory) of the target compound were obtained.

LC-MS (Method 3): R, = 1.42 min; MS (EIpos): m / z = 471 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.12 (s, 3H), 2.34 (s, 3H), 3.59 (s, 3H), 6.38 (d, IH), 6.82 (i.e. , IH), 7.17 (d, IH), 7.18-7.23 (m, 2H), 7.27-7.31 (m, 3H), 7.89 (s, IH), 9.03 (sbr, IH), 10.77 (s, IH), 11.27 (s, IH), 13.06 (sbr, IH).

Example 3

5-Methoxy-2 - {[3-methyl-4- (3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl) -1- (2-methylphenyl) -1H-pyrazol-5-yl] amino} benzoic acid

- -

47 mg (0.092 mmol) of the compound from Example 7A were taken up in 5 ml of dioxane / water (v / v = 4/1). After the addition of 0.184 ml (0.184 mmol) IN sodium hydroxide solution, the batch was stirred overnight at room temperature. The volatile components were largely removed on a rotary evaporator. Then the residue was taken up in water and slightly acidified with 1N hydrochloric acid. The precipitated product was filtered off, washed with a little water and dried overnight under high vacuum. 43 mg (89% of theory) of the target compound were obtained.

LC-MS (Method 2): R ₁ = 1.95 min; MS (EIpos): m / z = 496 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d _ö ): δ [ppm] = 2.13 (s, 3H), 2.40 (s, 3H), 3.47 (s, 3H), 3.57 (s, 3H), 6.38 (i.e. , IH), 6.79 (dd, IH), 7.15 (d, IH), 7.22 (m, IH), 7.29-7.36 (m, 3H), 7.61 (d, IH), 7.86 (dd, IH), 8.17 ( d, IH), 8.32 (s, IH), 9.14 (s, IH), 13.09 (sbr, IH).

Example 4

2- {[3-Methyl-4- (3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl) -1- (2-methylphenyl) -1 H -pyrazol-5-yl] amino} benzoic acid - -

100 mg (0.209 mmol) of the compound from Example 10A were taken up in 7.5 ml of dioxane / water (v / v = 4/1). After the addition of 0.417 ml (0.417 mmol) of 1N sodium hydroxide solution, the batch was stirred overnight at room temperature. The volatile components were largely removed on a rotary evaporator. Then the residue was taken up in water and slightly acidified with 1N hydrochloric acid. The precipitated product was filtered off, washed with a little water and dried overnight in a high vacuum. The residue was purified again by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). 52 mg (53% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 0.97 min; MS (EIpos): m / z = 466 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 2.15 (s, 3H), 2.40 (s, 3H), 3.46 (s, 3H), 6.41 (d, IH), 6.58 (t, IH ), 7.12 (t, IH), 7.18-7.39 (m, 4H), 7.61 (d, IH), 7.65 (dd, IH), 7.87 (dd, IH), 8.18 (d, IH), 8.31 (s, IH), 9.49 (s, IH), 12.98 (sbr, IH).

Example 5

2- {[3-Methyl-4- (3-methyl-4-oxo-3,4-dihydro-1,2,3-benzotriazin-6-yl) -1- (2-methylphenyl) -1H-pyrazole -5-yl] amino} benzoic acid - -

43 mg (0.089 mmol) of the compound from Example 13A were taken up in 5 ml of dioxane / water (v / v = 4/1). After the addition of 0.179 ml (0.179 mmol) of 1 N sodium hydroxide solution, the batch was stirred overnight at room temperature. The volatile components were largely removed on a rotary evaporator. Then the residue was taken up in water and slightly acidified with 1N hydrochloric acid. The precipitated product was filtered off, washed with a little water and dried overnight in a high vacuum. The residue was purified again by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). There were obtained 23 mg (51% of theory) of the target compound.

LC-MS (Method 4): R, = 1.21 min; MS (EIpos): m / z = 467 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 2.15 (s, 3H), 2.45 (s, 3H), 3.89 (s, 3H), 6.40 (d, IH), 6.59 (t, IH ), 7.12 (t, IH), 7.23 (m, IH), 7.27-7.34 (m, 2H), 7.39 (d, IH), 7.67 (dd, IH), 8.14 (s, 2H), 8.27 (s, IH), 9.58 (s, IH), 13.04 (sbr, IH).

Example 6

2- {[3-Methyl-4- (2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl) -1- (2-methylphenyl) -1 H -pyrazol-5-yl] amino} benzoic acid

135 mg (0.282 mmol) of the compound from Example 17A were dissolved in a mixture of 15 ml

Dioxane and 4 ml of water added. After the addition of 0.563 ml (0.563 mmol) IN

Sodium hydroxide solution, the mixture was stirred overnight at room temperature. An additional 0.141 ml (0.141 mmol) was added IN sodium hydroxide solution and stirred at 80 ⁰ C for 2 h. Then the fleeting ones

Components largely separated on a rotary evaporator. The residue was taken up in water and slightly acidified with 1N hydrochloric acid. It was extracted with ethyl acetate (3x) and the combined organic phases were washed with saturated aqueous sodium chloride solution. It was then dried with magnesium sulfate, concentrated on a rotary evaporator and dried under high vacuum. 109 mg (83% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 0.93 min; MS (EIpos): m / z = 466 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 2.14 (s, 3H), 2.31 (s, 3H), 2.42 (s, 3H), 6.41 (d, IH), 6.60 (t, IH ), 7.14 (mz, IH), 7.22 (m, IH), 7.27-7.33 (m, 2H), 7.36 (d, IH), 7.52 (dd, IH), 7.60 (d, IH), 7.67 (dd, IH), 7.98 (d, IH), 9.50 (s, IH), 12.13 (s, IH), 13.03 (sbr, IH).

Example 7

2 - {[4- (2,3-dimethyl-4-oxo-3,4-dihydroquinazolin-7-yl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-yl] amino} benzoic acid - 0 -

180 mg (0.365 mmol) of the compound from Example 2OA were taken up in a mixture of 15 ml of dioxane and 5 ml of water. After the addition of 0.729 ml (0.729 mmol) IN sodium hydroxide solution, the mixture was stirred overnight at room temperature. Then, the volatile components were largely separated on a rotary evaporator. The residue was taken up in water and slightly acidified with 1N hydrochloric acid. The precipitated target compound was filtered off, washed with a little water and then dried under high vacuum. 167 mg (95% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 1.00 min; MS (EIpos): m / z = 480 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 2.14 (s, 3H), 2.42 (s, 3H), 3.50 (s, 3H), 6.41 (d, IH), 6.59 (t, IH ), 7.13 (mz, IH), 7.23 (m, IH), 7.27-7.33 (m, 2H), 7.36 (d, IH), 7.53 (dd, IH), 7.60 (d, IH), 7.67 (dd, IH), 8.00 (d, IH), 9.51 (s, IH), 13.04 (sbr, IH).

Example 8

2 - {[3-methyl-4- (3-oxo-3,4-dihydro-6-yl) -l-phenyl-lH-pyrazol-5-yl] amino} benzoic acid

- 1 -

212 mg (0.470 mmol) of the compound from Example 23A were taken up in 15 ml of dioxane. After the addition of 4.70 ml (4.70 mmol) IN sodium hydroxide solution, the batch was stirred overnight at room temperature. Then, the volatile components were largely separated on a rotary evaporator. The residue was taken up in water and slightly acidified with 1N hydrochloric acid. The precipitated target compound was extracted with ethyl acetate (2x) and the combined organic phases were washed with a little water. After separation of the volatile components on a rotary evaporator was finally dried under high vacuum. 69 mg (33% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 0.96 min; MS (EIpos): m / z = 438 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ [ppm] = 2.42 (s, 3H), 6.27 (d, IH), 6.62 (t, IH), 7.13 (t, IH), 7.29 ( t, IH), 7.34-7.45 (m, 4H), 7.59 (d, 2H), 7.70 (d, IH), 7.75 (d, IH), 8.10 (s, IH), 9.64 (sbr, IH), 12.41 (s, IH), 13.05 (sbr, IH).

Example 9

2- {[3-Methyl-1 - (2-methylphenyl) -4- (3-oxo-3,4-dihydroquinoxaline-6-yl) -1 H -pyrazol-5-yl] amino} benzoic acid

86 mg (0.185 mmol) of the compound from Example 24A were taken up in 15 ml of dioxane. After addition of 1.85 ml (1.85 mmol) of 1N sodium hydroxide solution, the batch was reacted at room temperature for 48 h. Then, the volatile components were largely separated on a rotary evaporator. The residue was taken up in water and slightly acidified with 1N hydrochloric acid. The precipitated target compound was extracted with ethyl acetate (2x) and the combined organic phases were washed with a little water. After separation of the volatile components on a rotary evaporator was finally dried under high vacuum. 54 mg (57% of theory) of the target compound were obtained. - -

LC-MS (Method 10): Rt = 0.96 min; MS (EIpos): m / z = 452 [M + H] +.

IH-NMR (400 MHz, DMSO-d6): δ [ppm] = 2.13 (s, 3H), 2.42 (s, 3H), 6.41 (d, IH), 6.61 (t, IH), 7.14 (t, IH ), 7.23 (raz, IH), 7.27-7.42 (m, 5H), 7.69 (mz, 2H), 8.09 (s, IH), 9.52 (s, IH), 12.39 (s, IH), 13.02 (sbr, IH).

Example 10

2 - {[3-Methyl-4- (4-methyl-3-oxo-3,4-dihydro-quinoxalin-6-yl) -1-phenyl-1H-pyrazol-5-yl] amino} benzoic acid

20 mg (0.042 mmol) of the compound from Example 26A were taken up in 4 ml of dioxane. After addition of 1.85 ml (1.85 mmol) of 1N sodium hydroxide solution, the batch was reacted at room temperature for 48 h. Then, the volatile components were largely separated on a rotary evaporator. The residue was taken up in water and slightly acidified with 1N hydrochloric acid. The precipitated target compound was extracted with ethyl acetate (2x) and the combined organic phases were washed with a little water. After separation of the volatile components on a rotary evaporator was finally dried under high vacuum. There was obtained 21 mg (98% of theory) of the target compound in 91% purity (LC-MS).

LC-MS (Method 10): R, = 1.03 min; MS (EIpos): m / z = 466 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ [ppm] = 2.20 (s, 3H), 2.46 (s, 3H), 3.45 (s, 3H), 6.41 (d, IH), 6.60 ( t, IH), 7.15 (t, IH), 7.24 (mz, IH), 7.28-7.36 (m, 2H), 7.40 (d, IH), 7.47 (d, IH), 7.58 (s, IH), 7.67 (d, IH), 7.78 (d, IH), 8.16 (s, IH), 9.53 (sbr, IH), 13.06 (sbr, IH).

Example 11

2 - {[3-Methyl-1- (2-methylphenyl) -4- (2-oxo-1,2-dihydro-quinoxalin-6-yl) -1H-pyrazol-5-yl] amino} benzoic acid - -

80 mg (0.172 mmol) of the compound from Example 27A were taken up in 5.5 ml of dioxane. After the addition of 0.430 ml (0.430 mmol) IN sodium hydroxide solution, the mixture was reacted overnight at room temperature. Then, the volatile components were largely separated on a rotary evaporator. The residue was taken up in water and slightly acidified with 1N hydrochloric acid. The precipitated target compound was extracted with ethyl acetate (2x) and the combined organic phases were washed with a little water. After separation of the volatile components on a rotary evaporator was finally dried under high vacuum. There was obtained 77 mg (94% of theory) of the target compound in 94% purity (LC-MS).

LC-MS (Method 10): R, = 0.94 min; MS (EIpos): m / z = 452 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.15 (s, 3H), 2.39 (s, 3H), 6.42 (d, IH), 6.59 (t, IH), 7.15 (t , IH), 7.18-7.33 (m, 4H), 7.36 (d, IH), 7.63 (d, IH), 7.66 (d, IH), 7.79 (s, IH), 8.13 (s, IH), 9.44 ( s, IH), 12.40 (sbr, IH), 13.00 (sbr, IH).

Example 12

2- {[4- (2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl) -3-methyl-1-phenyl-1H-pyrazol-5-yl] amino} benzoic acid

- 4 -

18 mg (0.039 mmol) of the compound from Example 28A were taken up in 1.2 ml dioxane / water (5/1). After the addition of 0.077 ml (0.077 mmol) IN sodium hydroxide solution, the batch was reacted overnight at room temperature. The saponification was incomplete, so it was reacted again at 60 ⁰ C overnight. Then the volatile components on the

Rotary evaporator largely separated. The residue was taken up in water and slightly acidified with 1N hydrochloric acid. The precipitated target compound was isolated by filtration and washed with a little water. After separation of the volatile components on a rotary evaporator was finally dried under high vacuum. 16 mg (92% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 0.88 min; MS (EIpos): m / z = 454 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ [ppm] = 2.36 (s, 3H), 6.25 (d, IH), 6.61 (t, IH), 7.08-7.16 (m, 2H), 7.27 (t, IH), 7.39 (t, 2H), 7.59 (d, 2H), 7.68 (d, IH), 7.72 (d, IH), 7.90 (s, IH), 9.53 (s, IH), 11.08 ( s, IH), 11.20 (s, IH), 12.99 (sbr, IH).

Example 13

2- {[4- (2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl) -3-methyl-1- (2-methylphenyl) -1 H -pyrazol-5-yl] -amino } benzoic acid - 5 -

26 mg (0.054 mmol) of the compound from Example 29A were taken up in 1.2 ml dioxane / water (5/1). After the addition of 0.108 ml (0.108 mmol) IN sodium hydroxide solution, the batch was reacted overnight at room temperature. The saponification was incomplete, so it was reacted again at 60 ⁰ C overnight. Then the volatile components on the

Rotary evaporator largely separated. The residue was taken up in water and slightly acidified with 1N hydrochloric acid. The precipitated target compound was isolated by filtration and washed with a little water. After separation of the volatile components on a rotary evaporator was finally dried under high vacuum. 15 mg (53% of theory) of the target compound were obtained in 90% purity (LC-MS).

LC-MS (Method 10): R, = 0.89 min; MS (EIpos): m / z = 468 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.13 (s, 3H), 2.35 (s, 3H), 6.39 (d, IH), 6.59 (t, IH), 7.07-7.17 (m, 2H), 7.21 (m, IH), 7.26-7.35 (m, 3H), 7.63-7.73 (m, 2H), 7.90 (s, IH), 9.40 (s, IH), 11.08 (s, IH ), 11.20 (s, IH), 12.94 (sbr, IH).

Example 14

2- {[3-Methyl-1 - (2-methylphenyl) -4- (4-oxo-1,4-dihydroquinazolin-6-yl) -1 H -pyrazol-5-yl] amino} benzoic acid - -

67 mg (0.144 mmol) of the compound from Example 31A were dissolved in 4 ml dioxane / water (v / v = 3: 1) and combined with 290 μl IN sodium hydroxide solution. The mixture was stirred at room temperature overnight. It was then acidified with 1N hydrochloric acid. The mixture was extracted with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The organic phase was concentrated on a rotary evaporator. There were obtained 66 mg (98% of theory) of the target compound.

LC-MS (Method 10): R, = 0.91 min; MS (EIpos): m / z = 452 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 2.15 (s, 3H), 2.40 (s, 3H), 6.42 (d, IH), 6.56-6.60 (m, IH), 7.10-7.14 (m, IH), 7.20-7.31 (m, 3H), 7.36 (d, IH), 7.61 (d, IH), 7.66 (dd, IH), 7.86 (dd, IH), 8.03 (d, IH), 8.14 (d, IH), 9.48 (s, IH), 12.18 (d br, IH), 12.99 (s br, IH).

Example 15

2- {[3-Methyl-1 - (2-methylphenyl) -4- (4-oxo-1,4-dihydroquinazolin-7-yl) -1 H -pyrazol-5-yl] amino} benzoic acid

- -

72 mg (0.155 mmol) of the compound from Example 33A were dissolved in 4 ml dioxane / water (v / v = 3: 1) and admixed with 310 μl IN sodium hydroxide solution. The mixture was stirred at room temperature overnight. It was then acidified with 1N hydrochloric acid. The mixture was extracted with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The organic phase was concentrated on a rotary evaporator. There were obtained 71 mg (100% of theory) of the target compound.

LC-MS (Method 10): R, = 0.91 min; MS (EIpos): m / z = 452 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.15 (s, 3H), 2.44 (s, 3H), 6.42 (d, IH), 6.60 (t, IH), 7.12-7.16 (m, IH), 7.20-7.32 (m, 3H), 7.38 (d, IH), 7.60 (dd, IH), 7.66-7.68 (m, 2H), 8.02-8.04 (m, 2H), 9.51 (s , IH), 12.16 (s br, IH), 13.03 (s br, IH).

Example 16

2- {[4- (8-Fluoro-4-oxo-1,4-dihydroquinazolin-6-yl) -3-methyl-1- (2-methylphenyl) -1 H -pyrazol-5-yl] amino} benzoic acid

45 mg (0.093 mmol) of the compound from Example 37A were dissolved in 9 ml dioxane / water (v / v = 3: 1) and treated with 190 μl IN sodium hydroxide solution. The mixture was stirred at room temperature overnight. It was then acidified with 1N hydrochloric acid. The mixture was extracted with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The organic phase was concentrated on a rotary evaporator and the residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). 29 mg (66% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 0.94 min; MS (EIpos): m / z = 470 [M + H] ⁺ .

¹ H NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 2.15 (s, 3H), 2.42 (s, 3H), 6.40 (d, IH), 6.58-6.61 (m, IH), 7.11-7.16 (m, IH), 7.21-7.32 (m, 3H), 7.37 (d, IH), 7.67 (dd, IH), 7.76 (dd, IH), 7.96 (d, IH), 8.08 (d, IH), 9.51 (s br, IH), 12.41 (dbr, IH), 13.03 (s br, IH).

Example 17

2- {[3-Methyl-1 - (2-methylphenyl) -4- (4-oxo-3,4-dihydro-1,2,3-benzotriazin-6-yl) -1 H -pyrazol-5-yl ] amino} benzoic acid

78 mg (0.166 mmol) of the compound from Example 39A were dissolved in 3 ml of dioxane / water (v / v = 3: 1) and combined with 330 μl of 1N sodium hydroxide solution. The mixture was stirred at room temperature overnight. It was then acidified with 1N hydrochloric acid. The mixture was extracted with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The organic phase was concentrated on a rotary evaporator and the residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). 39 mg (51% of theory) of the target compound were obtained.

LC-MS (Method 10): R, = 0.98 min; MS (EIpos): m / z = 453 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.15 (s, 3H), 2.45 (s, 3H), 6.40 (d, IH), 6.56-6.60 (m, IH), 7.08 -7.12 (m, IH), 7.21-7.32 (m, 3H), 7.38 (d, IH), 7.67 (dd, IH), 8.10-8.15 (m, 2H), 8.23 (d, IH), 9.65 (s br, IH), 13.06 (s br, IH), 14.86 (s, IH).

- -

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

SmGM Smooth Muscle Cell Growth Media

Tris-HCl 2-amino-2- (hydroxymethyl) -1,3-propanediol hydrochloride

UtSMC Uterine Smooth Muscle Cells

BI. Indirect determination of adenosine antagonism via gene expression

Cells of the permanent line CHOKl (Chinese hamster ovary) are stably transfected with a reporter construct (CRE-luciferase) and the cDNA for the adenosine receptor subtypes A2a or A2b. A2a and A2b receptors are coupled to the adenylate cyclase via Gαs proteins. Receptor activation activates adenylate cyclase, thereby increasing the cAMP level in the cell. Via the reporter construct, a cAMP-dependent promoter, the change of the cAMP level is coupled to the luciferase expression.

For the determination of adenosine antagonism at the adenosine Al receptor subtype CHO Kl cells are also stably transfected, this time with a Ca ²⁺ -sensitive reporter construct (NFAT-TA-Luc, Clontech) and an Al-Gαl6 fusion construct. This receptor chimera is coupled to the phospholipase C in contrast to the native Al receptor (Gαi coupling). The luciferase is expressed here 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 IM HEPES (Cat. No 15630, Gibco), 20 ml / Liter of GlutaMAX (Cat. No. 35050-038, Gibco), 14 ml / liter MEM sodium pyruvate (Cat. No 11360-039; Gibco), 10 ml / liter PenStrep (Cat. No 15070-063, Gibco) Cultured at 37 ° C under 5% carbon dioxide and split twice a week.

For testing in 384- or 96-well plate format, the cells are seeded at 2000 and 5000 cells / well in 25 and 50 .mu.l / well sowing medium and until substance testing at 37 ° C. - 1 - cultured under 5% carbon dioxide. The A2a and A2b cells are seeded 24 h prior to substance testing in medium supplemented with 5% FCS, using the A2a cells as the basic medium DMEM / F12 and for the A2b cells OptiMEM (Cat. No 31985-047; Gibco) is used. The Al-Gαl6 cells are seeded 48 hours before substance testing in OptiMEM with 2.5% dialysed or activated carbon-treated FCS and additives. The substances are added to a final concentration of 1 x 10 ^"5 M to 1 x 10 ^{~ u} M to the test cultures, the DMSO content not exceeding on the cells 0.5%. The agonist is for the A2a and A2b cells NECA (5-N-Ethylcarboxamido-adenosine) in a final concentration of 30 nM, which corresponds approximately to the EC _50. For the Al-Gαl6 cells 25 nM CPA (N6-cyclopentyl-adenosine) is used as an agonist After the substance has been added, the cell plates are incubated for 3-4 h at 37 ° C. under 5% carbon dioxide, and the cells are then incubated with 25 μl of a solution consisting of 50% lysis reagent directly before the measurement. 30 mM disodium hydrogen phosphate, 10% glycerol, 3% Triton X-100, 25 mM TrisHCl, 2 mM dithiothreitol (DTT), pH 7.8) and 50% 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) t is detected by a luminescence reader. Determined are the IC ₅ o values, ie the concentration at which the luciferase response caused by the respective agonist is inhibited to 50%. The reference antagonist used is ZM241385 for the A2a and A2b cells and DPCPX (1,3-dipropyl-8-cyclopentylxanthine) for the Al-Gαl6 cells.

Alternative test procedure

The permanent cell lines are transfected into DMEM / F12 Glutamax (Cat. No 31331-028; Gibco) with 10% FCS (Fetal Calf Serum) and various additives (10 ml / liter IM HEPES (Cat. No 15630, Gibco), 14 ml / liter of MEM sodium pyruvate (Cat. No. 11360-039; Gibco) at 37 ° C under 5% carbon dioxide and split twice a week.

For testing in 384- or 96-well plate format, the cells are seeded at 2000 and 5000 cells / well in 25 and 50 .mu.l / well test medium (OptiMEM Glutamax with 2.5% charcoal-treated FCS, Hyclone) and up to substance testing at 37 ° C below 5% - -

Cultivated carbon dioxide. The A2a and A2b cells are seeded 24 hours prior to substance testing in OptiMEM with 2.5% charcoal-treated FCS (Hyclone). The Al-Gαl6 cells are seeded 48 hours before substance testing in OptiMEM glutamax with 2.5% charcoal-treated FCS and additives. The substances are added to a final concentration of 1 x 10 ^-5 M to 1 x 10 ^'11 M to the test cultures, the DMSO content not exceeding 0.5% of the cells. The agonist used for the A2a and A2b cells is NECA (5-N-ethylcarboxamidoadenosine) in a final concentration of 30 nM, which corresponds approximately to the ECso concentration. For the Al-Gal6 cells, 25 nM CPA (N6-cyclopentyl-adenosine) is used as agonist, which corresponds approximately to the EC ₇₅ concentration. 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 50 .mu.l of a solution consisting of 50% lysis reagent (Triton buffer, PAA Cat.No T21-160) and 50% luciferase substrate solution (2.5 mM ATP, 0.5 mM Luciferin, 0.1mM coenzyme A, 10mM tricine, 1.35mM magnesium sulfate, 15mM DTT, pH 7.8). The luciferase activity is detected with a luminescence reader. The IC ₅₀ values are determined, ie the concentration at which the luciferase response caused by the respective agonist is inhibited to 50%. The IC ₅₀ values are calculated using the computer program GraphPad PRISM (version 3.02). The reference antagonist used is ZM241385 for the A2a and A2b cells and DPCPX (1,3-dipropyl-8-cyclopentylxanthine) for the Al-Gαl6 cells.

B-2. Binding Studies on Membrane Preparations of Cells with Adenosine Al Receptors

For the production of cell membranes with human adenosine A1 receptors, Al receptor-stable over-expressing CHO cells (see Bl) were lysed and then differentially centrifuged. After lysis in binding buffer (50 mM tris- (hydroxymethyl) -aminomethane / IN hydrochloric acid, 5 mM magnesium chloride, pH 7.4 with an Ultra Turrax (Jahnke & Kunkel, Ika-Werk), the homogenate is treated with 1000 g at 4 ° C for Centrifuged for 10 minutes The resulting sediment - - Is discarded and the supernatant is centrifuged with 20000g at 4 ° C for 30 min. The supernatant is discarded and the sediment is resuspended in binding buffer and until binding experiment stored at - 70 ⁰ C.

For the binding experiment, 1 nM of ³ H-DPCPX (1,3-dipropyl-8-cyclopentylxanthine) (4.44 TBq / mmol, PerkinElmer) was incubated with 30 - 300 μg / ml human cell membranes in binding buffer for 60 minutes with 0.2 units / ml adenosine Deaminase (Sigma) (total test volume 0.2 ml) in the presence of the test substances at 30 ⁰ C in 96-well filter plates (FC / B glass fiber, Multiscreen Millipore) incubated. After completion of the incubation by suction of the unbound radioactivity, the plates are washed with binding buffer mixed with 0.1% bovine serum albumin and then dried at 40 ⁰ C overnight. Thereafter, liquid scintillator (Ultima Gold, Perkin Elmer) is added and the radioactivity remaining in the plates is measured in liquid scintillation counter (Microbeta, Wallac). Non-specific binding is defined as radioactivity in the presence of 1 μM DPCPX (Sigma) and is typically <25% of the total bound radioactivity. The binding data (IC50 and dissociation constant Ki) are determined by means of the program GraphPad Prism Version ¹ 4.0.

B-3. In vivo test for the detection of cardiovascular effects: blood pressure measurement in anesthetized rats

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

B-4. In v / vo test to demonstrate the cardiovascular effect: Blood pressure measurements on awake spontaneously hvpertensiven rats

A commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA is used for the blood pressure measurement on awake rats described below.

The system consists of 3 main components:

1. Implantable Transmitter (Physiotel® Telemetry Transmitter)

2. Receiver (Physiotel® Receiver) connected via a multiplexer (DSI Data Exchange Matrix) with a 3. Data acquisition computer are connected.

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

animal material

The investigations are carried out on adult female spontaneously hypertensive rats (SHR Okamoto) with a body weight of> 200 g. SHR / NCrl from Okamoto Kyoto School of Medicine, crossed in 1963 from male Wistar Kyoto rats with greatly elevated blood pressure and female with slightly elevated blood pressure, and in Fl 3 to U.S. Pat. National Institutes of Health.

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

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

transmitter implantation

The TAH PA - C40 telemetry transmitters are surgically implanted into the experimental animals under aseptic conditions at least 14 days before the first trial. The animals so instrumented are repeatedly used after healing of the wound and ingrowth of the implant.

For implantation, the fasting animals are anesthetized with pentobabital (Nembutal, Sanofi: 50 mg / kg i.p.) and shaved and disinfected on the ventral side. After opening the abdominal cavity along the alba line, the system's liquid-filled measuring catheter above the bifurcation is inserted cranially into the descending aorta and secured with tissue adhesive (VetBonD ™, 3M). The transmitter housing is fixed intraperitoneally to the abdominal wall musculature and the wound is closed in layers.

Postoperatively, an antibiotic is administered for infection prevention (Tardomyocel COMP Bayer 1ml / kg s.c.)

Substances and solutions

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

A solvent-treated group of animals is used as a control.

experimental procedure

The existing telemetry measuring device is configured for 24 animals. Each trial is registered under a trial number (VYear month day).

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

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

In the standard procedure duration is measured over every 10 seconds

• Systolic blood pressure (SBP)

Diastolic blood pressure (DBP)

• Mean arterial pressure (MAP)

• heart rate (HR)

• Activity (ACT)

The measured value acquisition is repeated computer-controlled in 5-minute intervals. The absolute value of the source data is corrected in the diagram with the currently measured barometric pressure (Ambient Pressure Reference Monitor, APR-I) and stored in individual data. Further technical details can be found in the extensive documentation of the manufacturer (DSI).

Unless otherwise stated, the administration of the test substances will take place at 9 o'clock on the day of the experiment. Following the application, the parameters described above are measured for 24 hours.

evaluation - -

After the end of the test, the collected individual data are sorted with the analysis software (DATAQUEST TM A.RT. TM ANALYSIS). The blank value is assumed to be 2 hours before the application, so that the selected data record covers the period from 7:00 am on the test day to 9:00 am on the following day.

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

B-fifth In vt'vo test to demonstrate the cardiovascular effect: diuresis studies on awake rats in metabolic cages

Wistar rats (200-400 g body weight) are kept with free access to food (Altromin) and drinking water. During the experiment, the animals are kept individually for 4 hours in metabolic cages suitable for rats of this weight class (Tecniplast Deutschland GmbH, D-82383 Hohenpeissenberg) with free access to drinking water. The substance to be tested is administered in a volume of 1 to 2 ml / kg body weight of a suitable solvent orally by gavage into the stomach, or administered intravenously. Animals serving as control receive only solvents via the corresponding route of administration. Controls and substance testing are done in parallel on the same day. Control groups and substance dose groups each consist of 4 to 8 animals. During the experiment, the urine excreted by the animals is continuously collected in a container on the floor of the cage. The urine volume per unit of time is determined separately for each animal, and the concentration of the sodium or potassium ions excreted in the urine is measured by means of standard flame photometric methods. In order to obtain a sufficient amount of urine, a defined amount of water is supplied to the animals at the beginning of the experiment by gavage (typically 10 ml per kg of body weight). Before the start of the experiment and after the end of the experiment, the body weight of the individual animals is determined.

B-sixth In vivo test for the detection of cardiovascular effect: effect of test substances in glycerol-induced acute renal failure)

Wistar rats (200-320 g body weight) are kept with free access to feed (Altromin) and drinking water. In each experiment in age-matched rats in mild ether anesthesia by intramuscular injection of a glycerol-water mixture (volume mixing ratio - -

1: 1, injection volume 10 ml / kg), triggered an acute renal failure in both hind limbs. The severity of renal failure may be further affected by the time (typically 14 to 24 hours) of discontinuation of drinking water intake prior to glycerol injection. The substance to be tested is administered in a volume of 1 to 2 ml / kg body weight of a suitable solvent orally by gavage into the stomach, or administered intravenously. Animals serving as control receive only solvents via the corresponding route of administration. Controls and substance testing are done in parallel on the same day. Control groups and substance dose groups each consist of 8 to 12 animals. In one experiment, a control collective of rats of the same age is examined simultaneously, which at the same time receive ether anesthesia and solvents but no intramuscular glycerol injection. The rats are kept individually in metabolic cages after substance administration or solvent administration (Tecniplast Deutschland GmbH, D-82383 Hohenpeissenberg). The urine is collected on the 1st and 2nd day after glycerol injection over a period of 24 hours. In urine, sodium, potassium, uric acid and creatinine are determined. The blood for the determination of urea, creatinine, uric acid and sodium takes place at the end of the urinary period by retroorbital puncture under mild ether anesthesia, or by cardiac puncture (48 hours after glycerol injection). Sodium or potassium ions. The determination of the sodium and potassium ions is measured by standard flame photometric methods. Creatinine, urea and uric acid are determined by standard enzymatic and biochemical methods.

B. 7 In v / vo test for the detection of cardiovascular effects: studies in rats with 5/6 nephrectomy-induced chronic renal failure

The detection of the kidney-protective effect of the test substances is carried out in rats with 5/6 nephrectomy (chronic renal failure). These rats are characterized by glomerular hyperfiltration and the development of progressive renal failure leading to end-stage renal disease and hypertension-induced left ventricular hypertrophy and cardiac fibrosis. In the experiment different groups are compared: a sham-operated control group, a group with 5/6 nephrectomy and groups treated with test substances with 5/6 nephrectomy. The test substances are administered orally. Renal failure due to 5/6 nephrectomy is induced by complete removal of the right kidney and after two more weeks by ligation of the upper and lower third of the remaining kidney. After the second surgery, the rats develop progressive renal failure (decrease in GFR) with proteinuria and hypertension. The heart is characterized by uremic hypertensive heart disease. Without treatment, rats will die of end-stage or end-stage renal disease between week 19 and 26 - -

Hypertension induced end organ damage. (Lime P, Godes M., Relle K., Rothkege Cl, Hucke A., Stasch JP and Hocher B .: NO-independent activation of soluble guanylate cyclase preventing disease progression in rats with 5/6 nephrectomy. Brit. J. Pharmacol 2006, 148, 853-859). To collect the urine, the animals are placed in metabolic cages for 24 hours. Sodium, potassium, calcium, phosphate and protein are determined. The serum concentrations of glucose, CrP (C-reactive peptide), ALAT (alanine aminotransferase), ASAT (aspartate aminotransferase), potassium, sodium, calcium, phosphate, urea and creatinine are determined with assay kits in an automatic analyzer. Protein concentrations in urine and serum are determined using a pyrogallol red molybdate complex reagent in an automatic analyzer. The glomerular filtration rate is calculated using creatinine clearance. Systolic blood pressure and heart rate are measured by plethysmography with a tail cuff on awake rats. Body weight is measured weekly. Plasma renin activity and aldosterone in urine are determined by commercially available radioimmunoassays. At the end of the study, all rats are killed. Blood samples are taken for the determination of glucose, creatinine, urea, liver enzymes, CrP, sodium, serum protein and plasma renin activity. Body and heart weights as well as the weights of the kidneys are measured.

C. Examples 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:

1,000 mg of the compound according to 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. - 1 -

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 according to 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 in a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

Claims

claims

(I), 1. Compounds of the formula (I)

in which

Q is phenyl or pyridyl,

R ¹ represents hydrogen, cyano, (Ci-C ₃₎ alkyl, trifluoromethyl, (C _{r C3)} -alkoxy or trifluoromethoxy,

R ^{2 is} phenyl, naphthyl or 5- or 6-membered heteroaryl,

where phenyl, naphthyl and 5- or 6-membered heteroaryl having 1 or 2 substituents independently of one another selected from the group halogen,

Cyano, (C 1 -C ₄ ) -alkyl, monofluoromethyl, difluoromethyl, trifluoromethyl, (C 1 -C ₄ ) -alkoxy, monofluoromethoxy, difluoromethoxy and trifluoromethoxy may be substituted,

R ^{3 is} hydroxycarbonyl, aminocarbonyl, cyanoaminocarbonyl, (C 1 -C 6 -alkylsulfonylaminocarbonyl, oxadiazolonyl or tetrazol-5-yl,

where oxadiazolonyl may be substituted by a methyl substituent,

R ^{4 is} hydrogen, halogen, (C 1 -C ₄ ) -alkyl, monofluoromethyl, difluoromethyl, trifluoromethyl, (C 1 -C ₄ ) -alkoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy,

R ^{5 is} hydrogen, halogen, (C 1 -C ₄ ) -alkyl, monofluoromethyl, difluoromethyl,

Trifluoromethyl, (C 1 -C ₄ ) -alkoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy,

R ^{6 is} a group of the formula - -

stands, where

* means the point of attachment to the pyrazole,

the ring U is phenyl, pyridyl, pyrimidinyl or pyrazinyl,

wherein phenyl, pyridyl, pyrimidinyl and pyrazinyl with 1 to 3

Substituents independently of one another can be substituted from the group halogen, trifluoromethyl, (C 1 -C ₄ ) -alkyl, hydroxyl, (C 1 -C ₄ ) -alkoxy and trifluoromethoxy,

wherein (C] _-C4) alkyl and (Ci-C ₄₎ -alkoxy in turn with 1 or 2 substituents independently selected from the group of hydroxy and (Ci-C ₄₎ -alkoxy,

ring V _{2 is} a 5- to 7-membered heterocycle fused to ring U and containing at least one nitrogen atom,

wherein the heterocycle may be substituted by 1 to 5 substituents selected from the group consisting of halogen, oxo, thiooxo, (C 1 -C ₄ ) -alkyl, (C 1 -C ₄ ) -alkoxy and (C 1 -C ₄ ) -alkylthio,

and their salts, solvates and solvates of the salts.

2. Compounds of formula (I) according to claim 1, in which

Q is phenyl,

R ^{1 is} hydrogen, cyano, methyl, ethyl or trifluoromethyl,

R ^{2 is} phenyl, - - where phenyl can be substituted by 1 or 2 substituents independently selected from the group of fluorine, chlorine, (dC ₄₎ -alkyl, trifluoromethyl, (C, -C ₄₎ alkoxy or trifluoromethoxy,

R ^{3 is} hydroxycarbonyl or methylsulfonylaminocarbonyl,

R ^{4 is} hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl,

Methoxy, ethoxy, difluoromethoxy or trifluoromethoxy,

R ^{5 represents} hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy,

R ^{6 is} a group of the formula

stands, where

* means the point of attachment to the pyrazole,

K ^{1 is} CR ³³ or N,

wherein

R ^{33 is} hydrogen, fluorine, chlorine or methyl,

K ^{2 is} CR ³⁴ or N, - - in which

R ^{34 is} hydrogen, fluorine, chlorine or methyl, K ^{3 is} CR ^35A R ^35B , NR ³⁶ or O, wherein R ^{35A is} hydrogen, fluorine or methyl,

R ^{35B is} hydrogen, fluorine or methyl, or

R ^35A and R ^35B together form an oxo or thiooxo group,

R ^{36 is} hydrogen or methyl; K ^{4 is} CR ^37A R ^37B or NR ³⁸ wherein

R ^{37A is} hydrogen, fluorine or methyl,

R ^{37B is} hydrogen, fluorine or methyl, or R ^37Λ and R ^37B together form an oxo or thiooxo group,

R ^{38 is} hydrogen or methyl, K ^{5 is} CR ³⁹ or N wherein

R ^{39 is} hydrogen, fluorine, chlorine or methyl, R ^{30 is} hydrogen, fluorine, chlorine or methyl,

R ^{31 is} hydrogen or methyl, R ^{32A is} hydrogen, fluorine or methyl, R ^{32B is} hydrogen, fluorine or methyl, - - or

R and R together form an oxo or thiooxo group,

and their salts, solvates and solvates of the salts.

3. Compounds of formula (I) according to claim 1 or 2, in which

for a group of the formula

stands, where

# means the point of attachment to the amino group,

R ^{3 is} hydroxycarbonyl,

R ^{4 is} hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy,

R ^{5 is} hydrogen or fluorine,

R ^{1 is} hydrogen or methyl,

R ^{2 is} phenyl,

where phenyl having 1 or 2 substituents independently of one another may be substituted from the group fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy,

R ^{6 is} a group of the formula

or

- - stands, where

* means the point of attachment to the pyrazole,

K ^{1 is} CR ³³ or N,

wherein

R ^{33 is} hydrogen,

K ^{5 is} CR ³⁹ or N,

wherein

R ^{39 is} hydrogen,

and their salts, solvates and solvates of the salts.

Compounds of formula (I) according to claim 1, in which

Q for a group of the formula

stands, where

# means the point of attachment to the amino group,

R ^{3 is} hydroxycarbonyl,

R ^{4 is} hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy,

R ^{5 is} hydrogen or fluorine,

R ^{1 is} methyl,

R ^{2 is} phenyl, wherein phenyl may be substituted with 1 or 2 substituents independently of one another selected from the group fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy,

for a group of the formula

stands, where

* means the point of attachment to the pyrazole,

K ^{1 is} CR ³³ or N,

wherein

R ^{33 is} hydrogen, fluorine, chlorine or methyl,

K ^{2 is} CR ³⁴ or N,

wherein

R ^{34 is} hydrogen, fluorine, chlorine or methyl,

K ^{5 is} CR ^39A or N,

wherein - -

R ^39A represents hydrogen, (C _{r C4)} alkyl or (C, -C ₄₎ alkoxy;

R ^{30 is} hydrogen, fluorine, chlorine or methyl,

R ³¹ is hydrogen or (C _r C ₄₎ alkyl,

R ^{36 is} hydrogen or (C 1 -C ₄ ) -alkyl,

R ^3S represents hydrogen or (C _r C ₄₎ -alkyl,

R ^ is hydrogen, (C _{r C4)} alkyl or (Ci-C ₄₎ alkoxy;

and their salts, solvates and solvates of the salts.

5. Compounds of formula (I) according to claim 1 or 4, in which

for a group of the formula

stands, where

# means the point of attachment to the amino group,

R is hydroxycarbonyl,

R ^{4 is} hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy,

R is hydrogen or fluorine,

R is methyl,

R is a group of the formula

- - stands, where

## is the point of attachment to the pyrazole,

R ^{40 represents} hydrogen, fluorine, chlorine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy,

R is a group of the formula

stands, where

the point of attachment to the pyrazole means

R> 3 "3 is hydrogen, fluorine, chlorine or methyl,

K ^{5 is} CR ^39A or N,

Wonn

R ^{39A is} hydrogen or methyl,

R, 38 is hydrogen or methyl,

and their salts, solvates and solvates of the salts.

Process for the preparation of compounds of the formula (I) as defined in claims 1 to 5, characterized in that - -

[A] a compound of the formula (H)

in which R ¹ and R ² each have the meanings given in claims 1 to 5,

in an inert solvent with a halogenating agent in a compound of formula (IH-A)

in which R ¹ and R ² each have the meanings given in claims 1 to 5

and

X ^{1 is} halogen, in particular bromine or iodine,

these are then reacted in an inert solvent in the presence of a base and a suitable palladium catalyst with a compound of the formula (IV)

in which R has the meaning given in claims 1 to 5

and

T ^{1 is} hydrogen or both radicals T ¹ together form a -C (CH ₂ ) ₂ -C (CH ₂ ) ₂ - or -CH ₂ C (CH ₃ ) ₂ CH ₂ bridge, to a compound of the formula (VA)

in which R ¹ , R ² and R ⁶ each have the meanings given in claims 1 to 5,

and these are subsequently reacted in an inert solvent in the presence of a suitable catalyst with a compound of the formula (VI-A)

in which Q, R ⁴ and R ⁵ each have the meanings given in claims 1 to 5

and

T ^{2 is} (C _r C ₄ ) -alkyl,

X ^{2 is} halogen, preferably bromine,

to a compound of formula (VE)

in which Q, T ² , R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ each have the meanings given in claims 1 to 5, - - implements,

or

[B] a compound of formula (II) in an inert solvent in the presence of a suitable catalyst with a compound of formula (VI-A) to give a compound of formula (HI-B)

in which Q, T ² , R ¹ , R ² , R ⁴ and R ^{5 are} each as defined above,

reacted, and then in an inert solvent with a halogenating agent in a compound of formula (V-B)

in which Q, T ² , X ¹ , R ¹ , R ² , R ⁴ and R ^{5 are} each as defined above,

überfuhrt and then this in an inert solvent in the presence of a base and a suitable palladium catalyst with a compound of formula (IV) to give a compound of formula (VII),

or

[C] a compound of the formula (VIII)

R ⁶ - X ³

(VID), - - in which R ^{6 has} the meaning given in claims 1 to 5

and

X ^{3 is} halogen, preferably bromine or iodine,

in an inert solvent in the presence of a suitable palladium catalyst with trimethylsilylacetonitrile to give a compound of the formula (IX)

R ⁶ -

CN

(K) in which R ^{6 has} the meaning given in claims 1 to 5,

and then this in an inert solvent in the presence of a suitable base with an ester of the formula (X)

in which R ^{1 has} the meaning given in claims 1 to 5

and

T ^{3 is} (C _r C ₄ ) -alkyl,

to a compound of formula (XI)

in which R ¹ and R ⁶ each have the meanings given in claims 1 to 5

and

Ak ^{+ represents} an alkali ion, preferably sodium,

and then reacted with a hydrazine of the formula (XS) - -

₂ HR ² -N _χ

^NH2 (X n-) in which R ² has the meaning given in claims 1 to 5,

converted into a compound of the formula (V-A), and further converting it into a compound of the formula (VII) by the process [A] described above,

and the respectively resulting compound of formula (VE) then by hydrolysis of the ester into a carboxylic acid of formula (I-1)

in which Q, R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ each have the meanings given in claims 1 to 5,

and optionally converting the resulting compounds of formula (I-1) with the corresponding (i) solvents and / or (ii) bases or acids into their solvates, salts and / or solvates of the salts.

7. A compound of formula (I) as defined in any one of claims 1 to 5 for the treatment and / or prophylaxis of diseases.

A compound of the formula (I) as defined in any one of claims 1 to 5 for use in a method for the treatment and / or prophylaxis of acutely decompensated and chronic heart failure, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema, nephropathy, acute and chronic renal failure, renal insufficiency and the syndrome of inappropriate ADH secretion (SIADH).

9. Use of a compound of the formula (I) as defined in any one of claims 1 to 5 for the manufacture of a medicament for the treatment and / or prophylaxis of acutely decompensated and chronic heart failure, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema, nephropathy , acute and chronic - -

Renal failure, renal insufficiency and the syndrome of inappropriate ADH secretion (SIADH).

10. A pharmaceutical composition comprising a compound of the formula (I) as defined in any one of claims 1 to 5, in combination with an inert, non-toxic, pharmaceutically suitable excipient.

11. A medicament containing a compound of formula (I) as defined in any one of claims 1 to 5, in combination with one or more further active ingredients selected from the group consisting of diuretics, angiotensin Aü antagonists, ACE inhibitors, beta receptors Blockers, mineralocorticoid receptor antagonists, organic nitrates, NO donors, guanylate cyclase stimulators, guanlylate cyclase activators, vasopressin

Antagonists and positive inotropic substances.

12. Medicament according to claim 10 or 11 for the treatment and / or prophylaxis of acutely decompensated and chronic heart failure, hypervolemic and euvolämischer hyponatremia, liver cirrhosis, ascites, edema, nephropathy, acute and chronic renal failure, renal failure and the syndrome of inappropriate ADH secretion

(SIADH).

13. A method for the treatment and / or prophylaxis of acutely decompensated and chronic heart failure, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema, nephropathy, acute and chronic renal failure, renal insufficiency and the syndrome of inappropriate ADH secretion (SIADH)

Humans and animals using an effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 5 or a pharmaceutical composition as defined in any one of claims 10 to 12.