EP2385942A1

EP2385942A1 - Benzimidazole and pyrazolopyridine derivatives for treating and/or preventing cardiovascular diseases

Info

Publication number: EP2385942A1
Application number: EP10701445A
Authority: EP
Inventors: Alexander Straub; Frank SÜSSMEIER; Frank Wunder; Johannes-Peter Stasch; Volkhart Min-Jian Li; Joachim Mittendorf
Original assignee: Bayer Pharma AG
Current assignee: Bayer Intellectual Property GmbH
Priority date: 2009-01-09
Filing date: 2010-01-05
Publication date: 2011-11-16
Also published as: CA2749048A1; DE102009004245A1; WO2010079120A1; US20130303559A1; US20120029002A1

Abstract

The present invention relates to novel benzimidazole and pyrazolopyridine derivatives, to methods for the production thereof, to the use thereof alone or in combination to treat and/or prevent illnesses, and to the use thereof to produce drugs for treating and/or preventing illnesses, in particular for treating and/or preventing cardiovascular diseases.

Description

BENZIMIDAZOL AND PYRAZOLOPYRIDINE DERIVATIVES FOR THE TREATMENT AND / OR PREVENTION OF CARDIOVASCULAR DISEASES

The present application relates to novel fused, heteroatom-bridged pyrazole and imidazole derivatives, 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 Disease prevention, in particular for the treatment and / or prevention of cardiovascular diseases.

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

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

A NO-independent treatment option for such diseases, which is aimed at influencing the cGMP pathway in organisms, is a promising approach on account of the expected high efficiency and low side effects. For therapeutic stimulation of soluble guanylate cyclase, only compounds such as organic nitrates have been used, whose action is based on NO. This is formed by bioconversion and activates the soluble guanylate cyclase by attack on the central iron atom of the heme. In addition to the side effects, the development of tolerance is one of the decisive disadvantages of this type of treatment.

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

Anellated pyrazole derivatives are described inter alia in WO 98/23619, WO 00/06568, WO 00/06569, WO 02/42299, WO 02/42300, WO 02/42301, WO 02/42302, WO 02/092596, WO 03 / 004503, WO 03/095451 and WO 2008/031513 as stimulators of soluble guanylate cyclase. However, it has been found that some of these compounds are sensitive to their physicochemical properties, such as their solubility, or to their in vivo properties, such as their behavior in the liver, their pharmacokinetic behavior, their dose-response relationship and / or their properties Metabolization path, have disadvantages.

Furthermore, WO 03/076408 describes indazole derivatives for the treatment of cardiovascular diseases and disorders of the central nervous system. WO 03/035005 discloses heteroindanes as cannabinoid mimetics for the treatment of pain and neurodegenerative diseases. 3-Aminoindazoles are claimed in WO 2007/075847 for the treatment of metabolic diseases.

It is an object of the present invention to provide novel substances which act as stimulators of soluble guanylate cyclase and have a similar or improved physicochemical, pharmacokinetic and / or therapeutic profile over the compounds known from the prior art.

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

L ~ ^AM ~ ^Q (I),

in which A represents O, S, -S (= O) -, S (= O) ₂ - or NR ¹ ,

in which

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

L is (C ₅ -C ₇ ) -cycloalkyl, phenyl, pyridyl, pyrimidinyl, furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl or isoxazolyl,

where phenyl, pyridyl, pyrimidinyl, furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl and isoxazolyl having 1 or 2 substituents selected independently of one another from the group halogen, cyano, Trifluoromethyl, chloromethyl and (C ₂ -C ₄ ) -alkynyl may be substituted,

and

where (C ₅ -C ₇ ) -cycloalkyl can be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine and (C 1 -C ₄ ) -alkyl,

M is a bicyclic heteroaryl group of the formula

stands, where

* stands for the point of attachment to the group A,

** stands for the point of attachment to the group Q,

T, U, V and W are each CR ² or N,

with the proviso that a maximum of two of the ring members T, U, V and W are simultaneously N,

and

wherein - A -

R ^{2 is} hydrogen, halogen, cyano, (C 1 -C ₄ ) -alkyl, trifluoromethyl, amino, (C 1 -C ₄ ) -alkoxy and trifluoromethoxy,

and

wherein, in the event that the substituent R ² occurs several times, its meanings may be the same or different,

and

Q is an unsaturated 5- or 6-membered heterocycle or a 5- or 6-membered heteroaryl,

wherein the 5- or 6-membered heterocycle and the 5- or 6-membered heteroaryl having 1 to 4 substituents independently selected from the group halogen, azido,

Nitro, cyano, oxo, thioxo, -R ³ , -C (= O) -R ³ , -C (= O) -OR ³ , -C (= O) -NR ³ R ⁴ , -O- (C = O) _n -R ³ , - OC (= O) -OR-OC (= O) -NR ³ R ⁴ , -S (O) _P -R ³ , -SO ₂ -OR ³ , -SO ₂ -NR ³ R ⁴ , -NR ³ - (C =O) _n -R ⁴ , -NR ³ -SO ₂ -R ⁴ , -NR ³ -C (= O) -OR ⁴ , -NR ⁵ -C (= O) -NR ³ R ⁴ and -NR ⁵ -SO ₂ -NR ³ R ⁴ may be substituted,

wherein

n is a number 0 or 1,

p is a number 0, 1 or 2,

R ^3, R ⁴ and R ⁵ are each independently hydrogen, (Ci-C ₆₎ -alkyl, (C ₂ -C ₆₎ alkenyl, (C ₃ -C ₈₎ -cycloalkyl, (C ₃ -C ₈₎ Cycloalkenyl, (C ₆ -C 10) -aryl, 4- to 8-membered heterocyclyl or 5- to 10-membered heteroaryl,

wherein R ³ , R ⁴ and R ^{5, in} turn, having 1 to 5 substituents independently selected from the group halogen, azido, nitro, cyano, trifluoromethyl, (C, -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylcarbonyl , (C ₁ -C ₆ ) -alkylcarbonyloxy, hydroxycarbonyl,

(Ci-C ₆₎ alkoxycarbonyl, aminocarbonyl, mono- (C _r _C6) alkyl- aminocarbonyl, di- (C iC ₆₎ alkylaminocarbonyl, hydroxy, trifluoromethoxy, (Ci-C ₆₎ alkoxy, oxo, mercapto , (C ₁ -C ₆₎ - alkylthio, amino, mono- (Ci-C ₆₎ -alkylamino, di- (C ₁ -C ₆₎ - alkylamino, formylamino, _(Ci-C6) alkylcarbonylamino, (C ₁ -C ₆ ) - Alkoxycarbonylamino, (C ₃ -C ₈ ) -cycloalkyl, (C ₃ -C ₈ ) -cycloalkenyl and 4- to 8-membered heterocyclyl may be substituted,

or

R ³ and R ^4, together with the radical to which they are both bonded, form a 4- to 8-membered heterocycle,

or

R ³ and R ^5, together with the radical to which they are both bonded, form a 4- to 8-membered heterocycle,

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

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

Compounds of the invention are also N-oxides of the compounds of the formula (I) and their salts, solvates and solvates of the salts.

Depending on their structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The present invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.

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 according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of chlorinated water. acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

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

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

In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" includes compounds which may themselves be biologically active or inactive, but are converted during their residence time in the body into compounds according to 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 in each case the number of carbon atoms specified. By way of example and preferably mention may be made of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2 Methylbutyl, 3-methylbutyl, n -hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl and 2-ethylbutyl.

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

Alkenyl in the context of the invention represents a linear or branched alkenyl radical having 2 to 6 carbon atoms and one or two double bonds. Preferred is a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms and one double bond. By way of example and by way of preference: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.

Cycloalkenyl is in the context of the invention a monocyclic carbocycle having 3 to 8 carbon atoms and a double bond. Examples which may be mentioned by way of example include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

Alkynyl in the context of the invention represents a linear or branched alkynyl radical having 2 to 4 carbon atoms and a triple bond. By way of example and preferably mention may be made of: ethynyl, n-prop-1-yn-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-one in-l-yl.

Alkylcarbonyl in the context of the invention is a linear or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms in the alkyl chain and a carbonyl group attached in position 1. By way of example and by way of preference: methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylpolyyl, n-butylcarbonyl, isobutylcarbonyl and tert-butylcarbonyl.

Alkylcarbonyloxy in the context of the invention represents a linear or branched alkylcarbonyl radical which is bonded via a sueraratomide and carries 1 to 6 or 1 to 4 carbon atoms in the alkyl chain. By way of example and by way of preference: methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy and tert-butylcarbonyloxy.

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

Alkylthio in the context of the invention is a linear or branched alkylthio radical having 1 to 6 or 1 to 4 carbon atoms. Examples which may be mentioned are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, n-pentylthio and n-hexylthio.

Alkoxycarbonyl in the context of the invention are a linear or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms and an oxygen-bonded carbonyl group. Preferred is a linear or branched alkoxycarbonyl radical having 1 to 4 carbon atoms in the alkoxy group. By way of example and preferably mention may be made of: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

Mono-alkylamino in the context of the invention represents an amino group having a linear or branched alkyl substituent which has 1 to 6 carbon atoms. Exemplary and Preferred are: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

Di-alkylamino in the context of the invention represents an amino group having two identical or different linear or branched alkyl substituents, each having 1 to 6 carbon atoms. Examples which may be mentioned are: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N-methylamino, N Ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

Mono-alkylaminocarbonyl in the context of the invention represents an amino group which is linked via a carbonyl group and which has a linear or branched alkyl substituent having 1 to 6 or 1 to 4 carbon atoms. Preferred is a mono-alkylaminocarbonyl radical having 1 to 4 carbon atoms in the alkyl group. By way of example and by way of preference: methylaminocarbonyl, ethylaminocarbonyl, 2'-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl and n-hexylaminocarbonyl.

Di-alkylaminocarbonyl in the context of the invention represents an amino group which is linked via a carbonyl group and which has two identical or different linear or branched alkyl substituents each having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a dialkylaminocarbonyl radical having in each case 1 to 4 carbon atoms per alkyl group. Examples which may be mentioned are: N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-NH-propylaminocarbonyl, Nn-butyl-N-methylaminocarbonyl, N-tert-butyl -N-methylaminocarbonyl, NH-pentyl-N-methylaminocarbonyl and N-w-hexyl-N-methylaminocarbonyl.

Alkylcarbonylamino in the context of the invention represents an amino group having a linear or branched alkylcarbonyl substituent which has 1 to 6 or 1 to 4 carbon atoms in the alkyl chain and is linked to the Ν-atom via the carbonyl group. By way of example and by way of preference: methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, n-butylcarbonylamino, iso-butylcarbonylamino and tert-butylcarbonylamino.

Alkoxycarbonylamino in the context of the invention represents an amino group having a linear or branched alkoxycarbonyl substituent which has 1 to 6 or 1 to 4 carbon atoms in the alkyl chain and is linked via the carbonyl group to the Ν-atom. By way of example and preferably mention may be made of: methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, n-butoxycarbonylamino, isobutoxycarbonylamino and tert.

Butoxycarbonylamino. Aryl in the context of the invention is an aromatic carbocycle having 6 or 10 ring carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

5- to 10-membered heteroaryl is in the context of the invention for a mono- or optionally bicyclic aromatic heterocycle (heteroaromatic) having a total of 5 to 10 ring atoms, up to three identical or different ring heteroatoms from the series N, O and contains S and is linked via a ring carbon atom or optionally 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, triazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxa zolyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [3,4-b] pyridinyl. Preference is given to monocyclic 5- or 6-membered heteroaryl radicals having up to three ring heteroatoms from the series N, O and / or S such as furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl , Oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl.

A 4- to 8-membered heterocycle is in the context of the invention for a monocyclic, saturated heterocycle having a total of 4 to 8 ring atoms containing one or two ring heteroatoms from the series N, O, S, SO and / or SO ₂ and is linked via a ring carbon atom or optionally a ring nitrogen atom. Preference is given to a 5- to 7-membered heterocycle having one or two ring heteroatoms from the series N, O and / or S, more preferably a 5 ^ or 6-membered heterocycle having one or two ring heteroatoms from the series N and Examples include: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl and hexahydro-l, 4-diazepinyl. Preference is given to pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl and morpholinyl.

An unsaturated 5- or 6-membered heterocycle is in the context of the invention for a monocyclic heterocycle having a total of 5 or 6 ring atoms, which contains up to four ring heteroatoms from the series N, O and / or S, via a ring carbon atom or optionally a ring nitrogen atom is linked and in the case of the five-membered ring contains a double bond and in the case of the six-membered ring contains one or two double bonds. Examples include: pyrrolinyl, dihydropyrazolyl, imidazolinyl, dihydrooxazolyl, dihydroisoxazolyl, dihydro-l, 2,4-triazolyl, dihydro-l, 2,4-oxadiazolyl, dihydro-l, 3,4-oxadiazolyl, dihydro-1,2, 4-thiadiazolyl, dihydropyranyl, 1,4-dihydropyridyl, tetrahydropyrimidinyl, 1,3-oxazinyl. Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.

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

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

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

A is O, S or NR ¹ ,

in which

R ^{1 is} hydrogen,

L is phenyl, thienyl, pyridyl or pyrimidinyl,

where phenyl, thienyl, pyridyl and pyrimidinyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl and trifluoromethyl,

M is a bicyclic heteroaryl group of the formula

stands in which

* stands for the point of attachment to the group A,

** stands for the point of attachment to the group Q,

T ¹ , U ¹ , V ¹ and W ^{1 are} each CR ^2A or N, wherein a maximum of two of the ring members T ¹ , U ¹ , V ¹ and W ^{1 are} simultaneously N,

and

in which

R ^{2A is} hydrogen or fluorine,

wherein a maximum of two of the radicals R ^{2A are} fluorine,

and

wherein, in the event that the substituent R ^2A occurs several times, its meanings may be the same or different,

T ² , U ² , V ² and W ^{2 are} each CR ^2B or N,

wherein a maximum of two of the ring members T ² , U ² , V ² and W ^{2 are} simultaneously N,

and

in which

R ^{2B is} hydrogen or fluorine,

wherein a maximum of two of the radicals R ^{2B are} fluorine,

and

wherein, in the event that the substituent R ^2B occurs several times, its meanings may be the same or different,

and

Q for a group of the formula

stands,

in which

# represents the point of attachment to the group M,

D is CH or N,

J is CR ⁸ , N or N ⁺ -O ^" ,

wherein

R ^{8 is} halogen, nitro, cyano, -R ³ , -C (= O) -R ³ , -C (= O) -OR ³ , -C (= O) -NR ³ R ⁴ , -O- (C = O) _n -R ³ , -OC (= O) -OR ³ , -OC (= O) -NR ³ R ⁴ , -S (O) _P -R ³ , -SO ₂ -OR ³ , -SO ₂ -NR ³ R ⁴ , -NR ³ - (C =O) _n -R ⁴ , -NR ³ -SO ₂ -R ⁴ , -NR ³ -C (= O) -OR ⁴ , -NR ⁵ -

C (= O) -NR ³ R ⁴ or -NR ⁵ -SO ₂ -NR ³ R ⁴ ,

wherein

n is a number O or 1,

p stands for a number O or 2,

R ³ , R ⁴ and R ^{5 are} each independently hydrogen, (Ci-C ₆ ) -

Alkyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkenyl, phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl .

in which R ³ , R ⁴ and R ^{5 in} turn have 1 to 3 substituents independently of one another selected from the group of fluorine, Chlorine, cyano, (C 1 -C ₄ ) -alkyl, trifluoromethyl, hydroxy, (C 1 -C ₄ ) -alkoxy, trifluoromethoxy, oxo, amino, mono- (C 1 -C ₄ ) -alkylamino and di- (C 1 -C ₄ ) alkylamino may be substituted,

or

R ³ and R ^4, together with the radical to which they are both bonded, can form a 5- to 7-membered heterocycle,

or

R ³ and R ^5, together with the radical to which they are both bonded, can form a 5- to 7-membered heterocycle,

R ⁹ represents hydrogen, (C _r _C6) alkyl or (C ₃ -C ₇₎ cycloalkyl,

where (C 1 -C ₆ ) -alkyl having 1 to 5 substituents selected independently of one another from the group consisting of (C ₃ -C ₇ ) -cycloalkyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy,

_(Ci-C4) acyloxy, amino, mono- (C _r C ₄₎ alkylamino, di- (C iC ₄₎ alkylamino, (C _r _C4) acylamino, hydroxycarbonyl, (Ci-C ₄₎ - Alkoxycarbonyl, aminocarbonyl, mono- (C ₁ -C ₄ ) -aminocarbonyl, di- (C ₁ -C ₄ ) -alkylaminocarbonyl and 5- or 6-membered heterocycle may be substituted,

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

A is S or NR ¹ ,

in which

R ^{1 is} hydrogen,

L is phenyl, pyridyl or pyrimidinyl,

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

M is a bicyclic heteroaryl group of the formula

stands in which

stands for the point of attachment to the group A,

** stands for the point of attachment to the group Q,

and

is CH or N,

U ^{1 is} CH,

W ¹ stands for CH,

V ^{1 stands} for CR ^2A

embedded image in which

R is hydrogen or fluorine,

for a group of the formula

stands, where

# represents the point of attachment to the group M,

stands for CR ⁸ or N,

embedded image in which

R ^{8 is} hydrogen, fluoro, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, phenyl, pyridyl, -NR ³ - (C = O) _n -R ⁴ , -NR ³ -C (= O ) -OR ⁴ or -NR ⁵ -C (= O) -NR ³ R ⁴ , wherein

n represents the number 0 or 1,

R ^{3 is} hydrogen or (C 1 -C ₄ ) -alkyl,

wherein (Ci-C ₄ ) -alkyl in turn with a substituent selected from the group fluorine, trifluoromethyl, hydroxy and

Methoxy can be substituted,

R ^{4 is} hydrogen, (C 1 -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,

in which (C 1 -C ₄ ) -alkyl in turn may be substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, hydroxy and methoxy,

R ⁵ is hydrogen or (C _r C ₄₎ alkyl,

R ^{6 is} hydrogen or amino,

R ^{7 is} hydrogen or amino,

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

Q for a group of the formula

stands, where

# represents the point of attachment to the group M,

J is CR ⁸ or Ν, wherein

R ^{8 is} pyridyl or -NR ³ -C (= O) -OR ⁴ ,

wherein

R ³ is hydrogen or (C _r C ₄₎ alkyl,

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

wherein (C _r C ₄₎ in turn with a substituent selected from the group of fluorine, trifluoromethyl, hydroxy and methoxy -alkyl may be substituted,

R ^{6 is} hydrogen or amino,

R ^{7 is} hydrogen or amino.

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

L is phenyl,

wherein phenyl may be substituted with a substituent fluorine.

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

M is a bicyclic heteroaryl group of the formula

stands in which

* stands for the point of attachment to the group A,

** stands for the point of attachment to the group Q,

and

T ^{1 is} CH or N, U ^{1 is} CH,

W ¹ stands for CH,

V ^{1 stands} for CR ^2A

wherein

R ^{2A is} hydrogen or fluorine.

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

M is a bicyclic heteroaryl group of the formula

stands in which

* stands for the point of attachment to the group A,

** stands for the point of attachment to the group Q,

and

T ^{2 is} CH or N,

U ^{2 is} CH,

W ^{2 is} CH,

V ^{2 is} CR ^2B or N

embedded image in which

R ^{2B is} hydrogen or fluorine.

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. Particularly preferred are combinations of two or more of the preferred ranges mentioned above.

The compounds of the formula (I) according to the invention can be prepared in analogy to methods described in the literature, for example by

[A] a compound of the formula (E)

in which A, L, T ¹ , U ¹ , V ¹ and W ¹ each have the meanings given above,

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

in which D, J, R ⁶ and R ⁷ each have the meanings given above,

and

X ^{1 represents} a suitable leaving group such as, for example, halogen, mesylate, tosylate or triflate,

to a compound of the formula (I-A)

(IA) in which A, D, J, L, T ¹ , U ¹ , V ¹ , W ¹ , R ⁶ and R ⁷ each have the meanings given above,

implements,

or

[B] a compound of the formula (IV)

in which A, L, T ² , U ² , V ² and W ² each have the meanings given above,

in an inert solvent with a halogenating agent in a compound of formula (V)

in which A, L, T ² , U ² , V ² and W ² each have the meanings given above,

and

X ^{2 is} halogen, in particular bromine,

transferred, then by standard methods into a tin species (VI)

in which A, L, T ² , U ² , V ² and W ² each have the meanings given above and

R ¹⁰ is (C _r _C4) alkyl,

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

to a compound of the formula (I-B)

in which A, D, J, L, T ² , U ² , V ² , W ² , R ⁶ and R ⁷ each have the meanings given above,

implements,

or

[C] a compound of the formula (VE)

in which A, L, T ² , U ² , V ² and W ² each have the meanings given above,

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

(Vm), in which J and R ⁶ each have the meanings given above,

to a compound of the formula (I-C)

in which A, J, L, T ² , U ² , V ² , W ² and R ⁶ each have the meanings given above,

implements,

if appropriate, the resulting compounds of the formulas (IA), (IB) and (IC) according to conventional literature further modified in the scope of the individual substituents and radicals given above and / or the resulting compounds of the invention optionally with the appropriate (i) solvents and / or (ii) converting acids or bases into their solvates, salts and / or solvates of the salts.

Inert solvents for process steps (H) + (ET) → (IA) and (VI) + (TS) → (IB) 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), N, N'-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 dimethylformamide and toluene and a mixture of dimethylformamide and toluene.

Suitable bases for process steps (II) + (ST) → (IA) and (VI) + (TS) → (IB) 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. Cesium carbonate is preferably used. As palladium catalyst for the process steps (II) + (IH) → (IA) and (VI) + (IH) → (IB) are, for example, palladium on activated carbon, palladium (II) acetate, tetrakis (triphenylphosphine) - palladium (O), bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (II) chloride and [1,1 'bis (diphenylphosphino) ferrocene] dichloroalladium (II) dichloromethane complex , optionally in combination with additional phosphine ligands such as (2-biphenyl) di-tert. -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-dimethyl-xanthene (xantphos) [cf. eg Hassan J. et al., Chem. Rev. 102, 1359-1469 (2002)].

The reactions (H) + (IE) → (IA) and (VI) + (IE) → (IB) are generally in a temperature range from +20 ⁰ C to +180 ⁰ C, preferably at +50 ⁰ C to + 120 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.

Inert solvents for process step (VQ) + (VIII) -> (IC) 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), N, N'-dimethyl propyleneurea (DMPU), N-methylpyrrolidone (.PHI.) , Pyridine, acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Preferred is dimethylformamide.

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 carbonates such as lithium, sodium, potassium or cesium carbonate, alkali metal bicarbonates such as sodium or potassium bicarbonate, alkali metal alcoholates such as sodium or potassium, sodium or Potassium ethoxide or potassium tert-butoxide, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, organometallic compounds such as butyl lithium or phenyllithium, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1.8 - diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 5-diazabicyclo [4.3.0] non-5-ene (DBN). Preference is given to sodium methoxide and triethylamine.

The reaction (VII) + (VIII) -> (IC) are generally in a temperature range from +20 ⁰ C to +180 ⁰ C, preferably at +50 ⁰ C to +120 ⁰ C, optionally in a microwave, carried out. 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 compounds of the formula (IH) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature.

Starting from compounds of the formula (IV) or (VE), compounds of the formula (I-B) or (I-C) can also be prepared analogously to 2 × 1 to the processes specified in WO 03/095451 and WO 2008/031513.

A compound of the formula (II) in which A is S can be prepared by reacting a compound of the formula (IX)

in which T, U, V and W each have the meanings given above,

in an inert solvent with a suitable halogenating agent, in particular with bromine, to give a compound of the formula (X)

in which T ¹ , U ¹ , V ¹ and W ¹ each have the meanings given above,

and

X ^{3 is} halogen, in particular bromine or iodine,

followed by reacting in an inert solvent in the presence of a suitable catalyst and a suitable base with a compound of the formula (XI)

HSL (X ₁ ^

in which L has the meaning given above, to a compound (II-A)

in which L, T, U, V and W each have the meanings given above,

responding.

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

Scheme 1:

[a) CuI, K ₂ CO ₃ , ethylene glycol, 2-propanol; b) Pd ₂ dba ₂ , XPHOS, Cs ₂ CO ₃ , toluene / DMF; c) Pd / C, H ₂ , pyridine; d) NMP, 2-propanol].

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

A compound of the formula (E) in which A is NH may be prepared by reacting a compound of the formula (XU)

in which T ¹ , U ¹ , V ¹ and W ¹ each have the meanings given above,

and

R ¹² is (C _r _C4) alkyl,

in an inert solvent in the presence of a suitable catalyst and a suitable base with a compound of the formula (XIS)

R ¹³ - O _N

BL R ¹³ - n κ ^u (XIII),

in which L has the meaning given above,

and

R ^{13 is} hydrogen or both radicals R ¹³ together form a -C (CH ₃ ) ₂ -C (CH ₃ ) ₂ - or -CH ₂ -C (CHj) ₂ -CH ₂ -BrUcICe form,

to a compound of formula (XTV)

in which L, T ¹ , U ¹ , V ¹ , W ¹ and R ¹² each have the meanings given above,

after cleavage of the carbamate under standard conditions to give a compound (HB)

in which L, T, U, V and W each have the meanings given above,

arrives.

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

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

Scheme 2:

[a) DIPEA, THF; b) Cu (OAc) ₂ , NEt ₃ , CH ₂ Cl ₂ ; c) KOH, ethanol; d) Pd ₂ dba ₂ , XPHOS, Cs ₂ CO ₃ , toluene / DMF].

Compounds of the formula (U) in which A represents O can be prepared in analogy to the process described in Examples 12A to 16A and as exemplified in the following synthesis scheme (Scheme 3). Scheme 3:

[PMB = p-methoxybenzyl a) NaOH, DMSO; b) NaH, DMF; c) SnCl ₂ , ethanol; d) tert-butyl nitrite, HCl (aq.); e) TFA; f) Pd ₂ dba ₂ , XPHOS, Cs ₂ CO ₃ , toluene / DMF].

Compounds of the formula (I) in which M represents a group of the formula

where *, **, T ² , U ² , V ² and W ² each have the meanings given above, can be prepared in analogy to processes known from the literature [cf. for example Bourdais J. et al., J. Heterocyclic Chem. 1980, 17, 555; Bourdais J et al., J. Heterocyclic Chem. 1980, 17, 1351; WO 2004/074290; WO 2005/080391], or as exemplified in the following synthesis schemes: - -

Scheme 4:

[a) CuI, K ₂ CO ₃ , ethylene glycol, 2-propanol; b) 1. Br ₂ , CH ₃ CO ₂ H, 2. Sn ₂ Bu ₆ , Pd (PPh ₃ ) ₄ , dioxane; c) Pd (PPh ₃ ) ₄ , toluene / DMF].

Scheme 5:

[a) (F ₃ CCO) ₂ O, pyridine, NEt ₃ ; b) Pd / BaSO ₄ , H ₂ , CH ₃ CO ₂ H; c) toluene, DCC; d) Br ₂ , CH ₃ CO ₂ H].

Compounds of the formula (I) in which Q is a group of the formula

where R ^{9 has} the abovementioned meaning can be prepared analogously to the processes described in WO 2008/031513.

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

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

The compounds according to the invention can therefore be used in medicaments for the treatment of cardiovascular diseases, for example for the treatment of hypertension and cardiac insufficiency, stable and unstable angina pectoris, pulmonary hypertension, peripheral and cardiovascular diseases, arrhythmias, for the treatment of thromboembolic disorders and ischaemias such as myocardial infarction, stroke, Transitory and ischemic attacks, peripheral circulatory disorders, reperfusion damage, for the prevention of restenosis such as after thrombolytic therapy, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasty (PTCA) and bypass, as well as for the treatment of arteriosclerosis, asthmatic diseases, erectile Dysfunction, female sexual dysfunction, are used by osteoporosis, glaucoma and gastroparesis.

In addition, the compounds of the invention may be used to treat primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic ulcers on the extremities, gangrenous, CREST syndrome, erythematosis, onychomycosis, rheumatic diseases, and the like used to promote wound healing. Furthermore, the compounds according to the invention are suitable for the treatment of urological diseases such as, for example, benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic hyperplasia (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS), diseases of the urogenital Systems including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as mixed, urgency, stress, or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, benign and malignant organs of the male and female urogenital system, kidney diseases such as acute or chronic renal failure, immunological kidney diseases such as kidney transplant rejection, glomerulonephritis, immune complex-induced kidney disease, glomerulopathies, nephritis, toxic nephropathy and obstructive uropathies.

Furthermore, the compounds according to the invention are suitable for the treatment of acute and chronic lung diseases, such as the respiratory distress syndromes (ALI, ARDS) and chronic obstructive pulmonary diseases (COPD), as well as for the treatment of acute and chronic renal insufficiency.

The compounds described in the present invention are also agents for controlling diseases in the central nervous system, which are characterized by disorders of the NO / cGMP system. In particular, they are suitable for improving the perception, concentration performance, learning performance or memory performance after cognitive disorders such as occur in situations / diseases / syndromes such as mild cognitive impairment, age-associated learning and memory disorders, age-associated memory loss, vascular dementia, cranial brain -Trauma, stroke, post-stroke dementia, post-traumatic traumatic brain injury, general attention deficit disorder, impaired concentration in children with learning and memory problems, Alzheimer's disease, dementia with Lewy Corpuscles, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, Sc hizophrenia with dementia or Korsakoff's psychosis. They are also suitable for the treatment of diseases of the central nervous system such as anxiety, tension and depression, centrally-nervous sexual dysfunctions and sleep disorders as well as for the regulation of pathological disorders of food, consumption and addictive substance intake.

Furthermore, the compounds according to the invention are also suitable for the regulation of the cerebral

Circulation and are effective agents for combating migraine dar. They are also suitable for the prophylaxis and control of the consequences of cerebral infarction (Apoplexia cerebri) such as stroke, cerebral ischemia and traumatic brain injury. Likewise, the compounds of the invention can be used to combat pain and tinnitus.

In addition, the compounds of the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents.

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

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

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

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

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

• organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerine, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-I, as well as inhalatives

NO;

Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP), such as inhibitors of phosphodiesterases (PDE) 1, 2 and / or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil and tadalafil; Antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;

Antihypertensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin Aü antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid Receptor antagonists and diuretics; 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-Co A 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 adsorbers, bile acid reabsorption inhibitors and lipoprotein (a) antagonists.

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

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

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

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

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban (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 Aü antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor - understood antagonists and diuretics.

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

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

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, 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 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 embursatan.

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 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 a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.

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.

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, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-I).

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 by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214) ,

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

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a bile acid reabsorption inhibitor, such as by way of example and preferably ASBT (= DBAT) 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 preferably 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 can be administered in a suitable manner, such as, for example, orally, parenterally, pulmonary, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally otically or as an implant or stent.

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

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

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

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

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

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

In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight, in order to achieve effective results. When administered orally, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.

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

The following embodiments illustrate the invention. The invention is not limited to the examples.

The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume.

A. Examples

Abbreviations and acronyms:

aq. aqueous solution calcd. calculated

DCI direct chemical ionization (in MS)

DMAP 4-N, N-dimethylaminopyridine

DMF dimethylformamide

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

ESI electrospray ionization (in MS)

Et ethyl gef. found h hour (s)

HPLC high pressure, high performance liquid chromatography

HRMS high-resolution mass spectrometry conc. concentrated

LC / MS liquid chromatography-coupled mass spectrometry

LiHMDS lithium hexamethyldisilazide

Me Methyl min minute (s)

MS mass spectrometry

NMR nuclear magnetic resonance spectrometry

Pd ₂ dba ₃ tris (dibenzylideneacetone) dipalladium

Ph phenyl

RT room temperature

Retention time (by HPLC) THF tetrahydrofuran

UV ultraviolet spectrometry v / v volume to volume ratio (of a solution) XPHOS dicyclohexyl- (2 ', 4', 6'-triisopropylbiphenyl-2-yl) -phosphine LC / MS and HPLC methods:

Method 1 (Preparative HPLQ:

Gilson Abimed HPLC; binary pump system; Column: ReproSil Cl 8, 250x30; Eluent A: water / 0.5% ammonia, eluent B: acetonitrile; Gradient: 0-3 min 60% B, 3.01-35 min 95% B, 35-40 min 95% B; Flow: 50 mL / min; UV detection at 210 nm.

Method 2 TLC-MS):

Instrument: Micromass QuattroPremier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9μ 50mm x 1mm; 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; Flow: 0.33 ml / min; Oven: 50 ^° C .; UV detection: 210 nm.

Method 3 CLC-MS ^* ):

Instrument: Micromass Quattro Micro MS with HPLC Agilent Series 1100; 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 → 4.01 min 100% A (flow 2.5 ml / min) → 5.00 min 100% A; Oven: 50 ^° C .; Flow: 2 ml / min; UV detection: 210 nm.

Method 4 CLC-MS):

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex syn ergi 2.5μ MAX-RP 100A Mercury 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 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 5 CLC-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: 50 ^° C .; UV detection: 210 nm. Method 6 (LC-MS):

Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 l, 8μ 50 x lmm; 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

3 - [(2-Fluoφhenyl) sulfanyl] -lH-pyrazolo [4,3-b] pyridine

10.63 g (43.38 mmol) of 3-iodo-lH-pyrazolo [4,3-b] pyridine, 1.24 g (6.51 mmol) of copper (I) iodide and 12.0 g (86.77 mmol) of potassium carbonate were added in an argon atmosphere with 4.84 ml (86.77 mmol) of 1,2-ethanediol, 250 ml of 2-propanol and 11.12 g (86.77 mmol) of 2-fluorothiophenol and stirred at 130 ⁰ C for 20 hours. The salts were filtered off with suction, silica gel was added to the filtrate, and the residue was chromatographed on a silica gel column with a gradient of cyclohexane / ethyl acetate = 10: 1 to 1: 1. 11.55 g (98% of theory) of Product in 90% purity (HPLC).

LC-MS (Method 6): R _t = 0.83 min

MS (ESIpos): m / z = 246.1 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 6.9-7.1 (m, 2H), 7.2-7.3 (m, 2H), 7.46 (dd, IH), 8.10 (d, IH), 8.55 (d, IH), 13.88 (broads, IH).

Example 2A

2- {3 - [(2-Fluorophenyl) sulfanyl] -1 H -pyrazolo [4,3-b] pyridin-1-yl} -5-nitropyrimidine-4,6-diamine

3 g (12.23 mmol) of 3 - [(2-fluorophenyl) sulfanyl] -1H-indazole, 3.48 g (18.35 mmol) of 2-chloro-5-nitropyrimidine-4,6-diamine [Bitterli et al., HeIv. Chim. Acta 1951, 34, 835], 560 mg (0.612 mmol) of tris (dibenzylideneacetone) dipalladium, 583 mg (1.22 mmol) of dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine and 5.58 g (17.12 mmol ) cesium carbonate were stirred in 50 ml of toluene and 50 ml DMF under argon for 18 hours at 90 ⁰ C. It was allowed to cool to room temperature, sucked from the solid, the solid washed with THF, evaporated in vacuo, and the evaporation residue stirred in a THF-water mixture. It was then evaporated in vacuo, slurried in dichloromethane-methanol, mixed with silica gel, evaporated in vacuo and chromatographed on a silica gel column with a gradient of dichloromethane-ethanol = 100: 1 to 50: 1. This gave 2.73 g (25.2% of theory) of the target compound in 45% purity (HPLC), which was used directly in the next step (Example 1).

LC-MS (Method 2): R, = 1.05 min

MS (ESIpos): m / z = 399.0 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Ci ₆ ): δ = 7.12 (t, IH), 7.25-7.4 (m, 3H), 7.6 (dd, IH), 8.63 (m, IH), 8.80 (broad s , 2H), 8.98 (broad s, 2H), 9.40 (d, IH).

Example 3A

Ethyl 3 - [(2-fluorophenyl) amino] -1H-indazole-1-carboxylate

9.77 g (47.61 mmol) of ethyl 3-amino-1H-indazole-1-carboxylate (preparation: DE 2458965, page 28), 9.99 g (71.41 mmol) of 2-fluorophenylboronic acid, 0.95 g (4.76 mmol) of copper (II) acetate - Monohydrate and 7.532 g (95.22 mmol) of pyridine were stirred in 329 ml of DMF at 20 ⁰ C for 18 hours. Subsequently, 1.8 l of water were added and extracted with ultrafine with ethyl acetate. The combined organic extracts were washed three times with saturated aqueous sodium chloride solution, dried with sodium sulfate and evaporated in vacuo. The residue was purified on silica gel with a cyclohexane / ethyl acetate gradient and the product-containing fraction was evaporated. 1.34 g (9.2% of theory) of the target compound were obtained.

LC-MS (Method 2): R, = 1.34 min

MS (ESIpos): m / z = 300.3 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 1:39 (t, 3H), 4.45 (q, 2H), 7.0-7.1 (m, IH), 7.21 (dd, IH), 7.29 (d, IH) , 7.38 (t, IH), 7.62 (t, IH), 8.09 (d, IH), 8.20-8.32 (m, 2H), 9.01 (s, IH).

Example 4A

N- (2-fluorophenyl) -1H-indazole-3-amine

1.47 g (4.92 mmol) of ethyl 3 - [(2-fluoro-phenyl) -amino] -H-indazole-1-carboxylate were admixed in 14.7 ml of ethanol with 1.1 g (19.7 mmol) of potassium hydroxide and heated to reflux for 10 minutes. Subsequently, 1.182 g (19.69 mmol) of acetic acid were added and the mixture in vacuo evaporated. The residue was purified on silica gel with a cyclohexane / ethyl acetate gradient (1: 0 → 1: 1) and the product-containing fraction was evaporated. There were obtained 0.98 g (80% of theory) of the target compound in 91% purity (HPLC).

LC-MS (Method 4): R, = 1.81 min

MS (ESIpos): m / z = 228.4 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 6.82 (m, IH), 7:01 (dd, IH), 7:08 (dd, IH), 7.18 (dd, IH), 7:32 (dd, IH), 7:39 (d, IH), 7.98 (d, IH), 8.03 (dd, IH), 8.35 (s, IH), 12.12 (s, IH).

Example 5A

2- {3 - [(2-Fluoφhenyl) amino] -lH-indazol-l-yl} -5-nitropyrimidine-4,6-diamine

980 mg (4.31 mmol) of N- (2-fluorophenyl) -1H-indazol-3-amine, 817 mg (4.31 mmol) of 2-chloro-5-nitropyrimidine-4,6-diamine [Bitterli et al., HeIv. Chim. Acta 1951, 34, 835], 79 mg (0.086 mmol) tris (dibenzylideneacetone) dipalladium, 103 mg (0.216 mmol) dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine and 1.97 g (6.04 mmol ) cesium carbonate were stirred in 16.3 ml of toluene and 16.3 ml DMF under argon for 4 hours at 90 ⁰ C. The mixture was allowed to cool to room temperature, filtered off from the solid, washed the solid with THF, evaporated in vacuo and chromatographed on a silica gel column with a gradient of cyclohexane / ethyl acetate = 5: 1 to 0: 1. 929 mg (51% of theory) of the target compound were obtained in 89% purity (HPLC).

LC-MS (Method 5): R, = 2.30 min

MS (ESIpos): m / z = 381.2 (M + H) ⁺ ¹ H NMR (400 MHz, DMSO-U ₆ ): δ = 7.02 (m, IH), 7.20 (dd, IH), 7.25 (dd, IH), 7.34 (dd, IH), 7.54 (dd, IH) , 8.20 (d, IH), 8.40 (dd, IH), 8.70 (broad d, 4H), 8.91 (s, IH), 8.99 (d, IH).

Example 6A

3 - [(2-fluorophenyl) sulfanyl] indazol--lH

20 g (82 mmol) of 3-iodo-1H-indazole, 22.65 g (164 mmol) of potassium carbonate and 2.34 g (12.29 mmol) of copper (I) iodide were dissolved under argon atmosphere with 480 ml of 2-propanol, 10.17 g (164 mmol ) 1,2-ethanediol and 21 g (164 mmol) of 2-fluorothiophenol and stirred at 130 ⁰ C for 20 hours. The reaction was cooled to room temperature, combined with silica gel, evaporated in vacuo and chromatographed on silica gel with a cyclohexane / ethyl acetate gradient (10: 1 → 4: 1). After evaporation of the product-containing fractions, 19.9 g (96% of theory) of the target compound were obtained in 97% purity (HPLC).

LC-MS (Method 2): R, = 1.22 min

MS (ESIpos): m / z = 245.2 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 6.95 (dd, IH), 7.02 (m, IH), 7.18 (dd, IH), 7.23-7.30 (m, 2H), 7.42 (t , IH), 7.51 (d, IH), 7.62 (d, IH), 13.65 (broads, IH).

Example 7A

2- {3 - [(2-Fluorophenyl) sulfanyl] -1H-indazol-1-yl} -5-nitropyrimidine-4,6-diamine

3 g (12.28 mmol) of 3 - [(2-fluoro-phenyl) -sulfanyl] -lH-indazole, 4.66 g (24.6 mmol) of 2-chloro-5-nitropyrimidine-4,6-diamine [Bitterli et al., HeIv. Chim. Acta 1951, 34, 835], 225 mg (0.246 mmol) of tris (dibenzylideneacetone) dipalladium, 351 mg (0.74 mmol) of dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine and 8.00 g (24.6 mmol ) Cesium carbonate was stirred in 50 ml of toluene and 50 ml of DMF under argon at 9O ⁰ C for 17 hours. It was allowed to cool to room temperature and sucked off the solid. The solid was then stirred with 150 ml of 1N hydrochloric acid. After suction, the residue was dried under high vacuum. 4.03 g (82.5% of theory) of the target compound were obtained.

LC-MS (Method 2): R _t = 1.32 min

MS (ESIpos): m / z = 398.1 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 7.18 (dd, IH), 7.28-7.42 (m, 4H), 7.44 (d, IH), 7.59 (dd, IH), 8.78 (s, 2H), 8.9-9.02 (broad s, 2H), 9.08 (d, IH).

Example 8A

3- (pyridin-2-ylsulfanyl) -1H-indazole

1.5 g (6.15 mmol) of 3-iodo-1H-indazole, 1.7 g (12.3 mmol) of potassium carbonate and 176 mg (0.922 mmol) of copper (I) iodide were dissolved under inert conditions with 36 ml of 2-propanol, 763 mg (12.3 mmol). 1,2-ethanediol and 6.83 g (61.5 mmol) 2-mercaptopyridine and stirred at 130 ⁰ C for 44 hours. The batch was cooled to room temperature, combined with silica gel, evaporated in vacuo and chromatographed on silica gel with a dichloromethane / methanol gradient (50: 1 → 40: 1). After evaporation of the product-containing fractions, 703 mg (47% of theory) of the target compound were obtained in 94% purity (HPLC) of the target compound.

LC-MS (Method 6): R, = 0.86 min

MS (ESIpos): m / z = 228.2 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 6.77 (d, IH), 7.13 (m, IH), 7.19 (dd, IH), 7.44 (dd, IH), 7.50-7.61 (m , 2H), 7.66 (d, IH), 8.35 (d, IH), 13.75 (s, IH).

Example 9A

5-Nitro-2- [3- (pyridin-2-ylsulfanyl) -lH-indazol-l-yl] pyritnidin-4,6-diamine

700 mg (3.1 mmol) of 3- (pyridin-2-ylsulfanyl) -1H-indazole, 1.17 g (6.16 mmol) of 2-chloro-5-nitropyrimidine-4,6-diamine [Bitterli et al., HeIv. Chim. Acta 1951, 34, 835], 56 mg (0.062 mmol) tris (dibenzylideneacetone) dipalladium, 88 mg (0.19 mmol) dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine and 2 g (6.2 mmol ) cesium carbonate were stirred in 12.5 ml of toluene and 12.5 ml DMF under argon for 17 hours at 90 ⁰ C. It was allowed to cool to room temperature and sucked off the solid. The solid was then stirred with 50 ml of 1N hydrochloric acid. After suction, the residue was washed with 30 ml of saturated aqueous sodium bicarbonate solution and 50 ml of water and then dried under high vacuum. 668 mg (55% of theory) of the target compound were obtained. - -

LC-MS (Method 6): R, = 0.94 min

MS (ESIpos): m / z = 381.0 (M + H) ⁺

¹ H NMR (400 MHz, DMSO- (I ₆ ): δ = 7.12 (d, IH), 7.21 (m, IH), 7.35 (dd, IH), 7.51 (d, IH), 7.57-7.71 (m , 2H), 8.38 (m, IH), 8.8 (broad s, 2H), 8.97 (broad s, 2H), 9.08 (d, IH).

Example IQA

3 - (pyrimidin-2-ylsulfanyl) -1H-indazole

1.5 g (6.15 mmol) of 3-iodo-1H-indazole, 1.7 g (12.3 mmol) of potassium carbonate and 176 mg (0.922 mmol) of copper (I) iodide were dissolved under argon atmosphere with 36 ml of 2-propanol, 763 mg (12.3 mmol ) 1,2-ethanediol and 6.83 g (61.5 mmol) of 2-mercaptopyrimidine and stirred at 130 ⁰ C for 44 hours. The batch was cooled to room temperature, combined with silica gel, evaporated in vacuo and chromatographed on silica gel with a dichloromethane / methanol eluent (20: 1). After evaporation of the product-containing fractions, 554 mg (32% of theory) of the target compound were obtained in 81% purity (HPLC).

LC-MS (Method 6): R, = 0.78 min

MS (ESIpos): m / z = 229.2 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 7.18 (dd, IH), 7.22 (t, IH), 7.41 (dd, IH), 7.52 (d, IH), 7.62 (d, IH ), 8.53 (d, 2H), 13.65 (s, IH).

Example IIA

5-Nitro-2- [3- (pyrimidin-2-ylsulfanyl) -1 H -indazol-1-yl] pyrimidine-4,6-diamine

670 mg (2.94 mmol) of 3- (pyrimidin-2-ylsulfanyl) -lH-indazole, 1.67 g (8.8 mmol) of 2-chloro-5-nitropyrimidine-4,6-diamine [Bitterli et al., HeIv. Chim. Acta 1951, 34, 835], 108 mg (0.117 mmol) of tris (dibenzylideneacetone) dipalladium, 210 mg (0.44 mmol) of dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine and 1.9 g (5.87 mmol ) cesium carbonate were stirred in 12 ml of toluene and 12 ml DMF under argon for 17 hours at 100 ⁰ C. Then another 556 mg of 2-chloro-5-nitropyrimidine-4,6-diamine, 54 mg (0.059 mmol) were added.

Tris (dibenzylideneacetone) dipalladium and 126 mg of dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine was added and stirred at 110 ⁰ C for a further 20 h. It was allowed to cool to room temperature and sucked off the solid. The filtrate was evaporated, taken up in acetonitrile and filtered. The filter cake was then stirred with 50 ml of 4N hydrochloric acid, filtered, washed with 30 ml of saturated aqueous sodium bicarbonate solution and then with 50 ml of water and then dried under high vacuum. 996 mg (84% of theory) of the target compound were obtained.

LC-MS (Method 6): R _t = 0.89 min

MS (ESIpos): m / z = 382.1 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 7.28 (dd, IH), 7.38 (dd, IH), 7.60 (m, 2H), 8.58 (d, IH), 8.71, 8.79, 8.82, 8.95 (4 broad s, 6H), 9.06 (d, IH).

Example 12A

3 - (2-Fluoro-4-nitrophenoxy) -1- (4-methoxybenzyl) -1H-indazole

0.40 g (1.57 mmol) of 1- (4-methoxybenzyl) -1H-indazol-3-ol (Palazzo, G. et al., J.Med.Chem. 1966, 9 (1), 38-41) were prepared in 4 Dissolved DMF, 75.5 mg of sodium hydride (60% in mineral oil, 1.89 mmol) and Ih stirred at RT. 0.28 g (1.73 mmol) of 1,2-difluoro-4-nitrobenzene were added to the suspension obtained and the mixture was stirred at RT for a further hour. The reaction was mixed with water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and freed from the solvent on a rotary evaporator. The residue thus obtained was purified by preparative HPLC (Method 1). 0.32 g (52% of theory) of the target compound were obtained.

LC-MS (Method 2): R, = 1.51 min,

MS (ESIpos): m / z = 394.1 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 3.70 (s, 3H), 5.50 (s, 2H), 6.87 (d, 2H), 7.17 (t, IH), 7.21 (d, 2H), 7.43 -7.49 (m, 2H), 7.59 (d, IH), 7.77 (d, IH), 8.12 (d, IH), 8.39 (dd, IH).

Example 13A

3-Fluoro-4- {[1- (4-methoxybenzyl) -1H-indazol-3-yl] oxy} aniline

0.31 g (0.79 mmol) of the compound from Example 12A were dissolved in 6 ml of ethanol and 1 ml of DMF, admixed with 0.71 g (3.15 mmol) of tin (II) chloride dihydrate and refluxed for 1 h. It was then diluted with 50 ml of 1 N sodium hydroxide solution and 50 ml of ethyl acetate, the organic phase was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and freed from the solvent on a rotary evaporator. The residue thus obtained was purified by preparative HPLC (Method 1). 0.18 g (61% of theory) of the target compound were obtained.

LC-MS (Method 2): R, = 1.29 min

MS (ESIpos): m / z = 364.2 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 3.69 (s, 3H), 5.37 (s, 2H), 6.36 (dd, IH), 6.47 (dd, IH), 6.84 (d, 2H) , 7.00-7.06 (m, 2H), 7.13 (d, 2H), 7.35-7.39 (m, 2H), 7.59 (d, IH).

Example 14A

3- (2-fluorophenoxy) -1- (4-methoxybenzyl) -1H-indazole

89.0 mg (0.86 mmol) of tert-butylnitrite were initially charged in 1.5 ml of DMF. At 5O ⁰ C, a solution of the compound from Example 13A in 1 mL of DMF was added dropwise so that the internal temperature did not exceed 50 ⁰ C. After completion of the addition, the mixture was stirred for a further 30 minutes at 50 ⁰ C and then stirred into 6 ml of half-concentrated hydrochloric acid. It was extracted with ethyl acetate, the organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and freed from the solvent on a rotary evaporator. The residue thus obtained was purified by preparative HPLC (Method 1). 74 mg (49% of theory) of the target compound were obtained.

LC-MS (Method 6): R, = 1.31 min

MS (ESIpos): m / z = 349.3 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 3.69 (s, 3H), 5.42 (s, 2H), 6.85 (d, 2H), 7.10 (t, Ih), 7.16 (d, 2H) , 7.19-7.34 (m, 3H), 7.38-7.44 (m, 2H), 7.50 (d, IH), 7.67 (d, IH). Example 15A

3- (2-fluorophenoxy) -1H-indazole

70 mg (0.2 mmol) of the compound from Example 14A were stirred in 1 ml of trifluoroacetic acid at 70 ⁰ C Ih. After cooling, the mixture was carefully stirred into 10 ml of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phase washed with saturated sodium chloride solution, dried over magnesium sulfate and freed from the solvent on a rotary evaporator. The residue thus obtained was purified by preparative HPLC (Method 1). 29 mg (63% of theory) of the target compound were obtained.

LC-MS (Method 2): R, = 1.17 min,

MS (ESIpos): m / z = 229.3 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 7.09 (t, Ih), 7.18-7.32 (m, 3H), 7.40 (m, 2H), 7.47 (d, IH), 7.50 (d, IH) , 12.39 (s, IH).

Example 16A

2- [3- (2-Fluoφhenoxy) -lH-mdazol-l-yl] -5-nitropyrimidine-4,6-diamine

25 mg (0.11 mmol) of the compound from Example 15A were dissolved in 0.5 ml of DMF, admixed with 5.7 mg of sodium hydride (60% strength in mineral oil, 0.14 mmol) and stirred at RT for 1 h. To the resulting suspension was added a solution of 22.8 mg (0.12 mmol) of 2-chloro-5-nitropyrimidine-4,6-diamine [Bitterli et al., HeIv. Chim. Ada 1951, 34, 835] in 1.5 ml of DMF and stirred at 80 ⁰ C for 1 h. The mixture was purified directly by preparative HPLC (method 1). 23 mg (49% of theory) of the target compound were obtained.

LC-MS (Method 6): R, = 1.10 min,

MS (ESIpos): m / z = 382.3 (M + H) ⁺

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 7.28-7.49 (m, 4H), 7.56 (t, IH), 7.64 (t, IH), 7.76 (d, IH), 8.71 (s, 2H) , 8.80 (s, 2H), 9.04 (d, IH).

Exemplary embodiments:

example 1

2- {3 - [(2-Fluoφhenyl) sulfanyl] -lH-pyrazolo [4,3-b] pyridin-l-yl} -pyrimidine-4,5,6-triamine

2.727 g (about 3.08 mmol, purity 45%) 2- {3 - [(2-Fluo-phenyl) -sulfanyl] -1H-pyrazolo [4,3-b] pyridin-1-yl} -5-nitropyrimidine-4,6 -diamine were shaken with 1.09 g of 10% palladium on charcoal in 250 ml of pyridine under 3.5 bar hydrogen pressure at 2O ⁰ C for 17 hours. The mixture was filtered, the pyridine was distilled off for the most part and the residue was dissolved in acetonitrile. Silica gel was added, evaporated in vacuo and chromatographed on a silica gel column with a cyclohexane-ethyl acetate mixture (1: 1). 980 mg (31% of theory) of the product were obtained in 79% strength by weight. Purity. A small amount (110 mg) of this was purified by preparative HPLC (Cromatorex C18 lOμm, 250x30 mm, flow 50 ml / min, run time: 38 min, acetonitrile / water gradient + 0.1% formic acid). Evaporation of the product-containing fractions gave 76 mg of a solid.

LC-MS (Method 3): R, = 1.55 min

MS (ESIpos): m / z = 369.2 (M + H) ⁺

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 3.88 (s, 2H), 6.15 (s, 4H), 7.03-7.1 (m, IH), 7.1-7.2 (m, IH), 7.22-7.35 ( m, 2H), 7.53 (dd, IH), 8.6 (m, IH), 9.14 (d, IH).

Example 2

Methyl (4,6-diamino-2- {3 - [(2-fluoro-phenyl) -arynino] -lH-indazol-1-yl} pyrirnidin-5-yl) carbamate formate

100 mg (0.29 mmol) of 2- {3 - [(2-fluoro-phenyl) -amino] -1H-indazol-1-yl} -pyrimidine-4,5,6-triamine were dissolved in 1 ml of 2-propanol with 54 mg (0.4 mmol ) Dimethyldicarbonat 18 hours at 20 ⁰ C stirred. The precipitated solid was filtered off with suction and purified by preparative HPLC (Reprosil C18 10 μm, 250 × 30 mm, flow 50 ml / min, run time: 38 min, acetonitrile / water gradient + 0.1% formic acid). 37 mg (30% of theory) of the target compound were obtained.

LC-MS (Method 6): R, = 0.79 min

MS (ESIpos): m / z = 409.3 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 6.20 (broad s, IH), 6.98 (m, IH), 7.18 (dd, IH), 7:19 to 7:30 (m, 2H), 7:49 (dd, IH ), 7.88 (broad s, IH), 8.10 (d, IH), 8.15 (s, IH), 8.30 (dd, IH), 8.65 (s, IH), 8.81 (d, IH), 12.7 (broad s, IH).

Example 3

2- {3 - [(2-Fluoφhenyl) sulfanyl] -lH-mdazol-l-yl} -pyrimidine-4,5,6-triamine

3.88 g (9.76 mmol) of 2- {3 - [(2-fluoro-phenyl) -sulfanyl] -1H-indazol-1-yl} -5-nitropyrimidine-4,6-diamine were mixed with 1559 g of 10% palladium on charcoal in 250 ml Pyridine shaken under 3.5 bar hydrogen pressure at 20 ⁰ C for 17 hours. The mixture was filtered and the pyridine distilled off. There were obtained 3.31 g (90% of theory) of the target compound.

LC-MS (Method 2): R, = 1.16 min

MS (ESIpos): m / z = 381.2 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 3.83 (s, 2H), 6.10 (s, 4H), 7.05-7.14 (m, 2H), 7.22-7.38 (m, 3H), 7.47 -7.66 (m, 2H), 8.78 (d, IH).

Example 4

2- [3- (pyridin-2-ylsulfanyl) -1 H -indazol-1-yl] pyrimidine-4,5,6-triamine

660 mg (1.74 mmol) of 5-nitro-2- [3- (pyridin-2-ylsulfanyl) -1H-indazol-1-yl] pyrimidine-4,6-diamine were mixed with 185 mg of 10% palladium on charcoal in 50 ml Pyridine below 3.5 bar Hydrogen pressure shaken at 20 ⁰ C for 17 hours. Then another 185 mg of 10% palladium on activated charcoal were added and the mixture was hydrogenated under the same conditions for a further 24 h. The reaction was filtered, the residue washed with ethyl acetate and the combined filtrates evaporated. 440 mg (70% of theory) of the title compound were obtained.

LC-MS (Method 6): R, = 0.78 min

MS (ESIpos): m / z = 351.1 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-dβ): δ = 3.83 (broad s, 2H), 6.08 (broad s, 4H), 6.93 (d, IH), 7.16 (m, IH), 7.28 (dd, IH ), 7.52 (m, 2H), 7.60 (dd, IH), 8.37 (m, IH), 8.82 (d, IH).

Example 5

2- [3- (pyrimidin-2-ylsulfanyl) -1 H -indazol-1-yl] pyrimidine-4,5,6-triamine

990 mg (2.60 mmol) of 5-nitro-2- [3- (pyrimidin-2-ylsulfanyl) -1H-indazol-1-yl] pyrirnidine-4,6-diamine were treated with 553 mg of 10% palladium on charcoal in 75 ml of pyridine under 3.5 bar hydrogen pressure at 20 ⁰ C shaken for 6 hours. The reaction was filtered and evaporated in vacuo. 312 mg (9% of theory) of a solid in 27% purity (HPLC) were obtained, which was reacted further directly without further purification.

LC-MS (Method 6): R, = 0.72 min

MS (ESIpos): m / z = 352.0 (M + H) ⁺

Example 6

2- [3- (2-fluorophenoxy) -1H-indazol-1-yl] pyrimidine-4,5,6-triamine

350 mg (0.92 mmol) of the compound from Example 16A were dissolved in 35 ml of pyridine, treated with 100 mg of palladium on carbon (10%) and hydrogenated at 3 bar hydrogen pressure for 7 h. The suspension was then filtered, the filtrate was freed from the solvent on a rotary evaporator and the residue was purified by preparative HPLC (method 1). 220 mg (68% of theory) of the target compound were obtained.

LC-MS (Method 6): R _t = 0.84 min

MS (ESIpos): m / z = 352.1 [M + H] ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 3.69 (s, 2H), 4.09 (s, 4H), 7.23-7.33 (m, 3H), 7.41-7.44 (m, 2H), 7.52 (t, IH), 7.65 (d, IH), 8.76 (d, IH).

Example 8

Methyl (4,6-diamino-2- {3 - [(2-fluoro-phenyl) -sulfanyl] -1H-pyrazolo [4,3-b] pyridin-1-yl} pyrimidin-5-yl) carbamate

200 mg (0.429 mmol) 2- {3 - [(2-fluorophenyl) sulfanyl] -1H-pyrazolo [4,3-b] pyridin-1-yl} pyrimidine-4,5,6-triamine (purity 79%) were stirred in 5 ml of 2-propanol and 0.5 ml of N-methylpyrrolidone with 80.51 mg (0.6 mmol) of dimethyl dicarbonate at 20 ⁰ C for 20 hours. The precipitated solid was filtered off, washed with 5 ml of propanol and purified in DMF by preparative HPLC (Cromatorex C18 10 μm, 250 × 30 mm, flow 50 ml / min, run time: 38 min, acetonitrile / water gradient + 0.1% formic acid). After evaporation of the product-containing fractions, 76 mg (40% of theory) of the target compound were obtained.

LC-MS (Method 3): R _t = 0.81 min

MS (ESIpos): m / z = 427.3 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 3.6 (s, 3H), 6.5 (broad s, 4H), 7.05-7.15 (m, IH), 7.18-7.24 (m, IH), 7.25 -7.38 (m, 2H), 7.55 (dd, IH), 7.95 (s, IH), 8.60 (m, IH), 9.24 (d, IH).

Example 9

Propan-2-yl- (4,6-diamino-2- {3 - [(2-fluoro-phenyl) -sulfanyl] -1H-pyrazolo [4,3-b] pyridin-1-yl} pyrimidin-5-yl) carbamate

100 mg (0.214 mmol) of 2- {3 - [(2-fluorophenyl) sulfanyl] -1H-pyrazolo [4,3-b] pyridin-1-yl} pyrimidine-4,5,6-triamine (purity 79%) were in 5 ml of pyridine at 0 ⁰ C with 33.3 mg (0.271 mmol) of isopropyl chloroformate and stirred at 20 ⁰ C for 18 hours. After evaporation, the residue was purified by preparative HPLC (Cromatorex Cl 8 10 μm, 250 × 30 mm, flow 50 ml / min, run time: 38 min, acetonitrile / water gradient + 0.1% formic acid). After evaporation of the product-containing fractions, 54 mg (43% of theory) of the target compound were obtained.

LC-MS (Method 3): R _t = 0.92 min

MS (ESIpos): m / z = 455.3 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.30 (m, 6H), 5.00 (m, IH), 5.18 (broad s, 4H), 5.68 (broad s, IH), 6.91-7.01 (m, IH), 7.02-7.11 (m, IH), 7.13-7.21 (m, 2H), 7.28 (m, partially occluded by CDC13 signal, IH), 7.4 (dd, IH), 8.60 (m, IH), 8.97 (d, IH).

Example 10

Methyl (4,6-diamino-2- {3 - [(2-fluorophenyl) sulfanyl] -1H-indazol-1-yl} pyrimidin-5-yl) carbamate

200 mg (0.544 mmol) of 2- {3 - [(2-fluoro-phenyl) -sulfanyl] -1H-indazol-1-yl} -pyrimidine-4,5,6-triamine were dissolved in 6.35 ml of 2-propanol and 0.64 ml of N-methylpyrrolidone with 102.2 mg (0.76 mmol) of dimethyl dicarbonate for 19 hours at 2O ⁰ C stirred. The precipitated solid was filtered off with suction and washed with 10 ml of 2-propanol. After drying under high vacuum, 172 mg (74% of theory) of the target compound were obtained.

LC-MS (Method 6): R, = 0.96 min

MS (ESIpos): m / z = 426.3 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 3.6 (s, 3H), 6.43 (broad s, 4H), 7.05-7.20 (m, 2H), 7.21-7.40 (m, 3H), 7.49 (d, IH), 7.52 (t, IH), 7.95 (s, IH), 8.9 (d, IH).

Example 11

Methyl (4,6-diamino-2- {3 - [(2-fluorophenyl) sulfanyl] -1 H -indazol-1-yl} pyrimidin-5-yl) ethylcarbamate

100 mg (0.235 mmol) of methyl (4,6-diamino-2- {3 - [(2-fluorophenyl) sulfanyl] -1H-indazol-1-yl} pyrimidin-5-yl) carbamate were initially charged in 1 ml of THF , At 0 ⁰ C with 47.4 mg (0.26 mmol) of bis (trimethylsilyl) sodium added, stirred for 30 minutes at ^{0 0} C, added dropwise with 73.3 ml (0.47 mmol) of iodoethane and then stirred at 20 ⁰ C for 20 hours. After addition of 0.1 ml of water, the mixture was purified by preparative HPLC (Cromatorex Cl 8 10 .mu.m, 250 × 30 mm, flow 50 ml / min, run time: 38 min, acetonitrile / water gradient + 0.1% formic acid). After evaporation of the product-containing fractions, 23 mg (21% of theory) of the target compound were obtained.

LC-MS (Method 6): R, = 1.08 min

MS (ESIpos): m / z = 454.1 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = II (t, 3H), 3.42-3.54 (m, 2H), 3.55 (s, 2H), 3.68 (s, IH), 6.53 (s, 4H), 7.05-7.19 (m, 2H), 7.23-7.39 (m, 3H), 7.50 (d, IH), 7.52 (dd, 1H) 8.92 (d, IH).

Example 12

Propan-2-yl- (4,6-diammo-2- {3 - [(2-fluoφhenyl) sulfanyl] -lH-mdazol-l-yl} pyrimidin-5-yl) carbamate

100 mg (0.272 mmol) of 2- {3 - [(2-Fluoφhenyl) sulfanyl] -lH-indazol-l-yl} -pyrimidine-4,5,6-triamine were dissolved in 5 ml of pyridine (at 0 ⁰ C and 33.3 mg 0.271 mmol) of isopropyl chloroformate was added and stirred at 20 ⁰ C for 18 hours. After evaporation, the residue was purified by preparative HPLC (Cromatorex C18 10 μm, 250 × 30 mm, flow 50 ml / min, run time: 38 min, acetonitrile / water gradient + 0.1% formic acid). After evaporation of the product-containing fractions, 109 mg (88% of theory) of the target compound were obtained.

LC-MS (Method 6): R, = 1.05 min

MS (ESIpos): m / z = 454.3 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.29 (d, 6H), 5.0 (qt, IH), 5.13 (broad s, 4H), 5.68 (broad s, IH), 6.60 (dd, IH) , 7.05 (dd, IH), 7.10-7.22 (m, 3H), 7.40-7.53 (m, 2H), 8.71 (d, IH).

Example 13

N- (4,6-Diamino-2- {3 - [(2-fluoφhenyl) sulfanyl] -lH-indazol-l-yl} pyrimidin-5-yl) acetamide

100 mg (0.272 mmol) of 2- {3 - [(2-fluorophenyl) sulfanyl] -1H-indazol-1-yl} pyrimidine-4,5,6-triamine were dissolved in 5 ml of pyridine at ⁰ ° C. with 21.3 mg ( 0.272 mmol) of acetyl chloride and stirred at 2O ⁰ C for 18 hours. After evaporation, the residue was purified by preparative HPLC (Reprosil C18 10 μm, 250 × 30 mm, flow 50 ml / min, run time: 38 min, acetonitrile / water gradient + 0.1% formic acid). After evaporation of the product-containing fractions, 62 mg (56% of theory) of the target compound were obtained.

LC-MS (Method 6): R, = 0.92 min

MS (ESIpos): m / z = 410.3 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 2:02 (s, 3H), 6:35 (broad s, 4H), 7:08 to 7:20 (m, 2H), 7:23 to 7:39 (m, 3H), 7.50 (d , IH), 7.53 (dd, IH), 8.55 (s, IH), 8.9 (d, IH).

Example 14

N- (4,6-diamino-2- {3 - [(2-fluoro-phenyl) -sulfanyl] -1H-indazol-1-yl} -pyrimidin-5-yl) -2-methyl-propanamide

100 mg (0.272 mmol) of 2- {3 - [(2-Fluoφhenyl) sulfanyl] -lH-indazol-l-yl} -pyrimidine-4,5,6-triamine were dissolved in 5 ml of pyridine (at 0 ⁰ C with 29 mg 0.272 mmol) of 2-methylpropionyl chloride and stirred at 20 ° C for 18 hours. After evaporation, the residue was purified by preparative HPLC (Reprosil Cl 8 10 μm, 250 × 30 mm, flow 50 ml / min, run time: 38 min, acetonitrile / water gradient + 0.1% formic acid). After evaporation of the product-containing fractions, 52 mg (43% of theory) of the target compound were obtained.

LC-MS (Method 6): R, = 1.00 min

MS (ESIpos): m / z = 438.3 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 1.12 (d, 6H), 2.62 (m, IH), 6.25 (broad s, 4H), 7:08 to 7:21 (m, 2H), 7.25-7.4 (m , 3H), 7.50 (d, IH), 7.54 (dd, IH), 8.59 (s, IH), 8.90 (d, IH).

Example 15

N- (4,6-diamino-2- {3 - [(2-fluorophenyl) sulfanyl] -1H-indazol-1-yl} pyrimidin-5-yl) -3,3,3-trifluoropropanamide

100 mg (0.272 mmol) of 2- {3 - [(2-Fluoφhenyl) sulfanyl] -lH-indazol-l-yl} -pyrimidine-4,5,6-triamine were dissolved in 5 ml of pyridine (at 0 ⁰ C with 80 mg 0.544 mmol) of 3,3,3-trifluoropropionyl chloride and 42 hours at 20 ⁰ C stirred. After evaporation, the residue was purified by preparative HPLC (Reprosil Cl 8 10 μm, 250 × 30 mm, flow 50 ml / min, run time: 38 min, acetonitrile / water gradient + 0.1% formic acid). After evaporation of the product-containing fractions, 22 mg (17% of theory) of the target compound were obtained.

LC-MS (Method 6): R, = 1.03 min

MS (ESIpos): m / z = 478.2 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 3:50 (q, 2H), 6.50 (broad s, 4H), 7:09 to 7:20 (m, 2H), 7:28 to 7:40 (m, 3H), 7.50 (d , IH), 7.56 (dd, IH), 8.90 (d, IH), 8.95 (s, IH).

Example 16

N- (4,6-Diarmno-2- {3 - [(2-fluoro-phenyl) sulfanyl] -H-indazol-1-yl} pyrimidin-5-yl) -3-methyl-butanamide

100 mg (0.272 mmol) of 2- {3 - [(2-fluorophenyl) sulfanyl] -lH-indazol-l-yl} -pyrimidine-4,5,6-triamine were dissolved in 5 ml of pyridine (at 0 ⁰ C with 39 mg 0.327 mmol) was added 3 -Methylbuttersäurechlorid and stirred at 20 ⁰ C for 18 hours. After evaporation, the residue was purified by preparative HPLC (Reprosil C18 10 μm, 250 × 30 mm, flow 50 ml / min, run time: 38 min, acetonitrile / water gradient + 0.1% formic acid). Evaporation of the product-containing fractions gave 58 mg (47% of theory) of the target compound.

LC-MS (Method 6): R _t = 1.05 min

MS (ESIpos): m / z = 452.3 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 0.98 (d, 6H), 2.10 (m, IH), 2.25 (d, 2H), 6.28 (broad s, 4H), 7.10- 7.20 (m, 2H ), 7.25-7.39 (m, 3H), 7.50 (d, IH), 7.55 (t, IH), 8.6 (s, 1H), 8.9O (d, IH).

Example 17

Methyl {4,6-diamino-2- [3- (pyridin-2-ylsulfanyl) -lH-indazol-l-yl] pyrimidin-5-yl} carbamate

100 mg (0.285 mmol) of 2- [3- (pyridin-2-ylsulfanyl) -1H-indazol-1-yl] pyrimidine-4,5,6-triamine were dissolved in 3 ml of 2-propanol and 0.3 ml of N-methylpyrrolidone 54 mg (0.4 mmol) of dimethyl dicarbonate for 19 hours at 20 ⁰ C stirred. The mixture was evaporated, treated with 10 ml of DMF and 50 ml of water and evaporated to half. The precipitated after 16 h solid was filtered off, washed with water and dried under high vacuum. 58 mg (48% of theory) of the target compound were obtained.

LC-MS (Method 6): R, = 0.81 min

MS (ESIpos): m / z = 409.0 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 3.62 (s, 3H), 6.45 (s, 4H), 7.0 (d, IH), 7.18 (m, IH), 7.3 (t, IH ), 7.55 (m, 2H), 7.6 (dd, IH), 7.95 (s, IH), 8.39 (d, IH), 8.92 (d, IH).

Example 18

Methyl {4,6-diamino-2- [3- (pyrimidin-2-ylsulfanyl) -1 H -indazol-1-yl] pyrimidin-5-yl} carbamate

210 mg (0.077 mmol) of 2- [3- (pyriniidin-2-ylsulfanyl) -1H-indazol-1-yl] pyrimidine-4,5,6-triamine were dissolved in 6.3 ml of 2-propanol and 0.63 ml of N-methylpyrrolidone 112 mg (0.837 mmol) of dimethyl dicarbonate for 19 hours at 20 ⁰ C stirred. After evaporation, the residue was purified by preparative HPLC (Cromatorex Cl 8 10 μm, 250 × 30 mm, flow 50 ml / min, run time: 38 min, acetonitrile / water gradient + 0.1% formic acid). Yield: 1 mg (0.7% of theory).

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

MS (ESIpos): m / z = 410.1 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-dβ): δ = 3.61 (s, 3H), 6.43 (broad s, 4H), 6.72 (s, IH), 7.28 (dd, IH), 7.32 (dd, IH) , 7.58 (m, 2H), 7.73 (m, IH), 8.52 (d, 2H).

Example 19

Propan-2-yl- {4,6-diamino-2- [3- (2-fluorophenoxy) -lH-indazol-l-yl] pyrimidin-5-yl} carbamate

80 mg (0.23 mmol) of the compound from Example 6 were dissolved in 2.8 ml of dichloromethane, combined with 0.02 ml (0.25 mmol) of pyridine and 30.7 mg (0.25 mmol) of isopropyl chloroformate while stirring with ice bath and stirred at RT for 1 h. The resulting precipitate was filtered, washed with a little dichloromethane and purified by preparative HPLC (Method 1). 80 mg (80% of theory) of the target compound were obtained.

LC-MS (Method 6): R _t = 0.96 min

MS (ESIpos): m / z (%) = 438.2 (100) (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-dβ): δ = 1.17 (broad s, 6H), 4.80 (sept., IH), 6.21 (s, 4H), 7.25-7.34 (m, 3H), 7.42-7.50 (m, 2H), 7.56 (t, IH), 7.69 (d, IH), 7.77 (s br, IH), 8.88 (d, IH).

Example 20

Methyl {4,6-diamino-2- [3- (2-fluorophenoxy) -1 H -indazol-1-yl] pyrimidin-5-yl} carbamate

Analogously to the procedure of Example 19, 80 mg (0.23 mmol) of the compound from Example 6 and 23.7 mg (0.25 mmol) of methyl chloroformate gave 46 mg (49% of theory) of the target compound.

LC-MS (Method 6): R, = 0.89 min,

MS (ESIpos): m / z = 410.2 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 3.56 (broad s, 3H), 6.28 (s, 4H), 7.25-7.34 (m, 3H), 7.42-7.51 (m, 2H), 7.56 (t , IH), 7.68 (d, IH), 7.86 (s br, IH), 8.88 (d, IH).

Example 21

2- {3 - [(2-Fluorophenyl) amino] -1 H -indazol-1-yl} pyrimidine-4,5,6-triamine formate

x HCOOH

630 mg (1.66 mmol) of 2- {3 - [(2-fluoro-phenyl) -moMo] -1H-indazol-1-yl} -5-nitropyrimidine-4,6-diamine were mixed with 150 mg of 10% palladium on charcoal in 147 ml Pyridine below 3.5 bar Hydrogen pressure shaken at 20 ⁰ C for 18 hours. The mixture was filtered, the pyridine was mostly distilled off and purified by preparative HPLC (Reprosil Cl 8 10 μm, 250 × 30 mm, flow 50 ml / min, run time: 38 min, acetonitrile / water gradient + 0.1% formic acid). Evaporation of the product-containing fractions gave 246 mg of a solid (42% of theory).

LC-MS (Method 2): R, = 1.16 min

MS (ESIpos): m / z = 381.2 (M + H) ⁺

¹ H NMR (400 MHz, DMSO- (I ₆ ): δ = 5.90 (s, 4H), 6.93 (m, IH), 7.10-7.28 (m, 3H), 7.43 (dd, IH), 8.03 (i.e. , IH), 8.12 (s, IH), 8.26 (dd, IH), 8.57 (s, IH), 8.70 (d, IH).

Example 22

Methyl (4,6-dianiino-2- {3 - [(2-fluoro-phenyl) -sulfanyl] -1H-indazol-1-yl} pyrimidin-5-yl) (2,2,2-trifluoroethyl) carbamate

100 mg (0:24 mmol) of methyl (4,6-diammo-2- {3 - [(2-fluorophenyl) sulfanyl] -lH-indazol-l- yl} pyrimidine-5-yl) carbamate were at 0 ⁰ C in 1 ml THF with 10.3 mg (0.26 mmol) sodium hydride

Stirred for 30 minutes and then with 73 mg (0.26 mmol) 2,2,2-

Trifluorethyltrichlormethansulfonat and stirred at 20 ⁰ C for 20 hours. The same amount of sodium hydride and 2,2,2-

Trifluorethyltrichlormethansulfonat added and stirred at 20 ⁰ C for 2 days. After addition of 0.1 ml of water, by preparative HPLC (Cromatorex Cl 8 lOμm, 250x30 mm, flow 50 ml / min, running time: 38 min, acetonitrile / water gradient + 0.1% formic acid). This gave 20 mg (17% of theory) of the target compound.

LC-MS (Method 6): R, = 1.12 min

MS (ESIpos): m / z = 508.0 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 3.65 (s, 3H), 4.12 (m, 2H), 6.68 (broad s, 4H), 7:08 to 7:20 (m, 2H), 7:28 to 7:40 (m , 3H), 7.50 (d, IH), 7.55 (dd, IH), 8.93 (d, IH).

B. Evaluation of Pharmacological Activity

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

BI. Vaso-relaxant effect in vitro

Rabbits are stunned and bled by a stroke of the neck. The aorta is harvested, detached from adherent tissue, divided into 1.5 mm wide rings and placed individually under bias in 5 ml organ baths with 37 ° C warm, carbogen-fumed Krebs-Henseleit solution of the following composition (in each case mM): NaCl: 119; KCl: 4.8; CaCl ₂ × 2 H ₂ O: 1; MgSO ₄ × 7H ₂ O: 1.4; KH ₂ PO ₄ : 1.2; _NaHCO3: 25; Glucose: 10. The force of contraction is detected with Statham UC2 cells, amplified and digitized via A / D converters (DAS-1802 HC, Keithley Instruments Munich) and registered in parallel on chart recorders. To create a contraction, phenylephrine is added cumulatively to the bath in increasing concentration. After several control cycles, the substance to be examined is added in each subsequent course in increasing dosages and the height of the contraction is compared with the height of the contraction achieved in the last predistortion. This is used to calculate the concentration required to reduce the level of the control value by 50% (IC ₅₀ -wt). The standard application volume is 5 μl, the DMSO content in the bath solution corresponds to 0.1%.

Representative IC 50 values for the compounds of the invention are shown in the following table:

B-2. Effect on recombinant guanylate cyclase reporter cell line

The cellular activity of the compounds of the invention is measured on a recombinant guanylate cyclase reporter cell line as described in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005).

B-3. Blood pressure measurement on anesthetized rats

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

B-4. Radiotelemetric blood pressure measurement 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:

Implantable transmitters (Physiotel® telemetry transmitters)

Receiver (Physiotel® Receiver), which is connected via a multiplexer (DSI Data Exchange Matrix) with a

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 hvpertensiven rats (SHR Okamoto) with a body weight of> 200 g. SHR / NCrl of Okamoto Kyoto School of Medicine, 1963 were crossed from male Wistar Kyoto rats with high blood pressure and female with slightly elevated blood pressure and delivered in the Fl 3 to the US 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 of 5 ml / kg body weight, the test substances are dissolved in suitable solvent mixtures or suspended in 0.5% Tylose.

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

experimental procedure

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

The instrumented rats living in the plant each have their own receiving antenna (1010 receivers, DSI). The implanted transmitters can be activated externally via a built-in magnetic switch. They will be put on the air during the trial run. The emitted signals can be recorded online by a data acquisition system (Dataquest ™ ART 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 for 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 here 2 hours before application, so that the selected data record covers the period from 7:00 am on the day of the experiment 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 day of the experiment in a separate folder containing the Test number carries. Results and test reports are sorted in folders and sorted by paper.

Literature:

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

B-fifth Determination of pharmacokinetic parameters after intravenous and oral administration

The substance to be examined is administered to animals (eg mouse, rat, dog) intravenously as a solution, the oral administration is carried out as a solution or suspension via a gavage. After substance administration, the animals are bled at fixed times. This is heparinized and then plasma is recovered therefrom by centrifugation. The substance is analytically quantified in the plasma via LC / MS-MS. The pharmacokinetic parameters such as AUC, C _013x , T _1Z2 (half-life) and CL (clearance) are calculated from the plasma concentration-time curves thus determined by means of a validated pharmacokinetic calculation program.

B-sixth Determination of solubility

Required reagents:

PBS buffer pH 7.4: 90.00 g NaCl pa (for example from Merck, Item No. 1.06404.1000), 13.61 g KH ₂ PO ₄ pa (for example from Merck, Item No. 1.04873.1000) and Weigh 83.35 g of 1 N NaOH (eg Bernd Kraft GmbH, article No. 01030.4000) into a 1 liter volumetric flask, make up with water and stir for about 1 hour;

• Acetate buffer pH 4.6: Weigh out 5.4 g of sodium acetate x 3 H ₂ O pa (eg from Merck, Item No. 1.06267.0500) into a 100 ml volumetric flask, dissolve in 50 ml of water, add 2.4 g of glacial acetic acid Make up to 100 ml with water, check the pH and if necessary adjust to pH 4.6;

Dimethylsulfoxide (e.g., Baker Co., Art No. 71572500);

• distilled water. Preparation of the calibration solutions:

Preparation of the starting solution for calibration solutions (stock solution): Approximately 0.5 mg of the test substance is accurately weighed into a 2 ml Eppendorf Safe-Lock tube (Eppendorf, Item No. 0030 120,094), to a concentration of 600 μg / ml mixed with DMSO (eg 0.5 mg of substance + 833 μl of DMSO) and shaken to complete dissolution by means of a vortexer.

Calibration solution 1 (20 μg / ml): Mix 34.4 μl of the stock solution with 1000 μl of DMSO and homogenize.

Calibration solution 2 (2.5 μg / ml): 100 μl of the calibration solution 1 are mixed with 700 μl of DMSO and homogenized.

Preparation of the sample solutions:

Sample solution for solubility up to 10 g / l in PBS buffer pH 7.4: Approximately 5 mg of the test substance are weighed exactly into a 2 ml Eppendorf Safe-Lock tube (Eppendorf, Item No. 0030 120,094) and added to a Concentration of 5 g / l with PBS buffer pH 7.4 added (eg, 5 mg of substance + 500 ul PBS buffer pH 7.4).

Sample solution for solubility up to 10 g / l in acetate buffer pH 4.6: Approximately 5 mg of the test substance are weighed exactly into a 2 ml Eppendorf-Safe-Lock tube (Eppendorf, Art No. 0030 120,094) and added to a concentration of 5 g / l with acetate buffer pH 4.6 added (eg 5 mg of substance + 500 ul acetate buffer pH 4.6).

Sample solution for solubility up to 10 g / l in water: Approximately 5 mg of the test substance are weighed exactly into a 2 ml Eppendorf-Safe-Lock tube (Eppendorf, Art No. 0030 120,094) and added to a concentration of 5 g / l mixed with water (eg 5 mg substance + 500 ul water).

Execution:

The sample solutions thus prepared are shaken for 24 hours at 1400 rpm in a temperature shaker (for example, Fa. Eppendorf Thermomixer comfort No. 5355 000.011 with alternating block No. 5362.000.019) at 20 ⁰ C. 180 μl of each of these solutions are taken off and transferred to Beckman Polyallomer Centrifuge Tubes (Item No. 343621). These solutions are centrifuged for 1 hour at about 223,000 xg (eg Beckman Optima L-90K Ultracentrifuge with Type 42.2 Ti rotor at 42,000 rpm). 100 μl of the supernatant are taken from each sample solution and diluted 1: 5, 1: 100 and 1: 1000 with the respectively used solvent (water, PBS buffer 7.4 or acetate buffer pH 4.6). Each dilution is bottled in a suitable vessel for HPLC analysis. Analvtik:

The samples are analyzed by RP-HPLC. Quantification is achieved by a two-point calibration curve of the test compound in DMSO. The solubility is expressed in mg / l. Analysis sequence: 1) Calibration solution 2.5 mg / ml; 2) Calibration solution 20 μg / ml; 3) Sample solution 1: 5; 4) Sample solution 1: 100; 5) Sample solution 1: 1000.

HPLC method for acids:

Agilent 1100 with DAD (Gl 315A), quat. Pump (G1311A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); Column: Phenomenex Gemini C18, 50 mm x 2 mm, 5 μ; Temperature: 40 ^° C .; Eluent A: water / phosphoric acid pH 2; Eluent B: acetonitrile; Flow rate: 0.7 ml / min; Gradient: 0-0.5 min 85% A, 15% B; Ramp: 0.5-3 min 10% A, 90% B; 3-3.5 min 10% A, 90% B; Ramp: 3.5-4 min 85% A, 15% B; 4-5 minutes 85% A, 15% B.

HPLC method for bases:

Agilent 1100 with DAD (G1315A), quat. Pump (G1311A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); Column: VDSoptilab Kromasil 100 C18, 60 mm x 2.1 mm, 3.5 μ; Temperature: 30 ^° C .; Eluent A: water + 5 ml perchloric acid / l; Eluent B: acetonitrile; Flow rate: 0.75 ml / min; Gradient: 0-0.5 min 98% A, 2% B; Ramp: 0.5-4.5 min 10% A, 90% B; 4.5-6 min 10% A, 90% B; Ramp: 6.5-6.7 min 98% A, 2% B; 6.7-7.5 min 98% A, 2% B.

C. Embodiments of Pharmaceutical Compositions

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

Tablet:

Composition:

100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

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

production:

The mixture of the compound according to the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

1000 mg of the inventive compound, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water.

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

production:

The rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h. Orally administrable solution:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound according to the invention corresponds to 20 g of oral solution.

production:

The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.

iv solution:

The compound of the invention is dissolved 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

- Patent claims

1. Compound of formula (I)

LAMQ _(I)>

in which

A represents O, S, -S (O) -, S (= O) ₂ - or NR ¹ ,

in which

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

where phenyl, pyridyl, pyrimidinyl, furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl and isoxazolyl having 1 or 2 substituents independently of one another are selected from the group halogen, cyano, (QC ^ -alkyl, trifluoromethyl, chloromethyl and (C ₂ -C ₄ ) Alkynyl may be substituted,

and

M is a bicyclic heteroaryl group of the formula

stands, where

* stands for the point of attachment to the group A,

** stands for the point of attachment to the group Q, T, U, V and W are each CR ² or N,

and

wherein

R ² is hydrogen, halogen, cyano, (Ci-C ₄₎ alkyl, trifluoro methyl, amino, (C _r C ₄₎ -alkoxy and trifluoromethoxy,

and

wherein in the event that the substituent R ² occurs several times, its

Meanings may be the same or different,

and

wherein the 5- or 6-membered heterocycle and the 5- or 6-membered

Heteroaryl having 1 to 4 substituents independently selected from the group halogen, azido, nitro, cyano, oxo, thioxo, -R ³ , -C (= O) -R ³ , -C (= O) -OR ³ , -C (= O) -NR ³ R ⁴ , -O- (C = O) _n -R ³ , -OC (= O) -OR-OC (= O) -NR ³ R ⁴ , -S (O) _P -R ³ , -SO ₂ - OR ³ , -SO ₂ -NR ³ R ⁴ , -NR ³ - (C =O) _n -R ⁴ , -NR ³ -SO ₂ -R ⁴ , -NR ³ -C ( = O) -OR ⁴ , -NR ⁵ -C (= O) - NR ³ R ⁴ and -NR ⁵ -SO ₂ -NR ³ R ⁴ may be substituted,

wherein

n is a number 0 or 1,

p is a number 0, 1 or 2,

R ^3, R ⁴ and R ⁵ are each independently hydrogen, (C _r _C6) - alkyl, (C ₂ -C ₆₎ alkenyl, (C ₃ -C ₈₎ -cycloalkyl, (C ₃ -C ₈₎ -

Cycloalkenyl, (C ₆ -C ₀₎ aryl, 4- to 10 stand-membered heteroaryl to 8-membered heterocyclyl or 5-, wherein R ³ , R ⁴ and R ^{5, in} turn, having 1 to 5 substituents independently selected from the group halogen, azido, nitro, cyano, trifluoromethyl, (Ci-Ce) -AIlCyI, (Ci-C ₆ ) alkylcarbonyl, (Ci -C ₆ ) -Alkylcarbonyloxy, hydroxycarbonyl, (C ₁ -C ₆ ) -alkoxycarbonyl, amino carbonyl, mono- (C ₁ -C ₆ ) -alkylaminocarbonyl, di- (CpC ₆ ) -alkylaminocarbonyl, hydroxy, trifluoromethoxy, (C 1 -C ₄ -alkyl) ₆₎ - alkoxy, oxo, mercapto, (Ci-C ₆₎ alkylthio, amino, mono- (Ci-C ₆₎ -alkylamino, di- (C _r _C6) alkylamino, formylamino, (C ₁ -C ₆ ) -alkoxycarbonylamino, (C ₃ -C ₈ ) -cycloalkyl, (C ₃ -C ₈ ) -cycloalkenyl and also be substituted by 4- to 8-membered heterocyclyl,

or

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

A is O, S or NR ¹ ,

in which

R ^{1 is} hydrogen,

L is phenyl, thienyl, pyridyl or pyrimidinyl,

where phenyl, thienyl, pyridyl and pyrimidinyl can be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl and trifluoromethyl, for a bicyclic heteroaryl group of the formula

stands in which

* stands for the point of attachment to the group A,

** stands for the point of attachment to the group Q,

T ¹ , U ¹ , V ¹ and W ^{1 are} each CR ^2A or N,

wherein a maximum of two of the ring members T ¹ , U ¹ , V ¹ and W ^{1 are} simultaneously N,

and

in which

R ^{2A is} hydrogen or fluorine,

wherein a maximum of two of the radicals R ^{2A are} fluorine,

and

T ² , U ² , V ² and W ^{2 are} each CR ^2B or N,

and

in which

R ^{2B is} hydrogen or fluorine,

wherein a maximum of two of the radicals R ^{2B are} fluorine, and

and

Q for a group of the formula

stands,

in which

# represents the point of attachment to the group M,

D is CH or N,

J is CR ⁸ , N or N ⁺ -O ^' ,

wherein

R ^{8 is} halogen, nitro, cyano, -R ³ , -C (= O) -R ³ , -C (= O) -OR ³ , -C (= O) -NR ³ R ⁴ , -O- (C = O) _n -R ³ , -OC (= O) -OR ³ , -OC (= O) -NR ³ R ⁴ , -S (O) _P -R ³ , -SO ₂ -OR ³ , -SO ₂ -NR ³ R ⁴ , -NR ³ - (C =O) _n -R ⁴ , -NR ³ -SO ₂ -R ⁴ ,

-NR ³ -C (= O) -OR ⁴ , -NR ⁵ -C (= O) -NR ³ R ⁴ or -NR ⁵ -SO ₂ -NR ³ R ⁴ ,

wherein

n is a number O or 1, p stands for a number 0 or 2,

R ³ , R ⁴ and R ^{5 are} each independently hydrogen, (C ₃ -C ₆ alkyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkenyl , Phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered

Heteroaryl stand,

wherein R ³ , R ⁴ and R ^{5, in} turn, having 1 to 3 substituents independently selected from the group fluorine, chlorine, cyano, (C i -C ₄ ) alkyl, trifluoromethyl, hydroxy, (C, -C ₄ ) alkoxy .

Trifluoromethoxy, oxo, amino, mono (QC ₄ ) alkylamino and di (Ci-C ₄ ) alkylamino may be substituted,

or

R ³ and R ⁵ together with the radical to which they are both bonded, a 5- to 7-membered

Can form heterocycle,

R ⁹ represents hydrogen, (C _r _C6) alkyl or (C ₃ -C ₇₎ cycloalkyl,

where (C 1 -C ₆ ) -alkyl having 1 to 5 substituents selected independently of one another from the group consisting of (C ₃ -C ₇ ) -cycloalkyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy, (C ₁ -C ₄ ) - Acyloxy, amino, mono- (C 1 -C ₄ ) -alkylamino, di-

(C 1 -C ₄ ) -alkylamino, (C 1 -C ₄ ) -acylamino, hydroxycarbonyl, (QC ₄ ) -alkoxycarbonyl, aminocarbonyl, mono- (C 1 -C ₄ ) -aminocarbonyl, di- (C 1 -C ₄ ) -alkylaminocarbonyl and 5- or 6-membered heterocycle may be substituted,

A compound of formula (I) according to claim 1 or 2, in which A is S or NR ¹ , wherein

R ^{1 is} hydrogen, L is phenyl, pyridyl or pyrimidinyl, wherein phenyl may be substituted with 1 or 2 substituents fluorine, M is a bicyclic heteroaryl group of the formula

where * represents the point of attachment to the group A,

** stands for the point of attachment to the group Q, and

T ^{1 is} CH or N,

U ^{1 is} CH, W ^{1 is} CH,

V ¹ for CR ^2A is where

R ^{2A is} hydrogen or fluorine, a group of the formula

stands, where

# represents the point of attachment to the group M,

J is CR ⁸ or N,

wherein

R ⁸ represents hydrogen, fluorine, (C _r _C4) alkyl, (C ₃ -C ₇₎ -cycloalkyl, phenyl, pyridyl, -NR ³ - (C = O) _n -R ^4, -NR ³ -C ( = O) -OR ⁴ or

-NR ⁵ -C (= O) -NR ³ R ⁴ ,

wherein

n represents the number 0 or 1,

R ^{3 is} hydrogen or stands,

R ^{4 is} hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,

R ⁵ is hydrogen or (C _r C ₄₎ alkyl,

or

R ³ and R ^4, together with the radical to which they are both bonded, can form a 5- to 7-membered heterocycle, R ^{6 is} hydrogen or amino,

R ^{7 is} hydrogen or amino,

4. A process for the preparation of compounds of the formula (I) as defined in claims 1 to 3, characterized in that

[A] a compound of the formula (H)

in which A, L, T ¹ , U ¹ , V ¹ and W ¹ each have the meanings given in claims 1 to 3,

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

in which D, J, R ⁶ and R ⁷ each have the meanings given in claims 1 to 3,

and

to a compound of the formula (I-A)

in which A, D, J, L, T ¹ , U ¹ , V ¹ , W ¹ , R ⁶ and R ⁷ each have the meanings given in claims 1 to 3,

implements,

or

[B] a compound of the formula (IV)

in which A, L, T ² , U ² , V ² and W ² each have the meanings given in claims 1 to 3,

in an inert solvent with a halogenating agent in one

Compound of the formula (V)

and

X ^{2 is} halogen, in particular bromine, transferred, then by standard methods into a tin species (FV)

in which A, L, T ² , U ² , V ² and W ² each have the meanings given in claims 1 to 3

and

R ^{10 is} (C ₁ -C ₄ ) -alkyl,

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

to a compound of the formula (I-B)

in which A, D, J, L, T ² , U ² , V ² , W ² , R ⁶ and R ⁷ each have the meanings given in claims 1 to 3,

implements,

or

[C] a compound of the formula (VII)

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

in which J and R ⁶ each have the meanings given in claims 1 to 3,

to a compound of the formula (I-C)

in which A, J, L, T ² , U ² , V ² , W ² and R ⁶ each have the meanings given in claims 1 to 3,

implements,

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

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

6. A compound of formula (I) as defined in any one of claims 1 to 3 for use in a method for the treatment and / or prevention of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, thromboembolic disorders and Arteriosclerosis.

Use of a compound of formula (I) as defined in any one of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prevention of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, thromboembolic disorders and arteriosclerosis ,

8. A pharmaceutical composition comprising a compound of the formula (I) as defined in any one of claims 1 to 3, in combination with an inert, non-toxic, pharmaceutically suitable

Excipient.

9. A medicament comprising a compound of formula (I) as defined in any one of claims 1 to 3, in combination with another active ingredient selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, antithrombotic acting agents, the blood pressure lowering agents as well as the fat metabolism changing agents.

10. Medicament according to claim 8 or 9 for the treatment and / or prevention of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, thromboembolic disorders and arteriosclerosis.

11. A method for the treatment and / or prevention of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, thromboembolic disorders and arteriosclerosis in humans and animals using an effective amount of at least one compound of formula (I), as in one of Claims 1 to 3, or a medicament as defined in any one of claims 8 to 10.