DE102011007890A1 - New fluoroalkyl-substituted pyrazolopyridine compounds are soluble guanylate cyclase stimulators, useful to treat e.g. heart disease, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disease or renal insufficiency - Google Patents

Abstract

Fluoroalkyl-substituted pyrazolopyridine compounds (I) are new. Fluoroalkyl-substituted pyrazolopyridine compounds of formula (I) and their N-oxides, salts, solvates, salts of N-oxides and solvates of the N-oxides or their salts are new. A : N or CR3; R3 : H, D, F, difluoromethyl, trifluoromethyl, 1-4C-alkyl, cyclopropyl or cyclobutyl; L : a1-CR4AR4B-(CR5AR5B) p-a2; a1 : point of attachment to the carbonyl group; a2 : point of attachment to the pyrimidine or triazine ring; p : 0-2; either R4A : H, F, 1-4C-alkyl, hydroxy or amino; and R4B : H, F, 1-4C-alkyl (optionally substituted with 1-3 substituents comprising F, trifluoromethyl, hydroxy, hydroxycarbonyl or 1-4C-alkoxycarbonyl), trifluoromethyl, 1-4C-alkoxycarbonylamino or phenyl; or R4A+C+R4B : 3-6 membered carbocycle or 4-6 membered heterocycle (both optionally substituted with 1 or 2 substituents comprising F or 1-4C-alkyl), oxo-group or 2-4C-alkenyl; R5A : H, F, 1-4C-alkyl or hydroxy; R5B : H, F, 1-4C-alkyl or trifluoromethyl; R1 : H or F; R2 : a3-(CR6AR6B) qCF 3; a3 : point of attachment to the pyrazolopyridine; R6A, R6B : H or F; and q : 1-3. Independent claims are included for: (1) the preparation of (I); and (2) a drug comprising (I) in combination with further active agents comprising organic nitrates, nitric oxide donors, cyclic guanosine monophosphate-phosphodiesterase inhibitors, antithrombotic agents, blood pressure lowering agents or lipid modifying agents. [Image] ACTIVITY : Cardiant; Antianginal; Hypotensive; Respiratory-Gen.; Vasotropic; Nephrotropic; Thrombolytic; Antiinflammatory; Antiarteriosclerotic; Antiarrhythmic; Cardiovascular-Gen.; Antibacterial; Immunosuppressive; Antiallergic; Cerebroprotective; Endocrine-Gen.; Antidiabetic; Antilipemic; Hemostatic; Anorectic; Ophthalmological; Antiulcer; Antianemic; Antiasthmatic; CNS-Gen.; Nootropic; Vulnerary; Neuroprotective; Antiparkinsonian; Anticonvulsant; Neuroleptic; Tranquilizer; Antidepressant; Hypnotic; Antimigraine; Gastrointestinal-Gen.; Dermatological; Cytostatic. MECHANISM OF ACTION : Soluble guanylate cyclase stimulator. The soluble guanylate cyclase stimulating activity of (I) was tested in a recombinant guanylate cyclase reporter cell line using an in vitro assay. The results showed that 5,5-dimethyl-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one exhibited a minimal effective concentration of 0.03 mu M.

Description

The present application relates to novel fluoroalkyl-substituted pyrazolopyridines, processes for their preparation, their use alone or in combinations for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular for the treatment and / or prophylaxis of cardiovascular disease.

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

Through the formation of cGMP and the resulting regulation of phosphodiesterases, ion channels and protein kinases, guanylate cyclase plays a crucial role in various physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion, neuronal signaling and diseases based on a disturbance of the above operations. Under pathophysiological conditions, the NO / cGMP system may be suppressed, leading, for example, to hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arterioclerosis, 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, tolerance development is one of the decisive disadvantages of this treatment.

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

As stimulators of soluble guanylate cyclase be in WO 00/06569 fused pyrazole derivatives and in WO 03/095451 Carbamate-substituted 3-pyrimidinyl-pyrazolopyridines disclosed. WO 2010/065275 discloses substituted pyrrolo and dithydropyridopyrimidines as sGC activators.

The object of the present invention was to provide new substances which act as potent stimulators of soluble guanylate cyclase and have the same or improved therapeutic profile compared to the compounds known from the prior art, for example with regard to their in vivo properties and / or their pharmacokinetic behavior ,

in welcher
A für Stickstoff oder CR³ steht,
wobei
R³ für Wasserstoff, Deuterium, Fluor, Difluormethyl, Trifluormethyl, (C₁-C₄)-Alkyl, Cyclopropyl oder Cyclobutyl steht,
L für eine Gruppe #-CR^4AR^4B-(CR^5AR^5B)_p-## steht,
wobei
# für die Anknüpfstelle an die Carbonylgruppe steht,
## für die Anknüpfstelle an den Pyrimidin- bzw. Triazinring steht,
p für eine Zahl 0, 1 oder 2 steht,
R^4A für Wasserstoff, Fluor, (C₁-C₄)-Alkyl, Hydroxy oder Amino steht,
R^4B für Wasserstoff, Fluor, (C₁-C₄)-Alkyl, Trifluormethyl, (C₁-C₄)-Alkoxycarbonylamino oder Phenyl steht,
worin (C₁-C₄)-Alkyl mit 1 bis 3 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Trifluormethyl, Hydroxy, Hydroxycarbonyl und (C₁-C₄)-Alkoxycarbonyl substituiert sein kann,
oder
R^4A und R^4B zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, eine Oxo-Gruppe, einen 3- bis 6-gliedrigen Carbocyclus oder einen 4- bis 6-gliedrigen Heterocyclus bilden,
worin der 3- bis 6-gliedrigen Carbocyclus und der 4- bis 6-gliedrigen Heterocyclus mit 1 oder 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor und (C₁-C₄)-Alkyl substituiert sein können,
oder
R^4A und R^4B zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, eine (C₂-C₄)-Alkenyl-Gruppe bilden,
R^5A für Wasserstoff (C₁-C₄)-Alkyl oder Hydroxy steht,
R^5B für Wasserstoff, Fluor, (C₁-C₄)-Alkyl oder Trifluormethyl steht,
R¹ für Wasserstoff oder Fluor steht,
R² für eine Gruppe der Formel *-(CR^6AR^6B)_qCF₃ steht,
wobei
* für die Anknüpfstelle an das Pyrazolopyridin steht,
q für eine Zahl 1, 2 oder 3 steht,
R^6A für Wasserstoff oder Fluor steht,
R^6B für Wasserstoff oder Fluor steht,
sowie ihre N-Oxide, Salze, Solvate, Salze der N-Oxide und Solvate der N-Oxide und Salze.The present invention relates to compounds of the general formula (I)

in which
A is nitrogen or CR ³ ,
in which
R ^{3 is} hydrogen, deuterium, fluorine, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl or cyclobutyl,
L represents a group # -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - ##
in which
# represents the point of attachment to the carbonyl group,
## is the point of attachment to the pyrimidine or triazine ring,
p is a number 0, 1 or 2,
R ^{4A is} hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl, hydroxy or amino,
R ^{4B is} hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, (C ₁ -C ₄ ) -alkoxycarbonylamino or phenyl,
in which (C ₁ -C ₄ ) -alkyl having 1 to 3 substituents independently of one another can be substituted from the group of fluorine, trifluoromethyl, hydroxy, hydroxycarbonyl and (C ₁ -C ₄ ) -alkoxycarbonyl,
or
R ^4A and R ^4B together with the carbon atom to which they are attached form an oxo group, a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle,
wherein the 3- to 6-membered carbocycle and the 4- to 6-membered heterocycle may be substituted with 1 or 2 substituents independently selected from the group fluorine and (C ₁ -C ₄ ) -alkyl,
or
R ^4A and R ^4B together with the carbon atom to which they are attached form a (C ₂ -C ₄ ) alkenyl group,
R ^{5A is} hydrogen (C ₁ -C ₄ ) -alkyl or hydroxy,
R ^{5B is} hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl or trifluoromethyl,
R ^{1 is} hydrogen or fluorine,
R ^{2 is} a group of the formula * - (CR ^6A R ^6B ) _q CF ₃ ,
in which
* represents the point of attachment to the pyrazolopyridine,
q is a number 1, 2 or 3,
R ^{6A is} hydrogen or fluorine,
R ^{6B is} hydrogen or fluorine,
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 formula (I) and their salts, solvates and solvates of the salts.

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

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

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

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

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

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

The present invention also includes all suitable isotopic variants of the compounds of the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound of the invention are those of hydrogen, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium) ¹³ C, ¹⁴ C , ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³³ S, ³⁴ S ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic Variants of a compound of the invention, such as in particular those in which one or more radioactive isotopes are incorporated, may be useful, for example for the study of the mechanism of action or the distribution of active ingredient in the body; Due to the comparatively easy production and detectability, compounds labeled with ³ H or ¹⁴ C isotopes in particular are suitable for this purpose. Moreover, the incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.

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

In the formula of the group which may be L or R ² , the end point of the line where the symbol #, ##, or * stands, is not a carbon atom or a CH ₂ group, but is part of the Binding to the respectively designated atom to which L or R ^{2 is} bonded.

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
In the context of the invention, alkyl is a linear or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl.
Carbocycle in the context of the invention is a monocyclic, saturated carbocycle having 3 to 6 ring carbon atoms. By way of example and preferably mention may be made of: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Alkenyl in the context of the invention represents a linear 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.
Alkoxycarbonyl in the context of the invention is a linear or branched alkoxy radical having 1 to 4 carbon atoms and an oxygen-bonded carbonyl group. By way of example and preferably mention may be made of: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
Alkoxycarbonylamino in the context of the invention represents an amino group having a linear or branched alkoxycarbonyl substituent which has 1 to 4 carbon atoms in the alkyl chain and is linked via the carbonyl group to the nitrogen atom. By way of example and preferably mention may be made of: methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, n-butoxycarbonylamino, isobutoxycarbonylamino and tert-butoxycarbonylamino.
Heterocycle in the context of the invention is a saturated heterocycle having a total of 4 to 6 ring atoms, which contains one or two ring heteroatoms from the series N, O, S, SO and / or SO ₂ and is linked via a ring carbon atom. Examples which may be mentioned are: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and Dioxidothiomorpholinyl. Preferred are azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and tetrahydropyranyl.
Halogen is in the context of the invention for fluorine, chlorine, bromine and iodine. Preference is given to bromine and iodine.

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 nitrogen or CR ³ ,
in which
R ^{3 is} hydrogen, fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl or cyclopropyl,
L represents a group # -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - ##
in which
represents the point of attachment to the carbonyl group,
## is the point of attachment to the pyrimidine or triazine ring,
p is a number 0 or 1,
R ^{4A is} hydrogen, fluorine, methyl, ethyl or hydroxy,
R ^{4B is} hydrogen, fluorine, methyl, ethyl, trifluoromethyl, methoxycarbonylamino or phenyl,
wherein methyl and ethyl may be substituted with 1 to 3 substituents independently of one another selected from the group fluorine, trifluoromethyl and hydroxy,
or
R ^4A and R ^4B together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl ring,
wherein the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and tetrahydropyranyl ring may be substituted with 1 or 2 substituents independently selected from the group consisting of fluorine and methyl,
R ^{5A is} hydrogen, fluorine, methyl, ethyl or hydroxy,
R ^5B is hydrogen, methyl, ethyl or trifluoromethyl,
R ^{1 is} hydrogen or fluorine,
R ^{2 is} 2,2,2-trifluoroethyl, 3,3,3-trifluoroprop-1-yl, 4,4,4-trifluorobut-1-yl or 3,3,4,4,4-pentafluorobut-1-yl,
and their salts, solvates and solvates of the salts.

Particularly preferred in the context of the present invention are compounds of the formula (I) in which
A is CR ³ ,
in which
R ^{3 is} hydrogen,
L represents a group # -CR ^4A R ^4B - (CR ^3A R ^5B ) _p - ##
in which
# represents the point of attachment to the carbonyl group,
## is the point of attachment to the pyrimidine ring,
p stands for a number 0,
R ^{4A is} hydrogen, methyl or hydroxy,
R ^{4B is} hydrogen, fluorine, methyl or trifluoromethyl,
or
R ^4A and R ^4B together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring,
wherein the cyclopropyl and the cyclobutyl ring may be substituted with 1 or 2 substituents independently selected from the group fluorine and methyl,
R ^{1 is} hydrogen or fluorine,
R ^{2 is} 3,3,4,4,4-pentafluorobutyl,
and their salts, solvates and solvates of the salts.

Particularly preferred in the context of the present invention are also compounds of the formula (I) in which
A is nitrogen,
L is a group -CR # ^4A R ^4B - (CR ^5A R ^5B) _p - is ##,
in which
# represents the point of attachment to the carbonyl group,
## is the point of attachment to the triazine ring,
p stands for a number 0,
R ^{4A is} hydrogen, fluorine, methyl or hydroxy,
R ^{4B is} hydrogen, fluorine, methyl or trifluoromethyl,
or
R ^4A and R ^4B together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring,
wherein the cyclopropyl and the cyclobutyl ring may be substituted with 1 or 2 substituents independently selected from the group fluorine and methyl,
R ^{1 is} hydrogen or fluorine,
R ^{2 is} 3,3,4,4,4-pentafluorobutyl,
and their salts, solvates and solvates of the salts.

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

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

In the context of the present invention, preference is also given to compounds of the formula (I) in which A is N or CH, and also their salts, solvates and solvates of the salts.

In the context of the present invention, preference is also given to compounds of the formula (I) in which A is CH, and also to their salts, solvates and solvates of the salts.

In the context of the present invention, preference is also given to compounds of the formula (I) in which A is N, and also to their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
L represents a group # -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - ##
in which
# represents the point of attachment to the carbonyl group,
## is the point of attachment to the pyrimidine or triazine ring,
p stands for a number 0,
R ^4A and R ^4B together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl ring,
and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
L represents a group # -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - ##
in which
# represents the point of attachment to the carbonyl group,
## is the point of attachment to the pyrimidine or triazine ring,
p stands for a number 0,
R ^4A and R ^4B together with the carbon atom to which they are attached form an azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl ring,
and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
L represents a group # -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - ##
in which
# represents the point of attachment to the carbonyl group,
## is the point of attachment to the pyrimidine or triazine ring,
p stands for a number 0,
R ^{4A is} hydrogen, fluorine, methyl, or hydroxy,
R ^{4B is} hydrogen, methyl or trifluoromethyl,
and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
L represents a group # -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - ##
in which
# represents the point of attachment to the carbonyl group,
## is the point of attachment to the pyrimidine or triazine ring,
p stands for a number 0,
R ^{4A is} hydrogen, fluorine, methyl, hydroxy or amino,
R ^{4B is} hydrogen, fluorine, methyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl,
and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
L represents a group # -CR ^4A R ^4B - (CR ^5A R5) _p - ##
in which
# represents the point of attachment to the carbonyl group,
## is the point of attachment to the pyrimidine or triazine ring,
p stands for a number 0,
R ^{4A is} hydroxy or amino,
R ^4B represents trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl,
and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
L represents a group # -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - ##
in which
# represents the point of attachment to the carbonyl group,
## is the point of attachment to the pyrimidine or triazine ring,
p stands for a number 0,
R ^{4A is} methyl,
R ^{4B is} methyl,
and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
L represents a group # -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - ##
in which
# represents the point of attachment to the carbonyl group,
## is the point of attachment to the pyrimidine or triazine ring,
p stands for a number 0,
R ^4A and R ^4B together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring,
wherein the cyclopropyl and the cyclobutyl ring may be substituted with 1 or 2 substituents independently selected from the group fluorine and methyl,
and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
R ^{2 is} 3,3,4,4,4-pentafluorobutyl,
and their salts, solvates and solvates of the salts.

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

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

in welcher R¹ und R² jeweils die oben genannten Bedeutungen haben,
[A] in einem inerten Lösungsmittel in Gegenwart einer geeigneten Base mit einer Verbindung der Formel (III)

in welcher L die oben genannte Bedeutung hat und
T¹ für (C₁-C₄)-Alkyl steht,
zu einer Verbindung der Formel (IV)

in welcher L, R¹ und R² jeweils die oben angegebenen Bedeutungen haben,
umsetzt, diese dann mit iso-Pentylnitrit und einem Iod-Äquivalent in eine Verbindung der Formel (V)

in welcher L, R¹ und R² jeweils die oben angegebenen Bedeutungen haben,
überführt, und diese im Anschluss in einen inerten Lösungsmittel in Gegenwart eines geeigneten Übergangsmetallkatalysators zu einer Verbindung der Formel (I-A)

in welcher L, R¹ und R² jeweils die oben angegebenen Bedeutungen haben,
umsetzt,
oder
[B] in einem inerten Lösungsmittel in Gegenwart einer geeigneten Base mit Hydrazinhydrat zu einer Verbindung der Formel (VI)

in welcher R¹ und R² jeweils die oben genannten Bedeutungen haben,
umsetzt, diese dann in einem inerten Lösungsmittel mit einer Verbindung der Formel (VII)

in welcher L die oben angegebene Bedeutung hat und
T⁴ für (C₁-C₄)-Alkyl steht,
zu einer Verbindung der Formel (VIII)

in welcher L, R¹, R² und T⁴ jeweils die oben angegebenen Bedeutungen haben,
reagiert, diese anschliessend mit Phosphorylchlorid in eine Verbindung der Formel (IX)

in welcher L, R¹, R² und T⁴ jeweils die oben angegebenen Bedeutungen haben,
überführt, und diese direkt mit Ammoniak zu einer Verbindung der Formel (X)

in welcher L, R¹, R² und T⁴ jeweils die oben angegebenen Bedeutungen haben,
umsetzt, und schliesslich in einem inerten Lösungsmittel in Gegenwart einer geeigneten Base zu einer Verbindung der Formel (I-B)

in welcher L, R¹ und R² jeweils die oben angegebenen Bedeutungen haben,
cyclisiert,
und gegebenenfalls die resultierenden Verbindungen der Formeln (I-A) und (I-B) gegebenenfalls mit den entsprechenden (i) Lösungsmitteln und/oder (ii) Säuren oder Basen in ihre Solvate, Salze und/oder Solvate der Salze überführt.The invention further provides a process for the preparation of the compounds of the formula (I) according to the invention which comprises reacting a compound of the formula (II)

in which R ¹ and R ² each have the meanings given above,
[A] in an inert solvent in the presence of a suitable base with a compound of formula (III)

in which L has the abovementioned meaning and
T ^{1 is} (C ₁ -C ₄ ) -alkyl,
to a compound of the formula (IV)

in which L, R ¹ and R ² each have the meanings given above,
then react this with iso-pentyl nitrite and an iodine equivalent in a compound of formula (V)

in which L, R ¹ and R ² each have the abovementioned meanings,
which is then converted into an inert solvent in the presence of a suitable transition metal catalyst to give a compound of the formula (IA)

in which L, R ¹ and R ² each have the meanings given above,
implements,
or
[B] in an inert solvent in the presence of a suitable base with hydrazine hydrate to give a compound of formula (VI)

in which R ¹ and R ² each have the meanings given above,
then reacting these in an inert solvent with a compound of formula (VII)

in which L has the meaning given above and
T ^{4 is} (C ₁ -C ₄ ) -alkyl,
to a compound of formula (VIII)

in which L, R ¹ , R ² and T ⁴ each have the meanings given above,
reacts, then this with phosphoryl chloride in a compound of formula (IX)

in which L, R ¹ , R ² and T ⁴ each have the meanings given above,
converted directly with ammonia to a compound of formula (X)

in which L, R ¹ , R ² and T ⁴ each have the meanings given above,
and finally in an inert solvent in the presence of a suitable base to give a compound of formula (IB)

in which L, R ¹ and R ² each have the meanings given above,
cyclized
and optionally the resulting compounds of the formulas (IA) and (IB), if appropriate, with the appropriate (i) solvents and / or (ii) acids or bases in their solvates, salts and / or solvates of the salts.

The compounds of the formulas (I-A) and (I-B) together form the group of the compounds of the formula (I) according to the invention.

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

Suitable bases for process step (II) + (III) are 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 such as sodium or potassium , Sodium or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,5-diazabicyclo [4.3. 0] non-5-ene (DBN). Preference is given to potassium tert-butoxide or sodium methoxide.

The reaction (II) + (III) is generally carried out in a temperature range from + 20 ° C to + 150 ° C, preferably at + 75 ° C to + 100 ° C, optionally in a microwave. The implementation can be at normal, elevated or at reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.

Process step (IV) → (V) takes place with or without solvent. Suitable solvents are all organic solvents which are inert under the reaction conditions. Preferred solvent is dimethoxyethane.

The reaction (IV) → (V) is generally carried out in a temperature range of + 20 ° C to + 100 ° C, preferably in the range of + 50 ° C to + 100 ° C, optionally in a microwave. The reaction can be carried out at normal, elevated or reduced pressure (for example in the range from 0.5 to 5 bar). Generally, one works at normal pressure.

The process step (IV) → (V) is generally carried out with a molar ratio of 10 to 30 mol Isopentylnitrit and 10 to 30 moles of the iodine equivalent based on 1 mol of the compound of formula (IV).

Suitable iodine sources in the reaction (IV) → (V) are, for example, diiodomethane or a mixture of cesium iodide, iodine and copper (I) iodide.

Inert solvents for process step (V) → (IA) are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1,2-ethanediol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or Diethylene glycol dimethyl ether, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Preferred is DMF.

The reduction (V) → (I-A) is carried out with hydrogen in conjunction with transition metal catalysts such as palladium (10% on activated carbon), Raney nickel or palladium hydroxide.

The reaction (V) → (I-A) is generally carried out in a temperature range of + 20 ° C to + 50 ° C. The reaction can be carried out at normal or elevated pressure (eg in the range from 0.5 to 5 bar). Generally, one works at normal pressure.

The reaction (VIII) → (IX) can be carried out in a solvent which is inert under the reaction conditions or without a solvent. Preferred solvent is sulfolane.

The reaction (VIII) → (IX) is generally carried out in a temperature range from + 70 ° C to + 150 ° C, preferably from + 80 ° C to + 130 ° C, optionally in a microwave. The reaction can be carried out at normal or elevated pressure (eg in the range from 0.5 to 5 bar). Generally, one works at normal pressure.

More preferably, the reaction (VIII) → (IX) is carried out without solvent in a temperature range from 0 ° C to + 50 ° C at atmospheric pressure.

Process step (IX) → (X) takes place in a solvent which is inert under the reaction conditions. Suitable solvents are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or also water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to acetonitrile.

The reaction (IX) → (X) is generally carried out in a temperature range from + 20 ° C to + 100 ° C, preferably from + 40 ° C to + 70 ° C, optionally in a microwave. The reaction can be carried out at normal or elevated pressure (eg in the range from 0.5 to 5 bar). Generally, one works at normal pressure.

The cyclization (X) → (IB) is carried out in a solvent which is inert under the reaction conditions, for example alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers, such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran (cf. THF), 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 (NMP), pyridine, acetonitrile or sulfolane. It is likewise possible to use mixtures of the solvents mentioned. Preferred is THF.

Suitable bases for process step (X) → (IB) are alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali hydrogen carbonates such as sodium or potassium bicarbonate, alkali metal such as sodium or potassium , Sodium or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,5-diazabicyclo [4.3. 0] non-5-ene (DBN). Preference is given to potassium tert-butoxide.

The reaction (X) → (I-B) is generally carried out in a temperature range from 0 ° C to + 50 ° C, preferably from + 10 ° C to + 30 ° C, optionally in a microwave. The reaction can be carried out at normal or elevated pressure (eg in the range from 0.5 to 5 bar). Generally, one works at normal pressure.

Alternatively, the cyclization to (I-B) takes place directly in the reaction (IX) → (X) without addition of further reagents.

In an alternative procedure of the process [D], the conversion (VI) + (VII) → (VIII) → (IX) → (X) → (I-B) is carried out simultaneously in a one-pot reaction without isolation of the intermediates.

The reactions (VIII) → (IX) → (X) → (I-B) are preferably carried out simultaneously in a one-pot reaction without isolation of the intermediates.

Inert solvents for process step (VI) + (VII) → (VIII) are, for example, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers, such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to methanol or ethanol.

The reaction (VI) + (VII) → (VIII) is generally carried out in a temperature range from + 50 ° C to + 120 ° C, preferably from + 50 ° C to + 100 ° C, optionally in a microwave. The reaction can be carried out at normal or elevated pressure (eg in the range from 0.5 to 5 bar). Generally, one works at normal pressure.

Inert solvents for process step (II) → (VI) are, for example, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers, such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferred is ethanol.

Suitable bases for process step (II) → (VI) are alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali hydrogen carbonates such as sodium or potassium bicarbonate, alkali metal such as sodium or potassium , Sodium or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,5-diazabicyclo [4.3. 0] non-5-ene (DBN). Preferably triethylamine.

The reaction (II) → (VI) is generally carried out in a temperature range from 0 ° C to + 60 ° C, preferably from + 10 ° C to + 30 ° C. The reaction can be carried out at normal or elevated pressure (eg in the range from 0.5 to 5 bar). Generally, one works at normal pressure.

[a): Hydrazinhydrat, NEt₃, EtOH b): EtOH c): 1. POCl₃; 2. konz. NH₃, Acetonitril]. Schema 2

[a): KOt-Bu, tert.-Butanol; b): Diiodmethan, iso-Pentylnitrit; c): Pd/C, Wasserstoff, DMF].The preparation processes described can be illustrated by the following synthesis schemes (Schemes 1 and 2): Scheme 1

[a): hydrazine hydrate, NEt ₃ , EtOH b): EtOH c): 1. POCl ₃ ; 2nd conc. NH ₃ , acetonitrile]. Scheme 2

[a): KOt-Bu, tert-butanol; b): diiodomethane, iso-pentylnitrite; c): Pd / C, hydrogen, DMF].

Other compounds of the invention may optionally also be prepared by conversions of functional groups of individual substituents, in particular those listed under L and R ³ , starting from the compounds of the formula (I) obtained by the above methods. These transformations are carried out by conventional methods known to those skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, elimination, alkylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of carbonamides, and introduction and removal of temporary protection groups.

in welcher R¹ die oben angegebene Bedeutung hat,
in einem inerten Lösungsmittel mit Hydrazinhydrat zur Verbindung der Formel (XII)

in welcher R¹ die oben angegebene Bedeutung hat,
zyklisiert, diese anschliessend in einem inerten Lösungsmittel in Gegenwart einer geeigneten Lewis-Säure zunächst mit Isopentylnitrit zum entsprechenden Diazoniumsalz umsetzt, und dieses dann direkt mit Natriumiodid in die Verbindung der Formel (XIII)

in welcher R¹ die oben angegebene Bedeutung hat,
überführt, diese im Folgenden in einem inerten Lösungsmittel in Gegenwart einer geeigneten Base mit der Verbindung der Formel (XIV) R²-X¹ (XIV), in welcher R² die oben angegebene Bedeutung hat und
X¹ für eine geeignete Abgangsgruppe, wie beispielsweise Halogen, Tosylat oder Mesylat, steht,
in eine Verbindung der Formel (XV)

in welcher R¹ und R² jeweils die oben angegebenen Bedeutungen haben,
überführt, diese anschließend in einem inerten Lösungsmittel mit Kupfercyanid zu einer Verbindung der Formel (XVI)

in welcher R¹ und R² jeweils die oben angegebenen Bedeutungen haben,
reagiert, und diese schließlich unter sauren Bedingungen mit einem Ammoniak-Äquivalent umsetzt.The compounds of the formula (II) can be prepared by reacting a compound of the formula (XI)

in which R ^{1 has} the meaning given above,
in an inert solvent with hydrazine hydrate to the compound of formula (XII)

in which R ^{1 has} the meaning given above,
cyclized, this then reacted in an inert solvent in the presence of a suitable Lewis acid first with isopentyl nitrite to the corresponding diazonium salt, and this then directly with sodium iodide in the compound of formula (XIII)

in which R ^{1 has} the meaning given above,
these are subsequently converted in an inert solvent in the presence of a suitable base with the compound of the formula (XIV) R ² -X ¹ (XIV), in which R ^{2 has} the meaning given above and
X ^{1 represents} a suitable leaving group, such as, for example, halogen, tosylate or mesylate,
into a compound of the formula (XV)

in which R ¹ and R ² each have the meanings given above,
then converted this in an inert solvent with copper cyanide to a compound of formula (XVI)

in which R ¹ and R ² each have the meanings given above,
reacts, and finally reacted under acidic conditions with an ammonia equivalent.

Inert solvents for process step (XI) → (XII) are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1,2-ethanediol, 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 (NMP), pyridine, acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to 1,2-ethanediol.

The reaction (XI) → (XII) is generally carried out in a temperature range of + 60 ° C to + 200 ° C, preferably at + 120 ° C to + 180 ° C. The reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.

Inert solvents for the reaction (XII) → (XIII) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO ), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. Preferred is DMF.

Suitable Lewis acids for process step (XII) → (XIII) are boron trifluoride-diethyl ether complex, cerium (IV) ammonium nitrate (CAN), tin (II) chloride, lithium perchlorate, zinc (II) chloride, indium (III) chloride or indium (III) bromide. Boron trifluoride diethyl ether complex is preferred.

The reaction (XII) → (XIII) is generally carried out in a temperature range of -78 ° C to + 40 ° C, preferably at 0 ° C to + 20 ° C. The reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.

Inert solvents for the reaction (XIII) + (XIV) → (XV) are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents, such as dimethylformamide (DMF). , Dimethylsulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile. Preferred is DMF.

Suitable bases for process step (XIII) + (XIV) → (XV) are alkali metal hydrides such as potassium hydride or sodium hydride, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali hydrogen carbonates such as sodium or potassium bicarbonate, alkali metal alcoholates such as sodium or potassium methoxide, 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 1,5-diazabicyclo [4.3.0] non-5-ene (DBN). Cesium carbonate is preferred.

The reaction (XIII) + (XIV) → (XV) is generally carried out in a temperature range from 0 ° C to + 60 ° C, preferably at + 10 ° C to + 25 ° C. The reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.

Inert solvents for process step (XV) → (XVI) are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents, such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferred is DMSO.

The reaction (XV) → (XVI) is generally carried out in a temperature range from + 20 ° C to + 180 ° C, preferably at + 100 ° C to + 160 ° C, optionally in a microwave. The reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.

The reaction (XVI) → (II) is carried out by the methods known in the art in a two-stage process initially to form the iminoester with sodium methoxide in methanol at 0 ° C to + 40 ° C and subsequent nucleophilic addition of an ammonia equivalent such as ammonia or Ammonium chloride in a suitable acid to form the amidine (III) at +50 to + 150 ° C.

Suitable acids for the formation of the amidine (II) are inorganic acids such as hydrochloric acid / hydrochloric acid, sulfuric acid, polyphosphoric acid or phosphoric acid or organic acids such as acetic acid, trifluoroacetic acid or formic acid. Preferably, hydrochloric acid or acetic acid are used.

[a): Hydrazinhydrat, 1,2-Ethandiol; b): iso-Pentylnitrit, NaI, THF; b): 1,1,1,2,2-Pentafluor-4-iodbutan, Cs₂CO₃, DMF; d): CuCN, DMSO, e): 1. NaOMe, McOH, 2. NH₄Cl, Esssigsäure].The described preparation process can be exemplified by the following synthesis scheme (Scheme 3): Scheme 3

[a): hydrazine hydrate, 1,2-ethanediol; b): iso-pentyl nitrite, NaI, THF; b): 1,1,1,2,2-pentafluoro-4-iodobutane, Cs ₂ CO ₃ , DMF; d): CuCN, DMSO, e): 1. NaOMe, MeOH, 2.NH ₄ Cl, acetic acid].

[a): TFA, Dioxan; b) NH₃; c) Trifluoressigsäureanhydrid].Alternatively, the compounds of the formula (II) are prepared as shown in the following synthesis scheme (Scheme 4):

[a): TFA, dioxane; b) NH ₃ ; c) trifluoroacetic anhydride].

[a): Schwefelsäure; b): Zink, Methanol, Eisessig; c): Trifluoressigsäureanhydrid, Dichlormethan].The compound of the formula (XI) is known from the literature [cf. z. B. Winn M., J Med. Chem. 1993, 36, 2676-7688 ; EP 634 413-A1 ; CN 1613849-A ; EP 1626045-A1 ; WO 2009/018415 ], can be prepared analogously to processes known from the literature or as shown in the synthesis scheme below (Scheme 5):

[a): sulfuric acid; b): zinc, methanol, glacial acetic acid; c): trifluoroacetic anhydride, dichloromethane].

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

The compounds of the present invention act as potent stimulators of soluble guanylate cyclase and have a similar or improved therapeutic profile over the compounds known in the art, such as in vivo properties such as pharmacokinetic and pharmacodynamic behavior and / or dose Impact relationship and / or its security profile. They are therefore suitable for the treatment and / or prophylaxis of diseases in humans and animals.

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

The compounds according to the invention are therefore suitable for the treatment and / or prophylaxis of cardiovascular, pulmonary, thromboembolic and fibrotic disorders. The compounds according to the invention can therefore be used in medicaments for the treatment and / or prophylaxis of cardiovascular diseases such as hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, atrial and ventricular arrhythmias, and conduction disorders such as atrio-ventricular blockade grade I-III (AB block I-III), supraventricular tachyarrhythm, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular Tachyarrhythmia, torsade de pointes tachycardia, atrial and ventricular extrasystoles, atrioventricular extrasystoles, sick sinus syndrome, syncope, AV node reentrant tachycardia, Wolff-Parkinson-White syndrome, of acute Ko autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), shock such as cardiogenic shock, septic shock and anaphylactic shock, aneurysms, premature ventricular contraction (PVC), for the treatment and / or prophylaxis of thromboembolic Diseases and ischaemias such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transitory and ischemic attacks, preeclampsia, inflammatory cardiovascular diseases, spasms of the coronary arteries and peripheral arteries, edema formation such as pulmonary edema, cerebral edema, renal edema or cardiac insufficiency-related edema, peripheral circulatory disorders, Reperfusion damage, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, for Prevention of restenosis such as after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart transplantation and bypass surgery, as well as microvascular and macrovascular damage (vasculitis), increased levels of fibrinogen and low density LDL, and increased levels of Plasminogen activator inhibitor 1 (PAI-1), as well as for the treatment and / or prophylaxis of erectile dysfunction and female sexual dysfunction.

For the purposes of the present invention, the term cardiac insufficiency also encompasses more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, valvular heart failure, cardiac valvulopathy, mitral valve stenosis, mitral valve insufficiency, Aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid regurgitation, pulmonary valve stenosis, pulmonary valvular insufficiency, combined heart valve defects, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure and systolic heart failure.

In addition, the compounds according to the invention may also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemias, dyslipidemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, abetelipoproteinaemia, sitosterolemia, xanthomatosis, Tangier's disease, obesity (obesity) and combined hyperlipidemias and the metabolic syndrome.

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

Furthermore, the compounds according to the invention are suitable for the treatment of urological diseases such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic hyperplasia (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS, including Feline's urological syndrome ( FUS)), diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as mixed, urge, stress, or overflow incontinence (MUI, UUI, SUI, OUT), Pelvic pain, benign and malignant diseases of the organs of the male and female urogenital system.

Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of kidney diseases, in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure. For the purposes of the present invention, the term renal insufficiency includes both acute and chronic manifestations of renal insufficiency, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosiderosis, tubulointerstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as renal transplant rejection, immune complex-induced kidney disease, nephropathy induced by toxic substances, contrast agent-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome abnormally reduced creatinine and / or water excretion, abnormally elevated blood levels of urinary ff, nitrogen, potassium and / or creatinine, altered activity of renal enzymes such. Glutamyl synthetase, altered urinary or urine abundance, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilatation, hyperphosphatemia and / or the need for dialysis. The present invention also encompasses the use of the compounds of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte imbalances (e.g., hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism ,

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

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

Furthermore, the compounds according to the invention are also suitable for regulating cerebral blood flow and are effective agents for combating migraine. They are also suitable for the prophylaxis and control of the consequences of cerebral infarct events (Apoplexia cerebri) such as stroke, cerebral ischaemias and craniocerebral trauma , Likewise, the compounds of the invention can be used to combat pain and tinnitus.

In addition, the compounds of the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for the treatment and / or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic inflammatory bowel disease (IBD, Crohn's Disease, UC), pancreatitis , Peritonitis, rheumatoid diseases, inflammatory skin diseases and inflammatory ocular diseases.

Furthermore, the compounds of the invention can also be used for the treatment and / or prophylaxis of autoimmune diseases.

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

Furthermore, the compounds of the invention for controlling postoperative scarring, z. Due to glaucoma surgery.

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

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

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

Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemia, vascular disease, renal insufficiency, thromboembolic disorders, fibrotic diseases and arteriosclerosis.

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

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

Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and arteriosclerosis.

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

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

• • organische Nitrate und NO-Dontoren, wie beispielsweise Natriumnitroprussid, Nitroglycerin, Isosorbidmononitrat, Isosorbiddinitrat, Molsidomin oder SIN-1, sowie inhalatives NO;
• • Verbindungen, die den Abbau von cyclischem Guanosinmonophosphat (cGMP) inhibieren, wie beispielsweise Inhibitoren der Phosphodiesterasen (PDE) 1, 2 und/oder 5, insbesondere PDE 5-Inhibitoren wie Sildenafil, Vardenafil und Tadalafil;
• • antithrombotisch wirkende Mittel, beispielhaft und vorzugsweise aus der Gruppe der Thrombozytemggregationshemmer, der Antikoagulantien oder der profibrinolytischen Substanzen;
• • den Blutdruck senkende Wirkstoffe, beispielhaft und vorzugsweise aus der Gruppe der Calcium-Antagonisten, Angiotensin AII-Antagonisten, ACE-Hemmer, Endothelin-Antagonisten, Renin-Inhibitoren, alpha-Rezeptoren-Blocker, beta-Rezeptoren-Blocker, Mineralocorticoid-Rezeptor-Antagonisten sowie der Diuretika; und/oder
• • den Fettstoffwechsel verändernde Wirkstoffe, beispielhaft und vorzugsweise aus der Gruppe der Thyroidrezeptor-Agonisten, Cholesterinsynthese-Inhibitoren wie beispielhaft und vorzugsweise HMG-CoA-Reduktase- oder Squalensynthese-Inhibitoren, der ACHT-Inhibitoren, CETP-Inhibitoren, MTP-Inhibitoren, PPAR-alpha-, PPAR-gamma- und/oder PPAR-delta-Agonisten, Cholesterin-Absorptionshemmer, Lipase-Inhibitoren, polymeren Gallensäureadsorber, Gallensäure-Reabsorptionshemmer und Lipoprotein(a)-Antagonisten

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

• • organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
• Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP), 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 antiplatelet agents, anticoagulants or profibrinolytic substances;
• Antihypertensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor Antagonists and diuretics; and or
• Lipid metabolism-modifying agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, the ECHT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein (a) antagonists

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

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

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

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

In a preferred embodiment of the invention, the compounds of 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-3112 , YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

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

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

Among the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and diuretics.

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

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

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin AII 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 of the present invention are used in combination with a loop diuretic such as furosemide, torasemide, bumetanide and piretanide with potassium sparing diuretics such as amiloride and triamterene with aldosterone antagonists such as spironolactone, potassium canrenoate and eplerenone and thiazide diuretics such as Hydrochlorothiazide, chlorthalidone, xipamide, and indapamide.

Among the lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ECHT 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 by way of example and preferably dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).

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

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

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

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

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

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

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

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

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

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

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

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

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

Parenteral administration can be carried out bypassing a resorption step (eg intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or using absorption (for example 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 z. As inhalation medicines (including powder inhalers, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg plasters), milk, pastes, foams, powdered powders, implants or star.

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

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

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

  calc.

  calculated

  DCI

  direct chemical ionization (in MS)

  DMF

  dimethylformamide

  DMSO

  dimethyl sulfoxide

  d. Th.

  the theory (at yield)

  eq.

  Equivalent (s)

  IT I

  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

  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

  R _t

  Retention time (by HPLC)

  THF

  tetrahydrofuran

  UV

  Ultraviolet spectrometry

  v / v

  Volume to volume ratio (of a solution)

LC / MS methods:

Method 1 (LC-MS):

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

Method 2 (LC-MS):

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

Starting compounds and intermediates:

Example 1 A

5-fluoro-3-iodo-1H-pyrazolo [3,4-b] pyridine

The synthesis is described in in WO 2006/130673 Example 4.

Example 2A

2,6-dichloro-5-fluoronicotinamide

A suspension of 25 g (130.90 mmol) of 2,6-dichloro-5-fluoro-3-cyanopyridine in conc. Sulfuric acid (125 ml) was stirred at 60-65 ° C for 1 h. After cooling to RT, the contents of the flask were poured into ice-water and extracted three times with ethyl acetate (100 ml each time). The combined organic phases were washed with water (100 ml) and then with saturated aqueous sodium bicarbonate solution (100 ml), dried and concentrated on a rotary evaporator. The resulting material was dried under high vacuum.
Yield: 24.5 g (90% of theory)
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.95 (br see 1H), 8.11 (br s, 1H), 8.24 (d, 1H).

Example 3A

2-chloro-5-fluoronicotinamide

To a suspension of 21.9 g (335.35 mmol) of zinc in methanol (207 ml) was added at RT 44 g (210.58 mmol) of 2,6-dichloro-5-fluoronicotinamide. Thereafter, acetic acid (18.5 ml) was added and stirred. Heated to reflux for 24 h. The contents of the flask were then decanted from the zinc and ethyl acetate (414 ml) and saturated aqueous sodium bicarbonate solution (414 ml) were added and the mixture was stirred thoroughly. The mixture was then filtered off with suction through kieselguhr and washed three times with ethyl acetate (517 ml each time). The organic phase was separated and the aqueous phase washed with ethyl acetate (258 ml). The combined organic phases were washed once with saturated aqueous sodium bicarbonate solution (414 ml), dried and concentrated in vacuo. The resulting solid was added with dichloromethane (388 mL) and stirred for 20 min. It was again filtered off with suction and washed with diethyl ether and sucked dry.
Yield: 20.2 g (53% of theory)
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.87 (brs, 1H), 7.99 (dd, 1H), 8.10 (brs, 1H), 8.52 (d, 1H).

Example 4A

2-chloro-5-fluornicotinonitril

A suspension of 46.2 g (264.66 mmol) of 2-chloro-5-fluorocarboxamide in dichloromethane (783 ml) was admixed with 81.2 ml (582.25 mmol) of triethylamine and cooled to 0 ° C. 41.12 ml (291.13 mmol) of trifluoroacetic anhydride were then slowly added dropwise with stirring and stirred at 0 ° C. for 1.5 h. The reaction solution was then washed twice with saturated aqueous sodium bicarbonate solution (each 391 ml), dried and concentrated in vacuo.
Yield: 42.1 g (90% of theory).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.66 (dd, 1H), 8.82 (d, 1H).

Example 5A

5-fluoro-1H-pyrazolo [3,4-b] pyridin-3-amine

A suspension of 38.5 g (245.93 mmol) of 2-chloro-5-fluoronicotinonitrile was initially charged in 1,2-ethanediol (380 ml), followed by addition of hydrazine hydrate (119.6 ml). It was heated to reflux with stirring for 4 h. On cooling, a solid precipitated, which was mixed with water (380 ml) and run at RT for 10 min. The suspension was then filtered off with suction through a frit, washed with water (200 ml) and with -10 ° C. cold THF (200 ml). The solid was dried under high vacuum over phosphorus pentoxide.
Yield: 22.8 g (61% of theory)
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 5.54 (s, 2H), 7.96 (dd, 1H), 8.38 (m, 1H), 12.07 (m, 1H).

Example 6A

5-fluoro-3-iodo-1H-pyrazolo [3,4-b] pyridine

THF (329 ml) was charged with 10 g (65.75 mmol) of 5-fluoro-1H-pyrazolo [3,4-b] pyridin-3-amine and cooled to 0 ° C. Subsequently, 16.65 ml (131.46 mmol) of boron trifluoride-diethyl ether complex were slowly added. The reaction mixture was further cooled to -10 ° C. Thereafter, a solution of 10.01 g (85.45 mmol) of isopentyl nitrite in THF (24.39 ml) was slowly added and stirred for a further 30 min. The mixture was diluted with cold diethyl ether (329 ml) and the resulting solid filtered off. The diazonium salt thus prepared was added in portions to a 0 ° C cold solution of 12.81 g (85.45 mmol) of sodium iodide in acetone (329 ml) and the mixture stirred for 30 min at RT. The reaction mixture was added to ice-water (1.81) and extracted twice with ethyl acetate (487 ml each time). The collected organic phases were washed with saturated aqueous sodium chloride solution (244 ml), dried, filtered and concentrated. 12.1 g (86% purity, 60% of theory) of the title compound were obtained as a solid.
LC-MS (Method 2): R _t = 1.68 min
MS (ESIpos): m / z = 264 (M + H) ⁺

Example 7A

5-fluoro-3-iodo-1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridine

5.0 g (19,010 mmol) of 5-fluoro-3-iodo-1H-pyrizolo [3,4-b] pyridine were introduced into DMF (100 ml), followed by 20.83 g (76,042 mmol) of 1,1,1,2,2 Pentafluoro-4-iodo-butane and 14.86 g (45.65 mmol) of cesium carbonate and 0.63 g (3.802 mmol) of potassium iodide were added. The mixture was stirred at 140 ° C overnight. It was then cooled and combined with a preliminary experiment, which was carried out analogously from 200 mg of 5-fluoro-3-iodo-1H-pyrazolo [3,4-b] pyridine. It was filtered off with suction from solids, washed with DMF, and the filtrate was then concentrated under high vacuum. The residue was purified by preparative HPLC (methanol: water gradient). 4.34 g (52% of theory) of the title compound were obtained.
LC-MS (Method 1): R _t = 1.30 min
MS (ESIpos): m / z = 410 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 2.84-3.00 (m, 2H), 4.79 (t, 2H), 7.93 (dd, 1H), 8.71 (dd, 1H).

Example 8A

5-fluoro-1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridine-3-carbonitrile

A suspension of 4.34 g (10.609 mmol) of Example 7A and 1045 g (11.670 mmol) of copper (I) cyanide were initially charged in DMSO (30 ml) and stirred at 150 ° C for 2 h. After cooling, the mixture was filtered through Celite, washed with ethyl acetate and THF and then four times with a solution of saturated aqueous ammonium chloride solution and conc. Extracted ammonia water (3: 1 v / v). The combined organic phases were washed with sat. washed aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo.
Yield: 3.19 g (97% of theory)
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 2.94-3.09 (m, 2H), 4.93 (t, 2H), 8.54 (dd, 1H), 8.88 (dd, 1H).

Example 9A

5-Fluoro-1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridine-3-carboximidamide acetate

To 0.559 g (10.351 mmol) of sodium methanolate in methanol (25 ml) was added 3.19 g (10.351 mmol) of Example 8A and stirred at RT for 2 h. Thereafter, 0.664 g (12.421 mmol) of ammonium chloride and acetic acid (2.31 ml) were added and heated to reflux overnight. It was then concentrated to dryness and the residue treated with ethyl acetate and 1N sodium hydroxide solution. The phases were separated. The aqueous phase was extracted again with ethyl acetate. The combined organic phases were combined and concentrated. The crude product was reacted further without further purification.
Yield: 2.67 g (37% of theory, purity about 56%)
LC-MS (Method 2): R _t = 0.68 min
MS (ESIpos): m / z = 326 (M + H) ⁺

Example 10A

Methyl-3,3-dicyano-2,2-dimethylpropanoate

In THF (91 ml), 1.816 g (45.411 mmol) of sodium hydride (60% in mineral oil) were slowly added with 3 g (45.411 mmol) of malononitrile. Subsequently, 5,876 ml (45,411 mmol) of methyl 2-bromo-2-methylpropanoate were added, and the mixture was passed at RT overnight. Thereafter, another 5.876 ml (45.411 mmol) of methyl 2-bromo-2-methylpropanoate were added and it was heated to 50 ° C overnight. Then again 1762 ml (13,623) mmol) of methyl 2-bromo-2-methylpropanoate was added and it was heated to 50 ° C for a further 4 h. The reaction mixture was then treated with saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. This gave 8.9 g of crude product, which was purified by chromatography on silica gel (cyclohexane-ethyl acetate 4: 1).
Yield: 6.47 g (85% of theory)
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.40 (s, 6H), 3.74 (s, 3H), 5.27 (s, 1H).

Example 11A

3-iodo-1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridine

10.00 g (40.813 mmol) of Example 1A were initially charged in DMF (170 ml), followed by 12.30 g (44,894 mmol) of 1,1,1,2,2-pentafluoro-4-iodobutane in DMF (30 ml) and 14,628 g (44,894 mmol) cesium carbonate added. The mixture was stirred for 2 days at RT. Subsequently, 12.30 g (44,894 mmol) of 1,1,1,2,2-pentafluoro-4-iodobutane and 14,628 g (44,894 mmol) of cesium carbonate were added again and stirred for 2 days at RT. Thereafter, 3,485 g (12,720 mmol) of 1,1,1,2,2-pentafluoro-4-iodobutane and 4,145 g (12,720 mmol) of cesium carbonate were added and stirred at RT overnight. After this time, 5.00 g (18,250 mmol) of 1,1,1,2,2-pentafluoro-4-iodobutane and 5,946 g (18,250 mmol) of cesium carbonate were again added and the mixture was stirred at room temperature for 6 days. The mixture was then stirred for 2 days at 70 ° C. It was filtered off with suction from solids, washed with DMF and then concentrated under high vacuum. The residue was purified by preparative HPLC (methanol: water (with 0.1% formic acid) gradient). 5.48 g (34% of theory) of the title compound were obtained.
LC-MS (Method 1): R _t = 1.23 min
MS (ESIpos): m / z = 392 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 2.87-3.00 (m, 2H), 4.81 (t, 2H), 7.33 (dd, 1H), 7.97 (dd, 1H), 8.65 (dd, 1H).

Example 12A

1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridine-3-carbonitrile

A suspension of 5,480 g (14,012 mmol) of Example 11A and 1,380 g (15,414 mmol) of copper (I) cyanide were initially charged in DMSO (50 ml) and stirred at 150 ° C for 3 h. After cooling, it was filtered through Celite and washed with ethyl acetate and THF. Thereafter, four times with a solution of saturated aqueous ammonium chloride solution and conc. Ammonia water (3: 1, v / v) and then washed with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated and then dried under high vacuum.
Yield: 3.59 g (88% of theory)
LC-MS (Method 2): R _t = 1.04 min
MS (ESIpos): m / z = 291 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 2.97-3.10 (m, 2H), 4.94 (t, 2H), 7.55 (dd, 1H), 8.51 (dd, 1H), 8.81 (dd, 1H).

Example 13A

1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridin-3-acetate carboximidarnid

To 0.668 g (12.371 mmol) of sodium methanolate in methanol (40 ml) was added 3.59 g (12.371 mmol) of Example 12A in methanol (20 ml) and kept at RT for 2 h. Thereafter, 0.794 g (14.845 mmol) of ammonium chloride and acetic acid (2762 ml) were added and heated to reflux overnight. The mixture was then concentrated to dryness and the residue was combined with ethyl acetate and 1N sodium hydroxide solution. It was stirred vigorously for about 1 h at RT. The resulting solid was filtered off with suction and washed with ethyl acetate and water. The residue dried in a high vacuum. 0.507 g (11% of theory) were obtained. The combined filtrates were separated into the phases and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated and then dried under high vacuum. This gave an additional 2.76 g (43% of theory, purity about 70%).
LC-MS (Method 2): R _t = 0.58 min
MS (ESIpos): m / z = 308 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.84 (s, 3H), 2.95-3.08 (m, 2H), 4.85 (t, 2H), 7.39 (dd, 1H), 8.63-8.67 ( m, 2H).

Example 14A

1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridin-3-carboximidohydrazid

0.6 g (about 1144 mmol) of the compound from Example 13A were dissolved in 10 ml of ethanol and treated at 0 ° C with 462 mg (4.574 mmol) of triethylamine and 71 mg (1144 mmol) of hydrazine hydrate (80% solution in water) , The mixture was stirred at RT overnight and then concentrated on a rotary evaporator. There were obtained 689 mg (about 60% purity) of the title compound.
LC-MS (Method 2): R _t = 0.57 min; MS (ESIpos): m / z = 323 (M + H) ⁺

Example 15A

5-fluoro-1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridin-3-carboximidohydrazid

0.62 g (0.901 mmol) of the compound from Example 9A (purity about 56%) were dissolved in 10.3 ml of ethanol and at 0 ° C with 456 mg (4.506 mmol) of triethylamine and 70 mg (1.126 mmol) hydrazine hydrate (80% Solution in water). The mixture was stirred at RT overnight and then concentrated on a rotary evaporator. A crude compound was obtained which was reacted further directly.
LC-MS (Method 1): R _t = 0.61 min; MS (ESIpos): m / z = 341 (M + H) ⁺

Example 16A

Methyl 2- {5-hydroxy-3- [1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -1,2,4 -titazin-6-yl} -2-methylpropanoate

The crude substance from Example 14A (Ca 1.144 mmol) was dissolved in 15 ml of ethanol and treated with 430 mg (2.288 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate (described in J. Am. Chem. Soc. 124 (14), 3680-3691; 2002 ). The mixture was stirred at RT overnight and then heated to reflux for 1 h. After cooling, the solid was filtered off with suction, washed with ethanol and the filtrate was concentrated. The residue was treated with diethyl ether and filtered from a precipitate and washed with diethyl ether. The filtrate was concentrated and the residue was purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). There were obtained 264 mg of the title compound (50% of theory).
LC-MS (Method 2): R _t = 1.03 min; MS (ESIpos): m / z = 461 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.46 (s, 6H), 3.06-3.17 (m, 2H), 3.57 (s, 3H), 4.95 (t, 2H), 7.51 (dd, 1H), 8.70 (dd, 1H), 8.75 (dd, 1H), 14.52 (s, 1H).

Example 17A

Methyl 2- {3- [5-fluoro-1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5-hydroxy-1 , 2,4-triazin-6-yl} -2-methylpropanoate

The crude substance from Example 15A (about 0.845 mmol) was dissolved in 10 ml of ethanol and treated with 318 mg (1.689 mmol) of dimethyl-2,2-dimethyl-3-oxobutanedioate (described in J. Am. Chem. Soc. 124 (14), 3680-3691; 2002 ). The mixture was stirred at RT overnight and then heated to reflux for 6 h. After cooling, the mixture was concentrated and the residue was purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). There were obtained 291 mg of the title compound (72% of theory).
LC-MS (Method 2): R _t = 1.04 min; MS (ESIpos): m / z = 479 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.46 (s, 6H), 3.07-3.14 (m, 2H), 3.56 (s, 3H), 4.94 (t, 2H), 8.40 (d, 1H), 8.85 (br s, 1H), 14.56 (s, 1H).

Example 18A

4-Amino-5,5-dimethyl-2- [1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5,7- dihydro-6H-pyrrolo [2,3-d] pyrimidin-6-one

500 mg (1.361 mmol) of Example 13A were initially charged in tert-butanol (7.5 ml) and treated with 183 mg (1361 mmol) of potassium tert-butoxide. Subsequently, 226 mg (1.361 mmol) of Example 10A in tert-butanol (2.5 ml) were added dropwise and the mixture was heated to reflux overnight. After cooling, ethyl acetate and water were added, the phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was methanol stirred and filtered with suction from a solid. This was vigorously washed with methanol and the combined filtrates were concentrated and then purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). There was obtained 127 mg of the title compound (21% of theory).
LC-MS (method 2): R _t = 0.93 min; MS (ESIpos): m / z = 442 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.36 (s, 6H), 2.91-3.04 (m, 2H), 4.88 (t, 2H), 6.83 (br s, 2H), 7.38 (dd, 1H), 8.63 (dd, 1H), 9.02 (dd, 1H), 11.01 (br s, 1H).

Example 19A

4-Amino-2- [5-fluoro-1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5,5-dimethyl- 5,7-dihydro-6H-pyrrolo pyrimidin-6-one [2,3-d]

520 mg (1,350 mmol) of Example 9A were initially charged in tert-butanol (10 ml) and treated with 181 mg (1.620 mmol) of potassium tert-butoxide. Subsequently, 224 mg (1350 mmol) of Example 10A in tert-butanol (2.5 ml) were added and the mixture was heated to reflux overnight. 112 mg (0.675 mmol) of Example 10A were then added again and the mixture was heated to reflux for a further 7.5 h. After cooling, the reaction mixture was added with water and ethanol, and treated for 1 h in an ultrasonic bath. The resulting precipitate was filtered off with suction and washed with water. The filter cake was stirred with a little ethanol (2-3 ml) and sucked off again. The solid was dried under high vacuum. There was obtained 212 mg of the title compound (34% of theory).
LC-MS (Method 1): R _t = 1.01 min; MS (ESIpos): m / z = 460 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.36 (s, 6H), 2.92-3.04 (m, 2H), 4.87 (t, 2H), 6.88 (br s, 2H), 8.71 (br s, 1H), 8.85 (dd, 1H), 11.01 (br s, 1H).

Example 20A

4-iodo-5,5-dimethyl-2- [1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5,7- dihydro-6H-pyrrolo [2,3-d] pyrimidin-6-one

155 mg (0.351 mmol) of Example 18A were initially charged in iso-pentylnitrite (1017 ml) and diiodomethane (2655 ml) and heated to 85 ° C for 2d. After cooling, it was filtered from a solid, washed with cyclohexane and then the solid was purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). There were obtained 39 mg of the title compound (20% of theory).
LC-MS (method 2): R _t = 1.21 min; MS (ESIpos): m / z = 553 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.44 (s, 6H), 2.96-3.06 (m, 2H), 4.94 (t, 2H), 7.48 (dd, 1H), 8.69 (dd, 1H), 8.79 (dd, 1H), 11.80 (br s, 1H).

Example 21A

2- [5-fluoro-1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -4-iodo-5,5-dimethyl- 5,7-dihydro-6H-pyrrolo pyrimidin-6-one [2,3-d]

142 mg (0.310 mmol) of Example 19A were initially charged in iso-pentyl nitrite (0.90 ml) and diiodomethane (2.4 ml) and heated at 85 ° C overnight. Subsequently, iso-pentyl nitrite (1 ml) was added again and heated to 85 ° C for a further 22 h. Thereafter, iso-pentyl nitrite (1 ml) was added again and heated to 85 ° C for a further 12 h. After cooling, it was purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). There were obtained 71 mg of the title compound (40% of theory).
LC-MS (Method 2): R _t = 1.28 min; MS (ESIpos): m / z = 571 (M + H) ⁺

EXAMPLES

example 1

7,7-dimethyl-3- [1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5,7-dihydro-6H- triazin-6-one pyrrolo [2,3-e] [1,2,4]

263 mg (0.571 mmol) of the compound from Example 16A were admixed with 4 ml of phosphoryl chloride and stirred at RT overnight. The reaction mixture was dissolved in 38 ml of acetonitrile and stirred with ice cooling into 24 ml of concentrated aqueous ammonia solution (33% strength). It was stirred for 2 days at RT. Subsequently, the reaction mixture was concentrated. The residue was taken up in water and ethanol and stirred at RT for 1 h. The resulting precipitate was filtered off with suction, and washed with water and ethanol. This residue was purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). 119 mg of the title compound were obtained (49% of theory).
LC-MS (method 2): R _t = 0.98 min; MS (EIpos): m / z = 428 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.47 (s, 6H), 2.96-3.07 (m, 2H), 4.95 (t, 2H), 7.48 (dd, 1H), 8.71 (dd, 1H), 8.85 (dd, 1H), 12.21 (br s, 1H).

Example 2

3-[5-Fluor-1-(3,3,4,4,4-pentafluorbutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-7,7-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazin-o-on

3- [5-fluoro-1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -7,7-dimethyl-5,7- dihydro-6H-pyrrolo [2,3-e] [1,2,4] triazin-o-one

290 mg (0.606 mmol) of the compound from Example 17A were admixed with 4,172 ml of phosphoryl chloride and stirred at RT overnight. The reaction mixture was dissolved in 40 ml of acetonitrile and cooled with ice in 27 ml of concentrated aqueous ammonia solution (33%) introduced. It was run for 2 days at room temperature. Subsequently, it was concentrated. The residue was taken up in water and ethanol and treated in an ultrasonic bath. A precipitate formed, which was filtered off with suction and washed with water, ethanol and then with diethyl ether. This residue was treated with DMF and then acetonitrile and water were added and again filtered with suction. The precipitate was washed with acetonitrile and water and then dried under high vacuum. There were obtained 149 mg of the title compound (52% of theory, purity 94%).
LC-MS (Method 2): R _t = 1.05 min; MS (EIpos): m / z = 446 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.47 (s, 6H), 2.96-3.07 (m, 2H), 4.95 (t, 2H), 8.56 (dd, 1H), 8.80 (brs, 1H), 12.21 (brs, 1H).

Example 3

5,5-dimethyl-2- [1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5,7-dihydro-6H- pyrrolo [2,3-d] pyrimidin-6-one

39 mg (0.071 mmol) of Example 20A were dissolved in DMF (4 ml) and added to 20 mg of palladium on carbon (10%) in 1 ml of DMF and hydrogenated at atmospheric pressure for 12 h. It was then filtered through Celite, washed with DMF and concentrated to dryness. The residue was purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). 22 mg of the title compound were obtained (74% of theory).
LC-MS (Method 2): R _t = 1.02 min; MS (ESIpos): m / z = 427 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.39 (s, 6H), 2.96-3.06 (m, 2H), 4.92 (t, 2H), 7.43 (dd, 1H), 8.66 -8.69 (m, 2H), 8.86 (dd, 1H), 11.61 (br s, 1H).

Example 4

2- [5-fluoro-1- (3,3,4,4,4-pentafluorobutyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5,5-dimethyl-5,7 dihydro-6H-pyrrolo [2,3-d] pyrimidin-6-one

39 mg (0.068 mmol) of Example 21A were dissolved in DMF (5 ml) and treated with 20 mg of palladium on carbon (10%) and hydrogenated for 12 h at atmospheric pressure. It was then filtered through Celite, washed with DMF and concentrated to dryness. The residue was purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). 8 mg of the title compound were obtained (74% of theory).
LC-MS (Method 2): R _t = 1.10 min; MS (ESIpos): m / z = 445 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.39 (s, 6H), 2.96-3.06 (m, 2H), 4.91 (t, 2H), 8.59 (dd, 1H), 8.65 (m, 1H), 8.76 (dd, 1H), 11.60 (br s, 1H).

B. Evaluation of Pharmacological Activity

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

B-1. 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 (each mM): sodium chloride: 119 ; Potassium chloride: 4.8; Calcium chloride dihydrate: 1; Magnesium sulfate heptahydrate: 1.4; Potassium dihydrogen phosphate: 1.2; Sodium hydrogencarbonate: 25; Glucose: 10. The force of contraction is detected with Statham UC2 cells, amplified and digitized via A / D 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 cycles of control, the substance to be tested is added in each subsequent run in increasing dosages and the height of the contraction is compared with the height of the contraction achieved in the last predistortion. This calculates the concentration required to increase the control value by 50% reduce (IC ₅₀ value). 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 according to the invention are given in the table below (Table 1): Table 1: Example no. IC ₅₀ [nM] 2 129 3 46

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 in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005) described, determined.

Representative values (MEC = minimum effective concentration) for the compounds of the invention are given in the table below (Table 2): TABLE 2 Example no. MEC [μM] 2 0.1 3 12:03

B-3. Radiotelemetric blood pressure measurement on awake, spontaneously hypertensive rats

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

The system consists of 3 main components:
Implantable Transmitters (Physiotel ^® Telemetry Transmitter)
Receiver (Physiotel ^® receiver), the DSI (Data Exchange matrix) with a through a multiplexer
Data acquisition computer
are connected.

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

animal material

The investigations are carried out on adult female spontaneously hypertensive rats (SHR Okamoto) with a body weight of> 200 g. SHR / NCrl of Okamoto Kyoto School of Medicine, 1963 were crossed out of male Wistar Kyoto rats with high blood pressure and female with slightly elevated blood pressure and reported in F13 to U.S. Pat. National Institutes of Health.

The test animals are housed individually in Makrolon cages type 3 after send 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 TA11 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 prophylaxis (Tardomyocel COMP Bayer 1 ml / kg sc)

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 ™ A.R.T. for WINDOWS, DSI) and processed accordingly. The storage of the data takes place in each case in a folder opened for this purpose which carries the test number.

In the standard procedure, duration is measured over 10 seconds:
Systolic blood pressure (SBP)
Diastolic blood pressure (DBP)
Arterial mean pressure (MAP)
Heart rate (HR)
Activity (ACT).

The measured value acquisition is repeated computer-controlled 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-1) and stored in individual data. Further technical details can be found in the extensive documentation of the manufacturer (DSI).

Unless otherwise stated, the administration of the test substances will take place 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.R T. 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 experiment day in a separate folder that bears the test number. Results and test reports are sorted in folders and sorted by paper.

literature

Klaus Witte, Kai Hu, Johanna Swiatek, Claudia Müssig, Georg Ertl and Björn Lemmer: Experimental heart failure in rats: effects on cardiovascular circadian rhythms and on myocardial β-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-4. Determination of pharmacokinetic parameters after intravenous and oral administration

The pharmacokinetic parameters of the compounds of the formula (I) according to the invention are determined in male CD-1 mice, male Wister rat and / or female beagle dogs. The application volume in mice is 5 mL / kg, in rats 5 mL / kg and in dogs 0.5 mL / kg. Intravenous administration is in mice and rats using a species-specific plasma / DMSO formulation (99/1) and in dogs by water / PEG400 / ethanol (50/40/10 or 30/60/10). Rats are placed in the right external jugular vein for ease of blood sampling prior to drug administration. The operation is carried out one day before the experiment under isoflurane anesthesia and with the administration of an analgesic (atropine / rimadyl (3/1) 0.1 mL s.c.). The substance administration is in mice i. v. bolus, in rats i. v. bolus or by means of a 15-minute infusion and dogs by means of a 15-minute infusion. The blood is taken in mice after 0.033, 0.083, 0.17, 0.5, 1, 2, 3, 4, 6, 7 and 24 hours and in dogs and rats with 15-minute infusion after 0.083, 0.25, 0.28 0.33, 0.42, 0.75, 1, 2, 3, 4, 6, 7 and 24 hours and in rats after i. v. bolus administration after 0.033, 0.083, 0.17, 0.5, 1, 2, 3, 4, 6, 7 and 24 hours. Oral administration of the solute by gavage is performed in all species based on a water / PEG400 / ethanol formulation (50/40/10). The blood sample in rats and dogs takes place here after 0.083, 0.17, 0.5, 0.75, 1, 2, 3, 4, 6, 7 and 24 hours. The blood is transferred to heparinized tubes at collection. So then the blood plasma is recovered by centrifugation and optionally stored at -20 ° C until further processing.

An internal standard is added to the samples of the compounds of the formula (I) according to the invention, calibration samples and QCs ( ZK 228859 ) followed by protein precipitation by acetonitrile in excess. After addition of an ammonium acetate buffer (0.01 M. pH 6.8) and subsequent vortexing, the mixture is centrifuged at 1000 g and the supernatant is measured by means of LC-MS / MS (API 4000, AB Sciex). Chromatographic separation is performed on an 1100 HPLC from Agilent. The injection volume is 10 μL. The separation column used is a Luna 5 μ C8 (2) 100 A, 50 × 2 mm, made by Phenomenex, heated to 40 ° C. A binary mobile phase gradient is run at 500 μL / min (A: 0.01 M ammonium acetate buffer pH 6.8, B: 0.1% formic acid in acetonitrile): 0 min. (90% A), 1 min. (90% A), 3 Min. (15% A), 4 minutes (15% A), 4.50 minutes (90% A), 6 minutes (90% A). The temperature of the Turbo V ion source is 500 ° C. The following MS instrument parameters are used: curtain gas 15 units, ion spray volume 4.8 kV, gas 1 45 units, gas 2 35 units, CAD gas 40 units. The quantification of the substances takes place on the basis of the peak heights or areas from extracted ion chromatograms of specific MRM experiments.

The pharmacokinetic parameters such as AUC, C _max , t _1/2 (terminal half-life), MRI (Mean Residence Time) and CL (clearance) are determined from the plasma concentration-time profiles determined using the validated pharmacokinetic calculation program KinEx (verses 2.5 and 3 ).

Since the substance quantification is carried out in plasma, the blood / plasma distribution of the substance must be determined in order to adjust the pharmacokinetic parameters accordingly. For this purpose, a defined amount of substance is incubated in heparinized whole blood of the corresponding species for 20 min in a tumble roll mixer. After centrifugation at 1000 g, the concentration in the plasma is measured (see above) and determined by quotient of the C _blood / C _plasma value.

C. Embodiments of Pharmaceutical Compositions

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

Tablet:

Composition:

• 100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
• Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

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

Orally administrable suspension:

Composition:

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

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

production:

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

Orally administrable solution:

Composition:

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

production:

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

i. v. solution:

The compound according to the invention is dissolved in a concentration below the saturation solubility in a physiologically tolerated solvent (for example isotonic saline solution, glucose solution 5% and / or PEG 400 solution 30%). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 98/16223 [0006]
• WO 00/06569 [0007]
• WO 03/095451 [0007]
• WO 2010/065275 [0007]
• EP 634413 A1 [0086]
• CN 1613849 A [0086]
• EP 1626045-A1 [0086]
• WO 2009/018415 [0086]
• WO 2006/130673 [0156]

Cited non-patent literature

• Wu et al., Blood 84 (1994), 4226 [0006]
• Mülsch et al., Brit. J. Pharmacol. 120 (1997), 681 [0006]
• Goldberg et al., J. Biol. Chem. 252 (1977), 1279 [0006]
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• ZK 228859 [0207]

Claims (10)

Compound of the formula (I)

in which A is nitrogen or CR ³ , where R ^{3 is} hydrogen, deuterium, fluorine, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl or cyclobutyl, L is a group # -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - ##, where the attachment site is the carbonyl group, ## is the point of attachment to the pyrimidine or triazine ring, p is a number 0, 1 or 2, R ^{4A is} hydrogen , Fluorine, (C ₁ -C ₄ ) -alkyl, hydroxy or amino, R ^{4B is} hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, (C ₁ -C ₄ ) -alkoxycarbonylamino or phenyl, wherein (C ₁ -C ₄ ) -alkyl may be substituted with 1 to 3 substituents independently selected from the group of fluorine, trifluoromethyl, hydroxy, hydroxycarbonyl and (C ₁ -C ₄ ) -alkoxycarbonyl, or R ^4A and R ^4B together with the carbon atom to which they are attached form an oxo group, a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle, wherein the 3- to 6 -gliedrigen carbocycle and the 4- to 6-membered heterocycle having 1 or 2 substituents independently selected from the group of fluorine and (C ₁ -C ₄ ) alkyl may be substituted, or R ^4A and R ^4B together with the carbon atom to which they are attached, a (C ₂ -C ₄₎ alkenyl group form, R ^5A represents hydrogen, fluorine, (C ₁ -C ₄₎ -alkyl or hydroxy, R ^5B is hydrogen, fluorine, (C ₁ - C ₄ ) -alkyl or trifluoromethyl, R ^{1 is} hydrogen or fluorine, R ^{2 is} a group of the formula * - (CR ^6A R ^6B ) _q CF ₃ , where * is the point of attachment to the pyrazolopyridine, q is a Number 1, 2 or 3, R ^{6A is} hydrogen or fluorine, R ^{6B is} hydrogen or fluorine, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts. A compound of the formula (I) according to Claim 1, in which A is nitrogen or CR ³ , where R ^{3 is} hydrogen, fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl or cyclopropyl, L is a group # -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - ##, where the attachment site is the carbonyl group, ## is the point of attachment to the pyrimidine or triazine ring, p is a number or 1, R ^{4A is} hydrogen, fluoro, methyl, ethyl or hydroxy, R ^{4B is} hydrogen, fluoro, methyl, ethyl, trifluoromethyl, methoxycarbonylamino or phenyl, wherein methyl and ethyl having from 1 to 3 substituents independently R ^4A and R ^4B together with the carbon atom to which they are attached, a cyclopropyl, cyclobutyl, cyclopentyl, Azetidinyl-, pyrrolidinyl, tetrahydrofuranyl-, be substituted from the group fluorine, trifluoromethyl and hydroxy, or Form piperidinyl or tetrahydropyranyl ring wherein the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and tetrahydropyranyl ring are substituted with 1 or 2 substituents independently selected from the group of fluorine and methyl R ^{5A is} hydrogen, fluorine, methyl, ethyl or hydroxy, R ^{5B is} hydrogen, fluorine, methyl, ethyl or trifluoromethyl, R ^{1 is} hydrogen or the like R is fluorine, R ^{2 is} 2,2,2-trifluoroethyl, 3,3,3-trifluoroprop-1-yl, 4,4,4-trifluorobut-1-yl or 3,3,4,4,4-pentafluorobut-1-yl and their salts, solvates and solvates of the salts. Compound of the formula (I) according to claim 1 or 2, in which A represents CR ^3, where R ³ is hydrogen, L is a group -CR # ^4A R ^4B - (CR ^5A R ^5B) _p - is ##, where # is the point of attachment to the carbonyl group, ## is the point of attachment to the pyrimidine ring, p is a number Q, R ^{4A is} hydrogen, fluorine, methyl or hydroxyl, R ^{4B is} hydrogen, fluorine, methyl or trifluoromethyl or R ^4A and R ^4B together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring wherein the cyclopropyl and the cyclobutyl ring having 1 or 2 substituents independently selected from the group consisting of fluorine and methyl R ^{1 is} hydrogen or fluorine, R ^{2 is} 3,3,4,4,4-pentafluorobutyl, and their salts, solvates and solvates of the salts. Compound of the formula (I) according to claim 1 or 2, in which A represents nitrogen L stands for a group # -CR ^4A R ^4B - (CR ^5A R ^5B) _p - ##, where is the point of attachment to the carbonyl group , ## represents the point of attachment to the triazine ring, p is a number 0, R ^{4A is} hydrogen, fluorine, methyl or hydroxyl, R ^{4B is} hydrogen, fluorine, methyl or trifluoromethyl, or R ^4A and R ^4B together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein the cyclopropyl and the cyclobutyl ring may be substituted with 1 or 2 substituents independently selected from the group of fluorine and methyl, R ^{1 is} hydrogen or fluorine, R ² represents 3,3,4,4,4-Pentafluorbut-1-yl, and the salts, solvates and solvates of the salts. Process for the preparation of compounds of the formula (I) as defined in claims 1 to 4, characterized in that the compound of the formula (II)

in which R ¹ and R ² each have the meanings given in claims 1 to 4, [A] in an inert solvent in the presence of a suitable base with a compound of formula (III)

in which L has the meaning given in claims 1 to 4 and T ^{1 is} (C ₁ -C ₄ ) -alkyl, to give a compound of formula (IV)

in which L, R ¹ and R ² each have the meanings given in claims 1 to 4, then reacting these with iso-pentyl nitrite and an iodine equivalent into a compound of the formula (V)

in which L, R ¹ and R ² each have the meanings given in claims 1 to 4, which is then converted into an inert solvent in the presence of a suitable transition metal catalyst to give a compound of the formula (IA)

in which L, R ¹ and R ² each have the meanings given in claims 1 to 4, or [B] in an inert solvent in the presence of a suitable base with hydrazine hydrate to give a compound of formula (VI)

in which R ¹ and R ² each have the meanings given in claims 1 to 4, then reacting these in an inert solvent with a compound of the formula (VII)

in which L has the meaning given in claims 1 to 4 and T ^{4 is} (C ₁ -C ₄ ) -alkyl, to give a compound of formula (VIII)

in which L, R ¹ , R ² and T ⁴ each have the meanings given in claims 1 to 4, reacting these subsequently with phosphoryl chloride in a compound of formula (IX)

in which L, R ¹ , R ² and T ^{4 are} each as defined above, and these are reacted directly with ammonia to give a compound of the formula (X)

in which L, R ¹ , R ² and T ^{4 in} each case have the abovementioned meanings, and finally in an inert solvent in the presence of a suitable base to give a compound of the formula (IB)

in which L, R ¹ and R ^{2 are} each as defined above, cyclized, and optionally the resulting compounds of formulas (IA) and (IB) optionally with the appropriate (i) solvents and / or (ii) acids or bases in their solvates, salts and / or solvates of the salts converted A compound of the formula (I) as defined in any one of claims 1 to 4 for the treatment and / or prophylaxis of diseases. Use of a compound of formula (I) as defined in any one of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic Diseases and arteriosclerosis. A pharmaceutical composition containing a compound of the formula (I) as defined in any one of claims 1 to 4, in combination with an inert, non-toxic, pharmaceutically suitable excipient. A pharmaceutical composition comprising a compound of the formula (I) as defined in any one of claims 1 to 4, in combination with another active ingredient selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, antithrombotic agents, the Antihypertensive agents and lipid metabolizing agents. Medicament according to claim 8 or 9 for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic diseases, fibrotic diseases and arteriosclerosis.