EP2590979A1

EP2590979A1 - Ring-fused pyrimidines and triazines and use thereof for the treatment and/or prophylaxis of cardiovascular diseases

Info

Publication number: EP2590979A1
Application number: EP11732409.5A
Authority: EP
Inventors: Markus Follmann; Johannes-Peter Stasch; Gorden Redlich; Jens Ackerstaff; Nils Griebenow; Andreas Knorr; Frank Wunder; Volkhart Min-Jian Li; Walter Kroh; Lars BÄRFACKER
Original assignee: Bayer Intellectual Property GmbH
Current assignee: Bayer Intellectual Property GmbH
Priority date: 2010-07-09
Filing date: 2011-07-05
Publication date: 2013-05-15
Also published as: KR20130132393A; CR20130008A; CL2013000083A1; CU20130007A7; SG186749A1; US20140350020A1; CN103097387B; WO2012004258A1; DOP2013000007A; JP6114189B2; ECSP13012379A; EP2682394A1; ZA201209434B; US9216978B2; CN103097387A; CN106977530A; EP2708539A1; JP2013532162A; MX2013000198A; WO2012004258A9

Abstract

The invention relates to novel ring-fused pyrimidines and triazines, to methods for the production thereof, use thereof on its own or combined for the treatment and/or prophylaxis of diseases and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular diseases.

Description

ANNELATED PYRIMIDINES AND TRIAZINES AND THEIR USE FOR TREATMENT OR PROPHYLAXIS OF HEART CIRCULAR DISEASES

The present application relates to novel fused pyrimidines and triazines, 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 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, which may, for example, lead to hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, 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 converts and activates the soluble guanylate cyclase by attack on the iron central atom of the heme. In addition to the side effects, tolerance development is one of the decisive disadvantages of this treatment.

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

WO 00/06569 discloses fused pyrazole derivatives and, in WO 03/095451, carbamate-substituted 3-pyrimidinyl-pyrazolopyridines as stimulators of soluble guanylate cyclase. WO 2010/065275 discloses substituted pyrrolo and dihydropyridopyrimidines as sGC activators. The object of the present invention was to provide new substances which act as stimulators of soluble guanylate cyclase and have a similar or improved therapeutic profile compared to the compounds known from the prior art, for example with respect to their in vivo properties and / or their pharmacokinetic behavior.

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

in which

A is nitrogen or CR, where 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 - #, where

* 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 represents} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl or hydroxyl,

R ^{4B is} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl, trifluoromethyl, (C 1 -C ₄ ) -alkoxycarbonyl-amino or phenyl, in which (C 1 -C 4 -alkyl having 1 or 2 substituents independently of one another selected from the group 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 having 1 or 2 substituents independently selected from the group fluorine and (Ci-C ₄ ) alkyl may be substituted, or

R ^4A and R ^4B together with the carbon atom to which they are attached, a

Form (C ₂ -C ₄ ) -alkenyl group,

R ^{5A is} hydrogen, fluorine, (C 1 -C 4) -alkyl or hydroxyl,

R is hydrogen, fluorine, (C 1 -C ₄ ) -alkyl or trifluoromethyl,

R ^{1 is} hydrogen or fluorine, R ^{2 is} benzyl, wherein benzyl is substituted by 1 to 3 substituents 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. Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids. Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of illustration, 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 according to the invention may exist in different stereoisomeric forms, ie in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in the case of atropisomers). The present invention therefore encompasses the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.

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

The present invention also includes all suitable isotopic variants of the compounds of the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ 0, ¹⁸ 0, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic variants of a compound of the invention, such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with ³ H or ¹⁴ C isotopes in particular are suitable for this purpose. In addition, 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). 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. Examples which may be mentioned by way of example include 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.

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

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.

In the context of the present invention, preference is given to compounds 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 represents a group * -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - #, where

* represents the point of attachment to the carbonyl group,

R ^4A represents hydrogen, fluorine, (C _r _C4) alkyl, hydroxy,

R ^{4B is} hydrogen, fluorine, (Ci-C alkyl or trifluoromethyl, 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, for hydrogen, fluorine, (Ci-C - Alkyl or hydroxy, R ^{5B is} hydrogen, fluorine, (C ¹ -C ₄ ) -alkyl or trifluoromethyl, R ^{1 is} hydrogen or fluorine, R ^{2 is} benzyl, where benzyl is substituted by 1 to 3 substituents fluorine, and their N-oxides, Salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

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

A is nitrogen or CR ³ , where

R ^{3 is} hydrogen, fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl or cyclopropyl,

L represents a group * -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - #, where

* represents the point of attachment to the carbonyl group,

# represents the point of attachment to the pyrimidine or triazine ring, p stands for a number 0 or 1,

R ^{4A is} hydrogen, fluorine, methyl, ethyl or hydroxy,

R ^{4B is} hydrogen, fluorine, methyl, ethyl, trifluoromethyl, methoxycarbonylammo or phenyl, wherein methyl and ethyl may be substituted with 1 or 2 substituents independently selected from the group of fluorine, trifluoromethyl and hydroxy, or

R ^4A and R ^4B together with the carbon atom to which they are attached, a

Form cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl ring, in which the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and tetrahydropyranyl ring may be substituted by 1 or 2 substituents independently of one another selected from the group consisting 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 fluorine,

R ^{2 is} benzyl, wherein benzyl is substituted by 1 to 3 substituents fluorine, and their salts, solvates and solvates of the salts.

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

A is nitrogen or CR ³ , where

R ^{3 is} hydrogen, difluoromethyl, trifluoromethyl, methyl, ethyl or cyclopropyl,

L represents a group * -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - #, where

* represents the point of attachment to the carbonyl group,

R ^{4A is} hydrogen, fluorine, methyl, ethyl or hydroxy,

R ^{4B is} hydrogen, fluorine, methyl, ethyl or trifluoromethyl, 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,

R ^{5A is} hydrogen, fluorine, methyl, ethyl or hydroxy,

R ^{5B is} hydrogen, fluorine, methyl, ethyl or trifluoromethyl,

R ^{1 is} hydrogen or fluorine,

R ^{2 is} benzyl, wherein benzyl is substituted by 1 or 2 substituents fluorine, and their salts, solvates and solvates of the salts.

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

A is CR ³ , where

R ³ L represents hydrogen, a group -CR * ^4A R ^4B - (CR ^5A R ^5B) _p - #, where

* represents the point of attachment to the carbonyl group,

# represents the point of attachment to the pyrimidine 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, a

Form 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} benzyl, where benzyl is substituted by 1 or 2 substituents fluorine, and their salts, solvates and solvates of the salts.

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

L represents a group * -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - #, where

* represents the point of attachment to the carbonyl group,

# represents the point of attachment to the triazine ring, p stands for a number 0,

R ^{4A is} hydrogen, fluorine or methyl,

R ^{4B is} hydrogen, fluorine, methyl or trifluoromethyl, or

R ^4A and R ^4B together with the carbon atom to which they are attached, a

Cyclopropyl or cyclobutyl ring in which 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} benzyl, wherein benzyl is substituted by 1 or 2 substituents fluorine, and their salts, solvates and solvates of the salts.

A is nitrogen or CR ³ , where

* represents the point of attachment to the carbonyl group,

# represents 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, fluorine, methyl or trifluoromethyl, or

R ^4A and R ^4B together with the carbon atom to which they are attached, a

Form cyclopropyl ring,

R ^{1 is} hydrogen or fluorine,

R ^{2 is} a group of the formula

stands, where

## is the point of attachment to the pyrazolopyridine ring, 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 - # where

* represents the point of attachment to the carbonyl group,

R ^4A and R ^4B together with the carbon atom to which they are attached, 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 - # where

* represents the point of attachment to the carbonyl group,

* represents 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, fluorine, 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 - #, where

* represents the point of attachment to the carbonyl group,

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 - #, where

* represents the point of attachment to the carbonyl group, # represents 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, a

Cyclopropyl or cyclobutyl ring in which 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} a group of the formula

stands, where

Another object of the present invention are compounds of formula (XV),

represents a group * -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - #, where

* represents the point of attachment to the carbonyl group,

# is the point of attachment to the triazine ring, p is a number 0, 1 or 2,

R ^{4A represents} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl or hydroxyl,

R ^{4B is} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl, trifluoromethyl, (C 1 -C ₄ ) -alkoxycarbonyl-amino or phenyl, in which (C 1 -C ₄ ) -alkyl having 1 or 2 substituents independently of one another selected from Group fluorine, trifluoromethyl, hydroxy, hydroxycarbonyl and (C ₁ -C 4) - alkoxycarbonyl may be substituted, or

R ^4A and R ^4B together with the carbon atom to which they are attached form a 3- to

Form a 6-membered carbocycle or a 4- to 6-membered heterocycle, wherein the 3- to 6-membered carbocycle and the 4- to 6-membered heterocycle having 1 or 2 substituents independently selected from the group fluorine and (C C4) -alkyl may be substituted, R ^5A is hydrogen, fluorine, (C _r _C4) alkyl or hydroxy,

R ^{5B is} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl or trifluoromethyl,

R ^{1 is} hydrogen or fluorine,

R ^{2 is} benzyl, where benzyl is substituted by 1 to 3 fluorine substituents,

T ^{4 is} (C _r C ₄ ) -alkyl, and their salts, solvates and solvates of the salts.

Another object of the present invention are compounds of formula (XIII),

represents a group * -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - #, where

* represents the point of attachment to the carbonyl group,

# is the point of attachment to the triazine ring, p is a number 0, 1 or 2,

R ^{4A represents} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl or hydroxyl,

R ^4B is hydrogen, fluorine, (Ci-C) alkyl, trifluoromethyl, (C _r _C4) alkoxycarbonyl amino or phenyl, wherein (C 1 -C 4) -alkyl having 1 or 2 substituents independently of one another can be substituted from the group of fluorine, trifluoromethyl, hydroxy, hydroxycarbonyl and (C 1 -C ₄ ) -alkoxycarbonyl, or

6-membered carbocycle or a 4- to 6-membered heterocycle, wherein the 3- to 6-membered carbocycle and the 4- to 6-membered heterocycle having 1 or 2 substituents independently selected from the group fluorine and (Ci-C4 ) Alkyl,

R ^{5A is} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl or hydroxyl,

R ^{5B is} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl or trifluoromethyl,

R ^{1 is} hydrogen or fluorine,

R ^{2 is} benzyl, where benzyl is substituted by 1 to 3 fluorine substituents,

In the context of the present invention, preference is also given to compounds of the formulas (XII) and (XV) in which

L represents a group * -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - #, where

* represents the point of attachment to the carbonyl group,

# is the point of attachment to the triazine ring, p is a number 0, 1 or 2,

R ^{4A is} hydrogen, fluorine, methyl, ethyl or hydroxy,

R ^{4B is} hydrogen, fluorine, methyl, ethyl or trifluoromethyl, or

R ^4A and R ^4B together with the carbon atom to which they are attached, a

Form cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl ring, R ^{5A represents} hydrogen, fluorine, methyl, ethyl or hydroxy,

R ^{5B is} hydrogen, fluorine, methyl, ethyl or trifluoromethyl,

R ^{1 is} hydrogen or fluorine,

R ^{2 is} benzyl, where benzyl is substituted by 1 or 2 substituents fluorine, T ^{4 is} methyl or ethyl, and their salts, solvates and solvates of the salts.

In the context of the present invention, preference is also given to compounds of the formulas (XIII) and (XV) in which

L represents a group * -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - #, where

* represents the point of attachment to the carbonyl group,

L represents a group * -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - #, in which

* represents the point of attachment to the carbonyl group,

# represents the point of attachment to the triazine ring, p is a number 0, R ^4A and R ^4B together with the carbon atom to which they are attached, one

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

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

The 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 abovementioned meanings, [A] in an inert solvent in the presence of a suitable base with a compound of the formula (III) in which L has the abovementioned meaning and

T ¹ is (C _r C ₄₎ -alkyl, to a compound of formula (IV)

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

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

[B] in an inert solvent in the presence of a suitable base with a compound of formula (VI)

represents a group * -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - #, where

* represents the point of attachment to the carbonyl group,

# is the point of attachment to the pyrimidine or triazine ring, p is a number 1 or 2,

R ^{4A represents} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl or hydroxyl, R ^{4B is} hydrogen, fluorine, (Ci-C) -alkyl or trifluoromethyl, or

R ^4A and R ^4B together with the carbon atom to which they are attached, a

Oxo group, form a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle,

R ^5A is hydrogen, fluorine, (C _r _C4) alkyl or hydroxy,

R ^{5B is} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl or trifluoromethyl, and

T ^{2 is} (C _r C ₄ ) -alkyl, to give a compound of formula (IV-B)

(IV-B) in which L ¹ , R ¹ and R ^{2 in} each case have the meanings given above, and then analogously to process [A] to give a compound of the formula (IB)

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

[C] in an inert solvent in the presence of a suitable base with a compound of the formula (VII)

(VII), in which L and R ³ each have the meanings given above, and

T ³ represents (C _r C ₄₎ -alkyl, to a compound of formula (VIII)

in which L, R, R, R and T are each as defined above, these are then reacted with phosphoryl chloride to give a compound of the formula (IX)

in which L, R, R, R and T in each case have the abovementioned meanings, these are subsequently converted in an inert solvent into a corresponding azide compound and these directly converted into a compound of the formula (X)

in which L, R ¹ , R ² , R ³ and T ³ each have the meanings given above, and then reducing these in an inert solvent in the presence of a suitable base to give a compound of the formula (IC)

in which L, R ¹ , R ² and R ³ each have the meanings given above, or

[D] in an inert solvent in the presence of a suitable base with hydrazine hydrate to give a compound of formula (XI)

(Xi)

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

then reacting these in an inert solvent with a compound of the formula (XII)

in which L has the meaning given above and

T is (C _r _C4) alkyl,

to a compound of the formula (XIII)

in which L, R ¹ , R ² and T ⁴ each have the abovementioned meanings, these are then reacted with phosphoryl chloride to give a compound of the formula (XIV)

in which L, R, R and T are each as defined above, and these are reacted directly with ammonia to give a compound of the formula (XV)

in which L, R, R and T 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 (ID)

in which L, R ¹ and R ^{2 are} each as defined above, cyclized, and optionally the resulting compounds of the formulas (IA), (IB), (IC) and (ID) optionally with the appropriate (i) solvents and / or (ii) converting acids or bases into their solvates, salts and / or solvates of the salts.

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

Inert solvents for process step (II) + (III) or (VI) - ^> (IV) 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 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) or (VI) -> (IV) 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 hydrogen carbonate, alkali metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 5-diazabicyclo [4.3.0] non-5-ene (DBN). Preference is given to potassium tert-butoxide or sodium methoxide. The reaction (II) + (III) or (VI) -> (IV) is generally in a temperature range from + 20 ° C to + 150 ° C, preferably at + 75 ° C to + 100 ° C, optionally in a microwave oven. 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 process step (IV) -> (V) is carried out 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 may be carried out at normal, elevated or reduced pressure (e.g., in the range of 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 moles of isopentyl nitrite and 10 to 30 moles of the iodine equivalent based on 1 mole of the compound of formula (IV). As iodine source in implementing (IV) - ^»■ (V) are suitable, for example, diiodomethane or a mixture of cesium, 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), NN'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝΜΡ), pyridine, acetonitrile or even 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 may be carried out at normal or elevated pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.

Inert solvents for process step (II) + (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 ethers, 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.

Suitable bases for process step (II) + (VII) -> (VIII) 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 methoxide, sodium or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l , 5-diazabicyclo [4.3.0] non-5-ene (DBN). Preference is given to sodium methoxide or sodium ethoxide.

The reaction (II) + (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 may be carried out at normal or elevated pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.

The reactions (VIII) -> (IX) and (XIII) -> (XIV) can be carried out in a solvent which is inert under the reaction conditions or without solvent. Preferred solvent is sulfolane. The reactions (VIII) - ^> (IX) and (XIII) - ^> (XIV) are generally carried out in a temperature range from + 70 ° C to + 150 ° C, preferably from + 80 ° C to + 130 ° C, if necessary in a microwave. The reaction can be carried out at normal or elevated pressure (for example in the range from 0.5 to 5 bar). Generally, one works at normal pressure.

Particularly preferably, the reaction (XIII) - ^> (XIV) without solvent in a temperature range of 0 ° C to + 50 ° C at atmospheric pressure.

The process step (IX) -> (X) is carried out by reaction with sodium azide with intermediate formation of the azide derivatives, which are further reduced directly to the corresponding amines. Inert solvents for the azide formation are, for example, 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'-dimethylpropylene urea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or sulfolane. It is likewise possible to use mixtures of the solvents mentioned. Preferred is DMF.

The azide is generally formed in a temperature range from + 50 ° C to + 100 ° C, preferably from + 60 ° C to + 80 ° C, at atmospheric pressure. The reduction is carried out in an inert solvent such as, for example, 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), NN'-dimethyl propyleneurea (DMPU), N-methylpyrrolidone (ΝΜΡ), pyridine, acetonitrile or even water. It is likewise possible to use mixtures of the solvents mentioned. Preferred is DMF.

The reduction takes place at + 10 ° C to + 30 ° C with hydrogen in conjunction with transition metal catalysts such as palladium (10% on activated carbon), platinum dioxide or palladium hydroxide, or without hydrogen with stannous chloride and hydrochloric acid.

Alternatively, the reaction (IX) -> (X) can also be carried out in a stage analogous to process step (XIV) -> (XV).

The process step (XIV) -> (XV) 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 (ΝΜΡ), pyridine, acetonitrile or else Water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to acetonitrile.

The reaction (XIV) -> (XV) 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 may be carried out at normal or elevated pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.

The cyclizations (X) -> (IC) and (XV) -> (ID) are 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 (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), NN ' dimethyl propyleneurea (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 the process steps (X) - » ^■ (IC) and (XV) -» ^■ (ID) 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 or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, l, 8-diazabicyclo [5.4.0] undec-7 -en (DBU) or l, 5-diazabicyclo [4.3.0] non-5-ene (DBN). Preference is given to potassium tert-butoxide. The reactions (X) -> (IC) and (XV) -> (ID) are generally carried out in a temperature range from 0 ° C to + 50 ° C, preferably from + 10 ° C to + 30 ° C, optionally in one Microwave. The reaction can be carried out at normal or elevated pressure (for example in the range from 0.5 to 5 bar). Generally, one works at normal pressure.

Alternatively, the cyclization to (I-C) or (I-D) directly in the reduction of the azide to the corresponding amine (X) or in the reaction (XIV) -> (XV) without the addition of other reagents.

In an alternative procedure of the methods [C] or [D], the transformations (IX) -> (X) -> (IC) or (XI) + (XII) -> (XIII) -> (XIV) - > (XV) -> (ID) carried out simultaneously in a one-pot reaction without isolation of the intermediates.

The reactions (XIII) - (XIV) - (XV) - (I-D) are preferably carried out simultaneously in a one-pot reaction without isolation of the intermediates.

Inert solvents for the process step (XI) + (XII) - ^> (XIII) 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 dimethacrylate 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 (ΝΜΡ), pyridine or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to methanol or ethanol.

The reaction (XI) + (XII) -> (XIII) 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 implementation can be carried out at normal or elevated pressure (eg in the range of 0.5 to 5 bar). Generally, one works at normal pressure.

Inert solvents for process step (II) -> (XI) 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), NN'-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) -> ^■ (XI) are alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali metal hydrogen carbonates such as sodium or potassium hydrogen carbonate, alkali metal alkoxides such as Sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1.5 Diazabicyclo [4.3.0] non-5-ene (DBN). Preferably triethylamine.

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

The preparation processes described can be illustrated by the following synthesis schemes (Schemes 1 to 4) by way of example:

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

[a): NaOMe, methanol, 65 ° C, b): CsI, I ₂ , Cul ₂ , iso-pentylnitrite, 1, 2-dimethoxyethane; c): Pd / C, hydrogen, DMF].

Scheme 3

[a): NaOMe, MeOH; b): POCl ₃ ; sulfolane; c): NaN ₃ , DMF; d): Pd / C, H ₂ , DMF; e) KOt-Bu, THF]. Scheme 4

[a): hydrazine hydrate, NEt ₃ , EtOH b): EtOH c): 1. POCl ₃ ; 2nd conc. NH _3, acetonitrile].

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), (IX) or (XIV) obtained by the above method. These transformations are carried out by conventional methods known to those skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, elimination, alkylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of carbonamides, and introduction and removal of temporary protection groups. The following synthetic schemes (Schemes 5, 6, 11, and 12) exemplify preferred transformations:

[a): selenium dioxide, dioxane; b): MeMgBr, THF c): CsF, (trifluoromethyl) trimethylsilane, dimethoxyethane].

-40-

Scheme 11 [a): piperidine, RT; b): trimethylsulfoxonium iodide, NaH, DMSO, RT -> 50 ° C].

The compounds of the formula (II) are known from the literature (see, for example, WO 03/095451, Example 6A) or can be prepared by reacting a compound of the formula (XVI)

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

² (XVII), in which R ^{1 has} the abovementioned meaning, then cyclized 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 into the compound of formula ( XVIII)

(XVIII) in which R ^{1 has} the abovementioned meaning, these are subsequently converted in an inert solvent in the presence of a suitable base with the compound of the formula (XIX)

^{R2 χ1} (XIX), 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, in a compound of the formula (XX)

(XX) in which R ¹ and R ² each have the meanings given above, then converting these in an inert solvent with copper cyanide to give a compound of the formula (XXI)

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

Inert solvents for process step (XVI) -> (XVII) 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 1, 2-ethanediol.

The reaction (XVI) -> (XVII) is generally carried out in a temperature range of + 60 ° C to + 200 ° C, preferably at + 120 ° C to + 180 ° C. The reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.

Inert solvents for the reaction (XVII) - ^[ (XVIII) 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), NN'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝΜΡ), pyridine or acetonitrile. Preferred is DMF.

Suitable Lewis acids for process step (XVII) -> (XVIII) 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 (XVII) -> (XVIII) is generally carried out in a temperature range of -78 ° C to + 40 ° C, preferably at 0 ° C to + 20 ° C. The reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.

Inert solvents for the reaction (XVIII) + (XIX) - ^> (XX) 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 (ΝΜΡ), pyridine, acetonitrile. Preferred is DMF.

Suitable bases for the process step (XVIII) + (XIX) -> (XX) are alkali metal hydrides such as potassium hydride or sodium hydride, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali metal bicarbonates such as sodium or potassium bicarbonate, alkali metal alcoholates such as sodium or potassium 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 l, 5-diazabicyclo [4.3.0] non-5-ene (DBN). Cesium carbonate is preferred.

The reaction (XVIII) + (XIX) -> (XX) 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 (XX) - ^> (XXI) 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 others Solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), NN'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝΜΡ), pyridine or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferred is DMSO.

The reaction (XX) -> (XXI) 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 may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.

The reaction (XXI) -> (II) is carried out according to the methods known in the art in a two-step 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.

The described preparation process can be exemplified by the following synthesis scheme (Scheme 7):

Scheme 7

x H ₃ CC0 ₂ H

[a): hydrazine hydrate, 1, 2-ethanediol; b): iso-pentyl nitrite, Nal, THF; b): 2-fluorobenzyl bromide, Cs ₂ C0 ₃ , DMF; d): CuCN, DMSO, e): 1. NaOMe, MeOH, 2. NH ₄ Cl, acetic acid]. Alternatively, the compounds of the formula (II) are prepared as shown by way of example in the synthesis scheme below (Scheme 13):

[a): TFA, dioxane; b) NH ₃ ; c) trifluoroacetic anhydride]. The compound of the formula (XVI) is known from the literature [cf. eg, 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 8):

Scheme 8

[a): sulfuric acid; b): zinc, methanol, glacial acetic acid; c): trifluoroacetic anhydride, dichloromethane]. The compounds of the formulas (III) and (VI) are commercially available, known from the literature, can be prepared analogously to processes known from the literature or as shown by way of example in the following synthesis schemes (Schemes 9 and 10):

Scheme 9

[a): 1. LiHMDS, -78 ° C, THF, 2.NBS; b): NaH, 50 ° C, THF].

Scheme 10

[a): NaOMe, MeOH, 65 ° C].

The compounds of the formula (VII) and (XII) are commercially available, known from the literature or can be prepared in analogy to literature-known rules.

The compounds of the invention are potent stimulators of soluble guanylate cyclase, have valuable pharmacological properties, and have an improved therapeutic profile, such as in their in vivo properties and / or their pharmacokinetic behavior. 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 by a direct stimulation of soluble guanylate cyclase and an intracellular cGMP increase. In addition, the compounds according to the invention enhance the action of substances which increase the cGMP level, such as, for example, EDHF (endothelium-derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

The compounds according to the invention are suitable for the treatment and / or prophylaxis of cardiovascular, pulmonary, thromboembolic and fibrotic disorders. The compounds according to the invention can therefore be used in medicaments for the treatment and / or prophylaxis of cardiovascular diseases such as hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, arrhythmia of the atria and the chambers and conduction disorders such for example atrio-ventricular blockades grade I-III (AB block I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular tachyarrhythmia, torsade de pointes tachycardia, atrial and ventricular extrasystoles, atrioventricular extrasystoles, Sick sinus syndrome, syncope, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), shock such as cardiogenic shock, septic shock, and the like anaphylactic shock, aneurysms, boxer vardicle contraction (PVC), for the treatment and / or prophylaxis of thromboembolic disorders and ischaemias such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transitory and ischemic attacks, preeclampsia, inflammatory cardiovascular diseases, spasms Coronary arteries and peripheral arteries, edema formation such as pulmonary edema, cerebral edema, renal edema or congestive heart failure, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, for the 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 LDL geri density and elevated 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 failure also includes more specific or related forms of disease such as acutely decompensated heart failure, right heart failure, left ventricular failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, valvular heart failure, cardiac valvulopathy, mitral valve stenosis, mitral valves - insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valvular insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac disease, 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 prostate enlargement (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS, including Feiine's urological syndrome ( FUS)), diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as mixed, urge, stress, or overflow incontinence (MUI, UUI, SUI, OUI), Pelvic pain, benign and malignant diseases of the organs of the male and female urogenital system. Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of kidney diseases, in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure. For the purposes of the present invention, the term renal insufficiency includes both acute and chronic manifestations of renal insufficiency, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulo-interstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney disease such as renal transplant rejection, immune complex-induced kidney disease diseases, nephropathy induced by toxic substances, contrast agent-induced nephropathy, diabetic and nondiabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, which are diagnostically characterized by, for example, abnormally decreased creatinine and / or water excretion, abnormally elevated blood levels urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes such as glutamylsynthetase, altered urinary or urine abundance, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilation, hyperphosphatemia and / or the need for dialysis. The present invention also encompasses the use of the compounds of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.

Furthermore, the compounds according to the invention are also suitable for the treatment and / or prophylaxis of asthmatic diseases, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including left heart disease, HIV, sickle cell anemia, thromboembolism (CTEPH), sarcoidosis, COPD or Pulmonary fibrosis-associated pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute respiratory tract syndrome (ARDS), acute lung injury (ALI), 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 diseases in the central nervous system, which are characterized by disorders of the NO / cGMP system. In particular, they are suitable for improving the perception, concentration, learning performance or memory performance after cognitive disorders, such as those found in situations / diseases / syndromes such as mild cognitive impairment, age-associated learning and memory disorders, age-associated memory loss, vascular dementia, cranial Brain trauma, stroke, post-stroke dementia, post-traumatic traumatic brain injury, general attention deficit disorder, impaired concentration in children with learning and memory problems, Alzheimer's disease, dementia with Lewy's disease. Corpuscles, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia , HIV Dementia, schizophrenia with dementia or Korsakoff's psychosis. They are also suitable for the treatment and / or prophylaxis of diseases of the central nervous system such as states of anxiety, tension and depression, central nervous 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 eye diseases.

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

Furthermore, the compounds according to the invention are 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 interventions), nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis).

Furthermore, the compounds according to the invention are suitable for combating postoperative scar formation, for example as a consequence of glaucoma operations. 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 ,

The compounds of the invention may be used alone or as needed in combination with other agents. Another object of the present invention are pharmaceuticals, containing at least one of the compounds according to the invention and one or more further active compounds, in particular for the treatment and / or prophylaxis of the abovementioned disorders. 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 thrombocyte aggregation inhibitors, 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 B-relaxer, beta-receptor blocker, mineralocorticoid receptor - antagonists and diuretics; and / or · fat metabolism-altering agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors , PPAR alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists.

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

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

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

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD 31 12, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and 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 B-relaxer, beta-receptor blocker, mineralocorticoid receptor Tor antagonists and diuretics understood.

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an 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 of 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 ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-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 ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

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

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

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

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

In a preferred embodiment of the invention, the compounds of the invention are used in combination with a bile acid reabsorption inhibitor, as exemplified 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 may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

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

For the oral administration are according to the prior art working, the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates, capsules (e.g. Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For other routes of administration, for example, inhalant medicaments (including powder inhalers, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal are suitable applying tablets, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered litter , Implants or stents. Preference is given to oral or parenteral administration, in particular oral administration.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitol oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers ( 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

Calculated

DCI direct chemical ionization (in MS)

DMF dimethylformamide

DMSO dimethyl sulfoxide

d. Th. Of theory (at yield)

eq. Equivalent (s)

ESI electrospray ionization (in MS)

Et ethyl

gef. Found

h hour (s)

HPLC high pressure, high performance liquid chromatography

HRMS high-resolution mass spectrometry

conc. concentrated

LC / MS liquid chromatography-coupled mass spectrometry

LiHMDS lithium hexamethyldisilazide

Me methyl

min minute (s)

MS mass spectrometry

NMR nuclear magnetic resonance spectrometry

Pd / C palladium on charcoal (10%)

Ph phenyl

RT room temperature

Retention time (on HPLC)

t-Bu tert-butyl

TFA trifluoroacetic acid

THF tetrahydrofuran

UV ultraviolet spectrometry

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

XPHOS dicyclohexyl- (2 ', 4', 6'-triisopropylbiphenyl-2-yl) -phosphine LC / MS methods:

Method 1 (LC-MS):

Instrament: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1,8μ 50 x 1mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A; Oven: 50 ° C; Flow: 0.40 ml / min; UV detection: 210 - 400 nm.

Method 2 (LC-MS):

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

Method 3 (LC-MS):

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

Method 4 (LC-MS):

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

Starting Compounds and Intermediates: Example 1A

1 - (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridine-3-carboximidamide hydrochloride

The synthesis of this compound is described in WO 03/095451, Example 6A. 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)

'H-NMR (400 MHz, DMSO-de): δ = 7.95 (brs, 1H), 8.11 (brs, 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. Acetic acid (18.5 ml) was then added and the mixture was heated to reflux with stirring 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 crystals were added with dichloromethane (388 ml) and stirred for 20 min. stirred. It was again filtered off with suction and washed with diethyl ether and sucked dry.

Yield: 20.2 g (53% of theory)

'H-NMR (400 MHz, DMSO-de): 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-fluoronicotinamide 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).

'H-NMR (400 MHz, DMSO-de): δ = 8.66 (dd, 1H), 8.82 (d, 1H). Example 5A

5-fluoro-lH-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) and then treated with hydrazine hydrate (119.6 ml). It was heated to reflux with stirring for 4 h. Upon cooling, the product precipitated. The crystals were mixed with water (380 ml) and stirred 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). Drying under high vacuum over phosphorus pentoxide. Yield: 22.8 g (61% of theory)

'H-NMR (400 MHz, DMSO-de): δ = 5.54 (s, 2H), 7.96 (dd, 1H), 8.38 (m, 1H), 12.07 (m, 1H).

Example 6A

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

10 g (65.75 mmol) of 5-fluoro-1H-pyrazolo [3,4-b] pyridin-3-amine were initially charged in THF (329 ml) and cooled to 0 ° C. Subsequently, 16.65 ml (131.46 mmol) of boron trifluoride-diethyl ether complex were added slowly. 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 (1.8 L) and extracted twice with ethyl acetate (487 mL each). 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. The crude product was reacted without further purification.

LC-MS (Method 2): R _t = 1.68 min

MS (ESIpos): m / z = 264 (M + H) + Example 7A

5-Fluoro-1- (2-fluorobenzyl) -3-iodo-1H-pyrazolo [3,4-b] pyridine

In DMF (217 ml), 12.1 g (about 39.65 mmol) of the compound from Example 6A were initially charged and then 8.25 g (43.62 mmol) of 2-fluorobenzyl bromide and 14.21 g (43.62 mmol) of cesium carbonate were added. The mixture was stirred at RT for two hours. The reaction mixture was then added to water (1.17 L) and extracted twice with ethyl acetate (502 mL). The collected organic phases were washed with saturated aqueous sodium chloride solution (335 ml), dried, filtered and concentrated. The residue was chromatographed on silica gel (eluent: petroleum ether / ethyl acetate 97: 3) and the product fractions were concentrated. This gave 9.0 g (61% of theory) of the title compound as a solid. The solid is taken up in ethyl acetate and washed with 10% aqueous sodium thiosulfate solution and then with saturated aqueous sodium chloride solution, dried and concentrated.

LC-MS (Method 2): R _t = 2.57 min

MS (ESIpos): m / z = 372 (M + H) ⁺ 1 H NMR (400 MHz, DMSO-d 6): δ = 5.73 (s, 2H), 7.13 - 7.26 (m, 3H), 7.33 - 7.41 ( m, 1H), 7.94 (dd, 1H), 8.69-8.73 (m, 1H).

Example 8A

5-fluoro-l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine-3-carbonitrile

A suspension of 16.03 g (43.19 mmol) of 5-fluoro-1- (2-fluorobenzyl) -3-iodo-1H-pyrazolo [3,4-b] pyridine (Example 7A) and 4.25 g (47.51 mmol) of copper cyanide were added DMSO (120 ml) and stirred at 150 ° C for 2 h. After cooling, the flask contents were cooled to about 40 ° C, to a solution of conc. Ammonia water (90 ml) and water (500 ml) were poured, mixed with ethyl acetate (200 ml) and stirred briefly. The aqueous phase was separated and extracted twice more with ethyl acetate (200 ml each time). The combined organic phases were washed twice with 10% aqueous sodium chloride solution (100 ml each), dried and concentrated in vacuo. The crude product was reacted without further purification. Yield: 11.1 g (91% of theory)

'H-NMR (400 MHz, DMSO-de): δ = 5.87 (s, 2H), 7.17-7.42 (m, 4H), 8.52 (dd, 1H), 8.87 (dd, 1H).

Example 9A

5-fluoro-l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine-3-carboximidamide acetate

To 2.22 g (41.07 mmol) of sodium methoxide in methanol (270 ml) were added 11.1 g (41.07 mmol) of 5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carbonitrile ( Example 8A) and stirred for 2 h at RT. Thereafter, 2.64 g (49.29 mmol) of ammonium chloride and acetic acid (9.17 ml) were added and heated to reflux overnight. It was then concentrated to dryness and the Residue was taken up in water (100 ml) and ethyl acetate (100 ml) and adjusted to pH 10 with 2N sodium hydroxide solution. It was stirred vigorously for about 1 h at RT. The resulting suspension was filtered off with suction and washed with ethyl acetate (100 ml), water (100 ml) and again ethyl acetate (100 ml). The residue is dried over Pphosphorpentoxid under high vacuum.

Yield: 9.6 g (78% of theory)

MS (ESIpos): m / z = 288 (M + H) ⁺

1H-NMR (400 MHz, DMSO-de): δ = 1.85 (s, 3H), 5.80 (s, 2H), 7.14 - 7.25 (m, 3H), 7.36 (m, 1H), 8.42 (dd, 1H) , 8.72 (dd, 1H). Example 10A

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

In THF (91 ml), 1.816 g (45.41 l 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 stirred 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 4h. 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 with 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) 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.40 (s, 6H), 3.74 (s, 3H), 5.27 (s, 1H). Example IIA

Methyl 3-bromotetrahydrofuran-3-carboxylate

5.0 g (38.419 mmol) of methyltetrahydrofuran-3-carboxylate (Journal of Organic Chemistry, 1996, 2690) were dissolved in 200 ml of THF and cooled to -78 ° C., followed by 76.83 ml (76.83 mmol) of bis (trimethylsilyl) lithium amide, (IM in THF). After 30 minutes at -78 ° C, 10.26 g (57.63 mmol) of N-bromosuccinimide suspended in 50 ml of THF were slowly added. Then it was allowed to warm to RT overnight. The reaction was mixed with water and extracted with ethyl acetate. The phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried with sodium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel (eluent: dichloromethane). 491 mg (6% of theory) of the title compound were obtained.

1H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 2.49 (ddd, 1H), 2.74 (ddd, 1H), 3.83 (s, 3H), 4.03-4.10 (m, 1H), 4.11-4.17 ( m, 2H), 4.31 (d, 1H).

Example 12A

Methyl 3 - (dicyanomethyl) tetrahydrofuran-3-carboxylate

440 mg (11.00 mmol) of sodium hydride (60% strength in mineral oil) were initially charged in 30 ml of THF and 726 mg (11.00 mmol) of malononitrile were added in portions. Thereafter, 2.3 g (11.00 mmol) of the compound obtained in Example 69A in THF (50 ml) was added. It was stirred for 6 h at RT and then heated to 50 ° C overnight. After cooling, the batch was washed with saturated aqueous sodium bicarbonate solution and extracted with water Extracted ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried with sodium sulfate, filtered and concentrated. The residue (2.66 g) was dried under high vacuum for 1 h and then reacted without further purification. Example 13A

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

5,887 g (19,256 mmol) of Example 1A were initially charged in tert-butanol (50 ml) and treated with 2,593 g (23.107 mmol) of potassium tert-butoxide. Subsequently, 3.2 g (19.256 mmol) of Example 10A in tert-butanol (25 ml) were added dropwise and the mixture was heated to reflux overnight. The next day another 0.64 g (3.851 mmol) of Example 10A was added and the mixture was heated to reflux for a further day. After cooling, a precipitate was filtered off, which was washed with diethyl ether. It was then slurried in water and filtered once more from and washed with diethyl ether. After drying under high vacuum, it was possible to obtain 6.65 g of the title compound (85% of theory).

LC-MS (Method 1): R _t = 0.90 min; MS (ESIpos): m / z = 404 (M + H) ⁺

'H-NMR (400 MHz, DMSO-ds): δ [ppm] = 1.35 (s, 6H), 5.82 (s, 2H), 6.82 (br s, 2H), 7.14-7.25 (m, 3H), 7.33 -7.40 (m, 2H), 8.63 (dd, 1H), 9.03 (dd, 1H), 10.98 (s br, 1H). Example 14A

4-Amino-2- [5-fluoro-l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridin-3-yl] -5,5-dim

6H-pyrrolo [2,3-d] pyrimidin-6-one

In analogy to the preparation of Example 2, 4.18 g (12.035 mmol) of Example 9A were reacted with 2.20 g (13.239 mmol) of Example 10A. 3.72 g of the title compound were obtained (73% of theory).

LC-MS (Method 1): R _t = 0.98 min; MS (ESIpos): m / z = 422 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.34 (s, 6H), 5.81 (s, 2H), 6.85 (br s, 2H), 7.13-7.25 (m, 3H), 7.36 (m, IH), 8.69 (dd, IH), 8.84 (dd, IH), 10.96 (s br, IH).

Example 15A

4'-Arrüno-2 '- [l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridin-3-yl] -4,5-dihydrospiro [to

pyrrolo [2,3-d] pyrimidin] -6 '(7'h) -one

In analogy to the preparation of Example 13A, 2,257 g (7,382 mmol) of Example 1A were reacted with 1,434 g (7,382 mmol) of Example 12A. 566 mg of the title compound were obtained (17% of theory).

Th.). LC-MS (Method 1): R _t = 0.84 min; MS (ESIpos): m / z = 432 (M + H)

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 2.20-2.37 (m, 2H), 3.71 (d, IH), 3.90 (q, IH), 4.10 (d, IH), 4.25- 4.31 (m, IH), 5.82 (s, 2H), 6.57 (br s, 2H), 7.12-7.25 (m, 3H), 7.33-7.41 (m, 2H), 8.64 (dd, IH), 9.02 (dd , IH), 11.96 (s br, IH).

Example 16A Ethyl {2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] -4-hydroxypyrimidin-5-yl} acetate

7.519 g (327 mmol) of sodium were added to ethanol (660 ml) and reacted completely under argon. Thereafter, 50.00 g (163.53 mmol) of Example 1A and, after 5 min, 40.45 g (188.01 mmol) of diethyl 2-formyl butanedioate (synthesis described in WO 2005/73234, page 43) were added. The mixture was then heated to reflux for 12 h. After cooling, the reaction mixture was treated with water and then with 1N hydrochloric acid. The precipitate which formed was filtered off with suction and washed successively with water-ethanol (1: 1, 200 ml), ethanol (100 ml) and finally with diethyl ether. After drying under high vacuum, 58.0 g of the title compound were obtained (83% of theory).

LC-MS (Method 1): R _t = 1.00 min; MS (ESIpos): m / z = 408 (M + H) ⁺ 'H-NMR (400 MHz, DMSO-ds): δ [ppm] = 1.19 (t, 3H), 3.48 (s, 2H), 4.09 ( q, 2H), 5.87 (s, 2H), 7.15 (t, 1H), 7.24 (t, 1H), 7.34-7.39 (m, 2H), 7.46 (dd, 1H), 8.10 (s br, 1H), 8.71 (dd, 1H), 8.74 (d, 1H), 12.83 (s br, 1H).

Example 17A

Ethyl {4-chloro-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} acetate

55.00 g (135 mmol) of Example 16A were initially charged in sulfolane (220 ml) and admixed with 41.40 g (270 mmol) of phosphoryl chloride. Thereafter, it was heated to 120 ° C for 1 h. After cooling, it was added to warm water (1 500 ml) and then neutralized with solid sodium bicarbonate. The precipitate which formed was filtered off with suction and washed with water. Thereafter, it was further purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 3: 2). After drying under high vacuum, 43.0 g of the title compound were obtained (73% of theory). LC-MS (Method 1): R _t = 1.20 min; MS (ESIpos): m / z = 426 (M + H)

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.21 (t, 3H), 3.96 (s, 2H), 4.15 (q, 2H), 5.90 (s, 2H), 7.16 (t, 1H), 7.22-7.27 (m, 2H), 7.36-7.39 (m, 1H), 7.49 (dd, 1H), 8.71 (dd, 1H), 8.84 (dd, 1H), 8.96 (s, 1H). Example 18A

Ethyl {4-azido-2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} acetate

10.00 g (23.482 mmol) of Example 17A were initially charged in DMF (200 ml) and treated with 2.290 g (35.223 mmol) of sodium azide. Thereafter, it was heated to 60 ° C for 1 h. After cooling, the reaction mixture was added to water and extracted three times with ethyl acetate. The organic phases were combined and washed once with saturated aqueous sodium chloride solution, then dried over sodium sulfate, filtered and concentrated. The residue was used without further purification in the next step.

LC-MS (Method 1): R _t = 1.16 min; MS (ESIpos): m / z = 433 (M + H) ⁺ Example 19A

Ethyl {4-amino-2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} acetate

10.15 g (23.482 mmol) of crude product from Example 18A were hydrogenated in DMF (400 ml) with palladium on carbon (10%) overnight at normal hydrogen pressure. It was then filtered through Celite and concentrated. The residue was used without further purification in the next step. LC-MS (Method 1): R _t = 0.83 min; MS (ESIpos): m / z = 407 (M + H) ⁺

Example 20A

Ethyl 1 - {4-chloro-2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridine-3-yl] pyrimidin-5-yl} cyclopropane carboxylate

1.00 g (2.348 mmol) of Example 17A were initially charged in THF (15 ml) and DMF (15 ml) and treated with 469 mg (11.741 mmol) of sodium hydride (60%) and stirred for 15 min at RT. Thereafter, 0.607 ml (7.054 mmol) of 1,2-dibromoethane were added and the mixture was stirred at RT for a further 30 min. The mixture was combined with water and ethyl acetate, the phases were separated and the organic Phase extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution and dried with sodium sulfate, filtered and concentrated. The title compound thus obtained (1.38 g, 75% purity) was used without further purification in the next step. LC-MS (Method 1): R _t = 1.26 min; MS (ESIpos): m / z = 452 (M + H) ⁺

Example 21A

Ethyl 1 - {4-azido-2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridine-3-yl] pyrimidin-5-yl} cyclopropane carboxylate

550 mg (about 0.913 mmol) of Example 20A were reacted in analogy to the procedure of Example 18A. The title compound thus obtained was used in the next step without further purification.

LC-MS (Method 1): R _t = 1.23 min; MS (ESIpos): m / z = 458 (M + H) ⁺ Example 22A Ethyl 1 - {4-amino-2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridine 3 -yl] pyrimidin-5-yl} cyclopropanecarboxylate

418 mg (0.913 mmol) of Example 21 A were hydrogenated in analogy to the procedure of Example 19A. The title binding thus obtained was used without further purification in the next step. LC-MS (Method 1): R _t = 0.86 min; MS (ESIpos): m / z = 433 (M + H) ⁺ Example 23A

1 - (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridine-3-carboximidohydrazide

20,000 g (65,414 mmol) of the compound from Example 1A were dissolved in 320 ml of ethanol and admixed at 0 ° C. with 26,477 g (261,656 mmol) of triethylamine and 4,093 g (65,414 mmol) of hydrazine hydrate (80% solution in water). The mixture was stirred at RT overnight and then concentrated on a rotary evaporator. This gave 26.84 g (100% of theory, 69% purity) of the title compound.

LC-MS (Method 3): R _t = 0.64 min; MS (ESIpos): m / z = 285 (M + H) ⁺ Example 24A

Diethyl-2- (difluoroacetyl) butanedioate

0.52 g (14.296 mmol) of sodium hydride (60% in mineral oil) were initially charged in THF (30 ml) and then at 0 ° C, a solution of 2.00 g (11437 mmol) of ethyl 4,4-difluoro-3-oxobutyrate in THF (20 ml) was added dropwise. After warming to RT and a further 30 min at this temperature, 2.865 g (17.156 mmol) of ethyl bromoacetate in THF (15 ml) were added and then heated to reflux overnight. After cooling, the batch was admixed with saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were dried with sodium sulfate, filtered and concentrated. After 5 minutes in a high vacuum, the title compound thus obtained (3.00 g, about 50% purity) was used without further purification in the next step.

Example 25A

Ethyl {4- (difluoromethyl) -2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] -6-hydroxypyrimidine

5-yl} acetate

In analogy to Example 16A, 1521 g (4.973 mmol) of Example 1A and 2.885 g (approximately 5.719 mmol) of Example 24A were reacted. After working up, purification was carried out by preparative HPLC (eluent: acetonitrile / water, gradient). 600 mg (26% of theory) of the title compound were obtained. LC-MS (Method 1): R _t = 1.08 min; MS (ESIpos): m / z = 458 (M + H) ⁺ Example 26A

Ethyl {4-chloro-6- (difluoromethyl) -2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} acetate

In analogy to Example 17A, 600 mg (1312 mmol) of Example 25 A were reacted. There were obtained 1.7 g of the title compound (about 36% purity, contaminated with sulfolane).

LC-MS (Method 1): R _t = 1.25 min; MS (ESIpos): m / z = 476 (M + H) ⁺

Example 27A

Ethyl 2- {4-chloro-6- (difluoromethyl) -2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridine-3-yl-pyrimidin-5-yl} -2- methylpropanoate

In analogy to 20A, 1.7 g (about 1.31 mmol) of Example 26A were reacted with methyl iodide. There were obtained 1.24 g of the title compound (about 36% purity, contaminated with sulfolane).

LC-MS (Method 1): R _t = 1.33 min; MS (ESIpos): m / z = 504 (M + H) ⁺ Example 28A

Ethyl 2- {4-azido-6- (difluoromethyl) -2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl-pyrimidin-5-yl} -2- methylpropanoate

In analogy to Example 18A, 1.24 g (about 1312 mmol) of Example 27A were reacted. There was obtained the title compound (contaminated with sulfolane), which was further reacted without determination of the yield, since the azide-containing solution was not further concentrated. LC-MS (method 1): R _t = 1.27 min; MS (ESIpos): m / z = 511 (M + H) ⁺ Example 29 A 1- (2,4-Difluorobenzyl) -3-iodo-1H-pyrazolo [3,4-b] pyridine

In analogy to the synthesis of Example 7A, 54.00 g (215.98 mmol) of 3-iodo-1H-pyrazolo [3,4-b] pyridine (synthesis described in WO 2006/130673, Example 4) with 50.18 g (237,578) of 2,4 - Implemented Difluorbenzylbromid. The crude product was mixed with ice-water, filtered off with suction and the precipitate was washed with isopropanol and pentane and then dried under high vacuum. There was obtained 76.7 g of the title compound (89% of theory). LC-MS (Method 1): R _t = 1.17 min; MS (ESIpos): m / z = 372 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ = 5.71 (s, 2H), 7.04-7.08 (m, 1H), 7.25-7.36 (m, 3H), 7.96 (dd, 1H), 8.65 (dd , 1H).

Example 30A

1 - (2,4-Difluorobenzyl) -1 H -pyrazolo [3,4-b] pyridine-3-carbonitrile

In analogy to Example 8A, 76.00 g (204.78 mmol) of Example 29A were reacted. 57.00 g (94% pure, 97% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.07 min; MS (ESIpos): m / z = 271 (M + H) ⁺ 'H-NMR (400 MHz, DMSO-de): δ = 5.86 (s, 2H), 7.07-7.12 (m, 1H), 7.27-7.32 (m, 1H), 7.44-7.50 (m, 1H), 7.55 (dd, 1H), 8.49 (dd, 1H), 8.81 (dd, 1H).

Example 31A

1 - (2,4-Difluorobenzyl) -1 H -pyrazolo [3,4-b] pyridine-3-carboximidamide acetate

In analogy to Example 9A, 56.00 g (207,221 mmol) of Example 30A were reacted. 19.00 g of the title compound were obtained (26% of theory).

LC-MS (Method 1): R _t = 0.60 min; MS (ESIpos): m / z = 288 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ = 1.81 (s, 3H), 5.80 (s, 2H), 7.03-7.08 (m, 1H), 7.26-7.37 (m, 2H), 7.41-7.44 (m, 1H), 8.61 (dd, 1H), 8.69 (dd, 1H).

Example 32A

Ethyl {2- [1- (2,4-difluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] -4-hydroxypyrimidin-5-yl} acetate

15 g (43187 mmol) of Example 31A were reacted analogously to the procedure of Example 16A. 14.30 g of the title compound (75% of theory) were obtained.

LC-MS (Method 1): R _t = 1.03 min; MS (ESIpos): m / z = 426 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.17 (t, 3H), 3.43 (s, 2H), 4.08 (q, 2H), 5.81 (s, 2H), 7.04 (ddd, IH), 7.28 (ddd, IH), 7.40-7.46 (m, 2H), 8.00 (s, IH), 8.67 (dd, IH), 8.77 (d, IH), 12.73 (s br, IH).

Example 33A

Ethyl {4-chloro-2- [1- (2,4-difluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} acetate

14.20 g (33.380 mmol) of Example 32A were reacted analogously to the procedure of Example 17A. 13.20 g of the title compound (88% of theory) were obtained.

LC-MS (Method 1): R _t = 1.23 min; MS (ESIpos): m / z = 444 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.21 (t, 3H), 3.95 (s, 2H), 4.15 (q, 2H), 5.87 (s, 2H), 7.06 (ddd, IH), 7.29 (ddd, IH), 7.36 (ddd, IH), 7.48 (dd, IH), 8.71 (dd, IH), 8.83 (dd, IH), 8.96 (s, IH).

Example 34A 1- (2,3-Difluorobenzyl) -3-iodo-1H-pyrazolo [3,4-b] pyridine

In analogy to the synthesis of Example 7A, 54.00 g (215.98 mmol) of 3-iodo-1H-pyrazolo [3,4-b] pyridine (synthesis described in WO 2006/130673 Example 4) were mixed with 50.18 g (237,578) 2,3- Implemented difluorobenzyl bromide. The crude product was mixed with ice-water, filtered off with suction and the precipitate was washed with isopropanol and pentane and then dried under high vacuum. There were obtained 73.00 g of the title compound (85% of theory).

LC-MS (Method 1): R _t = 1.13 min; MS (ESIpos): m / z = 372 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ = 5.79 (s, 2H), 7.04 (t, 1H), 7.14 - 7.20 (m, 1H), 7.33-7.43 (m, 2H), 7.98 (dd , 1H), 8.66 (dd, 1H). Example 35A

1 - (2,3-difluorobenzyl) -1 H -pyrazolo [3,4-b] pyridine-3-carbonitrile

In analogy to the synthesis of Example 8A, 72.00 g (194,002 mmol) of Example 34A were reacted. There were obtained 50.00 g (93% pure, 88% of theory) of the title compound. LC-MS (Method 3): R _t = 1.24 min; MS (ESIpos): m / z = 271 (M + H) ⁺

Tl NMR (400 MHz, DMSO-de): δ = 5.94 (s, 2H), 7.14-7.21 (m, 2H), 7.39-7.46 (m, 1H), 7.55 (dd, 1H), 8.51 (dd, 1H), 8.81 (dd, 1H). Example 36A 1- (2,3-Difluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboximidiimide acetate

In analogy to the synthesis of Example 9A, 49.00 g (181.318 mmol) of Example 35A were reacted. 29.00 g of the title compound were obtained (46% of theory).

LC-MS (Method 1): R _t = 0.62 min; MS (ESIpos): m / z = 288 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ = 1.81 (s, 3H), 5.88 (s, 2H), 7.04 (t, 1H), 7.13 - 7.19 (m, 1H), 7.36-7.45 (m , 2H), 8.63 (dd, 1H), 8.69 (dd, 1H).

Example 37A Ethyl {2- [1- (2,3-difluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] -4-hydroxypyrimidin-5-yl} acetate

15 g (43187 mmol) of Example 36A were reacted analogously to the procedure of Example 16A. 13.20 g of the title compound (69% of theory) were obtained. LC-MS (Method 1): R _t = 1.03 min; MS (ESIpos): m / z = 426 (M + H)

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.19 (t, 3H), 3.48 (s, 2H), 4.09 (q, 2H), 5.90 (s, 2H), 7.13-7.18 ( m, 2H), 7.36-7.43 (m, 1H), 7.47 (dd, 1H), 8.11 (s, 1H), 8.72-8.75 (m, 2H), 12.83 (s br, 1H). Example 38A

Ethyl {4-chloro-2- [1- (2,3-difluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} acetate

13.10 g (30.795 mmol) of Example 37A were reacted analogously to the procedure described in Example 17A. 12.10 g of the title compound (88% of theory) were obtained. LC-MS (Method 1): R _t = 1.23 min; MS (ESIpos): m / z = 444 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.21 (t, 3H), 3.96 (s, 2H), 4.15 (q, 2H), 5.95 (s, 2H), 7.07-7.09 ( t, 1H), 7.15-7.19 (m, 1H), 7.37-7.43 (m, 1H), 7.49 (dd, 1H), 8.71 (dd, 1H), 8.84 (dd, 1H), 8.96 (s, 1H) ,

Example 39A Ethyl 2- {4-chloro-2- [1- (2,3-difluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} -2- methylpropanoate

In analogy to Example 20A, 800 mg (1.802 mmol) of Example 38A were reacted with methyl iodide. There were obtained 1.00 g (purity 84%) of the title compound, which were reacted further without further purification. LC-MS (Method 1): R _t = 1.30 min; MS (ESIpos): m / z = 472 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.14 (t, 3H), 1.65 (s, 6H), 4.13 (q, 2H), 5.95 (s, 2H), 7.07 (t, 1H), 7.15-7.20 (m, 1H), 7.37-7.44 (m, 1H), 7.49 (dd, 1H), 8.72 (dd, 1H), 8.83 (dd, 1H), 9.06 (s, 1H).

Example 40A Ethyl 2- {4-azido-2- [1- (2,3-difluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} -2-methylpropanoate

1.00 g (about 1.80 mmol, 84% purity) of example 39A were reacted in analogy to example 18A. The title compound thus obtained was reacted further without further purification. A yield could not be determined because the azide-containing solution was not concentrated to dryness. LC-MS (method 1): R _t = 1.27 min; MS (ESIpos): m / z = 479 (M + H) ⁺ Example 41A

Ethyl 2- {4-amino-2- [1- (2,3-difluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} -2-methylpropanoate

The solution obtained in Example 40A was hydrogenated in analogy to Example 19A. The crude compound thus obtained (0.863 g, about 94% purity) was used without further purification in the next stage.

LC-MS (Method 1): R _t = 0.90 min; MS (ESIpos): m / z = 453 (M + H) ⁺ Example 42A 4-ethyl-1-methyl-2- (cyclopropylcarbonyl) butanedioate

In analogy to Example 24A, 2.00 g (14,069 mmol) of methyl 3-cyclopropyl-3-oxopropionate were reacted. There were obtained 3.62 g (about 80% purity) of the title compound, which was used without further purification in the next stage.

LC-MS (Method 1): R _t = 0.78 min; MS (ESIpos): m / z = 229 (M + H) ⁺ Example 43A

{4-Cyclopropyl-2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] -6-hydroxypyrimidin-5-yl} acetic acid

In analogy to Example 16A, 3.74 g (12,234 mmol) of Example 1A and 3.21 1 g of Example 42A were reacted. After working up, 763 mg (14% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.95 min; MS (ESIpos): m / z = 420 (M + H)

Example 44A

Methyl {4-cyclopropyl-2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] -6-hydroxypyrimidin-5-yl} acetate

762 mg (1.817 mmol) of Example 43A were initially charged in methanol (20 ml) and treated with 3 drops of conc. Sulfuric acid added. A slurry was obtained which could be stirred again by further addition of methanol (15 ml). It was heated to reflux for 1 h. After cooling, the product was filtered off with suction and washed with methanol and dried under high vacuum. 685 mg (87% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.07 min; MS (ESIpos): m / z = 434 (M + H) ⁺

Tl NMR (400 MHz, DMSO-de): δ [ppm] = 1.01-1.05 (m, 2H), 1.16-1.19 (m, 2H), 2.12-2.16 (m, 1H), 3.63 (s, 3H) , 3.72 (s, 2H), 5.85 (s, 2H), 7.14 (t, 1H), 7.20-7.25 (m, 1H), 7.31-7.39 (m, 2H), 7.49 (dd, 1H), 8.55 (dd , 1H), 8.70 (dd, 1H), 12.57 (s br, 1H).

Example 45A

Methyl {4-chloro-6-cyclopropyl-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4- b] pyridin-3-yl] pyrimidin-5-yl} acetate

683 mg (1.576 mmol) of Example 44A were initially charged in phosphoryl chloride (2.423 ml), treated with 470 mg (3.151 mmol) of diethylaniline and heated to 90 ° C for 2 days. After cooling, the mixture was added to warm water, the resulting precipitate was filtered off with suction and washed with water and dried under high vacuum. 724 mg (100% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.25 min; MS (ESIpos): m / z = 452 (M + H) ⁺

Example 46A

Methyl 2- {4-chloro-6-cyclopropyl-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} -2-methylpropanoate

In analogy to Example 20A, 712 mg (1576 mmol) of Example 45A were reacted with methyl iodide. There were 867 mg (about 75% purity) of the title compound, which were used without further purification in the next step.

LC-MS (Method 1): R _t = 1.39 min; MS (ESIpos): m / z = 480 (M + H) ⁺ Example 47A

Methyl 2- {4-azido-6-cyclopropyl-2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} -2- methylpropanoate

867 mg (about 1.355 mmol) of Example 46A were reacted in analogy to the procedure of Example 18A. The title compound thus obtained was used in the next step without further purification. A yield was not determined because the azide-containing solution was not concentrated to dryness.

LC-MS (method 1): R _t = 1.31 min; MS (ESIpos): m / z = 487 (M + H)

Example 48A Ethyl 2- {4-chloro-2- [1- (2,4-difluorobenzyl) -1H-pyrazolo [3,4- b] pyridin-3-yl] pyrimidin-5-yl} -2-methylpropanoate

In analogy to Example 20A, 800 mg (1.802 mmol) of Example 33A were reacted with methyl iodide. There were obtained 1.05 g (78% purity) of the title compound, which were used without further purification in the next step. LC-MS (method 1): R _t = 1.31 min; MS (ESIpos): m / z = 472 (M + H) ⁺

Example 49A

Ethyl 2- {4-azido-2- [1- (2,4-difluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} -2-methylpropanoate

1.05 g (about 1.736 mmol) of Example 48A were reacted in analogy to the procedure of Example 18A. The title compound thus obtained was used in the next step without further purification. A yield was not determined because the azide-containing solution was not concentrated to dryness. LC-MS (method 1): R _t = 1.27 min; MS (ESIpos): m / z = 479 (M + H) ⁺ Example 50A

Ethyl 2- {4-amino-2- [1- (2,4-difluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} methylpropanoate

The solution obtained under Example 49A was hydrogenated in analogy to the procedure of Example 19A. The title compound thus obtained (0.755 g, about 76% purity) was used without further purification in the next step.

LC-MS (Method 1): R _t = 0.91 min; MS (ESIpos): m / z = 453 (M + H) ⁺ Example 51A

2-methoxy-4-methyl-6-oxo-l, 4,5,6-tetrahydropyridin-3-carbonitrile

The synthesis of the compound is described: Heterocycles, 1985; 1135 - 1141.

Example 52A 2-Methoxy-6-oxo-4- (trifluoromethyl) -l, 4,5,6-tetrahydropyridine-3-carbonitrile

7.47 g (138.39 mmol) of sodium methoxide in methanol (85 ml) were initially taken with ice-cooling and treated in portions with 6.04 g (91.44 mmol) of malonodinitrile. 11.84 g (76.84 mmol) of methyl 4,4,4-trifluorocrotonate were then added dropwise with stirring, stirred at RT for 30 min and then heated to reflux for 1 h. The mixture was then concentrated to dryness in vacuo. The residue was added with water and extracted four times with ethyl acetate. The combined organic phases were dried with sodium sulfate, filtered and concentrated. Further purification was carried out by chromatography on silica gel (cyclohexane / ethyl acetate 3: 1). This gave 1.95 g of the title compound (11% of theory). LC-MS (Method 1): R _t = 0.61 min; MS (ESIpos): m / z = 221 (M + H) ⁺

Example 53A

4-Amino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5-methyl-5,8-dihydropyrido [2,3-d] pyrimidine 7 (6H) -one

2,174 g (7,112 mmol) of Example 1A and 1.3 g (7.823 mmol) of Example 51A were initially charged in 20 ml of methanol and then 423 mg (7.823 mmol) of sodium methoxide were added in portions at RT. The mixture was stirred for 10 min at RT and then heated overnight to reflux. After cooling, the reaction was treated with acetic acid (0.5 ml) and water (20 ml) and ice bath cooled. The precipitate was filtered off, washed with water and methanol and then dried under high vacuum. 2.51 g of the title compound were obtained (87% of theory).

LC-MS (Method 1): R _t = 0.85 min; MS (ESIpos): m / z = 404 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.04 (d, 3H), 2.31 (d, 1H), 2.79 (dd, 1H), 3.13-3.19 (m, 1H), 5.81 ( s, 2H), 6.93 (br s, 2H), 7.12-7.25 (m, 3H), 7.34-7.37 (m, 2H), 8.62 (dd, 1H), 9.14 (dd, 1H), 10.56 (s, 1H ).

Example 54A

4-Amino-2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] -5- (trifluoromethyl) -5,8-dihydropyrido [2,3-d ] pyrimidin-7 (6H) -one

694 mg (2.271 mmol) of Example 1A and 500 mg (2.271 mmol) of Example 14A were initially charged in 10 ml of tert-butanol and then treated at RT with 305 mg (2.725 mmol) of potassium tert-butoxide in portions. The mixture was stirred for 10 min at RT and then heated for 2 days to reflux. After cooling, the reaction mixture was treated with water and ethyl acetate. The precipitate was sucked off. The filtrate was concentrated, treated with a little ethyl acetate and diethyl ether and the resulting precipitate was filtered off with suction. The combined solids fractions were then dried under high vacuum. 588 mg of the title compound were obtained (53% of theory).

LC-MS (Method 1): R _t = 0.92 min; MS (ESIpos): m / z = 458 (M + H) 1 H NMR (400 MHz, DMSO-d 6): δ [ppm] = 2.63 (d, 1H), 3.19 (dd, 1H), 4.16-4.20 ( m, 1H), 5.83 (s, 2H), 7.13-7.40 (m, 7H), 8.63 (dd, 1H), 9.15 (dd, 1H), 10.85 (s, 1H). Example 55A

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

5.00 g (12.394 mmol) of Example 13A were initially charged in iso-pentyl nitrite (35.87 ml) and diiodomethane (1.16 mol, 93.71 ml) and heated to 85 ° C. for 12 h. After cooling, it was filtered off from solids, concentrated and then purified by chromatography on silica gel (mobile phase: first cyclohexane-dichloromethane gradient, then dichloromethane-methanol gradient). There were obtained 5.50 g of the title compound (67% of theory). LC-MS (method 1): R _t = 1.19 min; MS (ESIpos): m / z = 515 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.42 (s, 6H), 5.88 (s, 2H), 7.13-7.26 (m, 3H), 7.34- 7.38 (m, IH), 7.48 (dd, IH), 8.69 (dd, IH), 8.79 (dd, IH), 11.78 (s br, IH).

Example 56A

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

3,325 g (7,890 mmol) of Example 14A were reacted in analogy to Example 55A. There was obtained 3.65 g of the title compound (87% of theory, 61% purity).

LC-MS (Method 1): R _t = 1.26 min; MS (ESIpos): m / z = 533 (M + H) ⁺ 'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.42 (s, 6H), 5.87 (s, 2H), 7.14- 7.26 (m, 3H), 7.37 (m, 1H), 8.48 (dd, 1H), 8.77 (dd, 1H), 11.76 (s br, 1H).

Example 57A

2 '- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -4'-iodo-4,5-dihydrospiro [furan-3,5'-pyrrolo [2 , 3-d] pyrimidin] -6 '(7'h) -one

563 mg (1.305 mmol) of the compound obtained under Example 15A were initially charged in 1, 2-dimethoxyethane (7.5 ml) and then with 339 mg (1.305 mmol) cesium iodide, 165 mg (0.652 mmol) Iodine and 74 mg (0.391 mmol) of copper (I) iodide. Thereafter, iso-pentyl nitrite (1.04 ml) was added and heated at 60 ° C for 2 days. After cooling, the mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was washed twice with 5% aqueous sodium thiosulfate solution and once with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by preparative HPLC (acetonitrile / water (+0.05% formic acid) gradient). 98 mg of the title compound were obtained (14% of theory).

LC-MS (Method 1): R _t = 1.07 min; MS (ESIpos): m / z = 543 (M + H) ⁺

'H-NMR (400 MHz, DMSO-ds): δ [ppm] = 2.23-2.29 (m, IH), 2.50 (IH, partially under DMSO peak), 3.93 (d, IH), 4.04 (q, IH) , 4.16 (d, IH), 4.21-4.27 (m, IH), 5.88 (s, 2H), 7.13-7.26 (m, 3H), 7.34-7.40 (m, IH), 7.49 (dd, IH), 8.69 (dd, IH), 8.80 (dd, IH), 11.80 (s br, IH).

Example 58A

2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -4-iodo-5-methyl-5,8-dihydropyrido [2,3-d] pyrimidine 7 (6H) -one

530 mg (1314 mmol) of Example 53A were reacted analogously to the procedure of Example 57A. 171 mg of the title compound were obtained (25% of theory).

LC-MS (Method 1): R _t = 1.13 min; MS (ESIpos): m / z = 515 (M + H) ⁺

'H-NMR (400 MHz, DMSO-ds): δ [ppm] = 1.12 (d, 3H), 2.46 (partial signal under solvent, IH), 3.01 (dd, IH), 3.16-3.19 (m, IH) , 5.88 (s, 2H), 7.13-7.14 (m, 2H), 7.24 (t, IH), 7.34-7.38 (m, IH), 7.45 (dd, IH), 8.67 (dd, IH), 9.09 (dd , IH), 11.33 (s, IH). Example 59A

2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] -4-iodo-5- (trifluoromethyl) -5,8-dihydro-pyrido [2,3 -d] pyrimidin-7 (6H) -one

556 mg (1.216 mmol) of Example 54A were reacted in analogy to Example 57A. There were obtained 605 mg of the title compound (87% of theory).

LC-MS (Method 1): R _t = 1.15 min; MS (ESIpos): m / z = 569 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 2.74 (d, 1H), 3.38 (dd, 1H), 4.17-4.24 (m, 1H), 5.90 (s, 2H), 7.14- 7.17 (m, 2H), 7.24 (t, 1H), 7.33-7.40 (m, 1H), 7.48 (dd, 1H), 8.69 (dd, 1H), 9.01 (dd, 1H), 11.60 (s, 1H) ,

Example 60A

5-fluoro-l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridin-3-carboximidohydrazid

23,000 g (66.22 mmol) of Example 9A were dissolved in 322 ml of ethanol and treated at 0 ° C with 26,804 g (264.88 mmol) of triethylamine and 6.027 g (66.22 mmol) of hydrazine hydrate (55% solution in water). The mixture was stirred overnight at rt and then added to 1.715 l of a 10% aqueous sodium chloride solution and extracted twice with ethyl acetate. The combined organic phases were washed with 10% aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified on silica gel (eluent: dichloromethane / methanol, 95: 5). There were obtained 15,000 g (75% of theory) of the title compound.

LC-MS (Method 1): R _t = 0.58 min; MS (ESIpos): m / z = 303 (M + H) ⁺ H-NMR (400 MHz, DMSO-de): δ [ppm] = 5.38 (s, 2H), 5.54 (s, 2H), 5.72 ( s, 2H), 7.10-7.15 (m, 2H), 7.20-7.25 (m, 1H), 7.32-7.38 (m, 1H), 8.21 (dd, 1H), 8.64 (dd, 1H).

Example 61A

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

1,780 g (38.97 mmol) of Example 60A were dissolved in 353 ml of ethanol and treated with 14,667 g (77.94 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate (described in J. Am. Chem. Soc. 124 (14), 3680-3691; 2002). The mixture was heated to reflux overnight. After cooling, the solid was filtered off with suction, washed with a little ethanol and the filtrate was concentrated. The residue was purified on silica gel (eluent: dichloromethane / acetone, 95: 5). There was obtained 10,000 g (58% of theory) of the title compound.

LC-MS (Method 1): R _t = 1.07 min; MS (ESIpos): m / z = 441 (M + H) 'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.45 (s, 6H), 3.56 (s, 3H), 5.91 (s, 2H), 7.16 (dt, 1H), 7.22-7.31 ( m, 2H), 7.36-7.41 (m, 1H), 8.41 (dd, 1H), 8.83 (dd, 1H), 14.58 (s, 1H).

Example 62A 1- (2,3-Difluorobenzyl) -5-fluoro-3-iodo-1H-pyrazolo [3,4-b] pyridine

10,000 g (38.02 mmol) of Example 6A were dissolved in 270 ml of dimethylformamide, and 8,858 g (41.82 mmol) of 1- (bromomethyl) -2,3-difluorobenzene and 13,627 g (41.82 mmol) of cesium carbonate were added. It was stirred for 2 h at room temperature and then ethyl acetate and water were added. The organic phase was separated and the aqueous phase extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. There were obtained 8,460 g (56% of theory) of the target compound. The residue was used without further purification in the next step.

LC-MS (Method 1): R _t = 1.24 min; MS (ESIpos): m / z = 390 (M + H) ⁺ 'H-NMR (400 MHz, DMSO-de): δ [ppm] = 5.78 (s, 2H), 7.03-7.08 (m, 1H), 7.15-7.20 (m, 1H), 7.36-7.44 (m, 1H), 7.95 (dd, 1H), 8.72 (t, 1H).

Example 63A 1- (2,3-Difluorobenzyl) -5-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carbonitrile

8,470 g (21.25 mmol) of Example 62A were dissolved in 59 ml of dimethyl sulfoxide and treated with 2.093 g (23.37 mmol) of copper (I) cyanide. The mixture was stirred for 1.5 h at 150 ° C, then diluted with methanol and filtered through Celite. It was washed with methanol and the filtrate concentrated on Rotationsverdempfer. The residue was taken up in ethyl acetate and washed twice with a mixture of saturated aqueous ammonium chloride solution and 25% strength aqueous ammonia solution (v / v = 3: 1) and with saturated aqueous sodium chloride solution. The organic phase was separated, dried over sodium sulfate and concentrated on a rotary evaporator. 5,750 g (89% of theory, purity about 94%) of the target compound were obtained. The residue was used without further purification in the next step.

LC-MS (Method 1): R _t = 1.32 min; MS (ESIpos): m / z = 289 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 5.93 (s, 2H), 7.13-7.24 (m, 2H), 7.40-7.47 (m, 1H), 8.53 (dd, 1H), 8.88 (dd, 1H). Example 64A

1 - (2,3-difluorobenzyl) -5-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboximidamide acetate

0.433 g (18.81 mmol) of sodium were stirred in portions in 133 ml of methanol. After completion of the gas evolution 5,750 g (18.81 mmol) of Example 63A were added in portions and the mixture was stirred for 2 h at room temperature. There were added 1,208 g (22.57 mmol) of ammonium chloride and 4.394 g (73.17 mmol) of acetic acid and the mixture was refluxed overnight. After cooling, the batch was concentrated on a rotary evaporator and the residue was combined with ethyl acetate and 1N sodium hydroxide solution, forming a solid. The solid was filtered off with suction, washed with ethyl acetate and dried under high vacuum. 5,860 g (83% of theory) of the target compound were obtained.

LC-MS (Method 1): R _t = 0.60 min; MS (ESIpos): m / z = 306 (MC ₂ H ₃ O ₂ ) ⁺ 'H-NMR (400 MHz, DMSO-de): δ = 1.83 (s, 3H), 5.85 (s, 2H), 7.04 ( t, 1H), 7.13-7.19 (m, 1H), 7.36-7.43 (m, 1H), 8.44 (dd, 1H), 8.45 (s br, 2H), 8.74 (s, 1H).

Example 65A 1- (2,3-Difluorobenzyl) -5-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboximidohydrazide

5,680 g (15.55 mmol) of the compound from Example 64A were dissolved in 76 ml of ethanol and treated at 0 ° C with 6,293 g (62.19 mmol) of triethylamine and 0.973 g (15.55 mmol) of hydrazine hydrate (80% solution in water). The mixture was stirred at RT overnight and then concentrated by rotary evaporation. 5,850 g (99% of theory, purity 84%) of the title compound were obtained. The product was used without further purification in the next step. LC-MS (Method 1): R _t = 0.68 min; MS (ESIpos): m / z = 321 (M + H) ⁺

Example 66A

Methyl 2- {4- [1- (2,3-difluorobenzyl) -5-fluoro-1H-pyrazolo [3,4-b] pyridin-3-yl] -2-hydroxyphenyl} -2-methylpropanoate

5,850 g (15.40 mmol) of the compound from Example 65A were dissolved in 140 ml of ethanol, with 5,795 g (30.80 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate (described in J. Am. Chem. Soc., 124 (14 ), 3680-3691, 2002) and stirred overnight. The resulting solid was filtered off with suction, washed with a little ethanol and the filtrate was concentrated. The residue was stirred with diethyl ether, filtered off, washed with a little diethyl ether and dried under high vacuum. There were obtained 2,060 g (29% of theory) of the title compound.

LC-MS (Method 1): R _t = 1.03 min; MS (ESIpos): m / z = 459 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.45 (s, 6H), 3.56 (s, 3H), 5.94 (s, 2H), 7.10-7.21 (m, 2H), 7.42 ( q, 1H), 8.42 (dd, 1H), 8.83 (s, 1H), 14.53 (s br, 1H).

Example 67A 1- (2,4-Difluorobenzyl) -5-fluoro-3-iodo-1H-pyrazolo [3,4-b] pyridine

10,000 g (38.02 mmol) of Example 6A were dissolved in 270 ml of dimethylformamide and 8658 g (41.82 mmol) of 1- (bromomethyl) -2,4-difluorobenzene and 13,627 g (41.82 mmol) of cesium carbonate added. It was stirred for 2 h at room temperature and then ethyl acetate and water were added. The organic phase was separated and the aqueous phase extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. 8,340 g (53% of theory, purity about 93%) of the target compound were obtained. The residue was used without further purification in the next step.

LC-MS (Method 3): R _t = 1.45 min; MS (ESIpos): m / z = 390 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 5.71 (s, 2H), 7.07 (dt, 1H), 7.27 (dt, 1H), 7.33-7.39 (m, 1H), 7.94 ( dd, 1H), 8.72 (t, 1H). Example 68A

1 - (2,4-Difluorobenzyl) -5-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carbonitrile

8,340 g (20.07 mmol) of Example 67A were dissolved in 56 ml of dimethyl sulfoxide and treated with 1.977 g (22.07 mmol) of copper (I) cyanide. The mixture was stirred for 1.5 h at 150 ° C, then diluted with methanol and filtered through Celite. It was washed with methanol and the filtrate concentrated on Rotationsverdempfer. The residue was taken up in ethyl acetate and washed twice with a mixture of saturated aqueous ammonium chloride solution and 25% strength aqueous ammonia solution (v / v = 3: 1) and with saturated aqueous sodium chloride solution. The organic phase was separated, dried over sodium sulfate and concentrated on a rotary evaporator. 5,270 g (83% of theory, purity about 91%) of the target compound were obtained. The residue was used without further purification in the next step.

LC-MS (Method 1): R _t = 1.09 min; MS (ESIpos): m / z = 289 (M + H)

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 5.85 (s, 2H), 7.10 (dt, 1H), 7.30 (dt, 1H), 7.45-7.51 (m, 1H), 8.52 ( dd, 1H), 8.88 (t, 1H). Example 69 A 1- (2,4-Difluorobenzyl) -5-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboximidiimide acetate

0.383 g (16.68 mmol) of sodium were stirred in portions into 118 ml of methanol. After completion of gas evolution, 5,270 g (about 16.68 mmol) of Example 68A were added in portions and the mixture was stirred for 2 h at room temperature. 1.070 g (20.01 mmol) of ammonium chloride and 3.895 g (64.86 mmol) of acetic acid were added and the mixture was refluxed overnight. After cooling, the batch was concentrated on a rotary evaporator and the residue was combined with ethyl acetate and 1N sodium hydroxide solution, forming a solid. The solid was filtered off with suction, washed with ethyl acetate and dried under high vacuum. 5,640 g (93% of theory) of the target compound were obtained.

LC-MS (Method 1): R _t = 0.59 min; MS (ESIpos): m / z = 306 (MC ₂ H ₃ 0 ₂ ) ⁺

'H-NMR (400 MHz, DMSO-de): δ = 1.83 (s, 3H), 5.87 (s, 2H), 7.06 (t, 1H), 7.26-7.37 (m, 2H), 8.43 (dd, 1H ), 8.73 (s, 1H). Example 70A

1- (2,2-Difluorobenzyl) -5-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboximidohydrazide

5,640 g (15.44 mmol) of Example 69A were dissolved in 76 ml of ethanol and treated at 0 ° C with 6,249 g (61.76 mmol) of triethylamine and 0.966 g (15.44 mmol) of hydrazine hydrate (80% solution in water). The mixture was stirred at RT overnight and then concentrated by rotary evaporation. There were obtained 5.30 g (100% of theory, purity 93%) of the title compound. The product was used without further purification in the next step.

LC-MS (Method 1): R _t = 0.67 min; MS (ESIpos): m / z = 321 (M + H) ⁺

Example 71A

Methyl 2- {4- [1- (2,4-difluorobenzyl) -5-fluoro-1H-pyrazolo [3,4-b] pyridin-3-yl] -2-hydroxyphenyl} -2-methylpropanoate

5,300 g (about 15.42 mmol) of Example 69A were dissolved in 140 ml of ethanol, containing 5,805 g (30.85 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate (described in J. Am. Chem. Soc., 124 (14). , 3680-3691, 2002) and stirred overnight. The resulting solid was filtered off with suction, washed with a little ethanol and the filtrate was concentrated. The residue was stirred with diethyl ether, filtered off, washed with a little diethyl ether and dried under high vacuum. There were obtained 2,290 g (32% of theory) of the title compound.

LC-MS (Method 1): R _t = 1.03 min; MS (ESIpos): m / z = 459 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.44 (s, 6H), 3.55 (s, 3H), 5.86 (s, 2H), 7.07 (dt, 1H), 7.30 (dt, 1H), 7.42 (q, 1H), 8.43 (dd, 1H), 8.81 (s, 1H), 14.45 (s br, 1H). Example 72A

5-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5H-pyrrolo [2,3-d] pyrimidine-5,6 (7H) 5 oxime

700 mg (1,943 mmol) of Example 4 were suspended in acetic acid (14 ml) and treated with 281 mg (4.079 mmol) of sodium nitrite and a few drops of water. After 30 min at RT, water was added and a precipitate was filtered off, washed with water and then dried under high vacuum. 756 mg of the title compound (99% of theory) were obtained.

LC-MS (Method 1): R _t = 0.90 min; MS (ESIpos): m / z = 390 (M + H) ⁺ Example 73A

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

124 mg (0.319 mmol) of Example 72A were initially charged in trifluoroacetic acid (2.5 ml) and admixed with 41 mg (0.637 mmol) of zinc dust and stirred at RT overnight. It was then concentrated and the raw material (about 150 mg) used without further purification in the next stage.

LC-MS (Method 1): R _t = 0.69 min; MS (ESIpos): m / z = 376 (M + H) ⁺

Example 74A 1- (2,3-Difluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboximidohydrazide

In analogy to Example 70A, 10.00 g (28.791 mmol) of Example 36A were reacted. 11.74 g of the title compound were obtained in about 60% purity (81% of theory). The compound was used without further purification in the next step.

LC-MS (Method 1): R _t = 0.57 min; MS (ESIpos): m / z = 303 (M + H) Example 75A

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

Example 74A was dissolved in 300 ml of ethanol containing 8,037 g (42,710 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate (described in J. Am. Chem. Soc. 124 (14), 10.67 g (about 21.355 mmol). , 3680-3691, 2002) and stirred at 50 ° C overnight. After cooling, it was filtered from a precipitate and washed with ethanol. The residue was concentrated and then taken up in methanol (50 ml) and acetonitrile (50 ml) and purified by preparative HPLC (acetonitrile-water gradient). There was obtained 0.75 g (8% of theory) of the title compound.

LC-MS (Method 1): R _t = 0.98 min; MS (ESIpos): m / z = 441 (M + H) ⁺ Example 76A

1 - (2,4-Difluorobenzyl) -1 H -pyrazolo [3,4-b] pyridine-3-carboximidohydrazide

In analogy to Example 70A, 10.00 g (28.791 mmol) of Example 31A were reacted. This gave 9.31 g of the title compound in about 82% purity (87% of theory). The compound was used without further purification in the next step.

LC-MS (Method 1): R _t = 0.56 min; MS (ESIpos): m / z = 303 (M + H) ⁺ Example 77 A

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

6.80 g (about 18,446 mmol) of Example 76A were dissolved in 272 ml of ethanol, with 6,942 g (36,892 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate (described in J. Am. Chem. Soc., 124 (14). , 3680-3691, 2002) and stirred at 50 ° C overnight. After cooling, it was filtered from a precipitate and washed with ethanol. The residue was taken up in a lot of ethanol, whereupon a solid formed again. This was filtered off and washed with ethanol and diethyl ether. The solid was dried to give the title compound 2.21 g (26% of theory). The filtrate was concentrated and then purified by preparative HPLC (acetonitrile-water: water + 1% TFA-40: 55: 5). An additional 0.64 g (7% of theory) of the title compound was obtained. A total of 2.85 g (33% of theory) of the title compound was obtained.

LC-MS (Method 1): R _t = 1.03 min; MS (ESIpos): m / z = 441 (M + H) ⁺

Example 78A 5-Fluoro-3-iodo-1- (2,3,6-trifluorobenzyl) -1H-pyrazolo [3,4-b] pyridine

In DMF (170 ml), 10.0 g (38,021 mmol) of the compound from Example 6A were initially charged and then 9.41 g (41,823 mmol) of 2,3,6-trifluorobenzylbromide and 13.62 g (41.82 mmol) of cesium carbonate were added. The mixture was stirred at RT overnight. Subsequently, the reaction mixture was added to water (200 ml) and stirred for 15 minutes. A precipitate was filtered off, which was washed with water and then dried under high vacuum. 12.1 g of the title compound were obtained (78% of theory).

LC-MS (method 1): R _t = 1.24 min

MS (ESIpos): m / z = 408 (M + H) ⁺ 1 H NMR (400 MHz, DMSO-ds): δ = 5.78 (s, 2H), 7.16 - 7.22 (m, 1H), 7.51 - 7.59 ( m, 1H), 7.92 (dd, 1H), 8.73 (t, 1H).

Example 79A

5-Fluoro-1- (2,3,6-trifluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carbonitrile

In analogy to Example 8A, 12.1 g (29.72 mmol) of Example 78A were reacted. There were obtained 9.35 g of the title compound in 79% purity (81% of theory).

LC-MS (method 1): R _t = 1:08 min

MS (ESIpos): m / z = 307 (M + H) 1H-NMR (400 MHz, DMSO-d6): δ = 5.91 (s, 2H), 7.21 - 7.23 (m, 1H), 7.57 - 7.61 (m, 1H), 8.51 (dd, 1H), 8.89 (t, 1H).

Example 80A

5-Fluoro-1- (2,3,6-trifluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboximidiimide acetate

x CHgCOOH

In analogy to Example 9A, 9.1 g of the crude compound of Example 79A were reacted. This gave 7.77 g of the title compound (86% of theory).

LC-MS (Method 1): R _t = 0.61 min

MS (ESIpos): m / z = 324 (M + H) ⁺ Example 81A

5-Fluoro-1- (2,3,6-trifluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboximidohydrazide

In analogy to the synthesis of Example 70A, 7.77 g (20.271 mmol) of Example 80A were reacted. There were obtained 6.85 g of the title compound (99% of theory). The compound was used without further purification in the next step. LC-MS (Method 1): R _t = 0.59 min; MS (ESIpos): m / z = 339 (M + H)

Example 82A

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

6.85 g (20.271 mmol) of the compound from Example 81A were dissolved in 300 ml of ethanol, with 7.629 g (40.542 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate (described in J. Am. Chem. Soc. 124 (14 ), 3680-3691, 2002) and stirred overnight at 50 ° C. After cooling, it was filtered from a precipitate and washed with ethanol. The filtrate was concentrated and then purified by preparative HPLC (methanol: water 75:25). There was obtained 3.30 g (33% of theory) of the title compound.

LC-MS (Method 3): R _t = 1.24 min; MS (ESIpos): m / z = 477 (M + H) ⁺ Example 83A

Ethyl {2- [5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -4-hydroxypyrimidin-5-yl} acetate

2.00 g (5.73 mmol) of Example 9A and 1.42 g (6.58 mmol) of diethyl 2-formylbutandioate (synthesis described in WO 2005/73234, page 43) were initially charged in 50 ml of ethanol. Subsequently, 4.27 ml of sodium ethylate solution (21% strength in ethanol, 11.5 mmol) were added dropwise. Then it was heated to reflux for 9 h. After cooling, the reaction mixture was treated with 25 ml of water and then with 1N hydrochloric acid. The resulting precipitate was filtered off with suction and washed successively with methanol (20 ml) and with diethyl ether (20 ml). After drying under high vacuum, 1.53 g of the title compound were obtained (63% of theory).

LC-MS (Method 1): R _t = 1.04 min; MS (ESIpos): m / z = 426 (M + H) ⁺ H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.19 (t, 3H), 3.48 (s, 2H), 4.09 ( q, 2H), 5.86 (s, 2H), 7.16 (t, 1H), 7.24 (t, 1H), 7.31-7.34 (m, 2H), 8.11 (s br, 1H), 8.48 (d, 1H), 8.78 (s, 1H), 12.88 (s br, 1H).

Example 84A

Ethyl {4-chloro-2- [5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4- b] pyridin-3-yl] pyrimidin-5-yl} acetate

1.53 g (3.60 mmol) of Example 83A were initially charged in 3.35 ml (36.0 mmol) of phosphoryl chloride. Then, 0.684 ml (5.40 mmol) of N.N-dimethylaniline was added. Subsequently, lh was reacted in an oil bath at 150 ° C. The volatile components were separated on a rotary evaporator and then the residue was carefully stirred into 50 ml of 2M aqueous sodium carbonate solution. The mixture was stirred for 15 min and the solid filtered off. The solid was taken up in ethyl acetate, washed with saturated aqueous sodium chloride solution and the organic phase was dried with magnesium sulfate. The solvent was removed by distillation under reduced pressure and the residue was dried overnight under high vacuum. There was thus obtained 1.44 g of the title compound (90% of theory).

LC-MS (Method 1): R _t = 1.28 min; MS (ESIpos): m / z = 444 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.21 (t, 3H), 3.99 (s, 2H), 4.15 (q, 2H), 5.90 (s, 2H), 7.17 (dt, 1H), 7.21-7.31 (m, 2H), 7.38 (m, 1H), 8.55 (dd, 1H), 8.79 (dd, 1H), 8.96 (s, 1H).

Example 85A Ethyl 1- {4-chloro-2- [5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4- b] pyridin-3-yl] pyrimidin-5-yl} cyclopropanecarboxylate

1.44 g (3.24 mmol) of Example 84A were initially charged in 40 ml of THF / DMF (v / v = 1/1). Then, 410 mg (16.2 mmol, 95%) of sodium hydride was added in portions. The resulting solution was stirred for about 30 minutes (until gas evolution ceased). Then, 0.587 ml (6.81 mmol) of 1,2-dibromoethane was added and stirred at room temperature for 1 h. The reaction mixture was hydrolyzed with 50 ml of water and extracted with 50 ml of ethyl acetate. Then the organic phase was washed with 50 ml of water. The combined aqueous phases were extracted with ethyl acetate (2 × 30 ml) and then the combined organic phases were washed with saturated aqueous sodium chloride solution. After drying over magnesium sulfate, the solvent was removed on a rotary evaporator. This gave 1.51 g of the title compound in about 80% purity (yield 79% of theory). The raw material was used without further processing in the next stage.

LC-MS (Method 1): R _t = 1.36 min; MS (ESIpos): m / z = 470 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.10 (t, 3H), 1.46 (m, 2H), 1.65 (m, 2H), 4.08 (q, 2H), 5.90 (s, 2H), 7.17 (t, 1H), 7.21-7.29 (m, 2H), 7.37 (m, 1H), 8.53 (dd, 1H), 8.79 (m, 1H), 8.94 (s, 1H).

Example 86A

Ethyl 1- {4-azido-2- [5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} cyclopropanecarboxylate

1.51 g (2.57 mmol) of Example 85A were initially charged in 30 ml of DMF. Then 217 mg (3.34 mmol) of sodium azide were added. The mixture was then stirred at 60 ° C overnight. After cooling, the reaction mixture was added with 150 ml of water and extracted with ethyl acetate (3x70 ml). Then the combined organic phases were washed with saturated aqueous sodium chloride solution. After drying with magnesium sulfate, the solvent was removed on a rotary evaporator. This gave 1.15 g of the title compound in about 68% purity (93% of theory) contained. The raw material was used without further processing in the next stage. LC-MS (Method 1): R _t = 1.33 min; MS (ESIpos): m / z = 477 (M + H) ⁺ Example 87A

Ethyl 1 - {4-amino-2- [5-fluoro-1 - (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} cyclopropanecarboxylate

1.15 g (2.41 mmol) of Example 86A were initially charged in 30 ml of DMF. Then, 500 mg (10%) of palladium on charcoal was added. Hydrogen pressure was then hydrogenated at 1 atmosphere for 3 h. The reaction mixture was filtered through Celite. It was washed with DMF and the volatile components were separated on a rotary evaporator. The crude material thus obtained was dried in a high vacuum overnight. Thus, 1.28 g of crude material was obtained, which contained the title compound in about 90% purity (LC-MS). The material thus obtained was used without further purification.

LC-MS (Method 3): R _t = 1.11 min; MS (ESIpos): m / z = 451 (M + H) ⁺

Exemplary embodiments: Example 1

2- [l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b ^

d] pyrimidin-6-one

1.00 g (1944 mmol) of Example 55A were added in 425 mg of palladium on carbon (10%) in DMF (50 ml) and hydrogenated for 4 hours at normal hydrogen pressure. It was then filtered through Celite and concentrated to dryness. The residue was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). 500 mg of the title compound were obtained (66% of theory).

LC-MS (Method 1): R _t = 1.00 min; MS (ESIpos): m / z = 389 (M + H) ⁺

Tl NMR (400 MHz, DMSO-de): δ [ppm] = 1.38 (s, 6H), 5.86 (s, 2H), 7.13-7.17 (m, 1H), 7.21-2.26 (m, 2H), 7.34 -7.39 (m, 1H), 7.44 (dd, 1H), 8.64 (s, 1H), 8.67 (dd, 1H), 8.87 (dd, 1H), 11.61 (s br, 1H). Example 2

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

1.74 g (about 1,944 mmol) of Example 56A were reacted in analogy to Example 1. 644 mg of the title compound were obtained (78% of theory).

LC-MS (Method 1): R _t = 1.10 min; MS (ESIpos): m / z = 407 (M + H) ⁺ Tl NMR (400 MHz, DMSO-de): δ [ppm] = 1.38 (s, 6H), 5.85 (s, 2H), 7.14-7.18 (m, 1H), 7.21-2.28 (m, 2H), 7.35-7.40 (m, 1H), 8.59 (dd, 1H), 8.63 (s, 1H), 8.75 (dd, 1H), 11.58 (s br, 1H).

Example 3

2 '- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -4,5-dihydrospiro [furan-3,5'-pyrrolo [2,3-d] pyrimidine] -6 '(7'H) -one

96 mg (0.177 mmol) of Example 57A were reacted in analogy to Example 1. There was obtained 51 mg of the title compound (68% of theory). LC-MS (Method 1): R _t = 0.92 min; MS (ESIpos): m / z = 417 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 2.23-2.29 (m, 1H), 2.34-2.41 (m, 1H), 3.89 (d, 1H), 3.97 (d, 1H), 4.07-4.11 (m, 1H), 4.12-4.18 (m, 1H), 5.86 (s, 2H), 7.13-7.17 (t, 1H), 7.21-7.26 (m, 2H), 7.34-7.39 (m, 1H ), 7.44 (dd, 1H), 8.57 (s, 1H), 8.67 (dd, 1H), 8.87 (dd, 1H), 11.72 (s br, 1H). Example 4

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

9.46 g (23.276 mmol) of Example 19A were initially charged in THF (400 ml) and treated with 2.612 g (23.726 mmol) of potassium tert-butoxide. It was stirred for 1 h at RT and then treated with water and adjusted to pH = 5 with acetic acid and then stirred for 10 min at RT. It was then extracted three times with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution. Thereafter, the organic phase was dried over sodium sulfate, filtered and concentrated to dryness. The residue was slurried in methanol and filtered with suction. The filter cake was washed several times with methanol and then dried under high vacuum. This gave 6.61 g of the title compound as a solid (78% of theory).

LC-MS (method 1): R _t = 0.82 min; MS (ESIpos): m / z = 361 (M + H) ⁺

Tl NMR (400 MHz, DMSO-de): δ [ppm] = 3.68 (s, 2H), 5.85 (s, 2H), 7.14-7.18 (m, 1H), 7.21-2.27 (m, 2H), 7.34 -7.38 (m, 1H), 7.42 (dd, 1H), 8.49 (s, 1H), 8.67 (dd, 1H), 8.88 (dd, 1H), 1 1.58 (s, 1H). Example 5

2 '- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] spiro [cyclopropane-l, 5'-pyrrolo [2,3-d] pyrimidine] -6' (7'h) -one

394 mg (0.913 mmol) of Example 22A were reacted in analogy to the procedure under Example 4. There were obtained 186 mg of the title compound (53% of theory).

LC-MS (Method 1): R _t = 0.95 min; MS (ESIpos): m / z = 387 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.64 (ddd, 2H), 1.86 (ddd, 2H), 5.85 (s, 2H), 7.16 (t, 1H), 7.22-7.27 ( m, 2H), 7.34-7.38 (m, 1H), 7.42 (dd, 1H), 8.39 (s, 1H), 8.67 (dd, 1H), 8.87 (dd, 1H), 11.78 (s br, 1H).

Example 6

3- [l- (2-Fluorberizyl) -lH-pyrazolo [3,4-b] pyridin-3-yl] -5,7-dihydro-6H-pyrrolo [2,3-e] [l, 2,4 ] triazine-6-one

Step (a): Methyl {3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5-hydroxy-1,2,4-triazine yl} acetate

5,950 g (14,441 mmol) of the compound from Example 23A were dissolved in 70 ml of ethanol and admixed with 3,351 g (20,929 mmol) of dimethyl 2-oxobutanedioate (described in Synth. Commun. 9 (7), 603-7, 1979). The mixture was heated to reflux overnight. After cooling, the solid was filtered off, washed with a little ethanol and dried under high vacuum (purity to LC / MS = 43%).

Step (b): Methyl {5-amino-3- [1- (2-fluorobenzyl) -LH-yrazolo [3,4-b] pyridin-3-yl] -1,2,4-triazine-6 yljacetat

1,100 g (1,199 mmol) of the intermediate from stage a) were admixed with 14 ml of phosphoryl chloride and stirred at 100 ° C. for 1.75 h. After cooling, the reaction mixture was stirred into 100 ml of concentrated ammonia solution. It was stirred for 20 min. At RT. The resulting precipitate was filtered off and washed with a little water and dried under high vacuum. Step (c): 3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4- b] pyridin-3-yl] -5,7-dihydro-6H-pyrrolof 2,3-e1,21,2 , 4 jtriazin-6-one

The intermediate from step b) was dissolved in 350 ml of methanol and treated with 20 drops of 1 N sodium hydroxide solution (pH = 6). The mixture was stirred at RT overnight and concentrated on a rotary evaporator. The residue was purified on silica gel (eluent: dichloromethane / methanol, 96: 4). 67 mg (15% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.83 min; MS (EIpos): m / z = 362 [M + H] ⁺ . 'H-NMR (400 MHz, DMSO-de): δ [ppm] = 5.03 (s, IH), 5.82 (s, 2H), 7.14-7.18 (m, IH), 7.21-2.25 (m, 2H), 7.34-7.42 (m, 2H), 8.65-8.67 (m, 2H), 11.53 (s br, IH), 13.55 (s br, IH).

Example 7

4- (difluoromethyl) -2- [1- (2-fluorobenz

6H-pyrrolo [2,3-d] pyrimidin-6-one

The crude product from Example 28A (1.24 g, about 1312 mmol) was hydrogenated analogously to the procedure of Example 19A. It was then filtered through Celite and concentrated. The residue was purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid). 101 mg of the title compound were obtained (17% of theory).

LC-MS (Method 1): R _t = 1.07 min; MS (EIpos): m / z = 439 [M + H] ⁺ .

H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.44 (s, 6H), 5.89 (s, 2H), 7.08-7.40 (m, 5H), 7.47 (dd, IH), 8.69 (dd , IH), 8.92 (dd, IH), 12.00 (s br, IH).

Example 8 2 '- [1- (2,4-Difluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] spiro [cyclopropane-l, 5'-pyrrolo [2,3-d] pyrimidine ] -6 '(7'H) -on

Step (a): Ethyl 1- {4-chloro-2- [1- (2,4-difluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-ylcyclopropanecarboxylate

0.80 g (1.802 mmol) of Example 33A were dissolved in 15 ml of DMF under argon, combined with 360 mg (9,012 mmol) of sodium hydride (60% suspension in mineral oil) and stirred at RT for 15 min. Subsequently, 1.015 g (5.407 mmol) of 1,2-dibromoethane were added and stirred at RT for 2 h. Water and saturated aqueous sodium chloride solution were added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. 848 mg (purity 54%, 54% of theory) of the intermediate product were obtained

Step (b): Ethyl 1- {4-amino-2- [1- (2,4-difluorobenzyl) -LH-yrazolo [3,4-bJ-pyridin-3-yl-pyrimidin-5-yl] cyclopropanecarboxylate

The intermediate from step a) was dissolved in 13 ml of DMF and admixed with 95 mg (1.461 mmol) of sodium azide. The reaction mixture was stirred for 7 h at 60 ° C and added after cooling to water. It was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, treated with 10 ml of DMF and the ethyl acetate removed at 80 mbar on a rotary evaporator. The product-containing DMF solution was mixed with 20 ml of DMF and treated with 250 mg of palladium (10% on charcoal) and hydrogenated at atmospheric pressure overnight. The reaction solution was filtered through Celite and the filter cake was washed with DMF. The combined organic phases were concentrated on a rotary evaporator.

Steps (c): 2 '- [1- (2, 4-Difluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] spiro [cyclopropane-1,5-pyrrolof 2,3 -dJ-pyrimidine] -6 '(7'H) -one The intermediate from stage b) was taken up in 20 ml of THF, combined under an argon atmosphere with 109 mg (0.974 mmol) of potassium tert-butoxide and stirred for 2 h at RT. The reaction mixture was treated with water and adjusted to pH = 5 with acetic acid. It was stirred for 10 min. At RT and the mixture extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 50: 50-> 70:30). 101 mg of the title compound were obtained (25% of theory).

LC-MS (Method 1): R _t = 0.93 min; MS (EIpos): m / z = 405 [M + H] ⁺ .

Tl NMR (400 MHz, DMSO-ds): δ [ppm] = 1.62-1.65 (m, 2H), 1.85-1.88 (m, 2H), 5.82 (s, 2H), 7.07 (dt, 1H), 7.29 (dt, 1H), 7.34-7.44 (m, 2H), 8.39 (s, 1H), 8.67 (d, 1H), 8.87 (d, 1H), 1.77 (s br, 1H).

Example 9

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

Step (a): Methyl 2- {3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5-hydroxy-1,2,3-triazine 6-yl} -2-methylpropanoate

6.00 g (14.562 mmol) of the compound from Example 23A were dissolved in 70 ml of ethanol and treated with 2,740 g (14,562 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate (described in J. Am. Chem. Soc. 124 (14 ), 3680-3691; 2002). The mixture was heated to reflux overnight. To the solid was filtered off with suction, washed with a little ethanol, the filtrate was concentrated and dried under high vacuum.

Step (b): 3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -7,7-dimethyl-5,7-dihydro-6H-pyrrolof 2, 3-e] [1, 2, 4] triazine-6-one The intermediate from step a) was admixed with 35 ml of phosphoryl chloride and stirred overnight. The reaction mixture was dissolved in 500 ml of acetonitrile and stirred with ice cooling in 300 ml of concentrated ammonia solution. The mixture was stirred for 2 h at RT and the reaction mixture was concentrated on a rotary evaporator. The residue was stirred with water and ethyl acetate and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (eluent: methanol / water, gradient 30:70 → 90:10). There were obtained 701 mg (25% of theory) of the title compound.

LC-MS (Method 1): R _t = 0.96 min; MS (EIpos): m / z = 405 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.45 (s, 6H), 5.89 (s, 2H), 7.15 (dt, 1H), 7.21-7.27 (m, 2H), 7.34- 7.40 (m, 1H), 7.48 (dd, 1H), 8.71 (dd, 1H), 8.86 (dd, 1H), 12.16 (s, 1H).

Example 10

2 '- [1- (2,3-Difluorobenzyl) -1H-pyrazolo [3,4- b] pyridin-3-yl] spiro [cyclopropane-l, 5'-pyrrolo [2,3-d] pyrimidine] - 6 '(7'h) -one

Step (a): Ethyl 1- {4-chloro-2- [1- (2,3-difluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-ylcyclopropanecarboxylate:

0.80 g (1.802 mmol) of the compound obtained in Example 38A were dissolved in 15 ml of DMF under argon, admixed with 360 mg (9,012 mmol) of sodium hydride (60% suspension in oil) and stirred at RT for 15 min. Subsequently, 1.015 g (5.407 mmol) of 1,2-dibromoethane were added and stirred at RT for 2 h. Water and saturated aqueous sodium chloride solution were added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. 902 mg (purity 70%, 75% of theory) of the intermediate product were obtained. Step (b): Ethyl 1- {4-amino-2- [1- (2,3-difluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-ylcyclopropanecarboxylate:

The intermediate from step a) was dissolved in 13 ml of DMF and mixed with 131 mg (2.020 mmol) of sodium azide. The reaction mixture was stirred for 7 h at 60 ° C and added after cooling to water. It was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, treated with 10 ml of DMF and the ethyl acetate removed at 80 mbar on a rotary evaporator. The product-containing DMF solution was mixed with 20 ml of DMF and treated with 250 mg of palladium (10% on carbon) and hydrogenated at atmospheric pressure for 2 h. The reaction solution was filtered through Celite and the filter cake was washed with DMF. The combined organic phases were concentrated on a rotary evaporator.

Steps (c): 2 '- [1- (2, 3-Difluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] spiro [cyclopropane-1,5-pyrrolof 2,3 -dJ-pyrimidine] -6 '(7'H) -one

The residue was taken up in 25 ml of THF, combined under an argon atmosphere with 151 mg (1.346 mmol) of potassium tert-butoxide and stirred for 2 h at RT. The reaction mixture was treated with water and adjusted to pH = 5 with acetic acid. The mixture was stirred at RT for 10 min and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (eluent: acetonitrile / water with 0.1% of> formic acid, gradient 50: 50-> 70:30). There were obtained 227 mg of the title compound (42% of theory).

LC-MS (Method 1): R _t = 0.93 min; MS (EIpos): m / z = 405 [M + H] 'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.62-1.65 (m, 2H), 1.85-1.88 (m, 2H), 5.90 (s, 2H), 7.06-7.10 (m, IH ), 7.15-7.21 (m, IH), 7.37-7.46 (m, 2H), 8.39 (s, IH), 8.68 (dd, IH), 8.88 (dd, IH), 11.78 (s br, IH).

Example 11 2- [1- (2,3-Difluorobenzyl) -1H-pyrazolo [3,4-b] py

d] pyrimidin-6-one

0.86 g (about 1,800 mmol) of the compound obtained under example 41A were reacted in analogy to the procedure under example 4. There were obtained 331 mg of the title compound (45% of theory). LC-MS (Method 1): R _t = 0.98 min; MS (EIpos): m / z = 407 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.38 (s, 6H), 5.91 (s, 2H), 7.05 (t, IH), 7.14-7.20 (m, IH), 7.36- 7.41 (m, IH), 7.44 (dd, IH), 8.65 (s, IH), 8.68 (dd, IH), 8.88 (dd, IH), 11.59 (s br, IH).

Example 12

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

The solution obtained in Example 47A was hydrogenated in analogy to Example 19A. After purification by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid), 48 mg of the title compound were obtained (7% of theory). LC-MS (Method 1): R _t = 1.14 min; MS (EIpos): m / z = 429 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.14-1.18 (m, 2H), 1.27-1.30 (m, 2H), 1.48 (s, 6H), 2.23-2.27 (m, IH ), 5.84 (s, 2H), 7.12-7.25 (m, 3H), 7.33-7.38 (m, IH), 7.45 (dd, IH), 8.39 (s, IH), 8.66 (dd, IH), 8.69 ( dd, IH), 11.52 (s br, IH).

Example 13 2- [1- (2,4-Difluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5,5-dimethyl-5,7-dihydro-6H-pyrrolo [2, 3-d] pyrimidin-6-one

0.75 g (about 1.269 mmol) of the compound obtained under example 50A were reacted in analogy to the procedure under example 4. 193 mg of the title compound were obtained (37% of theory).

LC-MS (Method 1): R _t = 0.97 min; MS (EIpos): m / z = 407 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.38 (s, 6H), 5.83 (s, 2H), 7.06 (ddd, 1H), 7.26-7.38 (m, 2H), 7.43 ( dd, 1H), 8.64 (s, 1H), 8.68 (dd, 1H), 8.87 (dd, 1H), 11.59 (s br, 1H).

Example 14

2- [l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridin-3-yl] -5-methyl-5,8-dihydro-pyrido [2,3-d] pyrirm

7 (6H) -one

168 mg (0.327 mmol) of Example 58A were reacted in analogy to Example 1. There were obtained 71 mg of the title compound (56% of theory).

LC-MS (Method 1): R _t = 0.95 min; MS (ESIpos): m / z = 389 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.27 (d, 3H), 2.43 (dd, 1H), 2.76 (dd, 1H), 3.21-3.27 (m, 1H), 5.85 ( s, 2H), 7.12-7.26 (m, 3H), 7.33-7.43 (m, 2H), 8.61 (s, 1H), 8.66 (dd, 1H), 9.04 (dd, 1H), 11.20 (s, 1H) ,

Example 15

2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5- (trifluoromethyl) -5,8-dihydropyrido [2,3-d] pyrimidine-7 ( 6H) -one

603 mg (1.061 mmol) of the compound obtained in Example 59A were reacted in analogy to Example 1. 174 mg of the title compound were obtained (37% of theory).

LC-MS (Method 1): R _t = 1.01 min; MS (ESIpos): m / z = 443 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 2.75 (d, 1H), 3.29 (signal partially under water signal, 1H), 4.32-4.40 (m, 1H), 5.87 (s, 2H) , 7.13-7.26 (m, 3H), 7.34-7.40 (m, 1H), 7.44 (dd, 1H), 8.68 (dd, 1H), 8.77 (s, 1H), 9.06 (dd, 1H), 11.55 (s , 1H).

Example 16

2- [l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridin-3-yl] -5H-pyrrolo [2,3-d] pyrirmdin-5,6 (7H) -dione

2.00 g (5.550 mmol) of Example 4 were initially charged in dioxane (200 ml) and treated with 3.079 g (27.751 mmol) of selenium dioxide and heated to reflux for 2 h. After cooling, it was filtered and the Filtrate was concentrated and purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 1: 1). 890 mg of the title compound were obtained (42% of theory).

LC-MS (Method 1): R _t = 0.93 min; MS (ESIpos): m / z = 375 (M + H) ⁺

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 5.91 (s, 2H), 7.17 (ddd, 1H), 7.21-7.26 (m, 1H), 7.27-7.31 (ddd, 1H), 7.35 -7.41 (m, 1H), 7.51 (dd, 1H), 8.72 (dd, 1H), 8.87 (s, 1H), 8.89 (dd, 1H), 12.21

(s, 1H).

Example 17

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

200 mg (0.534 mmol) of Example 16 were initially charged in THF (10 ml) at 0 ° C. and admixed with 0.356 ml (1.069 mmol) of methylmagnesium bromide (3M solution in diethyl ether). After 15 min at 0 ° C was warmed to RT for 1 h. Subsequently, the batch was added to saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic phases were combined, washed once with water and once with saturated aqueous sodium chloride solution. It was then dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 55 mg of the title compound were obtained (53% of theory).

LC-MS (Method 1): R _t = 0.81 min; MS (ESIpos): m / z = 391 (M + H) 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.50 (s, 3H), 5.86 (s, 2H), 6.29 (s, 1H), 7.16 (ddd, 1H), 7.21-7.26 (m , 2H), 7.34-7.39 (m, 1H), 7.44 (dd, 1H), 8.61 (s, 1H), 8.68 (dd, 1H), 8.87 (dd, 1H), 11.53 (s, 1H).

Example 18

2- [l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] p ^

pyrrolo [2,3-d] pyrimidin-6-one

150 mg (0.401 mmol) of Example 16 were initially charged in 1,2-dimethoxyethane (3 ml) at RT and admixed with 6 mg (0.04 mmol) of cesium fluoride. Subsequently, 177 μΐ (1 .202 mmol) (trifluoromethyl) trimethylsilane were added dropwise and the mixture was stirred overnight at RT. Thereafter, the following reagents were again added: 1,2-dimethoxyethane (2 ml), cesium fluoride (20 mg) and (trifluoromethyl) trimethylsilane (177 μΐ). After another night, cesium fluoride (20 mg) and (trifluoromethyl) trimethylsilane (2,404 ml, 0.5 M in THF) were added again. The batch was stirred for a further 2 days and then stood for 2 more days without stirring at RT. It was then concentrated and the residue was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). 8 mg of the title compound were obtained (4% of theory).

LC-MS (Method 1): R _t = 1.01 min; MS (ESIpos): m / z = 445 (M + H)

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 5.88 (s, 2H), 7.16 (t, 1H), 7.22-7.29 (m, 2H), 7.35-7.41 (m, 1H), 7.47 (dd, 1H), 8.61 (s, 1H), 8.15 (s, 1H), 8.71 (dd, 1H), 8.76 (s, 1H), 8.87 (dd, 1H), 12.28 (s, 1H). Example 19

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

9,700 g (22,025 mmol) of the compound from Example 61A was admixed with 50 ml of phosphoryl chloride and stirred at RT overnight. The reaction mixture was dissolved in 150 ml of acetonitrile and stirred with ice cooling into a mixture of 1337 ml of concentrated aqueous ammonia solution (35% strength) and 1300 ml of acetonitrile. It was stirred for 2 days at room temperature. Subsequently, 300 g of sodium chloride were added. It formed 2 phases. The organic phase was separated and concentrated to dryness. The residue was taken up in ethyl acetate (150 ml). It formed a precipitate, which was sucked off over a frit. It was washed three times with water and then three times with ethyl acetate (5 ml). The residue was dried under high vacuum. There were obtained 4.58 g (51% of theory) of the title compound. LC-MS (Method 1): R _t = 0.99 min; MS (EIpos): m / z = 408 [M + H]

Tl NMR (400 MHz, DMSO-de): δ [ppm] = 1.45 (s, 6H), 5.88 (s, 2H), 7.15-7.30 (m, 3H), 7.35-7.41 (m, 1H), 8.56 (dd, 1H), 8.79 (dd, 1H), 12.18 (s br, 1H).

Example 20

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

2.060 g (4.49 mmol) of the compound from Example 66A were admixed with 22 ml of phosphoryl chloride and stirred at RT overnight. The reaction mixture was dissolved in 100 ml of acetonitrile and stirred with ice cooling into 290 ml of concentrated aqueous ammonia solution (35% strength). The mixture was stirred for 2 h at room temperature, then for 7 h at 50 ° C and the reaction mixture was then concentrated on a rotary evaporator. The residue was stirred with water and ethyl acetate and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was stirred with diethyl ether, filtered off, washed with a little diethyl ether and dried under high vacuum. 748 mg (37% of theory) of the title compound were obtained.

LC-MS (Method 3): R _t = 1.23 min; MS (EIpos): m / z = 426 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.45 (s, 6H), 5.94 (s, 2H), 7.09-7.21 (m, 2H), 7.41 (q, 1H), 8.57 ( dd, 1H), 8.80 (s, 1H), 12.18 (s br, 1H).

Example 21 3- [1- (2,4-Difluorobenzyl) -5-fluoro-1H-pyrazolo [3,4-b] pyridin-3-yl] -7,7-dimethyl-5,7-dihydro-6H- pyrrolo [2,3-e] [1, 2,4] triazine-6-one

2,290 g (5,000 mmol) of the compound from Example 71 A were admixed with 25 ml of phosphoryl chloride and stirred at RT overnight. The reaction mixture was dissolved in 120 ml of acetonitrile and stirred with ice cooling into 350 ml of concentrated aqueous ammonia solution (35% strength). The mixture was stirred for 2 h at room temperature, then for 6 h at 50 ° C and the reaction mixture was then concentrated on a rotary evaporator. The residue was stirred with water and ethyl acetate and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was stirred with diethyl ether, filtered off, washed with a little diethyl ether and dried under high vacuum. 1020 g (47% of theory) of the title compound were obtained.

LC-MS (Method 4): R _t = 1.06 min; MS (EIpos): m / z = 426 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.45 (s, 6H), 5.86 (s, 2H), 7.09 (dt, 1H), 7.29 (dt, 1H), 7.41 (q, 1H), 8.55 (dd, 1H), 8.79 (s, 1H), 12.19 (s br, 1H).

Example 22

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

75 mg (0.200 mmol) of Example 16 were initially charged in THF (5 ml) at 0 ° C. and admixed with 0.134 ml of a 3M solution of phenylmagnesium bromide in diethyl ether (0.401 mmol). After 15 min at 0 ° C was warmed to RT for 1 h. Subsequently, the batch was added to saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic phases were combined, washed once with water and once with saturated aqueous sodium chloride solution. It was then dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). 38 mg of the title compound were obtained (42% of theory). LC-MS (Method 1): R _t = 1.03 min; MS (ESIpos): m / z = 453 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 5.87 (d, 2H), 7.08 (s, 1H), 7.17 (dd, 1H), 7.22-7.29 (m, 2H), 7.33- 7.47 (m, 7H), 8.48 (s, 1H), 8.69 (dd, 1H), 8.88 (dd, 1H), 11.76 (br s, 1H).

Example 23

5-fluoro-2- [l- (2-fluorberizyl) -lH-pyrazolo [3,4-b] pyridin-3-yl] -5-methyl-5,7-dihydro-6H-pyrrolo [2,3- d] pyrimidin-6-one

100 mg (0.256 mmol) of Example 17 were initially charged in dichloromethane (4,795 ml) at -78 ° C., and 40.61 μl (0.307 mmol) of diethylaminosulfur trifluoride were added. The mixture was then warmed slowly to RT overnight. Thereafter, another 40.61 μΐ (0.307 mmol) of diethylaminosulfur trifluoride was added and the mixture was stirred at RT for a further night. The reaction was then diluted with dichloromethane and extracted with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). There was obtained 42 mg of the title compound (42% of theory). LC-MS (Method 1): R _t = 0.96 min; MS (ESIpos): m / z = 393 (M + H)

Tl NMR (400 MHz, DMSO-de): δ [ppm] = 1.82 (s, 3H), 5.88 (s, 2H), 7.16 (ddd, 1H), 7.21-7.28 (m, 2H), 7.34-7.40 (m, 1H), 7.46 (dd, 1H), 8.70 (dd, 1H), 8.86-8.89 (m, 2H), 12.01 (s, 1H).

Example 24 tert. Butyl {2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] -5-hydroxy-6-oxo-6,7-dihydro-pyrrolo [2 , 3-d] pyrimidin-5-yl} acetate

100 mg (0.267 mmol) of Example 16 were initially charged in THF (5 ml) at -45 ° C and treated with 1087 ml of an IM solution of bis (trimethylsilyl) lithium amide in THF and stirred for 30 min at -45 ° C. Subsequently, 126 mg (1.087 mmol) of tert-butyl acetate (dissolved in 5 ml of THF) was added dropwise. It was warmed to RT and stirred overnight at this temperature. The mixture was mixed with water and adjusted to pH = 4 with acetic acid. It was then extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). There were obtained 73 mg of the title compound (55% of theory).

LC-MS (Method 1): R _t = 0.96 min; MS (ESIpos): m / z = 491 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.17 (s, 9H), 3.05 (q, 2H), 5.87 (s, 2H), 6.59 (s, 1H), 7.16 (t, 1H), 7.22-7.28 (m, 2H), 7.35-7.40 (m, 1H), 7.45 (dd, 1H), 8.66 (s, 1H), 8.68 (dd, 1H), 8.87 (dd, 1H), 11.64 (s, 1H). Example 25

{2- [1- (2-Fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5-hydroxy-6-oxo-6,7-dihydro-5H-pyrrolo [2,3 -d] pyrimidin-5-yl} acetic acid

60 mg (0.122 mmol) of Example 24 were stirred in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) for 30 min at RT. It was then concentrated and the residue taken up in acetonitrile and treated with water. A precipitate was filtered off, which was washed with acetonitrile and dried under high vacuum. This gave 42 mg of the title compound (80% of theory).

LC-MS (Method 1): R _t = 0.80 min; MS (ESIpos): m / z = 435 (M + H) ⁺

'H-NMR (400 MHz, DMSO-ds): δ [ppm] = 3.02 (d, IH), 3.17 (d, IH), 5.87 (s, 2H), 6.53 (s, IH), 7.16 (t, IH), 7.21-7.26 (m, 2H), 7.34-7.39 (m, IH), 7.44 (dd, IH), 8.66 (s, IH), 8.68 (dd, IH), 8.88 (dd, IH), 11.56 (s, IH).

Example 26

Methyl {2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -6-oxo-6,7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-5-yl} carbamate

150 mg (about 0.319 mmol) of Example 73A were initially charged in pyridine (2 ml) and then methyl chloroformate (24 μΐ in 1 ml of dichloromethane) was added until complete conversion was achieved. It was then concentrated and the residue was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). There were obtained 1 1 mg of the title compound in 90% purity (7% of theory).

LC-MS (Method 1): R _t = 0.87 min; MS (ESIpos): m / z = 434 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 3.55 (s, 3H), 5.10 (d, IH), 5.86 (s, 2H), 7.16 (t, IH), 7.21-7.26 ( m, 2H), 7.35-7.38 (m, IH), 7.44 (dd, IH), 8.21 (d, IH), 8.46 (s, IH), 8.68 (dd, IH), 8.87 (dd, IH), 11.66 (s, IH).

Example 27

3- [l- (2,3-difluorobenzyl) -lH-pyrazolo [3,4-b] pyridin-3-yl] -7,7-dimethyl-5,7-dihydro-6H-pyrrolo [2,3- e] [1, 2,4] triazine-6-one

0.75 g (1.703 mmol) of the compound from Example 75A was admixed with 8 ml of phosphoryl chloride and stirred at RT overnight. The reaction mixture was then taken up in 120 ml of acetonitrile and stirred with ice cooling into 72 ml of concentrated ammonia solution (33% in water). It was stirred for 3 days at room temperature and the reaction mixture was then concentrated on a rotary evaporator. The residue was stirred with water and ethyl acetate and the aqueous phase extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (acetonitrile / water / water + 1% TFA-40: 55: 5) to give 134 mg of the title compound (19% of theory).

LC-MS (Method 4): R _t = 0.98 min; MS (EIpos): m / z = 408 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.46 (s, 6H), 5.94 (s, 2H), 7.07 (t, 1H), 7.15-7.19 (m, 1H), 7.37- 7.42 (m, 1H), 7.49 (dd, 1H), 8.72 (dd, 1H), 8.86 (dd, 1H), 12.19 (s br, 1H). Example 28

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

2.74 g (6.221 mmol) of the compound from Example 77A were admixed with 29 ml of phosphoryl chloride and stirred at RT overnight. The reaction mixture was then taken up in 430 ml of acetonitrile and stirred under ice-cooling into 260 ml of concentrated ammonia solution (33% in water). It was stirred overnight at room temperature and the reaction mixture was then concentrated on a rotary evaporator. The residue was stirred with water and ethyl acetate and the aqueous phase extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The residue was triturated with ethyl acetate and diethyl ether. A solid was filtered off with suction, which was then washed with diethyl ether and ethyl acetate. After drying under high vacuum, 2.13 g of the title compound were obtained in 94% purity (79% of theory).

LC-MS (Method 1): R _t = 0.93 min; MS (EIpos): m / z = 408 [M + H] Tl NMR (400 MHz, DMSO-de): δ [ppm] = 1.45 (s, 6H), 5.86 (s, 2H), 7.05-7.10 ( m, 1H), 7.26-7.32 (ddd, 1H), 7.34-7.40 (m, 1H), 7.48 (dd, 1H), 8.71 (dd, 1H), 8.85 (dd, 1H), 12.19 (s br, 1H).

Example 29

3- [5-fluoro-l- (2,3,6-trifluorobenzyl) -lH-pyrazolo [3,4-b] pyridin-3-yl] -7,7-dimethyl-5,7-dihydro-6H- pyrrolo [2,3-e] [1, 2,4] triazine-6-one

1.50 g (3.149 mmol) of the compound from Example 82A were admixed with 15 ml of phosphoryl chloride and stirred overnight. The reaction mixture was then taken up in 222 ml of acetonitrile and stirred under ice-cooling into 133 ml of concentrated ammonia solution (33% in water). It was stirred overnight at room temperature and the reaction mixture was then concentrated on a rotary evaporator. The residue was added with ethanol and water. A precipitate formed, which was filtered off and then washed with diethyl ether. After drying under high vacuum, 982 mg of the title compound were obtained (70% of theory). LC-MS (Method 1): R _t = 1.01 min; MS (EIpos): m / z = 444 [M + H] ⁺ .

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.44 (s, 6H), 5.92 (s, 2H), 7.21 (m, 1H), 7.57 (m, 1H), 8.54 (dd, 1H), 8.81 (dd, 1H), 12.19 (s br, 1H).

Example 30

2 '- [5-Fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] spiro [cyclopropane-l, 5'-pyrrolo [2,3-d] pyrimidine ] -6 '(7'h) -one

1.28 g (2.84 mmol) of Example 87A were reacted in analogy to the procedure of Example 4 with 478 mg (4.26 mmol) of potassium tert-butoxide in 60 ml of THF. There was obtained 426 mg of the title compound (36% of theory). LC-MS (Method 4): R _t = 1.04 min; MS (ESIpos): m / z = 405 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.63 (dd, 2H), 1.87 (dd, 2H), 5.85 (s, 2H), 7.17 (dt, 1H), 7.20-7.31 ( m, 2H), 7.38 (m, 1H), 8.38 (s, 1H), 8.59 (dd, 1H), 8.75 (dd, 1H), 11.77 (s br, 1H).

Example 31

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

500 mg (1.388 mmol) of Example 4 were initially charged in acetone (50 ml), treated with 0.274 ml (2.775 mmol) of piperidine and heated to reflux for 1 h. After cooling, it was filtered from a precipitate, washed with acetone and the filtrate was concentrated in vacuo. This residue was then purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate gradient). The material thus obtained was reslurried in ethyl acetate, filtered off, washed with ethyl acetate and dried under high vacuum. 101 mg of the title compound were obtained as a solid (18% of theory).

LC-MS (Method 4): R _t = 1.06 min; MS (ESIpos): m / z = 401 (M + H) ⁺

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 2.41 (s, 3H), 5.86 (s, 2H), 7.14-7.18 (m, 1H), 7.22- 7.28 (m, 2H), 7.33-7.41 (m, 1H), 7.44 (dd, 1H), 8.67 (dd, 1H), 8.83 (s, 1H), 8.90 (dd, 1H), 11.67 (s, 1H).

Example 32

2 '- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -2,2-dimethylspiro [cyclopropane-l, 5'-pyrrolo [2,3-d] pyrimidin] -6 '(7'h) -one

19.97 mg (0.499 mmol) of sodium hydride (60% in mineral oil) and 164 mg (0.749 mmol) of trimethylsulfoxonium iodide were placed under argon and admixed with 1.9 ml of DMSO. The mixture was stirred at RT for 1 h and then 100 mg (0.250 mmol) of Example 31 dissolved in DMSO (4.6 ml) were added dropwise. After 1 h at rt, the mixture was heated to 50 ° C for 6 h. The crude mixture was purified by preparative HPLC (acetonitrile-water (+ 0.05% formic acid) gradient). There were obtained 45 mg of the title compound (42% of theory). LC-MS (Method 1): R, = 1.07 min; MS (ESIpos): m / z = 415 (M + H) ⁺

1H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.41 (s, 3H), 1.44 (s, 3H), 1.73 (d, 1H), 1.92 (d, 1H), 5.85 (s, 2H ), 7.14-7.18 (m, 1H), 7.22-7.26 (m, 2H), 7.34-7.38 (m, 1H), 7.43 (dd, 1H), 8.47 (s, 1H), 8.67 (dd, 1H), 8.88 (dd, 1H), 11.69 (s, 1H).

B. Evaluation of Pharmacological Activity

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

Bl. Vessel-relaxing effect in vitro Rabbits are anesthetized by the stroke of the neck and bled to death. 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-gassed Krebs-Henseleit solution of the following composition (in each case mM): Sodium chloride: 119; Potassium chloride: 4.8; Calcium chloride dihydrate: 1; Magnesium sulfate heptahydrate: 1.4; Potassium dihydrogen phosphate: 1. 2; Sodium hydrogencarbonate: 25; Glucose: 10. The force of contraction is detected with Statham UC2 cells, amplified and digitized via A / D converters (DAS-1802 HC, Keithley Instruments Munich) and registered in parallel on chart recorders. To create a contraction, phenylephrine is added cumulatively to the bath in increasing concentration. After several control cycles, the substance to be examined is added in each subsequent course in increasing dosages and the height of the contraction is compared with the height of the contraction achieved in the last predistortion. This is used to calculate the concentration required to reduce the level of the control value by 50% (IC ₅ o value). The standard application volume is 5 μΐ, the DMSO content in the bath solution corresponds to 0.1%.

Representative IC ₅ o values for the compounds of this invention are in the following table (Table 1) represented:

Table 1 :

Example No. IC ₅₀ [nM]

1 12

2 12

7 45

8 13

10 6 Example No. IC ₅₀ [nM]

11 4

14 65

17 13

18 93

19 157

20 45

23 15

24,269

26,840

27 54

28 103

30 97

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

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

Representative values (MEC = minimum effective concentration) for the compounds according to the invention are given in the table below (Table 2):

Table 2:

Example No. MEC [μΜ]

1 0.01 Example No. MEC [μΜ]

2 0.01

3 0.03

4 0.03

5 0.03

6 0.03

7 0.03

8 0.03

9 0.03

10 0.03

11 0.03

12 0.1

13 0.1

14 0.1

15 0.3

16 1.0

17 0.1

18 0.03

19 0.03

20 0.03

21 0.1 Example No. MEC [μΜ]

22 0.03

23 0.03

24 0.3

25 1.0

26 0.3

27 0.03

28 0.3

29 0.1

30 0.03

77A 1.0

82A 0.3

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 transmitters)

- Receivers (Physiotel® receivers) connected to a data acquisition computer via a multiplexer (DSI Data Exchange Matrix). The telemetry system allows a continuous recording of blood pressure heart rate and body movement on awake animals in their habitual habitat.

animal material

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

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

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

transmitter implantation

The TAI 1 PA - C40 telemetry transmitters are surgically implanted into the experimental animals under aseptic conditions at least 14 days before the first trial. The animals so instrumented are repeatedly used after healing of the wound and ingrowth of the implant.

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

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

Substances and solutions

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

The existing telemetry measuring device is configured for 24 animals. Each trial is registered under a trial number (VYear month day). The instrumented rats living in the plant each have their own receiving antenna (1010 receivers, DSI).

The implanted transmitters can be activated externally via a built-in magnetic switch. They will be put on the air during the trial run. The emitted signals can be recorded online by a data acquisition system (Dataquest ™ 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 ART 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 Muessig, Georg Ertl and Bjorn Lemmer: Experimental heart failure in rats: effects on cardiovascular circadian rhythms and on myocardial beta-adrenergic signaling. Cardiovasc Res 47 (2): 203-405, 2000; Kozo Okamoto: Spontaneous hypertension in rats. Int Rev. Exp Pathol 7: 227-270, 1969; Maarten van den Buuse: Circadian Rhythms of Blood Pressure, Heart Rate, and Locomotor Activity in Spontaneously Hypertensive Rats as Measured with Radio Telemetry. Physiology & Behavior 55 (4): 783-787, 1994

B-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 rats 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 sc). Substance administration is carried out in mice and rats iv bolus and in dogs by infusion for 15 minutes. The blood is taken in rats after 0.033, 0.083, 0.17, 0.5, 1, 2, 3, 4, 6, 7 and 24 hours, in mice after 0.033, 0.083, 0.17, 0.5, 1, 2, 3, 4, 6, 7, 24, 48 and 72 hours and in dogs 0.083, 0.25, 0.28 0.33, 0.42, 0.75, 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). Rats were drawn in 0.083, 0.17, 0.5, 0.75, 1, 2, 3, 4, 6, 7 and 24 hours and in dogs 0.083, 0.17, 0.5, 0.75, 1, 2, 3, 4, 6, 7, 24, 30 and 48 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 (ZK 228859) is added to the samples of the compounds of the formula (I) according to the invention, calibration samples and QCs, and protein precipitation by means of acetonitrile follows 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 5μ C8 (2) 100A 50 × 2 mm from Phenomenex, tempered to 40 ° C. A binary mobile phase gradient at 500 μΕ / ητϊη is driven (A: 0.01M 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 sprayvoltage 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.

Pharmacokinetic parameters such as AUC, _Cmax , ti _{/ 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). calculated.

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 the quotient formation of the C _B i _u t cpiasma value is determined.

After intravenous administration of 0.3 mg / kg of Example 1, 18, 19 and 27 in rats, the following values were obtained:

Example 1 18 19 27

CL Biot [L / h / kg] 1.1 0.46 0.32 0.35 Terminal half-life [h] 0.9 1.4 3.0 5.6

Mean Residence Time [h] 1.2 1.9 4.0 7.3

C. Embodiments of Pharmaceutical Compositions

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

Tablet: composition:

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

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

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

Orally administrable suspension:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water. A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.

production:

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

Composition:

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

production:

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

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

Claims

claims

1. Compound of formula (I)

in which

A is nitrogen or CR, where

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 - #, where

* represents the point of attachment to the carbonyl group,

R ^{4A represents} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl or hydroxyl,

R ^{4B is} hydrogen, fluorine, (C _r C ₄ ) alkyl, trifluoromethyl, (C _r C ₄ ) alkoxycarbonylamino or phenyl, in which with 1 or 2 substituents independently of one another selected from the group fluorine, trifluoromethyl, hydroxy, hydroxycarbonyl and (C 1 -C 4 -alkoxycarbonyl may be substituted, or

R ^4A and R ^4B together with the carbon atom to which they are attached, a

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 having 1 or 2 substituents independently selected from the group fluorine and (Ci-C-alkyl may be substituted, or R ^4A and R ^4B together with the carbon atom to which they are attached, a

Form (C2-C4) -alkenyl group,

R ^{5A is} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl or hydroxyl,

R ^{5B is} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl or trifluoromethyl,

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

A is nitrogen or CR ³ , where

L represents a group * -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - #, where * represents the point of attachment to the carbonyl group, # represents the point of attachment to the pyrimidine or triazine ring, p stands for a number 0 or 1,

R ^{4A is} hydrogen, fluorine, methyl, ethyl or hydroxy,

R ^{4B is} hydrogen, fluorine, methyl, ethyl, trifluoromethyl, methoxycarbonyl-amino or phenyl, wherein methyl and ethyl may be substituted with 1 or 2 substituents independently 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, in which the cyclopropyl, cyclobutyl, cyclopentyl , Azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and tetrahydropyranyl ring having 1 or 2 substituents selected independently of one another from the group 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 fluorine, R ^{2 is} benzyl, where benzyl is substituted by 1 to 3 substituents fluorine, and their salts, solvates and solvates of the salts.

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

A stands for CR, in which

* represents the point of attachment to the carbonyl group,

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 cyclobutyl rings are substituted with 1 or 2 substituents independently selected from the group consisting of fluorine and methyl can,

R ^{1 is} hydrogen or fluorine,

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

A is nitrogen,

L represents a group * -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - #, where * represents the point of attachment to the carbonyl group,

R ^{4A is} hydrogen, fluorine or methyl,

R ^{4B is} hydrogen, fluorine, methyl or trifluoromethyl, or

R ^{1 is} hydrogen or fluorine,

5. A process for the preparation of compounds of the formula (I) as defined in claims 1 to 4, which comprises reacting a compound of the formula (II)

in which R ¹ and R ² each have the meanings given in claims 1 to 4, 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 _r C ₄₎ -alkyl, to a compound of formula (IV)

(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 to give a compound of the formula (V)

in which L, R ¹ and R ^{2 in} each case have the meanings given in claims 1 to 4, and these are subsequently 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

in which

L ^{1 represents} a group * -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - #, where

* represents the point of attachment to the carbonyl group,

# represents the point of attachment to the pyrimidine or triazine ring, p is a number 1 or 2,

R ^4A represents hydrogen, fluorine, (C _r _C4) alkyl or hydroxy,

R ^{4B is} hydrogen, fluorine, (Ci-C ₄ ) -alkyl or trifluoromethyl, or

R ^4A and R ^4B form, together with the carbon atom to which they are attached, an internal O x o group, a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle,

R ^5A is hydrogen, fluorine, (C _r _C4) alkyl or hydroxy,

R ^{5B is} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl or trifluoromethyl, and

T ^{2 is} (C _r C ₄ ) -alkyl, to give a compound of formula (IV-B)

(IV-B), in which L ¹ , R ¹ and R ^{2 are} each as defined in claims 1 to 4

Have meanings, and then this analogous to the method [A] further to a compound of formula (IB) in which L ¹ , R ¹ and R ² each have the meanings given in claims 1 to 4, or

in which L and R each have the meanings given in claims 1 to 4 and

T is (C _r C ₄₎ -alkyl, to a compound of formula (VIII)

in which L, R ¹ , R ² , R ³ and T ³ each have the meanings given in claims 1 to 4, then reacting these with phosphoryl chloride in a compound of formula (IX)

in which L, R ¹ , R ² , R ³ and T ^{3 in} each case have the meanings given in claims 1 to 4 transferred, these converted in the following in an inert solvent in a corresponding azide compound and these directly to a compound of Formula (X)

in which L, R ¹ , R ² , R ³ and T ³ each have the meanings given in claims 1 to 4, and then reducing these in an inert solvent in the presence of a suitable base to give a compound of formula (IC)

in which L, R ¹ , R ² and R ^{3 in} each case have the meanings given in claims 1 to 4, or

[D] in an inert solvent in the presence of a suitable base with hydrazine hydrate to give a compound of formula (XI) (xi), 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 (XII)

in which L has the meaning given in claims 1 to 4 and

T is (C _r C ₄₎ -alkyl, to a compound of formula (XIII)

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

(XIV), in which L, R ¹ , R ² and T ^{4 are} each as defined in claims 1 to 4, transferred, and these directly with ammonia to give a compound of formula (XV)

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

in which L, R ¹ and R ^{2 are} each as defined in claims 1 to 4 have cyclized, and optionally the resulting compounds of formulas (IA), (IB), (IC) and (ID) optionally with the corresponding ( i) solvents and / or (ii) acids or bases are converted into their solvates, salts and / or solvates of the salts.

6. Compound of formula (XV)

in which

L represents a group * -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - #, where

* represents the point of attachment to the carbonyl group, # is the point of attachment to the triazine ring, p is a number 0, 1 or 2,

R ^{4A represents} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl or hydroxyl,

R ^{4B is} hydrogen, fluorine, (C _r C ₄ ) alkyl, trifluoromethyl, (C _r C ₄ ) alkoxycarbonylamino or phenyl, in which (C 1 -C ₄ ) -alkyl having 1 or 2 substituents is selected independently of one another if it is 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 a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle, wherein the 3- to 6-membered carbocycle and the 4-6 - membered heterocycle having 1 or 2 substituents independently selected from the group fluorine and (Ci-C ₄ ) alkyl may be substituted,

R ^{5A is} hydrogen, fluorine, (C 1 -C 4) -alkyl or hydroxyl,

R ^{5B is} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl or trifluoromethyl, is hydrogen or fluorine, is benzyl, where benzyl is substituted by 1 to 3 substituents fluorine, is (C _r C ₄ ) -alkyl , their salts, solvates and solvates of salts.

7. Compound of formula (XIII)

represents a group * -CR ^4A R ^4B - (CR ^5A R ^5B ) _p - #, where

* represents the point of attachment to the carbonyl group,

# is the point of attachment to the triazine ring, p is a number 0, 1 or 2,

R ^{4A represents} hydrogen, fluorine, (C 1 -C ₄ ) -alkyl or hydroxyl,

R ^4A and R ^4B together with the carbon atom to which they are attached form a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle, wherein the 3- to 6-membered carbocycle and the 4-6 - membered heterocycle having 1 or 2 substituents independently selected from the group fluorine and (Ci-C alkyl may be substituted, for hydrogen, fluorine, (Ci-C alkyl or hydroxy, for hydrogen, fluorine, or trifluoromethyl,

R is hydrogen or fluorine,

R 2 is benzyl, where benzyl is substituted by 1 to 3 substituents fluorine, T ^{4 is} (C _r C ₄ ) alkyl, and their salts, solvates and solvates of the salts.

8. A compound of formula (I) as defined in any one of claims 1 to 4 for the treatment and / or prophylaxis of diseases.

A compound of the formula (XV) as defined in claim 6 for the treatment and / or prophylaxis of diseases.

A compound of the formula (XIII) as defined in claim 7 for the treatment and / or prophylaxis of diseases.

11. 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 compound of formula (I) as defined in any one of claims 1 to 4 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 diseases and arteriosclerosis.

A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 4, in combination with an inert, non-toxic, pharmaceutically acceptable

Excipient.

14. A pharmaceutical composition comprising a compound of 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 , antihypertensives and lipid metabolising agents.

15. Medicament according to claim 13 or 14 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.

16. A method for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and arteriosclerosis in humans and animals using an effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 4 or a pharmaceutical composition as defined in any one of claims 13 to 15.