MXPA06007982A - 6-amino-5-cyano-pyrimidine-4-ones used for improving perception, power of concentration, learning efficiency, and/or memory power - Google Patents

Abstract

The invention relates to novel cyanopyrimidinones, methods for the production thereof, and the use thereof for producing medicaments used for improving perception, power of concentration, learning efficiency, and/or memory capacity.

Description

CYANOPIRIMIDINONES DESCRIPTION OF THE INVENTION The invention relates to the new cyanopyrimidinones, the process for their preparation, and the use thereof to produce drugs to improve perception, concentration, learning and / or memory. The inhibition of the phosphodiesterases modulates the levels of the cyclic nucleotides 5 '-3' cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophase 5 '-3' (cGMP). These cyclic nucleotides cAMP and cGMP) are important second messengers and therefore play a central role in the transduction cascades of cellular signals. Each of them reactivates, among other things, but not exclusively, protein kinases. • The protein kinase activated by cAMP is called protein kinase A (PKA) and the protein kinase activated by cGMP is called protein kinase G (PKG). Activated PKA and PKG are capable in turn of phosphorylating a number of cellular effector proteins (eg, proteins of the ion channels, of the G-protein coupled receptors, structural). It is possible in this way that the second messengers cAMP and cGMP control a wide variety of physiological processes in a wide variety of organs. However, cyclic nucleotides are also capable of acting directly on REF: 174415 effector molecules. Thus, it is known, for example, that cGMP is able to act directly on the ion channels and thus is able to influence the concentration of cell ions (review in: Wei et al., Prog. Neurobiol., 1998 , 56: 37-64). Phosphodiesterases "(PDE) are a control mechanism to control the activity of cAMP and cGMP and thus these physiological processes." PDEs idolize cyclic monophosphates to inactive monophosphates AMP and GMP. fewer 21 PDE genes have now been described (Exp. Opin, Investig. Drugs 2000, 9, 1354-3784) These 21 PDE genes can be divided based on their sequence homology in 11 PDE families (for the nomenclature proposal, see http: // depts .. Washington.edu/pde/Nomenclature.html.) The individual PDE genes within a family are differentiated by letters (eg, PDE1A and PDE1B) .If different variants of splicing within A gene also appears, this is then indicated by an additional numbering after the letter (eg, PDE1A1) .PDE9A human was cloned and sequenced in 1998. The identity of amino acids with other PDEs does not exceed 34% (PDE8A) and is never less than 28% (PDE5A). Michaelis-Menten stant (Km) of 170 nM, PDE9A has high affinity for cGMP. In addition, PDE9A is selective for cGMP (Km for cAMP = 230 μM). PDE9A does not have a cGMP binding domain, suggesting the regulation of allosteric enzyme by cGMP. It was shown in a Western blot analysis that PDE9A is expressed in humans, among other parts in the testes, in the brain, in the small intestine, in skeletal muscle, in the heart, in the lung, in the thymus and in the spleen The highest expression was found in the brain, in the small intestine, in the heart and in the spleen (Fisher et al., J. Biol. Chem., 1998,273 (25): 15559-15564). The gene for human PDE9A is located on chromosome 21q22.3 and comprises 21 exons. To date, 4 alternative splice variants of PDE9A have been identified (Guipponi et al., Hum. Genet., 1998, 103: 386-392). Traditional PDE inhibitors do not inhibit human PDE9A. In this way, IBMX,. dipyridamole, SKF94120, rolipram and vinpocetine show inhibition on the isolated enzyme at concentrations up to 100 μM. An ICS0 of 35 μM has been demonstrated for zaprinast (Fisher et al., J. Biol. Chem., 1998,273 (25): 15559-15564). Murine PDE9A was cloned and sequenced in 1998 by Soderling et al. (J. Biol. Chem., '1998, 233 (19): 15553-15558). This one has, like the human form, high affinity for cGMP with a Km of 70 nM. Particularly high expression was found in the mouse kidney, brain, lung and heart. Murine PDE9A is not inhibited by IBMX at concentrations below 200 μM; the IC50 for zaprinast is 29 μM (Soderling et al., J. Biol. Chem., 1998, 233"(19): 15553-15558). It has been found that PDE9A is strongly expressed in some rat brain regions. These include the olfactory bulb, the hippocampus, the cortex, the basal ganglia and the basal procencephalus (Andreeva et al., J. Neurosci., 2001, 21 (22): 9068-9076). Basal procencephalon in particular plays an important role in the learning and memory processes - As already mentioned above, PDE9A is distinguished by having a particularly high affinity for cGMP.PDE9A is therefore active even at low physiological concentrations, in contrast to PDE2A (Km = 10; Martins et al., J. Biol. Chem., 1982, 257: 1973-1979), PDE5A (Km = 4 μm, Francis et al., J. Biol. Chem., 1980, 255: 620-626), PDE6A (Km 17 μM, Gillespie and Beavo, J. Biol. Chem., 1988, 263 (17): 8133-8141) and PDE11A (Km 0.52 μM, Fawcett et al., Proc. Nat. Acad. Sci., 2000, 97 (7): 3702-3707). In contrast to PDE2A (Murashima et al., Biochemistry, 1990, 29: 5285-5292), the catalytic activity of PDE9A is not increased by cGMP, because it has no GAF domain (cGMP binding domain by which PDE activity is allosterically increased) (Beavo et al., Current Opinion in Cell Biology, 2000, 12: 174-179). The PDE9A inhibitors can therefore lead to an increase in the baseline cGMP concentration. U.S. Patent No. 5,002,949 describes cyanopyrimidinones to inhibit white thrombus formations. WO02 / 06288 discloses cyanopyrimidinones having an antagonist effect of mGluR. WO95 / 10506 describes cyanopyrimidinones for the treatment of depression and Alzheimer's disease. European Patent EP-130735 describes cyanopyrimidines as cardiotonic agents. U.S. Patent No. 5,256,668 and W099 / 41253 describe cyanopyrimidines having an antiviral effect. The present invention relates to the compounds of the formula wherein A is phenyl, heteroaryl or a group of the formula wherein the phenyl and heteroaryl are optionally substituted with up to 2 radicals independently selected from the group of heteroaryl, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, trifluoromethoxy, benzyloxy and benzyl, wherein the alkyl of 1 to 6 carbon atoms is optionally substituted with a group of the formula -NR3R4 in which R3 is alkyl of 1 to 6 carbon atoms and R4 is hydrogen or (alkoxy of 1 to 6 carbon atoms) ( alkyl of 1 to 6 carbon atoms), and the heteroaryl is optionally substituted by alkoxy of 1 to 6 carbon atoms, R1 is cycloalkyl of 3 to 8 carbon atoms, alkyl of 1 to 6 carbon atoms, (alkoxy of 1 to 6 carbon atoms) (alkyl of 1 to 6 carbon atoms), benzyl or a group of the formula wherein the cycloalkyl of 3 to 8 carbon atoms is optionally substituted with hydroxyl, alkyl of 1 to 6 carbon atoms or trifluoromethyl, alkyl of 1 to 6 carbon atoms is optionally substituted with heteroaryl, cycloalkyl of 3 to 8 carbon or hydroxyl atoms, and benzyl is optionally substituted by alkoxy of 1 to 6 carbon atoms or halogen, R 2 is hydrogen, or R 1 and R 2 together with the nitrogen atom to which they are bonded form a heterocyclyl of 5 to 6 members which is optionally substituted with up to 2-substituents independently selected from each other from the group of alkyl of 1 to 6 carbon atoms, hydroxyl, cyano, oxo, heteroaryl, benzyl, formyl, alkylcarbonyl of 1 to 6 carbon atoms and one of The following groups . which are linked via the two oxygen atoms to one of the carbon atoms in the heterocycle, where the alkyl of 1 to 6 carbon atoms is optionally substituted with hydroxyl or heteroaryl, and the salts, solvates and / or solvates of the salts thereof. The compounds of the invention can, depending on their structure, exist in stereoisomeric forms (enantiomers, diastereoisomers) and tautomeric forms. The invention therefore relates to the enantiomers or diastereoisomers and the respective mixtures thereof. The stereoisomerically pure constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereoisomers. Salts that are preferred for the purposes of the invention are physiologically acceptable salts of the compounds of the invention. The physiologically acceptable salts of the compounds (I) include salts by acid addition of the mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid. The physiologically acceptable salts of the compounds of the formula (I) also include the conventional base salts such as, for example, and preferably, alkali metal salts (eg the sodium and potassium salts), alkaline earth metal salts ( for example calcium and magnesium salts), and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine , diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methyl-morpholine, dehydroabietylamine, arginine, lysine, ethylenediamine and methylpiperidine. The solvates refer, for the purposes of the invention, to those forms of the compounds that form, in the solid or liquid state, a complex by coordination with solvent molecules. Hydrates are a specific form of solvates in which coordination with water takes place. For the purposes of the present invention, substituents have the following meaning, unless otherwise specified: C 1 -C 6 -alkyl is a straight or branched chain alkyl radical having 1 to 6, preferably 1 to 4 carbon atoms. Preferred examples include methyl, ethyl, n-propyl, isopropyl, 2-butyl, tert-butyl, 2-pentyl, 3-pentyl and n-hexyl. Alkoxy of 1 to 6 carbon atoms is a straight or branched chain alkoxy radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms. Preferred examples include methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy. (C 1-6 alkoxy) (C 1-6 -alkyl) is a straight or branched chain alkoxy radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 atoms carbon, which is linked to a straight or branched chain alkyl radical having 1 to 6, preferably 1 to 4, particularly preferably having 2 to 3 carbon atoms. Preferred examples include methoxymethyl, 2-methoxyethyl, ethoxymethyl and 2-ethoxyethyl. C 1 -C 6 -alkylcarbonyl is a straight or branched chain alkylcarbonyl radical having from 1 to 6, preferably from 1 to 4 and particularly preferably from 1 to 3 carbon atoms. Preferred examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl and tert-butylcarbonyl. 3- to 8-membered cycloalkyl are saturated cycloalkyl radicals having from 3 to 8, preferably 3 to 6 and particularly preferably 5 to 6 carbon atoms in the ring. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Halogen is fluorine, chlorine, bromine and iodine. Fluorine, chlorine, bromine are preferred, and fluorine and chlorine are particularly preferred. Heteroaryl is an aromatic monocyclic radical having from 5 to 6 ring atoms and up to 3 heteroatoms from the series of sulfur, oxygen and / or nitrogen. Heteroaryls of 5 to 6 members ~ having up to 2 heteroatoms are preferred. The heteroaryl radical can be attached by a carbon or nitrogen atom. Preferred examples include thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl-, imidazolyl, pyridyl, pyrimidinyl and pyridazinyl. -. 5-6 membered heterocyclyl is a saturated or partially unsaturated, monocyclic heterocyclic radical having 5 to 6 ring atoms and up to 2 heteroatoms of the nitrogen series, oxygen, sulfur. Nitrogen and oxygen are preferred as heteroatoms. Preferred examples include pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyranyl, thiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. When the radicals in the compounds of the invention are optionally substituted, unless otherwise specified, substitution by up to three identical or different substituents is preferred. A further embodiment of the invention relates to the compounds of the formula (I) wherein A is phenyl, heteroaryl or a group of the formula wherein the phenyl and heteroaryl are optionally substituted with up to 2 radicals independently selected from each other from the group of heteroaryl, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, trifluoromethyl, trifluoromethoxy, benzyloxy and benzyl, where the alkyl of 1 to 4 carbon atoms is optionally substituted with a group of the formula -NR3R4 in which R3 is alkyl of 1 to 4 carbon atoms and R4 is hydrogen or (C1-C4 alkoxy) (alkyl of 1 to 4 carbon atoms), and the heteroaryl is optionally substituted with C 1 -C 4 -alkoxy, Rx is cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms, (C 1 -C 4 alkoxy) (C 1 -C 4 -alkyl), benzyl or a group of the formula wherein the cycloalkyl of 3 to 6 carbon atoms is optionally substituted with hydroxyl, alkyl of 1 to 4 carbon atoms or trifluoromethyl, alkyl of 1 to 4 carbon atoms is optionally substituted with heteroaryl, cycloalkyl of 3 to 6 carbon atoms or hydroxyl, and benzyl is optionally substituted by alkoxy of 1 to 4 carbon atoms or halogen, R 2 is hydrogen, or R 1 and R 2 together with the nitrogen atom to which they are bonded form a 5 to 6 membered heterocyclyl which is. optionally substituted with up to 2 substituents independently selected from each other from the group of alkyl of 1 to 4 carbon atoms, hydroxyl, cyano, oxo, heteroaryl, benzyl, formyl, alkylcarbonyl of 1 to 4 carbon atoms and one of the following groups > which are linked via the two oxygen atoms to one of the carbon atoms in the heterocycle, where the alkyl of 1 to 4 carbon atoms is optionally substituted with hydroxyl or heteroaryl, and the salts, solvates and / or »solvates of the salts of them. A further embodiment of the invention relates to the compounds of the formula (I) in which A is phenyl, thienyl or a group of the formula wherein phenyl and thienyl are optionally substituted with up to 2 radicals independently selected from each other from the group of pyridyl, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy from 1 to 4 carbon atoms, trifluoromethyl, trifluoromethoxy, benzyloxy and benzyl, wherein the alkyl of 1 to 4 carbon atoms is optionally substituted with a group of the formula -NR3R4 in which R3 is alkyl of 1 to 4 carbon atoms. carbon and R 4 is hydrogen or (C 1 -C 4 alkoxy) (C 1 -C 4 alkyl), and the -heteroaryl is optionally substituted with C 1 -C 4 alkoxy, R 1 is C 3 -cycloalkyl 6 carbon atoms, alkyl of 1 to 4 carbon atoms, (alkoxy of 1 to 4 carbon atoms) (alkyl of 1 to 4 carbon atoms), benzyl or a group of the formula where the cycloalkyl of 3 to 6 carbon atoms is optionally substituted with hydroxyl, alkyl of 1 to 4 carbon atoms or trifluoromethyl, alkyl of 1 to 4 carbon atoms is optionally substituted with hetexoaryl, cycloalkyl of 3 to 6 carbon atoms or hydroxyl, and benzyl is optionally substituted with alkoxy of 1 to 4 carbon atoms fluorine, chlorine or bromine, R 2 is hydrogen, or R 1 and R 2 together with the nitrogen atom to which they are bonded form a heterocyclyl. from 5 to 6 members selected from the group of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, which are optionally substituted with up to 2 substituents independently selected from each other of the alkyl group of 1 to 4 carbon atoms, hydroxyl, cyano, oxo, heteroaryl, benzyl, formyl, alkylcarbonyl of 1 to 4 carbon atoms and one of the following groups . which are linked via the two oxygen atoms to one of the carbon atoms in the heterocycle, where the alkyl of 1 to 4 carbon atoms is optionally substituted with hydroxyl or pyridyl, and the salts, solvates and / or solvates or salts thereof. A further embodiment of the invention relates to. the compounds of the formula (I) in which A is phenyl, thienyl or a group of the formula wherein the phenyl is optionally substituted with up to 2 radicals independently selected from each other from the group of pyridyl, fluorine, chlorine, methyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, benzyloxy and benzyl, wherein the methyl is optionally substituted with a group of the formula -NR3R4 in which R3 is methyl and R4 is hydrogen or 2-methoxyethyl, and pyridyl is optionally substituted with methoxy, Ra is cycloalkyl of 3 to 6 carbon atoms, methyl, ethyl, propyl, 2-methoxyethyl, benzyl or a group of the formula - where the cycloalkyl of 3 to 6 carbon atoms is optionally substituted with hydroxyl, methyl or trifluoromethyl, methyl, ethyl, propyl is optionally substituted with pyridyl, cyclopropyl or hydroxyl, and the benzyl is optionally substituted with methoxy, ethoxy, fluorine or chlorine, R 2 is hydrogen, or R 1 and R 2 together with the nitrogen atom at which are linked form a heterocyclyl of 5 to 6 members selected from the pyrrolidinyl group. piperidinyl, piperazinyl and morpholinyl, which is optionally substituted with up to 2 substituents independently selected from the other group of methyl, ethyl, propyl, tert-butyl, hydroxyl, cyano, oxo, pyridyl, benzyl, formyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl and one of the following groups , which are linked via the two oxygen atoms to one of the ... carbon atoms in the heterocycle, where methyl, ethyl and propyl are optionally substituted with hydroxyl or pyridyl, and the salts, solvates and / or solvates of the salts of them. A process for preparing the compounds of the invention of the formula (I) has been additionally found, characterized in that [A] a compound of the formula is initially converted- with a compound of the formula HNR2R2 (III), in which R1 and R2 have the meanings mentioned above, at elevated temperature in an inert solvent or even in the absence of a solvent to a compound of the formula wherein R1 and R2 have the meanings mentioned above, and the latter is then reacted in an inert solvent in the presence of a base with a compound of the formula X = CI, Brorl in which A has the meanings mentioned above, or in a modified sequence of the reactants [B] a compound of the formula (II) is initially converted with a compound of the formula (V) into an inert solvent in the presence of a base, to a compound of the formula in which _ XX A has the meanings mentioned above, and the latter is then reacted at elevated temperature in inert solvent, or even in the absence of a solvent with a compound of the formula (III), and the compounds of the formula (I) resulting in each in case they are reacted, where appropriate, with the (i) solvents and / or (ii) appropriate bases or acids, to give their solvates, salts and / or solvates of the salts. The compound of the formula (II) is known from the literature (R. Gompper, W. Toepfl, Chem. Ber. 1962, 95, 2861-2870). The compounds of the formulas (III) and (V) are commercially available, known from the literature or can be prepared in analogy to the known processes of the literature (see, for example, H. Gielen, C. Alonso-Alija, M Hendrix, U. Niewdhner, D. Schauss, Tetrahedron Lett., 2002, 43, 419-421). The solvents suitable for the passage of the process (II) + (III) - > (IV) are inert organic solvents, high boiling point, which are not changed under the reaction conditions. These preferably include toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide or sulfolane. It is likewise possible to carry out the reaction without solvent in the melt. The reaction is particularly preferably carried out without solvent or in dimethylformamide, acetonitrile or toluene. The reaction generally takes place in a temperature range of + 70 ° C to + 200 ° C, preferably in a temperature range of +100 ° C to +150 ° C. The reaction can be carried out under atmospheric pressure, high or reduced (for example 0.5 to 5 bar). This is generally carried out under atmospheric pressure. The compound of the formula (III) is in this case used in an amount of 1 to 2 mol, preferably in an equivalent amount of 1 mol, based on 1 mol of the compound of the formula (II). The solvents suitable for the process step (VI + (III) -> (I) are the usual organic solvents which are not changed under the reaction conditions, which preferably include dimethylformamide, dimethyl sulfoxide or acetonitrile. It is possible to carry out the reaction without a solvent The reaction is in particular preferably carried out without solvent or in acetonitrile The reaction generally takes place in a temperature range of + 50 ° C to + 150 ° C, preferably in a temperature range of + 7 ° C to + 100 ° C. The reaction can be carried out under atmospheric pressure, high or reduced pressure (for example 0.5 to 5 bar), which is generally carried out under atmospheric pressure The compound of the formula (III) is in this case used in an amount of 1 to 10 mol, preferably in an excess, of 3 to 10 mol, based on 1 mol of the compound of the formula (VI). suitable solvents for p process (IV) + (V) - >; (I) "or (II) + (V) -» (VI) are the usual organic solvents, which are not changed under the reaction conditions, These preferably include dimethylformamide, dimethyl sulfoxide, acetonitrile, dioxane or alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol or tert-butanol It is equally possible to use mixtures of the mentioned solvents, dimethylformamide or acetonitrile are particularly preferred for the process step (IV) + (V) - >(I), and the ethanol for the process step (II) + (V) -> (VI) The reaction generally takes place in a temperature range of + 50 ° C to + 150 ° C, preferably in a temperature range of + 70 ° C to +100 ° C. The reaction can be carried out under atmospheric pressure, high or reduced pressure (for example 0.5 to 5 bar) .These is generally carried out under atmospheric pressure.

Suitable bases for the process passage (IV) + (V) - (I) or (II) + (V) - (VI) are preferably alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate. cesium, or organic amine bases such as, for example, pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methyl-piperidine. Potassium carbonate or triethylamine are particularly preferred. The base is used, in this case, in an amount of 1.5 to 4 mol, preferably in an amount of 1.5 to 2 mol, based on 1 mol of the compound of the formula (IV) or (II). The compound of the formula (V) is used in an amount of 1 to 1.5 mol, preferably in an amount of 1. 2 mol, based on 1 mol of the compound of the formula (IV) or (II). The process of the invention can be illustrated by way of example by the following Reaction Schemes: Reaction Scheme I X = Cl, Br a) ethanol, triethylamine, 5-16 hours of reflux; acetonitrile, 85-90 ° C, 1-7 days.

Reaction Scheme II: X- = Cl, Br a) 1. toluene, boron trifluoride etherate, room temperature 30 minutes; 2. amine component R1R2NH, 150 ° C, 16 hours; or: fusion of the initial compounds at 150 ° C, 1-16 hours; b) DMF, triethylamine, 100 ° C, 16 hours or DMF, potassium carbonate, 90 ° C, 16 hours. The compounds of the invention show a valuable range of pharmacological effects that may not have been predicted. Those are distinguished in particular by the inhibition of PDE9A. It has surprisingly been found that the compounds of the invention are suitable for producing drugs to improve perception, concentration, learning or memory. The compounds of the invention can, by virtue of their pharmacological properties, be used alone or in combination with other medicaments to improve perception, concentration, learning and / or memory. The compounds of the invention are particularly suitable for improving perception, concentration, learning or memory after cognitive impairments such as those that occur in particular in situations / diseases / syndromes such as mild cognitive impairment, impairment of learning and associated memory at age, memory loss associated with age, vascular dementia, craniocerebral trauma, stroke, dementia that occurs after strokes (postapoplegia dementia), post-traumatic dementia, deterioration of general concentration, deterioration of concentration in children with learning and memory problems, Alzheimer's disease, Lewy body dementia, dementia with degeneration of the frontal lobes, including Pick syndrome, Parkinson's disease, progressive nuclear paralysis, "" dementia with corticobasal degeneration, amyotrophic lateral sclerosis (ALS) , Huntington's disease, multiple sclerosis , Thalamic degeneration, Creutzfeld-Jacob dementia, dementia for '"" HIV, schizophrenia with dementia or Korsakoff psychosis. The in vi tro effect of the compounds of the invention can be shown with the following biological assays: Inhibition of recombinant PDE1C PDE (GenBank / EMBL Accession Number: ? M_005020, Loughney et al. J. Biol. Chem. 1996 271, 796-806), PDE2A (GenBank / EMBL Accession Number: NM_002599, Rosman et al. Gene 1997 191, 89-95), PDE3B (GenBank / EMBL Accession Number: NM_000922, Miki et al., Genomics. 1996, 36, 476-485), PDE4B (GenBank / EMBL Accession Number: NM_002600, Obernolte et al., Gene 1993, 129, 239-247), PDE5A (GenBank / EMBL Accession Number:? M_001083, Loughney et al. Gene 1998, 216, 139-147), PDE7B (GenBank / EMBL Accession Number:? M_018945, Hetman et al., Proc. Nati, Acad. Sci. USA 2000, 97, 472-476), PDE8A (GenBank / EMBL Number Access: AF 056490, Fisher et al.

Biochem. Biophys. Res. Commun. 1998, 246, 570-577), PDE9A (Fisher et al., J. Biol. Chem., 1998, 273 (25): 15559-15564), PDE10A (GenBank / EMBL Accession Number: NM_06661, Fujishige et al. J Biol Chem. 1999, 274, 18438-45), PDE11A (GenBank / EMBL Accession Number: NM_016953, Fawcett et al., Proc. Nati, Acad. Sci. 2000, 97, 3702-3707) were expressed in Sf9 cells with the help of the Baculoviral expression of pFASTBAC (Gibco BRL). The test substances are dissolved in 100% DMSO and diluted in series to determine their effect on PDE9A. Typically, dilutions of 200 μM to 1.6 μM are prepared (resulting in final concentrations in the assay: 4 μM to 0.032 μM), 2 μl portions of the solutions of the diluted substance are introduced into the wells of the microtiter plates (Isoplate; Wallac Inc., Atlanta, Ga.). Then 50 μl of a dilution of the PDE9A preparation described above is added. The dilution of the PDE9A preparation is chosen so that less than 70% of the substrate is converted during the subsequent incubation (typical dilution: 1: 10000; dilution buffer: 50 mM Tris / HCl pH 7.5, 8.3 mM magnesium chloride, EDTA 1.7 M, 0.2% BSA). The substrate, 3 ', 5' - [8-3H] guanosine cyclic phosphate (1 μCi / μl, Amersham Pharmacia Biotech., Piscataway, NJ) is diluted 1: 2000 with assay buffer (50 mM Tris / HCl pH 7.5, 8.3 mM magnesium chloride, 1.7 mM EDTA) to a concentration of 0.0005 μCi / μl. The enzymatic reaction is finally initiated by the addition of 50 μl (0.025 μCi) of the diluted substrate. The assay mixtures are incubated at room temperature for 60 minutes and the reaction is stopped by the addition of 25 μl of a PDE9A inhibitor (for example the inhibitor of Preparation Example 1, final concentration 10 μM) dissolved in assay buffer. Immediately after this, 25 μl of a suspension containing 18 mg / ml of Yttrium Cinylation Proximity Spheres (Amersham Pharmacia Biotech., Piscataway, NJ) is added. The microtiter plates are sealed with a film and allowed to stand at room temperature for 60 minutes. The plates are then measured for 30 seconds per well in a Microbeta scintillation counter (Wallac Inc., Atlanta, GA). The IC50 values are determined from the graphical curve of the concentration of the substance versus percentage inhibition. The effect in vi tro of the test substances on PDE3B, PDE4B, PDE7B, PDE8A, PDE10A and PDE11A recombinants, is determined by the test protocol described above for PDE9A with the following adaptations: the substrate used is 3 ', 5' - cyclic phosphate of [5 ', 8 ~ 3 H] adenosine (1 μCi / μl, Amersham Pharmacia Biotech., Piscataway, NJ). The addition of an inhibiting solution to stop the reaction is unnecessary. Rather, the incubation of the substrate and PDE is followed directly by the addition of the Yttrium Cinylation Proximity Spheres as described above, and the reaction is stopped with this. To determine a corresponding effect on PDE1C, PDE2A - and PDE5A recombinants, the protocol is further adapted as follows: in the case of PDE1C, 10 -7 M calmodulin and 3 mM calcium chloride are added in addition to the reaction mixture. PDE2A 'is stimulated in the assay by the addition of 1 μM cGMP and evaluated using a BSA concentration of 0.01% .The substrate used for PDE1C and PDE2A is the 3 X 5' -cyclic phosphate of [ 5 8- 15 3H] adenosine (1 μCi / μl, Amersham Pharmacia Biotech., Piscataway, NJ) and for PDE5A is 3 ', 5' - [5 ', 8-3H] guanosine cyclic phosphate (1 μCi / μl Amersham Pharmacia Biotech., Piscataway, NJ.) Representative examples of the PDE9A inhibitory effect of the compounds of the invention are listed in Tables 1 to 3 based on IC50 values. Tables 1-3: Inhibition of PDE isoenzymes (human) by Examples 38, 112 and 113 Table 1: Example 38 Table 2: Example 112 Table 3: Example 113 Long-term empowerment Long-term empowerment is considered as a cellular correlation of learning and memory processes. The following method can be used to determine if inhibition of PDE9 has an influence on long-term potentiation: Rat hypocaps are placed at an angle of approximately 70 degrees towards the cutting blade (shredder). Slices of 400 μm thickness of the hippocampus are prepared. The slices are removed from the blade using a very soft, thoroughly moistened brush (of marten hair) and transferred to a glass container with fine nutrient solution (124 mM sodium chloride, 4.9 mM potassium chloride, magnesium sulfate heptahydrate 1.3 mM, 2.5 mM anhydrous calcium chloride, 1.2 mM potassium diacid phosphate, 25.6 M sodium hydrogen carbonate, 10 mM glucose, pH 7.4) gasified with 95% 0/5% C02. During the measurement, the slices are kept in a controlled temperature chamber under a high liquid level of 1 to 3 mm. The flow rate is 2.5 ml / minute. -The preliminary gasification took place under a slightly elevated pressure (approximately 1 atm) and through a microneedle in the prec ara. The slice chamber is connected to the prechamber in such a way that a microcirculation can be maintained. The microcirculation is driven by the 95% flow of 02/5% C02 flowing out of the microneedle. The slices of hippocampus prepared fresh are adapted in the slice chamber at 33 ° C for at least 1 hour. The level of stimulus is chosen so that the excitatory postsynaptic potentials (fEPSP) are 30% of the maximum excitatory postsynaptic potential (EPSP). A monopolar stimulation electrode consisting of layered stainless steel, and a biphasic constant-current stimulus generator (AM Systems 2100) are used for local stimulation of Schaffer collaterals (voltage: 1-5 V, pulse width of one polarity 0.1 ms, total pulse 0.2 ms). The glass electrodes (borosilicate glass with filament, 1.5 MOhm, diameter: 1.5 mm, tip diameter: 3-20 μm), filled with normal nutrient solution, are used to record excitatory post-synaptic potentials (fEPSP) at from the stratum radiatum. The field potentials are measured against a reference electrode of chlorinated silver located at the edge of the slice chamber using a DC voltage amplifier. The field potentials are filtered through a low pass filter (5 kHz). The slope of fEPSPs (pending fEPSP) is determined for the statistical analysis of the experiments. The registration, analysis and control of the experiment takes place with the help of a software program (PWIN) which was developed in the Department of Europhysiology. The formation of the slopes of average fEPSP at the respective time points and the construction of the diagrams, takes place with the help of the EXCEL software, with automatic data recording by means of an appropriate macro. Superfusion of hippocampal slices with a 10 μM solution of the compounds of the invention leads to a significant increase in LTP. The in vivo effect of the compounds of the invention can be shown, for example, as follows: Recognition test The social recognition test is a test of learning and memory. This measures the ability of rats to distinguish between known and unknown members of the same species. This test is therefore suitable for examining the learning or memory improving effect of the compounds of the invention. Adult rats housed in groups are placed in test cages 30 minutes before the start of the test. Four minutes before the start of the test, the test animal is placed in an observation box. After this adaptation time, a juvenile animal is placed inside with the test animal and the absolute time by which the adult animal inspects the juvenile is measured for 2 minutes (test 1). All behaviors clearly directed to the young animal are measured, for example, anogenital inspection, pursuit and grooming, during which the adult animal was not more than 1 cm from the young animal. The youth is then removed, and the adult is treated with a compound of the invention or vehicle and subsequently returned to their home cage. The test is repeated after a 24 hour retention time (test 2). A decreased social interaction time, compared to test 1, indicates that the adult rat remembers the young animal.

Adult animals receive intraperitoneal injections either within a defined period of time (eg, 1 hour) before test 1 or directly after test 1, either with the vehicle (10% ethanol, 20% Solutol , 70% physiological saline solution) or 0.1 mg / kg, 0.3 mg / kg, 1.0 mg / kg or 3.0 mg / kg of the compound of the invention dissolved in 10% ethanol, 20% Solutol, 70% saline solution physiological The rats treated with the vehicle show no reduction in social interaction time in test 2 compared to test 1. They consequently have forgotten that they have already had contact with the young animal. Surprisingly, the social interaction time in the second run after treatment with the compounds of the invention is significantly reduced compared to those treated with the vehicle. This means that the rats treated with the substance have remembered the young animal and thus the compounds of the invention show an improving effect on learning and memory. The new active ingredients can be converted in a known manner, to conventional formulations such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, by the use of pharmaceutically suitable, non-toxic, inert carriers or solvents.

In these cases, the therapeutically effective compound will be present in each case in a concentration of approximately 0.5 to 90% by weight in the entire mixture, for example in amounts that are sufficient to achieve the indicated dose range. The formulations are produced for example by diluting the active ingredients with solvents and / or carriers, where appropriate, with the use of emulsifiers and / or dispersants, being possible for example in the case where water is used as a diluent, wherever appropriate, the use of organic solvents as auxiliary solvents. The administration takes place in a conventional manner, preferably orally, transdermally or parenterally, especially perlingually or intravenously. However, this can also take place by inhalation through the mouth or nose, for example with the aid of a spray, or topically via the skin. It has generally been found to be advantageous to administer amounts of about 0.001 to 10, of an oral administration preferably about 0.005 to 3 mg / kg of body weight, to achieve effective results. However, it may be necessary, where appropriate, to deviate from the stated amounts, in particular as a function of body weight or the nature of the route of administration, the individual response to the medication, the nature of its formulation and the time or interval over which takes place in the administration. In this way, it may be sufficient in some cases to do so with less than the aforementioned minimum amount, while in other cases the upper limit established must be exceeded. - If larger amounts are administered, it may be advisable to divide these into a plurality of simple doses in the day. Unless stated otherwise, all established amounts refer to percentages by weight. The proportions of solvent, the proportions of dilution and the concentrations established for liquid / liquid solutions are based in each case on the volume. The statement "p / v" means "weight / volume." Thus, for example, "10% w / v" means 100 ml of solution or suspension containing 10 g of substance.

Abbreviations DCI direct chemical ionization (in MS) DMSO dimethyl sulfoxide ESI electroorbent ionization (in MS) h HPLC time (s) HPLC high-performance liquid chromatography LC-MS liquid chromatography-mass spectroscopy, - Coupled min min ( s) pf melting point 'MS mass spectroscopy NMR nuclear magnetic resonance spectroscopy Rf retention index (in TLC) TA room temperature Rt retention time (in HPLC) LC-MS and HPLC methods: Method 1: Instrument: Micromass Platform LCZ with Agilent HPLC 1100 series; column: Grom-Sil 120 0DS-4 HE, 50 mm x 2.0 mm, 3 μm; eluent A: 1 liter of water + 1 ml of 50% formic acid, eluent B: 1 liter of acetonitrile + 1 ml of 50% formic acid; gradient: 0.0 min 100% A - > 0.2 min 100% A - 2.9 min 30% A - '3.1 min 10% A - > 4.5 min 10% A; oven: 55 ° C; flow rate: 0.8 ml / min; LTV detection: 208-400 nm.

Method 2: Instrument: Micromass Quattro LCZ with Agilent HPLC 1100 series; column: Grom-Sil 120 0DS-4 HE, 50 'mm x 2.0 mm, 3 μm; eluent A: 1 liter of water + 1 ml of 50% formic acid, eluent B: 1 liter of acetonitrile + 1 ml of 50% formic acid; gradient: 0.0 min 100% A - > 0.2 min 100% A - 2.9 min 30% A - 3.1 min 10% A - > 4.5 min 10% A; oven: 55 ° C; flow rate: 0.8 ml / min; UV detection: 208-400 nm.

Method 3: Instrument: Micromass Platform LCZ with Agilent HPLC series 11Ó0; column: Phenomenex Synergi 2 μ Hydro-RP Mercury 20 mm x 4 m; eluent A: 1 liter of water + 0.5 ml of 50% formic acid, eluent B: 1 liter of acetonitrile + 0.5 ml of 50% formic acid; gradient: 0.0 min 90% A flow rate 1 ml / min - 2.5 min 30% A flow rate 2 ml / min - > 3.0 min 5% A flow rate 2 ml / min - 4.5 min 5% A flow rate 2 ml / min; oven: 50 ° C; uV detection: 210 nm.

Method 4: Instrument: Micromass Quattro LCZ with Agilent HPLC 1100 series; column: Phenomenex Synergi 2 μ Hydro-RP Mercury 20 mm x 4 mm; eluent A: 1 liter of water + 0.5 ml of 50% formic acid, eluent B: 1 liter of acetonitrile + 0.5 ml of 50% formic acid; gradient: 0.0 min 90% A flow rate 1 ml / min - > 2.5 min 30% of A flow rate 2 ml / min - > 3.0 min 5% A flow rate 2 ml / min - 4.5 min 5% A flow rate 2 ml / min; oven: 50 ° C; UV detection: 208-400 nm.

Method 5: MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance 2795; column: Phenomenex Synergi 2 μ Hydro-RP Mercury 20 mm x 4 mm; eluent A: 1 liter of water + 0.5 ml of 50% formic acid, eluent B: 1 liter of acetonitrile + 0.5 ml of 50% formic acid; gradient: 0.0 min 90% A flow rate 1 ml / min -2.5 min 30% A flow rate 2 ml / min - ^ 3.0 min 5% A flow rate 2 ml / min - > 4.5 min 5% A flow rate 2 ml / min; oven: 50 ° C; UV detection: 210 nm.

Method 6: MS instrument type: Micromass ZQ; HPLC instrument type: HP of the 1100 series; UV DAD; column: Phenomenex Synergi 2 μ Hydro-RP Mercury 20 mm x 4 mm; eluent A: 1 liter of water + 0.5 ml of 50% formic acid, eluent B: 1 liter of acetonitrile + 0.5 ml of 50% formic acid; gradient: 0.0 min 90% A flow rate 1 ml / min - > 2.5 min 30% of A flow rate 2 ml / min - > 3.0 min 5% A flow rate 2 ml / min - > 4.5 min 5% A flow rate 2 ml / min; oven: 50 ° C; UV detection: 210 nm.

Method 7: MS instrument type: Micromass ZQ; HPLC instrument type: HP of the 1100 series; UV DAD; column: Grom-Sil 120 0DS-4 HE 50 mm x 2 mm, 3.0 μm; eluent A: water + 500 μl of 50% formic acid / liter, eluent B: acetonitrile + 500 μl of 50% formic acid / liter; gradient: 0.0 min 0% B - > 2.9 min 70% B - 3.1 min 90% B - 4.5 min 90% B; oven: 50 ° C; flow rate: 0.8 ml / min; UV detection: 210 nm.

Method 8: MS instrument type: Micromass ZQ: HPLC instrument type: Waters Alliance 2790; column: Grom-Sil 120 0DS-4 HE 50 mm x 2 mm, 3.0 μ; eluent A: water + 500 μl of 50% formic acid / liter, eluent B: acetonitrile + 500 μl of 50% formic acid / liter; gradient: 0.0 min 5% B - > 2.0 min 40% of B - > 4.5 min 90% of B - > 5.5 min 90% of B; flow rate: 0.0 min 0.75 'ml / min - 4.5 min 0.75 ml / min - 5.5 min 1.25 ml / min; oven: 45 ° C; UV detection: 210 nm.

Method 9: MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance 2790; column: Grom-Sil 120 ODS- 4 HE 50 mm x 2 mm, 3.0 μm; eluent A: water + 500 μl of 50% formic acid / liter, eluent B: acetonitrile + 500 μl of 50% formic acid / liter; gradient: 0.0 min 0% B - 2..9 min 70% B - 3.1 min 90% B - 4.5 min 90% B; oven: 45 ° C; flow rate: 0.8 ml / min; UV detection: 210 nm.

Method 10: MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance 2795; column: Merck Chromolith SpeedROD RRP-18e 50 mm x 4.6 mm; eluent A: water + 500 μl of 50% formic acid / liter of intensity, eluent B: acetonitrile + 500 μl of 50% formic acid; gradient: 0.0 min 10% B - 3.0 min 95% B - > 4.0 min 95% B; oven: 35 ° C; flow rate: 0.0 min 1.0 ml / min - 3.0 min 3.0 ml / min - 4.0 min 3.0 ml / min; UV detection: 210 nm.

Method 11: MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance 2790; column: Uptisphere C 18 50 mm x 2.0 mm, 3.0 μm; eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; gradient: 0.0 min 5% B - > 2.0 min 40% of B - > 4.5 min 90% B - 5.5 min 90% B; oven: 45 ° C; flow rate: 0.0, min 0.75 ml / min - > 4.5 min 0.75 ml / min - > 5.5 min 1.25 ml / min; UV detection: 210 nm.

Method 12: Instrument: HP 1100 with DAD detection; column: Kromasil RP-18, 60 mm x 2 mm, 3.5 μm; eluent A: 5 ml of HC104 / liter of water, eluent B: acetonitrile; gradient: 0 min 2% B - > 0.5 min 2% B - > 4.5 min 90% of B - > 6.5 min 90% of B; flow rate: 0.75 ml / min; temperature: 30 ° C; UV detection: 210 nm.

Method 13: Instrument: HP 1100 with DAD detection; Kromasil RP-18 column, 125 mm x 4 mm, 5 μm; eluent A: 5 ml of HC104 / liter of water, eluent B: acetonitrile; gradient: 0 min 2% B -min 2% B - > 4.5 min 90% B - 6.5 min 90% B; flow rate: 0.75 ml / min; temperature: 30 ° C; UV detection: 210 nm.

Initial compounds: The amidines required for the following reactions are prepared from the corresponding nitriles or esters by the method of Gielen H., Alonso-Alija C, Hendrix M., Niew-dhner U., Schauß D., '- Tetrahedron Lett. 43, 419-421 (2002).

Example IA 5 2- (3,4-Dichlorofenyl) ethanamidine hydrochloride 2.88 g (54 mmol) of ammonium chloride are suspended in 50 ml of toluene under an argon atmosphere and cooled to 0 ° C. After the dropwise addition of 27 ml of a solution of 2 M trimethylaluminum in toluene, the mixture is warmed to room temperature and then stirred for 1.5 hours. 5 g (27 mmol) of 3,4-dichlorophenylacetonitrile are added, and the mixture is stirred at 80 ° C overnight. After cooling to 0 ° C, 50 ml of methanol are added dropwise to 0 drop. The product is separated from the precipitated solid by filtration with suction, and the filter cake press is washed several times with methanol. The combined filtrates are evaporated to dryness, and the residue is then suspended in dichloromethane / methanol 10: 1 and again filtered with suction. The concentration of the filtrate gives 6.2 g (77% of theory) of the title compound. MS (ESIpos): m / z = 203 [M + H] +.

Example 2A 6-methoxypyr idin-3-ylboronic acid 1 g (5.32 mmol) of 5-bromo-2-methoxypyridine was dissolved in 10 ml of absolute tetrahydrofuran and cooled to -78 ° C. 0.4 g (6.38 mmol) of a solution of 1.6 M n-butyllithium in hexane is added, which results in a yellow solution which is stirred at the given temperature for 30 minutes. The addition of 3 g (15.9 mmol) of triisopropyl borate is followed by stirring for an additional hour, during which the solution is warmed to -20 ° C. Water is added, and the mixture is stirred overnight. The crude solution is acidified to pH 5 with 1N hydrochloric acid and extracted twice with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated, resulting in a pale brown solid which is suspended in diethyl ether and filtered. 0.38 g (47% of theory) of the product are isolated. MS (ESIpos): m / z = 154 [M + H] + X H NMR (DMSO-d 6, 300 MHz):) = 3.83 (s, 3 H), 6.76 (d, 1 H), 8.0 (dd, 1H), 8.52 (s, 1H).

Example 3A [2- (6-methoxypyridin-3-yl) phenyl] methyl acetate 1. 35 g (5.89 mmol) of the methyl (2-bromophenyl) acetate is introduced together with 1 g (6.55 mmol) of the 6-methoxypyridin-3-ylboronic acid and 1.98 g (13.09 mmol) of cesium fluoride in 20 ml of 1 , 2-dimethoxyethane under argon atmosphere. After the addition of 0.22 g (0.19 mmol) of tetrakis (triphenylphosphine) palladium (0), the reaction mixture is stirred at 100 ° C for 4 hours. Cooling to room temperature is followed by the addition of a mixture of ethyl acetate and water and extraction with ethyl acetate. After the organic phase has been dried over magnesium sulfate and the solvent removed in vacuo, the residue is purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 9: 1). 1.1 g (68% of theoretical) of the product are obtained. LC-MS (method 5): Rt = 2.1 min., MS (ESIpos): m / z = 258 [M + H] + X H NMR (DMSO-dg, 300 MHz): d = 3.51 (s, 3H), 3.63 (s, 2H), 3.9 (s, 3H), 6.89 (d, 1H), 7.26 (m, 1H), 7.38 (m, 3H), 7.63 (dd, 1H), 8.08 (, 1H). ' Example 4A 2- [2- (6-Methoxypyridin-3-yl) f-enyl] ethanimidamide hydrochloride 1.14 g (21.37 mmol) of ammonium chloride was suspended in 20 ml of toluene under an argon atmosphere and cooled to 0 °. C. After the dropwise addition of 10.7 ml of a 2 M trimethylaluminum solution in toluene, the mixture is warmed to room temperature and then stirred for 1.5 hours. 1.1 g (4.27 mmol) of methyl [2- (6-methoxypyridin-3-yl) phenyl] acetate was added, and the mixture was stirred at 80 ° C for two days. After cooling to 5 ° C, 50 ml of methanol are added dropwise. The product is separated from the precipitated solid by filtration with suction, and the filter cake press is washed several times with methanol. The combined filtrates are evaporated to dryness, and the residue is then suspended in dichloromethane / methanol 10: 1, and again filtered with suction. The concentration of the filtrate results in 0.5 g (46% of theory) of the title compound. LC-MS (method 5): Rt = 0.94 min., MS (ESIpos): m / z = 242 [M + H] + NMR? Ñ (DMSO-d6, 300 MHz): d = 3.79 (s, 2H) , 3.9 (s, 3H), 6.89 (d, 1H), 7.31 (m, 2H), 7.46 (m, 2H), 7.68 (dd, 1H), 8.13 (m, 1H), 8.72 (s, 1H), 8.8 (s, 2H).

Example 5A 2- [2- (6-methoxypyridin-3-yl) benzyl] -4- (methylsulfane) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile 0. 55 g (1.96 mmol) of 2- [2- (6-methoxypyridin-3-yl) phenyl] ethanimidamide hydrochloride are dissolved together with 0.4 g (1.96 mmol) of 2-cyano-3, 3-dimethylthioprop-2-enoate. of methyl and 0.79 g (7.81 mmol) of triethylamine in 20 ml of dioxane, and is stirred at 90 ° C overnight. The solvent is then removed in vacuo, apart from about 2 ml, and acetonitrile is added to the remaining solution, after which the product is precipitated. Filtration is followed by washing with acetonitrile and methanol, and the product is dried under a high vacuum. 276 mg (38% of theory) of the title compound are obtained. LC-MS (method 5): Rt = 2.08 min., MS (ESIpos): m / z = 365 [M + H] + NMR y (DMS0-d6, 300 MHz): d = 2.31 (s, 3H), 3.9 (s, 3H), 3.98 (s, 2H), 6.89 (d, 1H), 7.28 (m, 1H), 7.39 (m, 3H), 7.63 (dd, 1H), 8.08 (m, 1H).

Example 6A 2-benzyl-4- (methylsulfane) -6-oxo-l, 6-dihydro-5-pyrimidinecarbonitrile 100 mg (0.59 mmol) of 2-phenylethanamidine hydrochloride are dissolved together with 119 mg (0.59 mmol) of methyl 2-cyano-3, 3-dimethylthioprop-2-enoate and 237 mg (2.34 mmol) of triethylamine in 2 ml of ethanol and stir at 70 ° C for 5 hours. The solvent is then removed in vacuo, and the residue is taken up in 50 ml of dichloromethane and washed with 2 M hydrochloric acid. After the organic phase has been dried over magnesium sulfate, the solvent is removed in vacuo, and the residue it is subjected to flash chromatography on silica gel (mobile phase: dichloromethane / methanol 200: 1, 100: 1). 75 mg (50% of theory) of the title compound are obtained. HPLC (method 12): R t = 4.2 min. MS (ESIpos): m / z = 258 [M + H] X Example 7A 2- (3-methylbenzyl) -4- (methylsulphane) -6-oxo-l, 6-dihydro-5-pyrimidinecarbonyl 1. 45 g (9.83 mmol) of 2- (3-methylphenyl) ethanamidine hydrochloride are dissolved together with 2 g (9.83 mmol) of methyl 2-cyano-3, 3-dimethylthioprop-2-enoate and 2 g (19.67 mmol). of triethylamine in 40 ml of ethanol and stirred at 70 ° C for 5 hours. The solvent is then removed in vacuo, and the residue is purified by preparative HPLC. 0.4 g (15% of theory) of the product are obtained. LC-MS (method 2): Rt = 2.83 min., MS (ESIpos): m / z = 272 [M + H] + aH NMR (DMSO-d6, 300 MHz): d = 2.25 (s, -3H) , 2.50 (s, 3H), 3.91 (s, 2H), 7.19 (m, 4H).

Example 8A 2- (2-methylbenzyl) -4- (methylsulfane) -6-oxo-l, 6-dihydro-5-pyrimidinecarbonitrile 3 g (16.45 mmol) of 2- (2-methylphenyl) ethanamidine hydrochloride are dissolved together with 3.3 g (16.45 mmol) of methyl 2-cyano-3, 3-dimethylthioprop-2-enoate and 6.6 g (64.9 mmol). of triethylamine in 60 ml of dioxane and stirred at 90 ° C overnight. After removal of the triethylammonium salts by filtration, the filtrate is concentrated and the residue is triturated with dichloromethane. 3.6 g (81% of theory) of the product are obtained. LC-MS (method 10): Rt = 2.13 min., MS (ESIpos): m / z = 272 [M + H] +.

Example 9A 2- (2-fluorobenzyl) -4- (methylsulfane) -6-oxo-l, 6-dihydro-5-pyrimidinecarbonitrile 3. 5 g (18.5 mmol) of 2- (2-fluorophenyl) ethanamidine hydrochloride are dissolved together with 3.8 g (18.5 mmol) of methyl 2-cyano-3, 3-dimethylthioprop-2-enoate and 7.5 g (74.2 mmol) triethylamine in 50 ml of dioxane and stirred overnight at 90 ° C. After removal of the triethylammonium salts by filtration, the filtrate is concentrated and the residue is taken up in ethyl acetate.The product is precipitated by the addition 1 N hydrochloric acid and water 3.8 g (75% of theory) of the title compound are obtained LC-MS (method 10): Rt = 2.03 min., MS (ESIpos): m / z = 276 [M + H] + X H NMR (DMSO-d 6, 300 MHz): d = 2.31 (s, 3 H), 4.06 (s, 2 H), 7.19 (m, 2 H), 7.41 (m, 2 H).

Example 10A 2- (2-Ethoxybenzyl) -4- (methylsulfanyl) -6-oxo-l, 6-dihydro-5-pyrimidinecarbonitrile 4.2 g (19.7 mmol) of 2- (2-ethoxyphenyl) ethanamidine hydrochloride are dissolved together with 4.0 g (19.7 mmol) of methyl 2-cyano-3, 3-dimethylthioprop-2-enoate and 7.9 g (78.7 mmol) of triethylamine in 80 ml of dioxane are stirred at 90 ° C overnight. After removal of the triethylamine salts by filtration, the filtrate is concentrated and the residue is taken up in ethyl acetate. The product is precipitated by the addition of 1 N hydrochloric acid and water. 5.3 g (90% of theory) of the title compound. LC-MS (method 3): Rt = 2.32 min., MS (ESIpos): m / z = 302 [M + H] + aH NMR (DMSO-d6, 300 MHz): d = 1.19 (t, 3H), 2.30 (s, 3H), 3.99 (q, 2H + s, 2H), 6.93 (m, 2H), 7.27 (m, 2H).

Example 11A 2- (3-chlorobenzyl) -4- (methylsulfane) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 2A, 0.5 g (2.00 mmol) of 2- (3-chlorophenyl) ethanamidine hydrobromide are reacted with 0.41 g (2.00 mmol) of 2-cyano-3,3-dimethylthioprop-2-enoate. of methyl and 0.81 g (8.01 mmol) of triethylamine to give 0.5 g (86% of theory) of the title compound. HPLC (method 12): Rt = 4.4 min. MS (DCI, NH3): m / z = 292 [M + H] +, 309 [M + H] X Example 12A 2- (4-chlorobenzyl) -4- (methylsulfane) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 2A, 10 g (48.8 mmol) of 2- (4-chlorophenyl) ethanamidine hydrochloride are reacted with 9.91 g (48.8 mmol) of 2-cyano-3,3-dimethylthioprop-2-enoate. of methyl and 19.7 (195 mmol) of triethylamine to give 7.00 g (49% of theory) of the title compound. HPLC (method 12): Rt = 4.35 min. MS (ESIpos): m / z = 292 [M + H] +.

Example 13A 2- (3,4-dichlorobenzyl) -4- (methylsulfanyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 2A, 1.00 g (4.17 mmol) of 2- (3,4-dichlorophenyl) ethanamidine hydrochloride is reacted with 0.85 g (4.17 mmol) of 2-cyano-3,3-dimethylthioprop-2. Methyl-enoate and 1.69 (16.7 mmol) of triethylamine to give 0.6 g (44% of theory) of the title compound. HPLC (method 12): R t = 4.7 min. MS (INN, NH3): m / z = 343 [M + H] X Example 14A 2- (3-Fluorobenzyl) -4- (methylsulfanyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 2A, 100 g (0.43 mmol) of 2- (3-fluorophenyl) ethanamidine hydrochloride is reacted with 87 g (0.43 mmol) of 2-cyano-3,3-dimethylthioprop-2-enoate. of methyl and 174 mg (1.72 mmol) of triethylamine to give 28 mg (24% of theory) of the title compound. HPLC (method 12): R t = 4.2 min. MS (ESIpos): m / z = 276 [M + H] X Example 15A 4- (Methylsulfane) -6-oxo-2- [3- (trifluoromethyl) benzyl] -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 2A, 0.5 g (2.10 mmol) of 2- [3- (trifluoromethyl) phenyl] -etanamidine hydrochloride is reacted with 0.43 g (2.10 mmol) of 2-cyano-3, 3-dimethylthiopropyl Methyl ennate and 0.85 g (8.38 mmol) of triethylamine to give 0.4 g (59% of theory) of the title compound. HPLC (method 12): Rt = 4. 4 min. MS (ESIpos): m / z = 326 [M + H] +.

Example 16A 4- (Methylsulfane) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 2A, 3.10 g (17.6 mmol) of 2- (3-thienyl) ethanamidine hydrochloride is reacted with 3.57 g (17.6 mmol) of 2-cyano-3,3-dimethylthioprop-2-enoate. of methyl and 7.10 (70.2 mmol) of triethylamine to give 2.19 g (47% of theory) of the title compound. HPLC (method 12): Rt = 4. 1 min. MS (ESIpos): m / z = 263. 9 [M + H] +.

Example 17A (2E / Z) -2-cyano-3- (cyclohexylamino) -3-methylthioprop-2-enoate methyl 0. 6 g (2.9 mmol) of methyl 3, 3-bis (methylthio) -2-cyanoacrylate were stirred with 0.29 g (2.9 mmol) of -cyclohexylamine in 20 ml of acetonitrile at room temperature for 1 hour. The volatile constituents were removed in vacuo. 0.74 g (98% of theory) of the product was obtained as a yellow oil. HPLC (method 12): R t = 4.85 min. MS (DCI, NH3): m / z = 254.9 [M + H] +, 272 [M + NH4] +.

Example 18A (2E / Z) -2-cyano-3- (clopentylamino) -3-methylthioprop-2-enoate methyl 0. 3 g (1.47 mmol) of methyl 3, 3-bis (methylthio) -2- cyanoacrylate is heated with 0.13 g (1.47 mmol) of cyclopentylamine in 3 ml of acetonitrile at 70 ° C for 30 minutes. The volatile constituents are then removed in vacuo. 0.35 g are obtained. (98% of theoretical) of the product as, a yellow oil. HPLC (method 12): R t = 4.6 min. MS (DCI, NH3): m / z = 241 [M + H] +, 258 [M + NH4] +.

Modalities and Emplasses: The following compounds are prepared by the general synthetic route described in Reaction Scheme I: Reaction Scheme I: X = Cl, Br a) ethanol, triethylamine, 5-16 hours of reflux; b) acetonitrile, 85-90 ° C, 1-7 days.

Example 1 2- (3,4-dichlorobenzyl) -6-oxo-4- (1-piperidinyl) -1,6-dihydropyrimidine-5-carbonitrile 100 mg (0.34 mmol) of 2- (3,4-dichlorobenzyl) -4- (methylsulfanyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile is stirred with 261 mg (3.07 mmol) of piperidine at 85 ° C. C for 16 hours. After removal of the volatile constituents in vacuo, the residue was purified by preparative HPLC. 42 mg (38% of theory) of the title compound are obtained. HPLC (method 12): Rt = 4.8 min. MS (ESIpos): m / z = 363 [M + H] + NMR x ((DMSO-de, 200 MHz): d = 1.45-1.70 (m, 6H), 3.73-3.89 (m, 6H), 7.35 (dd, 1H), 7.57-7.66 (m, 2H), 11.1 (s, 1H).

Example 2 2-Benzyl-6-oxo-4- (1-piperidinyl) -1, β-dihydropyrimidine-5-carbonitrile 43 mg (0.17 mmol) of 2-benzyl-4- (methylsulfanyl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile were suspended in 0.3 ml of acetonitrile and stirred with 42.7 mg (0.50 mmol) of piperidine at 85 ° C for 16 hours. The resulting crude product was then purified by preparative HPLC. 11 mg (22% of theory) of the title compound are obtained. HPLC (method 12): Rt = 4.3 min. MS (ESIpos): m / z = 295 [M + H] + NMR y (CD30D, 300 MHz): d = 1.59-1.77 (m, 6H), 3.83 (s, 2H), 3.93 (t, 4H), 7.24-7.34 (m, 5H).

Example 3 4- [4- (2-hydroxyethyl) -1-piperidinyl] -2- (3-methylbenzyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile 0. 1 g (0.37 mmol) of 2- (3-methylbenzyl) -4- (methylsulfanyl) -6-oxo-l, 6-dihydro-5-pyrimidinecarbonitrile is heated with 0.142 g (1.16 mmol) of 2- (4- piperidinyl) ethan-1-ol in 3 ml of acetonitrile at 90 ° C under an argon atmosphere for seven days.After cooling to room temperature, the crude product is purified by preparative HPLC. % of theory) of the title compound as a colorless solid LC-MS (method 7): Rt = 3.01 min., MS (ESIpos): m / z = 353 [M + H] + NMR y (DMSO-de, 300 MHz): d = 1.05 (m, 2H), 1.36 (m, 2H), 1.69 (m, 3H), 2.25 (s, 3H), 2.89 (t, 2H), 3.42 (t, 2H), 3.68 ( s, 2H), 4.51 (d, 2H), 7.18 (m, 4H).

Example 4 4- (Cyclopentylamino) -2- (3-methylbenzyl) -6-oxo-l, 6-dihydro-5-pyrimidinecarbonitrile 0. 1 g (0.37 mmol) of 2- (3-methylbenzyl) -4- (methylsulfanyl) -6-oxo-l, 6-dihydro-5-pyrimidinecarbonitrile is heated with 0.31 g (3.65 mmol) of cyclopentylamine in 3 ml of acetonitrile at 30 ° C under argon overnight. After cooling to room temperature, the crude product is purified by preparative HPLC. 0.03 g (26% of theory) of the title compound was obtained as a colorless solid. LC-MS (method 10): Rt = 2.27 min., MS (ESIpos): m / z = 309 [M + H] +.

Example 5 4- [(2S) -2- (Hydroxymethyl) -1-pyrrolidinyl] -2- (3-methylbenzyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile 0. 1 g (0.37 mmol) of 2- (3-methylbenzyl) -4- (methylsulfanyl) -6-oxo-l, 6-dihydro-5-pyrimidinecarbonitrile is heated with O.'ll g (1.1 mmol) of (S) - (+) -2-pyrrolidinemethanol in 3 ml of acetonitrile at 90 ° C under argon for five days.

After cooling to room temperature, the crude product is purified by preparative HPLC. 0.035 g (29% of theory) of the title compound was obtained as a colorless solid. LC-MS (method 7): Rt = 2.91 min., MS (ESIpos): m / z = 325 [M + H] + X H NMR (DMSO-de, 300 MHz): d 1.94 (m, 4H), 2.28 (s, 2H), 3.76 (m, 3H), 3.70 (s, 2H), 3.81 (m, 2H), 4.4 (m, 1H), 7.15 (m, 4H), 12.34 (s, 1H).

Example 6 4- [4- (2-hydroxyethyl) -1-piperidinyl] -2- (2-methylbenzyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile 0. 1 g (0.37 mmol) of 2- (2-methylbenzyl) -4- (methylsulfanyl) -6-oxo-l, 6-dihydro-5-pyrimidinecarbonitrile is heated with 0.14 g (1.1 mmol) of 2- (4-piperidinyl) ) ethan-1-ol in 3 ml of acetonitrile at 90 ° C under argon for five days. After cooling to room temperature, the crude product is purified by preparative HPLC. 13 mg (10% of theory) of the title compound was obtained as a colorless solid. LC-MS (method 5): Rt = 1.74 min., MS (ESIpos): m / z = 353 [M + H] + NMR 'XH (DMSO-de, 300 MHz): d = 1.06 (m, 2H) , 1.34 (m, 2H), 1.68 (m, 3H), 2.30 (s, 3H), 3.00 (t, 2H), 3.42 (t, 2H), 3.80 (s, 2H), 4.51 (d, 2H), 7.16 (m, 4H), 12.33 (s, 1H).

Example 7 2- (2-Fluorobenzyl) -4- [4- (2-hydroxyethyl) -1-piperidinyl] -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile 0. 1 g (0.37 'mmol) of 2- (2-fluorobenzyl) -4- (methylsulfanyl) -6-oxo-l, 6-dihydro-5-pyrimidinecarbonitrile is heated with 0.14 g (1.1 mmol) of 2- (4- piperidinyl) ethan-1-ol in 3 ml of acetonitrile at 90 ° C under argon for six days. After cooling to room temperature, the crude product is purified by preparative HPLC. 31 mg (24% of theory) of the title compound was obtained as a colorless solid. LC-MS (method 2): R t = 2.94 min., MS (ESIpos): m / z = 357 [m + H] + X H NMR (DMSO-de, 300 MHz): d = 1.01 (m, 2H), 1.33 (m, 2H), 1.67 (m, 3H), 2.97 (t, 2H), 3.41 (dd, 2H), 3.87 (s, 2H), 4.32 (t, 1H), 4.47 (d, 2H), 7.16 (m, 2H), 7.36 (m, 2H), 12.38 (s, 1H).

Example 8 2- (2-Ethoxybenzyl) -4- [4- (2-hydroxyethyl) -1-piperidinyl] -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile 0. 1 g (0.37 mmol) of 2- (2-ethoxybenzyl) -4- (methylsulfanyl) -6-oxo-l, 6-dihydro-5-pyrimidinecarbonitrile is heated with 0.13 g (0.99 mmol) of 2- (4-piperidinyl) ) ethan-1-ol in 3 ml of acetonitrile at 90 ° C under argon for five days. After cooling to room temperature, the crude product is purified by preparative HPLC. 45 mg (43% of theory) of the title compound was obtained as a colorless solid. LC-MS (method 6): R t = 2.01 min., MS (ESIpos): m / z = 383 [M + H] + X H NMR (DMSO-de, 200 MHz): d = 1.04 (m, 2H), 1.23 (t, 3H), 1.34 (m, 2H), 1.67 (m, 3H), 2.94 (t, 2H), 3.41 (t, 2H), 3.87 (s, 2H), 3.96 (q, 2H), 4.48 (d, 2H), 6.92 (m, 2H), 7.17 (m, 2H), 12.26 (s, 1H).

Example 9 2- (3-Chlorobenzyl) -6-oxo-4- (propylamino) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.34 mol) of 2- (3-chlorobenzyl) -4- (methyl-sulfanyl) -6-oxo-l, 6-dihydrbpyrimidine-5-carbonitrile was reacted with 203 mg (3.43 mmol) of n-propylamine to give 12 mg (12% of theory) of the title compound. HPLC (method 12): Rt = 4.4 min. MS (ESIpos): m / z = 303 [M + H] + NMR ñ (DMSO-de, 200 MHz): d = 0.75 (t, 3H), 1.40 (m, 2H), 3.23 (m, 2H), 3.83 (s, 2H), 7.23-7.38 (m, 4H), 7.42 (s, 1H), 12.34 (s, 1H).

EXAMPLE 10 2- (3-Chlorobenzyl) -4- (cyclopentylamino) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2- (3-chlorobenzyl) -4- (methyl-sulfanyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile were reacted with 292 mg (3.43 mmol) of cyclopentylamine to give 10 mg (9% of theory) of the title compound. HPLC (method 12): R t = 4.6 min. MS (ESIpos): m / z = 329 [M + H] + 1 H NMR (DMSO-d 6, 200 MHz): d = 1.38-1.85 (, 8H), 3.82 (s, 2H), 4.20-4.37 (m, 1H), 7.23-7.46 (m, 4H), 7.66-7.80 (s, 1H), 12.25-12.44 (s, 1H).

Example 11 3- (3-Chlorobenzyl) -6-oxo-4- (1-pyrrolidinyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2- (3-chlorobenzyl) -4- (methyl-sulfanyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile was reacted with 244 g. mg (3.43 mmol) of pyrrolidine to give 29 mg (27% of theory) of the title compound. HPLC (method 12): Rt - 4.4 min. MS (ESIpos): m / z = 315 [M + H] + X H NMR (DMS0-d6, 200 MHz): d = 1.80-1.95 (m, 4H), 3.58-3.71 (, 4H), 3.79 (s, 2H), 7.25-7.45 (m, 4H), 12.28-12.39 (s, 1H).

Example 12 4- (4,4-dimethylpiperidin-1-yl) -2- (3-chlorobenzyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 150 mg (0.51 mmol) of 2- (3-chlorobenzyl) -4- (methyl-sulfanyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile were reacted with 582 mg (5.14 mmol) of 4,4-dimethylpiperidine to give 96 mg (52% of theory) of the title compound. HPLC (method 12): Rt = 4.8 min. MS (ESIpos): m / z = 357 [M + H] + aH NMR (DMSO-de, 200 MHz): d = 0.96 (s, 6H), 1.30-1.41 (m, 4H), 3.75-3.87 (m , 6H, sa 3.81), 7.24-7.45 (m, 4H), 12.39 (s, 1H).

Example 13 2- (3-Chlorobenzyl) -4- [(2-methoxyethyl) amino] -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg was reacted (0.34). mmol) of 2- (3-chlorobenzyl) -4- (methyl-sulfanyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile with 257 mg (3.43 mmol) of 2-methoxyethylamine to give 61 mg (.56 % of theory) of the title compound. HPLC (method 12): Rt = 4.0 min. MS (ESIpos): m / z = 319 [M + H] + NMR? Ñ (CDC13, 300 MHz): d = 3.38 (s, 3H), 3.53 (t, 2H), 3.75 (q, 2H), 3.88 (s, 2H), 6.00 (t, 1H), 7.25-7.31 (m, 3H), 7.38 (s, 1H), 12.56 (s, 1H).

Example 14 2- (3-Chlorobenzyl) -4- (morpholin-4-yl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 150 mg (0.51 mmol) of 2- (3-chlorobenzyl) -4- (methyl-sulfanyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile were reacted with 448 mg (5.14 mmol) of morpholine to give 109 mg (63% of theory) of the title compound. HPLC (method 12): Rt = 4.0 min. MS (ESIpos): m / z = 331 [M + H] + X H NMR (DMSO-de, 200 MHz): 8 = 3.59-3.69 (t, 4H), 3.79-3.90 (m, 6H, sa 3.82), 7.25-7.44 (m, 4H), 12.53 (s, 1H).

Example 15 2- (3-Chlorobenzyl) -4- (4-methylpiperazin-1-yl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2- (3-chlorobenzyl) -4- (methyl-sulfanyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile were reacted with 343 mg (3.43 mmol) of N-methylpiperazine to give 101 mg (84% of theory) of the title compound. HPLC (method 12): Rt = 3.5 min. MS (ESIpos): m / z = 344 [M + H] + X H NMR (DMS0-d6, 200 MHz): d 2.18 (s, 3H), 2.35 (t, 4H), 3.79-3.88 (, 6H, sa 3.82), 7.25-7.44 (m, 4H), 12.48 (s, 1H).

Example 16 2- (3-Chlorobenzyl) -4- [(2-methoxybenzyl) amino] -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2- (3-chlorobenzyl) -4- (methyl-sulfanyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonyltryl were reacted with 470 mg (3.43 mmol) of 2-methoxybenzylamine to give 37 mg (28% of theory) of the title compound. HPLC (method 12): R t = 4.6 min. MS (ESIpos): m / z = 381 [M + H] + aH NMR (DMSO-d6, 300 MHz): d = 3.77 (s, 2H), 3.79 (s, 3H), 4.52 (d, 2H), 6.84 (t, 1H), 6.92-6.99 (m, 2H), 7.12 (d, 'lH), 7.19-7.33 (m, 4H), 8.14 (t, 1H), 12.39 (s, 1H).

Example 17 2- (4-chlorobenzyl) -4- (cyclobutylamino) -6-oxo-l, 6-dihydropyrimidn-5-carbonitrile In analogy to the preparation of Example '1, 100 mg (0.34 mmol) of 2 were reacted - (4-chlorobenzyl) -4- (methyl-sulfanyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile with 244 mg (3.43 mmol) of cyclobutylamine to give 15 mg (14% of theory) of the compound of Title. HPLC (method 12): R t = 4.5 min. MS (ESIpos): m / z = 315 [M + H] + X H NMR (DMSO-de, 300 MHz): d = 1.50-1.67 (, 2H), 2.03-2.15 (, 4H), 3.79 (s, 2H) ), 4.37-4.51 (m, 1H), 7.31-7.43 (m, 4H), 8.00 (s, 1H), 12.33 (s, 1H).

Example 18 2- (4-Chlorobenzyl) -6-oxo-4- (1-pyrrolidinyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2- (4-chlorobenzyl) -4- (methyl-sulfanyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile was reacted with 244 g. mg (3.43 mmol) of pyrrolidine to give 45 mg (42% of theory) of the title compound. HPLC (method 12): Rt = 4.4 min. MS (ESIpos): m / z = 315 [M + H] + X H NMR (CD3OD, 300 MHz): d = 1.88-2.03 (m, 4H), 3.69-3.86 (m, 6H, sa 3.82), 7.25- 7.35 (, 4H).

Example 19 4- (Cyclopentylamino) -2- (3-fluorobenzyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile "." - In analogy to the preparation of Example 1, 100 mg (0.36 mmol) of 2- (3-fluorobenzyl) -4- (methyl-sulfanyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile were reacted with 309 mg (3.63 mmol) of cyclopentylamine to give 12 mg (11% of theory) of the title compound. HPLC (method 12): Rt = 4.4 min. MS (ESIpos): m / z = 313 [M + H] + aH NMR (DMSO-d6, 200 MHz): d = 1.29-1.71 (m, 8H), 3.89 (s, 2H), 3.98-4.14 (, 1H), 7.11-7.42 (m, 4H), 7.63-7.75 (s, 1H), 12.34-12.43 (s, 1H).

Example 20 2- (3-Fluorobenzyl) -6-oxo-4- (1-piperidinyl) -1,6-dihydropyrimidine-5-carbonitrile " In analogy to the preparation of Example 1, 100 mg (0.36 mmol) of 2- (3-fluorobenzyl) -4- (methyl-sulfanyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile were reacted with 309 mg (3.63 mmol) of piperidine to give 40 mg (35% of theory) of the title compound. HPLC (method 12): Rt = 4.3 min. MS (ESIpos): m / z = 313 [M + H] + H NMR (DMSO-d6, 200 MHz): d = 1.40-1.66 (m, 6H), 3.66-3.76 (m, 4H), 3.76 (s) , 2H), 7.12-7.42 (m, 4H), 12.27-12.41 (s, 1H).

Example 21 6-0x0-4- (1-piperidinyl) -2- [3- (trifluoromethyl) benzyl] -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg was reacted (0.31). mmol) of 4- (methylsulfanyl) -6-0x0-2- [3- (trifluoromethyl) benzyl] -1,6-dihydropyrimidine-5-carbonitrile with 262 mg (3.07 mmol) of piperidine to give 26 mg (22% of the theoretical) of the title compound. HPLC (method 12): R t = 4.7 min. MS (ESIpos): m / z = 363 [M + H] + X H NMR (DMSO-de, 200 MHz): d = 1.43-1.70 (m, 6H), 3.71-3.83 (, 4H), 3.93 (s, 2H), 7.51-7.78 (m, 4H), 12.42 (s, 1H).

Example 22 6-Oxo-4- (propylamine) -2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile was reacted with 224 mg ( 3.80 mmol) of n-propylamine to give 14 mg (13% of theory) of the title compound. HPLC (method 12): R t = 4.1 min. MS (ESIpos): m / z = 275.2 [M + H] + - 2 H NMR (DMSO-de, 300 MHz): d = 0.79 (t, 3H), 1.46 (m, 2H), 3.29 (m, 2H) , 3.81 (s, 2H), 7.06 (d, 1H), 7.33 (s, 1H), 7.49 (m, 1H), 7.87 (s, 1H), 12.27 (s, 1H).

Example 23 4- (Cyclopropylamino) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) ~ 6-OXO-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile was reacted with 217 mg ( 3.80 mmol) of cyclopropylamine to give 44 mg (43% of theory) of the title compound. HPLC (method 12): Rt = 3.8 min. MS (ESIpos): m / z = 273 [M + H] + X H NMR (DMSO-d 6, _ 300 MHz): d = 0.60-0.78 (m, 4H), 2.84-2.98 (, 1H), 3.80 (s) , 2H), 7.08 (d, 1H), 7.35 (s, 1H), 7.49 (, 1H), 7.85-8.05 (s, 1H), 12.32 (s, 1H).

Example 24 4- (Cyclopentylamino) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 150 mg (0.57 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile were reacted with 485 mg ( 5.70 mmol) of cyclopentylamine to give 46 mg (26% of theory) of the title compound. HPLC (method 12): Rt = 4.4 min. MS (ESIpos): m / z = 301.2 [M + H] + 2 H NMR (DMSO-de, 300 MHz): d = 1.40-1.91 (i, 8H), 3.81 (s, 2H), 4.36 (m, 1H ), 7.07 (d, 1H), 7.34 (s, 1H), 7.50 (m, 1H), 7.65 (s, 1H), 12.28 (s, 1H).

Example 25 6-0x0-4- (1-pyrrolidinyl) -2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile was reacted with 270 mg (3.80 mmol) of pyrrolidine to give 64 mg (59% of theory) of the title compound. HPLC (method 12): R t = 4.1 min. MS (ESIppos): m / z = 287 [M + H] + X H NMR (DMSO-d 6, 300 MHz): d = 1.80-1.96 (m, 4H), 3.60-3.76 (m, 4H), 3.78 (s) , 2H), 7.08 (d, 1H), 7.35 (s, 1H), 7.48 (m, 1H), 12.27 (s, 1H).

Example 26 4- (4-methylpiperidin-1-yl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1 ,. 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile were reacted with 377 mg (3.80 mmol) of 4-methylpiperidine to give 65 mg (54% of theory) of the title compound. HPLC (method 12): R t = 4.5 min. MS (ESIpos): m / z = 315 [M + H] + 1 H NMR (DMSO-d 6, 300 MHz): d = 0.91 (d, 3H), 1.05-1.18 (t, 2H), 1.62-1.77 (, 3H), 3.06 (t, 2H), 3.80 (s, 2H), 4.61 (d, 2H), 7.07 (d, 1H), 7.34 (s, 1H), 7.49 (, 1H), 12.32 (s, 1H) .

Example 27 4- (4,4-dimethylpiperidin-1-yl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -β-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile was reacted with 430 mg ( 3.80 mmol) of 4,4-dimethylpiperidine to give 42 mg (34% of theory) of the title compound. HPLC (method 12): R t = 4.6 min. MS (ESIpos): m / z = 329 [M + H] + E NMR (DMSO-de, 300 MHz): d = 0.97 (s, 6H), 1.37 (t, 4H), 3.77-3.87 (m, 6H , sa 3.80), 7.06 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H), 12.31 (s, 1H).

Example 28 4- [4- (tert-butyl) piperidin-1-yl] -6-oxo-2- (J3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-0x0-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile were reacted with 536 mg ( 3.80 mmol) of 4-tert-butylpiperidine to give 57 mg (42% of theory) of the title compound. HPLC (method 12): R t = 4.9 min. MS (ESIpos): m / z = '357 [M + H] + X H NMR (DMSO-de, 200 MHz): d = 0.82 (s, 9H) 1.02-1.42 (m, 3H), 1.74 (d, 2H ),. 2.96 (t, 2H), 3.78 (s, 2H), 4.72 (d, 2H), 7.06 (d, 1H), 7.33 (s, 1H), 7.49 (m, 1H), 12.35- (s, 1H).

EXAMPLE 29 4- (4-hydroxypiperidin-1-yl) -6-oxo-2- (3-thienymethyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-0x0-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile was reacted with 384 mg ( 3.80 mmol) of piperidin-4-ol to give 47 mg (39% of theory) of the title compound. HPLC (method 12): Rt = 3.50 min. MS (ESIpos): m / z = 317 [M + H] + NMR y (DMSO-de, 200 MHz): d = 1.29-1.50 (m, 2H), 1.72-1.90 (m, 2H), 3.42-3.60 (m, 2H), 3.68-3.86 (, 3H, s to 3.79), 4. 10-4.26 (m, 2H), 4.83 (d, 1H, OH), 7.07 (d, 1H), 7.35 (s, 1H), 7.50 (, 1H), 11.79-12.29 (s, 1H, NH).

EXAMPLE 30 4- [4- (2-Hydroxyethyl) piperidin-1-yl] -6-oxo-2- (3-thienylmethyl) 1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2 ~ (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile were reacted with 491 mg (3.80 mmol) of 2- (4-piperidinyl) ethan-1-ol to give 64 mg (49% of theory) of the title compound. HPLC (method 12): R t = 3.70 min. MS (ESIpos): m / z = 345 [M + H] + X H NMR (DMSO-d 6, 300 MHz): d = 1.02-1.20 (m, 2H), 1.32-1.42 (q, 2H), 1.68-1.81 (m, 3H), 3.05 (t, 2H), 3.44 (q, 2H), 3.80 (s, 2H), 4.34 (t, 1H, OH), 4.62 (d, 2H), 7.06 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H), 12.31 (s, 1H, NH).

Example 31 4- [(2-methoxyethyl) amino] -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg was reacted (0.38). mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile with 285 mg (3.80 mmol) of 4-methoxyethylamine to give 76 mg (69% of theoretical ) of the title compound. HPLC (method 12): Rt = 3. 1 min. MS (ESIpos): m / z = "291 [M + H] + 1 H NMR (DMSO-de, 300 MHz): d = 3.20 (s, 3H), 3.35-3.42 (m, 2H), 3.47-3.56 ( m, 2H), 3.82 (s, 2H), 7.07 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H), 7.79 (s, 1H), 12.33 (s, 1H).

EXAMPLE 32 4- (1, 4-d? Oxa-8-azaspiro [4.5] dec-8-yl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile was reacted with 544 mg ( 3.80 mmol) of 1,4-dioxa-8-azaspiro [4, 5] decane to give 65 mg (48% of theory) of the title compound. HPLC (method 12): Rt = 4.0 min. MS (ESIpos): m / z = 359 [M + H] + 2 H NMR (DMSO-d 6, 300 MHz): d = 1.70 (t, 4H), 3.81 (s, 2H), 3.86-3.95 (m, 8H , sa 3.92), 7.07 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H), 12.41 (s, 1H).

Example 33 4- (7,11-dioxa-3-azaspiro [5.5] undec-3-yl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile was reacted with 597 mg ( 3.80 mmol) of 1,5-dioxa-9-azaspiro [5.5] undecane to give 86 mg (61% of theory) of the title compound. HPLC (method 12): Rt = 4.0 min. MS (ESIpos): m / z = 373 [M + H] + 2 H NMR (DMSO-d 6, 200 MHz): d = 1.56 (m, 2H), 1.82-1.94 (m, 4H), 3.75-3.92 (m , 10H, sa 3.80), 7.07 (d, 7H), 7.35 (s, 1H), 7.50 (m, 1H), 12.43 (broad s, 1H).

EXAMPLE 34 4- (4-Methylpiperazin-1-yl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile was reacted with 380 mg ( 3.80 mmol) of N-methylpiperazine to give 36 mg (30% of theory) of the title compound. HPLC (method 12): Rt = 3.2 min. MS (ESIpos): m / z = 316 [M + H] + X H NMR (DMSO-de, 200 MHz): d = 2.19 (s, 3H), 2.37 (t, 4H), 3.77-3.91 (m, 6H , sa 3.80), 7.07 (d, 1H), 7.35 (s, 1H), 7.50 (m, 1H), 12.43 (s, 1H).

Example 35 6-0x0-4- (piperazin-1-yl) -2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 80 mg (0.30 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile were reacted with 326 mg ( 3.80 mmol) of piperazine to give 45 mg (49% of theory) of the title compound. HPLC (method 12): Rt = 3.15 min. MS (ESIpos): m / z = 302 [M + H] + 2 H NMR (DMSO-de, 200 MHz): d = 2.75 (t, 4H), 3.76-3.82 (m, 6H, sa 3.80), 7.06 ( d, 1H), 7.34 (s, 1H), 7.49 (m, 1H).

Example 36 4- (Benzylamino) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -d-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile were reacted with 407 mg ( 3-80 mmol) of benzylamine to give 43 mg (35% of theory) of the title compound. HPLC (method 12): Rt = 4.3 min. MS (ESIpos): m / z = 323 [M + H] + NMR y (DMSO-de, 200 MHz): d = 3.80 (s, 2H), 4.52 (d, 2H), 6.95.95 (d, 1H), 7.16-7.32 (m, 6H), 7.45 (m, 1H), 8.49 (t, 1H) ', 12.40 (s, 1H).

Example 37 4- [(2-methoxybenzyl) amino] -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile was reacted with 521 mg ( 3.80 mmol) of 2-methoxybenzylamine to give 62 mg (46% of theory) of the title compound. HPLC (method 12): Rt = 4.4 min. MS (ESIpos): m / z = 353 [M + H] + aH NMR (DMSO-de, 300 MHz): d = 3.75 (s, 2H), 3.80 (s, 3H), 4.56 (d, 2H), 6.84-6.90 (m, 2H), 6.96-7.04 (m, 2H), 7.16 (s, 1H) 7.23 (t, 1H), 7.39 m, 1H) 15 (t, 1H), 12.34 (s, 1H) EXAMPLE 38 4- [4- (2-Hydroxyethyl) piperidin-1-yl] -2- [2- (6-methoxypyridin-3-yl) benzyl] -6-oxo-l, 6-dihydropyrimidine-5-carbonitrile In analogy to the preparation of Example 1, 80 mg (0.22 mmol) of 2- [2- (6-methoxypyridin-3-yl) -benzyl] -4- (methylsulfanyl) -6-oxo-1, 6 were reacted -dihydropyrimidine-5-carbonitrile with 85 mg (0.65 mmol) of 2- (4-piperidine) ethan-1-ol to give 62 mg (63% of theory) of the title compound. The following compound is prepared by the general synthetic route described in Reaction Scheme II: Reaction Scheme II: X = Cl, Br a) 1. toluene, boron trifluoride etherate, room temperature, 30 min .; 2. amine component R1R2NH, 150 ° C, 16 hours; or: fusion of the initial compounds at 150 ° C, 1-16 hours; b) DMF, triethylamine, 100 ° C, 16 hours or DMF, potassium carbonate, 90 ° C, 16 hours.

Example 39 4- (Cyclohexylamino) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile 69. 5 mg (0.39 mmol) of 2- (3-thienyl) ethanamidine hydrochloride are dissolved together with 100 mg (0.39 mmol) of (2E / z) -2-cyano-3- (cyclohexylamino) -3-methylthioprop-2 Methyloate and 159 mg (1.57 mmol) of triethylamine in 0.5 ml of DMF and stir at 100 ° C overnight. The cooled mixture is taken up in a small amount of water and extracted with dichloromethane. The dichloromethane phase is dried over sodium sulfate and concentrated, and the residue is subjected to flash chromatography on silica gel (mobile phase :, dichloromethane, then dichloromethane / methanol 200: 1, 100: 1). 23 mg (19% of theory) of the product were obtained. HPLC (method 12): R t = 4.55 min. MS (DCI, NH3): m / z = -315 [M + H] + X H NMR (DMSO-de, 400 MHz): d 0.98-1.43 (m, 5H), 1.53-1.74 (m, 5H), 3.78 -3.94 (m, 3H, sa 3.82), 7.06 (d, 1H), 7.33 (s, 1H), 7.50 (, 1H), 7.54 (m, 1H), 12.28 (s, 1H).

Example 40 4- (4-formylpiperazin-1-yl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile 11. 3 mg (0.17 mmol) of imidazole are introduced together with 33.6 mg (0.33 mmol) of triethylamine and 7.64 mg (0.17 mmol) of formic acid in 5 ml of dichloromethane under an argon atmosphere and cooled to 0 ° C. Then a solution of 21.1 mg (0.17 mmol) of oxalyl chloride in dichloromethane is added dropwise, and the mixture is then stirred for 15 minutes. 50 mg (0.17 mmol) of 6-oxo-4- (piperazin-1-yl) -2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile are added and the mixture is stirred at room temperature. the night. This is then washed with 1N potassium bisulfate solution, the dichloromethane phase is dried over sodium sulfate and concentrated, and the residue is subjected to flash chromatography on silica gel (mobile phase: dichloromethane / methanol 100: 1, 80: 1, 60: 1). 16 mg (29% of theory) of the title compound were obtained. HPLC (method 12): Rt = 3.4 min. MS (ESIpos): m / z = 330 [M + H] + NMR y (DMSO-dg, 200 MHz): d = 3.42-3.54 (m, 4H), 3.79-3.94 (m, 6H, sa 3.82), 7.09 (d, 1H), 7.36 (s, 1H), 7.51 (, 1H), 8.06 (s, 1H), 12.55 (s, 1H).

Example 41 4- (4-Acetylpiperazin-1-yl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile 50 mg (0.17 mmol) of 6-oxo-4- (piperazin-1-yl) -2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile are dissolved together with 34 mg (0.33 mmol) of triethylamine in DMF and stirred with 14.3 mg (0.18 mmol) of acetyl chloride at room temperature overnight. The mixture is then diluted with dichloromethane and washed with water. The organic phase is separated and dried over sodium sulfate and the residue is subjected to flash chromatography on silica gel (mobile phase: dichloromethane / methanol 100: 1, 80: 1, 60: 1). 42 mg (74% of theory) of the title compound were obtained. HPLC (method 12): Rt = 3.5 min. MS (ESIpos): m / z = 344 [M + H] + X H NMR (DMSO-d 6, 300 MHz): d = 2.02 (s, 3 H), 3.50-3.61 (m, 4 H), 3.80-3.95 (m , 6H, sa 3.82), 7.08 (d, 1H), 7.36 (s, 1H), 7.50 (m, 1H), 12.47 (s, 1H).

Example 42 4- (4-ethylpiperazin-1-yl) -6-oxo-2- (3-thienylmethyl) -1,6- '• dihydropyrimidine-5-carbonitrile 50 mg (0.17 mmol) of 6-oxo-4- (piperazin-1-yl) -2- (3-thienylmethyl) -1,6-dihydropyrimidin-5-carbonitrile are dissolved together with 34 mg (0.33 mmol) of triethylamine in DMF and, after the addition of 19.9 mg (0.18 mme -1) of bromoethane, are stirred at room temperature overnight. The mixture is then diluted with dichloromethane and washed with water. The organic phase is separated and dried over sodium sulfate, and the residue is subjected to flash chromatography on silica gel (mobile phase: dichloromethane / methanol 100: 1, 80: 1, 60: 1, 40: 1). 38 mg (70% of theory) of the title compound were obtained. HPLC (method 12): Rt = 3.3 min. MS (ESIpos.): M / z = 330 [M + H] + NMR and (DMSO-d6, 300 -MHz): d = 1.00 (t, 3H), 2.34 (q, 2H), 2.42 (t ,. 4H), 3.80 (s, 2H), 3.86 (t, 4H), 7.06 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H), 12.39 (s, 1H). The exemplary modalities listed in the following table are prepared in analogy to the examples described above: It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (12)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. The compounds of the formula characterized because A is phenyl, heteroaryl or a group of the formula wherein the phenyl and heteroaryl are optionally substituted with up to 2 radicals independently selected from the group of heteroaryl, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, trifluoromethoxy, benzyloxy and benzyl, wherein the alkyl of 1 to 6 carbon atoms is optionally substituted with a group of the formula -NR3R4 in which R3 is alkyl of 1 to 6 carbon atoms and R4 is hydrogen or (alkoxy of 1 to 6 carbon atoms) ( alkyl of 1 to 6 carbon atoms). , and the heteroaryl is optionally substituted by alkoxy of 1 to 6 carbon atoms, R1 is cycloalkyl of 3 to 8 carbon atoms, alkyl of 1 to 6 carbon atoms, (alkoxy of 1 to 6 carbon atoms) 1 to 6 carbon atoms), benzyl or a group of the formula where the cycloalkyl of 3 to 8 carbon atoms is optionally substituted with hydroxyl, alkyl of 1 to 6 carbon atoms or trifluoromethyl, alkyl of 1 to 6 carbon atoms is optionally substituted with heteroaryl, cycloalkyl of 3 to 8 carbon atoms or hydroxyl, and benzyl is optionally substituted with alkoxy of 1 to 6 carbon atoms or halogen, R 2 is hydrogen, or R 1 and R 2 together with the nitrogen atom to which they are bonded form a 5- to 6-membered heterocyclyl which is optionally substituted with up to 2 substituents independently selected from each other from the group of alkyl of 1 to 6 carbon atoms, hydroxyl, cyano, oxo, heteroaryl, benzyl, formyl, alkylcarbonyl of 1 to 6 carbon atoms and one of the following groups which are linked via the two oxygen atoms to one of the carbon atoms in the heterocycle, where the alkyl of 1 to 6 carbon atoms is optionally substituted with hydroxyl or heteroaryl, and the salts, solvates and / or solvates of the salts thereof .

2. The compounds according to claim 1, characterized in that A is phenyl, heteroaryl or a group of the formula wherein phenyl and heteroaryl are optionally substituted with up to 2 radicals independently selected from the group of heteroaryl, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, trifluoromethyl, trifluoromethoxy, benzyloxy and benzyl, wherein the alkyl of 1 to 4 carbon atoms is optionally substituted with a group of the formula -NR3R4 in which R3 is alkyl of 1 to 4 carbon atoms and R4 is hydrogen or (alkoxy of 1 to 4 carbon atoms) ( alkyl of 1 to 4 carbon atoms), and the heteroaryl is optionally substituted by alkoxy of 1 to 4 carbon atoms, R1 is cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms, (alkoxy of 1 a-4 carbon atoms) (alkyl of 1 to 4 carbon atoms), benzyl or a group of the formula wherein the cycloalkyl of 3 to 6 carbon atoms is optionally substituted with hydroxyl, alkyl of 1 to 4 carbon atoms or trifluoromethyl, alkyl of 1 to 4 carbon atoms is optionally substituted with heteroaryl, cycloalkyl of 3 to 6 carbon atoms or hydroxyl, and benzyl is optionally substituted by alkoxy of 1 to 4 carbon atoms or halogen, R2 is hydrogen, or R1 and R2 together with the nitrogen atom to which they are bonded form a heterocyclyl of 5 to 6 members which is optionally substituted with up to 2 substituents independently selected from each other from the group of alkyl of 1 to 4 carbon atoms, hydroxyl, cyano, oxo, heteroaryl, benzyl, formyl, alkylcarbonyl of 1 to 4 carbon atoms and one of the following groups which are linked via the two oxygen atoms to one of the carbon atoms in the heterocycle, where the alkyl of 1 to 4 carbon atoms is optionally substituted with hydroxyl or heteroaryl, and the salts, solvates and / or solvates of the salts thereof .

3. The compounds according to claims 1 and 2, characterized in that A is phenyl, thienyl or a group of the formula wherein phenyl and thienyl are optionally substituted with up to 2 independently selected radicals from each other from the group of pyridyl, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms alkoxy of 1 to 4 carbon atoms, trifluoromethyl, trifluoromethoxy, benzyloxy and benzyl, wherein the alkyl of 1 to 4 carbon atoms is optionally substituted with a group of the formula -NR3R4 in which R3 is alkyl of 1 to 4 atoms carbon and R 4 is hydrogen or (C 1 -C 4 alkoxy) (C 1 -C 4 alkyl), and the pyridyl is optionally substituted with C 1 -C 4 alkoxy, R 1 is C 3 -cycloalkyl 6 carbon atoms, alkyl of 1 to 4 carbon atoms, (alkoxy of 1 to 4 carbon atoms) (alkyl of 1 to 4 carbon atoms), benzyl or a group of the formula wherein the cycloalkyl of 3 to 6 carbon atoms is optionally substituted with hydroxyl, alkyl of 1 to 4 carbon atoms or trifluoromethyl, alkyl of 1 to 4 carbon atoms is optionally substituted with pyridyl, cycloalkyl of 3 to 6 carbon atoms or hydroxyl, and benzyl is optionally substituted with alkoxy of 1 to 4 carbon atoms fluorine, chlorine or bromine, R 2 is hydrogen, or R 1 and R-22 together with the nitrogen atom to which they are bonded form a heterocyclyl of 5 to 6 members selected from the group of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, which are optionally substituted with up to 2 substituents independently selected from each other from the group of alkyl of 1 to 4 carbon atoms, hydroxyl, cyano, oxo, heteroaryl, benzyl, formyl, alkylcarbonyl of 1 to 4 carbon atoms and one of the following groups . i which are linked via the two oxygen atoms to one of the carbon atoms in the heterocycle, where the alkyl of 1 to 4 carbon atoms is optionally substituted with hydroxyl or pyridyl, and the salts, solvates and / or solvates or salts of them.

4. The compounds according to claims 1, 2 and 3 characterized in that A is phenyl, thienyl or a group of the formula wherein the phenyl is optionally substituted with up to 2 radicals independently selected from each other from the group of pyridyl, fluorine, chlorine, methyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, benzyloxy and benzyl, wherein the methyl is optionally substituted with a group of the formula -NR3R4 in which R3 is methyl and R4 is hydrogen or 2-methoxyethyl, and pyridyl is optionally substituted with methoxy, R1 is cycloalkyl of 3 to 6 carbon atoms, methyl, ethyl, propyl, 2-methoxyethyl, benzyl or a group of the formula wherein the cycloalkyl of 3 to 6 carbon atoms is optionally substituted with hydroxyl, methyl or trifluoromethyl, methyl, ethyl, propyl is optionally substituted with pyridyl, cyclopropyl or hydroxyl, and the benzyl is optionally substituted with methoxy, ethoxy, fluorine or chlorine , R 2 is hydrogen, or R 1 and R 2 together with the nitrogen atom to which they are linked form a heterocyclyl of 5 to 6 members selected from the group of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, which is optionally substituted with up to 2 substituents independently selected one of the other group of methyl, ethyl, propyl, tert-butyl, hydroxyl, cyano, oxo, pyridyl, benzyl, formyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl and one of the following groups, which are linked via the two oxygen atoms to one of the carbon atoms in the heterocycle, where methyl, ethyl and propyl are optionally substituted with hydroxyl or pyridyl, and the salts, solvates and / or solvates of the salts thereof.

5. The processes for the preparation of the compounds of the formula (I), characterized either by [A] a compound of the formula is initially converted with a compound of the formula HNRV (III), in which R1 and R2 have the meanings mentioned above, at elevated temperature in an inert solvent or even in the absence of a solvent to a compound of the formula in which R1 and R2 have the meanings mentioned above, and the latter is then reacted in an inert solvent in the presence of a base with a compound of the formula X = CI, Brorl wherein A has the meanings mentioned above, or in a modified sequence of the reactants [B] a compound of the formula (II) is initially converted with a compound of the formula (V) into an inert solvent in the presence of a base , to a compound of the formula wherein A has the meanings mentioned above, and the latter is then reacted at elevated temperature in inert solvent, or even in the absence of a solvent with a compound of the formula (III), and the compounds of the formula (I) resulting in each case are reacted, where appropriate, with the (i) solvents and / or (ii) appropriate bases or acids, to give their solvates, salts and / or solvates of the salts.

6. The compounds according to any of claims 1 to 4, characterized in that they are for the treatment and / or prophylaxis of diseases.

7. A medicament, characterized in that it comprises at least one of the compounds according to any of claims 1 to 4, and at least one pharmaceutically acceptable carrier or excipient, essentially non-toxic. The use of the compounds according to any of claims 1 to 4, for the production of a medicament for the prophylaxis and / or treatment of impairment of perception, concentration, learning and / or memory. 9. The use according to claim 8, wherein the deterioration is a consequence of Alzheimer's disease. The use of the compounds according to any of claims 1 to 4, for the production of a medicament for improving perception, concentration, -the learning and / or memory. 11. A method for controlling impairments of perception, concentration, learning and / or memory in humans or animals, characterized in that an effective amount of the compounds is administered according to claims 1 to 4. 12. The method according to claim 11, characterized in that the deterioration is a consequence of Alzheimer's disease.