EP1599479A1

EP1599479A1 - Substituted imidazotriazines

Info

Publication number: EP1599479A1
Application number: EP03735677A
Authority: EP
Inventors: Martin Hendrix; David BRÜCKNER; Arno Friedl; Irene Gerlach; Volker Hinz; Jörg Keldenich; Frank Mauler; Ulrich Niewöhner; Dagmar Karthaus; Karl-Heinz Schlemmer; Adrian Tersteegen; Özkan Yalkinoglu
Original assignee: Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 2002-07-08
Filing date: 2003-06-25
Publication date: 2005-11-30
Also published as: DE10230605A1; WO2004005290A1; US7202243B2; AU2003238043A1; US20060166993A1; CA2491500A1; JP2005536485A

Abstract

The invention relates to novel substituted imidazotriazines, to methods for the production thereof, and to their use for producing medicaments for the treatment and/or prophylaxis of cancer and neurodegenerative diseases, particularly Parkinson's disease and schizophrenia.

Description

Substituted imidazotriazines

The invention relates to new substituted imidazotriazines, processes for their preparation and their use for the manufacture of medicaments for the treatment and / or prophylaxis of cancer and neurodegenerative diseases, in particular Parkinson's disease and schizophrenia.

The cyclic nucleotides cGMP and cAMP are among the most important intracellular messengers. Phosphodiesterases (PDEs) play an important role in regulating the concentrations of cGMP and cAMP. So far there are 11

Phosphodiesterase isoenzyme groups known (PDE 1-7: Beavo et al. Mol.

Pharmacol. 1994, 399-405; PDE 8-10: Soderling and Beavo Curr. Opin. Cell Biol.

2000, 12, 174-179; PDE 11: Fawcett et al. Proc. Natl. Acad. Be. U: S.A. 2000, 97, 3702-3707).

The PDE 10A hydrolyzes both cAMP and cGMP (Fujishige J. Biol. Chem. 1999, 274, 18438-18445). Transcribed PDE 10A was identified primarily in the putamen and caudate nucleus regions of the brain, as well as in thyroid and testicular tissue. Compared to normal tissue, the PDE IOA mRNA is also increasingly expressed in certain tumor tissues, such as tissues of breast, liver, colon and lung tumors.

Parkinson's disease is a chronically progressive, neurodegenerative disease characterized by the loss of dopaminergic neurons of the substantia nigra. The massive disturbances of the dopaminergic neurotransmission caused thereby lead to a serious malfunction of the movement-controlling extrapyramidal system. The main characteristics of early signs and symptoms of Parkinson's disease are rest tremor, slowness of movement, muscle stiffness, and unstable posture. The current medications for Parkinson's disease are of a symptomatic nature, with substitution therapy with L-dopa being the most frequently used form of therapy. Neither preventive nor restorative therapies are currently available (Mendis et al., Can. J. Neurol 1999, 26, 89-103).

Parkinson's idiopathic disease is a chronic, progressive neurological disorder that belongs to a broader classification of neurological diseases called parkinsonism. It is clinically defined by the appearance of at least two of the four cardinal symptoms: bradykinesia, resting tremor, muscle stiffness, and postural and movement disorders.

Pathologically, the idiopathic form of Parkinson's disease is characterized by the loss of pigmented nerve cells, particularly in the area of the substantia nigra of the brain. The idiopathic Parkinson's disease makes up about 75% of all Parkinsonism diseases. The remaining 25% of cases are referred to as atypical Parkinsonism and include clinical pictures such as multiple

System atrophy, striatonigral degeneration or vascular parkinsonism.

Schizophrenia is a chronic psychiatric illness that is characterized by psychoses, so-called "negative symptoms" such as apathy and social seclusion, subtle cognitive deficits and a lack of illness. The

The aetiology and exact pathophysiology of schizophrenia and related schizoaffective disorders are still not known exactly today (Kurachi, Psychiatry Clin. Neurosci. 2003, 57, 3-15; Lewis and Levitt, Ann. Rev. Neurosci. 2002, 25, 409- 432). Postmortem examinations in the brain of schizophrenic individuals showed abnormal cell distributions in different brain regions, and neuroimaging studies revealed changes in brain activation patterns in schizophrenia patients (Goff et al., Med. Clin. N. Am. 2001, 85, 663-689) , There are indications that cGMP may be involved in the pathogenesis of psychoses. For example, Gattaz et al. (Gattaz et al., Br. J. Psychiatry 1983, 142, 288-291) reported that the levels of cGMP in the cerebrospinal fluid were more schizophrenic

Patients are changed. It was also shown that the gift of the classic Antipsychotic haloperidol increases the cGMP content of the cerebrospinal fluid ^" (Gattaz et al., Biol. Psychiatry 1984, 19, 1229-35).

Although the details of the neuroanatomical basis of schizophrenic disorders are still the subject of medical research, it could be shown that, among other things, the basal ganglia play an important role in these diseases (e.g. Shenton et al., Schizophr. Res. 2001, 49, 1- 52 ).

The synthesis of 4-amino-2,5-diphenyl-7-memyltmo-imidazo [5, l-fJ- [1,2,4] triazines is known from Synthesis 1989, 843-847.

No. 3,941,785 describes 2-amino-imidazo [5, l-f] - [l, 2,4] triazines as PDE inhibitors with spasmolytic activity for the treatment of asthma, bronchitis, chronic heart failure and skin diseases.

EP-A 1 250 923 describes the use of selective PDE10 inhibitors, such as e.g. Papaverine, used to treat central nervous system disorders such as Parkinson's disease.

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

in which R ^{1 is} hydrogen or -CC ₆ alkyl, ^{'• ■} = ^"

R ^{5 is} hydrogen, formyl, d-Ce-alkyl, C ₁ -C ₆ -alkyl-sulfonyl, C ₃ -C ₈ -cycloalkylcarbonyl or (3 to 8-membered heterocyclyl) carbonyl, alkylcarbonyl having up to 3 substituents - independently selected from the series halogen, hydroxyl, amino, carboxy, Cj _. - C ₆ alkoxy, C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkylamino and a 3 to 8-membered heterocyclyl substituted with up to 3 dC ₃ alkyl substituents - may be substituted,

or

R ¹ and R ⁵ together with the nitrogen atom to which they are attached form a 5 to 8-membered heterocycle which, with up to 3 substituents - independently of one another selected from the series halogen, hydroxy,

Cι-C ₆ -Aιkyl, Ci-C _ö alkoxy, C ₆ -C ₁₀ aryl, amino and alkyl amino dC _ό - may be substituted,

R ² Ci-C _ö alkyl or C ₃ -C ₄ cycloalkyl,

R ³ methyl,

A is an oxygen atom or NH,

and

R ⁴ C ₆ -C ₁₀ aryl, which has up to 3 substituents - independently selected from the series halogen, formyl, carboxyl, carbamoyl, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, -Ce-alkyl, Ci-Cβ- Alkoxy, l, 3-dioxa-propane-l, 3-diyl, Ci-Ce-alkylthio and -NR ⁶ R ⁷ - can be substituted, embedded image in which

R ⁶ and R ⁷ are independently hydrogen, Ci-C _δ -alkyl or _(Cj-C6 _-. Alkyl) carbonyl stand mean

and their salts, solvates or solvates of the salts.

Depending on their structure, the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and their respective mixtures. The stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers.

In the context of the invention, salts which are physiologically acceptable are the salts

Compounds (I) preferred.

Physiologically acceptable salts of the compounds (T) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,

Ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds (I) also include salts more commonly

Bases, such as, for example and preferably, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, for example and preferably emylamine, diethylamine, Triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclo-hexylamine, Dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, del ydroabietyl-arnine, arginine, lysine, ethylenediamine and methylpiperidine.

In the context of the invention, solvates are those forms of the compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvate, in which coordination takes place with water.

In the context of the present invention, unless otherwise stated, the substituents have the following meaning:

Ci-Ce-alkoxy stands for a straight-chain or branched alkoxy radical having 1 to 6, preferably 1 to 4, particularly preferably having 1 to 3 carbon atoms. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Q-Ce-alkylamino stands for a straight-chain or branched alkylamino radical having 1 to 6, preferably 1 to 4, particularly preferably having 1 to 3 carbon atoms. Nonlimiting examples include methylamine, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino and n-hexylamino, dimemylamino, diethylamino, di-n-propylarnino, diisopropylamino, di-t-butylamino, Di-n-pentylarnino, di-n-hexylamino, E & ylmemylamino, isopropylmemylamino, n-butylethylamino, n-hexyl-i-penlylamino.

Ct-Ce-alkyl represents a straight-chain or branched alkyl radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

(C _1: C ₆ alkyl) carbonyl represents a straight-chain or branched alkylcarbonyl radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms. Non-limiting examples include acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl.

(3 to 8-membered cycloalkyl) carbonyl stands for monocyclic cycloalkyl bonded via a carbonyl group. Non-limiting examples include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and cycloheptylcarbonyl.

(3 to 8-membered heterocyclyl) carbonyl stands for a heterocyclyl bonded via a carbonyl group. Non-limiting examples include tetrahydrofuran-2-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrrohdin-3-ylcarbonyl, pyrrolinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl and perhydroazepinylcarbonyl.

Ci-Ce-alkylsulfonyl represents a straight-chain or branched alkylsulfonyl radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms. Nonlimiting examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.

C -C ₆ -Akylthio represents a straight-chain or branched alkylthio radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms. Non-limiting examples include methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.

Cά-Cio-Ary! stands for an aromatic radical with 6 to 10 carbon atoms. Non-limiting examples include phenyl and naphthyl.

Halogen stands for fluorine, chlorine, bromine and iodine. Fluorine, chlorine, bromine are preferred, fluorine and chlorine are particularly preferred.

3 to 8-membered heterocyclyl stands for a mono- or polycyclic, preferably mono- or bicyclic, non-aromatic radical with generally 4 to 8, preferably 5 to 8 ring atoms and up to 3, preferably atoms up to 2 Heterό- ^"or hetero groups selected from N, O, S, SO, SO _2. The heterocyclyl residues can be saturated or partially unsaturated. Not -limiting examples include 5- to 8-membered, monocyclic saturated heterocyclyl radicals having up to two hetero ring atoms from the series O, N and S, such as tetrahydrofuran-2-yl,

Pyrrolidin-2-yL pyrrolidin-3-yl, pyrrolinyl, piperidinyl, molinyl, perhydro azepinyl.

5 to 8-membered heterocycle stands for a mono- or polycyclic, heterocyclic radical with 5 to 8 ring atoms and up to 3, preferably 2 hetero atoms or hetero groups from the series N, O, S, SO, SO ₂ , where at least one of the heteroatoms or hetero groups is a nitrogen atom. 5- to 7-membered

Heterocyclyl is preferred. Mono- or bicyclic heterocyclyl is preferred.

Monocyclic heterocyclyl is particularly preferred. O, N and S are preferred as heteroatoms. The heterocyclyl residues can be saturated or partially unsaturated. Saturated heterocyclyl residues are preferred. 5- to 7-membered, monocyclic saturated heterocyclyl with up to two heteroatoms from the series O, N and S is particularly preferred. Non-limiting examples include pyrrolinyl,

Piperidinyl, morpholinyl, perhydroazepinyl.

C ₃ -C ₄ cycloalkyl stands for monocyclic cycloalkyl, such as. B. cyclopropyl and cyclobutyl.

If radicals in the compounds according to the invention are optionally substituted, a substitution with up to three identical or different substituents is preferred, unless otherwise specified.

The compounds according to the invention can also be present as tautomers, as is shown below by way of example for A = NH:

Another embodiment of the invention relates to compounds of the formula (I)

in which

R ^{1 is} hydrogen,

R ^{5 is} hydrogen, (C ₃ -C ₆ -cycloalkyl) carbonyl, (4 to 6-membered heterocyclyl) carbonyl or (Ci-d-Alkyrjcarbonyl, wherein alkylcarbonyl with hydroxy or

Amino can be monosubstituted,

R ² dC _ö alkyl,

R ³ methyl,

A is an oxygen atom or NH,

and

R ^{4 is} phenyl, which can be substituted with up to 3 substituents, independently of one another selected from the group consisting of halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy and their salts, solvates or solvates of the salts. ^• - ^"

Another embodiment of the invention relates to compounds of the formula (I)

in which

R ^{5 is} hydrogen, (C ₃ -C6-cycloalkyl) carbonyl, (4 to 6-membered heterocyclyl) carbonyl or (C] .- C ₃ -alkyl) carbonyl, where alkylcarbonyl can be monosubstituted with hydroxy or amino, and

R ¹ , R ² , R ³ , R ⁴ and A have the meanings given above

and their salts, solvates or solvates of the salts.

Another embodiment of the invention relates to compounds of the formula (I)

in which

R ^{2 is} dC ₆ alkyl, and

R ¹ , R ⁵ , R ³ , R ⁴ and A have the meanings given above

and their salts, solvates or solvates of the salts.

Another embodiment of the invention relates to compounds of the formula (T)

in which

R ^{4 is} phenyl, which can be substituted by 1 to 3 (dC ₆ ) alkoxy radicals, and R ¹ , R ⁵ , R ² , R ³ and A have the meanings given above

and their salts, solvates or solvates of the salts.

Another embodiment of the invention relates to compounds of the formula (I)

in which

R ^{4 represents} 3,4,5-trimethoxyphenyl, and

R ¹ , R ⁵ , R ² , R ³ and A have the meanings given above.

The invention further relates to processes for the preparation of the compounds according to the invention by reacting

[A] compounds of the formula (II),

in which

R ¹ , R ⁵ , R ² and R ^{3 have} the meaning given above,

with compounds of the formula (ffl), R ^' (JTI)

\

A - H

in which

R ⁴ and A have the meaning given above,

or

[B] compounds of the formula (Ia),

in which

R, R, R and A have the meaning given above,

with compounds of the formula (IV),

R / (rv) in which

R ^{5 has} the meaning given above and X ^{1 represents} halogen, preferably bromine or chlorine, or hydroxyl,

to compounds of the formula (Ib),

in which

R, R, R, R and A have the meanings given above,

or

[C] Compounds of the formula

in which

R, R, R and A have the meanings given above,

with compounds of the formula (VT),

in which

R ¹ and R ^{5 have} the meaning given above

and a further reaction of the resulting compounds (I) optionally with the corresponding (i) solvents and / or (ii) bases or acids to give their solvates, salts or solvates of the salts.

The reaction according to process [A] can generally be carried out in inert solvents, if appropriate in the presence of base and auxiliary reagents, preferably in a temperature range from 20 to 120 ° C. at atmospheric pressure or without solvent in the melt.

Auxiliary reagents are, for example, potassium fluoride or dimethylaminopyridine, and / or crown ether, preferably 15-crown-5, 18-crown-8 or 12-crown-4.

If X ^{1 is} halogen, the reaction according to process [B] can generally be carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to 50 ° C. at atmospheric pressure.

If X ^{1 is} hydroxy, the reaction can generally be carried out in inert solvents, if appropriate in the presence of a base, in the presence of customary solvents

Condensing agents, preferably in a temperature range from 20 ° C to 50 ° C at normal pressure. Condensing agents are, for example, carbodiimides such as, for example, N-N'-dethyl, N, N, '-' dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylamino-isopropyl) -N '-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium- 3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis- (2nd -oxo-3-oxazolidinyl) -phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazol-l-yl) -N, N, N ', N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-l- (2H) -pyridyl) -l, l, 3,3-tetramethyluronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-l-yl) -N, N , N ', N'-tetramemyl uromurnhexafluorophosphate (HATU), or 1-hydroxyb enztriazol (HOBt), or benzotriazol-l-yloxytris (dimethylammo) -phosphomumhexafluorophosphate (BOP), or mixtures of these compounds.

The combination of N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBt) and the combination of benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP ) and triethylamine.

Inert solvents for processes [A] and [B] are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, Tetrahydrofuran, 1,2-dimethoxyethane, or

Diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or nitroalkanes such as nitromethane, or carboxylic acid esters such as ethyl acetate, N-alkylated carboxamides such as dimethylformamide, dimethylacetamide, or ketones such as acetone, 2-butoxide, or alkyl such as dimethyl sulfoxide, or acyl nitriles such as acetonitrile or heteroaromatics such as pyridine. Preferred for process [A] are pyridine, glycol di methyl ether, tetrahydrofuran, dioxane or dimethyl sulfoxide and preferably for the ^" process [B] if X ^{1 is} halogen, are tetrahydrofuran or methylene chloride and, if X ^{1 is} hydroxy, tetrahydrofuran, dimethylformamide or methylene chloride.

Bases for processes [A] and [B] are, for example, alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, alkali metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethanolate or potassium tert-butoxide, amides such as sodium amide , Lithium bis (trimethylsilyl) amide, lithium diisopropylamide, organometallic compounds such as

Butyllithium or phenyllithium, Alkalihydri.de such as sodium hydride, alkylamines such as triethylamine or diisopropylethylamine, N-methylmoφholin, N-methylpiperidine, 4-dimethylaminopyridine, or DBU. Preferred for process [A] are sodium hydride, triethylamine, potassium tert-butoxide or DBU, and preferred for process [B], if X ^{1 is} halogen, is triethylamine.

The reaction according to process [C] is generally carried out in inert solvents, optionally in the presence of a base, in the presence of catalysts, preferably in a temperature range from 50 to 150 ° C. at atmospheric pressure.

Inert solvents are, for example, hydrocarbons such as benzene, xylene, toluene, toluene is preferred.

Bases are, for example, alkali alcoholates such as potassium tert-butoxide or alkali carbonates such as cesium carbonate, sodium or potassium carbonate.

Catalysts are palladium complexes which can be used preformed or can be generated in situ from a suitable palladium source, such as, for example, bis (dibenzylidene acetone) palladium (O) or tetrakis-iriphenylphosphine palladium (O) and a suitable phosphine ligand. The use of is particularly preferred

2,2'-bis (diphenylphosphino) -l, -binaphthalene (BLNAP) as a phosphine ligand. The compounds (LLT), (IV) and (VI) are known or can be synthesized from the corresponding starting materials analogously to known processes.

The compounds (V) can be prepared using the appropriate starting materials analogously to process [A].

To prepare the compounds (Ia), compounds of the formula (VTI),

in which

R> 2, R, R and A have the meanings given above,

with reducing agents and optionally in the presence of catalysts, such as

Convert palladium to activated carbon.

The reaction is generally carried out in inert solvents, preferably in a temperature range from 20 to 150 ° C. at atmospheric pressure to 3 bar.

Reducing agents are, for example, hydrogen, tin dichloride or titanium trichloride; hydrogen or tin dichloride is preferred.

Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, TσlüoL hexane, "cyclohexane or petroleum fractions, amides such as dimethylformamide, dimethylacetamide, alkyl nitriles such as acetonitrile, heteroaromatics such as pyridine, methanol, ethanol, isopropanol or (when using tin dichloride are preferred ) Dimethylformamide.

Compounds (VII) can be prepared using the appropriate starting materials analogously to process [A].

To prepare the compounds (LT), compounds of the formula (VTfl),

in which

R, ι, R, R and R have the meanings given above,

with 1,2,4-triazole in the presence of a chlorinating agent, preferably phosphorus oxychloride, phosphorus pentachloride, sulfuryl chloride and / or thionyl chloride.

The reaction is generally carried out in inert solvents, if appropriate in

Presence of a base, preferably in a temperature range from -20 ° C to 20 ° C at normal pressure (see e.g. Knutsen et al., J. Chem. Soc, Perkin Trans 1, 1985, 621-630; A. Kraszewski, J. Stawinski, Tetrahedron Lett. 1980, 21, 2935). The inert solvents of the type mentioned for processes [A] and [B] can be used for the reaction; pyridine, trichloromethane, diethylphenylamine, dioxane or acetonitrile are preferred.

The bases recommended for processes [A] and [B] can be used; triethylamine, pyridine or diethylphenylamine are preferred.

To prepare the compounds (VILT), compounds of the formula (IX)

in which

R, ι, R, R and R have the meanings given above,

with suitable dehydration reagents (e.g. Lewis acids), preferably phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid or methyl sulfonic acid chloride.

The reaction is generally carried out in inert solvents, preferably in a temperature range from 40 to 80 ° C at normal pressure (see e.g. Charles et al.

J. Chem. Soc, Perkin Trans 1, 1980, 1139).

Suitable inert solvents are those mentioned for processes [A] and [B]; 1,2-dichloroethane is preferred. To prepare the compounds (IX), compounds of the formula (X),

or their salts, e.g. Hydrochloride salts,

in which

R ¹ , R ⁵ and R ^{3 have} the meanings given above,

with compounds of the formula (XI),

in which

R has the meaning given above and

Y ^{1 represents} halogen, preferably bromine or chlorine, or hydroxy.

If Y ^{1 represents} halogen, the reaction can generally be carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to 50 ° C. under normal pressure. Suitable inert solvents are those mentioned for processes [A] and [B]; tetrahydrofuran or methylene chloride are preferred.

Suitable bases are those recommended for methods [A] and [B]

Triemylamin.

If Y ^{1 is} hydroxy, the reaction can generally be carried out in inert solvents, if appropriate in the presence of a base, in the presence of customary condensing agents, preferably in a temperature range from 20 ° C. to 50 ° C.

Normal pressure.

Suitable inert solvents are those mentioned for processes [A] and [B]; tetrahydrofuran, dimethylformamide or methylene chloride are preferred.

Suitable condensing agents are those recommended for process [B] or mixtures thereof.

Suitable bases are those mentioned for processes [A] and [B].

The compounds (XI) are known or can be synthesized from the corresponding starting materials by known processes.

To prepare the compounds (X), compounds of the formula (IXa), in which

R, ι, R and R have the meanings given above,

react with an acid.

The reaction can generally be carried out in inert solvents, preferably in a temperature range from 20 ° C. to 100 ° C. at normal pressure.

Suitable inert solvents are those which are suitable for the reduction of (VLT); methanol or ethanol are preferred.

Acids are, for example, trifluoroacetic acid, sulfuric acid, hydrogen chloride, hydrogen bromide and acetic acid or mixtures thereof, optionally with the addition of water; hydrogen chloride or hydrogen chloride / water are particularly preferred.

In a further process, compounds of the formula (XII),

or their salts, e.g. Hydrochloride or hydrobromide salts,

in which R ¹ and R ^{5 have} the meanings given above,

in the first stage with hydrazine,

and the resulting reaction product in a second stage with compounds of the formula (XHI),

in which

R ² and R ^{3 have} the meanings given above, and

R ^{8 represents} -C ₄ alkyl, preferably methyl or ethyl.

The reaction of the first stage can generally be carried out in inert solvents, preferably in a temperature range from -10 ° C to 50 ° C at normal pressure (cf. e.g. K. M. Doyle, F. Kurzer, Synthesis 1974, 583).

The reaction of the second stage can generally be carried out in inert solvents, preferably in a temperature range from 20 to 80 ° C. at normal pressure. Inert solvents for the reactions of the first and second stages are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, amides such as dimethylformamide, alkyl sulfoxides such as dimethyl sulfoxide, methanol or are preferred ethanol.

The compounds (IXa) can be obtained using compounds (XIT) and compounds (Xül),

in which R ^{2 represents} methyl,

be prepared under the same conditions as compounds (IX).

To prepare the compounds (XII), compounds of the formula (XTV),

in which

R ¹ and R ^{5 have} the meanings given above and

Y ^{2 represents} cyano or methoxycarbonyl,

- if Y ^{2 is} cyano - with ammonium bromide or chloride and gaseous ammonia at 140 ° C to 150 ° C in an autoclave, or with lithium bis (trimethylsilyl) amine and hydrogen chloride in diethyl ether (see RT Boere, et al ., J.

Organomet. Chem. 1987, 331, 161-167) - if Y ^{2 is} methoxycarbonyl - react with trimethylaluminum in a carbon "hydrogen, for example hexane and with ammonium chloride.

If Y ^{2 is} methoxycarbonyl, the reaction can in general be carried out in inert solvents, preferably in a temperature range from first at -20 ° C. and then at 20 ° C. to 80 ° C. under normal pressure (cf., for example, RS Garigipati, Tetrahedron Lett. 1990 , 31, 1969-1972).

Suitable inert solvents are those which are suitable for processes [A] and [B], preferably toluene.

The compounds (XTV) are known or can be synthesized from the corresponding starting materials in analogy to known processes.

Instead of compounds (XU), compounds of the formula (XV),

in which

R ¹ and R ^{5 have} the meanings given above,

can be used, which can be prepared according to K. M. Doyle, F. Kurzer, Synthesis 1974, 583.

The compounds (XV) are known or can be synthesized from the corresponding starting materials analogously to known processes. To prepare the compounds (XILT), compounds of the formula (XVI),

in which

R ² and R ^{3 have} the meanings given above,

with compounds of the formula (XVII),

in which

R ^{8 has} the meaning given above and

X ^{2 represents} halogen, preferably chlorine or bromine.

The reaction is generally carried out in inert solvents, if appropriate in the presence of a base and a catalyst such as dimethylaminopyridine, preferably in a temperature range from 20 to 80 ° C. at atmospheric pressure (see, for example, Charles, J.

Chem. Soc, Perkin Trans. 1, 1980, 1139).

Suitable inert solvents are those mentioned for processes [A] and [B], preferably tetrahydrofuran or diethyl ether. Suitable bases are those for those recommended analogously to those in processes [A] and [B] - ^r ; ^" preferred pyridine, sodium hydride, potassium tert-butoxide, lithium diisopropylamide, piperidine or triethylamine.

The compounds (XVII) are known or can be synthesized from the corresponding starting materials analogously to known processes.

To prepare the compounds (XVI), compounds of the formula (XViπ),

in which

R ^{3 has} the meaning given above,

with compounds of the formula (XIX),

O

(

X> A _R2 XIX)

in which

R has the meaning given above and

X represents halogen, preferably chlorine or bromine.

The reaction is generally carried out in inert solvents, if appropriate in

Presence of a base, optionally in the presence of trimethylsilyl chloride, preferably in a temperature range from -10 to 50 ° C at normal pressure. Suitable inert solvents are those mentioned for processes [A] and [B], preferably methylene chloride.

Suitable bases include those recommended for processes [A] and [B], preferably triethylamine, sodium or potassium hydroxide in aqueous solution.

The compounds (XVIH) and (XIX) are known or can be synthesized from the corresponding starting materials analogously to known processes.

The methods described in WO 99/24433 and EP-A 1 092 719 may also be used for the synthesis of intermediate compounds (1).

Functional groups are optionally protected during the syntheses with suitable protective groups which can subsequently be split off again (see, for example, BTW Greene, P. Wuts, "Protective Groups in Organic Synthesis", 2nd ed., Wiley; New York, 1991 ).

The methods described above can be exemplified by the following formula schemes:

Scheme 1:

DMAP, pyridine

Scheme 2:

The compounds according to the invention are suitable for use as medicaments in the treatment of humans and animals. The compounds according to the invention show an unforeseeable, valuable spectrum of pharmacological activity. They stand out as PDE LOA inhibitors.

It was possible for the first time to show a selective PDE lOA inhibition in animal models, which establishes a connection between PDE lOA inhibitors and Parkinson's disease.

Due to their pharmacological properties, the compounds according to the invention, alone or in combination with other medicaments for the treatment and or prevention of Parkinson's disease, in particular idiopathic Parkinson's disease, and cancer diseases, in particular tumors, and for the treatment of schizophrenia be used.

Parkinson's idiopathic disease is a chronic, progressive neurological disorder that belongs to a broader classification of neurological diseases called parkinsonism. It is clinically defined by the occurrence of at least two of the four cardinal symptoms: bradykinesia, resting tumor, muscle stiffness and postural and movement disorders. The idiopathic form of Parkinson's disease is pathologically caused by the loss of pigmented

Characterized nerve cells, especially in the area of the substantia nigra of the brain. Idiopathic Parkinson's disease accounts for approximately 75% of all Parkinson's diseases. The remaining 25% of cases are referred to as atypical Parkinsonism and include clinical pictures such as multiple system atrophy, striatonigral degeneration or vascular Parkinsonism.

In the context of the present invention, the definition of tumors includes both benign and malignant tumors and thus, for example, also benign neoplasias, dysplasias, hyperplasias, and also neoplasias with metastasis formation. Other examples of tumors are carcinomas, sarcomas, carcinosarcomas, tumors of the hematopoietic organs, tumors of the nerve tissue, for example the brain or Tumors from skin cells. Tumor formation leads to uncontrolled or insufficiently controlled cell division. The tumor can be localized, but it can also infiltrate the surrounding tissue and then settle in a new location through the lymphatic system or through the bloodstream. Thus there are primary and secondary tumors. Primary tumors originated in the organ in which they are found. Secondary tumors have established themselves in another organ through metastasis and then spread to their new location.

Abnormal basal ganglia function is not only relevant for psychoses, schizophrenia and related schizoaffective disorders, but also plays a role in other neuropsychiatric changes such as depression (Kapur, Biol. Psychiatr. 1992, 32, 1-17; Lafer, et al, Psychiatr Clin. North. 1997, 20, 855-896) and ailments (Jetty, et al., Psychiatric Clin. North. 2001, 24, 75-97).

Furthermore, the compounds according to the invention are suitable for the treatment of further diseases which can be treated by influencing the cGMP level and / or the cAMP level, such as dementia, stroke, traumatic brain injury, Alzheimer's disease, dementia with frontal lobe degeneration, Lewy - Body dementia, vascular dementia, attention deficit syndromes, attention and concentration disorders, mood disorders, psychoses, neuroses, mania or manic-depressive disorders, Pick's disease, pain and epilepsy.

The in vitro activity of the compounds according to the invention can be shown with the following biological assays: In Vitro Enzvm Inhibition Tests: - ^"

Inhibition of PDE 10A

PDE 10A (WO 01/29 199, Fig. IA) is in Sf9 insect cells (Invitrogen, Carlsbad,

CA) with the help of the Bac-to-Bac ™ baculovirus expression system from Life Technologies (Gaithersburg, MD) expressed in full length. 48 hours after the infection, the cells are harvested and in 20 ml (per IL culture) lysis buffer (50 mM Tris-HCl, pH 7.4, 50 mM NaCl, 1 mM MgCl ₂ , 1.5 mM EDTA, 10% glycerol plus 20 μL protease inhibitor Cocktail Set HI [CalBiochem, La Jolla, CA USA]) suspended. The cells are sonicated at 4 ° C for 1 minute and then centrifuged at 10,000 ° C for 30 minutes at 4 ° C. The supernatant (PDE 10A preparation) was collected and stored at -20 ° C.

The test substances are used to determine their in vitro activity on PDE 10A

100% DMSO dissolved and serially diluted. Typically, dilution series from 200 μM to 1.6 μM are produced (resulting final concentrations in the test: 4 μM to 0.032 μM). In each case 2 μL of the diluted substance solutions are placed in the wells of microtiter plates (Isoplate; Wallac Inc., Atlanta, GA). Then 50 μL of a dilution of the PDE 10A preparation described above are added. The dilution of the PDE 10A preparation is chosen so that less than 70% of the substrate is converted during the later incubation (typical dilution: 1: 10000; dilution buffer: 50 mM Tris / HCl pH 7.5, 8.3 mM MgCl ₂ , 1.7 mM EDTA, 0.2% BSA). The substrate, [5 ', 8- ³ H] adenosine 3', 5'-cyclic phosphate (1 uCi / ul; Amersham Pharmacia Biotech.

Piscataway, NX) is diluted 1: 2000 with assay buffer (50 mM Tris / HCl pH 7.5, 8.3 mM MgCl ₂ , 1.7 mM EDTA) to a concentration of 0.0005 μCi / μL. The enzyme reaction is finally started by adding 50 μL (0.025 μCi) of the diluted substrate. The test batches are incubated for 60 min at 20 ° C. and the reaction by adding 25 μL of a suspension with 18 mg / mL yttrium

Scintillation Proximity Beads (Amersham Pharmacia Biotech., Piscataway, NJ.) stopped. The microtiter plates are sealed with a film and left to stand for 60 min at ^" 20 ° C. The plates are then measured for 30 s per well in a Microbeta scintillation counter (Wallac Inc., Atlanta, GA). IC ₅₀ values are determined on the basis of the graphic Application of the substance concentration against the percentage inhibition determined.

The following examples may show the PDE IOA-inhibiting activity of the compounds according to the invention:

Inhibition of PDEs 1-5, 7-9 and 11

Recombinant PDE IC (GenBank / EMBL Accession Number: NM_005020, Loughney et al. J. Biol. Chem. 1996 271, 796-806), PDE 2A (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), PDE 4B (GenBank / EMBL Accession Number: NM_002600, Obernolte et al. Gene. 1993 129, 239-247), PDE 5A ( GenBank / EMBL Accession Number: NM_001083, Loughney et al. Gene 1998 216, 139-147), PDE 7B (GenBank / EMBL Accession Number: NM_018945, Hetman et al. Proc. Natl. Acad. Sei. USA 2000

97, A12-A16), PDE 8A (GenBank / EMBL Accession Number: AF_056490, Fisher et al. Biochem. Biophys. Res. Commun. 1998 246, 570-577), PDE 9A (GenBank / EMBL Accession Number: NM_002606, Fisher et al. J. Biol. Chem. 1998 273, 15559-15564), PDE HA (GenBank / EMBL Accession Number: NM_016953, Fawcett et al. Proc. Natl. Acad. Be 2000 97, from 3702 to 3707) were expressed in Sf9 cells ^"dit aid of pFASTBAC baculovirus expression system (GibcoBRL).

The in vitro effect of test substances on recombinant PDE 3B, PDE 4B, PDE 7B, PDE 8A and PDE HA is described after that for PDE 10A

Test protocol determined. To determine a corresponding effect on recombinant PDE IC, PDE 2A, PDE5A and PDE 9A, the protocol is adapted as follows: With PDE IC, additional calmodulin (10 ^"7 M) and CaCl ₂ (3 mM) are added to the reaction mixture. PDE 2A is stimulated in the test by adding cGMP (1 μM) and tested with a BSA concentration of 0.01% for PDE 5A and

PDE 9A is used as a substrate [8- ³ H] cGMP (Amersham Pharmacia Biotech., Piscataway, NJ).

The suitability of the compounds according to the invention for the treatment of Parkinson's disease can be shown in the following animal models:

Haloperidol catalepsy of the rat

The neuroleptic haloperidol is a high affinity antagonist on the dopamine D2 receptor. In humans and animals, the administration of a higher dose causes

Haloperidol is a transient blockade of doparninergic neurotransmission. This blockage leads to a disruption of extrapyramidal motor skills, so-called catalepsy, in which a given posture is maintained longer than normal. Animal neuroleptic catalepsy is generally considered a model for sedentary lifestyle and rigidity in Parkinson's patients (Elliott et al.,

J Neural Transm [P-D Sect] 1990; 2: 79-89). The time it takes an animal to change a given position is used as an index of the degree of catalepsy (Sanberg et al., Behav. Neurosci. 1988; 102: 748-59).

In the catalepsy experiments, male rats are randomly divided into groups that receive either vehicles or different dosages of those to be tested Connections are applied. Each rat receives one 1.5mg / kg haloperidol. The cataleptic behavior of the animals is recorded 120 min after the haloperidol administration. The compounds to be tested are applied to the rats at such a time interval before the catalepsy test that the maximum plasma concentration is reached at the time of the behavioral test.

To measure the cataleptic behavior, the animal is placed with both front paws on a wooden block of 9 x 5.5 x 5.5 cm height x depth x width. The time it takes an animal to take both paws off the block is recorded as the length of catalepsy. After 180 seconds, the animals are removed from the block.

6-hydroxydopamine (6-OH-DA lesion in the rat

The degeneration of dopaminergic nigrostriatal and striatopallidal neurotransmission is the main characteristic of Parkinson's disease

The clinical picture of Parkinson's disease can largely be simulated in an animal model in which the neurotoxin 6-OH-DA is injected intracerebrally in rats.

For the experiments described, male rats (Harlan Winkelmann,

Germany; Weight at the start of the test: 180 - 200 g) kept under controlled conditions (humidity, temperature) and a 12 hour light-dark cycle. If they are not in an experiment, the animals have free access to water and feed.

The animals were given Pargyline (Sigma, St. Louis, MO, USA; 50 mg / kg ip) and desmethylimipramine hydrochloride (Sigma; 25 mg / kg ip) 30 minutes before the lesion on the day of surgery to improve the metabolism of 6-hydroxydopamine to prevent or to prevent the absorption of 6-hydroxydopamine in noradrenergic structures. After induction of anesthesia by sodium pentobarbital

(50 mg / kg ip) the test animals are fixed in a stereotactic frame. The lesion of the nigrostriatal neurotransmission occurs through a unilateral, ^" single injection of 8 μg 6-OH-DA hydrobromide (Sigma, St. Louis, MO, USA), dissolved in 4 μl of a 0.01% ascorbic acid saline solution. The solution is slowly injected (1 μl / min.) The coordinates of the injection are according to König and Klippel: 2.4 mm anterior, 1.49 mm lateral, 2.7 mm ventral. After the injection, the injection needle was left in situ for 5 minutes to ensure the diffusion of the neuro- to facilitate toxins.

After the operation, the animals are placed on a hot plate and returned to their cages under control after awakening, where they receive food and water ad libidum.

In the verum group, the animals are treated with substance one day after the operation until the end of the experiment 28 days after the operation.

Such 6-OHDA-injured animals are divided into different treatment groups, which receive either vehicles or different dosages of the compound to be examined. For comparison purposes, a group of pseudo-injured animals is also carried (0.9% sodium chloride solution in water is injected instead of 6-OHDA).

The motor failures resulting from the lesion are quantified using the following tests, as described in the relevant literature:

a) Staircase test (coordination test of the front paws):

Barneoud et al: Effects of complete and partial lesions of the dopaminergic mesotelencephalic system on skilled forelimb use in the rat. Neuroscience 1995, 67, 837-848. b) Accelerating Rotarod Test (balancing test): ^'' -

Spooren et al .: Effects of the prototypical mGlu ₅ receptor antagonist 2-methyl-6- (phenylethynyl) pyridine on rotarod, locomotor activity and rotational responses in unilateral 6-OHDA-lesioned rats. Eur. J. Pharmacol. 2000, 406, 403-410.

c) Traction measurement of the front paws:

Dunnet et al .: A laterised grip strength test to evaluate unilateral nigrostriatal lesions in rats. Neurosci. Lett. 1998, 246, 1-4.

The suitability of the compounds according to the invention for the treatment of schizophrenia can be shown in the following animal models:

Catalepsy test in rats

The effect of test substances on the function of the basal ganglia can be investigated in the animal model using the so-called catalepsy test on rats (Sanberg et al., Behav. Neurosci. 1988, 102, 748-759). Catalepsy is staying in a certain body position, accompanied by increased muscle tone. If a normal one

If the animal is brought into an unusual position, it changes its posture within a few seconds, whereas a cateptic animal remains in the imposed position for a long time. The time that elapses before a forced position is corrected can be used as a measure of the intensity of catalepsy. The antipsychotic haloperidol also dissolves in sufficiently high levels

Dosage cataleptic behavior (e.g. Chartoff et al., J. Pharmacol. Exp. Therap. 291, 531-537). EP-A 1 250 923 describes that the selective PDE10 inhibitor papaverin triggers potentiation of haloperidol catalepsy.

The effect of the selective PDE10 inhibitors is examined in the animal model mentioned. A low dose of haloperidol (0.3mg / kg sc) is given 30 minutes before Catalepsy test given alone or administered with the compound. To measure the cataleptic behavior, both front paws of the rat are placed on a wooden block 9 cm high and 5.5 cm wide x 5.5 cm deep. The time it takes for an animal to pull its front paw off the block is recorded as the duration of catalepsy. All rats are released after 60 seconds at the latest

Taken wooden block. The data collected from each treatment group (10 animals each) are statistically analyzed using analysis of variance (ANOVA).

The new active compounds can be converted into the customary formulations in a known manner, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions,

Suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable carriers or solvents. Here, the therapeutically active compound should be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts that are sufficient to achieve the stated dosage range.

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.

The application is carried out in the usual way, preferably orally, transdermally or parenterally, in particular perlingually or intravenously. However, it can also be inhaled through the mouth or nose, for example with the aid of a spray, or topically via

Skin.

In general, it has proven to be advantageous to administer amounts of approximately 0.001 to 10, preferably approximately 0.005 to 3 mg / kg of body weight when administered orally in order to achieve effective results. Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the drug, the type of its formulation and the time or interval at which the administration takes place , So it may be sufficient in some cases, with less than the above

Minimum amount to get by, while in other cases the specified upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.

Unless otherwise stated, all quantities relate to percentages by weight. Solvent ratios, dilution ratios and concentration details of liquid / liquid solutions each relate to the volume. "W / v" means "weight / volume". For example, "10% w / v" means: 100 ml of solution or suspension contain 10 g of substance.

Abbreviations:

Section. absolutely aq. watery

BINAP 2,2'-bis (diρhenylphosphino) - 1,1'-binaphthalene

Bn benzyl

Boc tert-butoxycarbonyl

BSA Bovine Serum Albumin cGMP cyclic guanosine 3 ', 5' monophosphate

CDI N, N carbonyldiimidazole

CH cyclohexane

DBU 1,8-diazabicyclo [5.4.0] undec-7-ene

TLC thin layer chromatography

DCI direct chemical ionization (for MS)

DCM dichloromethane

DIC diisopropyl carbodiimide

DLEA N, N-diisopropylemylamine

DMA N, N-dimethylacetamide

DMAP 4-N, N-dimethylaminopyridine

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

EDC N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide x HCl

EDTA ethylenediamine-tetra-acetic aeid

EE ethyl acetate (ethyl acetate)

EI electron impact ionization (for MS)

Eq equivalent (s)

ESI electrospray ionization (for MS)

Mp melting point sat. saturated

HATU O- (7-AÄabenzotriazol-l-yl) -N, NN'N'-tetιamemylurorιium-

hexafluorophosphate HBTU O- (Benzotτiazol-1 -yl) -NN, N ', N'-tetramethylüromürn hexafluorophosphate

HOBt 1 -hydroxy-1H-benzotriazole x H ₂ O

HPLC high pressure, high performance liquid chromatography

Concentrated

Boiling point

LC-MS liquid chromatography-coupled mass spectroscopy

LDA LitMum-N, N-diisopropylamide

Literature (position)

Solution

MG molecular weight

MS mass spectroscopy

NMR nuclear magnetic resonance spectroscopy

PyBOP benzotriazol-l-yloxy-tris (pyrrolidino) phosρhonium-

hexafluorophosphate

RF reflux

Rf retention index (at DC)

RP reverse phase (with HPLC)

RT 20 ° C

Rt retention time (with HPLC)

TBTU O- (Benzotriazol-1 -yl) -N N, N ', N'-tetramethyluronium-

tetrafluoroborate

TEA triemylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TRIS tris (hydroxymethyl) aminomethane v / v volume-to-volume ratio (a solution) dil. Dilute aq. aqueous

Dec. decomposition HPLC and LC-MS methods:

Method 1 (HPLC)

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm x 2 mm, 3.5 μm; Eluent: A = 5 ml HClO ₄ / l H ₂ O, B = acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; Flow: 0.75 ml / min; Temp .: 30 ° C; Detection UV 210 nm.

Method 2 (LC-MS) Instrument: Micromass Quattro LCZ, HPllOO; Column: Symmetry C18, 50 mm x

2.1 mm, 3.5 µm; Eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0 min 90% A - »4.0 min 10% A - 6.0 min 10% A; Oven: 40 ° C; Flow: 0.5 ml min; UV detection: 210 nm.

Method 3 (LC-MS)

Instrument: Micromass Platform LCZ, HPllOO; Column: Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; Eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0min 90% A - 4.0 min 10% A - »6.0 min 10% A; Oven: 40 ° C; Flow: 0.5 ml min; UV detection: 210 nm.

starting compounds

Example IA

4-Nitroberi2θlcarboximidamid hydrochloride

21:40 g (400 mmol) of ammonium chloride are suspended in a Dreihälskolben with ^{"thermometer,} condenser, dropping funnel and mechanical stirrer under an argon atmosphere in 200 ml of anhydrous toluene and cooled to 0 ° C. 400 mmol of trimethylaluminum (200 ml of 2 M solution in hexane) are added dropwise , and the batch is stirred at 20 ° C. until no more gas evolution is observed (approx. 2

Hours). 19.75 g (133 mmol) of 4-nitrobenzonitrile are then added to the mixture and the reaction mixture is stirred at 80 ° C. overnight.

After cooling to 0 ° C., 250 ml of methanol are added dropwise to the mixture and the mixture is stirred vigorously at 20 ° C. The reaction mixture is filtered and the

Wash the residue well with methanol. The filtrate is concentrated, the residue is slurried with dichloromethane / methanol 10/1. The insoluble solid consisting of ammonium chloride is filtered off, the filtrate is concentrated again and the product is obtained as a solid.

Total yield: 19.53 g (73 d. Th.)

MS (DCI): m / z = 183 (M + NFLt-HCrf.

Example 2A

3-Nitrobenzolcarboximidamid hydrochloride

7.22 g (135 mmol) of ammonium chloride are reacted analogously to Example IA with 135 mmol of trimethylaluminum (67.5 ml of 2 M solution in hexane) and 10 g (67.51 mmol) of 3-nitrobenzonitrile. Overall yield: 9.7 g (71% of theory) - ^{J "}

HPLC (method 1): R _t = 1.57 min. MS (ESIpos): m / z = 166 (M + H-HC1) ⁺ .

Example 3A 4-Bromberιzolcarboximidamid hydrobromide

In the autoclave, 4-bromobenzonitrile (36.4 g, 0.2 mol), ammonium bromide (39.2 g, 0.4 mol) and ammonia gas (34.0 g, 2 mol) are heated to 140-150 ° C. for 9 hours under autogenous pressure. The contents of the autoclave are concentrated and stirred with ethanol. The residue is filtered off and rested again with ethanol! The extracts are combined and concentrated to about 100 ml. The precipitated solid is filtered off, washed with ethanol and dried.

Yield 21.4 g (38% of theory)

1H-NMR (400 MHz, DMSO-de): δ = 7.75 (d, 2H), 7.87 (d, 2H) 9.10 (s, 3H).

Example 4A Ethyl 3- (acetylamino) -2-oxobutanoate

N-Acetyl-alanine (4.92 g, 37.5 mmol), 9.10 ml pyridine and 150 mg DMAP are dissolved in 200 ml THF and the solution is brought to a boil. At the boiling point, 8.6 ml (10.5 g, 75 mmol) of ethyl oxalyl chloride are added dropwise; after the addition has ended, the mixture is stirred at the boil for a further 3 h. After cooling, the reaction mixture is poured onto 600 ml of ice water, extracted with ethyl acetate (4 x 150 ml), the combined organic phases are saturated with 200 ml. Washed sodium chloride solution, dried over sodium sulfate and concentrated. The material obtained is immediately dissolved in ethanol and further reacted.

Example 5 A

N- {1 - [3- (4-nitrophenyl) -5-oxo-4,5-dihydro-1, 2,4-triazin-6-yl] ethyl} acetamide

7.30 g (7.09 ml, 145.82 mmol) of hydrazine hydrate are added dropwise to 24.50 g (121.5 mmol) of 4-nitrobenzene carboxinήdamide hydrochloride from Example IA in 250 ml of ethanol. The mixture is stirred at 20 ° C. for one hour. After this time, 34.12 g (182.28 mmol) of ethyl 3- (acetylamino) -2-oxobutanoate from Example 4A in ethanol are added, and the reaction mixture is stirred at a bath temperature of 70-80 ° C. for 4 h and then at 20 ° C. for 12 h , The mixture is concentrated and the residue is purified by flash chromatography (mobile phase: ethyl acetate, then dichloromethane / methanol 30: 1).

Yield: 14.80 g (40% of theory).

HPLC (method 1): R _t = 3.11 min. MS (ESIpos): m / z = 304 (M + H) ⁺ . ^■ - 1 ^~

1H-NMR (400 MHz, MeOH-dj): δ = 1.49 (d, 3H), 1.99 (s, 3H), 5.23 (q, 1H), 8.26 (d,

2H), 8.41 (d, 2H) both NHs cannot be seen.

Example 6 A

N- {l- [3- (3-nitrophenyl) -5-oxo-4,5-dihydro-l, 2,4-triazin-6-yl] ethyl} acetamide

To 9.70 g (48.11 mmol) of 3-Nilrobenzene carboximidamide hydrochloride from Example

2A in 200 ml of ethanol, 2.89 g (2.81 ml, 57.73 mmol) of hydrazine hydrate are added dropwise. The mixture is stirred at 20 ° C. for one hour. After this time, 13.51 g (72.17 mmol) of ethyl 3- (acetylamino) -2-oxobutanoate from Example 4A in ethanol are added, and the reaction mixture is 4 hours at 70-80 ° C bath temperature, then 12 hours at 20 ° C stirred. The mixture is concentrated and the residue is purified by flash chromatography (mobile phase: ethyl acetate, then dichloromethane / methanol 30: 1).

Yield: 1.93 g (13% of theory).

HPLC (method 1): R _t = 3.07 min.

MS (ESIpos): mz = 304 (M + H) ⁺ .

1H-NMR (300 MHz, MeOH-d ₄ ): δ = 1.49 (d, 3H), 1.99 (s, 3H), 5.21 (q, 1H), 7.81 (t,

1H), 8.42 (d, 1H), 8.52 (d, 1H), 8.93 (s, 1H) both NHs not seen. Example 7A

N- {l- [3- (4-bromophenyl) -5-oxo-4,5-dihydro-l, 2,4-triazin-6-yl] ethyl} acetamide

3.50 ml of hydrazine hydrate (3.60 g, 27.5 mmol) are added to 4-bromobenzene carboximidamide hydrobromide from Example 3A (11.8 g) in 150 ml of ethanol, and the mixture is stirred for 1 h. After this time, ethyl 3- (acetylamino) -2-oxobutanoate from Example 4A (16.8 g) in 76 ml of ethanol is added dropwise and the reaction mixture is stirred for 3 h at 80 ° C. bath temperature, then at 20 ° C. overnight. The mixture is concentrated and the residue is purified by flash chromatography (mobile phase: dichloromethane / methanol 95: 5).

Yield: 4.58 g (15% of theory)

MS (ESI): m z = 337 (M + ELy

1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.54 (d, 3H), 2.07 (s, 3H), 5.26-5.41 (m, 1H), 7.51

(br. s, 1H), 7.66 (d, 2H), 8.12 (d, 2H).

Example 8A

5,7-dimethyl-2- (4-nitrophenyl) imidazo [5, l-fl [l, 2,4] triazin-4 (3H) -one

A solution of 13.76 g (8.13 mmol) of N- {l- [3- (4-NitiOphenyl) -5-öxό-4,5-dihydrό- l, 2,4-triazm-6-ylJethyl} acetamide from Example 5A in 150 ml of 1,2-dichloroethane are mixed with 20.87 g (12.69 ml of 136.11 mmol) of phosphoryl chloride while cooling in an ice bath. The mixture is stirred at 65 ° C. for 4 h. After cooling, it is hydrolyzed with aqueous sodium hydrogen carbonate solution. The solvent of the organic phase is removed in vacuo and the residue is purified by flash chromatography (mobile phase gradient: dichloromethane / methanol 200: 1-100: 1-50: 1).

Yield: 10.6 g (82% of theory)

MS (ESI): m / z = 286 (M + H) ⁺ .

1H-NMR (300 MHz, MeOH-c): δ = 2.61 (s, 3H), 2.66 (s, 3H), 8.22 (d, 2H), 8.42 (d,

2H).

Example 9A

5,7-dimethyl-2- (3-mtroρhenyl) imidazo [5, l-f] [l, 2,4] triazin-4 (3H) -one

A solution of 1.93 g (6.36 mmol) of N- {l- [3- (3-nitrophenyl) -5-oxo-4,5-dihydrol, 2,4-triazin-6-yl] ethyl} acetamide from example 6A in 1,2-dichloroethane is with

2.93 g (1.78 ml, 19.09 mmol) of phosphoryl chloride were added. The mixture is stirred at 95 ° C. for 3 h. After cooling, it is hydrolyzed with a few drops of aqueous sodium hydrogen carbonate solution. The solvent is removed in vacuo and the residue is purified by flash chromatography (mobile solvent: dichloromethane / methanol 100: 1-50: 1-30: 1-20: 1). Yield: 1.46 g (80% of theory)

HPLC (method 1): R _t = 3.47 min. MS (ESI): m / z = 286 (M + H) ⁺ .

Example 10A

2- (4-bromophenyl) -5,7-dimethylimidazo [5, 1 -f] [1, 2,4] triazin-4 (3H) -one

A solution of 10.0 g (29.66 mmol) of N- {l- [3- (4-bromophenyl) -5-oxo-4,5-dihydrol, 2,4-triazin-6-yl] ethyl} from Example 7A 13.64 g (8.30 ml 88.98 mmol) of phosphoryl chloride are added to 340 ml of 1,2-dichloroethane. The mixture is boiled under reflux for 15 h. After cooling, the solvent is removed. The

The residue is stirred with diethyl ether and suction filtered. The crystals are stirred with 150 ml of saturated aqueous sodium hydrogen carbonate solution for 1 h, then diluted with 100 ml of water. After 30 min, the solid is filtered off, washed well with water and washed with petroleum ether.

Yield: 9.30 g (98% of theory)

MS (ESI): m / z = 319 (M + H) ⁺ HPLC (method 1): R _t = 3.79 min. 1H-NMR (300 MHz, DMSO-d ₆ ): δ - 2.63 (s, 3H), 2.75 (s, 3H), 7.82 (d, 2H), 7.97 (d,

2H), 12.43 (br. S, 1H). Example 11 A -

5,7-Dimemyl-2- (4-mtrophenyl) -4- (lH-l, 2,4-triazol-l-yl) imidazo [5, l-f] [l, 2,4] triazine

2.53 g (1.54 ml 16.51 mmol) of phosphoryl chloride become under argon to a solution of 1.57 g (5.50 mmol) of 5,7-dimethyl-2- (4-nitrophenyl) imidazo [5, lf] [l, 2,4] triazine 4 (3H) -one from Example 8A in 10 ml of dry pyridine was added dropwise at 0 ° C., and the mixture was stirred at 20 ° C. for 30 min. Then 3.42 g (49.53 mmol) of 1,2,4-triazole are added and the mixture is stirred at RT overnight. The reaction mixture is concentrated, the residue is mixed with aqueous sodium hydrogen carbonate solution, and the mixture is extracted with dichloromethane. The organic phase is dried (sodium sulfate) and the solvent is removed in vacuo. The residue is purified by flash chromatography (mobile phase: dichloromethane / methanol 100: 1).

Yield: 1.06 g (57% of theory)

MS (ESI): m / z = 337 (M + H) ⁺

Example 12A

5,7-Dimethyl-2- (3-nitroρhenyl) -4- (1H-1, 2,4-triazol-1-yl) imidazo [5, 1-f] [1, 2,4] triazine

2.35 g (15.35 mmol) of phosphoryl chloride are added under argon to a solution of 1.46 g (5.12 mmol) of 5,7-dimethyl-2- (3-mtrophenyl) irmdazo [5, lf] [l, 2,4] triazine 4 ( 3H) -one from Example 9A is added dropwise in 50 ml of dry pyridine at 0 ° C. and the mixture is stirred at RT for 30 min. Then 3.18 g (46.06 mmol) of 1,2,4-triazole are added and the mixture is stirred at 20 ° C. for 3 h. The reaction mixture is concentrated, the residue is mixed with aqueous sodium hydrogen carbonate solution and the mixture is extracted with dichloromethane. The organic phase is dried (sodium sulfate) and the solvent is removed in vacuo. The residue is purified by flash chromatography (mobile phase: dichloromethane / methanol 100: 1).

Yield: 0.736 g (43% of theory)

MS (ESI): m / z = 337 (M + H) ⁺ HPLC (method 1): R _t = 3.96 min.

1H-NMR (200 MHz, CDC1 ₃ ): δ = 2.86 (s, 3H), 2.92 (s, 3H), 7.73 (t, 1H), 8.30 (s, 1H), 8.40 (d, 1H), 8.73 ( d, 1H), 9.21 (s, 1H), 9.43 (s, 1H). Example 13A ^.

2- (4-bromophenyl) -5,7-dimethyl-4- (lH-l, 2,4-triazol-l-yl) imidazo [5, l-fj [l, 2 ₅ 4] triazine

11.53 g (7.0 ml 75.20 mmol) of phosphoryl chloride are added under argon to a solution of 8.00 g (25.07 mmol) of 2- (4-bromophenyl) -5,7-dimethylimidazo [5, l-fJ [l, 2,4] tri- azin-4 (3H) -one from Example 10A in 250 ml of dry pyridine was added dropwise at 0 ° C. and the mixture was stirred at RT for 30 min. 15.58 g (225.59 mmol) of 1,2,4-triazole are then added, and the mixture is stirred at 20 ° C. overnight. The

The reaction mixture is concentrated, the residue is mixed with aqueous sodium hydrogen carbonate solution and the mixture is extracted with dichloromethane. The organic phase is dried (sodium sulfate) and the solvent is removed in vacuo. The residue is purified by flash chromatography (mobile phase: dichloromethane / methanol 100: 1).

Yield: 7.98 g (86% of theory)

MS (DCI / NH ₃ ): m / z = 370 (M + H) ⁺ 1H-NMR (200 MHz, MeOH-d): δ = 2.89 (s, 3H), 2.96 (s, 3H), 7.82 (d , 2H), 8. 46

(d, 2H), 8.52 (s, 1H), 9.83 (s, 1H). Example 14A

5,7-dimethyl-2- (4-nitrophenyl) -4- (3,4,5-trimethoxyphenoxy) imidazo [5, l-fl [l, 2,4] - triazine

A solution of 40 mg (0.33 mmol) of potassium tert-butoxide and 60 mg (0.33 mmol) of 3,4,5-trimethoxyphenol in 50 ml of tetrahydrofuran is stirred for 30 min. 70 mg (0.22 mmol) of 5,7-dimethyl-2- (4-nitrophenyl) -4- (lH-l, 2,4-triazol-l-yl) imidazo [5, lf] [1,2 , 4] triazine from Example 11A and the mixture is heated at 70 ° C. for 3 h. After cooling, the solvent is removed and the residue is purified by chromatography. (Mobile phase gradient: dichloromethane / methanol 200: 1- 100: 1).

Yield: 76 mg (75% of theory)

MS (ESI): m / z = 452 (M + H) ⁺

HPLC (method 1): R _t = 4.29 min.

1H-NMR (300 MHz, CDC1 ₃ ): δ = 2.75 (s, 3H), 2.79 (s, 3H), 3.88 (s, 6H), 3.92 (s,

3H), 6.59 (s, 2H), 8.25 (d, 2H), 8.33 (d, 2H). Example 15A ^" - ^"

5,7-Dimethyl-2- (3-mtrophenyl) -4- (3,4,5-trimethoxyphenoxy) imidazo [5, l-f] [1,2,4] -triazine

A solution of 175.17 mg (1.04 mmol) of potassium tert-butoxide and 287.53 mg (1.56 mmol) of 3,4,5-trimethoxyphenol in 20 ml of tetrahydrofuran is stirred for 30 minutes. 350 mg (1.04 mmol) of 5,7-dimethyl-2- (3-ninOphenyl) -4- (lH-l, 2,4-triazol-l-yl) imidazo [5, l-fJ [l, 2,4] triazine from Example 12A and heated the mixture to 70 ° C. for 2 h. After cooling, the solvent is removed and the residue with

Dichloromethane and IN sodium hydroxide solution and extracted. The organic phase is separated off, dried and the crude product is purified by flash chromatography. (Mobile phase: dichloromethane / methanol 100: 1).

Yield: 403 mg (86% of theory)

MS (ESI): m / z = 452 (M + H) ⁺ HPLC (method 1): R _t = 4.29 min.

1H-NMR (300 MHz, CDC1 ₃ ): δ = 2.76 (s, 3H), 2.80 (s, 3H), 3.90 (s, 6H), 3.93 (s, 3H), 6.63 (s, 2H), 7.59 ( t, 1H), 8.28 (d, 1H), 8.47 (d, 1H), 9.00 (s, 1H). Example 16A

2- (4-bromophenyl) -5,7-dimethyl-4- (3,4,5-trimethoxyphenoxy) imidazo [5, l-f] [l, 2,4] - triazine

A solution of 1.82 g (16.21 mmol) of potassium tert-butoxide and 2.99 g (16.21 mmol) of 3,4,5-trimethoxyphenol in 100 ml of tetrahydrofuran is stirred for 30 minutes. 4.0 g (10.80 mmol) of 2- (4-bromophenyl) -5,7-dimethyl-4- (lH-l, 2,4-triazol-l-yl) - imidazo [5, lf] [l, 2,4] triazine from Example 13A and heated the mixture at 70 ° C for 3 h. After cooling, the solvent is removed and the residue with

Dichloromethane and IN sodium hydroxide solution and extracted. The organic phase is separated off, dried and the crude product is purified by flash chromatography. (Mobile phase: dichloromethane / methanol 200: 1-100: 1).

Yield: 5.20 g (99% of theory)

MS (ESI): mz = 485 (M + H) ⁺ HPLC (method 1): R _t = 4.59 min.

1H-NMR (300 MHz, CDC1 ₃ ): δ = 2.73 (s, 3H), 2.75 (s, 3H), 3.87 (s, 6H), 3.91 (s, 3H), 6.59 (s, 2H), 7.53 ( d, 2H), 8.02 (d, 2H). Example 17A

5,7-Dimethyl-2- (4-mtrophenyl) -N- (3,4,5-tome oxyphenyl) imidazo [5,1-fJ [1,2,4] -triazin-4-amine

A solution of 130 mg (0.39 mmol) 5,7-dimethyl-2- (4-nitτophenyl) -4- (lH-l, 2,4-triazol-l-yl) imidazo [5, l-fJ [l, 2,4] triazine from Example HA in DMF is mixed with 111 mg (0.58 mmol) 3,4,5-trimethoxyaniline and 80 mg (0.58 mmol) potassium carbonate. The reaction mixture is stirred at 90 ° C. overnight. After cooling, the solvent is removed on a rotary evaporator, the residue is mixed twice with toluene and the solvent is removed again in vacuo. The product is stirred with a little methanol and suction filtered.

Yield: 128 mg (74% of theory)

MS (ESI): m / z = 451 (M + H) ⁺ HPLC (method 1): R _t = 4.31 min.

1H-NMR (300 MHz, CDC1 ₃ ): δ = 2.74 (s, 3H), 2.80 (s, 3H), 3.90 (s, 3H), 3.94 (s, 6H), 6.59 (s, 2H), 7.07 ( s, 2H), 7.13 (br. s, 1H), 8.29 (d, 2H), 8.52 (d, 2H). Example 18A ^"~

5,7-Dimethyl-2- (3-mtroρhenyl) -N- (3,4,5-methoxyρhenyl) imidazo [5, l-fJ [l, 2,4] - azm-4-amine

To a solution of 350 mg (1.04 mmol) 5,7-dimethyl-2- (3-nitrophenyl) -4- (lH-l, 2,4-triazol-l-yl) imidazo [5, lf] [l, 2,4] triazine from Example 12A in DMF is mixed with 290 mg (1.56 mmol) 3,4,5-trimethoxyaniline and 220 mg (1.56 mmol) potassium carbonate. The reaction mixture is stirred at 90 ° C. overnight. After cooling, the solvent is removed on a rotary evaporator, the residue is treated twice with toluene and the solvent is removed under vacuum. The product is stirred with a little methanol and suction filtered.

Yield: 342 mg (73% of theory)

MS (ESI): m / z = 451 (M + H) ⁺ HPLC (method 1): R _t = 4.36 min.

1H-NMR (300 MHz, CDC1 ₃ ): δ = 2.76 (s, 3H), 2.82 (s, 3H), 3.90 (s, 3H), 3.97 (s, 6H), 7.08 (s, 2H), 7.16 ( br. s, 1H), 7.63 (t, 1H), 8.32 (d, 1H), 8.68 (d, 1H), 9.14 (s,

1H). Example 19A

N- [2- (4-bromophenyl) -5,7-dimethylimidazo [5, l-fj [1,2,4] triazin-4-yl] -N- (3,4,5-trimethoxyphenyl) amine

A solution of 4.0 g (10.80 mmol) of 2- (4-bromophenyl) -5,7-dimethyl-4- (lH-l, 2,4-triazol-l-yl) imidazo [5, lf] [1,2 , 4] triazine from Example 13A in DMF is mixed with 2.97 g (16.21 mmol) of 3,4,5-trimethoxyamine and 2.24 g (16.21 mmol) of potassium carbonate. The reaction mixture is stirred at 90 ° C. overnight. After cooling, the solvent is removed on a rotary evaporator, the residue is treated twice with toluene and the toluene is stripped off again. The crude product is stirred out with a little methanol and suction filtered.

Yield: 3.60 g (69% of theory)

MS (ESI): m / z = 484 (M + H) ⁺ HPLC (method 1): R _t = 4.61 min.

1H-NMR (300 MHz, CDC1 ₃ ): δ = 2.71 (s, 3H), 2.78 (s, 3H), 3.89 (s, 3H), 3.93 (s, 6H), 7.06 (br. S, 1H), 7.09 (s, 2H), 7.56 (d, 2H), 8.22 (d, 2H). Example 20A '- ^""

N-2-tert-Butoxycarbonyl-Nl- (4- {5,7-dimethyl-4 - [(3,4,5-1rimethoxyphenyl) - amino] imidazo [5, 1 -f \ [1, 2.4] triazin-2-yl} phenyl) glycinamide

A solution of 46 mg (0.26 mmol) of BOC-glycine in dichloromethane is mixed with 35 mg (0.26 mmol) of HOBt and 72 mg (0.71 mmol) of 4-methylmorpholine. The mixture is cooled to -20 ° C. and 50 mg (0.26 mmol) EDC are added. The mixture is stirred for 30 min while warming to RT. Then at -20 ° C

100 mg (0.24 mmol) N- [2- (4-aminoρhenyl) -5,7-dimethyumidazo [5, lf] [l, 2,4] triazin-4-yl] -N- (3,4, 5-trimethoxyphenyl) amine from Example 3 was added. The mixture is stirred at 20 ° C. for 24 hours. To complete the reaction, the entire amount of the starting materials - with the exception of the compound from Example 3 - is added again and the mixture is stirred for a further 24 h. The solvent is removed in vacuo, the residue is purified by HPLC.

Yield: 41 mg (30% of theory)

MS (ESI): m / z = 578 (M + H) ⁺ Manufacturing examples ^' - ^"

example 1

4- [5,7-dimethyl-4- (3,4,5-trimethoxyphenoxy) imidazo [5, l-f] [l, 2,4] triazin-2-yl] aniline

Under argon, 70 mg (0.17 mmol) of 5,7-dimethyl-2- (4-nitrophenyl) -4- (3,4,5-trimethoxyphenoxy) imidazo [5, l-fI [1,2,4] triazine Example 14A dissolved in methanol. The mixture is mixed with 20 mg palladium on carbon (10%). At 3 bar

Hydrogen pressure is hydrogenated for 5 h. The catalyst is then filtered off from the reaction mixture and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography. (Mobile phase: dichloromethane / methanol 80: 1).

Yield: 65 mg (93% of theory)

MS (ESI): m / z = 422 (M + H) ⁺ HPLC (method 1): R _t = 3.79 min.

1H-NMR (300 MHz, MeOH-dt): δ = 2.66 (s, 3H), 2.67 (s, 3H), 3.83 (s, 3H), 3.85 (s, 6H), 6.63 (d, 2H), 6.73 (s, 2H), 7.86 (d, 2H). Example 2 ^" - ^'

N- {4- [5,7-Dimethyl-4- (3,4,5-trimemoxyphenoxy) imidazo [5, l-f] [l, 2,4] triazin-2-yl] phenyl} acetamide

A solution of 10 mg (0.09 mmol) acetic acid in dichloromethane is mixed with 10 mg (0.09 mmol) HOBt and 20 mg (0.21 mmol) 4-methylmorpholine. The mixture is cooled to -20 ° C. and 20 mg (0.09 mmol) EDC are added. The mixture is stirred for 30 minutes. 30 mg (0.07 mmol) of 4-

Add [5,7-dimethyl-4- (3,4,5-trimethoxyphenoxy) imidazo [5, lf] [1,2,4] triazin-2-yl] from Example 1, and the batch is added for 5 hours Stirred at 20 ° C. Then the solution is washed with aqueous 1N potassium hydrogen sulfate solution and saturated aqueous sodium hydrogen carbonate solution. The organic phase is dried and concentrated under reduced pressure. The residue is purified by flash chromatography (mobile phase: dichloromethane / methanol 100: 1-80: 1-60: 1).

Yield: 15 mg (45% of theory)

MS (ESI): m / z = 464 (M + H) ⁺

HPLC (method 1): R _t = 3.84 min.

1H-NMR (400 MHz, MeOH-d ^): δ = 2.13 (s, 3H), 2.69 (s, 3H), 2.72 (s, 3H), 3.84 (s,

3H), 3.85 (s, 6H), 6.75 (s, 2H), 7.59 (d, 2H), 8.07 (d, 2H). Example 3 ^•. - ^{,. :}

N- [2- (4-aminophenyl) -5,7-dimethylimidazo [5, l-f] [1,2,4] triazin-4-yl] -N- (3,4,5-trimethoxyphenyl) amine

Analogously to Example 1, 620 mg (1.38 mmol) of 5,7-dimethyl-2- (4-nitrophenyl) -N- (3,4,5-trimethoxyphenyl) inήdazo [5, lf] [l, 2,4] azm- 4-an in Example 17A in the presence of 200 mg of palladium on carbon (10%) hydrogenated.

Yield: 290 mg (50% of theory)

MS (ESI): m / z = 421 (M + H) ⁺ HPLC (method 1): R _t = 3.50 min. 1H-NMR (300 MHz, CDC1 ₃ ): δ = 2.69 (s, 3H), 2.76 (s, 3H), 3.88 (s, 3H), 3.94 (s,

6H), 6.71 (d, 2H), 6.99 (s, 1H), 7.14 (s, 2H), 8.17 (d, 2H).

Example 4 -

N- (4- {5,7-dimethyl-4 - [(3,4,5-trimethoxyphenyl) amino] imidazo [5, l-f] [l, 2,4] triazin

2-yl} phenyl) acetamide

Analogously to Example 2, 14.28 mg (0.24 mmol) acetic acid, 32.14 mg (0.24 mmol) HOBt, 72.17 mg (0.71 mmol) 4-methylmorpholine, 45.6 mg (0.24 mmol) EDC and 100 mg (0.24 mmol) N- [2- ( 4-aminophenyl) -5,7-dimethylimidazo [5, lf] [1,2,4] triazin-4-yl] -N- (3,4,5-trimethoxyphenyl) amine from Example 3. The processing takes place via HPLC separation.

Yield: 32 mg (29% of theory)

MS (ESI): mz = 463 (M + H) ⁺

1H-NMR (300 MHz, CDC1 ₃ ): δ = 2.21 (s, 3H), 2.71 (s, 3H), 2.78 (s, 3H), 3.89 (s, 3H), 3.94 (s, 6H), 7.04 ( s, 1H), 7.12 (s, 2H), 7.59 (d, 2H), 8.32 (d, 2H). Example 5 ^r

4- [5,7-Dimethyl-4- (3, 4,5-trimethoxyphenoxy) imidazo [5, 1-fj [1, 2,4] triazin-2-yl] -N, N-diethylaniline

To a solution of 40 mg (0.08 mmol) of 4- [5,7-dimethyl-4- (3,4,5-trimethoxyphenoxy) imidazo [5, lf] [1,2,4] triazin-2-yl ] aniline from Example 1 in methanol, 10 mg (0.08 mmol) sodium cyanoborohydride and 10 mg (0.17 mmol) acetaldehyde are added and the mixture is stirred at 20 ° C. After the reaction time, 2N hydrochloric acid is added. The methanol is removed under reduced pressure and the aqueous residue is washed with dichloromethane, made alkaline with sodium hydroxide and extracted twice with dichloromethane. The organic phase is dried over sodium sulfate and purified by chromatography (mobile phase: dichloromethane / methanol 80: 1 - 60: 1 - 40: 1 plus drops of NH ₄ OH)

Yield: 4 mg (10% of theory)

MS (ESI): m / z = 478 (M + H) ⁺ HPLC (method 1): R _t = 3.69 min. 1H-NMR (300 MHz, MeOH- _t ): δ = 1.11 (t, 6H), 2.66 (s, 3H), 2.68 (s, 3H), 3.36 (q,

4H), 3.83 (s, 3H), 3.85 (s, 6H), 6.61 (d, 2H), 6.69 (s, 2H), 7.88 (d, 2H). Example 6 -

3- [5,7-Dimethyl-4- (3,4,5-trimethoxyphenoxy) imidazo [5, l-f] [l, 2,4] triazin-2-yl] aniline

Analogously to Example 1, 400 mg (0.89 mmol) of 5,7-dimethyl-2- (3-nitrophenyl) -4- (3,4,5-trimethoxyphenoxy) imidazo [5, lf] [1,2,4] triazine Example 15A hydrogenated in the presence of 120 mg palladium on carbon (10%).

Yield: 350 mg (94% of theory)

MS (ESI): m / z = 422 (M + H) ⁺ HPLC (method 1): R _t = 3.69 min.

1H-NMR (200 MHz, DMSO-de): δ = 2.61 (s, 3H), 2.65 (s, 3H), 3.71 (s, 3H), 3.79 (s, 6H), 5.26 (br. S, 2H) , 6.63-6.72 (d, IH), 6.84 (s, 2H), 7.08 (t, IH), 7.15-7.22 (d, IH),

7.35 (s, IH).

Example 7 -

N- [2- (3-Aminoρhenyl) -5,7-dimemylimidazo [5, l-f] [1,2,4] triazin-4-yl] -N- (3,4,5-trimethoxyphenyl) amine

Analogously to Example 1, 340 mg (0.76 mmol) of 5,7-dimethyl-2- (3-nitrophenyl) -N- (3,4,5-trimemoxyphenyl) imidazo [5, lf] [1,2,4] triazine 4-amine from Example 18A in the presence of 110 mg of palladium on carbon (10%) hydrogenated.

Yield: 231 mg (72% of theory)

MS (ESI): m / z = 421 (M + H) ⁺ HPLC (method 1): R _t = 3.51 min.

1H-NMR (500 MHz, DMSO-de): δ = 2.54 (s, 3H), 2.69 (s, 3H), 3.68 (s, 3H), 3.82 (s, 6H), 5.21 (s, 2H), 6.68 (d, IH), 7.11 (t, IH), 7.34 (s, 2H), 7.42 (d, IH), 7.48 (s, IH),

8.66 (s, IH).

Example 8 -

5,7-dimethyl-2- [4- (4-moφholinyl) phenyl] -4- (3,4,5-trimethoxyphenoxy) imidazo [5, l-f] [1,2,4] triazine

2 mg (0.004 mmol) of bis (dibenzylideneacetone) palladium (O) and 3 mg (0.004 mmol) of 2,2'-bis (diphenylphosphino) -1, r-binaphthyl are placed in a Schlerik vessel under argon. It is dissolved in a little anhydrous toluene and stirred at 20 ° C. for 15 minutes (solution A).

28 mg (0.29 mmol) of sodium tert-butoxide are placed in a second Schlenk tube under argon. Then 100 mg (0.21 mmol) of 2- (4-bromophenyl) -5,7-dimethyl-4- (3,4,5-trimethoxyphenoxy) imidazo- [5, lf] [l, 2,4] triazine from Example 16A, 22 mg (0.25 mmol) of Moφholin and 2 ml of anhydrous toluene were added. Solution A is also added and the whole is stirred at 100 ° C overnight. Then, after cooling, the mixture is suctioned off through a glass frit. The filtrate is evaporated to dryness under reduced pressure and purified by flash chromatography (cyclohexane / ethyl acetate 10: 1 - 4: 1 - 3: 2 - 1: 1).

Yield: 65 mg (64% of theory)

MS (ESI): m / z = 492 (M + H) ⁺ HPLC (method l): R _t = 4.22 min. ^"r"

1H-NMR (300 MHz, DMSO-d ₆ ): δ = 2.60 (s, 3H), 2.64 (s, 3H), 3.17-3.24 (m, 4H),

3.68-3.75 (m, 7H, s at 3.72), 3.79 (s, 6H), 6.83 (s, 2H), 7.00 (d, 2H), 7.92 (d, 2H).

Example 9

N- {3- [5,7-Dimethyl-4- (3,4,5-ιrimethoxyphenoxy) imidazo [5, l-f] [1,2,4] triazin-2-yl] phenyl} acetamide

Analogously to Example 2, 14.25 mg (0.24 mmol) acetic acid, 32.06 mg (0.24 mmol) HOBt, 72.00 mg (0.71 mmol) 4-methylmoφholin, 50.03 mg (0.26 mmol) EDC and 100 mg (0.24 mmol) 3- [5.7 -Dimethyl-4- (3,4,5-trimethoxyphenoxy) imidazo [5, l-f] [l, 2,4] triazin-2-yl] aniline from Example 6.

Yield: 100 mg (91% of theory)

MS (ESI): m / z = 464 (M + H) ⁺ HPLC (method 1): R _t = 3.89 min. 1H-NMR (300 MHz, CDC1 ₃ ): δ = 2.19 (s, 3H), 2.79 (s, 3H), 2.84 (s, 3H), 3.88 (s,

6H), 3.92 (s, 3H), 6.59 (s, 2H), 7.37 (t, IH), 7.80 (d, IH), 7.89 (d, IH), 8.09 (s, IH). Example 10

N- (3- {5,7-Dimethyl-4 - [(3,4,5-Mememoxyph ^ 2-yl} phenyl) acetamide

Analogously to Example 2, 14 mg (0.21 mmol) of acetic acid, 31 mg (0.23 mmol) of HOBt, 63 mg (0.62 mmol) of 4-methylmoφholin, 44 mg (0.23 mmol) of EDC and 87 mg (0.21 mmol) of 3- [5.7 -Dimethyl-4- (3,4,5-1ximethoxvphenoxy) inήdazo- [5, l-fJ [l, 2,4] triazin-2-yljanilin from Example 7 implemented.

Yield: 91 mg (95% of theory)

MS (ESI): mz = 463 (M + H) ⁺ HPLC (method 1): R _t = 3.92 min.

1H-NMR (300 MHz, DMSO-d ₆ ): δ = 2.06 (s, 3H), 2.59 (s, 3H), 2.70 (s, 3H), 3.69 (s, 3H); 3.82 (s, 6H), 7.31 (s, 2H), 7.40 (t, IH), 7.75 (d, IH), 7.91 (d, IH), 8.38 (s, IH), 8.81 (s, IH), 10.06 (s, IH). Example 11 - ^r

N- (3- {5,7-Dimethyl-4 - [(3,4,5-trimethoxyphenyl) amino] imidazo [5, l-f] [1,2,4] triazin-2-yl} phenyl) methanesulfonamide

A solution of 80 mg (0.19 mmol) of 3- [5,7-dimethyl-4- (3,4,5-trimethoxyphenoxy) imidazo [5, l-fJ [l, 2,4] triazin-2-yl] aniline from Example 7, 20 mg (0.19 mmol) methanesulfonyl chloride and 40 mg (0.38 mmol) triethylamine in dichloromethane is stirred at 20 ° C. overnight. It is washed with aqueous sodium bicarbonate solution, the organic phase is dried and purified by HPLC.

Yield: 19 mg (20% of theory)

MS (ESI): mz = 499 (M + H) ⁺

HPLC (method 1): R _t = 3.87 min.

1H-NMR (300 MHz, DMSO-d ₆ ): δ = 2.59 (s, 3H), 2.70 (s, 3H), 2.98 (s, 3H), 3.69 (s,

3H); 3.82 (s, 6H), 7.26 (s, 2H), 7.36 (d, IH), 7.48 (t, IH), 7.98 (d, IH), 8.11 (s, IH),

8.76 (s, IH), 9.83 (br. S, IH). Example 12 - ^r

4- {5,7-Dimethyl-4 - [(3,4,5-trimethoxyphenyl) amino] imidazo [5, l-f] [1,2,4] triazin-2-yl} phenylformamide

16 mg (0.24 mmol) of imidazole, 48 mg (0.48 mmol) of triethylamine and 11 mg (0.24 mmol) of formic acid in 4 ml of dichloromethane are introduced under argon, cooled to 0 ° C. and added dropwise with a solution of 30 mg (0.24 mmol) of oxalic acid - Added dichloride to dichloromethane. The mixture is allowed to warm to 20 ° C. and 100 mg (0.24 mmol) of N- [2- (4-aminophenyl) -5,7-dimethylimidazo [5, l-f] [l, 2,4] triazin-4- yl] -N- (3,4,5-trimethoxyphenyl) arnine from Example 3. It is stirred overnight and then washed with aqueous sodium hydrogen carbonate solution. The organic phase is dried and purified by flash chromatography (DicWorme on methanol 100: 1).

(see T. Kitagawa et al., Chem. Pharm. Bull, 42 (9), 1994, 1931-1934)

Yield: 56 mg (53% of theory)

MS (ESI): m / z = 449 (M + H) ⁺

HPLC (method 1): R _t = 3.76 min.

1H NMR (300 MHz, DMSO-d ₆ ): δ - 2.69 (s, 3H), 2.76 (s, 3H), 3.70 (s, 3H); 3.82 (s,

6H), 7.29 (s, 2H), 7.69 (d, 2H), 8.20 (d, 2H), 8.32 (s, IH), 8.71 (s, IH), 10.36 (br. S,

IH). Example 13

N- (4- {5,7-Dimethyl-4 - [(3,4,5-1rimethoxyphenyl) ammo] imidazo [5, l-f [l, 2,4] triazin-2-yl} phenyl) propanamide

Analogously to Example 2, 13 mg (0.17 mmol) of propionic acid, 23 mg (0.17 mmol) of HOBt, 47 mg (0.46 mmol) of 4-methylmoφholin, 33 mg (0.17 mmol) of EDC and 65 mg (0.21 mmol) of N- [2- ( 4-Armnophenyl) -5,7-dimethylimidazo [5, l-fJ [l, 2,4] triazin-4-yl] -

N- (3,4,5-trimethoxyphenyl) amine from Example 3 implemented.

Yield: 45 mg (61% of theory)

MS (ESI): m / z = 477 (M + H) ⁺

HPLC (method 1): R _t = 4.10 min.

1H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.09 (t, 3H), 2.34 (q, 2H), 2.58 (s, 3H), 2.69 (s,

3H), 3.70 (s, 3H), 3.84 (s, 6H), 7.31 (s, 2H), 7.70 (d, 2H), 8.18 (d, 2H), 8.69 (br. S,

IH), 10.0 (br. S, IH). Example 14 -

N ¹ - (4- {5,7-Dimethyl-4 - [(3,4,5-trimethoxyphenyl) amino] imidazo [5, lf | [1,2,4] - triazin-2-yl} phenyl) glycinamide

740 mg (6.49 mmol) of trifluoroacetic acid are added dropwise to a solution of 40 mg (0.07 mmol) from Example 20A in 5 ml of dichloromethane and the mixture is stirred at 20 ° C. for 6 h. After the solvent has been stripped off, the residue is dried under high vacuum and purified by HPLC.

Yield: 27 mg (81% of theory)

MS (ESI): m / z = 478 (M + H) ⁺ HPLC (method 1): R _t = 3.58 min.

1H-NMR (400 MHz, MeOH-c,): δ = 2.74 (s, 3H), 2.80 (s, 3H), 3.84 (s, 3H), 3.91 (s, 2H), 3.92 (s, 6H), 7.30 (s, 2H), 7.71 (d, 2H), 8.31 (d, 2H). Example 15

N- (4- {5,7-Dimemyl-4 - [(3,4,5-trimethoxyphenyl) amino] imidazo [5, l-fJ [l, 2,4] triazin-2-yl} phenyl) -2 -hydroxyacetamid

A solution of 50 mg (0.12 mmol) of N- [2- (4-aminophenyl) -5,7-dimethylimidazo [5, lf] [1,2,4] triazin-4-yl] -N- ( 3,4,5-trimethoxyphenyl) amine from Example 3 in DMF is mixed with 18 mg (0.24 mmol) glycolic acid, 90 mg (0.24 mmol) HATU and 46 mg (0.24 mmol) EDC. The mixture is stirred at 20 ° C. overnight. The solvent is removed under reduced pressure and the residue is purified by HPLC.

Yield: 25 mg (44% of theory)

MS (ESI): m / z - 479 (M + H) ⁺ HPLC (method 1): R _t = 3.76 min.

1H-NMR (300 MHz, MeOH-cLi): δ = 2.76 (s, 3H), 2.82 (s, 3H), 3.87 (s, 3H), 3.95 (s, 6H), 4.20 (s, 2H), 7.32 (s, 2H), 7.74 (d, 2H), 8.29 (d, 2H). Example 16 "- ^{r ~}

4- ({4- [5,7-Dimemyl-4- (3,4,5-trimethoxyphenoxy) imidazo [5, 1-fj [1, 2,4] triazin-2-yl] - phenyl} amino) - 4-oxobutanoic acid

A solution of 100 mg (0.24 mmol) of N- [2- (4-aminophenyl) -5,7-dimethylimidazo [5, lf] [l, 2,4] ιriazm-4-yl] -N- (3rd , 4,5-trimethoxyphenyl) amine from Example 3 and 77 mg (0.76 mmol) dihydro-2,5-furanedione dissolved in dichloromethane is stirred under reflux for 16 h. The mixture is evaporated to dryness and the residue is purified by flash chromatography with eluent dichloromethane / methanol.

Yield: 127 mg (quant.)

LC-MS (Method 2): R _t = 2.59 min.

MS (ESf): m / z = 522 [M + H] ⁺

MS (ESI-): m / z = 520 [MH] ^"

1H-NMR (200 MHz, DMSO-d ₆ ): δ = 2.46-2.61 (m, 4H, with DMSO signal), 2.62

(s, 3H), 2.66 (s, 3H), 3.72 (s, 3H), 3.79 (s, 6H), 6.86 (s, 2H), 7.68 (d, 2H), 8.00 (d, 2H), 10.22 ( s, IH), 12.23 (br. s, IH). Example 17 -

5,7-dimethyl-2- [4- (l-pyrolidmyl) phenyl] -4- (3,4,5-trimethoxyphenoxy) imidazo [5, l-fj [l, 2,4] triazine

Example 18

5,7-dimethyl-2- [4- (l-piperidinyl) phenyl] -4- (3,4,5-trimethoxyphenoxy) imidazo [5, l-fj [1,2,4] triazine

General preparation instructions for the compounds of Examples 17 and 18: 1 eq. the compound from Example 16A is with 1.2 eq. Amine, 1.4 eq. Sodium tert-butoxide, 0.02 eq. BINAP and 0.02 eq. Bis (dibenzylidene acetone) palladium suspended in xylene. The mixture is stirred at 140 ° C. for 16 h. Then the solvent is removed in vacuo, the residue is taken up in toluene and again evaporated to dryness in vacuo. The product is cleaned by HPLC.

Example l9

N- {4- [5,7-Dimethyl-4- (3,4,5-trimethoxyphenoxy) imidazo [5, 1-fj [1, 2,4] triazin-2-yl] phenyl} propanamide

Example 20

N- {4- [5,7-Dimethyl-4- (3,4,5-memoxyphenoxy)] lmidazo [5, l-f [l, 2,4] triazm- ^ phenyl} cyclopropanecarboxamide

Example 21

N- {4- [5,7-Dimethyl-4- (3,4,5-trimethoxyρhenoxy) imidazo [5, 1-fj [1, 2,4] triazin-2-yl] phenyl} cyclopentane carboxamide

Example 22 N- {4- [5,7-Dimethyl-4- (3,4,5-trimemoxyphenoxy) imidazo [5, lf] [1,2,4] triazin-2-yl] phenyl} -2- hydroxypropanamide Example 23 ^' - ^"

N- {4- [5,7-Dimethyl-4- (3,4,5-trimemoxyphen ^ phenyl} tetrahydro-2-furancarboxamide

Example 24

N- {4- [5,7-Dimethyl-4- (3,4,5-trimethoxyρhenoxy) imidazo [5, 1-fj [1, 2,4] triazin-2-yl] phenyl} tetrahydro-3- furancarboxamide

Example 25 N- {4- [5,7-Dimethyl-4- (3,4,5-trimethoxyphenoxy) imidazo [5, 1-f] [1, 2,4] triazin-2-yl] phenyl} tetrahydro -2H-pyran-4-carboxamide

Example 26

N ¹ - (4- {5,7-Dimethyl-4 - [(3,4,5-trimethoxyphenyl) amino]] Lmidazo [5, lf] [l, 2,4] - triazin-2-yl} phenyl) -beta-alaninamide

Example 27

N ¹ - {4- [5,7-Dimethyl-4- (3,4,5-trimethoxyphenoxy) imidazo [5, l-fj [l, 2,4] triazin-2-yl] phenyl} -N ² , N ² -dimethylglycinamide

Example 28

N- {4- [5,7-Dimethyl-4- (3,4,5-trimethoxyphenoxy) imidazo [5, l-fj [l, 2,4] triazin-2-yl] phenyl} -2- ( 4-methyl-1-piperazinyl) acetamide

General synthesis instructions for the compounds of Examples 19 to 28:

1 eq. of compounds from Example 1 or 3 is with 1.2 eq. Acid, 1.2 HATU, 1.2 eq EDC x HCl dissolved in dichloromethane and stirred at RT for 16 h. The solvent is then removed in vacuo, the residue is taken up in toluene and the solution is again evaporated to dryness in vacuo. The product is cleaned by HPLC. The compound of Example 26 is dissolved by Reim narrowing in dichloromethane and ^"treated with 10 eq. Of trifluoroacetic acid. Then, it is stirred for 6 h at RT, following the solvent under reduced pressure is removed and the product purified by HPLC.

Claims

Claims ^" - ^'

1. Compounds of the formula

in which

R ^{1 is} hydrogen or d-Cβ-alkyl,

R ^{5 is} hydrogen, formyl, -CC ₆ alkyl, (CrCe-alky carbonyl, Ci-Cβ-

Alkylsulfonyl, (C ₃ -C ₈ -cycloalkyl) carbonyl or (3 to 8-membered heterocyclyl) carbonyl, where alkylcarbonyl with up to 3 substituents - independently selected from the series halogen, hydroxy, amino, carboxy, -Ce-alkoxy, C _ö -Cio-aryl, -C-C ₆ alkylamino and a 3 to 8-membered heterocyclyl substituted with up to 3 Cι-C ₃ alkyl substituents - may be substituted

or

R ¹ and R ⁵ together with the nitrogen atom to which they are attached form a 5 to 8-membered heterocycle which, with up to 3 substituents - selected independently of one another from the series halogen, hydroxy, C ₁ -C ₆ -alkyl, Cι- C ₆ alkoxy, C ₆ -C ₁₀ aryl, amino and CrC _ö alkylamino - may be substituted R ² dC _ö alkyl or C ₃ -C ₄ cycloalkyl, ^"" - ^"

R ³ methyl,

A is an oxygen atom or NH,

and

R ^{4 is} C ₆ -C ₁₀ aryl which, with up to 3 substituents, is selected independently of one another from the series halogen, formyl, carboxyl, carbamoyl, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, C ₁ -C ₆ alkyl, d-Cβ-alkoxy, l, 3-dioxa-propane-l, 3-diyl, dC _ö alkylthio and -NR R - may be substituted,

wherein

R ⁶ and R ⁷ independently of one another represent hydrogen, dC _ö -alkyl or (-C-C ₆ - alkyl) carbonyl,

mean,

and their salts, solvates or solvates of the salts.

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

R ^{1 is} hydrogen,

R ^{5 is} hydrogen, (C ₃ -C ₆ -cycloalkyl) carbonyl, (4 to 6-membered heterocyclic) carbonyl or (Ci-d-alkycarbonyl, where alkylcarbonyl can be monosubstituted with hydroxy or amino, R ² d-Ce alkyl,

R ³ methyl,

A is an oxygen atom or NH,

and

R ^{4 is} phenyl, which can be substituted by up to 3 substituents, independently of one another, selected from the series halogen, d-C0-alkyl and C ₁ -C ₆ -alkoxy

and their salts, solvates or solvates of the salts.

Compounds according to formula (I) according to claims 1 and 2, in which

R ^{1 is} hydrogen,

R ^{5 is} hydrogen, (C ₃ -C6-cycloalkyl) carbonyl, (4 to 6-membered heterocyclicl) carbonyl or (Ci-d-Alkyrjcarbonyl, wherein alkylcarbonyl with

Hydroxy or amino can be monosubstituted,

R ² dC _ö alkyl,

R ³ methyl,

A is an oxygen atom or NH,

and R ^{4 is} phenyl, which may be substituted by 1 to 3 (C ₁ -C 6) alkoxy radicals, ^" , and

and their salts, solvates or solvates of the salts.

4. A process for the preparation of the compounds according to claim 1, characterized in that

[A] Compounds of the formula

in which

R, ι, R, R and R have the meanings given in claim 1,

with compounds of the formula

R ^' \ (in),

A - H

in which

R ⁴ and A have the meanings given in Claim 1, or

[B] Compounds of the formula

in which

R ² , R ³ , R ⁴ and A have the meanings given in Claim 1,

with compounds of the formula

X ¹ _R s ^ ^λ (TV),

in which

R ^{5 has} the meaning given above and

X ^{1 represents} halogen, preferably bromine or chlorine, or hydroxy,

to compounds of the formula

in which

R _> 5 ³ , R, R ^ R ⁴ and A have the meanings given in claim 1,

or

[C] Compounds of the formula

in which

R> 2 ^z , τ R> 3 ³ , r R> 4 ⁴ and A have the meanings given in Claim 1,

with compounds of the formula H - "

I

_R1 ^ ^N ^ _{R5 (} vi ₎ ,

in which

R ¹ and R ^{5 have} the meanings given in Claim 1,

and optionally reacting the compounds (I) resulting from [A], [B] or [C] with the corresponding (i) solvents and or (ii) bases or acids to give their solvates, salts or solvates of the salts.

5. Compounds according to the invention according to claims 1 to 3 for the treatment and / or prophylaxis of diseases.

6. Medicament containing at least one of the compounds according to claims 1 to 3 and at least one pharmaceutically acceptable, essentially non-toxic carrier or excipient.

7. Use compounds according to claims 1 to 3 for the manufacture of a medicament for the treatment and / or prophylaxis of neurodegenerative diseases.

8. Use of the compounds according to claims 1 to 3 for the manufacture of a medicament for the treatment and / or prophylaxis of cancer and psychiatric disorders.

9. Use according to claim 7, wherein the neurodegenerative disease

Parkinson's disease.

10. Use according to claim 8, wherein the psychiatric disease is schizophrenia.

11. A method for combating cancer, neurodegenerative diseases and psychiatric diseases in humans or animals by administering an effective amount of the compounds from claims 1 to 3.

12. The method of claim 11, wherein the neurodegenerative disease

Parkinson's disease.

13. The method of claim 11, wherein the psychiatric disorder is schizophrenia.