NO328804B1 - New dihydropterinones, methods for their preparation and their use - Google Patents

Description

The present invention relates to new dihydropteridinones, methods for their preparation and their use.

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

in which

R<1> means a residue selected from the group consisting of hydrogen, NH2, XH, halogen and

a Ci-C3 alkyl group optionally substituted with one or more halogen atoms,

R<2>a group selected from hydrogen, CHO, XH, -X-C1-C2-alkyl and an optionally

substituted C 1 -C 3 alkyl group,

R<3>, R4 are the same or different and denote a group selected from optionally substituted Ci-

C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, aryl, heteroaryl, C 1 -C 10 -cycloalkyl,

-X-aryl, -X-heteroaryl, -X-cycloalkyl, -NR<8->aryl, -NR<8->heteroaryl, -NR<8->cycloalkyl or -NR<8->heterocycloalkyl;

Ca-Ca-heterocycloalkyl, X-heterocycloalkyl or a group selected from hydrogen,

halogen, COXR<8>, CON(R<8>)2, COR<8>andXR<8>, or

R3 and R<4> together form a 2- to 5-membered alkyl bridge, which may contain 1 to 2

heteroatoms,

R<5>hydrogen or a group selected from optionally substituted C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl and -C3-C6-cycloalkyl, or

R3 and R5 or R4 and R5 together denote a saturated or unsaturated C3-C4 alkyl bridge which may contain 1 to 2 heteroatoms,

R6 denotes optionally substituted aryl or heteroaryl,

R7 denotes hydrogen or -CO-X-Ci-C4-alkyl, and

X denotes in each case independently, O or S,

R8 denotes in each case, independently of each other, hydrogen or a group selected from optionally substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and phenyl,

where, unless otherwise stated,

are the substituents of the optionally substituted alkyl groups selected from the halogen atoms fluorine, chlorine, bromine or iodine, a group selected from among -CN, -OCOCH3, aryl, heteroaryl, saturated or unsaturated heterocycloalkyl, an amino group, a saturated or unsaturated bicyclic ring system,

the substituents of optionally substituted alkynyl groups are chosen from the halogen atoms fluorine, chlorine, bromine or iodine,

the substituents of the optionally substituted alkynyl groups are chosen from among the halogen atoms, fluorine, chlorine, bromine or iodine,

the substituents of the optionally substituted aryl groups are selected from -OH, -NO2, -CN, -OCHF2, -OCF3, -NH2, halogen, -Ci-Cio-alkyl, -O-Ci-C3-alkyl, -N-methyl- tetrahydrooxazinyl, -COOH, -COO-Ci-C4-alkyl, -CONH2, -CONH-Ci-Ci0-alkyl, -CONH-C3-C8-cycloalkyl, -CONH-heterocycloalkyl, -CONH-heteroaryl, -CONH-aryl, - CONHMeCi-C3-alkyl, benzimidazole or a group of formula

the substituents of the optionally substituted heteroaryl group are selected from among -OH, -NO2,

-CN, -OCHF2, -OCF3, -NH2, halogen, -Ci-Ci0-alkyl, -0-d-C3-alkyl, -N-methyl-

tetrahydrooxazinyl, -COOH, -COO-Ci-C4-alkyl, CONH2, phenyl, heteroaryl, -CONH-Ci-Cio-alkyl, -CONH-C3-C8-cycloalkyl, -CONH-heteroaryl, -CONH-aryl, -CONHMeCi -C3-alkyl, benzimidazole or a group of formula

the substituents of an optionally substituted cycloalkyl group are selected from among one or more oxygen atoms linked via a double bond, where the cycloalkyl groups may also be linked to a benzene ring, and, unless otherwise stated,

by the term "aryl" used in the above definition is meant an aromatic ring system with 6 to 14 carbon atoms,

by the term "heteroaryl" used in the above definition is meant a 5-10 membered mono- or bicyclic heteroaryl ring in which up to three carbon atoms can be replaced by one or more heteroatoms selected from oxygen, nitrogen or sulphur,

by the term "cycloalkyl" used in the above definitions is meant a saturated or unsaturated cycloalkyl group with 3 to 8 carbon atoms,

by the term "cycloalkyl" used in the above definitions is meant a 5-, 6- or 7-membered, saturated or unsaturated, heterocyclic group which may contain nitrogen, oxygen or sulfur as the heteroatom, while each of the above-mentioned heterocyclic groups may optionally also be linked to a benzene ring,

optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally pharmaceutically acceptable acid addition salts thereof.

Background for the invention

Pteridinone derivatives are known as active substances with antiproliferative action from the state of the art. WO 01/019825 describes the use of pteridinone derivatives for the treatment of tumor and viral diseases.

The resistance of many tumor types requires the development of new drugs for tumor control.

It is the task of the present invention to provide new compounds with anti-inflammatory and antiproliferative action.

Detailed description of the invention

Surprisingly, it was found that compounds of the general formula (I), in which the residues X and R<1>to R7 have the following meanings, act as inhibitors of specific cell cycle kinases. Thus, the compounds according to the invention can be used, for example, for the treatment of diseases which are related to the activity of specific cell cycle kinases and are characterized by strong or anomalous cell proliferation.

The present invention further relates to the compound according to claim 1, in which X and R<6> have the indicated meaning, and

R<1> means hydrogen,

R<2> represents a group selected from CHO, OH, and CH3 group,

R<3>, R4 are the same or different and denote a group selected from hydrogen, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, or R3 and R<4 >indicate together a C2-C5 alkyl bridge,

R<5>denotes a group selected from optionally substituted C1-C10-alkyl, C2-C-10-alkenyl, C2-C10-alkynyl, and C3-C6-cycloalkyl, or

R3 and R5 or R4 and R<5> together denote a saturated or unsaturated C3-C4 alkyl bridge, which may contain 1 to 2 heteroatoms, and

R<7> is hydrogen

optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, as well as optionally their pharmacologically acceptable acid addition salts.

Preferred are compounds according to claim 1 or 2, below

R<1->R5,R7,R<8>and X have the indicated meaning, and

R6 a residue with the general formula

in which

n is 1, 2, 3 or 4,

R<9>denotes a group selected from optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -CONH-C1-C10-alkylene, -O-aryl, -O-heteroaryl, - O-cycloalkyl, -O-heterocycloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl or a group selected from -O-Ci-C6-alkyl-Q<1>, -CONR<8->Ci-Ci0-alkyl-Q< 1>, -CONR<8->C2-Ci0-alkenyl-Q<1>, -CONR<8->Q<2>, halogen, OH, -SO2R<8>, -SO2N(R<8>)2 >-COR<8>,

-COOR<8>,-N(R<8>)2, -NHCOR<8>, CONR<8>OCrC10alkylQ<1>and CONR<8>OQ<2>,

Q<1> denotes hydrogen, -NHCOR<8>, or a group selected from optionally substituted

-NH-aryl-, -NH-heteroaryl-, aryl-, heteroaryl-, C3-C8-cycloalkyl- and heterocycloalkyl group, Q<2>denotes hydrogen or a group selected from among an optionally substituted aryl-, heteroaryl-, Ca-Ca-heterocycloalkyl, C3-Ca-cycloalkyl and CrC4-alkyl-C3-C8-cycloalkyl - group, R<10> are the same or different and is a group selected from optionally substituted Ci-Ce-alkyl, C2-C6 -alkenyl and C2-C6-alkynyl, -0-C1-C6-alkyl, -0-C2-C6-alkenyl, -0-C2-C6-alkynyl, C3-C6-heterocycloalkyl and C3-C6-cycloalkyl, or a group selected from hydrogen, -CONH2, -COOR8, -OCON(R<8>)2, -N(R8)2> - NHCOR<8>, -NHCON(R<8>)2, -NO2 and halogen,

or

neighboring groups R<9>and R<10> together form a bridge with the general formula

Y indicates O, S or NR<11>,

m indicates 0, 1 or 2

R 11 denotes hydrogen or C 1 -C 2 alkyl, and

R<12> denotes hydrogen or a group selected from optionally substituted phenyl,

pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, -Ci-C3-alkyl-phenyl, -Ci-C3-alkyl-pyridyl, -Ci-C3-alkyl-pyrazinyl, -Ci-C3-alkyl-pyrimidinyl and -Ci-C3-alkyl -pyridazinyl,

R<13> denotes C1-C6-alkyl,

optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, as well as optionally their pharmacologically acceptable acid addition salts.

Particularly preferred are compounds according to one of claims 1 to 3, wherein

R3-R6, R8 and X have the indicated meaning, and

R<1> means hydrogen,

R<2>CH3, and

R<7>hydrogen,

optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, as well as optionally their pharmacologically acceptable acid addition salts.

Particularly preferred are compounds of formula I according to one of claims 1 to 4 for use as medicine.

A further object of the invention is a compound of the formula I according to one of claims 1 to 4 for use as a drug with antiproliferative action

A further object of the invention is the use of a compound of the formula I for the production of a drug for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases.

A further object of the invention are pharmaceutical preparations containing as active ingredient one or more compounds of the general formula (I) according to one of claims 1 to 4 or their physiologically acceptable salts, possibly in combination with usual excipients and/or carriers

A further object of the invention is a method for the preparation of a compound of the general formula (I),

in which

R1-R7 and X have the meanings specified in claims 1 to 4, characterized in that a compound of the general formula (II)

in which

R<1->R<5> and X have the meaning stated in claims 1 to 4 and L is a leaving group, is reacted with an optionally substituted compound of the general formula (III)

in which

R6 and R<7> have the meaning specified in claims 1 to 4.

A further object of the invention is a compound with the formula (II),

in which

R<1->R<5> and X have the meaning specified in claims 1 to 4.

A further object of the invention is a method for the preparation of a compound of the general formula (I),

in which

R<6>means a residue with the general formula,

R<9>an optionally substituted group -CONH-CrCi0-alkylene or

a group selected from -CONR<8->Ci-Ci0-alkyl-Q<1>, -CONR<8->Ci-Ci0-alkenyl-Q<1>, -CONR<8->Q<2>, and -COOR<8>,

R1-R5,R7, R<10>, n and X have the meaning stated in claims 1 to 4, and R8 is, as defined in claim 1, characterized in that a compound of the general formula (IA)

in which

R<1> to R5, R7, R<10> and n have the meaning specified in claims 1 to 4, and

L means a departure group,

is reacted with a primary or secondary amine to form the corresponding amide or with an alcohol to form the corresponding ester.

Alkyl groups and alkyl groups, which are a component of other residues, are defined as branched and straight-chain alkyl groups with 1 to 10 carbon atoms, preferably 1-6, particularly preferably 1-4 carbon atoms, for example: methyl, ethyl, propyl, butyl, pentyl, hexyl , heptyl, octyl, nonyl and decyl. Unless otherwise stated, the aforementioned designations propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl include all of the possible isomeric forms. For example, the designation propyl includes the two isomeric residues n-propyl and iso-propyl, the designation butyl n-butyl, iso-butyl, sec. butyl and tert.-butyl, the designation pentyl, iso-pentyl, neopentyl etc. In the previously mentioned alkyl groups, one or more hydrogen atoms may possibly be replaced by other residues. For example, these alkyl groups can be substituted with the halogen atoms fluorine, chlorine, bromine or iodine. The substituents fluorine and chlorine are preferred. Particularly preferred is the substituent chlorine. Optionally, all hydrogen atoms in the alkyl group can also be replaced.

Likewise, in the aforementioned alkyl groups, if nothing else is described, possibly one or more hydrogen atoms may for example be replaced by an optionally substituted residue selected from the group consisting of CN, OCOCH3, aryl, preferably phenyl, heteroaryl, preferably thienyl, thiazolyl, imidazolyl , pyridyl, pyrimidyl or pyrazinyl, saturated or unsaturated heterocycloalkyl, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, an amine residue, preferably methylamine, benzylamine, phenylamine or heteroarylamine, saturated or unsaturated bicyclic ring systems, preferably benzimidazolyl and cycloalkyl, preferably cyclohexyl or cyclopropyl.

Alkyl bridge means, unless otherwise specified, branched and straight-chain alkyl groups with 2 to 5 carbon atoms, for example propylene, isopropylene, n-butylene, iso-butyl, sec. butyl and tert.-butyl etc. Propylene and butylene bridges are particularly preferred. In the aforementioned alkyl bridges, 1 to 2 C atoms may optionally be replaced by one or more heteroatoms selected from the group oxygen, nitrogen or sulphur.

Branched and straight-chain alkylene groups with 2 to 10 carbon atoms, preferably 2-6 carbon atoms, particularly preferably 2-3 carbon atoms, are considered alkenyl groups (also when it is a component of other residues), provided they have at least one double bond. For example: Ethenyl, propenyl, butenyl, pentenyl etc. Unless otherwise mentioned, the previously mentioned designations propenyl, butenyl etc. include all of the possible isomeric forms. For example, the term butylene includes n-butenyl, 1-methylpropenyl, 2-methylpropenyl, 1.1-dimethylethenyl, 1.2-dimethylethenyl etc.

In the aforementioned alkenyl groups, unless otherwise described, one or more hydrogen atoms may be replaced by other residues. For example, these alkyl groups can be substituted with the halogen atoms fluorine, chlorine, bromine or iodine. The substituents fluorine and chlorine are preferred. Particularly preferred is the substituent chlorine. All hydrogen atoms in the alkenyl group can also optionally be replaced.

Branched and straight-chain alkynyl groups with 2 to 10 carbon atoms are referred to as alkynyl groups (also when they are a component of other residues), provided they have at least one triple bond, for example ethynyl, propargyl, butynyl, pentynyl, hexynyl, etc., preferably ethynyl or propynyl.

In the aforementioned alkynyl groups, if nothing else is described, possibly one or more hydrogen atoms may be replaced by other residues. For example, these alkyl groups can be substituted with the halogen atoms fluorine, chlorine, bromine or iodine. The substituents fluorine and chlorine are preferred. Particularly preferred is the substituent chlorine. All hydrogen atoms in the alkynyl group can also optionally be replaced.

The term aryl stands for an aromatic ring system with 6 to 14 carbon atoms, preferably 6 or 10 carbon atoms, preferably phenyl, which, unless otherwise described, can for example carry one or more of the substituents mentioned below: OH, NO2, CN , -OCHF2, -OCF3, -NH2, halogen, for example fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, Ci-Cio-alkyl, preferably Ci-Cs-alkyl, preferably C1-C3-alkyl, particularly preferably methyl or ethyl, -O-Ci-C3-alkyl, preferably -O-methyl or -O-ethyl, - N-methyl -tetrahydro-oxazinyl, -COOH, -COO-Ci-C4-alkyl, preferably

-COOCH2CH3, -COO-C(CH3)3or -COOCH3, -CONH2,

-CONH-CrC10-alkyl, under which this alkyl can optionally be further substituted, optionally substituted -CONH-C3-C6-cycloalkyl, preferably optionally substituted -CONH-cyclopentyl, optionally substituted -CONH-heterocycloalkyl, preferably piperidinyl, pyrrolidinyl or piperazinyl, optionally substituted -CONH-heteroaryl, preferably optionally substituted -CONH-pyridyl, - optionally substituted -CONH-aryl, preferably optionally substituted-CONH-phenyl, -CONMeCi-C3-alkyl, under which this alkyl may optionally be further substituted, preferably -CONMeCH2- pyridyl, benzimidazole or

a remainder with the formula

Examples of 5-10-membered mono- or bicyclic heteroaryl rings in which up to three C atoms can be replaced by one or more heteroatoms selected from the group oxygen, nitrogen or sulfur are furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole mentioned, under which each of the previously mentioned heterocycles may optionally be further condensed to a benzene ring, preferably benzimidazole, and under which these heterocycles .unless otherwise described , for example can carry one or more of the subsequently mentioned substituents OH, NO2, CN, -OCHF2, -OCF3, -NH2, halogen, preferably fluorine or chlorine, Ci-Cio-alkyl, preferably Ci-Cs-alkyl, preferred Ci-C3-alkyl, particularly preferably methyl or ethyl, -O-Ci-C3-alkyl, preferably -O-methyl or -O-ethyl, -methyl-N-tetrahydro-oxazinyl, -COOH, -COO-C1-C4 -alkyl, preferably -COO-C(CH3)3 or -COOCH3, -CONH2, optionally substituted unsaturated phenyl, optionally substituted heteroaryl, preferably optionally substituted pyridyl or pyrazinyl, -CONH-Ci-Cio-alkyl, whereby this alkyl in turn may optionally be substituted, optionally substituted -CONH-C3-C6-cycloalkyl, preferably optionally substituted -CONH -cyclopentyl, optionally substituted -CONH-heteroaryl, preferably optionally substituted -CONH-pyridyl, - optionally substituted -CONH-aryl, preferably optionally substituted -CONH-phenyl, -CONMeCrC3-alkyl, whereby this alkyl in turn may optionally be substituted, preferably -CONMeCH2-pyridyl, benzimidazole or a residue of the formula

Cycloalkyl residues are defined as saturated or unsaturated cycloalkyl residues with 3-8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl, where each of the aforementioned cycloalkyl residues optionally further carries one or more substituents, preferably =0, or may be fused to a benzene ring.

"=0" means an oxygen atom connected through a double bond.

Mentioned as heterocycloalkyl residues, if nothing else is described in the definitions, are 5-, 6- or 7-membered, saturated or unsaturated heterocycles, which as heteroatoms can contain nitrogen, oxygen or sulphur, for example tetrahydrofuran, tetrahydrofuranone, y-butylrolactone, a -pyran, γ-pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine , diazepan, oxazine, tetrahydro-oxazinyl, isothiazole, pyrazolidine mentioned, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, where the heterocycle may optionally be substituted.

Halogen is generally referred to as fluorine, chlorine, bromine or iodine.

As leaving group L is designated, the same or different, a leaving group such as chlorine, bromine, iodine, methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl, preferably chlorine.

The compounds according to the invention can exist in the form of the individual optical isomers, mixtures of the individual enantiomers, diastereomers or racemates, in the form of tautomers as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids - such as, for example, acid addition salts with halogen hydrogen acids, for example hydrochloric or hydrobromic acid, or organic acids, such as for example oxalic, fumaric, diglycol or methanesulphonic acid.

The substituent R<1> can mean a residue selected from the group consisting of hydrogen, NH2,

XH, preferably OH, halogen, preferably fluorine or chlorine, and an optionally substituted Ci-C3 alkyl group, preferably methyl or ethyl, with one or more, preferably one, two or three halogen atoms, preferably fluorine or chlorine. Particularly preferred is the substituent R<1>hydrogen.

The substituent R<2> can mean a residue selected from the group consisting of hydrogen, CHO, XH, preferably OH, -X-Ci-C2-alkyl, preferably -0-CH3 or -0-CH2CH3, and an optionally substituted Ci-C3- alkyl group, wherein the alkyl group preferably consists of 1 to 2 carbon atoms, particularly preferably of one carbon atom and may optionally be substituted, preferably with halogen atoms, particularly preferably with fluorine atoms. Particularly preferred is the substituent R<2>methyl.

The substituents R3 and R4 can be the same or different and mean a residue selected from the group consisting of optionally substituted C1-C10-alkyl, preferably C1-C6-alkyl, preferably C1-C4-alkyl, particularly preferred methyl, ethyl or propyl, particularly preferred methyl or ethyl,

C 2 -C 10 alkenyl, preferably ethenyl or propenyl, preferably ethenyl,

C2-C10-alkynyl, preferably ethynyl or propynyl, aryl, preferably optionally substituted phenyl, heteroaryl, Ca-Ca-cycloalkyl, preferably cyclopropyl and cyclobutyl, C3-C8-heterocycloalkyl, -X-aryl, -X-heteroaryl, -X- cycloalkyl, -X-heterocycloalkyl, -NR<8->aryl,

-NR<8->heteroaryl, -NR<8->cycloalkyl and

-NR<8->heterocycloalkyl, or

a residue selected from the group consisting of hydrogen, halogen, COXR<8>, CON(R<8>)2, COR<8> and XR<8>, preferably hydrogen, or

the residues R3 and R<4> can together mean a 2- to 5-membered alkyl bridge, preferably an ethylene, propylene or butylene bridge, whereby the propylene or butylene bridge can contain 1 to 2 heteroatoms, preferably oxygen, nitrogen or sulphur, particularly preferred an ethylene bridge.

Particularly preferred is the substituent R<3>methyl or ethyl. The substituent R4 is particularly preferably hydrogen or methyl. Particularly preferred are compounds in which R<3> and R<4> are methyl.

All residues in the meaning of R3 and R<4> mentioned may optionally be substituted.

The radical R5 can mean hydrogen or a radical selected from the group consisting of optionally substituted Ci-Cio-alkyl, for example Ci-C6-alkyl-aryl or Ci-C6-alkyl-heteroaryl, preferably Ci-C6-alkyl, particularly preferred Ci-Cs -alkyl, particularly preferably propyl, butyl, pentyl, hexyl, -CH2-cyclohexyl, (CH2)1_2cyclopropyl or (CH2)4-OCOCH3, C2-C10-alkenyl, preferably propenyl, butenyl, pentenyl or hexenyl, preferably propenyl or hexenyl,

C2-C10-alkynyl, preferably propynyl, butynyl or pentynyl, preferably propynyl,

aryl, preferably phenyl, heteroaryl, -C3-C6-cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and -C3-C6-cycloalkenyl, preferably cyclohexenyl or cyclopentenyl, , or the substituents

R3 and R5 or R4 and R5 together form a saturated or unsaturated C3-C4 alkyl bridge, which may contain 1 to 2 heteroatoms, preferably oxygen, sulfur or nitrogen.

All residues in the meaning of R<5> mentioned may optionally be substituted.

The substituent R6 can mean optionally substituted aryl, or heteroaryl, preferably aryl, preferably phenyl.

Particularly preferably, the substituent R<6> means a phenyl residue, which can be substituted with one of the subsequently described residues R<9> and R<10>, under which the phenyl ring can carry one of the residues R<9>, preferably in the para position, and one, two, three or four, preferably one or two of the residues R<10>, preferably in the ortho or meta position.

The substituent R7 can mean hydrogen or -CO-X-Ci-C4-alkyl, preferably hydrogen.

X independently means O or S, preferably O.

The residues R<8> mentioned in the definition of the substituents R3 and R<4> independently mean hydrogen or a residue selected from the group consisting of optionally substituted d-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and phenyl, preferably hydrogen or C1-C2 alkyl.

The substituent R<9> can mean a residue selected from the group consisting of optionally substituted Ci-C6-alkyl, preferably Ci-C4-alkyl, preferably methyl, ethyl or propyl, particularly preferably methyl, C2-C6-alkenyl, C2-C6- alkynyl, -CONH-Ci-Ci0-alkylene, preferably -CONH-d-C3-alkylene, preferably -CONH-Ci-C2-alkylene, -O-aryl, preferably O-C6-do-aryl, particularly preferred O-phenyl , -O-heteroaryl, -O-cycloalkyl, preferably O-C3-C6-cycloalkyl, particularly preferred O-cyclopropyl,

-O-heterocycloalkyl, aryl, preferably C6-C10-aryl, particularly preferred phenyl, heteroaryl, cycloalkyl, preferably C3-C6-cycloalkyl, particularly preferred cyclopropyl, and heterocycloalkyl, or

a residue selected from the group consisting of -0-d-C6-alkyl-Q<1>, -CONR<8>-d-do-alkyl-Q<1>,

-CONR<8>-d-do-alkenyl-Q<1>, -CONR<8->Q<2>, halogen, for example fluorine, chlorine, bromine or

iodine, OH, -S02R<8>, -S02N(R<8>)2, -COR<8>,-COOR<8>,-N(R<8>)2, -NHCOR<8>, CONR< 8>OCrCi0-alkylQ<1> and CONR<8>OQ<2>, wherein Q<1> and Q<2> have the aforementioned meanings. Preferably R<9> one of the following residues means -CONH-Ci-Cio-alkyl, preferably -CONH-Ci-C3-alkyl, particularly preferably -CONH-Ci-C2-alkyl, where this alkyl may optionally in turn be substituted with CN, optionally substituted aryl, preferably optionally substituted phenyl, heteroaryl, preferably thienyl, thiazolyl, imidazolyl, pyridyl, pyrimidyl or pyrazinyl, saturated or unsaturated heterocycloalkyl, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, an amine residue, preferably methylamine, benzylamine, phenylamine or heteroarylamine, saturated or unsaturated bicyclic ring systems, preferably benzimidazolyl and cycloalkyl, preferably cyclohexyl. Furthermore, R<9> preferably means -CONH-heteroaryl, preferably -CONH-pyridyl, -CONH-C3-C10-cycloalkyl, preferably -CONH-cyclopropyl -CONH-cyclobutyl or -CONH-cyclopentyl, particularly preferably -CONH-cyclopropyl; -CONH-C3-C10-heterocycloalkyl, -CONH-C6-C10-aryl, preferably -CONH-phenyl, COO-C1-C3-alkyl, particularly preferred COOCH3, COOH, halogen, preferably F or chlorine, OH or a remainder with the formula

All residues listed in the definition of R<9> can optionally be substituted, preferably with one or more of the residues selected from the group consisting of OH, OCH3, Cl, F, CH3, COOH, CONHCH2f and CONHCH2-pyrazinyl-CH3.

The compounds according to the invention can be produced according to the synthesis methods A and B described below, in which the substituents with the general formulas (A1) to (A6) have the previously mentioned meanings. These procedures must be understood as illustrating the invention.

Procedure A

Step 1A

A compound with the formula (A1) is reacted with a compound with the formula (A2) to a compound with the formula (A3) (Scheme 1A). This reaction can be carried out according to WO 0043369 or WO 0043372. The compound (A1) is commercially available, for example from City Chemical LLC, 139 Allings Crossing Road, West Haven, CT, 06516, USA. The compound (A2) can be prepared according to regulations known from the literature (a) F. Effenberger, U. Burkhart, J. Willfahrt LiebigsAnn. Chem. 1986, 314-333; b) T. Fukuyama, C-K. Jow, M. Cheung, Tetrahedron Lett. 1995, 36, 6373-6374; c) R. K. Olsen, J. Org. Chem. 1970, 35, 1912-1915; d) F.E. Dutton, B.H. Byung Tetrahedron Lett. 1998, 30, 5313-5316; e) J.M. Ranajuhi, M.M. Joulli Synth. Commun. 1996, 26, 1379-1384.

In step 1A, 1 equivalent of the compound (A1) and 1 to 1.5 equivalents, preferably 1.1 equivalents of a base, preferably potassium carbonate, potassium hydrogen carbonate, sodium carbonate or sodium hydrogen carbonate, calcium carbonate, particularly preferably potassium carbonate, are stirred in a diluent, for example acetone, aqueous acetone, tetrahydrofuran, diethyl ether or dioxane, preferably acetone or diethyl ether, particularly preferably acetone.

At a temperature of 0 to 15 °C, preferably 5 to 10 °C, 1 equivalent of an amino acid with the formula (A2) dissolved in an organic solvent, for example acetone, tetrahydrofuran, diethyl ether or dioxane, preferably acetone, is added dropwise. The reaction mixture is heated with stirring to a temperature of 18°C to 30°C, preferably approx. 22°C, and then stirred for a further 10 to 24 hours, preferably approx.

12 hours. The diluent is then distilled off, the residue mixed with water and the mixture extracted two to three times with an organic solvent, for example, diethyl ether or ethyl acetate, preferably ethyl acetate. The combined organic extracts are dried and the solvent distilled off. The remainder (compound A3) can be used without prior purification in step 2.

Step 2A

The compound (A3) obtained in step 1A is reduced on the nitro group and cyclized to the compound with the formula (A4) (Scheme 2A).

In step 2A, 1 equivalent of the nitro compound (A3) is dissolved in an acid, preferably dilute glacial acetic acid, formic acid or hydrochloric acid, preferably glacial acetic acid, and heated to 50 to 70 °C, preferably approx. 60 °C. Then a reducing agent, for example zinc, tin or iron, preferably iron powder, is added until the end of the exothermic reaction and stirred for 0.2 to 2 hours, preferably 0.5 hours, at 100 to 125 °C, preferably at approx. 117 °C. After cooling to room temperature, the iron salt is filtered off and the solvent is distilled off. The residue is taken up in a solvent or a solvent mixture, for example ethyl acetate or dichloromethane/methanol 9/1 and half-saturated NaCl solution, and filtered over diatomaceous earth, for example. The organic phase is dried and evaporated. The residue (compound (A4)) can be purified chromatographically or by means of crystallization or used as a crude product in step 3A of the synthesis.

Step 3A

The compound (A4) obtained in step 2A can be converted by electrophilic substitution according to Scheme 3A to the compound with the formula (A5).

In step 3A, 1 equivalent of the amide with the formula (A4) is dissolved in an organic solvent, for example dimethylformamide or dimethylacetamide, preferably dimethylacetamide, and cooled to approx. -5 to 5 °C, preferably 0 °C.

Then 0.9 to 1.3 equivalents of sodium hydride and 0.9 to 1.3 equivalents of alkyl halide, for example methyl iodide, are added. The reaction mixture is stirred for 0.1-3 hours, preferably approx. 1 hour, at approx. 0 to 10 °C, preferably at approx. 5 °C, and can possibly be allowed to stand for a further 12 hours in this temperature range. The reaction mixture is evaporated and extracted with water and an organic solvent, preferably dichloromethane, ethyl acetate. The organic phase is evaporated. The residue (compound (A5)) can be purified chromatographically, preferably over silica gel.

Step 4A

The amination of the compound (A5) obtained in step 3A to the compound with the formula (A7) (Scheme 4A) can be carried out according to the methods known from the literature of the variants 4.1 A (a) M.P.V. Boarland, J.F.W. McOmi J. Chem. Soc. 1951, 1218-1221; b) F.H.S. Curd, F.C. Rose J. Chem. Soc. 1946, 343-348., 4.2 A (a) Banks J. Am. Chem. Soc. 1944, 66, 1131 b) Ghosh and Dolly J. Indian Chem. Soc. 1981, 58, 512-513.

For example, in variant 4.1, A becomes 1 equivalent of the compound (A5) and 1 to 3 equivalents, preferably approx. 2 equivalents of the compound (A6) without solvent or an organic solvent such as sulfolane, dimethylformamide, dimethylacetamide, toluene, N-methylpyrrolidone, dimethylsulfoxide, or dioxane, preferably sulfolane heated over 0.1 to 4 hours, preferably 1 hour, at 100 to 220 °C, preferably at approx. 160 °C. After cooling, crystallizes by adding org. solvents or solvent mixtures, for example diethyl ether/methanol, ethyl acetate, methylene chloride, or diethyl ether, preferably diethyl ether/methanol 9/1, the product (A7) or purified chromatographically.

For example, in variant 4.2 A 1 equivalent of the compound (A5) and 1 to 3 equivalents of the compound (A6) are stirred with acid, for example 1-10 equivalents of 10-38% hydrochloric acid and/or an alcohol, for example ethanol, propanol, butanol , preferably ethanol under reflux for 1 to 48 hours, preferably approx. 5 hours.

The precipitated product (A7) is filtered off and optionally washed with water, dried and crystallized from a suitable org. solvent.

In the event that R6 has the meaning of an optionally substituted benzimidazole, the preparation of the compounds (A6) can take place according to methods known from the literature, for example corresponding to the following scheme:

Thus, for example, 33 mmol of the compound (Z1), 49 mmol of the compound (Z2) and 49 mmol of 1-ethoxycarbonyl-2-ethoxydihydroquinoline (EEDQ) are stirred in 50 ml of an organic solvent, preferably dimethylformamide, at approx. 100 to 130 °C, preferably at approx. 115 °C, 1 to 4 hours, preferably approx. 3 hours. The cooled reaction solution is then added to 50 to 400 ml, preferably approx. 200 ml of a water/ethyl acetate mixture (mixing ratio approx. 1:1). The formed crystals (Z3) are filtered off and washed.

Then 4.2 mmol of the compound (Z3) are stirred with 12.5 mmol of stannous chloride and 30 mmol of potassium carbonate for approx. 50 ml of an organic diluent, preferably ethyl acetate at approx. 22 °C 4 to 48 hours, preferably approx. 24 hours. After adding 22 g of diatomaceous earth, it is extracted with an organic diluent or a diluent mixture, preferably with a mixture of dichloromethane / methanol (9:1), the combined extracts evaporated and the formed precipitate (Z4) or the formed crystals (Z4) isolated .

Step 5A

In the event that R<9> has the meaning -CONR<8->CrCi0-alkyl-Q<1>, -CONH-CrC5-alkylene or -CONR<8->Q<2>, where the substituents have the aforementioned meanings, the preparation of the compounds according to the invention can take place according to methods known from the literature, for example corresponding to Scheme 5A.

The compound (A7') obtained in step 4A can either be converted by saponification and subsequent amination to the amide with the general formula (A10) (Scheme (5A) Variant 5.1 A, or by saponification with subsequent transfer into the acid chloride (A9) and subsequent amination (Form (5A) Variant 5.2A,

Variant 5.1 A:

In Variant 5.1 A, for example, 20 mmol of the ester (A7') in approx. 100 ml of a base, preferably 1N sodium hydroxide solution or lithium hydroxide solution and approx. 500 ml of an alcohol heated, for example with ethanol, dioxane or methanol, preferably methanol, to complete reaction of the ester. The alcohol is then distilled off. The rest will be occupied for approx. 200 ml of water and acidified while cooling with acid, for example hydrochloric acid, preferably with 2 N hydrochloric acid. The product (A8) is filtered off and dried. For example, approx. 0.5 mmol of the compound (A8) dissolved with approx. 0.5 mmol O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and approx. 1.4 mmol, diisopropylethylamine (DIPEA) in approx. 5 ml of an organic diluent, for example tetrahydrofuran, dimethylformamide, N-methylpyrrolidione, dimethylacetamide, preferably dimethylformamide. After adding approx. 0.75 mmol, of an amine forming the substituent R<9>, the reaction mixture is stirred for 0.1 to 24 hours, preferably approx. 12 hours at 20°C to 100°C. Through, for example, crystallization or chromatographic purification, the product with the formula (A10) is obtained.

Variant 5.2 A:

In variant 5.2 A, for example, approx. 1 mmol of the acid (A8) in approx. 2.7 ml, thionyl chloride suspended. The mixture is heated to 40°C to 80°C, preferably approx. 50 °C and at a constant temperature, 2 to 10 drops, preferably approx. 3 drops, dimethylformamide. Then stir until the reaction is complete at 90°C. Excess thionyl chloride is distilled off.

About. 1 mmol of the formed acid chloride (A9) is dissolved in approx. 30 ml of an organic diluent, for example dichloromethane. After adding an amine that forms the substituent R<9>, it is stirred at approx. 22°C. The formed precipitate is filtered off and washed with water. The remaining residue is washed with an organic diluent, for example methanol. The mother liquor is, for example, chromatographically purified and evaporated. The product (A10) is returned.

Procedure B

As an alternative to the method described above, as shown in Form B, according to methods known from the literature, an amination of the compound (A3) and then a cyclization of the product (B1) to the compound (B2) can first be carried out in connection with step 1A. The further substitution of the compound (B2) for the compound (A7) can take place, for example, analogously to step 3A.

The new compounds with the general formula (I) can be synthesized analogously to the following synthesis examples. However, these examples are only to be understood as examples of the method for further illustrating the invention without limiting its object.

Example 63 and Example 109:

For the synthesis of compounds 63 and 109, an intermediate compound 4 is first obtained

produced as described below.

38.9 ml (0.263 mol) of 2-bromobutyric acid ethyl ester and 36.4 g (0.263 mol) of potassium carbonate were placed in 350 ml of ethyl acetate, and then quickly added dropwise 46.7 ml (0.402 mol) of isoamylamine dissolved in 70 ml of ethyl acetate. It was boiled for 20 h under reflux. The salt formed was filtered off, the filtrate evaporated, mixed with 50 ml of toluene and evaporated again to dryness.

Yield: 54.3 g of a compound 1 (red oil)

54.3 g of compound 1, dissolved in 400 ml of acetone and 30.7 g (0.222 mol) of potassium carbonate were cooled with stirring to 8° C., mixed with a solution of 43.1 g (0.222 mol) of 2,4-dichloro -5-nitropyrimidine in 250 ml of acetone and then stirred for 24 h at RT.

The resulting suspension was evaporated, the residue extracted with water and ethyl acetate, the organic phase washed with water and NaCl solution, dried over MgSCM and evaporated to dryness.

Yield: 87.3 g of a compound 2 (brown oil)

44.1 g of compound 2 was dissolved in 800 ml of glacial acetic acid, heated to 65° C. and mixed in portions with 36 g of iron powder. It was then stirred for 3 h at 70° C, the precipitate filtered off and the filtrate evaporated.

The residue was placed in dichloromethane / methanol 90:10 on silica gel, evaporated and purified by means of column chromatography (eluent: ethyl acetate / cyclohexane 1:1).

The residue was precipitated from ethyl acetate/petroleum ether.

Yield: 16.1 g of a compound 3 (beige powder)

16.1 g of compound 3 was dissolved in 75 ml of dimethylacetamide and cooled under a nitrogen atmosphere with stirring to 5°C. Then 2.51 g (0.063 mol) NaH, 60% dispersion in mineral oil, was added, during which the temperature temporarily rose to 16° C. After 30 min. 3.94 ml (0.063 mol) of methyl iodide dissolved in 75 ml of dimethylacetamide was added, stirred and 24 h at 22°C.

The solvent was evaporated, mixed with 200 ml of water and the formed precipitate filtered off, then stirred out with petroleum ether.

Yield: 15.1 g of a compound 4 (yellow powder)

<1>H-NMR(250 MHz): = 7.80 (1H, s), 4.35 (m, 1H), 3.92 (m, 1H), 3.22 (s, 3H), 3.14 (m, 1H), 1 .81 (m, 2H), 1.60-1.40 (m, 3H), 0.90 (m, 6H), 0.70 (t, 3H).

Synthesis of Example 63

2.5 g of compound 4, 1.43 g of 4-amino-3-methoxybenzoic acid, 1.25 ml of conc. hydrochloric acid, 150 ml dist. water and 37.5 ml of ethanol were boiled for 10 h under reflux. The precipitate was filtered off, washed with water and stirred in methanol. The precipitate was then recrystallized using petroleum ether and ether.

Yield: 1.6 g of a compound 5 (white powder)

0.2 g of compound 5, 5 ml of benzylamine, 0.16 g of TBTU, 0.17 g of DIPEA were dissolved in 2 ml of dimethylformamide (DMF) and stirred for 48 h at room temperature. The reaction mixture was then taken up in methylene chloride, washed with water and the organic phase evaporated. When petroleum ether/ethyl acetate 9:1 is added, the product precipitates as light beige crystals.

Yield: 0.18 g. M.p.: 178°C

Synthesis of Example 109:

5 g of 2-amino-5-nitroaniline, 6.03 g of 4-pyridylcarboxylic acid, 12.1 g of EEDQ are dissolved in 50 ml of DMF and stirred at 115°C for 1.75 h, then the DMF is distilled off in vacuo and the reaction mixture is then heated at 180°C for 1 h. The residue is taken up in 30 ml of DMF, mixed with 200 ml of water and 100 ml of ethyl acetate. The formed crystal slurry is filtered off and washed with water, ethyl acetate and ether.

Yield: 5.8 g of a compound 6

2 g of compound 6 is mixed with 0.2 g of Pd/C 5% in 30 ml of ethanol and hydrogenated in the presence of hydrogen. It is then evaporated and crystallized from ethanol and toluene. Yield: 1.75 g of white powder of a compound 7.

0.2 g of compound 5, 0.28 g of compound 7, 0.001 g of sodium tert-butylate, 2.5 ml of ethylene glycol dimethyl ether, 0.006 g of palladium(II) acetate and 0.22 g of 2-(di-tert-butylphosphino)biphenyl are dissolved in 1.5 ml of N-methylpyrrolidone (NMP). It is then heated for 0.5 h to 160°C. The reaction mixture is then purified over 20 g of silica gel and the product crystallized from ether, ethyl acetate and petroleum ether.

Yield: 0.04 g yellow crystals. Melting point: 180°C

Example 218 , 58 and 4:

For the synthesis of compounds 218, 58 and 4, an intermediate compound 11 is first obtained

produced as described below.

55.8 g of DL-alanine methyl ester x HCI was dissolved in 500 ml of methanol, then 76.1 ml of 30% sodium methylate solution was added and the salt was filtered off. 37.8 g of trimethylacetaldehyde was added to the filtrate and then allowed to stand for 22 h. This was followed by the addition of 9.5 g of 10% Pd/C, it was hydrogenated for 3.1 h at 0.5 bar and 20° C. The reaction mixture was filtered off over diatomaceous earth and evaporated. The residue was taken up in diethyl ether, the salts filtered over diatomaceous earth and the filtrate evaporated.

Yield: 55.8 g of a compound 8 (clear liquid)

48.5 g of 2,4-dichloro-5-nitropyrimidine was placed in 400 ml of diethyl ether, 41.0 g of potassium hydrogen carbonate added in 400 ml of water cooled to -5° C. 43.3 g of compound 8 was dissolved in 400 ml of diethyl ether and added dropwise at -5° C. It was stirred for 1 h at -5° C and 2 h at 0° C, then warmed to room temperature and the reaction mixture was allowed to stand for 24 h. The organic phase was separated, dried over MgSO^ and evaporated to dryness. Yield: 79.2 g of a compound 9 (yellow resin)

79.0 g of compound 9 was dissolved in 1000 ml of glacial acetic acid and heated to 70°C. After removing the heat source, 52 g of iron was added in portions. The temperature rose to approx. 110° C, it was stirred for 1 h at this temperature. The suspension was filtered hot and the filtrate evaporated.

The residue was taken up in ethyl acetate and mixed with 150 ml conc. HCI, the organic phase separated and the aqueous phase extracted several times with dichloromethane. The combined organic phases were evaporated, applied to silica gel and purified by means of column chromatography (eluent: petroleum ether/ethyl acetate 1:1).

As the isolated substance was still heavily contaminated, it was once again purified over silica gel. The desired compound crystallized out, the crystals were filtered off. The mother liquor was evaporated and recrystallized from ethyl acetate/diethyl ether.

Yield: 17.63 g of a compound 10

7.6 g of compound 10 and 6.4 ml of methyl iodide were placed in 75 ml of dimethylacetamide (DMA) and cooled to -15° C. 1.25 g of NaH, 60% dispersion in mineral oil, was added portionwise, stirred for 30 min . at -10° to -5° C. Then 150 ml of ice water was added, crystals filtered off, washed with water and petroleum ether. The crystals were taken up in dichloromethane, filtered through diatomaceous earth and the filtrate evaporated to dryness. It was recrystallized from petroleum ether.

Yield: 6.3 g of compound 11 (beige crystals)

<1>H-NMR (250 MHz): = 7.73 (1H, s), 4.35 (d, 1H), 4.25 (m, 1H), 3.35 (s, 3H), 2, 55 (d, 1H), 1.31 (d, 3H), 0.95 (s, 9H).

Synthesis of Example 218

0.2 g of the compound 11, 3,5-difluoro-4-hydroxyaniline and 0.75 ml of sulfolane were heated for 15 min at 130°C, 15 min at 140°C and 10 min at 170°C. Then it was mixed with

ether, the supernatant decanted and the residue crystallized from methanol/ether and recrystallized again from methanol.

Yield: 0.15 g of white crystals. Melting point: >250°C

Synthesis of Example 4

6.3 g of compound 11 is dissolved in 25 ml of sulfolane at 100°C, then mixed with 4.0 g of 4-aminobenzoic acid ethyl ester and heated for 1 h at 170°C. The batch was then mixed with 50 ml of ether. After initial crystallization, a further 50 ml of ether and 50 ml of methanol were added. The crystals were recrystallized from methanol.

Yield: 6.6 g of a compound 12 (yellowish crystals), mp: from 65°C decomposition occurs

3.55 g of compound 12 was slurried in 250 ml of methanol and mixed at 60°C with 25 ml of 4N caustic soda. After 6 h, 15 ml of glacial acetic acid were added, the formed crystals were filtered off and washed with methanol/ether.

Yield: 1.2 g of a compound 13 (white crystals)

1.5 g of compound 13 was dissolved in 7.5 ml of thionyl chloride and heated for 1 h at 80°C. Then thionyl chloride was distilled off, the residue stirred with ether, the crystals filtered off and washed with ether.

Yield: 1.7 g of a compound 14 (yellow crystals)

0.18 g of 3-aminopyridine was dissolved in 10 ml of tetrahydrofuran (THF) and mixed with 0.4 ml of triethylamine. Then 0.22 g of compound 14 was added and stirred for 16 h at room temperature. The batch was evaporated to dryness, taken up in ethyl acetate, extracted with water, re-evaporated and the product crystallized from ethyl acetate.

Yield: 0.07 g (beige crystals), mp: 215-216°C

Synthesis of Example 58

0.05 g of compound 13 was slurried in 10 ml of dichloromethane, then mixed with 0.15 ml of DIPEA and 0.05 g of TBTU. The solution was then stirred for 30 min and mixed with 0.01 ml of 4-picolylamine. After 18 h, the batch was mixed with 20 ml of water, the organic phase separated and the product purified by means of silica gel chromatography, then recrystallized from ethyl acetate/petroleum ether.

Yield: 0.044 g (white crystals), mp: 238-240X

Example 65 and 125

For the synthesis of compounds 65 and 125, an intermediate compound 18 is first obtained

produced as described below.

28.3 g of isobutylamine, 36 g of R,S-2-bromopropionic acid ethyl ester and 28 g of potassium carbonate were boiled in 150 ml of ethyl acetate for 6 h under reflux.

After cooling, the salt was filtered off and the mother liquor evaporated.

The residue was mixed with 100 ml of toluene and evaporated to dryness.

Yield: 37.2 g of a compound 15 (yellow oil)

38.4 g of 2,4-dichloro-5-nitropyrimidine was placed in 300 ml of diethyl ether, 30 g of potassium hydrogen carbonate added to 300 ml of water and cooled to 0°C. 37.0 g of compound 15 was dissolved in 300 ml of diethyl ether and added dropwise at 0°-3° C. After 3 h the phases were separated, the organic phase dried and evaporated to dryness.

Yield: 71.6 g of a compound 16

40.0 g of compound 16 was dissolved in 300 ml of glacial acetic acid and heated to 70°C. After removing the heat source, 30 g of iron was added in portions. The temperature rose to 110°C. The reaction mixture was cooled to 90° C. and stirred for 20 min. at this temperature. It was then filtered hot and the filtrate evaporated. The residue was stirred with 300 ml of water and 300 ml of dichloromethane and filtered through diatomaceous earth. The phases were separated. The organic phase was washed with water, dried over MgSO 4 and evaporated to dryness. It was stirred into petroleum ether.

Yield: 26.7 g of a compound 17

15.0 g of compound 17 was placed in 100 ml of DMA, 4.13 ml of methyl iodide added and cooled to 5°C. 2.60 g of NaH was added in portions as a 60% dispersion in mineral oil. The temperature rose to 13°C.

After 30 min. 300 ml of ice water were added, the precipitated crystals were filtered off and washed with petroleum ether.

Yield: 13.9 g of a compound 18

<1>H-NMR (250 MHz): = 7.95 (1H, s), 4.30 (m, 1H), 3.95 (m, 1H), 3.24 (s, 3H), 2.95 (m, 1H) , 2.05 (m, 1H), 1.30 (d, 3H), 0.96 (d, 3H), 0.92 (d, 3H).

Synthesis of Example 65

2.1 g of compound 18 was stirred in 10 ml of sulfolane with 4-aminobenzoic acid ethyl ester mixed and for 2 h at 160°C. It was then mixed with ether and the precipitated crystals washed with ether:

Yield: 3.0 g of a compound 19

3 g of compound 19 were mixed with 200 ml of methanol and 25 ml of 4N NaOH and stirred for 4 h at 60°C. It was then mixed with glacial acetic acid, the precipitated crystals filtered off and washed with ether.

Yield: 2.3 g of a compound 20 (white crystals)

0.1 g of compound 20 was slurried in 3 ml of dichloromethane and 3 ml of DMF and then mixed with 0.13 g of DIPEA, 0.095 g of TBTU and 0.045 g of hydroxybenzotriazole (HOBt). The solution was then stirred for 30 min and mixed with 0.035 g of N-methyl-3-picolylamine. After 0.5 h, the batch was mixed with water and 1 g of potassium carbonate, the aqueous phase extracted twice with 50 ml of ethyl acetate each time and the product purified by means of silica gel chromatography and then recrystallized from ethanol/acetone.

Yield: 0.08 g

Synthesis of Example 125

3.7 g of compound 20, 3.8 g TBTU, 1.6 g HOBt, 5 ml DIPEA were dissolved in 40 ml DMF and stirred for 4 h at room temperature. The batch was evaporated, taken up in 200 ml of ethyl acetate and extracted twice with 5 ml of 5% potassium carbonate solution each time. The organic phase was evaporated, the precipitated crystals were filtered off and washed with ethyl acetate and ether.

Yield: 1.65 g of a compound 21 (yellowish crystals)

0.486 g of compound 21 was boiled with 0.33 g of 1,2-phenylenediamine in 10 ml of toluene for 0.5 h under reflux, then the batch was evaporated. the residue was mixed with 100 ml of ethyl acetate, and the organic phase extracted twice with water. The organic phase was evaporated, the precipitated crystals were filtered off and washed with a little ethyl acetate. Yield: 0.25 g of a compound 22 (white crystals)

0.22 g of compound 22 was stirred in 20 g of polyphosphoric acid for 0.5 h at 150°C, then put on ice and mixed with ammonia. It was then extracted twice with 100 ml of ethyl acetate each time, and the organic phase was washed with water and evaporated. The precipitated product (crystals) was filtered off and washed with ethyl acetate and ether.

Yield: 0.115 g yellowish crystals, mp: 287°C (Decomposition)

Example 171

For the synthesis of compound 171, an intermediate compound 27 is first prepared

34.4 g of N-isopentyl-benzylamine, 36.2 g of 2-bromo-propionic acid ethyl ester and 42.0 g of potassium carbonate were placed in 250 ml of DMF and stirred for 3 h at 110° C. After cooling, the inorganic salts were filtered off, the filtrate evaporated. the residue was extracted with water and diethyl ether, the organic phase washed with water, dried and evaporated to dryness. Yield: 55.5 g of a compound 23

55.5 g of compound 23 was placed in 600 ml of ethanol and hydrogenated with 20 ml of 32% HCI and 6 g of 10% Pd/C at 20°C and 5 bar for 20 min. It was then filtered

through diatomaceous earth and evaporated. The residue was mixed with 400 ml of diethyl ether, the precipitate filtered off and washed with diethyl ether.

Yield: 23.5 g of a compound 24, m.p. 105°C

23.5 g of compound 24 was dissolved in 200 ml of water and mixed with 20.0 g (0.103 mol) of 2,4-dichloro-5-nitropyrimidine in 400 ml of diethyl ether. After cooling the reaction mixture to -10°C, 50.0 g (0.499 mol) of potassium carbonate was added portionwise. It was stirred for 1 h at -5°C and 1 h at 0°C and then warmed to room temperature. Aqueous phase was separated, the organic phase washed with water, dried and evaporated to dryness.

Yield: 36.9 g of a compound 25

20.0 g of compound 25 was dissolved in 280 ml of glacial acetic acid and heated to 70°C. After removing the heat source, 17 g of iron was added. The temperature rose to 100°C, and then it was stirred for 30 min. at this temperature.

It was then filtered hot and the filtrate evaporated. the residue was mixed with 300 ml of dichloromethane and 30 ml of 32% HCl, the phases separated, the aqueous phase extracted with dichloromethane, the combined organic phases washed with water and aqueous ammonia solution, dried and evaporated to dryness. The residue was stirred out with diethyl ether. Yield: 10.5 g of a compound 26, mp: 182°-185°C

2.7 g of compound 26 and 2.5 ml of methyl iodide were placed in 27 ml of DMA and cooled to -10° C. 0.45 g of NaH, 60% dispersion in mineral oil, was added and stirred for 30 min. at -5° C. Then 10 g of ice and 5 ml of 2N HCI were added and evaporated. The residue was extracted with ethyl acetate and water, the organic phase was dried, evaporated to dryness and filtered through silica gel.

Yield: 3.0 g of compound 27 (oil)

<1>H-NMR (250 MHz): = 7.67 (1H, s), 4.32-4.07 (m, 2H), 3.32 (s, 3H), 3.08 (m, 1H), 1, 70-1.50 (m, 3H), 1.42 (d, 3H), 0.95 (m, 6H).

Synthesis of Example 171

0.28 g of compound 27, 0.9 ml of sulfolane and 0.22 g of p-aminobenzoic acid benzylamide were stirred for 0.5 h at 170°C, the batch then mixed with ether and the crystals filtered off. The product was recrystallized from ethanol.

Yield: 0.15 g. M.p.: 228-240°C, (yellowish crystals)

Analogous to the previously described method, i.a. the compounds of formula (I) listed in Table 1 obtained.

The abbreviations X2, X3, X4, X5 and X6 used in Table 1 stand for a connection to a position in the general formula listed under Table 1 instead of the corresponding residues R2, R3, R4, R5 and R6.

In the table above, the abbreviations X<1> to X<6> are in them

indicated residues for the bond linking the individual residue to the corresponding group R<1> to R<6>.

It was found that the compounds of the general formula (I) are distinguished by the diverse application possibilities in the therapeutic field. Emphasis should be placed on such application possibilities where inhibition of specific cell cycle kinases plays a role, in particular the inhibitory effect on the proliferation of cultured human tumor cells, but also on the proliferation of other cells, such as endothelial cells.

As could be shown by FACS analysis, the inhibition of proliferation, which is effected by the compounds according to the invention, is mediated through an arrest of the cells particularly in the G2/M phase of the cell cycle. The cells stop, depending on the cell used, for a certain period of time in this cell cycle phase, before the programmed cell death is initiated. An arrest in the G2/M phase of the cell cycle is triggered, for example, by inhibition of specific cell cycle kinases. Studies in model organisms such as schizosaccharomyces pombe or xenopus or investigations in human cells have shown that the transition from the G2 phase to mitosis is regulated through the CDK1/Cyclin B kinase (Nurse, 1990). This kinase, which is referred to as "mitosis-promoting factor" (MPF), phosphorylates and thereby regulates a number of proteins, for example nuclear lamins, kinesin-like motor proteins, condensins (Kondensine) and golgi matrix proteins that play an important role in the breakdown of the nuclear membrane (Nuclear Hole), at centrosome- separation, building up of the mitotic spindle apparatus, chromozonal condensation and breakdown of the golgi apparatus (Nigg. E., 2001). A murine cell line with a temperature-sensitive CDK1 kinase mutant shows, after a rise in temperature, a rapid breakdown of the CDK-1 kinase and a subsequent arrest in the G2/M phase (Th'ng et al., 1990). The treatment of human tumor cells with inhibitors against CDK1/Cyclin B, such as butyrolactone, likewise leads to arrest in the G2/M phase and subsequent apoptosis (Nishio, et al. 1996). A further kinase that plays a role in the G2 and mitosis phase is homo-like kinase 1 (Plk1), which is responsible for maturation of centrosomes, for activation of the phosphatase Cdc25C, as well as for activation of the anaphase-promoting complex (Glover et al. ., 1998, Qian et al. 2001). The injection of Plk1 antibodies leads to a G2 arrest in non-transformed cells while tumor cells arrest in mitosis (Lane and Nigg, 1996). In addition to this, essential functions for the protein kinase aurora B during entry into mitosis were also described. Aurora B phosphorylates histone H3 on Ser11 and thus initiates chromosome condensation. (Hsu, J.Y et al., 2000). A specific cell cycle arrest in the G2/M phase can also be triggered, for example, by inhibition of specific phosphatases such as cdc25C (Russell and Nurse, 1986). Yeast with a defective cdc25 gene stops in the G2 phase, while an overexpression of cdc25 leads to a premature entry into the mitosis phase (Russell and Nurse, 1987) An arrest in the G2/M phase can also be triggered by inhibition of specific motor proteins, so-called kinesins , such as Eg5 (Mayer et al., 1999) or through microtubule stabilizing or destabilizing agents (for example colchichi, taxol, etoposide, vinblastine, vincristine), (Schiff and Horwitz, 1980).

Due to their biological properties, the compounds of the general formula 1 according to the invention, their isomers and their physiologically tolerable salts are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation.

Examples of such diseases include: viral infections (for example HIV and Kaposi's sarcoma); inflammation and autoimmune diseases (eg, colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and or parasitic infections; leukemias, lymphomas and solid tumors; skin diseases (for example, psoriasis); bone diseases; cardiovascular diseases (eg restenosis and hypertrophy). Furthermore, they are useful in protecting proliferating cells (for example hair, intestinal, blood and progenitor cells) against DNA damage through radiation, UV treatment and/or cytostatic treatment (Davis et al., 2001). The new compounds can be used for prevention, short-term or long-term treatment of the aforementioned diseases, and in combination with other active substances that are used for the same indications, for example cytostatics.

The effect of the compounds according to the invention was determined in a cytotoxicity test on

cultured human tumor cells and/or in a FACS analysis for example with Hel_aS3 cells. The compounds showed in both test methods a good to very good activity, i.e. as an example an EC 50 value in the HeLaS3 cytotoxicity test of less than 5 μmol, usually less than 1 Mmol.

Measurement of the cytotoxicity of cultured human tumor cells

To measure the cytotoxicity of cultured human tumor cells, cells from the cervical carcinoma tumor cell line Hel_aS3 (obtained from the American Type Culture Collection (ATCC)) were cultured in Ham's F12 medium (Life Technologies) and 10% fetal calf serum (Life Technologies) and harvested in log- growth phase. The HeLaS3 cells were then placed in 96-well plates (Costar) at a density of 1000 cells per well. well and incubated overnight in an incubator (at 37°C and 5% CO2) whereby on each plate 6 wells were filled with medium only (3 wells for medium control, 3 wells for incubation with reduced AlamarBlue). The active substances were added in different concentrations (dissolved in DMSO, final concentration: 1%) to the cells (always as a triplicate determination). After 72 hours of incubation, 20 µl AlamarBlue (AccuMed International) was added to each well and the cells were incubated for a further 7 hours. As a control, 20pl reduced AlamarBlue (AlamarBlue reagent that was autoclaved for 30 min.) was added to 3 wells respectively. After 7 hours of incubation, the color conversion of the AlamarBlue reagent in the individual wells was determined in a Perkin Elmer fluorescence spectrophotometer (excitation 530 nm, emission 590 nm, 15 slits, integral time 0.1). The amount of converted AlamarBlue reagent represents the metabolic activity of the cell. The relative cell activity was calculated as a percentage of the control (HeLa S3 cells without inhibitor) and the active substance concentration that inhibits the cell activity by 50% (IC<50>) was calculated. The values were here calculated from the mean value of three individual determinations - with correction for the blank value (Leerwert)

(the medium control).

FACS analysis

Propidium iodide (Pl) binds stoichiometrically to double-stranded DNA and is thus suitable for determining the percentage of cells in the G1, S, and G2/M phases of the cell cycle based on the cellular DNA content. Cells in the G0 and G1 phase have a diploid DNA content (2N), while cells in G2 or mitosis have a 4N DNA content.

For a P1 staining, for example, 0.4 million HeLaS3 cells were seeded in a 75 cm<2> cell culture flask, after 24 hours either 1% DMSO was added as a control or the substance in different concentrations (1% DMSO). The cells were incubated for 24 hours with the substance or with DMSO, before the cells were washed with 2 x PBS and detached with trypsin/EDTA. The cells were centrifuged (1000 rpm, 5 min, 4 °C) and the cell pellet was washed 2 times with PBS, before the cells were resuspended in 0.1 ml of PBS. The cells were then fixed for 16 hours at 4°C or alternatively for 2 hours at -20°C with 80% ethanol. The fixed cells (10<6> cells) were centrifuged (1000 RPM, 5 min, 4°C) and washed with PBS and then centrifuged once more. The cell pellet was resuspended with 2 ml of triton X-100 in 0.25% PBS and incubated for 5 min on ice, before adding 5 ml. PBS and again centrifuged. The cell pellet was resuspended in 350 µl of P1 staining solution (0.1 mg/ml RNase A, 10 µg/ml Prodium iodide in 1x PBS). The cells were incubated for 20 minutes in the dark with the staining buffer, before being transferred into test tubes for FACS scanning. The DNA measurement took place in a Becton Dickinson FACS analysis device with an argon laser (500 mW, emission 488 nm) and with the DNA Cell Quest program (BD). The logarithmic P1 fluorescence was determined with a band-pass filter (BP 585/42). The quantification of the cell population in the individual cell cycle phases was carried out with the ModFit LT program from Becton Dickinson.

The compounds with the general formula (I) can be used alone or in combination with other active substances according to the invention, possibly also in combination with further pharmacologically active active substances. Suitable application forms are for example tablets, capsules, suppositories, solutions, especially solutions for injection (s.c., i.v., i.m.) and infusion - juice, emulsions or dispersible powders. Hereby, the proportion of pharmaceutically active compound(s) must always lie in the range from 0.1-90% by weight, preferably 0.5-50% by weight of the total composition, i.e. in amounts sufficient to enter the specified dosage range. The mentioned doses can, if necessary, be given several times a day. Consequently, tablets can for example be prepared by mixing the active substance(s) with known excipients, for example within inert diluents, such as calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch or albinic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or agents to achieve a depot effect such as carboxymethyl cellulose, callulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.

Consequently, coatings can be produced by coating cores, produced analogously to

the tablets, with agents commonly used for dragee coatings, for example collidon or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Likewise, the dragee sleeve can also consist of several layers to achieve a depot effect whereby the excipients mentioned above can be used with the tablets.

Juices containing the active substances according to the invention or active substance combinations may further contain a sweetener such as saccharin, cyclamate, glycerin or sugar as well as a taste-enhancing agent, for example flavoring substances such as vanillin or orange extract. They may also contain suspension aids or thickeners, such as sodium carboxymethyl cellulose, crosslinking agents, for example condensation products of fatty alcohols with ethylene oxide or protective substances such as p-hydroxybenzoate.

Injection and infusion solutions are prepared in the usual way, for example with the addition of isotonizers, preservatives, as well as p-hydroxybenzoates or stabilizing agents such as alkali salts of ethylenediaminetetraacetic acid, possibly using emulsifiers and/or dispersants where, for example, when using water as a diluent, it may be used organic solvents as solvents or helpless agents, and then filled into injection bottles or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations of active substances can, for example, be prepared by mixing the active substance with inert carriers such as milk sugar or sorbitol and encapsulating in gelatin capsules.

Suitable suppositories can, for example, be prepared by mixing with suitable carriers, such as neutral fat or polyethylene glycol, respectively their derivatives.

Excipients include, for example, water, pharmaceutically harmless organic solvents, as well as paraffins (for example, petroleum fractions), vegetable oils (for example, peanut or sesame oil), mono- or polyfunctional alcohols (for example, ethanol or glycerin), carriers such as natural stone flour (e.g. kaolin, clay, talc, chalk) synthetic stone flours (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane, milk and grape sugar), emulsifiers (e.g. lignin, sulphite liquor, methyl cellulose, starch and polyvinylpyolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The application takes place in the usual way, preferably orally or transdermally, particularly preferably orally. In the case of oral use, the tablets can of course in addition to the aforementioned carriers also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin or the like. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions, in addition to the auxiliaries mentioned above, various taste-improving agents or dyes can be added to the active substances. In the case of parenteral use, solutions of the active substances can be used using suitable liquid carrier materials. The dosage for intravenous use is 1-1000 mg per hour preferably between 5-500 mg per hour.

Nevertheless, it may be necessary to deviate from the mentioned quantity and in particular depending on the body weight respectively the method of application, the individual relationship to the drug, the way it is formulated and the time respectively the interval at which the administration takes place. Thus, in some cases less than the aforementioned minimum quantity may be sufficient, while in other cases the aforementioned upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute these in several individual doses during the day.

The following formulation examples illustrate the present invention:

Pharmaceutical formulation examples

Finely ground active substance, milk sugar and part of the corn starch are mixed together. The mixture is sieved, after which it is moistened with a solution of polyvinylpyrrolidone in water, crushed, moisture granulated and dried. The granulate, the rest of the cornstarch and the magnesium stearate are sieved and mixed together. The mixture is pressed

tablets of suitable shape and size.

The finely ground active substance, part of the corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the rest of the corn starch and water into a granule, which is dried and sieved. To this is added the sodium carboxymethyl starch and the magnesium stearate, mixed and pressed into tablets of a suitable size.

The active substance is dissolved at its own pH or possibly pH 5.5-6.5 in water and sodium chloride is added as an isotonizing agent. The prepared solution is pyrogen-free filtered and the filtrate is filled under aseptic conditions into ampoules which are then sterilized and melted again. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

Claims (11)

1) Compounds with the general formula (I), in which R<1>means a residue selected from the group consisting of hydrogen, NH2, XH, halogen and a Ci-C3-alkyl group optionally substituted with one or more halogen atoms, R<2>a group selected from hydrogen, CHO, XH, -X-d-C2-alkyl and an optionally substituted d-C3-alkyl group, R<3>, R4 are the same or different and denote a group selected from optionally substituted C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl, C3-C10-cycloalkyl, -X-aryl , -X-heteroaryl, -X-cycloalkyl, -NR<8->aryl, -NR<8->heteroaryl, -NR<8->cycloalkyl or -NR<8->heterocycloalkyl; C3-C6 heterocycloalkyl, X-heterocycloalkyl or a group selected from hydrogen, halogen, COXR<8>, CON(R<8>)2, COR<8> and XR<8>, or R3 and R<4> together form a 2- to 5-membered alkyl bridge, which can contain 1 to 2 heteroatoms, R<5>hydrogen or a group selected from optionally substituted C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl and -C3-C6-cycloalkyl, or R3 and R5 or R4 and R <5> together indicate a saturated or unsaturated C3-C4 alkyl bridge, which may contain 1 to 2 heteroatoms, R6 denotes optionally substituted aryl or heteroaryl, R7 denotes hydrogen or -CO-X-CrC4-alkyl, and X denotes in each case independently, O or S, R8 denotes in each case, independently of each other, hydrogen or a group selected from optionally substituted d-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and phenyl, where, unless otherwise stated, are the substituents of the optionally substituted alkyl groups selected from the halogen atoms fluorine, chlorine, bromine or iodine, a group selected from among -CN, -OCOCH3, aryl, heteroaryl, saturated or unsaturated heterocycloalkyl, an amino group, a saturated or unsaturated bicyclic ring system, the substituents of optionally substituted alkynyl groups are chosen from the halogen atoms fluorine, chlorine, bromine or iodine, the substituents of the optionally substituted alkynyl groups are chosen from among the halogen atoms, fluorine, chlorine, bromine or iodine, the substituents of the optionally substituted aryl groups are selected from -OH, -NO2, -CN, -OCHF2, -OCF3, -NH2, halogen, -Ci-Ci0-alkyl, -O-Ci-C3-alkyl, -N-methyl- tetrahydrooxazinyl, -COOH, -COO-Ci-C4-alkyl, -CONH2, -CONH-Ci-Ci0-alkyl, -CONH-C3-C8-cycloalkyl, -CONH-heterocycloalkyl, -CONH-heteroaryl, -CONH-aryl, - CONHMeCi-C3-alkyl, benzimidazole or a group of formula the substituents of the optionally substituted heteroaryl group are selected from among -OH, -NO2, -CN, -OCHF2, -OCF3, -NH2, halogen, -Ci-Ci0-alkyl, -O-Ci-C3-alkyl, -N-methyl- tetrahydrooxazinyl, -COOH, -COO-CrC4-alkyl, CONH2, phenyl, heteroaryl, -CONH-Ci-Cio-alkyl, -CONH-C3-C8-cycloalkyl, -CONH-heteroaryl, -CONH-aryl, -CONHMeCi- C3-alkyl, benzimidazole or a group of formula the substituents of an optionally substituted cycloalkyl group are selected from among one or more oxygen atoms linked via a double bond, where the cycloalkyl groups may also be linked to a benzene ring, and, unless otherwise stated, by the term "aryl" used in the above definition is meant an aromatic ring system with 6 to 14 carbon atoms, by the term "heteroaryl" used in the above definition is meant a 5-10 membered mono- or bicyclic heteroaryl ring in which up to three carbon atoms can be replaced by one or more heteroatoms selected from oxygen, nitrogen or sulphur, by the term "cycloalkyl" used in the above definitions is meant a saturated or unsaturated cycloalkyl group with 3 to 8 carbon atoms, by the term "cycloalkyl" used in the above definitions is meant a 5-, 6- or 7-membered, saturated or unsaturated, heterocyclic group which may contain nitrogen, oxygen or sulfur as the heteroatom, while each of the above-mentioned heterocyclic groups may optionally also be linked to a benzene ring, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally pharmaceutically acceptable acid addition salts thereof. 2) Compounds according to claim 1, wherein X and R<6>have the indicated meaning, and R<1> means hydrogen, R<2> represents a group selected from CHO, OH, and CH3 group, R<3>, R4 are the same or different and denote a group selected from hydrogen, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, or R3 and R<4 >indicate together a C2-C5 alkyl bridge, R<5>denotes a group selected from optionally substituted CrCi0-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, and C3-C6-cycloalkyl, or R3 and R5 or R4 and R5 together denote a saturated or unsaturated C3-C4 alkyl bridge, which may contain 1 to 2 heteroatoms, and R 7 is hydrogen optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, as well as optionally their pharmacologically acceptable acid addition salts. 3) Compounds according to claim 1 or 2, under which R<1->R5,R7,R<8>and X have the indicated meaning, and R6 a residue with the general formula in which n is 1, 2, 3 or 4, R<9>denotes a group selected from optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, -CONH-C1-C10-alkylene, -O-aryl, -O-heteroaryl, - O-cycloalkyl, -O-heterocycloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl or a group selected from -O-CrC6-alkyl-Q<1>, -CONR<8->Ci-Ci0-alkyl-Q<1> , -CONR<8->C2-Ci0-alkenyl-Q<1>, -CONR<8->Q<2>, halogen, OH, -SO2R<8>, -SO2N(R<8>)2, - COR8 -COOR<8>,-N(R<8>)2, -NHCOR<8>, CONR<8>OCrC10alkylQ<1>and CONR<8>OQ<2>, Q<1> denotes hydrogen, -NHCOR<8>, or a group selected from optionally substituted -NH-aryl-, -NH-heteroaryl-, aryl-, heteroaryl-, C3-C8-cycloalkyl- and heterocycloalkyl group, Q<2> denotes hydrogen or a group selected from an optionally substituted aryl, heteroaryl, C3-C8-heterocycloalkyl, C3-C8-cycloalkyl and CrC4-alkyl-C3-C8-cycloalkyl group, R<10> are the same or different and is a group selected from optionally substituted C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, -0-C1-C6-alkyl, -0-C2-C6 -alkenyl, -O-C2-C6-alkynyl, C3-C6-heterocycloalkyl and C3-C6-cycloalkyl, or a group selected from hydrogen, -CONH2, -COOR<8>, -OCON(R<8>)2 , -N(R<8>)2, - NHCOR8-NHCON(R8)2 , -N02 and halogen, or neighboring groups R<9>and R<10> together form a bridge with the general formula Y indicates O, S or NR<11>, m denotes 0, 1 or 2R11 denotes hydrogen or CrC2-alkyl, and R<12> denotes hydrogen or a group selected from optionally substituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, -d-C3-alkyl- phenyl, -C1-C3-alkyl-pyridyl, -d-C3-alkyl-pyrazinyl, -C1-C3-alkyl-pyrimidinyl and -C1-C3-alkyl-pyridazinyl, R<13> denotes CrC6-alkyl, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, as well as optionally their pharmacologically acceptable acid addition salts. 4) Compounds according to one of claims 1 to 3, wherein R3-R6,R<8>and X have the indicated meaning, and R<1> means hydrogen, R<2>CH3, and R<7>hydrogen, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, as well as optionally their pharmacologically acceptable acid addition salts. 5) Compound with formula I according to one of claims 1 to 4 for use as a medicine. 6) Compound with formula I according to one of claims 1 to 4 for use as a medicinal product with antiproliferative action. 7) Use of a compound of the formula I for the manufacture of a drug for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases. 8) Pharmaceutical preparations containing as active ingredient one or more compounds with the general formula (I) according to one of claims 1 to 4 or their physiologically acceptable salts, possibly in combination with common excipients and/or carriers. 9) Process for the preparation of a compound of the general formula (I), in which R<1->R<7> and X have the meaning specified in claims 1 to 4, characterized in that a compound with the general formula (II) in which R<1->R<5> and X have the meaning stated in claims 1 to 4 and L is a leaving group, is reacted with an optionally substituted compound of the general formula (III) in which R6 and R<7> have the meaning specified in claims 1 to 4. 10) Compound of formula (II), in which R<1->R<5> and X have the meaning specified in claims 1 to 4. 11) Process for the preparation of a compound of the general formula (I), in which R6 means a residue of the general formula, R<9>an optionally substituted group -CONH-CrCio-alkylene or a group selected from -CONR<8->Ci-Ci0-alkyl-Q<1>, -CONR<8->Ci-Ci0-alkenyl-Q<1>, -CONR<8>-Q<2>, and -COOR<8>, R1-R5,R7, R<10>, n and X have the meaning stated in claims 1 to 4, and R8 is as defined in claim 1, characterized in that a compound of the general formula (IA) wherein R<1> to R<5>, R<7>, R<10> and n have the meaning stated in claims 1 to 4, and L means a leaving group, is reacted with a primary or secondary amine to form the corresponding amide or with an alcohol to form the corresponding ester.