EP1748997A1

EP1748997A1 - Substituted thiophene-2-carboxylic acid amides, the production thereof and the use thereof as drugs

Info

Publication number: EP1748997A1
Application number: EP05745599A
Authority: EP
Inventors: Roland Pfau; Henning Priepke; Kai Gerlach; Wolfgang Wienen; Annette Schuler-Metz; Herbert Nar; Sandra Handschuh
Original assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2004-05-13
Filing date: 2005-05-07
Publication date: 2007-02-07
Also published as: JP2007537179A; US20050256107A1; WO2005111013A1; CA2562714A1

Abstract

The present invention concerns new substituted thiophene-2-carboxylic acid amides of general formula (I), in which A and R<1> to R<8c> are as defined in claim 1, tautomers, enantiomers, diastereomers, mixtures and salts thereof, in particular the physiologically compatible salts thereof with inorganic or organic acids or bases, which have valuable properties.

Description

Substituted thiopheπ-2-carboxamides, their preparation and their use as medicaments

The present invention relates to new substituted thiophene-2-carboxamides of the general formula

their tautomers, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, which have valuable properties.

The compounds of the above general formula I and their tautomers, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, and their stereoisomers have valuable pharmacological properties, in particular an antithrombotic effect and a factor Xa inhibitory effect.

The present application thus relates to the new compounds of the general formula I above, their preparation, the pharmaceutical compositions containing the pharmacologically active compounds, their preparation and use.

A first embodiment of the present invention comprises those compounds of the general formula I in which A is a radical of the general formula

means

in the

m is the number 1 or 2,

R ^8a each independently represent a hydrogen or halogen atom or a Cι alkyl _-5 alkyl, hydroxy, hydroxy-Cι _-5, Cι _-5 alkoxy, Cι-Cι _-5 alkoxy, alkyl ₅ , Amino-, Cι _-5 -alkylamino-, Di- (C _1-5 -alkyl) -amino-, Amino-Cis-alkyl-, Cι _-5 -Alkylamino-Cι _-5 -alkyl-, Di- (Cι _{- 5} -alkyl) -amino-Cι _-5 -alkyl-, Aminocarbonyl, Cι _-5 -alkylaminocarbonyl, di- (C _-5 -alkyl) -aminocarbonyl- or Cι-5-alkylcarbonylamino group means, with the above-mentioned substituted 5- to 7-membered radicals A which, optionally with R ^8a as Substituents introduced heteroatoms F, CI, Br, I, O or N are not separated by exactly one carbon atom from a heteroatom from the group N, O, S,

R ^8b each independently represents a hydrogen atom or a C ₅ alkyl group,

R ^8c each independently of one another a hydrogen atom, a C-ι. ₅ -alkyl-, d- ₅ -alkylcarbonyl-, -Cι _-5 -alkyloxycarbonyl- or Cι _-5 -alkylsulfonyl group,

X ^{1 represents} an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8c group,

X ^{2 is} an oxygen atom or an -NR ^8b group,

X ^{3 is} an oxygen or sulfur atom, an -NR ^8c group,

X ^{4 is} a carbonyl or sulfonyl group,

X ^{5 is} an oxygen atom, an -NR ^8b - or methylene group,

X ^{6 is} an oxygen or sulfur atom or an -NR ^8c group,

X ^{7 represents} a methylene or carbonyl group,

R ^{1 is} a hydrogen or halogen atom, a C _-3 alkyl or C _{3 -3} alkoxy group, where the hydrogen atoms of the C _1-3 alkyl or C ₃ -C ₃ alkoxy group can optionally be completely or partially replaced by fluorine atoms represents a C _2-3 alkenyl, C _2-3 alkynyl, nitrile, nitro or amino group, R ^{2 represents} a hydrogen or halogen atom or a C _{3 -3} alkyl group,

R ^{3 represents} a hydrogen atom or a Cι _-3 alkyl group,

R ⁴ and R ⁵ each independently of one another are a hydrogen atom, a C ₂ -6-alkenyl or C _2-6 -alkynyl group, a straight-chain or branched Cι- ₆ -alkyl group, the hydrogen atoms of the straight-chain or branched C-ι- ₆ - Alkyl group may optionally be wholly or partly replaced by fluorine atoms, and which may optionally be replaced by a nitrile, hydroxyl, C 1 -C ₅ -alkyloxy group, where the hydrogen atoms of the C 5 _-5 -alkyloxy group may optionally be wholly or partly replaced by fluorine atoms, an allyloxy -, Propargyloxy-, benzyloxy-, C _1-5 -alkylcarbonyloxy-, Cι _-5 -alkyloxycarbonyloxy-, carboxy-Cι _-5 -alkyloxy-, Cι- ₅ -alkyloxycarbonyl-Cι- ₅ -alkyloxy-, mercapto-, d- ₅ -Alkylsulfanyl-, C-ι- ₅ -alkylsulfonyl-, carboxy-, Cι _-5 -alkyloxycarbonyl-, aminocarbonyl-, C-ι- ₅ -alkylaminocarbonyl-, di- (Cι- alkyl) aminocarbonyl-, C ₃ -6-Cycloalkyleniminocarbonyl-, aminosulfonyl-, C1-5-AI- kylaminosulfonyl-, di- (Cι- ₅ -alkyl) -aminosulfonyl-, C _3-6 - Cycloalkyleniminosulfonyl-, amino-, ds-alkylamino-, di- (Cι _-5 -alkyl) -amino-, Cι _-5- alkylcarbonylamino-, Cι _-5 -alkylsulfonylamino-, Λ / - (Cι-5-alkylsulfonyl) -C _1-5 -alkylamino- or C ₃ - ₆ -cycloalkylcarbonylamino group can be substituted, a carboxy-, aminocarbonyl, Cι _-5 -alkylaminocarbonyl-, C ₃ - ₆ -cycloalkylaminocarbonyl-, di- (Cι- ₅ -alkyl) -aminocarbonyl-, Cι- ₅ alkoxycarbonyl, C _4-6 cycloalkyleneiminocarbonyl group, alkyl, phenyl, heteroaryl, phenyl-Cι _-5 or heteroaryl d- ₅ alkyl group which is optionally monosubstituted in the phenyl or heteroaryl moiety to trisubstituted by identical or different substituents selected from the group consisting of halogen atoms, d- ₅ -Alkyl-, di- (C-ι _-5 -alkyl) -amino-, hydroxy-, d _-5 -alkyloxy, mono-, di- or trifluoromethoxy, carboxy and d- ₅ -alkyloxycarbonyl groups can be substituted .

a 3- to 7-membered cycloalkyl, cycloalkylenimino, cycloalkyl

C-ι- ₅ alkyl or cycloalkyleneimino-Cι- ₃ alkyl group, in which in 4- to 7-membered cycles in the cyclic part a methylene group optionally by an -N (R ^8c ) group, an oxygen or sulfur atom or an -S (O) - or -S (0) ₂ - group can be replaced, or in which, in the case of 4- to 7-membered cycles in the cyclic part, two adjacent methylene groups together, optionally together with a -C (0) N (R ^8b ) - or -S (O) ₂ N (R ^8b ) group can be replaced, or in which in the case of 6- to 7-membered cycles in the cyclic part three adjacent methylene groups together, optionally with a substituted -OC (0) N (R ^8b ) - or -N (R ^8b ) C (0) N (R ^8b ) - or -N (R ^8b ) S (O) ₂ N (R ^8b ) group can be replaced, with the proviso that one like 3- to 7-membered cycloalkyl, cycloalkylenimino, cycloalkyl-Cι _-5 -alkyl or cycloalkylenimino-d- ₃ -alkyl group, defined above, in which two heteroatoms from the group oxygen and nitrogen are substituted by exactly one optionally substituted -CH ₂ - Gru ppe are separated from each other, is excluded, wherein a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-Ci.s-alkyl or cycloalkyleneimino-d- ₃ -alkyl group as defined above on one or two -CH ₂ - groups by in each case one or two Cι _-3 -Alkyl groups can be substituted, means, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached, a C _3- 8 cycloalkyl or C _3-8 cycloalkenyl form, wherein one of the methylene groups of a C _4-8 cycloalkyl group through an oxygen or sulfur atom or a -N (R ^8c ) -, or a carbonyl, sulfinyl or sulfonyl group can be replaced, and / or two directly adjacent methylene groups of a C ₄ - ₈ cycloalkyl group together by a -C (0) N (R ^8b ) - or - S (0) ₂ N (R ^8b ) group can be replaced, and / or three directly adjacent methylene groups of a Cβ-β-cycloalkyl group together by one -OC (0) N (R ^8b ) -, N (R ⁸⁾ C (O) N (R ^8b) - or -N (R ^8b) S (O) ₂ N (R ^8b) group may be replaced, where one or two carbon atoms of a C _{_3-8} cycloalkyl group optionally substituted independently by in each case one or two identical or different halogen atoms or C _-5 alkyl, nitrile, hydroxy, d ₅ alkyloxy, C _-5 alkylcarbonyloxy, carboxy d ₅ alkyl, C _1-5 Alkyloxycarbony l-Cι _-5 -alkyl, C _1-5 -alkylsulfanyl-, d- ₅ -alkylsulfonyl-, carboxy-, Cι _-5 -alkyloxycarbonyl-, aminocarbonyl-, Cι-5-alkylaminocarbonyl-, di- (Cι _-5 - alkyl) - aminocarbonyl, C ₃ - ₆ -Cycloalkyleniminocarbonyl-, aminosulphonyl, Cι-5-alkylaminosulfonyl-, di- (Cι-5-alkyl) -aminosuIfonyl-, C _3-6 -cycloalkyleniminosuIfonyl-, amino-, d _-5 -alkylamino-, di- (Cι _-5 -alkyl) -amino- , Cι _-5 -Alkylcarbonylamino-, d _-5 -alkyl-. sulfonylamino, Λ / - (Cι _-5 alkylsulfonyl) _-5 -Cι alkylamino or C _3- 6-Cycloalkylcarbonylaminogruppen may be substituted,

wherein one or two carbon atoms of a C _3- 8-cycloalkenyl group optionally substituted independently by one or two identical or different C ₁ - ₅ - alkyl, nitrile, carboxy-Cι _-5 -alkyl, C ₁ _-5 alkyloxycarbonylC _-5 -alkyl,

Carboxy-, d _-5 -alkyloxycarbonyl-, aminocarbonyl-, Cι- ₅ -alkylaminocarbonyl-, di- (d _-5 -alkyl) -aminocarbonyl-, C _3-6 -cycloalkyleniminocarbonyl-, aminosulfonyl-, Cι-5-alkylaminosulfonyl- , Di- (Cι _-5 -alkyl) -aminosulfonyl-, C ₃ - ₆ cycloalkyleneiminosulfonyl groups can be substituted,

and one or two carbon atoms of a C _4- s cycloalkenyl group which are not bonded to another carbon atom by a double bond, optionally independently of one another by in each case one or two identical or different halogen atoms or hydroxyl, C 5 _-5 -alkyloxy, d- 5-alkylcarbonyloxy-, d-5-alkylsulfanyl-, Cι _-5 -alkylsulfonyl-, amino-, d _-5 -alkylamino-, di- (C-ι. ₅ -alkyl) -amino-, Cι-5-alkylcarbonylamino- , C _1-5 -Alkylsulfonylamino-, / V- (d _-5 -AlkyIsulfonyl) -Cι .. ₅ -alkylamino- or

C3-6-cycloalkylcarbonylamino groups can be substituted,

with the proviso that such a C _3-8 cycloalkyl or C - ₈ cycloalkenyl group formed together from R ⁴ and R ^{5 contains} two heteroatoms in the cycle from the group consisting of oxygen and nitrogen by exactly one optionally substituted -CH ₂ Group are separated from each other, and / or in which one or both methylene groups of the cycle, which are directly connected to the carbon atom to which the radicals R ⁴ and R ^{5 are} attached, are replaced by a heteroatom from the group consisting of oxygen, nitrogen and sulfur, and / or in which one substituent bound to the cyclic group, which is characterized in that one hetero atom from the group oxygen, nitrogen, sulfur and halogen atom is bonded directly to the cyclic group, from another hetero atom from the group oxygen, nitrogen and sulfur, with the exception of the sulfone group is separated by exactly one, optionally substituted, methylene group, and / or in which two oxygen atoms are directly connected to one another, is excluded,

R ^{6 represents} a hydrogen, fluorine, chlorine, bromine or iodine atom, a nitrite group, a C _-3 alkyl group or a C _{3 -3} alkoxy group, the hydrogen atoms of the d _-3 alkyl or C ₃ - ₃ - The alkoxy group can optionally be completely or partially replaced by fluorine atoms,

where, unless stated otherwise, the term "heteroaryl group" mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group is an imino group optionally substituted by a d- ₃ -alkyl, phenyl or phenyl-Cι _-3 alkyl group, an oxygen or sulfur atom or an optionally by a C _-3 alkyl, phenyl, amino -C _2-3 -alkyl-, Cι- ₃ -alkylamino-C _-3 -alkyl-, di- (d _-3 -alkyl) -amino-C2-3-alkyl-, a C ₃ -6- cycloalkylenimino-Cι - ₃ -alkyl- or phenyl-C _1-3 -alkyl group substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or an imino group optionally substituted by a C ₃ -C ₃ -alkyl or phenyl -C _{3 -3} alkyl group and two or contains three nitrogen atoms, and also to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms, optionally by a fluorine, chlorine or bromine atom, a d- ₃ -alkyl-, hydroxy-, C-- _3- alkyloxy group, amino, C- ι _-3 alkylamino, di- (d _-3 alkyl) - amino or C ₃ - ₆ -Cycloalkyleniminogruppe substituted Phe nyl ring can be fused on and the bond takes place via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,

Unless otherwise stated, the term "halogen atom" mentioned above in the definitions means an atom from the group fluorine, chlorine, bromine and iodine,

where the alkyl, alkenyl, alkynyl and alkoxy groups contained in the definitions mentioned above, which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the dialkylations mentioned above Radicals, for example the dialkylamino groups, can be the same or different,

and the hydrogen atoms of the methyl or ethyl groups contained in the definitions mentioned above can be replaced in whole or in part by fluorine atoms,

their tautomers, their enantiomers, their diastereomers, their mixtures and their salts.

Examples of monocyclic heteroaryl groups are the pyridyl, N-oxy-pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, [1, 2,3] triazinyl, [1, 3,5] triazinyl, [1 , 2,4] triazinyl, pyrrolyl, imidazolyl, [1, 2,4] triazolyl, [1, 2,3] triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, [1, 2 , 3] oxadiazolyl, [1, 2.4] oxadiazolyl, furazanyl, thiophenyl, thiazolyl, isothiazolyl, [1, 2.3] thiadiazolyl, [1, 2.4] thiadiazolyl or [1 , 2,5] thiadiazolyl group.

Examples of bicyclic heteroaryl groups are the benzimidazolyl, benzofuranyl, benzo [c] furanyl, benzothiophenyl, benzo [c] thiophenyl, benzothiazolyl, benzo [c] isothiazolyl, benzo [e] isothiazolyl, benzooxazolyl, benzo c] isoxazolyl-, benzo [αf | isoxazolyl-, benzo [1, 2.5] oxadiazolyl-, benzo [1, 2.5] thiadiazolyl-, benzo [1., 2.3] thiadiazolyl-, benzo [αd [ 1, 2,3] triazinyl, benzo [1, 2,4] triazinyl, benzotriazolyl, cinnolinyi, quinolinyl, Λ / -oxy-quinolinyl, isoquinolinyl, quinazolinyl, Λ / -oxy-quinazolinyl- , Quinoxalinyl, phthalazinyl, indolyl, isoindolyl or 1-oxa-2,3-diaza-indenyl group.

Examples of the C ₆ alkyl groups mentioned above in the definitions are the methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, te / t-butyl, 1- Pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyi, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,2-dimethyl-3-butyl or 2,3-dimethyl-2-butyl group.

Examples of those mentioned above in the definitions d- ₅ -Alkyloxy groups are the methyloxy, ethyloxy, 1-propyloxy, 2-propyloxy, n-butyloxy, sec-butyloxy, ferf-butyloxy, 1-pentyloxy, 2-pentyloxy, 3- Pentyloxy or neo-pentyloxy group.

Examples of those mentioned above in the definitions

C _2-6 alkenyl groups are the ethenyl, 1-propen-1-yl, 2-propen-1-yl, 1-buten-1-yl, 2-buten-1-yl, 3-butene -1 -yl-, 1-penten-1-yl-, 2-penten-1-yl-, 3-penten-1-yl-, 4-penten-1 -yl-, 1-hexen-1-yl- , 2-Hexen-1 -yl-, 3-Hexen-1-yl-, 4-Hexen-1 -yl-, 5-Hexen-1-yl-, But-1-en-2-yl-, But- 2-en-2-yl, but-1-en-3-yl, 2-methyl-prop-2-en-1-yl, pent-1-en-2-yl, pent-2- en-2-yl-, pent-3-en-2-yl-, pent-4-en-2-yl-, pent-1-en-3-yl-, pent-2-en-3-yl- , 2-methyl-but-1-en-1-yl-, 2-methyl-but-2-en-1-yl-, 2-methyl-but-3-en-1-yl-, 2-ethyl- prop-2-en-1-yl-, hex-1-en-2-yl-, hex-2-en-2-yl-, hex-3-en-2-yl-, hex-4-en- 2-yl, hex-5-en-2-yl, hex-1-en-3-yl, hex-2-en-3-yl, hex-3-en-3-yl, hex -4-en-3-yl-, hex-5-en-3-yl-, hex-1-en-4-yl-, hex-2-en-4-yl-, hex-3-en-4 -yl, hex-4-en-4-yl, hex-5-en-4-yl, 4-methyl-pent-1-en-3-yl, 3-methyl-pent-1-ene -3-yl-, 2-methyl-pent-1-en-3-yl-, 2,3-dimethyl-but-1-en-3-yl-, 3,3-dimethyl-but-1-en- 2-yl or 2-ethyl-but-1-en-3-yl group,

Examples of the C _2-6 alkynyl groups mentioned above in the definitions are the ethynyl, 1-propynyl, 2-propynyl, 1-butyn-1-yl, 1-butyn-3-yl, 2-butyne -1-yl-, 3-butyn-1-yl-, 1-pentyn-1-yl-, 1-pentyn-3-yl-, 1-pentyn-4-yl-, 2-pentyn-1-yl- , 2 .pentin-3-yl-, 3-pentin-1-yl-, 4-pentin-1-yl-, 2-methyl-1-butyn-4-yl-, 3-methyl-1-butyn-1 -yl-, 3-Methyl-1-butin-3-yl-, 1-Hexin-1-yl-, 2-Hexin-1-yl-, 3-Hexin-1-yl-, 4-Hexin-1- yl-, 5-hexin-1-yl-, 1-hexin-3-yl-, 1-hexin-4-yl-, 1-hexin-5-yl-, 2-hexin-4-yl-, 2- Hexin-5-yl-, 3-hexin-5-yl-, 3-methyl-1-pentin-3-yl-, 4-

Methyl-1-pentin-3-yl-, 3-methyl-1-pentin-4-yl-, 4-methyl-1-pentin-4-yl-, 4-methyl-2-pentin-4-yl-, 4-methyl-2-pentin-1-yl, 2,2-dimethyi-3-butyn-1-yl or 2-ethyl-3-butyn-1-yl group.

A group which can be converted into a carboxy group in vivo includes, for example, a carboxy group esterified with an alcohol, ii.n. "De _^, r is the alcoholic moiety is preferably a d- ₆ alkanol, a phenyl-Cι- ₃ -alkanol, a C _3-9 -CycIoalkanol, a C _{_5-7} -Cycloalkenol, a C _{_3-5} alkenol, a phenyl C _3-5 -alkenol, a C ₃ - ₅ -alkinol or phenyl-C _3-5 -alkinol with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond, a C _{3- 8-} cycloalkyl-d- _3- alkanol or an alcohol of the formula

R ⁹ -CO-O- (R ¹⁰ CR ¹¹ ) -OH,

in which R ⁹ is a Cι _-8 alkyl, C ₅ -7-CycloaIkyl-, phenyl or phenyl-Cι alkyl group _-3,

R ^{10 represents} a hydrogen atom, ad _-3 -alkyl, C ₅ -7-cycloalkyl or phenyl group and R ^{11 represents} a hydrogen atom or ad- ₃ -alkyl group,

to understand.

The preferred radicals which can be split off from a carboxy group in vivo are ad- ₆ -alkoxy group such as the methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, n-pentyloxy, π-hexyioxy or cyclohexyloxy group or one Phenyl-Cι- ₃ alkoxy group as the benzyloxy group into consideration.

A group which can be converted into a hydroxyl group in vivo is, for example, a hydroxyl group esterified with a carboxylic acid, in which the carboxylic acid part is preferably a -C ₇ alkane acid, a phenyl C ₃ _-3 alkanoic acid, a C ₃ g cycloalkyl carboxylic acid, a C _{5 -7} -Cycloalkencarbonsäure, a C _3-7 -AI kensäure, a phenyl C _{_3-5} alkenoic, a C _3-7 -Alkinsäure or phenyl-C _3-5 -alkinsäure, where individual methylene groups in the carboxylic acid radical may be replaced by oxygen atoms can be understood with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond. A C ₇ -acyl group such as the formyl, acetyl, n-propionyl, isopropionyl, r? -Propanoyl, n-butanoyl, π-pentanoyl, n- come as preferred residues which can be split off from a hydroxyl group in vivo. Hexanoyl or cyclohexylcarbonyl group or a benzoyl group and also one

Methoxyacetyl, 1-methoxypropionyl; 2-methoxypropionyl or 2-methoxyethoxyacetyl group into consideration.

Those compounds of the general formula I in which A, R ⁴ and / or R ⁵ contain a group which can be converted into a carboxy or hydroxyl group in vivo are prodrugs for those compounds of the general formula I in which A, R ⁴ and / or R ^{5 contains} a carboxy or hydroxyl group.

A second embodiment of the present invention comprises those compounds of the general formula I in which

A is a radical of the general formula

means in the

m is the number 1 or 2,

R ^8a each independently represent a hydrogen or halogen atom or a Cι alkyl _-5 alkyl, hydroxy, hydroxy-Cι _-5, Cι _-5 alkoxy, Cι _-5 _alkoxy-5 Cι- alkyl , Amino-, d _-5 -alkylamino-, di- (-Cι _-5 -alkyl) -amino-, amino-Cι _-5 -aIkyl-, Cι _-5 -alkylamino-Cι _-5 -alkyl-, Di- (d - ₅ -Alkyl) -amino-Cι- ₅ alkyl, aminocarbonyl, d _-5 -alkylaminocarbonyl, di- (d _-5 -alkyl) aminocarbonyl or d-5-alkylcarbonylamino group, with those mentioned above substituted 5- to 7-membered radicals A, the heteroatoms F, CI, Br, I, O or N optionally introduced with R ^8a as substituents are not separated from a heteroatom from the group N, O, S by exactly one carbon atom,

R ^8b each independently represents a hydrogen atom or a d- ₅ alkyl group,

R ^8c each independently represent a hydrogen atom, a Cι _-5 alkyl, d-5-alkylcarbonyl, Cι _-5 alkyloxycarbonyl- or ds-alkylsulfonyl means

X ^{1 represents} an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8c group,

X ^{3 is} an oxygen or sulfur atom, an -NR ^8c group,

X ^{4 represents} a carbonyl or sulfonyl group,

R ^{1 is} a halogen atom, a d-3-alkyl or d _-3 -alkoxy group, where the hydrogen atoms of the C-3-alkyl or d _-3 -alkoxy group can optionally be wholly or partly replaced by fluorine atoms, a C _2-3 Means alkenyl, C _-3 alkynyl, nitrile, nitro or amino group, R ^{2 represents} a hydrogen or halogen atom or ad _-3 alkyl group,

R ^{3 represents} a hydrogen atom or a C 3 alkyl group,

R ⁴ and R ⁵ are each independently a hydrogen atom, a C _2-6 or C _2-6 -AlkenyI- -AlkinyIgruppe, a linear or branched Cι _-6 alkyl group, wherein the hydrogen atoms of the straight-chain or branched alkyl group Cι- ₆ can optionally be wholly or partly replaced by fluorine atoms, and which can optionally be replaced by a nitrile, hydroxy or a Cι _-5 alkyloxy group, where the hydrogen atoms of the Cι _-5 alkyloxy group can optionally be wholly or partly replaced by fluorine atoms, an allyloxy , Propargyloxy-, Benzyloxy-, Cι _-5 -Alkylcarbonyloxy-, Cι _-5 -Alkyloxycarbonyloxy-, Carboxy-Cι _-5 -alkyloxy-, Cι- ₅ -Alkyloxycarbonyl-Cι- ₅ -alkyloxy-, Mercapto-, Cι- ₅ - Alkylsulfanyl, Cι. ₅ -Alkylsulfonyl-, carboxy-, Cι- ₅ -alkyloxycarbonyl-, aminocarbonyl-, Ci.s-alkylaminocarbonyl-, di- (d. ₅ -alkyl) -aminocarbonyl-, C _3-6 -cycloalkyleniminocarbonyl-, aminosulfonyl-, Cι _-5 -AI- kylaminosulfonyl-, di- (Cι- -alkyl) -aminosuIfonyl-, C ₃ - ₆ -cycloalkyleniminosulfonyl-, amino-, Cι _-5 -alkylamino-, di- (Cι _-5 -alkyl) -amino- , Cι _-5 -alkylcarbonylamino-, Cι- ₅ -alkyl- sulfonylamino-, Λ / - (Cι..5-alkylsulfonyl) -Cι- ₅ -alkylamino- or C ₃ . ₆ -Cycloalkylcarbonylamino group can be substituted, a carboxy, aminocarbonyl, Cι _-5 -alkylaminocarbonyl-, C ₃ - ₆ -Cycioalkylaminocarbonyl-, di- (d _-5 -alkyl) -aminocarbonyl-, Cι- ₅ -alkoxycarbonyl-, C _-6 -cycloalkyleneiminocarbonyl group, a phenyl-, heteroaryl-, phenyl-d _-5 -alkyl- or heteroaryl-

Cι- ₅ alkyl group which is optionally monosubstituted in the phenyl or heteroaryl moiety to trisubstituted by identical or different substituents selected from the group consisting of halogen atoms, _d-5 alkyl, di (d _-5 alkyl) amino, Hydroxy, Cι _-5 alkyloxy, mono-, di- or trifluoromethoxy, carboxy and d- ₅ alkyloxycarbonyl groups can be substituted,

a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl- d- ₅ -alkyl or cycloalkylenimino-Cι-3-alkyl group, in which in 4- to 7-membered cycles in the cyclic part a methylene group optionally by a -N (R ^8o ) group, an oxygen or sulfur atom or an -S (O) - or -S (0) ₂ - group can be replaced, or in the case of 4- to 7-membered cycles in the cyclic part two adjacent methylene groups together may optionally be replaced by a -C (O) N (R ^8b ) - or -S (0) ₂ N (R ^8b ) group, or in the case of 6- to 7-membered cycles in the cyclic part three adjacent methylene groups together optionally with a substituted -OC (0) N (R ^8b ) - or -N (R ^8b ) C (O) N (R ^8b ) - or -N (R ^8b ) S (O) ₂ N (R ^8b ) Group can be replaced, with the proviso that a 3- to 7-membered cycloalkyl, cycloalkylenimino, cycloalkyl-d _-5 -alkyl or cycloalkylenimino-d- ₃ -alkyl group, as defined above, in which two heteroatoms from the Group oxygen and stick are separated from each other by exactly one optionally substituted -CH ₂ group, is excluded, wherein a 3- to 7-membered cycloalkyl, cycloalkylenimino, cycloalkyI -CC 5 _-5 -alkyl or cycloalkyleneimino -C _{-3 -3} -alkyl group as defined above on one or two -CH ₂ groups by one or two d- ₃ -Alkyl groups can be substituted, means, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached, a C ₃ - ₈ cycloalkyl or C _3-8 cycloalkenyl form, wherein one of the methylene groups of a ds-cycloalkyl group through an oxygen or sulfur atom or a - N (R ^8c ) -, or a carbonyl, sulfinyl or sulfonyl group can be replaced, and / or two directly adjacent methylene groups of a d- ₈ -cycloalkyl group together by a -C (O) N (R ^8b ) - or - S (O) ₂ N (R ^8b ) group can be replaced, and / or three directly adjacent methylene groups of a C _6- 8 cycloalkyl group together by one -OC (0) N (R ^8b ) -, - N (R ^8b ) C (O) N (R ^8b ) - or -N (R ^8b ) S (O) ₂ N (R ^8b ) group can be replaced, where one or two carbon atoms ^"of a C _3-8 cycloalkyl group are optionally independent of one another in each case one or two identical or different halogen atoms or d _-5 alkyl, nitrile, hydroxy, C 5 alkyloxy, C _-5 alkylcarbonyloxy, carboxy C 5 alkyl, C _-5 alkyloxycarbonyl C ι- ₅ -alkyl, d _-5 -alkylsulfanyl-, d- ₅ -alkylsulfonyl-, carboxy-, Cι _-5 -alkyloxycarbonyl-, aminocarbonyl-, Cι _-5 -alkylaminocarbonyl-, di- (d _-5 -alkyl) - aminocarbonyl, C ₃ - ₆ -Cycloalkyleniminocarbonyl-, aminosulphonyl, d- ₅ -Alkylaminosulfonyl-, di- (Cι _-5 -alkyl) -aminosulfonyl-, C ₃ - ₆ -cycloalkyleniminosulfonyl-, amino-, d _-5 -alkylamino-, di- (Cι _-5 -alkyl) -amino- , C _1-5 -alkylcarbonylamino-, d _-5 -alkyl-sulfonylamino-, / V- (d _-5- alkylsulfonyl) -Cι _-5 -alkylamino- or C ₃ . ₆ -cycloalkylcarbonylamino groups can be substituted,

where one or two carbon atoms of a C ₃ - ₈ cycloalkenyl group optionally independently of one another by in each case one or two identical or different C 5 _-5 alkyl, nitrile, carboxy-d _-5 alkyl, C 5 _-5 -alkyloxycarbonyl-C _-5 alkyl,

Carboxy-, d _-5 -alkyloxycarbonyl-, aminocarbonyl-, -Cι - ₅ -AI ky lami nocarbonyl-, di- (Cι _-5 -alkyl) -ami nocarbonyl-, C ₃ - ₆ -cycloalkyleniminocarbonyl-, aminosulfonyl-, Cι- ₅ -Alkylaminosulfonyl-, di- (-Cι- ₅ -alkyl) -aminosulfonyl-, C ₃ -6-Cycloalkyleniminosulfonylgruppen can be substituted,

and one or two carbon atoms of a C _4- β-cycloalkenyl group which are not bonded to another carbon atom by a double bond, optionally independently of one another in each case by one or two identical or different halogen atoms or hydroxyl, Cι-5-alkyloxy, Ci.s -Alkylcarbonyloxy-, Cι _-5 -Alkylsulfany! -, d _-5 -Alkylsulfonyl-, amino, Cι _-5 -alkylamino-, di- (Cι- ₅ alkyl) -amino-, d- ₅ -Alkylcarbonylamino-, Cι _-5- Alkylsulfonylamino-, ^ - (Ci-s-Alkylsulfony -Ci.s-alkylamino- or

C ₃ - ₆ -Cycloalkylcarbonylaminogruppen may be substituted,

with the proviso that those composed of R ⁴ and R ⁵ formed C _3-8 cycloalkyl or C _{_3-8} cycloalkenyl group, in the two heteroatoms in the ring selected from oxygen and nitrogen, by precisely one optionally substituted -CH ₂ group are separated from each other, and / or in which one or both methylene groups of the cycle, which are directly connected to the carbon atom to which the radicals R ⁴ and R ^{5 are} attached, are replaced by a hetero atom from the group consisting of oxygen, nitrogen and sulfur, and / or in which one the cyclic group-bound substituent, which is characterized in that one hetero atom from the group oxygen, nitrogen, sulfur and halogen atom is bonded directly to the cyclic group, from another hetero atom from the group oxygen, nitrogen and sulfur, with the exception of the sulfone group, is separated by exactly one, optionally substituted, methylene group, and / or in which two oxygen atoms are directly connected to one another, is excluded,

R ^{6 represents} a fluorine, chlorine, bromine or iodine atom, a nitrite group, a C ₃ alkyl group, or a C ₃ alkoxy group, the hydrogen atoms of the C ₃ alkyl or C ₃ alkoxy group optionally can be replaced in whole or in part by fluorine atoms,

where, unless stated otherwise, the term "heteroaryl group" mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group is an imino group optionally substituted by a d- ₃ -alkyl, phenyl or phenyl-C ₃ -C ₃ -alkyl group, an oxygen or sulfur atom or an optionally by a C _{3 -3} -alkyl, phenyl, amino -C _2-3 -alkyl-, Cι- ₃ -alkylamino-C ₂ -3-alkyl-, di- (Cι- ₃ -alkyl) -amino-C _2-3 -alkyl-, a C _3- 6- cycloalkyIenimino -Cι _-3 -alkyl- or phenyl-Cι _-3 -alkyl group substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or _ .. ■ one optionally by a Cι- ₃ alkyl or phenyl-Cι _-3 alkyl group contains substituted imino group and two or three nitrogen atoms, and also to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms, optionally by a fluorine, chlorine or bromine atom, a C _1-3 alkyl, hydroxy, Cι _-3 - Alkyloxy group, amino, C-ι _-3 alkylamino, di- (Cι _-3 alkyl) - amino or C ₃ - ₆ cycloalkyleneimino group substituted phenyl ring can be fused on and the bond takes place via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,

A third embodiment of the present invention comprises those compounds of the general formula I in which

A is a radical of the general formula

, or means

in the m is the number 1 or 2,

R ^8a each independently represent a hydrogen or halogen atom or a d _-5 alkyl, hydroxy, hydroxy-Cι _-5 alkyl, d _-5 alkoxy, _d-δ alkoxy-d. 5-alkyl, amino, d. ₅ -alkylamino-, di- (Cι _-5 -alkyl) -amino-, amino-ds-alkyl-, Cι _-5 -alkylamino-Cι _-5 -alkyl-, di- (Cι _-5 -alkyl) -amino- d _-5 -alkyl-, aminocarbonyl-, d _-5 -alkylaminocarbonyl-, di- (d _-5 -alkyl) -aminocarbonyl- or Ci.s-alkylcarbonylamino group, with the above-mentioned substituted 5- to 7-membered radicals A the heteroatoms F, CI, Br, I, O or N, optionally introduced with R ^8a as substituents, are not separated from a heteroatom from the group N, O, S by exactly one carbon atom,

R ^8b are each independently a hydrogen atom or a Cι means _-5 alkyl group,

R ^8c each independently represents a hydrogen atom, a C ₅ alkyl, Ci.s aikylcarbonyl, d 5 alkyloxycarbonyl or d ₅ alkyl sulfonyl group,

X ^{1 represents} an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8c group,

X ^{3 is} an oxygen atom or an -NR ^8c group,

X ^{4 represents} a carbonyl or sulfonyl group,

R ^{1 is} a halogen atom, a d-3-alkyl or d- ₃ alkoxy group, where the hydrogen atoms of the C _{3 -3} -alkyl or d _-3- alkoxy group can optionally be replaced in whole or in part by fluorine atoms, or represents a nitrite group,

R ^{2 represents} a hydrogen or halogen atom or a methyl group, R ^{3 represents} a hydrogen atom or a methyl group,

R ⁴ is a hydrogen atom, a C _2-6 alkenyl or C _2-6 alkynyl group, a linear or branched Cι _-6 alkyl group, wherein the hydrogen atoms of the straight-chain or branched Cι- _C6 alkyl group optionally wholly or partially replaced by fluorine atoms may be, and which may optionally be replaced by a nitrile, hydroxy or a C ₅ alkyloxy group, where the hydrogen atoms of the d ₅ alkyloxy group may be replaced in whole or in part by fluorine atoms, a benzyloxy, d _-5 alkylcarbonyloxy , Cι- ₅ -alkyloxycarbonyloxy-, carboxy-d _-5 -alkyloxy-, d _-5 -alkyloxycarbonyl- Cι _-5 -alkyloxy-, d- ₅ -AlkylsuIfanyl-, d _-5 -alkylsulfonyl-, carboxy-, Ci.s -Alkyloxycarbonyl-, aminocarbonyl-, d _-5 -alkylaminocarbonyl-, di- (Cι _-5 -alkyl) -aminocarbonyl-, C _3-6 -cycloalkyleniminocarbonyl-, aminosulfonyl-, Cι _-5 -alkylaminosulfonyl-, di- (Cι _{- 5-} alkyl) -aminosulfonyl-, C _3-6 -cycloalkyleniminosulfonyl-, amino-, -Cι _-5 -alkylamino-, di- (d _-5 -alkyl) - amino-, Cι _-5 -Alkylcarbonylamino-, d _-5 -Alkylsulfonylamino- or Λ / - (Cι _-5 -Alkylsulfonyl) -Cι _-5 -alkylamino group can be substituted, a carboxy, aminocarbonyl, d-5-alkylaminocarbonyl, C3-6-cycloalkylaminocarbonyl -, Di- (Cι _-5 -alkyl) aminocarbonyl-, Cι _-5 -alkoxycarbonyl-, C _4- 6-cycloalkyleniminocarbonyl group, a phenyl, heteroaryl, phenyl-Cι _-5 -alkyl- or heteroaryl- d- _5th -alkyl group, optionally in the phenyl or heteroaryl moiety, one to three times by identical or different substituents selected from the group consisting of halogen atoms, Cι _-5 -alkyl-, di- (Cι _-5 -alkyl) -amino-, hydroxy-, C-ι _-5 alkyloxy, mono-, di- or trifluoromethoxy, carboxy and Cι- ₅ alkyloxycarbonyl groups can be substituted, a 3- to 7-membered cycloalkyl, cycloalkylenimino, cycloalkyl d-5-alkyl- or cycloalkylenimino-Cι- ₃ -alkyl group, in which in 4- to 7-membered cycles in the cyclic part a methylene group optionally by an -N (R ^8c ) group, an oxygen or sulfur atom or a - S (O) - or -S (0) ₂ group can be replaced, or in which, in the case of 4- to 7-membered cycles in the cyclic part, two adjacent methylene groups together, if appropriate, by one -C (0) N (R ^8b ) - or -S (0) ₂ N (R ^8b ) group can be replaced, or

in which in the case of 6- to 7-membered cycles in the cyclic part three adjacent methylene groups together optionally substituted by one - OC (O) N (R ^8b ) - or -N (R ^8b ) C (0) N (R ^8b ) - or -N (R ^8b ) S (0) ₂ N (R ^8b ) group can be replaced,

with the proviso that a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-d _-5 -alkyl or cycloalkylenimino-d- _3- alkyl group as defined above contains exactly two heteroatoms from the group oxygen and nitrogen an optionally substituted -CH ₂ group are separated from one another is excluded,

where a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-Cι- ₅ alkyl or cycloalkylenimino-d- ₃ -alkyl group as defined above on one or two -CH ₂ groups by one or two d _-3 Alkyl groups can be substituted,

means

a hydrogen atom, a C _2-6 alkenyl or C _2-6 alkynyl group,

a straight-chain or branched Cι _-6 alkyl group, the hydrogen atoms of the straight-chain or branched d- ₆ -alkyl group can optionally be completely or partly replaced by fluorine atoms, and which can optionally be substituted by a Cι- ₅ -alkyloxy group, where the hydrogen atoms of the Ci.s-alkyloxy group can optionally be completely or partly replaced by fluorine atoms , or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C _{_3-8} -cycloalkyl or C ₃ form -8-cycloalkenyl group, wherein one of the methylene groups of a C -s cycloalkyl group through an oxygen atom or a -N (R ⁸⁰ ) -, or a carbonyl or sulfonyl group can be replaced, and / or two directly adjacent methylene groups of a C _4-8 cycloalkyl group together by a -C (O) N (R ^8b ) - or - S (0) ₂ N (R ^8b ) group can be replaced, and / or three directly adjacent methylene groups of a C _6-8 - cycloalkyl group together by one -OC (O) N (R ^8b ) -, - N (R ^8b ) C (O ) N (R ^8b ) - or -N (R ^8b ) S (O) ₂ N (R ^8b ) group can be replaced, where one or two carbon atoms of a C3-8-cycloalkyl group may optionally be replaced independently by one or two of the same or different halogen atoms or C _-5 alkyl, nitrile, hydroxy, C _-5 alkyloxy, C _-5 alkylcarbonyloxy, carboxy d ₅ alkyl, C _-5 alkyloxycarbonyl C _-5 alkyl , Cι _-5 -A lkylsulfanyl-, d-5-alkylsulfonyl-, carboxy-, C-ι _-5 -alkyloxycarbonyl-, aminocarbonyl-, Cι- ₅ -alkylaminocarbonyl-, di- (Cι- ₅ -alkyl) - aminocarbonyl-, C _3-6 - Cycloalkyleniminocarbonyl-, aminosulfonyl-, d- ₅ -alkylaminosulfonyl-, di- (Cι _-5 -alkyl) -aminosulfonyl-, C ₃ - ₆ -cycloalkylene iminosulfonyl-, amino-, Cι- ₅ -alkylamino-, di- (Cι _-5 -alkyl) -amino-, Cι- ₅ -alkylcarbonylamino-, Cι _-5 -alkyl- sulfonylamino-, or Λ / - (Cι _-5 -alkylsulfonyl) -C _1-5 -alkylamino groups can be substituted,

where one or two carbon atoms are one

C _{_3-8} cycloalkenyl optionally substituted independently from each other by one or two identical or different Cι _-5 - alkyl, nitrile, carboxy-Cι _-5 -alkyl,. ₅ -alkyloxycarbonyl-Cι- ₅ -alkyl, carboxy-, d _-5 -alkyloxycarbonyl-, aminocarbonyl-, d- ₅ -alkylaminocarbonyl-, di- (d _-5 -alkyl) -aminocarbonyl-,

C ₃ - ₆ -cycloalkyleneiminocarbonyl-, aminosulfonyl, Cι _-5 -alkylaminosulfonyl-, di- (Cι _-5 -alkyl) -aminosulfonyl-, C _3-6 -cycloalkyleneiminosulfonyl groups may be substituted,

and one or two carbon atoms of a C -s-

Cycloalkenyl group, which are not bound by a double bond to another carbon atom, optionally independently of one another by one or two identical or different fluorine atoms or hydroxy ^, Cι _-5 -alkyloxy-, Cι- ₅ -alkylcarbonyloxy-, Cι _-5 -alkylsulfanyl- , Cι _-5 -AkylsulfonyI-,

Amino-, Cι _-5 -alkylamino-, di- (Cι _-5 -alkyl) -amino-, Ci.s-alkylcarbonylamino-, Cι _-5 -alkylsulfonylamino-, Λ / - (Cι _-5 -alkylsulfonyl) -Cι _{- 5} alkylamino or C _3-6 cycloalkylcarbonylamino groups can be substituted,

with the proviso that those composed of R ⁴ and R ⁵ formed C _3-8 cycloalkyl or C _{_3-8} cycloalkenyl group, in the two heteroatoms in the ring selected from oxygen and nitrogen, by precisely one optionally substituted -CH ₂ group are separated from each other, and / or in one or both methylene groups of the cycle, which are directly are connected to the carbon atom to which the radicals R ⁴ and R ^{5 are} attached, are replaced by a hetero atom from the group consisting of oxygen, nitrogen and sulfur, and / or in which a substituent which is bound to the cyclic group and which is distinguished by that a hetero atom from the group oxygen, nitrogen, sulfur and halogen atom is bonded directly to the cyclic group, is separated from another hetero atom from the group oxygen, nitrogen and sulfur, with the exception of the sulfone group, by exactly one, optionally substituted, methylene group, and / or in which two oxygen atoms are directly connected to one another is excluded,

R ^{6 is} a fluorine, chlorine, bromine or iodine atom, a Nitriigruppe, a Cι _-3 alkyl or a Cι- ₃ alkoxy group, the hydrogen atoms of the d- ₃ alkyl or C _1-3 alkoxy group can be completely or partially replaced by fluorine atoms, if appropriate,

where, unless stated otherwise, the term "heteroaryl group" mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a d- ₃ alkyl, phenyl or phenyl-C _1-3 alkyl group, an oxygen or sulfur atom or an optionally by a C _-3 alkyl, phenyl, amino-C _2-3 alkyl, d.3-alkylamino C _2-3 alkyl, di (C _{3 -3} alkyl) amino C _2-3 alkyl, a C _3-6 - CycloalkyIenimino-Cι- ₃ alkyl or phenyl-Cι _-3 -alkyl group substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or an optionally by a Cι _-3 -Alkyl- or phenyl-d _-3 -alkyl group substituted imino group and two or, three nitrogen atoms, and also to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms one optionally by a fluorine, chlorine or bromine atom, a Cι _-3 - Alkyl, hydroxy, d _-3 -alkyloxy group, amino, C-ι _-3 -alkylamino, di- (d _-3 -alkyl) - amino- or C _3-6 -cycloalkyleneimino group substituted phenyl ring can be fused and the Binding takes place via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,

where the alkyl, alkenyl, alkynyl and alkoxy groups which have more than two carbon atoms and, unless stated otherwise, can be straight-chain or branched, and the alkyl groups in the abovementioned dialkylated radicals, for example the dialkylamino groups, can be the same or different,

and wherein the hydrogen atoms are those mentioned in the above Definitions containing methyl or ethyl groups can be replaced in whole or in part by fluorine atoms,

A fourth embodiment of the present invention comprises those compounds of the general formula I in which

A is a radical of the general formula

means in the

m is the number 1 or 2,

R ^8a each independently of one another a hydrogen or halogen atom or a C _1-3 alkyl, hydroxy, hydroxy -CC _-3 alkyl, -C ₃ alkoxy, d. ₃ -alkoxy-d. ₃ -alkyl-, amino-, Cι- ₃ -alkylamino-, di- (Cι _-3 -alkyl) -amino-, amino-Cι _-3 -alkyl-, Cι _-3 -alkylamino-Cι _-3 -alkyl-, Di- (Cι _-3 -alkyl) -amino-Cι- ₃ -alkyl-, aminocarbonyl-, Cι _-3 -alkylaminocarbonyl-, di- (Cι _-3 -alkyl) -aminocarbonyl- or Cι _-3- alkylcarbonylamino group, where in the above-mentioned substituted 5- to 7-membered radicals A the heteroatoms F, CI, Br, I, O or N, optionally introduced with R ^8a as substituents, are not separated from a heteroatom from the group N, O, S by exactly one carbon atom,

R ^8b each independently represents a hydrogen atom or a d- ₃ -alkyl group,

R ^8c each independently represents a hydrogen atom, ad _-3- alkyl, d-3-alkylcarbonyl, Cι _-4 -alkyloxycarbonyl or C _1-3 -alkylsulfonyl group,

X ^{1 represents} an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8c group,

X ^{3 is} an oxygen atom or an -NR ^8c group,

X ^{4 represents} a carbonyl or sulfonyl group,

R ^{1 is} a fluorine, chlorine, bron> or iodine atom, a C ₃ alkyl or C ₃ alkoxy group, the hydrogen atoms of the d ₃ alkyl or C ₃ alkoxy group optionally being wholly or partly by Fluorine atoms can be replaced

R ^{2 represents} a hydrogen or halogen atom or a methyl group,

R ^{3 represents} a hydrogen atom,

R ^{4 is} a hydrogen atom, a C _2-4 alkenyl or C _2-4 alkynyl group, a straight-chain or branched C _-4 alkyl group, the hydrogen atoms of the straight-chain or branched C _-4 alkyl group optionally being replaced in whole or in part by fluorine atoms can be, and optionally by a nitrile, hydroxy ad ₃ -alkyloxy group, the hydrogen atoms of the Cι- ₃ alkyloxy group can optionally be wholly or partly replaced by fluorine atoms, a benzyloxy, d _-3 -alkylcarbonyloxy, Cι- ₃ alkyloxycarbonyl-Cι _-3 -alkyloxy-, -C-3-alkyloxycarbonyl, aminocarbonyl, Cι _-3- alkylaminocarbonyl-, di- (Cι _-3 -alkyl) -aminocarbonyl-, C ₃ - ₆ -cycloalkyleniminocarbonyl-, aminosulfonyl-, C _1-3 -AI- kylaminosulfonyl-, di- (Cι _-3 -alkyl) - aminosulfonyl-, C ₃ - ₆ -cycloalkyleneiminosulfonyl-, amino-, d-3-alkylamino-, di- (Cι _-3 -alkyl) - amino-, d- ₃ -alkylcarbonylamino-, d- ₃ -alkylsulfonylamino-, or / V ^ ds-Alkylsulfony -ds-alkylamino group can be substituted, a phenyl, heteroaryl, phenyl-Cι _-3 alkyl or heteroaryl C _1-3 alkyl, optionally in the phenyl or heteroaryl part by one to three times same or different substituents selected from the group consisting of halogen atoms, Cι _-3 alkyl, di (Cι _-3 alkyl) amino, hydroxy, Cι ₃ alkyloxy, mono-, di- or trifluoromethoxy , Carboxy and C ι- ₃ alkyloxycarbonyl groups can be substituted means

R is a hydrogen atom, a C _2-4 alkenyl or C ₂ - alkynyl group, a straight-chain or branched C ₄ alkyl group, it being possible for the hydrogen atoms of the straight-chain or branched d- alkyl group to be replaced in whole or in part by fluorine atoms, and which may optionally be substituted by a C ₃ alkyloxy group, where the hydrogen atoms of the d ₃ alkyloxy group may optionally be wholly or partly replaced by fluorine atoms, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached a C _{_3-8} cycloalkyl or C _3-8 cycloalkenyl form,

wherein one of the methylene groups of a C _4-8 cycloalkyl group can be replaced by an oxygen atom or an -N (R ^8c ) group, and / or

two directly adjacent methylene groups of a C _-8 cycloalkyl group can be replaced together by a -C (0) N (R ^8b ) - or ^■ S (0) ₂ N (R ^8b ) group, and / or

three directly adjacent methylene groups of a Cβ-β-cycloalkyl group together by a -OC (O) N (R ^8b ) -, - N (R ^8b ) C (0) N (R ^8b ) - or -N (R ^8b ) S ( 0) ₂ N (R ^8b ) group can be replaced,

where one or two carbon atoms of a C _3-8 cycloalkyl group, optionally independently of one another, each with a C1-3 alkyl, hydroxy, C _{3 -3} alkyloxy, C _{3 -3} alkylcarbonyloxy, C ₃ alkyloxycarbonyl, amino -, -Cι _-3- Alkylamino-, di- (Cι _-3 -alkyl) - amino-, d _-3 -Alkylcarbonylamino-, or d _-3 -Alkyl- sulfonylamino group may be substituted,

where one or two carbon atoms of a C ₃ . ₈ -cycloalkenyl group, optionally independently of one another, in each case by one or two identical or different d _-3 -

Alkyl groups can be substituted,

and one or two carbon atoms of a C -s cycloalkenyl group, which are not bound to a different carbon atom by a double bond, optionally independently of one another by one or two identical or different hydroxy, Cι _-3 alkyloxy, or di (Cι _-3- alkyl) - amino group can be substituted, with the proviso that those composed of R ⁴ and R ⁵ formed C _3-8 cycloalkyl or C _3- 8-cycloalkenyl in which two heteroatoms in the ring selected from oxygen and nitrogen, by precisely one optionally substituted -CH ₂ group are separated from one another, and / or in which one or both methylene groups of the cycle, which are connected directly to the carbon atom to which the radicals R ⁴ and R ^{5 are} attached, by a hetero atom from the group consisting of oxygen, nitrogen and sulfur are replaced, and / or in which a substituent bonded to the cyclic group, which is characterized in that a hetero atom from the group oxygen, nitrogen, sulfur and halogen atom is bonded directly to the cyclic group, from another hetero atom from the group oxygen , Nitrogen and sulfur, with the exception of the sulfone group, is separated by exactly one, optionally substituted, methylene group, and / or in which two oxygen atoms are directly linked v are connected, is excluded,

represents a fluorine, chlorine, bromine or iodine atom, a methyl group, or a methoxy group, the hydrogen atoms of the methyl or

The methoxy group can optionally be completely or partially replaced by fluorine atoms, where, unless stated otherwise, the term "heteroaryl group" mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C ₃ alkyl, phenyl or phenyl C ₃ alkyl group, an oxygen or sulfur atom or an optionally substituted by a _-3 alkyl, phenyl or amino C _2. ₃ -alkyl-, Cι _-3 -alkylamino-C _2-3 -alkyl-, di- (Cι- ₃ -alkyl) -amino-C _2-3 -alkyl-, a C _3-6 - cycloalkylenimino-d- ₃ - alkyl or phenyl-d _-3 -alkyl group substituted imino group or an oxygen or sulfur atom and in addition a nitrogen atom or an imino group optionally substituted by a d _-3 -alkyl or phenyl-Cι _-3 -alkyl group and two or three nitrogen atoms , and also the monocyclisc mentioned above hen heteroaryl groups via two adjacent carbon atoms, optionally by a fluorine, chlorine or bromine atom, a Cι _-3 alkyl, hydroxy, d _-3 alkyloxy group, amino, Cι _-3 alkylamino, di (Cι _{- 3-} alkyl) - amino- or C _3-6 -cycloalkyleneimino group substituted phenyl ring can be fused on and the binding takes place via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,

Unless otherwise stated, the term "halogen atom" mentioned above in the definitions means an atom from the group fluorine, chlorine, bromine and iodine, where the alkyl, alkenyl, alkynyl and alkoxy groups which have more than two carbon atoms and, unless stated otherwise, may be straight-chain or branched and the alkyl groups in the abovementioned dialkylated radicals, for example the dialkylamino groups, contained in the definitions mentioned above , can be the same or different,

A fifth embodiment of the present invention comprises those compounds of the general formula I in which

A is a radical of the general formula

in the

m is the number 1 or 2, R ^8a each independently of one another is a hydrogen or halogen atom or a C _1-3 alkyl, hydroxy, hydroxy-Cι _-3 alkyl, C _{-3 -3} alkoxy, d-3-alkoxy-d-3-alkyl -, Amino-, C _1-3 -alkylamino-, di- (Cι _-3 -alkyl) -amino-, amino-Cι _-3 -alkyl-, Cι _-3 -alkylamino-Cι _-3 -alkyl- or Di- (-C-3-alkyl) -amino-Cι _-3 alkyl group means, in the case of the above-mentioned substituted 5- to 7-membered radicals A, the heteroatoms F, CI, Br, I, O or optionally introduced with R ^8a as substituents N are not separated from a heteroatom from the group N, O, S by exactly one carbon atom,

R ^8b each independently represents a hydrogen atom or a d- ₃ -alkyl group,

R ^8c each independently represents a hydrogen atom, ad _-3 -alkyl- d- ₃ -alkylcarbonyl or Cι- -alkyloxycarbonyl group,

X ^{1 represents} an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8c group,

X ^{3 is} an oxygen atom or an -NR ^8c group,

X ^{4 represents} a carbonyl group,

R ^{1 represents} a fluorine, chlorine, bromine or iodine atom, a methyl or methoxy group, it being possible for the hydrogen atoms of the methyl or methoxy group to be replaced in whole or in part by fluorine atoms,

R ^{2 represents} a hydrogen or fluorine atom,

R ^{3 represents} a hydrogen atom,

R ^{4 is} a hydrogen atom, a straight-chain or branched d _-4 -alkyl group, where the hydrogen atoms of the straight-chain or branched C _-4 alkyl group may optionally be wholly or partly replaced by fluorine atoms, and which may optionally be replaced by a hydroxy, a C 1. ₃ alkyloxy group wherein the hydrogen atoms of the ₃ d- alkyloxy group may be replaced by fluorine atoms, optionally wholly or partially, a benzyloxy, Cι _-3 alkylcarbonyloxy, d- ₃ -alkyloxycarbonyl, aminocarbonyl, Cι _-3 -alkylaminocarbonyl- , Di- (Cι _-3 -alkyl) -aminocarbonyl-, C ₃ - ₆ -cycloalkyleniminocarbonyl-, aminosulfonyl-, C-ι- ₃ -Aikylaminosulfonyl-, Di- (C _1-3 -alkyl) -aminosulfonyl-, C _{3 -6-} Cycloalkyleniminosulfonyl-, amino-, -Cι _-3 -alkylamino-, di- (Cι _-3 -alkyl) - amino-, d _-3 -alkylcarbonylamino-, or Cι- ₃ -alkylsulfonylamino group can be substituted,

a phenyl, heteroaryl, phenyl-d _-3 -alkyl or heteroaryl-d- ₃ -alkyl group which, in the phenyl or heteroaryl part, is optionally selected one to three times by identical or different substituents selected from the group consisting of halogen atoms, ₃ alkyl, di (C _{3 -3} alkyl) amino, hydroxyl, C _{3 3} alkyloxy, mono-, di or trifluoromethoxy groups may be substituted,

means

a hydrogen atom,

a straight-chain or branched Cι- alkyl group, where the hydrogen atoms of the straight-chain or branched Cι _-4 alkyl group can optionally be wholly or partly replaced by fluorine atoms, and optionally by a d-3-alkyloxy group, the hydrogen atoms of the Cι _-3 - Alkyloxy group can optionally be completely or partially replaced by fluorine atoms, can be substituted, means or

R ⁴ and R together with the carbon atom to which they are attached, a C ₃ ⁵ - wherein one of the methylene groups of a C _-8 cycloalkyl be replaced by an oxygen atom or a group -N (R ^8c) form ₈ cycloalkyl group, can, and / or two directly adjacent methylene groups of a C _-8- cycloalkyl group together can be replaced by a -C (O) N (R ^8b ) - or - S (0) ₂ N (R ^8b ) group, and / or three directly adjacent methylene groups of a C _6- 8 cycloalkyl group together by a -OC (0) N (R ^8b ) -, - N (R ^8b ) C (O) N (R ⁸ ) - or -N (R ^8b ) S (O) ₂ N (R ^8b ) group can be replaced, where one or two carbon atoms of a C _3-8 cycloalkyl group, if appropriate independently of one another, in each case by ad _-3 - alkyl, hydroxy, Cι _-3 alkyloxy, Cι _-3 -Alkylcarbonyloxy-, d- ₃ -Alkyloxycarbonyl-, Cι _-3 -Alkylamino-, Di- (Cι _-3 -alkyl) -amino-, d- ₃ -Alkylcarbonylamino-, or d _-3 -Alkylsulfonylamino group may be substituted , with the proviso that such a C ₃ together formed from R ⁴ and R ⁵ . ₈ -cycloalkyl group in which two heteroatoms in the cycle from the group oxygen and nitrogen are separated from one another by exactly one optionally substituted -CH ₂ group, and / or in which one or both methylene groups of the cycle, which are directly connected to the carbon atom to which the radicals R ⁴ and R ^{5 are} attached, are replaced by a hetero atom from the group consisting of oxygen, nitrogen and sulfur, and / or in which one the cyclic group-bound substituent, which is characterized in that one hetero atom from the group oxygen, nitrogen, sulfur and halogen atom is bonded directly to the cyclic group, from another hetero atom from the group oxygen, nitrogen and sulfur, with the exception of the sulfone group, is separated by exactly one, optionally substituted, methylene group, and / or in which two oxygen atoms are directly connected to one another, is excluded,

R ^{6 represents} a fluorine, chlorine, bromine or iodine atom, a methyl group or a methoxy group, where the hydrogen atoms of the methyl group or methoxy group can optionally be wholly or partly replaced by fluorine atoms,

where, unless stated otherwise, the term "heteroaryl group" mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group is an imino group optionally substituted by a d- ₃ -alkyl, phenyl or phenyl-Cι _-3 alkyl group, an oxygen or sulfur atom or an optionally substituted by a Cι> _-3 alkyl, phenyl, Amino-C ₂ - ₃ -alkyl-, Cι _-3 -alkylamino-C ₂ -3-alkyl-, di- (Cι-3-alkyl) -amino-C ₂ - ₃ -alkyl-, a C _3-6 - Cycloalkylenimino-Cι.3-alkyl or phenyl-d _-3 -Alkylgruppe substituted imino group or an oxygen or sulfur atom and in addition a nitrogen atom or an optionally substituted by a d _-3 -alkyl or phenyl-Cι _-3 -alkyl group and contains two or three nitrogen atoms, and also to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms, optionally by a fluorine, chlorine or bromine atom, a Cι_ ₃ alkyl, hydroxy, Cι _-3 alkyloxy group, amino, d _-3 alkylamino, di- (d _-3 alkyl) - amino or C _3- 6-substituted Cycloalkyleniminogmppe Phen yl ring can be fused and the bond via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused phenyl ring. he follows,

where the alkyl and alkoxy groups contained in the definitions mentioned above, which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the dialkylated radicals mentioned above, for example the dialkylamino groups, can be identical or different . and the hydrogen atoms of the methyl or ethyl groups contained in the definitions mentioned above can be replaced in whole or in part by fluorine atoms,

A sixth embodiment of the present invention comprises those compounds of the general formula I in which

A is a radical of the general formula

means

in the

m is the number 1 or 2,

R ^{8a are} each independently a hydrogen or. Halogen atom or a C _-3 alkyl, hydroxy, hydroxy C _-3 alkyl, d _-3 alkoxy, C _-3 alkoxy C ₃ alkyl, amino, C _-3 alkyl amino-, di- (Cι _-3- alkyl) -amino-, amino-Cι _-3 -alkyl-, ds-alkylamino-Ci-s-alkyl-, or di- (Cι- ₃ -alkyl) -amino-Cι _-3- alkyl group means, in the case of the above-mentioned substituted 5- to 7- membered radicals A, the heteroatoms F, CI, Br, I, O or N, optionally introduced with R ^8a as substituents, are not separated from a heteroatom from the group N, 0, S by exactly one carbon atom,

R ^8c each independently represents a hydrogen atom, ad _-3 -alkyl-, d- ₃ -alkylcarbonyl-, or -CC -alkyloxycarbonyl,

X ^{1 represents} an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8c group,

X ^{3 is} an oxygen atom or an -NR ^8c group,

X ^{4 represents} a carbonyl group,

R ^{2 represents} a hydrogen or fluorine atom,

R ^{3 represents} a hydrogen atom,

R ^{4 is} a hydrogen atom, a straight-chain or branched Cι- alkyl group, where the hydrogen atoms of the straight-chain or branched Cι _-4 alkyl group can optionally be wholly or partly replaced by fluorine atoms, and which may optionally be replaced by a hydroxy, a Cι. ₃ -alkyloxy group, where the hydrogen atoms of the d- ₃ -alkyloxy group can optionally be wholly or partly replaced by fluorine atoms, a benzyloxy-, Cι _-3 -alkylcarbonyloxy- Cι- ₃ -alkyloxycarbonyl-, aminocarbonyl, Cι _-3 -alkylaminocarbonyl-, Di- (C-ι- ₃ -alkyl) -aminocarbonyl-, C3-6-cycloalkyleniminocarbonyl-, Aminosulfonyl-, d _-3 alkylaminosulfonyl, di- (C _1-3 alkyl) -aminosulfonyl-, C _3- 6-Cycloalkyleniminosulfonyl-, amino, Cι _-3 alkylamino, di- (Cι _-3 alkyl ) - Amino, Cι _-3 alkylcarbonylamino, or Cι _-3 alkylsulfonylamino group can be substituted, a phenyl, heteroaryl, phenyl-Cι- ₃ -AIkyl- or heteroaryl- Cι-3-alkyl group, which in the phenyl or heteroaryl part optionally one to three times by identical or different substituents selected from the group consisting of halogen atoms, d _-3 -alkyl-, di- (d- ₃ -alkyl) -amino-, hydroxy-, C-ι _-3 -alkyloxy -, Mono-, di- or trifluoromethoxy groups can be substituted, means

R> 5 ° is a hydrogen atom, a straight-chain or branched C 1 -C ₄ -alkyl group, where the hydrogen atoms of the straight-chain or branched d- ₄ -alkyl group can optionally be completely or partially replaced by fluorine atoms, and which may optionally be replaced by a d- ₃ - Alkyloxy group, where the hydrogen atoms of the -C ₃ alkyloxy group can optionally be wholly or partly replaced by fluorine atoms, can be substituted, means, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C3 _-8- cycloalkyl group, whereby one of the methylene groups of a C _-8- cycloalkyl group can be replaced by an oxygen atom or an -N (R ^8o ) group . where one or two carbon atoms of a C ₃ . ₈ -CycloaIkylgruppe optionally independently of each other by a Cι _-3 - alkyl, hydroxy, d _-3 -alkyloxy, or di- (d _-3 -alkyl) amino group may be substituted,

with the proviso that such a C ₃ -8-cycloalkyl group, formed together from R ⁴ and R ⁵ , in which two heteroatoms in the cycle from the group oxygen and nitrogen are separated from one another by exactly one optionally substituted -CH ₂ group, and / or in which one or both methylene groups of the cycle, which are directly connected to the carbon atom to which the radicals R ⁴ and R ^{5 are} attached, are replaced by a hetero atom from the group consisting of oxygen, nitrogen and sulfur, and / or in which a substituent attached to the cyclic group, which is characterized in that a hetero atom from the group oxygen, nitrogen, sulfur and halogen atom is bonded directly to the cyclic group, from another hetero atom from the group oxygen, nitrogen and sulfur, with the exception of Sulfone group separated by exactly one, optionally substituted, methylene group, and / or in which two oxygen atoms are directly connected to one another,

is excluded R ^{6 represents} a fluorine, chlorine, bromine or iodine atom,

where, unless stated otherwise, the term "heteroaryl group" mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C ₃ alkyl, phenyl or phenyl d ₃ alkyl group, an oxygen or sulfur atom or an optionally substituted by a C ₃ alkyl, phenyl, amino C _2-3 alkyl, Cι _-3 alkylamino-C2-3-alkyl, di- ₍₃ Cι- -alkyl) -amino-C _2-3 -alkyl, C _3-6 - Cycloalkylenimino-d-3-alkyl - or phenyl-C _1-3 -alkyl group substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or an imino group optionally substituted by a d _-3 -alkyl or phenyl-Cι- ₃ -alkyl group and two or three nitrogen atoms, and also the aforementioned monocyclic He teroaryl groups via two adjacent carbon atoms, optionally by a fluorine, chlorine or bromine atom, a C _-3 alkyl, hydroxy, d _-3 alkyloxy group, amino, C ₃ alkyl alkyl, di (d _-3 alkyl) - amino or C ₃ - ₆ -Cycloalkyleniminogruppe substituted phenyl ring can be fused and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused phenyl ring, Unless otherwise stated, the term "halogen atom" mentioned above in the definitions means an atom from the group fluorine, chlorine, bromine and iodine,

where the alkyl and alkoxy groups contained in the definitions mentioned above, which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the dialkylated radicals mentioned above, for example the dialkylamino groups, can be identical or different .

A seventh embodiment of the present invention comprises those compounds of the general formula I in which

A is a radical of the general formula

, or means

in the m is the number 1 or 2,

R ^{8a are} each independently a hydrogen or halogen atom or ad _-3 alkyl, hydroxy, hydroxy d _-3 alkyl, C _-3 alkoxy, d ₃ alkoxy d. ₃ -alkyl-, amino-, Cι _-3 -alkylamino-, di- (Cι _-3 -alkyl) -amino-, amino-Cι _-3 -alkyl-, Cι _-3 -alkylamino-Cι _-3 -alkyl-, or di- (-C ₃ -alkyl) -amino-Cι- ₃ alkyl group, wherein in the above-mentioned substituted 5- to 7-membered radicals A, the heteroatoms F, CI, Br, I optionally introduced with R ^8a as substituents , O or N are not separated from a hetero atom from the group N, O, S by exactly one carbon atom,

R ^8c each independently represents a hydrogen atom, a C ₃ alkyl, C ₃ alkylcarbonyl or C 1 alkyloxycarbonyl group,

X ^{1 represents} an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8c group,

X ³ is an oxygen atom or an -NR ^8o group,

R ^{1 represents} a fluorine, chlorine or bromine atom, a methyl, trifluoromethyl or methoxy group,

R ^{2 represents} a hydrogen or fluorine atom,

R ^{3 represents} a hydrogen atom,

R ^{4 is} a straight-chain or branched C _-4 alkyl group, where the hydrogen atoms of the straight-chain or branched C _-4 alkyl group may optionally be wholly or partly replaced by fluorine atoms, and which may optionally be replaced by a hydroxy, a d- ₃ alkyloxy group, where the hydrogen atoms of the d- ₃ -alkyloxy group can optionally be completely or partially replaced by fluorine atoms, a benzyloxy-, d- ₃ -alkylcarbonyloxy-, d-3-alkyloxycarbonyl-, aminocarbonyl-, Cι _-3 -alkylaminocarbonyl-, di- (Cι _-3 -alkyl) -aminocarbonyl-, C ₃ -6-cycloalkyleniminocarbonyl-, aminosulfonyl-, Cι, ₃ -alkylaminosulfonyl-, di- (C _1-3 -alkyl) -aminosulfonyl-, C3-6-cycloalkyleniminosulfonyl-, amino-, Cι _-3 -alkylamino-, di- (Cι _-3 -alkyl) - amino-, Cι _-3- alkylcarbonylamino-, or Cι _-3 -Alkylsulfonylamino group can be substituted, a phenyl, heteroaryl, phenyl-Cι _-3 alkyl or heteroaryl-d- ₃ -alkyl group, which in the phenyl or heteroaryl part optionally selected one to three times by identical or different substituents can be substituted from the group consisting of halogen atoms, d _-3 -alkyl, di- (Cι- ₃ -alkyl) -amino, hydroxy, d-3-alkyloxy, mono-, di- or trifluoromethoxy groups,

R ^{5 is} a hydrogen atom, or a straight-chain or branched d _-4 -alkyl group, where the hydrogen atoms of the straight-chain or branched Cι- ₄ alkyl group can optionally be wholly or partly replaced by fluorine atoms, and which may be replaced by a Cι- ₃ alkyloxy group, where the hydrogen atoms of the d- _3- alkyloxy group can optionally be wholly or partly replaced by fluorine atoms, can be substituted, means, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C _3-8 cycloalkyl group, one of the methylene groups of a C _4-8 cycloalkyl group can be replaced by an oxygen atom or an -N (R ^8c ) group,

where one or two carbon atoms of a C ₃ -s-cycloalkyl group optionally independently of one another by in each case a C1-3

Alkyl, hydroxy, Cι _-3 alkyloxy or di (Cι _-3 alkyl) amino group may be substituted,

with the proviso that such a C _3-8 cycloalkyl group, formed together from R ⁴ and R ⁵ , in which two heteroatoms in the cycle from the group oxygen and nitrogen are separated from one another by exactly one optionally substituted -CH ₂ group, and / or in which one or both methylene groups of the cycle which are directly connected to the carbon atom to which the radicals R ⁴ and R ^{5 are} attached are replaced by a heteroatom from the group consisting of oxygen, nitrogen and sulfur, and / or in which a substituent attached to the cyclic group, which is characterized in that a hetero atom from the group oxygen, nitrogen, sulfur and halogen atom is bonded directly to the cyclic group, from another hetero atom from the group oxygen, nitrogen and sulfur, with the exception of Sulfone group separated by exactly one, optionally substituted, methylene group, and / or in which two oxygen atoms are directly connected to one another, is excluded

R ^{6 represents} a chlorine or bromine atom,

where, unless stated otherwise, the term "heteroaryl group" mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C ₃ alkyl, phenyl or phenyl C ₃ alkyl group, an oxygen or sulfur atom or an optionally by a d ₃ alkyl, phenyl, amino C _2-3 -alkyl-, Cι _-3 -alkylamino-C _2-3 -alkyl-, di- (Cι _-3 -alkyl) -amino-C _2-3 -alkyl-, a C _3-6 - cycloalkylenimino-d- ₃ - contains alkyl or phenyl-C _-3 -alkyl group substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or an imino group optionally substituted by a d _-3 -alkyl or phenyl-d- _3- alkyl group and two or three nitrogen atoms, and also the monocyclic ones mentioned above Heteroaryl groups on two adjacent carbon atoms, optionally by a fluorine, chlorine or bromine atom, a C _{3 -3} alkyl, hydroxy, d ₃ alkyloxy group, amino, C _{3 -3} alkylamino, di (C 1 -s alkyl) - amino or C ₃ - ₆ -Cycloalkyleniminogruppe substituted phenyl ring can be fused and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused phenyl ring, Unless otherwise stated, the term "halogen atom" mentioned above in the definitions means an atom from the group fluorine, chlorine, bromine and iodine,

An eighth embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 1, 2, 3, 4, 5, 6 and 7 in which R ⁴ and R ^{5 are} not hydrogen.

A ninth embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 1, 2, 3, 4, 5, 6, 7 and 8 in which R ⁶ denotes a bromine atom.

A 10th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 1, 2, 3, 4, 5, 6, 7, 8 and 9 in which R ⁴ and R ^{5 are} not hydrogen and R ^{6 is} a bromine atom ,

An 11th embodiment of the present invention comprises those compounds of the general formula I in which A is a radical of the general formula

means in which m is the number 1 or 2,

R ^8a each independently represent a hydrogen or fluorine atom or a Cι _-5 alkyl, hydroxy, hydroxy-alkyl Cι _-5, d _-5 alkoxy, _C1-5 alkoxy-Cι. ₅ -alkyl-, amino-, d _-5 -alkylamino-, di- (Cι _-5 -alkyl) -amino-, amino-Cι _-5 -alkyl-, d _-5 -alkylamino-Cι. ₅ -alkyl-, di- (Cι _-5 -alkyl) -amino-Cι _-5 -alkyl-, Aminocarbonyl-, d _-5 -alkylaminocarbonyl-, di- (d _-5 -alkyl) -aminocarbonyl- or Cι- ₅ -alkylcarbonylamino group means, in the case of the above-mentioned substituted 5- to 7-membered radicals A which are optionally with R ^8a as Substituents introduced heteroatoms F, O or N are not separated by exactly one carbon atom from a heteroatom from the group N, O, S, and two substituents R ^8a on the same or different carbon atoms can represent a _5- alkylene group,

R ^8b each independently represents a hydrogen atom or a C ₅ alkyl group,

X ^{1 is} an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8c group,

R ^8c each independently represents a hydrogen atom, a d-5-alkyl, Cι- ₅ alkylcarbonyl, Cι _-5 -alkyloxycarbonyl or d _-5 -alkylsulfonyl group,

X ^{2 is} an oxygen atom or an -NR ^8b group,

X ^{3 is} an oxygen or sulfur atom, an -NR ^8c group,

X ^{4 is} a carbonyl or sulfonyl group,

X ^{5 is} an oxygen atom, an -NR ^8b - or methylene group,

X ^{6 is} an oxygen or sulfur atom or an -NR ^8c group,

X ^{7 represents} a methylene or carbonyl group,

R ^{1 is} a hydrogen, fluorine, chlorine, bromine or iodine atom, a C ₃ alkyl or C ₃ alkoxy group, the hydrogen atoms of the d ₃ alkyl or C ₃ alkoxy group optionally completely or partly due to fluorine atoms can be replaced, means a C _2-3 alkenyl, C ₂ -3 alkynyl, nitrile, nitro or amino group,

R ^{2 represents} a hydrogen or halogen atom or a C-ι _-3 alkyl group,

R ^{3 represents} a hydrogen atom or a C 3 alkyl group,

R ⁴ and R ⁵ each independently represent a hydrogen atom, a C _2-6 alkenyl or C _2-6 alkynyl group, a straight-chain or branched d _-6 -alkyl group, the hydrogen atoms of the straight-chain or branched d-6-alkyl group optionally may be replaced in whole or in part by fluorine atoms, and which may optionally be replaced by a C3-5-cycloalkyl group, a nitrile, hydroxyl or a Ci.s-alkyloxy group, the hydrogen atoms of the d-5-alkyloxy group optionally being wholly or partly replaced by fluorine atoms can be an allyloxy, propargyloxy, benzyloxy, Cι _-5 -Alkylcarbonyloxy-, d _-5 -alkyloxycarbonyloxy-, carboxy-d-5-alkyloxy-, Cι _-5 -alkyloxycarbonyl-Cι _-5 -alkyloxy-, mercapto -, -C-5-Alkylsulfanyl-, d _-5 -AlkyIsulfonyl-, carboxy-, Ci-s-alkyloxycarbonyl-, aminocarbonyl-, C-ι-5-alkylaminocarbonyl-, di- (Cι _-5 -alkyl) -aminocarbonyl- , C ₃ - ₆ -Cycloalkyleniminocarbonyl-, aminosulfonyl-, -Cι _-5 -AI- kylaminosulfonyl-, di- (Cι _-5 -alkyl) -aminosulfonyl-, C _3-6 -cycloalkyleneiminosulfonyl-, amino-, -Cι- ₅ -alkylamino-, di- (Cι _-5 -alkyl) -amino-, Cι- ₅ -alkylcarbonylamino-, Cι _-5 -alkyl- sulfonylamino-, Λ / - (Cι..5-alkylsulfonyl) -Cι .. ₅ -alkylaιτιino- or C3-6-cycloalkylcarbonylamino group can be substituted, a carboxy, aminocarbonyl, d _-5 -alkylamino nocarbonyl, C ₃ -6-cycloalkylaminocarbonyl, di - (-Cι _-5 -alkyl) -aminocarbonyl-, d- ₅ alkoxycarbonyl, C _4-6 cycloalkyleneiminocarbonyl group,

a phenyl, heteroaryl, phenyl-Cι _-5 -alkyl or heteroaryl-d- ₅ -alkyl group, which in the phenyl or heteroaryl part optionally one to three times selected by the same or different substituents from the group consisting of halogen atoms, Cι- ₅ ~ alkyl, di (Cι _-5 -alkyl) amino, hydroxy, Cι _-5 alkyloxy, mono-, di- or trifluoromethoxy, carboxy and Cι- ₅ alkyloxycarbonyl groups can be substituted,

a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl, Ci.s-alkyl or cycioalkylenimino-d _-3 -alkyl group, in which in 4- to 7-membered cycles in the cyclic part a methylene group optionally by a -N (R ^8c ) group, an oxygen or sulfur atom or an -S (O) - or -S (0) ₂ - group can be replaced, or in the case of 4- to 7-membered cycles in the cyclic part two adjacent methylene groups together can optionally be replaced by a -C (O) N (R ^8b ) - or -S (O) ₂ N (R ^8b ) group, or in the case of 6- to 7-membered cycles in the cyclic part three adjacent methylene groups together optionally with a substituted -OC (0) N (R ^8b ) - or -N (R ^8b ) C (O) N (R ^8b ) - or -N (R ^8b ) S (O) ₂ N (R ^8b ) -Group can be replaced, with the proviso that a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyI-Cι _-5 -alkyl- or cycloalkylenimino-Cι- ₃ -alkyl group as defined above, in which two heteroatoms from the Group oxygen and St Nitrogen by exactly one optionally substituted -CH ₂ group wherein a composition as defined above, 3- to 7-membered cycloalkyl, Cycloalkylenimino-, cycloalkyl-Cι alkyl or Cycloalkylenimino _{-5-Cι-3-alkyl} group at one or two -CH ₂ is separated excluded - groups by in each case one or two C _-3 alkyl groups can be substituted, means, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C _3-8 cycloalkyl or C _3-8 cycloalkenyl form, wherein a C _{_3-8} cycloalkyl or C β-cycloalkenyl group at a single Carbon atom can be substituted by a C _2-5 alkylene group or at the same time on two different carbon atoms by a Cι _-4 alkylene group to form a corresponding spirocycle or a bridged bicyclus, one of the methylene groups of a C _4- s cycloalkyl or C ₅ -s cycloalkenyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above can be replaced by an oxygen or sulfur atom or an -N (R ^8c ) -, or a carbonyl, sulfinyl or sulfonyl group, and / or two directly adjacent methylene groups of a C _-8- cycloalkyl group can be replaced together by a -C (0) N (R ^8b ) -, - C (0) O- or -S (O) ₂ N (R ^8b ) group can, and / or three directly adjacent M ethylene groups of a C ₆ - ₈ - cycloalkyl group together through a -OC (0) N (R ^8b) -, - N (R ^8b) C (O) N (R ^8b) - or -N (R ^8b ) S (O) ₂ N (R ⁸ ) group can be replaced,

wherein 1 to 3 carbon atoms to a C-s-cycloalkyl or one, a corresponding spirocyclic as described above or a corresponding bridged bicyclic group optionally substituted independently by one or two fluorine atoms or one or two same or different Cι _-5 alkyl, nitrile -, Hydroxy-, Cι- alkyloxy-, d _-5 -alkylcarbonyloxy-, carboxy-Cι-5-alkyl-, -Cι _-5 -alkyloxycarbonyl-Cι- ₅ -alkyl-, d _-5 -alkylsulfanyl-, d- _5th Alkylsulfonyl, carboxy, d _-5 alkyloxycarbonyl,

Aminocarbonyl-, d _-5 -alkylaminocarbonyl-, di- (Cι _-5 -alkyl) - aminocarbonyl-, C _3-6 -cycloalky! Eniminocarbonyl-, aminosulfonyl-, Cι- ₅ -alkylaminosulfonyl-, Di- (Cι _-5 - alkyl) -aminosulfonyl-, C ₃ -6-cycloalkyleneiminosulfonyl-, amino-, Cι- ₅ -alkylamino-, di- (Cι _-5 -alkyl) -amino-, d _-5 -alkylcarbonylamino-, d _-5 -alkyl- sulfonylamino, Λ / - (C-ι _-5- alkylsulfonyl) -Cι .. ₅ alkylamino or C ₃ -6-cycloalkylcarbonylamino groups may be substituted,

wherein 1 to 2 carbon atoms of a Cs-s-cycloalkenyl group optionally substituted independently of one another by in each case a C _1-5 -

Alkyl, nitrile, carboxy-Cι _-5 alkyl, Cι- ₅ alkyloxycarbonyl-Cι alkyl _-5, carboxy, d _-5 alkyloxycarbonyl, aminocarbonyl, Cι- ₅ alkylaminocarbonyl, di- (d- ₅ -alkyl) -aminocarbonyI-, C ₃ -6-cycloalkyleneiminocarbonyl-, aminosulfonyl-, -Cι- ₅ -alkylaminosulfonyl-, di- (d _-5 -alkyl) -aminosulfonyl-,

C _3-6 -cycloalkyleneiminosulfonyl groups can be substituted,

and 1 to 2 carbon atoms of a C _4-8 cycloalkenyl group, which are not bound by a double bond to another carbon atom, optionally independently of one another by one or two fluorine atoms or a hydroxy, Cι _-5 -alkyloxy-, d-5-alkylcarbonyloxy -, Cι- ₅ -Alkylsulfanyl-, d _-5 -alkylsulfonyl-, amino-, d _-5 -alkylamino-, di- (d _-5 -alkyl) -amino-, d- ₅ -alkylcarbonylamino-, Cι _-5 -alkylsulfonylamino-, Λ / - (Cι-5-alkylsulfonyl) -Cι- alkylamino or C ₃ - ₆ cycloalkylcarbonylamino groups can be substituted,

with the proviso that those composed of R ⁴ and R ⁵ is C _3-8 cycloalkyl or formed C _{_3-8} cycloalkenyl group or a as described above, a corresponding spirocyclic or a corresponding bridged bicyclic system, in which two heteroatoms in the cycle from the group oxygen and nitrogen are separated from one another by exactly one optionally substituted -CH ₂ group, and / or in which one or both methylene groups of the cycle which are connected directly to the carbon atom on which the radicals R ⁴ and R ^{5 are} connected, are replaced by a hetero atom from the group oxygen, nitrogen and sulfur, and / or in which a substituent bound to the cyclic group, which is characterized in that a hetero atom from the group oxygen, nitrogen, sulfur and halogen atom directly is bound to the cyclic group by another heteroatom from the group of oxygen, nitrogen and sulfur, with the exception of the sulfone group, by exactly one given if substituted, methylene group is separated, and / or in which two oxygen atoms are connected directly to one another, and / or in which a heteroatom from the group consisting of oxygen, nitrogen and sulfur is connected directly to a carbon atom, which is connected to a further carbon atom by a double bond and / or which contains a cycle with three ring members, one or more of which corresponds to the group oxygen or sulfur atom or -N (R ^8c ) group, is excluded,

R ^{6 represents} a hydrogen, fluorine, chlorine, bromine or iodine atom, a nitrite group, a C ₃ alkyl group, or a C ₃ alkoxy group, the hydrogen atoms of the C ₃ alkyl or C _{3 group} Alkoxy group can optionally be completely or partially replaced by fluorine atoms,

R ^{7 is,} independently of one another, a C ₃ alkyl, where the hydrogen atoms can optionally be replaced in whole or in part by fluorine atoms, hydroxy, C _{3 3} alkyloxy, where the hydrogen atoms can be replaced in whole or in part by fluorine atoms, amino , d- ₃ -Alkylamino-, di- (Cι _-3 -alkyl) -amino-, C3- ₆ -cycloalkylenimino-, carboxy-, nitrile-, Cι- ₃ -alkoxycarbonyl-, aminocarbonyl-, C -ι _-3 - Alkylaminocarbonyl- or a di (Cι _-3 alkyl) aminocarbonyl group, where, unless stated otherwise, the term "heteroaryl group" mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, wherein the 6-membered heteroaryl group has one, two or three nitrogen atoms and the 5-membered heteroaryl group has an imino group which is optionally substituted by a C ₃ -C ₃ -alkyl, phenyl or phenyl-C _1-3 -alkyl group, an oxygen or sulfur atom or an optionally you rch a Cι_ ₃ alkyl, phenyl, amino-C ₂ . ₃ -alkyl-, Cι- ₃ -alkylamino-C ₂ - ₃ -alkyl-, di- (Cι. ₃ -alkyl) -amino-C _2-3 -alkyl-, a C ₃ - ₆ - Cycloalkylenimino-Cι-3-alkyl or phenyl-C _-3 alkyl substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or an optionally substituted by a Cι-3-alkyl or phenyl-d- alkyl ₃ Contains imino group and two or three nitrogen atoms, and also to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms, optionally by a fluorine, chlorine or bromine atom, a -C ₃ alkyl, hydroxy, d _-3 alkyloxy group, amino -, -Cι _-3- Alkylamino-, Di- (d _-3 -alkyl) - amino- or C _3-6 -cycloalkylenimino group substituted phenyl ring .ancondensed and the bond via a nitrogen atom or via a carbon atom of the heterocyclic part or a condensed one Phenyl ring takes place,

where the alkyl, alkenyl, alkynyl and alkoxy groups which have more than two carbon atoms and, unless stated otherwise, can be straight-chain or branched, and the alkyl groups in the abovementioned dialkylated radicals, for example the dialkylamino groups, contained in the definitions mentioned above , can be the same or different,

and wherein the hydrogen atoms are those mentioned in the above

Unless otherwise stated, definitions containing methyl or ethyl groups can be replaced in whole or in part by fluorine atoms, their tautomers, their enantiomers, their diastereomers, their mixtures and their salts.

Examples of monocyclic heteroaryl groups are the pyridyl, Λ / -oxy-pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, [1, 2,3] triazinyl,

[1, 3.5] triazinyl, [1, 2.4] triazinyl, pyrrolyl, imidazolyl, [1, 2.4] triazolyl,

[1, 2,3] triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, [1, 2,3] oxadiazolyl,

[1, 2.4] oxadiazolyl, furazanyl, thiophenyl, thiazolyl, isothiazolyl,

[1, 2,3] thiadiazolyl, [1, 2,4] thiadiazolyl or [1, 2,5] thiadiazolyl group.

Examples of bicyclic heteroaryl groups are the benzimidazolyl, benzofuranyl, benzo [c] furanyl, benzothiophenyl, benzo [c] thiophenyl, benzothiazolyl, benzo [c] isothiazolyl, benzo [α sothiazolyl, benzooxazolyl, benzo [ ] isoxazolyl, benzo [c /] isoxazolyl, benzo [1, 2.5] oxadiazolyl, benzo [1, 2.5] thiadiazolyl, benzo [1, 2.3] thiadiazolyl, benzo [αf | [ 1, 2,3] triazinyl, benzo [1, 2,4] triazinyl, benzotriazolyl, cinnolinyl, quinolinyl, Λ / -oxy-quinolinyl, isoquinolinyl, quinazolinyl, Λ / -oxy-quinazolinyl- , Quinoxalinyl, phthalazinyl, indolyl, isoindolyl or 1-oxa-2,3-diaza-indenyl group.

Examples of the above-mentioned in the definitions Cι _-6 alkyl groups are methyl, ethyl, 1-propyl, 2-propyl, π-butyl, sec-butyl, 1 tert-butyl, -pentyl , 2-pentyl, 3-pentyl, neo-pentyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 3-methyl-2-pentyl, 4- Methyl 2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,2-dimethyl-3-butyl or 2,3-dimethyl-2-butyl group.

Examples of the d- ₅ alkyloxy groups mentioned above in the definitions are the methyloxy, ethyloxy, 1-propyloxy, 2-propyloxy, n-butyloxy, sec-butyloxy, ferf-butyloxy, 1-pentyloxy , 2-pentyloxy, 3-pentyloxy or neo-pentyloxy group.

Examples of the C _2-6 alkenyl groups mentioned above in the definitions are the ethenyl, 1-propen-1-yl, 2-propen-1-yl, 1-buten-1-yl, 2-butene 1-yl, 3-buten-1-yl, 1-pentene-1-yl, 2-pentene-1-yl, 3-pentene-1-yl , 4-penten-1-yl-, 1-hexen-1-yl-, 2-hexen-1-yl-, 3-hexen-1-yl-, 4-hexen-1 -yl-, 5-hexen 1-yl-, but-1-en-2-yl-, but-2-en-2-yl-, but-1-en-3-yl-, 2-methyl-prop-2-en- 1 - yl, pent-1-en-2-yl, pent-2-en-2-yl, pent-3-en-2-yl, pent-4-en-2-yl, pent-1 - en-3-yl-, pent-2-en-3-yl-, 2-methyl-but-1-en-1-yl-, 2-methyl-but-2-en-1-yl-, 2 - methyl-but-3-en-1-yl-, 2-ethyl-prop-2-en-1-yl-, hex-1-en-2-yl-, hex-2-en-2-yl- , Hex-3-en-2-yl, hex-4-en-2-yl, hex-5-en-2-yl, hex-1-en-3-yl, hex-2-ene -3-yl-, hex-3-en-3-yl-, hex-4-en-3-yl-, hex-5-en-3-yl-, hex-1-en-4-yl-, Hex-2-en-4-yl-, Hex-3-en-4-yl-, Hex-4-en-4-yl-, Hex-5-en-4-yl-, 4-methylpent- 1-en-3-yl-, 3-methyl-pent-1-en-3-yl-, 2-methyl-pent-1-en-3-yI-, 2,3-dimethyl-but-1-ene -3-yl, 3,3-dimethyl-but-1-en-2-yl or 2-ethyl-but-1-en-3-yl group,

Examples of the above-mentioned in the definitions of C ₂ - ₆ alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1-butyn-1 -yl, 1-butyn-3-yl, 2-butyne -1-yl-, 3-butyn-1-yl-, 1-pentyn-1-yl-, 1-pentyn-3-yl-, 1-pentyn-4-yl-, 2-pentyn-1-yl- , 2-pentyn-3-yl-, 3-pentyn-1-yl-, 4-pentyn-1-yl-, 2-methyl-1-butyn-4-yl-, 3-methyl-1-butyn-1 -yl-, 3-Methyl-1-butyn-3-yl-, 1-Hexin-1-yl-, 2-Hexin-1-yl-, 3-Hexin-1-yl-, 4-Hexin-1- yl-, 5-hexin-1-yl-, 1-hexin-3-yl-, 1-hexin-4-yl-, 1-hexin-5-yl-, 2-hexin-4-yl-, 2- Hexin-5-yl-, 3-hexin-5-yl-, 3-methyl-1-pentin-3-yl-, 4-methyl-1-pentin-3-yl-, 3-methyl-1-pentine 4-yl-, 4-methyl-1-pentin-4-yl-, 4-methyl-2-pentin-4-yl-, 4-methyl-2-pentin-1 -yl-, 2,2-dimethyi- 3-butyn-1-yl or 2-ethyl-3-butyn-1-yl group.

A group which can be converted into a carboxy group in vivo is, for example, a carboxy group esterified with an alcohol, in which the alcoholic part is preferably a C ₆ alkanol, a phenyl C ₃ alkanol, a C _3-9 cycloalkanol, a C _5-7 -CycloaIkenol, a C _3-5 alkenol, a phenyl C _3-5 alkenol, a C _{_3-5} -alkynol or phenyl-C _3-5 -alkynol, with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a C _3-8 -cycloalkyl-d- _3- alkanol or an alcohol of the formula

R ⁹ -CO-O- (R ¹⁰ CR ¹¹ ) -OH, in the

R ^{9 is} a C ₈ alkyl, C _5-7 cycloalkyl, phenyl or phenyl C 3 _-3 alkyl group, R ^{10 is} a hydrogen atom, a C ₃ alkyl, C ₅ - ₇ cycloalkyl or Phenyl group and

R ^{11 represents} a hydrogen atom or a C _-3 alkyl group,

to understand.

The preferred radicals which can be split off from a carboxy group in vivo are a C 6 alkoxy group such as the methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy or cyclohexyloxy group or one Phenyl-Cι- ₃ alkoxy group as the benzyloxy group into consideration.

A group which can be converted into a hydroxyl group in vivo is, for example, a hydroxyl group esterified with a carboxylic acid, in which the carboxylic acid part is preferably a -C ₇ alkane acid, a phenyl C ₃ alkanoic acid, a C _3-9 cycloalkyl carboxylic acid

C5-7-Cycloalkencarbonsäure, a C _3-7 alkenoic, a phenyl-C3-5 alkenoic acid, a C _{_3-7} -Alkinsäure or phenyl-C _{_3-5} -alkinsäure, where individual methylene groups of the carboxylic acid group may be replaced by oxygen atoms with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond.

The preferred radicals which can be split off from a hydroxyl group in vivo are ad-7-acyl groups such as formyl, acetyl, n-propionyl, isopropionyl, n-propanoyl, n-butanoyl, n-pentanoyl, n-hexanoyl - or

Cyclohexylcarbonylgruppe or a benzoyl group and also a methoxyacetyl, 1-methoxypropionyl, 2-methoxypropionyl or 2-methoxyethoxyacetyl group into consideration. Those compounds of the general formula I in which A, R ⁴ and / or R ⁵ contain a group which can be converted into a carboxy or hydroxyl group in vivo are prodrugs for those compounds of the general formula I in which A, R ⁴ and / or R ^{5 contains} a carboxy or hydroxyl group.

A 12th embodiment of the present invention comprises those compounds of the general formula I in which

A is a radical of the general formula

or means

in the

m is the number 1 or 2,

R ^8a alkyl- are each independently a hydrogen or fluorine atom or a Cι _-5 alkyl, hydroxy, hydroxy-Cι _-5, d _-5 alkoxy, Cι _-5 -alkoxy-Cι- ₅ -alkyl-, amino-, Cι _-5 -alkylamino-, di- (Cι _-5 -alkyl) -amino-, amino-Cι _-5 -alkyl-, d _-5 -alkylamino-C _1-5 -alkyl- , Di- (-C _-5 -alkyl) -amino -Cι _-5 -alkyl-, aminocarbonyl-, d _-5 -alkylaminocarbonyl-, di- (d _-5 -alkyl) -aminocarbonyl- or Cι _-5 -alkylcarbonylamino group, in the case of the above-mentioned substituted 5- to 7-membered radicals A, the heteroatoms F, O or N optionally introduced with R ^8a as substituents are not separated by exactly one carbon atom from a heteroatom from the group N, O, S, and two substituents R ^8a can represent ad _-5 alkylene group on the same or different carbon atoms,

R ^8b each independently represents a hydrogen atom or a C ₅ alkyl group,

X ^{1 represents} an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8c group,

R ^8c each independently represents a hydrogen atom, a C 5 alkyl, C ₅ alkylcarbonyl, Ci.s alkyloxycarbonyl or d _-5 alkylsulfonyl group,

X ^{3 is} an oxygen or sulfur atom, an -NR ^8c group,

X ^{4 represents} a carbonyl or sulfonyl group,

R ^{1 is} a halogen atom, a d- ₃ alkyl or d _-3 alkoxy group, where the hydrogen atoms of the d _-3 alkyl or C _{3 -3} alkoxy group can optionally be completely or partially replaced by fluorine atoms, a C _2-3 Means alkenyl, C _2-3 alkynyl, nitrile, nitro or amino group,

R ^{2 represents} a hydrogen or halogen atom or a C _{3 -3} alkyl group,

R ^{3 represents} a hydrogen atom or ad _-3 alkyl group, R ⁴ and R ^{5 are} each independently a hydrogen atom, a C _2-6 alkenyl or C _2-6 alkynyl group, a straight-chain or branched de-alkyl group, the hydrogen atoms of the straight-chain or branched C ₆ alkyl group optionally being whole or can be partially replaced by fluorine atoms, and which may optionally be replaced by a C _3-5 cycloalkyl group, a nitrile, hydroxyl, ad ₅ -alkyloxy group, the hydrogen atoms of the Cι- ₅ -AlkyIoxygruppe optionally being completely or partially replaced by fluorine atoms can, an allyloxy, propargyloxy, benzyloxy, Cι- ₅ alkylcarbonyloxy, ds-alkyloxycarbonyloxy, carboxy-d- ₅ -alkyloxy, Cι _-5 -alkyloxycarbonyl-d _-5 -alkyloxy-, mercapto, Cι _-5 -Alkylsulfanyl-, Cι _-5 -alkylsulfonyl-, carboxy-, Ci.s-alkyloxycarbonyl-, aminocarbonyl-, d- ₅ -alkylaminocarbonyl-, di- (Cι _-5 -alkyl) -aminocarbonyl-, C ₃ - ₆ -Cycloalkyleniminocarbonyl-, aminosulfonyl-, -Cι _-5 -AI- kylaminosulfonyl-, di- (Cι _-5 -alkyl) -aminosu lfonyl-, C ₃ - ₆ -cycloalkyleniminosulfonyl-, amino-, d- ₅ -alkylamino-, di- (Cι _-5 -alkyl) -amino-, Cι _-5 -AIkyIcarbonylamino-, d _-5 -alkyl- sulfonylamino-, ^ (ds-Alkylsulfony -Ci-s-alkylamino or C _3-6 cycloalkylcarbonylamino group may be substituted, a carboxy, aminocarbonyl, d _-5 -alkylamino nocarbonyl-, C ₃ . ₆ -cycloalkylaminocarbonyl-, di- (Cι _-5 -alkyl) -aminocarbonyl-, d- ₅ -alkoxycarbonyl-, C _4-6 -cycloalkyleniminocarbonyl group, a phenyl, heteroaryl, phenyl-Cι _-5 -alkyl- or heteroaryl- Ci.s-alkyl group, which in the phenyl or heteroaryl part, optionally one to three times by identical or different substituents selected from the group consisting of halogen atoms, d- ₅ alkyl, di (Cι _-5 alkyl) amino, hydroxy, d _-5 alkyloxy, mono-, di- or trifluoromethoxy ^ carboxy and Ci.s-alkyloxycarbonyl groups can be substituted .

a 3- to 7-membered cycloalkyl, cycloalkylenimino, cycloalkyl- d- ₅ -alkyl or cycloalkylenimino -CC _-3 alkyl group, in which in 4- to 7-membered cycles in the cyclic part a methylene group optionally by a -N (R ^8c ) group, an oxygen or sulfur atom or an -S (O) - or -S (0) - group can be replaced, or in the case of 4- to 7-membered cycles in the cyclic part two adjacent methylene groups together can optionally be replaced by a -C (O) N (R ^8b ) - or -S (O) ₂ N (R ^8b ) group, or in which in the case of 6- to 7-membered cycles in the cyclic part three adjacent methylene groups together optionally by a substituted -OC (O) N (R ^8b ) - or -N (R ^8b ) C (O) N (R ^8b ) - or -N (R ^8b ) S (0) ₂ N (R ^8b ) - Group can be replaced, with the proviso that a 3- to 7-membered cycloalkyl, cycloalkylenimino, cycloalkyl-d _-5 -alkyl or cycloalkylenimino-d- _3- alkyl group, as defined above, in the two heteroatoms from the group Oxygen and stick are separated from each other by exactly one optionally substituted -CH ₂ group, is excluded, with a 3- to 7-membered cycloalkyl-, cycloalkyleneimino-, cycloalkyl-d-5-alkyl- or cycloalkyleneimino-Cι _-3 - as defined above alkyl group on one or two -CH ₂ - groups can be substituted by one or two C _-3 alkyl groups, means or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C _3-8 cycloalkyl or C3-8 cycloalkenyl group, one C _3-8 cycloalkyl or C _4-8 cycloalkenyl group on one single carbon atom can be substituted by a C _2-5 alkylene group or at the same time on two different carbon atoms by a Cι _-4 -AlkyIengruppe to form a corresponding spirocycle or a bridged bicyclus, one of the methylene groups of a C -s-cycloalkyl or C _5-8 - Cycloalkenyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above can be replaced by an oxygen or sulfur atom or an -N (R ^8c ) -, or a carbonyl, sulfinyl or sulfonyl group, and / or two directly adjacent methylene groups of a C _4-8 cycloalkyl group are replaced together by a -C (0) N (R ^8b ) -, - C (O) O or -S (0) ₂ N (R ^8b ) group can be, and / or three directly adjacent meth ylene groups of a C _6-8 cycloalkyl group together by an -OC (0) N (R ^8b ) -, - N (R ^8b ) C (O) N (R ^8b ) - or -N (R ⁸ ) S (0) ₂ N (R ^8b ) group can be replaced, where 1 to 3 carbon atoms of a Cs-s-cycloalkyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above, optionally independently of one another, in each case by one or two fluorine atoms or one or two identical or different d _-5 alkyl, nitrile Hydroxy-, Cι _-5 -Alkyloxy-, d _-5 -Alkylcarbonyloxy-, carboxy-Cι _-5 - alkyl-, -Cι _-5 -AIkyloxycarbonyl-Cι. ₅ alkyl, Cι _-5 alkylsulphanyl, Ci.s-alkylsulfonyl, carboxy, Cι _-5 alkyloxycarbonyl, aminocarbonyl, d _-5 alkylaminocarbonyl, di- (d _-5 alkyl) - aminocarbonyl -, C _3-6 -cycloalkyleneiminocarbonyl-, aminosulfonyl-,

Cι-5-alkylaminosulfonyl-, di- (d- ₅ -alkyl) -aminosulfonyl-, C _3-6 -cycloalkyleniminosulfonyl-, amino-, Cι- ₅ -alkylamino-, di- (Cι- ₅ -alkyl) -amino- , d _-5 -alkylcarbonylamino-, Cι _-5 -AlkyI- sulfonylamino-, / V- (d _-5 -alkylsulfonyl) -Cι _-5 -alkylamino- or C _3-6 -cycloalkylcarbonylamino groups may be substituted,

wherein 1 _3-8 cycloalkenyl optionally substituted independently by a Cι _-5 alkyl, nitrile, carboxy-d- alkyl or 2 carbon atoms of a C _5, Ci- _δ alkyloxycarbonyl-Ci _δ alkyl, carboxy -, d-5-alkyloxycarbonyl, aminocarbonyl,

Cι- ₅ -alkylaminocarbonyl-, di- (Cι- ₅ -alkyl) -aminocarbonyI-, C ₃ - ₆ -cycloalkyleniminocarbonyl-, aminosulfonyl-, Cι- ₅ -alkylaminosulfonyl-, di- (d- ₅ -alkyl) -aminosulfonyl- , C ₃ - ₆ -CycloalkyleniminosulfonyIgruppen may be substituted,

and 1 to 2 carbon atoms of a C _4-8 cycloalkenyl group, which are not bound by a double bond to another carbon atom, optionally independently of one another by one or two fluorine atoms or a hydroxy, Cι _-5 -alkyloxy-, Cι- ₅ -alkylcarbonyloxy -, -Cι _-5 -Alkylsulfanyl-, ds-Alkylsulfonyl-,

Amino-, d _-5 -alkylamino-, di- (Cι. ₅ -alkyl) -amino-, d-5-alkylcarbonylamino-, d _-5 -alkylsulfonylamino-, Λ / - (Cι _-5 -alkylsulfonyl) -Cι _{- 5} alkylamino or C ₃ - ₆ -Cycloalkylcarbonylaminogruppen may be substituted,

with the proviso that such a C ₃ -s-cycloalkyl or C ₃ - ₈ cycloalkenyl group formed together from R ⁴ and R ⁵ or a corresponding spirocycle or a as described above Corresponding bridged bicycles in which two heteroatoms in the cycle from the group oxygen and nitrogen are separated from one another by exactly one optionally substituted -CH ₂ group, and / or in which one or both methylene groups of the cycle which are directly connected to the carbon atom, to which the radicals R ⁴ and R ^{5 are} attached, are replaced by a hetero atom from the group consisting of oxygen, nitrogen and sulfur, and / or in which a substituent is attached to the cyclic group and is distinguished by the fact that a hetero atom from the group Oxygen, nitrogen, sulfur and halogen atom is bonded directly to the cyclic group, is separated from another hetero atom from the group oxygen, nitrogen and sulfur, with the exception of the sulfone group, by exactly one, optionally substituted, methylene group, and / or in the two Oxygen atoms are directly connected to each other, and / or in which a heteroatom from the group oxygen, nitrogen and sulfur is directly connected to a carbon atom which is connected to a further carbon atom by a double bond and / or which contains a cycle with three ring members, one or more of which are oxygen or sulfur atoms or -N (R ^8c ) - Group corresponds, is excluded

R ^{6 represents} a fluorine, chlorine, bromine or iodine atom, a nitrite group, a d- ₃ alkyl group, or a d _-3 alkoxy group, the hydrogen atoms of the C _{3 -3} alkyl or C _{3 -3} alkoxy group entirely or can be partially replaced by fluorine atoms,

R ⁷ independently of one another ad _-3 -alkyl-, where the hydrogen atoms may optionally be replaced in whole or in part by fluorine atoms, hydroxy-, Cι _-3 -alkyloxy-, where the hydrogen atoms may in whole or in part be replaced by fluorine atoms, amino- , Cι _-3 -alkylamino-, di- (Cι _-3 -alkyl) -amino-, C ₃ -6-cycloalkylenimino-, carboxy-, nitrile, Cι-3-alkoxycarbonyl-, aminocarbonyl-, C _1-3 - Represents alkylaminocarbonyl or a di (Cι _-3 alkyl) aminocarbonyl group,

where, unless stated otherwise, the term "heteroaryl group" mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C _1-3 alkyl, phenyl or phenyl C _-3 alkyl group, an oxygen or sulfur atom or an optionally substituted by a C _1-3 alkyl, phenyl, amino-C _2-3 -alkyl-, Cι. ₃ -alkylamino-C _2-3 -alkyl-, di- (Cι _-3 -alkyl) -amino-C ₂ - ₃ -alkyl-, a C _3-6 - cycloalkylenimino-d -3-alkyl or phenyl-d _-3 -alkyl group substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or an imino group optionally substituted by a d _-3 -alkyl or phenyl-Cι _-3 -alkyl group and two or three Contains nitrogen atoms, and also to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms, optionally by a fluorine, chlorine or bromine atom, a C _{3 -3} alkyl, hydroxy, C _{3 -3} alkyloxy group, amino, C _{3 -3} alkylamino , Di- (Cι _-3 -alkyl) - amino- or C _3-6 -cycloalkylenimino group substituted phenyl ring can be fused on and the binding takes place via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,

where the alkyl, alkenyl, alkynyl and alkoxy groups which have more than two carbon atoms and which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the abovementioned dialkylated radicals, for example the dialkylamino groups, can be the same or different,

and where the hydrogen atoms of the methyl or ethyl groups contained in the above-mentioned definitions may, unless otherwise stated, be replaced in whole or in part by fluorine atoms,

A 13th embodiment of the present invention comprises those compounds of the general formula I in which A is a radical of the general formula

or means

in the

m is the number 1 or 2,

R ^8a each independently represent a hydrogen or fluorine atom or a Cι _-5 alkyl, hydroxy, hydroxy-d alkyl _-5, d _-5 alkoxy, Cι- ₅ alkoxy-Cι. ₅ -alkyl-, amino-, -C-5-alkylamino-, di- (C _1-5 -alkyl) -amino-, amino-Cι- ₅ -alkyl-, Cι- ₅ -alkylamino-Cι-5-alkyl- , Di- (d _-5 -alkyl) amino-Cι- ₅ alkyl, aminocarbonyl, d _-5- alkylaminocarbonyl, di- (C _1-5 -alkyl) aminocarbonyl or Ci.s-alkylcarbonylamino group , wherein in the above-mentioned substituted 5- to 7-membered radicals A, the heteroatoms F, O or N optionally introduced with R ^8a as substituents are not separated by exactly one carbon atom from a heteroatom from the group N, O, S, and two Substituents R ^8a on the same or different carbon atoms ad _-5 alkylene group can represent

R ^8b each independently represents a hydrogen atom or a Ci.s-alkyl group,

X ^{1 represents} an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8c group,

R ^8c each independently represents a hydrogen atom, a C _1-5 alkyl, ds-alkylcarbonyl, C _1-5 alkyloxycarbonyl or ds-alkylsulfonyl group,

X ³ is an oxygen atom or an -NR ^8o group,

X ^{4 represents} a carbonyl or sulfonyl group,

R ^{1 is} a fluorine, chlorine, bromine or iodine atom, a C ₃ alkyl or C ₃ alkoxy group, the hydrogen atoms of the C _1-3 alkyl or C ₃ alkoxy group optionally being wholly or partly by Fluorine atoms can be replaced, or means a nitrile group,

R ^{2 represents} a hydrogen or halogen atom or a methyl group,

R ^{3 represents} a hydrogen atom or a methyl group,

R ^{4 is} a C _2-6 alkenyl or C _2-6 alkynyl group, a straight-chain or branched C _1-6 alkyl group, where the hydrogen atoms of the straight-chain or branched d- ₆ alkyl group can optionally be replaced in whole or in part by fluorine atoms , and which may be replaced by a C _3-5 ~ cycloalkyl group, a nitrile, hydroxy, a Cι _-5 -alkyloxy group, where the hydrogen atoms of the d _-5 -alkyloxy group may be replaced in whole or in part by fluorine atoms, a benzyloxy, d- ₅ -alkylcarbonyloxy-, Cι _-5 -alkyloxycarbonyloxy-, carboxy- Cι _-5 -alkyloxy-, Cι _-5 -alkyloxycarbonyl-Cι- ₅ -alkyloxy-, Cι _-5 -alkylsulfanyl-, d- ₅ -alkylsulfonyl-, Carboxy-, C _1-5 -alkyloxycarbonyl-, aminocarbonyl-, d- ₅ -alkylaminocarbonyl-, di- (d _-5 -alkyl) -aminocarbonyl-, C _3-6 -cycloalkyleneiminocarbonyl-, aminosulfonyl-, d _-5- alkylaminosulfonyl -, Di- (Cι- ₅ -alkyl) -aminosulfonyl-, C ₃ - ₆ -cycloalkyleniminosulfonyl-, amino-, Cι- ₅ -alkylamino-, di- (Cι _-5 -alkyl) -amino-, d _-5 - Alkylcarbonylamino-, C _1-5 -alkylsulfonylamino-, or a Λ / - (-Cι _-5 -alkylsulfonyl) - d _-5 -alkylamino group can be substituted,

a carboxy, aminocarbonyl, d _-5 alkylaminocarbonyl, C _3- 6 cycloalkylaminocarbonyl, di- (Cι _-5 alkyl) aminocarbonyl, Cι- ₅ alkoxycarbonyl, C _{4-6-Cycloalkyleniminocarbonylgruppe,}

a phenyl, heteroaryl, phenyl-Cι _-5 -alkyl or heteroaryl-d- ₅ -alkyl group, which in the phenyl or heteroaryl part optionally one to three times selected by the same or different substituents from the group consisting of halogen atoms, d _{- 5} -alkyl-, di- (Cι _-5 -alkyl) -amino-, hydroxy-, -Cι _-5 -alkyloxy, mono-, di- or trifluoromethoxy, carboxy and d- ₅ -alkyloxycarbonyl groups can be substituted,

a 3- to 7-membered cycloalkyl, cycloalkylenimino, cycloalkyl- d- ₅ -alkyl or cycloalkylenimino -CC _-3 alkyl group, in which in 4- to 7-membered cycles in the cyclic part a methylene group optionally by a -N (R ^8c ) group, an oxygen or sulfur atom or an -S (O) - or -S (0) ₂ group may be replaced, or in the case of 4- to 7-membered cycles in the cyclic part two adjacent methylene groups together may optionally be replaced by a -C (O) N (R ^8b ) - or -S (O) ₂ N (R ^8b ) group, or in which in the case of 6- to 7-membered cycles in the cyclic part three adjacent methylene groups together, optionally substituted by one - OC (0) N (R ^8b ) - or -N (R ^8b ) C (0) N (R ^8b ) - or -N (R ^8b ) S (0) ₂ N (R ^8b ) group can be replaced, with the proviso that a 3- to 7-membered cycloalkyl-, cycloalkylenimino-, cycloalkyl-d _-5 -alkyl as defined above - or CycloaIkylenimino-Cι- ₃ alkyl group, in which two heteroatoms from the group oxygen and nitrogen are separated from one another by exactly one optionally substituted -CH ₂ group, is excluded, with a 3- to 7-membered cycloalkyl group as defined above , Cycloalkylenimino-, Cycloalkyl-d _-5 -alkyl- or Cycloalkylenimino- d- ₃ -alkyl group on one or two -CH ₂ groups can each be substituted by one or two Cι- ₃ -alkyl groups, means

R ⁵ is a hydrogen atom, a C _2-6 -alkenyl or C ₂ - ₆ alkynyl group, a linear or branched Cι _-6 alkyl group, wherein the hydrogen atoms are replaced of linear or branched d- ₆ -AIkylgruppe optionally fully or partially substituted by fluorine atoms , and which may optionally be substituted by a d- _5- alkyloxy group, where the hydrogen atoms of the Ci.s-alkyloxy group may optionally be wholly or partly replaced by fluorine atoms, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C _3-8 cycloalkyl or C _3-8 cycloalkenyl group, the Qa-s-cycloalkyl or C. ₈ cycloalkenyl group on one single carbon atom by a C ₂ - ₅ alkylene group or simultaneously to different two carbon atoms by a d-4-alkylene group to form a corresponding spirocyclic or a bridged bicyclic system may be substituted,

wherein one of the methylene groups of a C _{_4-8} cycloalkyl or C _5-8 - cycloalkenyl group or a as described above, corresponding spirocyclic or a corresponding bridged bicyclic by an oxygen or sulfur atom or a -N (R ^8c) -, or a carbonyl or sulfonyl group can be replaced, and / or

two directly adjacent methylene groups of a C _-8 cycloalkyl group together by a -C (0) N (R ^8b ) -, -

C (0) 0 or -S (0) ₂ N (R ^8b ) group can be replaced, and / or

three directly adjacent methylene groups of a Cβ-s-cycloalkyl group together by a -OC (0) N (R ^8b ) -, - N (R ^8b ) C (O) N (R ^8b ) - or

-N (R ^8b ) S (O) ₂ N (R ^8b ) group can be replaced,

where 1 to 3 carbon atoms of a C _3-8 cycloalkyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above, optionally independently of one another, in each case by one or two fluorine atoms or one or two identical or different C ₅ alkyl, Nitrile, hydroxyl, Ci-s-alkyloxy, Cι _-5 -alkylcarbonyloxy-, carboxy-d _-5 - alkyl, Cι _-5 -alkyloxycarbonyl-d _-5 -alkyl-, Cι- ₅ -alkylsulfanyl-, Cι - _5- alkylsulfonyl-, carboxy-, C _1-5 -alkyloxycarbonyl-,

Aminocarbonyl, Cι _-5 -alkylaminocarbonyl-, di- (Cι _-5 -alkyl) - aminocarbonyl-, C ₃ - ₆ -cycloalkyleniminocarbonyl-, aminosulfonyl-, d-5-alkylaminosulfonyl-, di- (C _-5 -alkyl ) -aminosulfonyl-, C _3-6 -Cycloalkyleniminosulfonyl-, Amino-, -Cι _-5 -alkylamino-, Di- (Cι _-5 -alkyl) -amino-, Cι _-5 -Alkylcarbonylamino-, Cι _-5 -AlkyI- sulfonylamino-, or / V ^ ds-AlkylsuIfonyO-ds-alkylamino groups can be substituted,

where 1 to 2 carbon atoms of a C _3-8 cycloalkenyl group optionally independently of one another by ad _-5- alkyl, nitrile, carboxy-d- _5- alkyl, d- ₅ -alkyloxycarbonyl -CC _-5 alkyl, carboxy -, Ci-s-alkyloxycarbonyl-, aminocarbonyl-, Cι- ₅ -alkylaminocarbonyl-, di- (Cι- ₅ -alkyl) -aminocarbonyl-,

C ₃ . _6- cycloalkyleneiminocarbonyl, aminosulfonyl, Ci - ₅ alkylamino nosu If onyl, di (C _{1 -5} alkyl) aminosulfonyl, C ₃ - ₆ cycloalkyleneiminosulfonyl groups can be substituted,

and 1 to 2 carbon atoms of a C ₄ -s-cycloalkenyl group, which are not bound by a double bond to another carbon atom, optionally independently of one another by one or two fluorine atoms or a hydroxy, Cι _-5 -alkyloxy-, d- ₅ -alkylcarbonyloxy -, -Cι _-5 -AlkylsuIfanyl-, Cι- ₅ -Alkylsulfonyl-, Amino-, Cι _-5 -Alkylamino-, Di- (Cι _-5 -alkyl) -amino-

Cι- ₅ -alkylcarbonylamino-, d _-5 -alkylsulfonylamino-, Λ / - (Cι- ₅ -alkylsulfonyl) -Cι- ₅ alkylamino or C _3-6 cycloalkylcarbonylamino groups can be substituted,

with the proviso that those composed of R ⁴ and R ⁵ is C _3-8 cycloalkyl or formed C _{_3-8} cycloalkenyl group or a as described above, a corresponding spirocyclic or a corresponding bridged bicyclic system, in which two heteroatoms are separated from one another in the cycle from the group oxygen and nitrogen by exactly one optionally substituted -CH ₂ group, and / or in which one or both methylene groups of the cycle, which are directly connected to the carbon atom to which the radicals R ⁴ and R ^{5 are} attached, are replaced by a hetero atom from the group consisting of oxygen, nitrogen and sulfur, and / or in which one the cyclic group-bound substituent, which is characterized in that one hetero atom from the group oxygen, nitrogen, sulfur and halogen atom is bonded directly to the cyclic group, from another hetero atom from the group oxygen, nitrogen and sulfur, with the exception of the sulfone group, is separated by exactly one, optionally substituted, methylene group, and / or in which two oxygen atoms are directly connected to one another, and / or in which a heteroatom from the group consisting of oxygen, nitrogen and sulfur is connected directly to a carbon atom which is bonded by a double bond to is connected to a further carbon atom, and / or which contains a cycle with three ring members, of which e one or more of the group corresponding to oxygen or sulfur atom or -N (R ^8c ) group is excluded,

a fluorine, chlorine, bromine or iodine atom, a nitrite group, one

C ₃ alkyl group, or ad ₃ alkoxy group means, where the hydrogen atoms of the C ₃ alkyl or C ₃ alkoxy group may optionally be wholly or partly replaced by fluorine atoms, R ⁷ independently of one another ad _-3 -alkyl-, where the hydrogen atoms can optionally be replaced in whole or in part by fluorine atoms, hydroxy-, Cι- ₃ -alkyloxy-, where- the hydrogen atoms can be replaced in whole or in part by fluorine atoms, amino -, Cι- ₃ -alkylamino-, di- (d _-3 -alkyl) -amino-, C _3-6 -cycloalkylenimino-, carboxy-, nitrile-, d- ₃ -Aikoxycarbonyl-, aminocarbonyl-, C -ι _{- 3} -Alkylaminocarbonyl- or a di- (-C-3-alkyl) -aminocarbonyIgruppe represents

where, unless stated otherwise, the term "heteroaryl group" mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C ₃ alkyl, phenyl or phenyl C ₃ alkyl group, an oxygen or sulfur atom or an optionally substituted by a ₃ alkyl, phenyl, amino C ₂ - ₃ -alkyl-, Cι _-3 -alkylamino-C _2- 3 -alkyl-, di- (Cι _-3 -alkyl) -amino-C _2-3 -alkyl-, a C _3- 6-, cycloalkylenimino-C _-3 -alkyl- or phenyl-Cι _-3 -alkyl group substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or an imino group optionally substituted by a Cι _-3- alkyl or phenyl-C-ι _-3 -alkyl group and two or three Contains nitrogen atoms, and also to the monoc mentioned above yclischen heteroaryl groups over two adjacent carbon atoms one optionally by a fluorine, chlorine or bromine atom, a Cι _-3 alkyl, hydroxy, Cι _-3 alkyloxy group, amino, Cι- ₃ alkylamino, di- (Cι- ₃ -alkyl) - amino or C ₃ - ₆ -Cycloalkyleniminogruppe substituted phenyl ring can be fused and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused phenyl ring,

where the alkyl, alkenyl, alkynyl and alkoxy groups which have more than two carbon atoms and, unless stated otherwise, may be straight-chain or branched and the alkyl groups in the abovementioned dialkylated radicals, for example the dialkylamino groups, contained in the definitions mentioned above , can be the same or different,

A 14th embodiment of the present invention comprises those compounds of the general formula I in which

A is a radical of the general formula

means

in the

m is the number 1 or 2,

R ^8a each independently of one another is a hydrogen or fluorine atom or a -C 3 alkyl, hydroxy, hydroxy C _{3 -3} alkyl, C ₃ alkoxy, C ₃ alkoxy C 3 alkyl , Amino-, d _-3 -alkylamino-, di- (d _-3 -alkyl) -amino-, amino-Cι _-3 -alkyl-, Cι-3-alkylamino-Cι- ₃ -alkyl-, Di ^ ds- alky -amino-ds-alkyl-, aminocarbonyl-, d _-3 -alkylaminocarbonyl-, di- (Cι _-3 -alkyl) -aminocarbonyl- or Cι-3-alkylcarbonylamino group, with the above-mentioned substituted 5- to 7- membered radicals A, the heteroatoms F, O or N, optionally introduced with R ^8a as substituents, are not separated by exactly one carbon atom from a heteroatom from the group N, O, S, and two substituents R ^8a on the same or different carbon atoms are C _{1 -5} Can represent alkylene group,

R ^8b each independently represents a hydrogen atom or a C ₃ alkyl group,

X ^{1 represents} an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8c group,

R ^8c each independently represents a hydrogen atom, a C _-3 alkyl, d _-3 alkylcarbonyl, C _-4 alkyloxycarbonyl or d _-3 alkyl sulfonyl group, X ^{3 is} an oxygen atom or an -NR ^8c group,

X ^{4 represents} a carbonyl or sulfonyl group,

R is a fluorine, chlorine, bromine or iodine atom, a d _-3 alkyl or a C ₃ alkoxy group, the hydrogen atoms of the d _-3 alkyl or C ₃ alkoxy group optionally in whole or in part by fluorine atoms can be replaced

R ^{2 represents} a hydrogen or halogen atom or a methyl group,

R ^{3 represents} a hydrogen atom,

R ^{4 is} a C _2-4 alkenyl or C. ₄ -alkynyl group, a straight-chain or branched C 1 -C alkyl group, it being possible for the hydrogen atoms of the straight-chain or branched C 1 -C alkyl group to be replaced in whole or in part by fluorine atoms, and which may optionally be replaced by a C ₃ - ₅ cycloalkyl group, a nitrile, Hydroxy-, ad _-3 -alkyloxy group, where the hydrogen atoms of the Cι _-3 -alkyloxy group can optionally be wholly or partly replaced by fluorine atoms, a benzyloxy-, -Cι-3-alkylcarbonyloxy-, d _-3 -alkyloxycarbonyl-C-ι- ₃ -alkyloxy-, Cι- ₃ -alkyloxycarbonyl-, aminocarbonyl-, d _-3 -alkylaminocarbonyl-, di- (Cι- ₃ -aikyl) -aminocarbonyl-, C ₃ - ₆ -cycloalkyleniminocarbonyl-, aminosulfonyl-, d- ₃ - Alkylaminosulfonyl-, di- (Cι. ₃ -alkyl) -aminosulfonyl-, C ₃ - ₆ -cycloalkyleniminosulfonyl-, amino-, Cι. ₃ -Alkylamino-, di- (Cι _-3 alkyl) - amino, Cι _-3 alkylcarbonylamino, Cι- ₃ alkylsulfonylamino, or a Λ / - (Cι- ₃ alkylsulfonyl) -Cι _-3 alkylamino group can be substituted, a phenyl, heteroaryl, phenyl -CC ₃ alkyl or heteroaryl d ₃ alkyl group, those in the phenyl or heteroaryl moiety optionally mono- to triple-selected by the same or different substituents selected from the group consisting of halogen atoms, C _{3 -3} alkyl, di (C _{3 -3} alkyl) amino, hydroxy, C _{3 -3} Alkyloxy, mono-, di- or trifluoromethoxy, carboxy and Cι- ₃ alkyloxycarbonyl groups may be substituted,

R ^{5 is} a hydrogen atom, a C _2-4 alkenyl or C _2- alkynyl group, a straight-chain or branched C 1 -C alkyl group, it being possible for the hydrogen atoms of the straight-chain or branched C _{4 -4} alkyl group to be replaced in whole or in part by fluorine atoms , and which may be substituted by a Cι- ₃ alkyloxy group, where the hydrogen atoms of the d- ₃ alkyloxy group may optionally be wholly or partly replaced by fluorine atoms, means, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C _3-8 cycloalkyl or C _3-8 cycloalkenyl group,

.Wherein the C _3- 8 cycloalkyl or C ₄ -8 cycloalkenyl group on a single carbon atom by a C _2-5 alkylene group or simultaneously on two different carbon atoms by a Cι- ₄ alkylene group to form a corresponding spirocycle or one bridged bicyclic may be substituted, wherein one of the methylene groups of a C -s-cycloalkyl or C _5-8 - cycloalkenyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above by an oxygen or sulfur atom or a sulfonyl or -N (R ^8c ) group can be replaced, and or

two directly adjacent methylene groups of a C _{_4-8} cycloalkyl group together by a -C (0) N (R ^8b) -, - C may be replaced (0) 0-, or -S (0) ₂ N (R ^8b) group , and or

three directly adjacent methylene groups of a C _6-8 - cycloalkyl group together by a -OC (0) N (R ^8b ) -, - N (R ^8b ) C (O) N (R ^8b ) - or -N (R ^8b ) S (0) ₂ N (R ^8b ) group can be replaced,

where 1 to 3 carbon atoms of a C _3-8 cycloalkyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above, optionally independently of one another, by ad- ₃ -alkyl-, hydroxy-,

Cι. ₃ -alkyloxy-, Cι-3-alkylcarbonyloxy-, C _1-3 -alkyloxycarbonyl-, amino-, Cι- -alkylamino-, di- (d- ₃ -alkyl) -amino-, d- ₃ -alkylcarbonylamino-, d _-3- alkylsulfonylamino groups can be substituted,

wherein 1 to 2 carbon atoms of a C-8 cycloalkenyl group optionally substituted independently by C ₁ ₃ - may be substituted alkyl group, - ₃

and 1 to 2 carbon atoms of a ds-cycloalkenyl group, which are not bound by a double bond to another carbon atom, optionally independently of one another by a hydroxyl, Cι. ₃ -alkyloxy-, di- (Cι _-3 -alkyl) -amino group can be substituted,

with the proviso that such a C3-8 cycloalkyl or C _3-8 cycloalkenyl group formed together from R ⁴ and R ⁵ or a corresponding spirocycle or a as described above Corresponding bridged bicycles in which two heteroatoms in the cycle from the group oxygen and nitrogen are separated from one another by exactly one optionally substituted -CH ₂ group, and / or in which one or both methylene groups of the cycle which are directly connected to the carbon atom, to which the radicals R ⁴ and R ^{5 are} attached, are replaced by a hetero atom from the group consisting of oxygen, nitrogen and sulfur, and / or in which a substituent is attached to the cyclic group and is distinguished by the fact that a hetero atom from the group Oxygen, nitrogen, sulfur and halogen atom is bonded directly to the cyclic group, is separated from another hetero atom from the group oxygen, nitrogen and sulfur, with the exception of the sulfone group, by exactly one, optionally substituted, methylene group, and / or in the two Oxygen atoms are directly connected to each other, and / or in which a heteroatom from the group oxygen, nitrogen and sulfur is directly connected to a carbon atom which is connected to a further carbon atom by a double bond and / or which contains a cycle with three ring members, one or more of which are oxygen or sulfur atoms or -N (R ^8o ) - Group corresponds, is excluded

R ^{6 represents} a fluorine, chlorine, bromine or iodine atom, a methyl group or a methoxy group, it being possible for the hydrogen atoms of the methyl or methoxy group to be replaced in whole or in part by fluorine atoms,

R ⁷ independently of one another is a C ₃ alkyl, where the hydrogen atoms can optionally be replaced in whole or in part by fluorine atoms, hydroxy, C _{3 -3} alkyloxy, where the hydrogen atoms can be replaced in whole or in part by fluorine atoms, amino , d- ₃ -Alkylamino-, di- (Cι- ₃ -alkyl) -amino-, C _3-6 -cycloalkyleneimino-, carboxy-, nitrile-, Cι-3-alkoxycarbonyl-, aminocarbonyl-, C ι- ₃ - Represents alkylaminocarbonyl or a di (Cι- ₃ alkyl) aminocarbonyl group,

where, unless stated otherwise, the term "heteroaryl group" mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C ₃ alkyl, phenyl or phenyl C ₃ alkyl group, an oxygen or sulfur atom or an optionally substituted by a C ₃ alkyl, phenyl, amino C _2-3 -alkyl-, Cι. ₃ -Alkylamino-C ₂ - ₃ -alkyl-, di- (Cι. ₃ -alkyl) -amino-C _2-3 -alkyl-, a C ₃ - ₆ - cycloalkylenimino-Cι- ₃ - contains alkyl or phenyl-C _{3 -3} -alkyl-substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or an imino group optionally substituted by a C- ₃ -alkyl or phenyl-C _{-3 -3-} alkyl group and two or three nitrogen atoms, and also to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms, optionally by a fluorine, chlorine or bromine atom, a C-ι _-3 -alkyl, hydroxyl, d _-3 -alkyloxy group, amino, Cι _-3 - Alkylamino-, di- (d _-3 -alkyl) - amino- or C _3-6 -cycloalkyleneimino group substituted phenyl ring can be fused on and the binding takes place via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,

A 15th embodiment of the present invention comprises those compounds of the general formula I in which A is a radical of the general formula

, or means

in the

m is the number 1 or 2,

R ^8a each independently of one another a hydrogen or fluorine atom or a d-3-alkyl, hydroxy, hydroxy-Cι _-3 alkyl, d _-3 alkoxy, d-3-alkoxy-d. ₃ -alkyI-, amino-, Cι. ₃ -alkylamino-, di- (C _1-3 -alkyl) -amino-, amino-C ^ s-alkyl-, ds-alkylamino-Ci-s-alkyl-, or di- (Cι _-3 -alkyl) - amino-Cι _-3 -alkyl group means, in the case of the above-mentioned substituted 5- to 7-membered radicals A, the heteroatoms F, O or N optionally introduced with R ^8a as substituents are not replaced by exactly one carbon atom from a heteroatom from the group N, O, S are separated, and two substituents R ^8a on the same or different carbon atoms can represent a C _-5 alkylene group,

R ^8b each independently represents a hydrogen atom or a d- ₃ -alkyl group,

X ¹ is an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8o group, R ^8c each independently represents a hydrogen atom, a C ₃ alkyl, d ₃ alkyl carbonyl group or a C 1 alkyloxycarbonyl group,

X ^{3 is} an oxygen atom or an -NR ^8c group,

X ^{4 represents} a carbonyl group,

R ^{1 represents} a fluorine, chlorine, bromine or iodine atom, a methyl or a methoxy group, where the hydrogen atoms of the methyl or methoxy group can optionally be completely or partially replaced by fluorine atoms,

R ^{2 represents} a hydrogen or fluorine atom or a methyl group,

R ^{3 represents} a hydrogen atom,

R ^{4 is} a C ₂ - alkenyl or C _2- alkynyl group, a straight-chain or branched C _1-4 alkyl group, it being possible for the hydrogen atoms of the straight-chain or branched C _-4 alkyl group to be replaced in whole or in part by fluorine atoms, and which may be replaced by a nitrile, hydroxyl, ad ₃ -alkyloxy group, where the hydrogen atoms of the C ₃ -3 -alkyloxy group may be replaced in whole or in part by fluorine atoms, a benzyloxy, C _1-3 alkylcarbonyloxy-d- ₃ -Alkyloxycarbonyl-, Aminocarbonyl-, C _1-3 -Alkylaminocarbonyl-, Di- (ds-alky -aminocarbonyl-, C ₃ -6-Cycloalkyleniminocarbonyl-, aminosulfonyl-, Cι _-3 -Alkylaminosulfonyh Di- (Cι _-3 -alkyl) -aminosulfonyl-, C ₃ -6-Cycloalkyleniminosulfonyl-, amino-, -Cι _-3 -Alkylamino-, di- (Cι _-3 -alkyl) -, amino-, Cι- ₃ -Alkylcarbonylamino-, or Cι _-3 -Alkylsulfonylamino group substituted may be a phenyl, heteroaryl, phenyl-C-ι alkyl _-3 or heteroaryl d- ₃ -alkyl group, which in the phenyl or heteroaryl part may be selected one to three times by identical or different substituents selected from the group consisting of halogen atoms, C _{3 -3} alkyl-, di- (C ₃ -3 alkyl) amino, Hydroxy, Cι _-3 alkyloxy, mono-, di- and trifluoromethoxy groups can be substituted, means

R is a hydrogen atom, a straight-chain or branched Cι _-4 -alkyl group, where the hydrogen atoms of the straight-chain or branched Cι- alkyl group can optionally be wholly or partly replaced by fluorine atoms, and optionally by a Cι- ₃ alkyloxy group, the hydrogen atoms being the d- ₃ alkyloxy group can optionally be wholly or partly replaced by fluorine atoms, can be substituted, means, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C ₃ -s-cycloalkyl or C _-8 -cycloalkenyl group, the C _3-8 -cycloalkyl or C _-8- cycloalkenyl group on a single Carbon atom can be substituted by a C _2-5 alkylene group or at the same time on two different carbon atoms by a Cι-4 alkylene group to form a corresponding spirocycle or a bridged bicyclus, one of the methylene groups of a C _4-8 cycloalkyl or C ₅ - ₈ - Cycloalkenyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above through an oxygen or sulfur atom or a sulfonyl or -N (R ^8c ) group can be replaced, and / or

two directly adjacent methylene groups of a C _4-8 cycloalkyl group together by a -C (0) N (R ^8b ) -, -

C (O) 0 or -S (0) ₂ N (R ^8b ) group can be replaced, and / or

three directly adjacent methylene groups of a C ₆ -s cycloalkyl group together by one -OC (0) N (R ^8b ) -, - N (R ^8b ) C (O) N (R ^8b ) - or

-N (R ^8b ) S (O) ₂ N (R ^8b ) -Grupρe can be replaced,

wherein 1 to 2 carbon atoms of a C _{_3-8} cycloalkyl group or a like, corresponding spirocyclic or a corresponding bridged bicyclic described above optionally substituted independently from each other by a C ₃ alkyl, hydroxy, d-3-alkyloxy, d _-3 -alkylcarbonyloxy-, d- ₃ -alkyloxycarbonyl-, Cι- ₃ -alkylamino-, di- (d- ₃ -alkyl) -amino-, Cι- ₃ -alkylcarbonylamino-, Cι _-3- alkylsulfonylamino groups can be substituted,

with the proviso that such a C ₃ -s-cycloalkyl or C _4-8 cycloalkenyl group formed together from R ⁴ and R ⁵ or a corresponding spirocycle or a corresponding bridged bicyclus as described above, in which two heteroatoms in the cycle from the group oxygen and nitrogen are separated from one another by exactly one optionally substituted -CH ₂ group, and / or in which one or both methylene groups of the cycle which are connected directly to the carbon atom on which the radicals R ⁴ and R ^{5 are} connected, are replaced by a heteroatom from the group consisting of oxygen, nitrogen and sulfur, and / or in which a substituent bonded to the cyclic group, which is characterized in that a heteroatom from the group oxygen, nitrogen, sulfur and halogen atom is bonded directly to the cyclic group, from another heteroatom from the group oxygen, nitrogen and Sulfur, with the exception of the sulfone group, is separated by exactly one, optionally substituted, methylene group, and / or in which two oxygen atoms are directly connected to one another, and / or in which a heteroatom from the group of oxygen, nitrogen and sulfur is directly connected to a carbon atom which is connected by a double bond to a further carbon atom and / or which contains a cycle with three ring members, one or more of which corresponds to the group oxygen or sulfur atom or -N (R ^8c ) group, is excluded,

R ^7, independently of one another, is a C _-3 alkyl, where the hydrogen atoms can optionally be wholly or partly replaced by fluorine atoms, hydroxy, d _-3 alkyloxy, the hydrogen atoms optionally can be replaced in whole or in part by fluorine atoms, amino, Cι- ₃ alkylamino, di (Cι _-3 alkyl) amino, C ₃ - ₆ cycloalkyleneimino, carboxy nitrile, C _{-3 -3} alkoxycarbonyl -, Aminocarbonyl-, C _1-3 -AkkylaminocarbonyI- or a di- (-C-3-alkyl) -aminocarbonyl group,

where, unless stated otherwise, the term "heteroaryl group" mentioned above in the definitions is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group being one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C ₃ -C ₃ -alkyl, phenyl or phenyl-d _-3- alkyl group, an oxygen or sulfur atom or an optionally substituted by a _{-3 -3-} alkyl, phenyl, amino-C _2-3 -alkyl-, -C-3-alkylamino-C _2-3 -alkyl-, di- (Cι _-3 -alkyl) -amino-C ₂ -3-alkyl-, a C _3-6 - cycloalkylenimino-C-ι- 3-alkyl or phenyl-Cι _-3 -alkyl group substituted imino group or an oxygen or sulfur atom and in addition a nitrogen atom or

^{• contains} an imino group optionally substituted by a d- ₃ -alkyl or phenyl-Cι _-3 -alkyl group and two or three nitrogen atoms, and also to the monocyclic heteroaryl groups mentioned above via two adjacent carbon atoms, one optionally by a fluorine, chlorine or Bromine, a C _-3 alkyl, hydroxy, d ₃ alkyloxy group, amino, d _-3 alkylamino, di (C ₃ alkyl) amino or C ₃ - ₆ cycloalkyleneimino group substituted phenyl ring can be condensed and the bond takes place via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,

where the alkyl, alkynyl and alkoxy groups which have more than two carbon atoms and, unless stated otherwise, can be straight-chain or branched, and the alkyl groups in the above-mentioned dialkylated radicals, for example the dialkylamino groups, are identical or are contained in the abovementioned definitions can be different

and wherein the hydrogen atoms are those mentioned in the above

Unless otherwise stated, definitions containing methyl or ethyl groups can be replaced in whole or in part by fluorine atoms,

A 16th embodiment of the present invention comprises those compounds of the general formula I in which

A is a radical of the general formula

means

in the

m is the number 1 or 2,

R ^8a each independently of one another is a hydrogen or fluorine atom or a C ₃ alkyl, hydroxy, hydroxy C 3 alkyl, d ₃ alkoxy, C 1. ₃ -alkoxy-Cι- ₃ -alkyl-, amino-, Cι _-3 -alkylamino-, di- (Cι _-3 -alkyl) -amino-, amino-d-3-alkyl-, -Cι _-3 -alkylamino-Cι , ₃ -alkyl- _> di- (Cι _-3 -alkyl) -amino-Cι _-3 alkyl group means, in the case of the above-mentioned substituted 5- to 7-membered radicals A, the heteroatoms F optionally introduced with R ^8a as substituents, O or N are not separated by exactly one carbon atom from a hetero atom from the group N, O, S, and two substituents R ^8a on the same or different carbon atoms can represent a C _-5 alkylene group,

R ^{8b represents} a hydrogen atom or a C _-3 alkyl group,

X ^{1 represents} an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8c group,

R ^8c each independently represent a hydrogen atom, a Cι _-3 alkyl, d- ₃ alkylcarbonyl, or a C _1-4 alkyloxycarbonyl group,

X ^{3 is} an oxygen atom or an -NR ^8c group,

X ^{4 represents} a carbonyl group,

R ^{1 is} a fluorine, chlorine, bromine or iodine atom, a methyl or a Means methoxy group, where the hydrogen atoms of the methyl or methoxy group can optionally be completely or partially replaced by fluorine atoms,

R ^{2 represents} a hydrogen or fluorine atom,

R ^{3 represents} a hydrogen atom,

R ^{4 is} a straight-chain or branched C 1 -C alkyl group, where the hydrogen atoms can optionally be replaced in whole or in part by fluorine atoms, and which may optionally be replaced by a hydroxyl group, a d-3-alkyloxy group, the hydrogen atoms in the C _1-3 alkyloxy group entirely or can be partially replaced by fluorine atoms, a benzyloxy, Cι- ₃ -alkylcarbonyloxy-, C _1-3 -alkyloxycarbonyl, aminocarbonyl, Cι _-3 -alkylaminocarbonyl-, di- (d _-3 -alkyl) -aminocarbonyl-, C3- ₆ -Cycloalkyleniminocarbonyl-, aminosulphonyl, d _-3 -AI- kylaminosulfonyl-, di- (Cι _-3 alkyl) -aminosulfonyl-, C _3-6 -Cycloalkyleniminosulfonyl-, amino, Cι- ₃ alkylamino, Di- (d _-3 -alkyl) - amino-, C _1-3 -alkylcarbonylamino-, or Cι _-3- alkylsulfonylamino group may be substituted, a heteroaryl-Cι _-2 alkyl or C-linked heteroaryl group, the heteroaryl group being selected from the group consisting of pyrrolyl, oxazolyl, imidazolyl, furanyl, thiophenyl, thiazolyl, 1, 2,3-triazo lyl, 1, 2,4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl and pyrazinyl, and those in the heteroaryl part optionally selected one to two times by identical or different substituents selected from the group consisting of halogen atoms, d _-3 -alkyl-, hydroxy-, C _1-3 alkyloxy, mono-, di- and trifluoromethoxy groups can be substituted, means

R ^{5 is} a hydrogen atom, a straight-chain or branched C 1 -C alkyl group, where the hydrogen atoms can optionally be replaced in whole or in part by fluorine atoms, and which can optionally be replaced by a d- ₃ -alkyloxy group, the hydrogen atoms in the d- _3- alkyloxy group optionally being completely or partially replaced by fluorine atoms may, may be substituted, means, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C _3-7 cycloalkyl or C _-7 cycloalkenyl group, the C _3-7 cycloalkyl or C _4-7 cycloalkenyl group on one single carbon atom can be substituted by a C _2-5 alkylene group or at the same time on two different carbon atoms by a C-ι- alkylene group to form a corresponding spirocycle or a bridged bicyclus, one of the methylene groups being a C _-7 cycloalkyl or C4 ₇ - cycloalkenyl group or one, a corresponding spirocyclic as described above or a corresponding bridged bicyclic group may be replaced by an oxygen or sulfur atom or a sulfonyl or -N (R ^8G) group, and / or two directly adjacent methylene groups a C _4-8 cycloalkyl group together can be replaced by a -C (0) N (R ^8b ) - or - C (0) O group, 1 to 2 carbon atoms being one or a corresponding spirocycle or a corresponding bridged bicyclus as described above, optionally independently of one another, by a d-3-alkyl, hydroxy, d- ₃ -alkyloxy-, di- (d _-3 -alkyl) -amino group can be substituted,

with the proviso that a C those composed of R ⁴ and R ⁵ formed ₃ -7-cycloalkyl or C _-7 cycloalkenyl or a as described above, a corresponding spirocyclic or a corresponding bridged bicyclic system in which one of the methylene groups Cycles which are directly connected to the carbon atom to which the radicals R ⁴ and R ^{5 are} attached are replaced by a heteroatom from the group consisting of oxygen, nitrogen and sulfur, and / or in which a substituent attached to the cyclic group, the is characterized in that a hetero atom from the group oxygen and nitrogen is bonded directly to the cyclic group, is separated from another hetero atom from the group oxygen, nitrogen and sulfur, with the exception of the sulfone group, by exactly one, optionally substituted, methylene group, and / or in which a heteroatom from the group consisting of oxygen, nitrogen and sulfur is directly connected to a carbon atom which is connected by a double bond g is connected to a further carbon atom, and / or which contains a cycle with three ring members, one or more of which corresponds to the group oxygen or sulfur atom or -N (R ^8c ) group,

is excluded, r- or bromine means Unless otherwise stated, the term "halogen atom" mentioned above in the definitions means an atom from the group fluorine, chlorine, bromine and iodine,

A 17th embodiment of the present invention comprises those compounds of the general formula I in which

A is a radical of the general formula

in the

m is the number 1 or 2,

R ^8a each independently of one another is a hydrogen or fluorine atom or a C _-3 alkyl, hydroxy, hydroxy C _{3 -3} alkyl, C ₃ alkoxy, C 3 alkoxy C 1. 3-alkyl, amino, Cι _-3 alkylamino, di- (Cι _-3 alkyl) -amino, amino-Cι _-3 alkyl, Cι _-3 alkylamino-d _-3 alkyl, Di- (-C ₃ alkyl) -C _-3 alkyl group means, in the case of the above-mentioned substituted 5- to 7-membered radicals A, the heteroatoms F, O or N optionally introduced with R ^8a as substituents are not by exactly a carbon atom is separated from a hetero atom from the group N, O, S,

R ^{8b represents} a hydrogen atom or ad _-3 alkyl group,

X ^{1 represents} an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8c group,

R ^{8c represents} a hydrogen atom, ad _-3 -alkyl-, d _-3 -alkylcarbonyl-, or a Cι- -alkyloxycarbonyl group,

X ^{3 represents} an oxygen atom or an -NR ^8c group,

R ^{1 represents} a chlorine or bromine atom, a methyl, trifluoromethyl or a methoxy group,

R ^{2 represents} a hydrogen or fluorine atom,

R ^{3 represents} a hydrogen atom,

R ^{4 is} a methyl group which may optionally be substituted by a hydroxy, methoxy, benzyloxy, methoxycarbonyl or pyridin-4-yl group, or represents a furan-2-yl, 1-methyl-pyrazin-3-yI, phenyl, pyridin-3-yl or pyrazin-2-yl group,

R ^{5 represents} a hydrogen atom or a methyl group, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached, a C ₃ - ₆ cycloalkyl, or form a C _5- 6-cycloalkenyl group, wherein the C ₃ -6 cycloalkyl or C ₅ -6-cycloalkenyl group of a single carbon atom can be substituted by a C _2-4 alkylene group or at the same time on two different carbon atoms by a Cι _-3 alkylene group to form a corresponding spirocycle or a bridged bicyclus, one of the methylene groups of a C _4-6 cycloalkyl- or C ₅ -β- cycloalkenyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above can be replaced by an oxygen atom or an -N (R ^8c ) group, with the proviso that such a group, consisting of R ^4, and R ⁵ is C _3-6 cycloalkyl or formed C ₅ - ₆ cycloalkenyl group or a as described above, a corresponding spirocyclic or a corresponding bridged bicyclic system in which one of the methylene groups Cycl us, which are directly connected to the carbon atom to which the radicals R ⁴ and R ^{5 are} attached, are replaced by a hetero atom from the group consisting of oxygen and nitrogen, and / or in which a hetero atom from the group consisting of oxygen and Nitrogen is directly connected to a carbon atom which is connected by a double bond to a further carbon atom and / or which contains a cycle with three ring members, one or more of which corresponds to the group oxygen atom or -N (R ^8c ) group is

R ^{6 represents} a chlorine or bromine atom

where the alkyl and alkoxy groups contained in the above-mentioned definitions, which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the above-mentioned dialkylated radicals, for example the dialkylamine groups, are the same or different could be,

An 18th embodiment of the present invention includes those

Compounds of general formula I according to embodiments 9, 10, 11, 12, 13, 14, 15, 16 or 17, in which R ⁴ and R ^{5 are} not hydrogen. A 19th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, in which R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclic group which is defined as in the 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th or 18th embodiment.

A 20th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, in which R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclic group, each as in the 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th or 19th embodiment is defined, in the case of the cyclic group a methylene group being replaced by an oxygen atom or an N (R ^8c ) group.

A 21st embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19, in which R ⁴ and R ⁵ together with the The carbon atom to which they are attached form a cyclic group which, as in the 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th or 19th embodiment described by corresponding substitution represents a bridged bicyclus or a spirocyclic group.

A 22nd embodiment of the present invention includes those

Compounds of the general formula I according to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, in which R ⁴ and R ⁵ together with the carbon atom to which they are attached, a cyclic group

'^' or

represents. A 23rd embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, in which R ⁴ and R ⁵ together with the carbon atom to which they are attached is a bridged bicyclic group

represents.

A 24th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23, in which the rest A the group

means.

A 25th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23, in which the rest A the group

means. A 26th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 in which R ^{6 represents} a bromine atom.

A 27th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 in which R ^{6 represents} a chlorine atom.

A 28th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 , 26 or 27, in which R ^{1 represents} a fluorine, chlorine or bromine atom or a methyl or trifluoromethyl group.

A 29th embodiment of the present invention comprises those compounds of the general formula I corresponding to embodiments 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 , 26 or 27 in which R ^{1 represents} a hydrogen atom.

For example, the following preferred compounds of general formula I are mentioned:

(1) 5-chloro-thiophene-2-carboxylic acid Λ / - {(1?) - 2-benzyloxy-1 - [3-chloro-4- (4-methyl- [1,4] diazepan-1-yl ) phenylcarbamoyl) ethyl} -amide,

(2) 5-chloro-thiophene-2-carboxylic acid Λ / - {1 - [3-bromo-4- (4-methyl-piperazin-1 - yl) phenylcarbamoyl] ethyl} amide, (3) 5 -Chlorothiophene-2-carboxylic acid Λ / - {(1 ft) -1- [3-chloro-4- (4-methyl-. [1, 4] diazepan-1-yl) phenylcarbamoyl] -2- hydroxy-ethyl} -amide, (4) 5-bromo-thiophene-2-carboxylic acid Λ / - {(1?) - 2-benzyloxy-1 - [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) -phenylcarbamoyl] -ethyl} -amide, 5) 5-Bromo-thiophene-2-carboxylic acid / V- {1 - [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) -phenylcarbamoyl] -1-methyl-ethyl } amide,

6) 5-chloro-thiophene-2-carboxylic acid Λ / - {1 - [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) -phenylcarbamoyl] -1-methyl-ethyl } amide,

7) 5-bromo-thiophene-2-carboxylic acid Λ / - {1- [3-chloro-4- (morpholin-4-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide,

8) 5-chloro-thiophene-2-carboxylic acid Λ / - {1- [3-methyl-4- (morpholin-4-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide,

9) 5-Bromo-thiophene-2-carboxylic acid / V - {(1 F?) - 1 - [3-chloro-4- (morpholin-4-yl) - phenylcarbamoyl] -2-methoxy-ethyl} -amide , 5-Bromo-thiophene-2-carboxylic acid Λ / - {1- [3-chloro-4- (pyrazolidin-1-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide, 5-chloro-thiophene- 2-carboxylic acid / V- {1 - [3-methyl-4- (pyrazolidin-1-yl) phenylcarbamoyl] -1-methyl-ethyl} -amide, 5-bromo-thiophene-2-carboxylic acid / V- ^{(1?) - 1- [3-chloro-4- (pyrazolidin-1-yl) - phenylcarbamoyl] -2-methoxy-ethyl} -amide, 5-bromo-thiophene-2-carboxylic acid-Λ / - { 1- [3-chloro-4- (tetrahydropyridazin-1-yl) -phenylcarbamoyl] -1-methyl-ethyl} -amide, 5-chloro-thiophene-2-carboxylic acid Λ / - {1- [3-methyl- 4- (tetrahydropyridazin-1-yl) -phenylcarbamoyl] -1-methyl-ethyl} -amide, 5-bromo-thiophene-2-carboxylic acid / V - {(1 f?) - 1 - [3-chloro-4 - (tetrahydropyridazin-1-yl) -phenylcarbamoyl] -2-methoxy-ethyl} -amide, 5-bromo-thiophene-2-carboxylic acid Λ / - {1- [3-chloro-4- (2-methyl-tetrahydropyridazine -1-yl) -phenylcarbamoyl] -1-methyl-ethyl} -amide, 5-chloro-thiophene-2-carboxylic acid Λ / - {1- [3-methyl-4- (2-methyl-tet rahydropyridazin-1-yl) -phenylcarbamoyl] -1-methyl-ethyl} -amide, 5-bromo-thiophene-2-carboxylic acid / V - {(1 f?) - 1 - [3-chloro-4- (2 -methyl-tetrahydropyridazin-1-yl) -phenylcarbamoyl] -2-methoxy-ethyl} -amide, 5-bromo-thiophene-2-carboxylic acid / V- {1- [3-chloro-4 - ([1, 2 ] oxazinan-2-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide, 5-chloro-thiophene-2-carboxylic acid Λ / - {1 - [3-methyl-4 - ([1, 2] oxazinan -2-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide, 5-bromo-thiophene-2-carboxylic acid Λ / - {(1 f?) - 1 - [3-chloro-4 - ([1 , 2] oxazinan-2- yl) -phenylcarbamoyl] -2-methoxy-ethyl} -amide,

(22 5-bromo-thiophene-2-carboxylic acid / V- {1- [3-chloro-4 - ([1, 2] oxazepan-2-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide,

(23 5-chloro-thiophene-2-carboxylic acid / V- {1- [3-methyl-4 - ([1, 2] oxazeρan-2-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide,

(24 5-Bromo-thiophene-2-carboxylic acid / V - {(1 R) -1 - [3-chloro-4 - ([1, 2] oxazepan-2-yl) -phenylcarbamoyl] -2-methoxy- ethyl} amide,

(25 5-Bromo-thiophene-2-carboxylic acid / V- {1 - [3-chloro-4- (2-oxopiperazin-4-yl) phenylcarbamoyl] ethyl} amide, (26 5-bromo -thiophene-2-carboxylic acid / V- {1- [3-chloro-4- (tetrahydro-pyridazin-3- on-1-yl) phenylcarbamoyl] ethyl} amide,

(27 5-Bromo-thiophene-2-carboxylic acid / V- {1- [3-bromo-4- (4-methyl- [1, 4] diazepan-1-yl) -phenylcarbamoyl] -1-methyl-ethyl } amide,

(28 5-Bromo-thiophene-2-carboxylic acid / V- {1- [3-trifluoromethyl-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl] -1-methyl-ethyl } amide,

(29 5-Bromo-thiophene-2-carboxylic acid Λ / - {1 - [3-trifluoromethoxy-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl] -1-methyl-ethyl } amide,

(30 5-chloro-thiophene-2-carboxylic acid Λ / - {1 - [3-trifluoromethyl-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl] -1-methyl-ethyl } -amide, (31 5-chloro-thiophene-2-carboxylic acid- / V - {(1 ^/:) - 1- [3-methyl-4- (4-methyl- [1, 4] diazepan-1-? yl) -phenylcarbamoyl] -3-methylsulfanyl-propyl} -amide,

(32 5-chloro-thiophene-2-carboxylic acid - - {1- [3-methyl-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl] -1-phenylmethyl} - amide,

(33 5-chloro-thiophene-2-carboxylic acid Λ / - {1- [3-methyl-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl] -1- [pyridine- 3-yl] methyl} -amide,

(34 5-chloro-thiophene-2-carboxylic acid Λ / - {1- [3-methyl-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl] -2- [imidazole- 4-yl] -ethyl} -amide,

(35 5-chloro-thiophene-2-carboxylic acid Λ / - {1- [3-methyl-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl] -3- (dimethylaminocarbonyl) -propyl} - amide,

(36 5-bromo-thiophene-2-carboxylic acid Λ / - {1-methyl- [3-methyl-4- (2,5-dimethyl-pyrrolidin-1-yl) phenylcarbamoyl] ethyl} amide,

(37; 5-bromo-thiophene-2-carboxylic acid Λ / - {1- [3-methyl-4- (2,6-dimethyl-piperidine- 1-yl) -phenylcarbamoyl] -cyclopentyl} -amide,

(38) 5-Bromo-thiophene-2-carboxylic acid Λ / - {4- [3-methyl-4- (2,6-dimethyl-piperidin-1-yl) phenylcarbamoyl] tetrahydropyran-4-yl} - amide,

(39) 5-Bromo-thiophene-2-carboxylic acid Λ / - {1-methyl-4- [3-methyl-4- (2,6-dimethyl-morpholin-4-yl) phenylcarbamoyl] piperazin-4 yl} amide,

(40) 5-Bromo-thiophene-2-carboxylic acid Λ / - {3- [3-chloro-4- (2,2-dimethyl-pyrrolidin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} - amide,

(41) 5-Chloro-thiophene-2-carboxylic acid Λ / - {1 - [3-chloro-4- (4-methyl- [1, 4] diazepan- 1-yl) phenylcarbamoyl] ethyl} amide , (42) 5-chloro-thiophene-2-carboxylic acid / V - {(1 R) -1- [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl ] -2-phenyl-ethyl} -amide,

(43) 5-chloro-thiophene-2-carboxylic acid Λ / - {1 - [3-chloro-4- (3-oxopiperazin-1-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide,

(44) 5-bromo-thiophene-2-carboxylic acid Λ / - {1 - [3-chloro-4- (3-oxopiperazin-1-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide,

(45) 5-chloro-thiophene-2-carboxylic acid Λ / - {1- [3-chloro-4- (morpholin-4-yl) phenylcarbamoyl] ethyl} amide,

(46) 5-chloro-thiophene-2-carboxylic acid Λ / - {1 - [4- (4-methyl- [1, 4] diazepan-1-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide , (47) 5-Bromo-thiophene-2-carboxylic acid Λ / - {1- [4- (4-methyl- [1, 4] diazepan-1-yl) - phenylcarbamoyl] -1-methyl-ethyl} - amide,

(48) 5-chloro-thiophene-2-carboxylic acid Λ / - {4- [3-chloro-4- (4-methyl- [1, 4] diazepan- 1-yl) phenylcarbamoyl] tetrahydropyran-4- yl} -amide,

(49) 5-Bromo-thiophene-2-carboxylic acid Λ / - {4- [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl] tetrahydropyran-4- yl} -amide,

(50) 5-chloro-thiophene-2-carboxylic acid / V - {(1 f?) - 1 - [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) -phenylcarbamoyl ] -1-methyl-2-phenyl-ethyl} -amide,

(51) 5-Bromo-thiophene-2-carboxylic acid Λ / - {(1 fl) -1 - [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) -phenylcarbamoyl] -1-methyl-2-phenyl-ethyl} -amide, (52) 5-bromo-thiophene-2-carboxylic acid Λ / - {1 - [4- (2,5-dimethyl-pyrrolidin-1-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide, (53) 5-chloro-thiophene-2-carboxylic acid / V- {1 - [4- (2,5-dimethyl-pyrrolidin-1-yl) phenylcarbamoyl] -1-methyl-ethyl} -amide, (54 5-Bromo-thiophene-2-carboxylic acid Λ / - {1 - [3-chloro-4- (4-methyl- [1, 4] diazepan- 1 -yl) -phenylcarbamoyl] -cyclopent-1 -yl } amide,

(55 5-Bromo-thiophene-2-carboxylic acid / V- {1- [3-methyl-4- (4-acetyl- [1, 4] diazepan-1-yl) -phenylcarbamoyl] -cyclopent-1-yl } amide,

(56 5-chloro-thiophene-2-carboxylic acid Λ / - {1-methyl-1 - [4- (4-methyl-piperazin-1 - yl) phenylcarbamoyl] ethyl} amide,

(57 5-chloro-thiophene-2-carboxylic acid Λ- {1- [3-chloro-4- (morpholin-4-yl) phenylcarbamoyl] -1-methyl-ethyl} -amide,

(58 5-chloro-thiophene-2-carboxylic acid / V- {1 - [4- (4-methyl-piperazin-1-yl) phenylcarbamoyl] ethyl} amide,

(59 5-Bromo-thiophene-2-carboxylic acid / V- {3- [3-methyl-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} amide .

(60; 5-chloro-thiophene-2-carboxylic acid / V- {3- [3-methyl-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} - amide,

(61 5-chloro-thiophene-2-carboxylic acid / V- {2- [4- (2-methyl-tetrahydro-pyridazin-1-yl) phenylcarbamoyl] bicyclo [2.2.1] hept-2-yl} amide,

(62 5-Chloro-thiophene-2-carboxylic acid / V- {3- [3-chloro-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} amide .

(63 5-chloro-thiophene-2-carboxylic acid V- {3- [3-bromo-4- (2-methyltetrahydropyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} amide,

(64 5-chloro-thiophene-2-carboxylic acid Λ / - {3- [3-fluoro-4- (2-methyltetrahydropyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} amide .

(65 5-Chlorothiophene-2-carboxylic acid / V- {3- [3-trifluoromethyl-4- (2-methyltetrahydro-pyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} amide .

(66 5-chloro-thiophene-2-carboxylic acid / V- {3- [4- (2-methyl-tetrahydro-pyridazin-1-yl) phenylcarbamoyI] tetrahydrofuran-3-yl} amide,

(67; 5-chloro-thiophene-2-carboxylic acid / V- {2- [3-methyl-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl] bicyclo [2.2.1] hept -2-yl} -amide,

(68 5-chloro-thiophene-2-carboxylic acid / V- {2- [3-methyl-4- (2-methyl-tetrahydropyridazin-1-yl) -phenylcarbamoyl] -7-oxa-bicyclo [2.2. 1] hept-2-yl} amide,

(69 5-chloro-thiophene-2-carboxylic acid / V- {3- [3-methyl-4 - ([2-methyl- [1, 2] diazepan-1-yl) phenylcarbamoyl] tetrahydrofuran-3- yl} -amide,

(70 5-chloro-thiophene-2-carboxylic acid / V- {3- [3-methyl-4- (5-methyl [1, 4,5] oxadiazepan-4-yl) -phenylcarbamoyl] -tetrahydrofuran-3-yl} -amide, (71) 5-bromo-thiophene-2-carboxylic acid Λ / - {3- [4- (5th -methyi- [1, 4,5] oxadiazepan-4-yl) -phenylcarbamoyl] -tetrahydrofuran-3-yI} -amide,

their tautomers, their enantiomers, their diastereomers, their mixtures and their salts, the compounds

(I) 5-chloro-thiophene-2-carboxylic acid Λ / - {(1?) - 2-benzyloxy-1- [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl ) -phenylcarbamoyl) -ethyl} -amide, (2) 5-chloro-thiophene-2-carboxylic acid Λ / - {1- [3-bromo-4- (4-methyl-piperazin-1-yl) -phenylcarbamoyl] ethyl} amide,

(3) 5-chloro-thiophene-2-carboxylic acid / V - {(1 f?) - 1 - [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl ] -2-hydroxy-ethyl} amide,

(4) 5-bromo-thiophene-2-carboxylic acid Λ / - {(1 f?) - 2-benzyloxy-1 - [3-chloro-4- (4-methyl- [1, 4] diazepan-1- yl) -phenylcarbamoyl] -ethyl} -amide,

(5) 5-Bromo-thiophene-2-carboxylic acid Λ / - {1 - [3-chloro-4- (4-methyl- [1, 4] diazepan- 1 -yl) -phenylcarbamoyl] -1 -methyl- ethyl} amide,

(6) 5-chloro-thiophene-2-carboxylic acid Λ / - {1 - [3-chloro-4- (4-methyl- [1, 4] diazepan- 1 -yl) -phenylcarbamoyl] -1 -methyl- ethyl} -amide, (7) 5-bromo-thiophene-2-carboxylic acid Λ / - {1 - [3-chloro-4- (morpholin-4-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide .

(8) 5-Bromo-thiophene-2-carboxylic acid Λ / - {1- [3-trifluoromethyl-4- (4-methyl- [1, 4] diazepan-1-yl) -phenylcarbamoyl] -1-methyl- ethyl} amide,

(9) 5-chloro-thiophene-2-carboxylic acid / V- {1 - [3-trifluoromethyl-4- (4-methyl- [1, 4] diazepan-1-yl) -phenylcarbamoyl] -1-methyl- ethyl} amide,

(10) 5-chloro-thiophene-2-carboxylic acid / V- {1 - [3-chloro-4- (4-methyl- [1, 4] diazepan- 1-yl) phenylcarbamoyl] ethyl} amide .

(II) 5-chloro-thiophene-2-carboxylic acid / V - {(1 f?) - 1 - [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl ] -2-phenyl-ethyl} -amide, (12) 5-chloro-thiophene-2-carboxylic acid Λ / - {1- [3-chloro-4- (3-oxopiperazin-1-yl) phenylcarbamoyl ] -1-methyl-ethyl} -amide, (13) 5-bromo-thiophene-2-carboxylic acid / V- {1 - [3-chloro-4- (3-oxopiperazin-1-yl) phenylcarbamoyl ] -1-methyl-ethyl} -amide, (14 5-chloro-thiophene-2-carboxylic acid / V- {1- [3-chloro-4- (morpholin-4-y!) Phenylcarbamoyl] ethyl} amide,

(15 5-chloro-thiophene-2-carboxylic acid Λ / - {1 - [4- (4-methyl- [1, 4] diazepan-1-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide,

(16 5-bromo-thiophene-2-carboxylic acid / V- {1 - [4- (4-methyl- [1, 4] diazepan-1-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide,

(1 5-chloro-thiophene-2-carboxylic acid- V- {4- [3-chloro-4- (4-methyl- [1, 4] diazepan- 1-yl) phenylcarbamoyl] tetrahydropyran-4-yl} amide,

(18 5-bromo-thiophene-2-carboxylic acid Λ- {4- [3-chloro-4- (4-methyl- [1, 4] diazepan- 1-yl) phenylcarbamoyl] tetrahydropyran-4-yl} amide,

(19 5-Chloro-thiophene-2-carboxylic acid Λ / - {(1 / ϊ?) - 1- [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) -phenylcarbamoyl ] -1-methyl-2-phenyl-ethyl} -amide,

(20 5-Bromo-thiophene-2-carboxylic acid Λ / - {(1 f?) - 1 - [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) -phenylcarbamoyl] -1-methyl-2-phenyl-ethyl} -amide, (21 5-bromo-thiophene-2-carboxylic acid Λ / - {1- [4- (2,5-dimethyl-pyrrolidin-1-yl) phenylcarbamoyl ] -1-methyl-ethyl} -amide,

(22 5-chloro-thiophene-2-carboxylic acid Λ / - {1 - [4- (2,5-dimethyl-pyrrolidin-1-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide,

(23 5-Bromo-thiophene-2-carboxylic acid Λ / - {1- [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) -phenylcarbamoyl] -cyclopent-1-yl } amide,

(24 5-Bromo-thiophene-2-carboxylic acid Λ / - {1- [3-methyl-4- (4-acetyl- [1, 4] diazepan-1-yl) -phenylcarbamoyl] -cyclopent-1-yl } amide,

(25 5-chloro-thiophene-2-carboxylic acid Λ- {1-methyl-1 - [4- (4-methyl-piperazin-1 - yl) phenylcarbamoyl] ethyl} amide, (26 5-chloro thiophene-2-carboxylic acid Λ- {1- [3-chloro-4- (morpholin-4-yl) phenylcarbamoyl] -1-methyl-ethyl} -amide,.

(27 5-chloro-thiophene-2-carboxylic acid / V- {1- [4- (4-methyl-piperazin-1-yl) phenylcarbamoyl] ethyl} amide,

(28 5-Bromo-thiophene-2-carboxylic acid Λ / - {3- [3-methyl-4- (2-methyltetrahydropyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} amide .

(29 5-Chloro-thiophene-2-carboxylic acid Λ / - {3- [3-methyl-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} amide .

(30 5-chloro-thiophene-2-carboxylic acid / V- {3- [4- (2-methyl-tetrahydro-pyridazine- 1 -yl) -phenylcarbamoyl] -tetrahydrofuran-3-yl} -amide,

(31) 5-chloro-thiophene-2-carboxylic acid Λ / - {2- [3-methyl-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl] bicyclo [2.2.1] hept -2-yl} -amide,

(32) 5-chloro-thiophene-2-carboxylic acid Λ / - {2- [3-methyl-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl] -7-oxa-bicyclo [2.2 .1] hept-2-yl} -amide,

(33) 5-chloro-thiophene-2-carboxylic acid Λ / - {3- [3-methyl-4- (5-methyl- [1, 4,5] oxadiazepan-4-yl) phenylcarbamoyl] tetrahydrofuran 3-yl} -amide,

(34) 5-Bromo-thiophene-2-carboxylic acid / V- {3- [4- (5-methyl- [1, 4,5] oxadiazepan-4-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} -amide, (35) 5-bromo-thiophene-2-carboxylic acid Λ / - {1 - [3-chloro-4- (2-methyltetrahydropyridazin-1-yl) phenylcarbamoyl] -1-methyl-ethyl} amide,

(36) 5-Chlorothiophene-2-carboxylic acid / V- {1- [3-methy) -4- (2-methyltetrahydropyridazin-1-yl) phenylcarbamoyl] -1-methylethyl} amide .

(37) 5-Bromo-thiophene-2-carboxylic acid / V - {(1?) - 1 - [3-chloro-4- (2-methyltetrahydropyridazin-1-yI) phenylcarbamoyl] -2-methoxy- ethyl} amide,

(38) 5-bromo-thiophene-2-carboxylic acid / V- {1- [3-chloro-4- (2-oxopiperazin-4-yl) phenylcarbamoyl] ethyl} amide,

(39) 5-Bromo-thiophene-2-carboxylic acid / V- {3- [3-chloro-4- (2,2-dimethyl-pyrrolidin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} - amide, (40) 5-chlorothiophene-2-carboxylic acid / V- {3- [3-chloro-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl } amide,

(41) 5-chloro-thiophene-2-carboxylic acid Λ / - {3- [3-bromo-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} - amide,

(42) 5-chloro-thiophene-2-carboxylic acid Λ / - {3- [3-fluoro-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} - amide,

(43) 5-chloro-thiophene-2-carboxylic acid / V- {3- [3-trifluoromethyl-4- (2-methyltetrahydro-pyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} - amide,

(44) 5-chloro-thiophene-2-carboxylic acid - / - {3- [3-methyl-4 - ([2-methyl- [1, 2] diazepan-1-yl) phenylcarbamoyl] tetrahydrofuran-3 yl} amide,

their tautomers, their enantiomers, their diastereomers, their mixtures and their salts are particularly preferred. According to the invention, the compounds of the general formula I are obtained by processes known per se, for example by the following processes:

(a) To prepare a compound of the general formula

in which A and R ¹ to R ^{3 are defined} as mentioned in claim 1:

1) Representation of a compound of general formula (II) in which R ^{3 represents} a hydrogen atom and A, R and R ^{2 are defined} as mentioned in claim 1:

i) reduction of the nitro group of a compound of the general formula (III)

in which A, R ¹ and R ^{2 are defined} as mentioned in claim 1:

The reduction of the nitro group is advantageously carried out, for example, in a solvent or solvent mixture such as water, aqueous ammonium chloride solution, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, acetic anhydride with base metals such as iron, zinc, tin or sulfur compounds such as ammonium sulfide, sodium sulfide or Sodium dithionite or by catalytic hydrogenation with hydrogen, for example under a pressure between 0.5 and 100 bar, but preferably between 1 and 50 bar, or with hydrazine as a reducing agent, advantageously in the presence of a catalyst such as Raney nickel, palladium-carbon, platinum oxide, platinum on mineral fiber or rhodium, or with complex hydrides such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, diisobutyl aluminum hydride, advantageously in a solvent or solvent mixture such as water, methanol, ethanol, isopropanol, pentane, hexane, cyclohexane, heptane, benzene, toluene, xylene, ethyl acetate, methyl propionate , Glycol dimethyl ether, diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, Λ-methylpyrrolidinone, or else / V-ethyl-diisopropylamine, / V-Cι _-5 -alkylmorpholine, Λ / -Cι _-5 -alkylpiperidine, Λ / -C _1-5 -alkylpyrrolidine Triethylamine, pyridine, for example at temperatures between -30 and 250 ° C, preferred However, between 0 and 150 ° C, carried out.

The compounds of the general formula (III) can be obtained as follows:

a) Nucleophilic substitution with a compound of the general formula

A - H (IV), in which A is defined as mentioned in claim 1, on the aromatic of the general formula

in which R ¹ and R ^{2 are defined} as mentioned in claim 1. The nucleophilic substitution is advantageously carried out in a solvent or solvent mixture such as ethanol, isopropanol, benzene, chlorobenzene, toluene, xylene, glycol, glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformamide, / V-methylpyrrolidinone, tetralin, dimethyl sulfoxide, sulfolane or methylene chloride, chloroform, chloroform -Ethyl- diisopropylamine, Λ / -Cι. ₅ -Alkylmorpholin, Λ / -Cι- ₅ -alkylpiperidine, Λ / -Cι- ₅ -alkylpyrrolidine, triethylamine, pyridine, for example at temperatures between -30 and 250 ° C, but preferably between 0 and 150 ° C, optionally appropriately in the presence of bases such as potassium carbonate, sodium carbonate, potassium ferf-butoxide, sodium ethanolate, potassium hexamethyldisilazane, sodium hydride or lithium diisopropylamide.

b) transition metal-catalyzed coupling reaction of a compound of the general formula

in which R ¹ and R ^{2 are defined} as mentioned in claim 1 and Z ^{1 represents} a chlorine, bromine or iodine atom or a triflate group.

The reaction is advantageously carried out in a solvent or solvent mixture such as benzene, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether, fer-butyl methyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, N- Methyl pyrrolidinone, tetralin, dimethyl sulfoxide, methylene chloride, chloroform or carbon tetrachloride, for example at temperatures between -30 and 250 ° C, but preferably between 0 and 150 ° C, advantageously in the presence of transition metal catalysts such as nickel on activated carbon, palladium carbon, tetrakis (triphenylphosphine ) palladium (0), tris (dibenzylideneacetone) dipalladium (O), palladium (II) acetate, palladium (II) chloride, bis (triphenylphoshin) - palladium (II) chloride, bis (tricyclohexylphosphine) palladium (II) chloride, bis (triethylphosphine) palladium (II) chloride, bis (tri-o-tolylphosphine) palladium (II) chloride, optionally in the presence of ligands such as triphenylphosphine, tri-σ-tolylphosphine, Tri-tert.-butylphosphine, 1,3-bis (diphenylphosphino) propane, 2,2'-bis (diphenylphosphino) -1, 1'-dinaphthyl, 1,1'-bis (diphenylphosphino) ferrocene, Xantphos, and expediently in the presence of a base such as sodium methoxide, sodium ethanolate, sodium tert-butoxide, potassium f ert.-butylate, sodium-ready-butyldimethyl-silanoate, potassium hexamethyldisilazane, lithium diisopropylamide, potassium carbonate, rubidium carbonate, cesium carbonate, potassium phosphate, sodium hydride, optionally in the presence of a complexing agent such as 18-crown-6-ether and expediently using an inert gas atmosphere (for example nitrogen or argon) and optionally carried out under pressure.

c) Nucleophilic substitution with a compound of the general formula

in which Y ^{1 represents} a hydroxyl, amino, hydrazino or thiol function optionally blocked by a corresponding protective group and n represents a number between 0 and 4, on the aromatic of the general formula

in which R ¹ and R ^{2 are defined} as mentioned in claim 1, and subsequent ring closure by reaction with a compound of the general formula

in the Z ² a carboxylic acid or sulfonic acid protective group such as methyl or tert-butyl groups and Z ³ a nucleofugic leaving groups such as chlorine, bromine or iodine atoms or triflate, mesylate or tosylate groups, E the carbonyloxy or sulfonyloxy group and n a number represents between 0 and 4, wherein individual methylene groups can be substituted as described in claim 1 or replaced by optionally substituted heteroatoms or other groups.

The initial nucleophilic aromatic substitution of (V) with (VII) is carried out, for example, as described under (a) 1) i) a).

The subsequent alkylation of the resulting compound with the compound of general formula (VIII) is advantageously carried out in a solvent or solvent mixture such as benzene, chlorobenzene, toluene, xylene, glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformamide, N-methylpyrrolidinone, tetralin, dimethyl sulfoxide, sulfolane, methylene chloride , Chloroform, carbon tetrachloride, Λ / -ethyl-diisopropylamine, Λ / -Cι _-5 alkylmorpholine, Λ / -Cι-5-alkylpiperidine, Λ / -Cι. _5- alkylpyrrolidine, triethylamine, pyridine, for example at temperatures between -30 and 250 ° C, but preferably between 0 and 150 ° C, advantageously in the presence of bases such as pyridine, triethylamine, p-dimethylaminopyridine, potassium carbonate, sodium carbonate, potassium terf. -butylate, sodium methoxide, sodium ethanolate or basic ion exchanger.

Where appropriate, the deblocking of the nucleophilic group Y ¹ and the protective group Z ² by methods known from the literature or how generally described below.

A ring closure by intramolecular acylation / sulfonylation is expediently carried out in a solvent or solvent mixture such as benzene, chlorobenzene, toluene, xylene, glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformamide, N-methylpyrrolidinone, tetralin, dimethylsulfoxide, sulfolane, tetrachloro-chloroform diisopropylamine, Λ / -Cι _-5 alkylmorpholine, Λ / -Cι _-5 alkylpiperidine, Λ / -d _-5 alkylpyrrolidine, triethylamine, pyridine, for example at temperatures between -30 and 250 ° C, but preferably between 0 and 150 ° C, expediently achieved in the presence of bases such as pyridine, triethylamine, p-dimethylaminopyridine, potassium carbonate, sodium carbonate, potassium te / t-butoxide, sodium methoxide, sodium ethoxide or basic ion exchanger.

ii) Transition metal-catalyzed coupling reaction of a compound of the general formula

The reaction is advantageously carried out in a solvent or solvent mixture such as benzene, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether, te / t-butyl methyl ether, ethylene glycol dimethyl ether, Diethylene glycol dimethyl ether, sulfolane, dimethylformamide, N-methylpyrrolidinone, tetralin, dimethyl sulfoxide, methylene chloride, chloroform or carbon tetrachloride, for example at temperatures between -30 and 250 ° C, but preferably between 0 and 200 ° C, advantageously in the presence of transition metal catalysts such as tetrakis (triphenylphosphine) - palladium (O), tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate, palladium (II) chloride, bis (tripheylphoshin) palladium (II) chloride, bis (tricyclohexylphosphine) palladium (II) chloride, bis (triethylphosphine) palladium (II) chloride, bis (tri-o-tolylphosphine) palladium (II) chloride, optionally in the presence of ligands such as triphenylphosphine, tri-o- tolylphosphine, tri-ferf.butylphosphine, 1,3-bis (diphenylphosphino) propane, 2,2'-bis (diphenylphosphino) -1, 1 'dinaphthyl, 1,1' bis (diphenylphosphino) - ferrocene, xantphos, or for example in the presence of a transition metal catalyst such as copper (I) iodide, copper r (l) -bromide or copper (l) -acetate and expediently in the presence of a base such as tetramethylguanidine, tetramethylethylenediamine or Λ /, / V'-dimethylethylenediamine and expediently in the presence of a base such as sodium methoxide, sodium ethanolate, sodium tert-butoxide, Potassium finished.-butylate, sodium ferf.-butyldimethyl-silanoate, potassium hexamethyldisilazane, lithium diisopropylamide, potassium carbonate, rubidium carbonate, cesium carbonate, potassium phosphate,

Sodium hydride, optionally carried out in the presence of a complexing agent such as 18-crown-6-ether and expediently using an inert gas atmosphere (for example nitrogen or argon) and optionally under pressure.

iii) Ring closure metathesis of a compound of the general formula

in which R ¹ and R ^{2 are defined} as described in claim 1, Z ^{7 is} an optionally substituted amino group or the nitro group, E is a bond or a methylene, iminocarbonyl or imino group which is optionally substituted in accordance with the description mentioned in claim 1 or an oxygen atom where I and o independently of one another represent identical or different numbers between 1 and 3 which, for example, by a sequence of nucleophilic substitution according to (a) 1) i) a) and alkylation according to (a) 1) i) b) described procedure can be obtained with appropriate reagents or other methods known from the literature, optionally followed by reduction, if Z ^{7 represents} a nitro group, according to the procedure described under (a) 1) i).

The ring closure by metathesis reaction is expediently carried out in a solvent or solvent mixture such as benzene, chlorobenzene, toluene, xylene, methanol, ethanol, propanol, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformamide, Λ / - Methylpyrrolidinone, tetralin, dimethyl sulfoxide, sulfolane, methylene chloride, chloroform, carbon tetrachloride, pyridine, in the presence of a catalyst such as benzylidene-bis (tricyclohexylphosphine) dichloro-ruthenium (Grubbs 1st generation catalyst) or benzylidene [1, 3-bis ( 2,4,6-trimethylphenyl) -2-imidazolidinylidene] dichloro (tricyclohexylphosphine) ruthenium (2nd generation Grubbs catalyst), for example at temperatures between -30 and 250 ° C, but preferably between 0 and 150 ° C, appropriately carried out under an inert gas atmosphere, for example argon. The cyclic systems obtained in this way contain a double bond, which by hydrogenation with hydrogen, advantageously in a solvent or solvent mixture such as methanol, ethanol, propanol, ethyl acetate, propyl formate, tetrahydrofuran, dioxane, an / -Methylmorpholin, Λ / -Methylpyrrolidin, triethylamine, Acetic acid, formic acid, Λ /, Λ / -dimethylformamide or diethyl ether and expediently in the presence of a catalyst such as Raney nickel, palladium-carbon, platinum, platinum oxide or rhodium on mineral fiber for example at temperatures between -10 and 250 ° C, but preferably between 0 and 150 ° C, can be converted into a saturated cyclic compound, optionally with simultaneous reduction of any nitro group present as R ⁷ , or by a suitable addition reaction or an epoxidation, for example with

Dimethyldioxirane, m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide in the presence of catalytic amounts of metal oxides such as tungsten oxide or stereosiectively with fe / t-butyl hydroperoxide in the presence of (R, R) - or (S, S) - tartaric acid diethyl ester and titanium (IV) isopropoxide with the following Epoxy opening with suitable nucleophiles and optionally subsequent derivatization of the resulting hydroxyl groups, advantageously in a solvent or solvent mixture such as water, acetone, ethyl formate, ethyl acetate, tert-butyl methyl ether, dichloromethane, chloroform, carbon tetrachloride, formic acid or acetic acid at temperatures between -40 and 150 ° C, preferably between -15 and 90 ° C can be further derivatized to the configurations described in claim 1.

iv) Hetero-Diels-Alder reaction of a compound of the general formula

in which R ¹ and R ^{2 are defined} as described in claim 1, Z ^{7 represents} an optionally substituted amino group blocked by a protective group or the nitro group, which can be obtained, for example, by oxidation of an aniline, for example with potassium peroxodisulfate, using processes known from the literature a compound of the general formula

in which R ^8a and m are defined as described in claim 1, optionally followed by reduction, if Z ^{7 represents} a nitro group, according to the procedure described under (a) 1) i), or cleavage of a protective group which may be present.

The ring closure by hetero-Diels-Alder reaction is expediently carried out in a solvent or solvent mixture such as methanol, ethanol, propanol, diethyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformamide, N-methylpyrrolidinone, tetralin, Dimethyl sulfoxide, sulfolane, methylene chloride, chloroform, carbon tetrachloride, pyridine, optionally in the presence of a catalyst such as aluminum trichloride, boron trifluoride, zinc chloride, titanium (IV) chloride, lithium perchlorate, ytterbium (III) triflate or chloro-trimethylsilane, for example at temperatures between -30 and 250 ° C, but preferably between -10 and 150 ° C. The cyclic systems obtained in this way contain a double bond which can be further derivatized analogously to the processes described under (a) 1) iii).

2) Representation of a compound of the general formula (II) in which R ^{3 is} a d- ₃ -alkyl group and A and R ¹ to R ^{3 are defined} as mentioned in claim 1:

Reductive amination of a compound of the general formula (II) in which R ^{3 represents} a hydrogen atom and A and R ¹ to R ^{3 are defined} as mentioned in claim 1:

The reaction with the corresponding R ³ aldehyde (formaldehyde or paraformaldehyde for R ³ methyl, acetaldehyde or paraldehyde for R ³ ethyl, propionaldehyde for R ³ propyl) is advantageously carried out in a solvent or solvent mixture such as methanol, ethanol, propanol, isopropanol, Butanol, tetrahydrofuran, dioxane, diethyl ether, te / ϊ.-butyl methyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, sulfolane, Dimethylformamide, / V-methylpyrrolidinone, tetralin, dimethyl sulfoxide, methylene chloride, chloroform or carbon tetrachloride, for example at temperatures between -30 and 250 ° C, but preferably between -10 and 150 ° C, optionally in the presence of a base such as sodium methoxide, sodium ethanolate, sodium te / t-butoxide, potassium te / t-butoxide, sodium terf.-butyldimethyl silanoate, potassium hexamethyldisilazane, lithium diisopropylamide, potassium carbonate, rubidium carbonate, cesium carbonate, potassium phosphate, sodium hydride, optionally in the presence of a complexing agent such as 18-crown-6-ether carried out, followed by reduction of the resulting imide by hydrogenation with hydrogen, for example under a pressure between 0.5 and 100 bar, but preferably between 1 and 50 bar, advantageously in the presence of a catalyst such as Raney nickel, palladium-carbon, platinum oxide, platinum on mineral fiber or rhodium, or with complex hydrides such as lithium aluminum hydride, Na trium borohydride, sodium cyanoborohydride, diisobutyl aluminum hydride, for example at temperatures between -30 and 250 ° C, but preferably between 0 and 150 ° C.

(b) To prepare a compound of the general formula

in which A and R "1 b: is" D R6 ^{D are defined} as mentioned in claim 1:

1) Acylation of a compound of the general formula where Z ^{8 represents} a protective group for the carboxyl function which can subsequently be cleaved off by processes known from the literature, and A and R ¹ to R ^{5 are defined} as mentioned in claim 1, where (XIV) is obtained according to the procedure described under (b) 2) can be, with a carboxylic acid or a reactive carboxylic acid derivative of the general formula

in which R ^{6 is defined} as mentioned in claim 1 and Q represents a hydroxy or -CC alkoxy group, a halogen atom or an acyloxy group.

The acylation is conveniently carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, sodium hydroxide solution or sulfolane, optionally in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.

However, the acylation can also be carried out with the free acid, if appropriate in the presence of an acid-activating agent or a dehydrating agent, for example in the presence of Isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, Λ /, / V-dicyclohexylcarbodiimide, / V, / V-dicyclohexyl-carbodiimide / 1-V / dehydroxy-hydroxydimide / 1-benzodydroxy-1 / V-dicyclohexyl-carbodiimide / 1-benzodydroxy-1 / V-carbonyldiimidazole, 0- (benzotriazol-1-yl) -Λ /, / V, / V, Λr-tetramethyl uronium tetrafluoroborate / methylmorpholine, 0- (benzotriazol-1-yl) -Λ /, Λ /, / V, / V- tetramethyl-uronium tetrafluoroborate // V-ethyldiisopropylamine, O- pentafluorophenyl-Λ /, Λ /, Λ / ', Λ / -tetramethyluronium-hexafluorophosphate triethylamine, Λ /, Λ /' - thionyldiimlorkosphole / tripyl tetrachloride or tripyl at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.

2) Acylation of a compound of the general formula

in which A and R ¹ to R ^{3 are defined} as mentioned in claim 1,

with a carboxylic acid or a reactive carboxylic acid derivative of the general formula

(XVII), or (XVIII),

in which R ⁴ to R ^{6 are defined} as mentioned in claim 1, Q is a hydroxy or C 1 alkoxy group, a halogen atom or an acyloxy group and Z ^{6 represents} a protective group which can subsequently be split off by processes known from the literature, it being possible to obtain (XVIII) by the procedure described under (b) 1).

The acylation can be carried out analogously to that described under (b) 1).

However, the acylation can also conveniently be carried out in a solvent or solvent mixture such as dichloromethane, trichloromethane, benzene, chlorobenzene, toluene, xylene, hexamethyldisiloxane, acetonitrile,, / -ethyl-diisopropylamine, Λ / -C _1-5 -alkylmorpholine, Λ / -C _{1 -5-} alkylpiperidine, Λ / -C _-5 - alkylpyrrolidine, triethylamine, pyridine, in the presence of 4-trifluoromethylbenzoic acid anhydride, silver triflate and titanium (IV) chloride, advantageously in the presence of a dehydrating agent such as molecular sieve, sodium sulfate, magnesium sulfate, or in the presence of 4-trifluoromethyl-benzoic anhydride and ytterbium (III) triflate, water being able to be added to the solvent mixture, for example at temperatures between -30 and 250 ° C, but preferably between 0 and 150 ° C (I Shiina, M. Miyashita, M. Nagai, T. Mukaiyama; Heterocycles 1995, 40 (1), 141-148.).

Other methods for amide coupling are described, for example, in P.D. Bailey, I.D. Collier, K.M. Morgan in "Comprehensive Functional Group Interconversions", vol. 5, page 257ff., Pergamon 1995.

In the reactions described above, any reactive groups present, such as hydroxyl, carboxy, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups which are split off again after the reaction. For example, the protective radical for a hydroxyl group is the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group, as protective residues for a carboxyl group, the trimethylsilyl, methyl, ethyl, ferf.butyl, benzyl or tetrahydropyranyl group and

as a protective radical for an amino, alkylamino or imino group, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, te / t.-butoxycarbonyl,

Benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and, in addition, the phthalyl group for the amino group.

Further protecting groups and their splitting off are in T.W. Greene, P.G.M. Wuts, "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999.

The subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by means of ether cleavage, e.g. B. in the presence of iodotrimethylsilane, at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl residue is split off, for example by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide,

Dimethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ° C., but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 1 to 5 bar.

A methoxybenzyl group can also be split off in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile at temperatures between 0 and 50 ° C, but preferably at room temperature.

A methoxy group is advantageously eliminated in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between -35 and -25 ° C.

However, a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.

A finished butyl or te / t-butoxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.

A phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene water or dioxane at temperatures between 20 and 50 ° C.

An allyloxycarbonyl radical is split off by treatment with a catalytic amount of tetrakis (triphenylphosphine) palladium (0), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100 ° C, preferably at room temperature and under inert gas, or by treatment with a catalytic amount of tris (triphenylphosphine) rhodium (l) chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo [2.2. 2] octane at temperatures between 20 and 70 ° C.

Furthermore, the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.

For example, the compounds of general Formula I, which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of the general formula I with at least two asymmetrical ones Due to their physicochemical differences, carbon atoms can be separated into their diastereomers by methods known per se, for example by chromatography and / or fractional crystallization, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.

The separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative obtained in this way, e.g. due to different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids are e.g. the D and L forms of tartaric acid or dibenzoyl tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Suitable optically active alcohols are, for example, (+) - or (-) - menthol, and optically active acyl radicals in amides are, for example, the (+) - or (-) - menthyloxycarbonyl radicals.

Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids. Examples of suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. In addition, the new compounds of formula I thus obtained, if they contain a carboxy group, can then optionally be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts. Suitable bases here are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

As already mentioned in claim 1, the compounds of the general formula I and their tautomers, their enantiomers, their diastereomers and their physiologically tolerable salts have valuable pharmacological properties, in particular an antithrombotic action, which is preferably based on an action which influences thrombin or factor Xa, for example on a thrombin-inhibiting or factor Xa-inhibiting effect, on an effect which prolongs the aPTT time and / or on an inhibiting effect on related serine proteases such as, for. B. urokinase, factor VIIa, factor IXa, factor Xla and factor Xlla.

The compounds listed in the experimental part were examined for their effect on the inhibition of factor Xa as follows:

Methodology:

Enzyme kinetic measurement with a chromogenic substrate. The amount of p-nitroaniline (pNA) released from the colorless chromogenic substrate by human factor Xa is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used. The inhibition of enzyme activity (relative to the solvent control) is determined by the test substance concentrations of test substance at different therefrom and the IC ₅ o calculated as the concentration which inhibits the factor Xa used by 50%.

Material: Tris (hydroxymethyl) aminomethane buffer (100 mmol) and sodium chloride (150 mmol), pH 8.0 plus 1 mg / ml Human Albumin Fraction V, protease-free

Factor Xa (Calbiochem), specific activity: 217 lU / mg, final concentration: 7 lU / ml per reaction mixture

Substrate S 2765 (Chromogenix), final concentration: 0.3 mM / l (1 KM) per reaction mixture

Test substance: final concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 μmol / l

Procedure: 10 μl of a 23.5-fold more concentrated starting solution of the test substance or solvent (control), 175 μl TRIS / HSA buffer and 25 μl factor Xa working solution of 65.8 U / L are incubated for 10 minutes at 37 ° C. After adding 25 μl of S 2765 working solution (2.82 mmol / L), the sample is measured in a photometer (SpectraMax 250) at 405 nm for 600 seconds at 37 ° C.

Evaluation:

1. Determination of the maximum increase (deltaOD / minutes) over 21 measuring points.

2. Determination of the% inhibition based on the solvent control.

3. Create a dose-response curve (% inhibition vs substance concentration). ,

4. Determination of the IC ₅₀ by interpolation of the X value (substance concentration) of the dose-response curve with Y = 50% inhibition.

All the compounds tested had IC ₅ o-values less than 100 mol / L are.

The compounds prepared according to the invention are generally well tolerated.

Due to their pharmacological properties, the new compounds and their physiologically tolerable salts are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as, for example, the prevention and treatment of deep vein thrombosis, the prevention of reocclusion after bypass surgery or angioplasty (PT ( C) A), as well as occlusion in peripheral arterial diseases, as well as prevention and treatment of pulmonary embolism, disseminated intravascular coagulation and severe sepsis, prevention and prophylaxis of DVT in patients with exacerbation of COPD, treatment of uicerative colitis, prophylaxis and treatment of coronary thrombosis, prophylaxis of stroke, and prevention of occlusion of shunts.

In addition, the compounds according to the invention are for antithrombotic support in thrombolytic treatment, such as, for example, with alteplase, reteplase, tenecteplase, staphylokinase or streptokinase, for preventing long-term restenosis after PT (C) A, for the prophylaxis and treatment of ischemic incidents in patients of all forms coronary heart disease, to prevent metastasis and growth of tumors and inflammatory processes, e.g. suitable for the treatment of pulmonary fibrosis, for the prophylaxis and treatment of rheumatoid arthritis, for the prevention or prevention of fibrin-dependent tissue adhesions and / or scar tissue formation and for the promotion of wound healing processes.

Because of their pharmacological properties, the new compounds and their physiologically tolerable salts are also suitable for the treatment of Alzheimer's and Parkinson ^'s diseases. A rational this results, for example, from the following findings, from which it can be concluded that thrombin inhibitors or factor Xa inhibitors, by inhibiting thrombin formation or activity, could represent valuable medicaments in the treatment of Alzheimer's and Parkinson ^'s disease. Clinical and experimental studies suggest that neurotoxic mechanisms, for example the inflammation associated with the activation of proteases in the coagulation cascade, are involved in the death of neurons as a result of brain trauma. Various studies indicate that thrombin is involved in neurodegenerative processes, for example as a result of a stroke, repeated bypass surgery or traumatic brain injuries. For example, increased thrombin activity could still be demonstrated days after peripheral nerve injury. It has also been shown that thrombin causes neurite retraction, as well as glia proliferation and apoptosis in primary cultures of neurons and neuroblastoma cells (for an overview, see: Neurobiol. Aging 2004, 25 (6), 783-793). In addition, various in vitro studies on the brains of patients with Alzheimer's disease indicate that thrombin plays a role in the pathogenesis of this disease (Neurosci. Lett. 1992, 146, 152-54). Enrichment of immunoreactive thrombins has been demonstrated in neurite plaques in the brains of Alzheimer's patients. It has been shown in vitro that thrombin also plays a role in the regulation and stimulation of the production of the "amyloid precursor protein" (APP) and in the cleavage of the APP into fragments which are detected in the amyloid plaques in the brain of Alzheimer's patients can. Furthermore it could be shown that thrombin-induced microglial activation leads to degeneration of nigral dopaminergic neurons in vivo. These findings lead to the conclusion that microglial activation - triggered by endogenous substance (s) such as thrombin - is involved in the neuropathological process of cell death of dopaminergic neurons, as occurs in patients with Parkinson ^'s disease (J. Neurosci. 2003, 23 , 5877-86).

The dosage required to achieve an appropriate effect is expediently in the case of intravenous administration 0.01 to 3 mg / kg, preferably 0.03 to 1.0 mg / kg, and in the case of oral administration 0.03 to 30 mg / kg, preferably 0.1 to 10 mg / kg, in each case 1 to 4 times a day.

For this purpose, the compounds of formula I prepared according to the invention, optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin,

Incorporate water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxy methyl cellulose or fatty substances such as hard fat or their suitable mixtures into conventional galenical preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.

The new compounds and their physiologically tolerable salts can be used therapeutically in combination with acetylsalicylic acid, with platelet aggregation inhibitors such as fibrinogen receptor antagonists (for example abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of the coagulation system and their recombinant analogs, for example C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (e.g. clopidogrel, ticlopidine), with P ₂ T receptor antagonists (e.g. Cangrelor) or with combined thromboxane receptor antagonists / synthetase inhibitors (e.g. Terbogrel).

The following examples are intended to explain the invention in more detail, but without restricting its scope:

Experimental part

As a rule, melting points, IR, UV, ¹ H-NMR and / or mass spectra are available for the compounds produced. Unless otherwise stated, R _f values were determined using ready-made silica gel 60 F ₂₅₄ TLC plates (E. Merck, Darmstadt, Item No. 1.05714) without chamber saturation. The R _f values determined under the name Alox were determined using ready-made aluminum oxide 60 F ₂₅ TLC plates (E. Merck, Darmstadt, Item No. 1.05713) without chamber saturation. The Rf values determined under the name Reversed-Phase-8 were determined using ready-made RP-8 F ₂₅ 4s DC plates (E. Merck, Darmstadt, Article No. 1.15684) without chamber saturation. The ratios given for the flow agents relate to volume units of the respective solvents. Silica gel from Millipore (MATREX ™, 35-70 μm) was used for chromatographic purifications. If further details on the configuration are missing, it remains open whether it is pure stereoisomers or enantiomer / diastereomer mixtures.

The following abbreviations are used in the test descriptions:

Boc terf.-butoxycarbonyl

DIPEA Λ / -Ethyl-diisopropylamine

DMSO dimethyl sulfoxide

DMF / V, / V-dimethylformamide sat. saturated h hour (s)

HATU 0- (7-azabenzotriazol-1-yl) -Λ /, Λ /, Λ ', Λ / -tetramethyluronium' hexafluorophosphate i. Vak. in a vacuum conc. Concentrated min minute (s)

NMM Λ / -Methyl morpholine

NMP / V-methyl-pyrrolidin-2-one

0 ortho

PfTU 0-pentafluorophenyl- / V, Λ /, Λ / ', / V-tetramethyluronium hexafluorophosphate PPA propanephosphonic acid cycloanhydride quant. quantitatively

Rf retention factor

Rt retention time rac. Race mixed

TBTU 0- (benzotriazol-1-yl) -Λ /, / V, / V, / V-tetramethyluronium tetrafluoroborate

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran tert. tertiary

Σ Yield across all stages described analogously

The HPLC / MS data for Examples 24 through 26 were generated under the following conditions:

(a) HP1 00 HPLC + diode array detector with Waters ZQ2000 mass spectrometer and Gilson 215 autosampler

The mobile phase used was: A: water with 0.1% TFA B: acetonitrile with 0.1% TFA

Time in min% A% B flow rate in ml / min 0.0 95 5 1.00

0.4 95 5 1.00

4.0 2 98 1.00

4.35 2 98 1.00

4.5 95 5 1.00

A Waters X-Terra ™ MS Cι ₈ 3.5 m, 4.6 mm x 50 mm column was used as the stationary phase (column temperature: constant at 40 ° C)

The diode array detection was carried out in the wavelength range 210-500 nm Range of mass spectrometric detection: m / z 120 to m / z 1000

The HPLC data of the other examples were generated under the following conditions as far as indicated:

(b) Waters ZMD, Alliance 2695 HPLC, Waters 2700 Autosampier, Waters

996 diode array detector

The following was used as the mobile phase:

A: Water with 0.13% TFA

B: Acetonitrile with 0.10% TFA

Time in min% A% B flow rate in ml / min

0.0 95 5 1.00

0.7 95 5 1.00

5.2 2 98 1.00

5.7 2 98 1.00

6.0 95 5 1.00

6.5 95 5 1.00

A Varian column, Microsorb 100 Cι ₈ 3 μm, 4.6 mm x 50 mm, batch no. 2231108 (column temperature: constant at 25 ° C) served as the stationary phase.

example 1

5-chloro-thiophene-2-carboxylic acid / V - {(1 F?) - 2-benzyloxy-1 - [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) - phenylcarbamoyl) ethyl} -amide

(a) 3-Chloro-4- (4-methv 1, 4ldi zepan-1-yl) -1-nitro-benzene

2.00 g (11.4 mmol) of 3-chloro-4-fluoro-1-nitro-benzene are mixed in 20 ml of DMSO with stirring at room temperature with 1.42 ml (11.4 mmol) of 1-methyl- [1, 4] diazepane for 2 hours heated to 90 ° C and stirred for 16 hours at room temperature. After narrowing i. Vak. the residue is mixed with water, the precipitate is filtered off, dissolved in ethyl acetate, dried over sodium sulfate and i. Vak. grown on silica gel. The residue is purified by chromatography on silica gel (eluent gradient: dichloromethane / methanol = 95: 5 → 70:30). Yield: 2.77 g (90%)

R _f value: 0.17 (silica gel; dichloromethane / methanol = 95: 5) Cι ₂ H ₁₆ CIN ₃ 0 ₂ (269.73) mass spectrum: (M + H) ⁺ = 270/272 (chlorine isotopes)

(b) 3-Chloro-4- (4-methyl-H, 41diazepan-1 -vO-aniline

1.00 g (3.71 mmol) of 3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) -1-nitro-benzene are mixed with 370 mg of Raney nickel in 75 ml of ethyl acetate and in a Parr - Apparatus hydrogenated at room temperature for 1.5 h at 50 psi hydrogen pressure. The Raney nickel is then filtered off and the filtrate i. Vak. concentrated. The residue is purified by chromatography on silica gel

(Eluent gradient: dichloromethane / methanol = 90:10 -> 0: 100).

Yield: 630 mg (71%) R _f value: 0.14 (silica gel; dichloromethane / methanol = 9: 1)

Cι ₂ Hι ₈ CIN ₃ (239.74)

Mass spectrum: (M + H) ⁺ = 240/242 (chlorine isotopes) (c) (2ffl-3-Benzyloxy-2-Boc-amino- / V-r3-chloro-4- (4-methyl-π .41diazepan-1-vD-phenvII-propionic acid amide

'400 / l (3.6 mmol) NMM and 930 mg (2.9 mmol) TBTU are added to 777 mg (19.1 mmol) 0-benzyl- / V-Boc-D-serine in 3 ml DMF and then under a nitrogen atmosphere at room temperature stirred for 15 min. Then 630 mg (2.6 mmol) of 3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) aniline are added and the mixture is stirred for a further 2 hours at room temperature. Then the reaction mixture is poured into water, extracted with ethyl acetate, the combined organic phases are dried over sodium sulfate and i. Vak. completely restricted. Yield: 1.58 g (quant.)

R _f value: 0.90 (silica gel; dichloromethane / methanol = 4: 1) C ₂₇ H ₃₇ CIN ₄ 0 ₄ (517.06) mass spectrum: (M + H) ⁺ = 517/519 (chlorine isotopes)

(d) (2f?) - 2-Amino-3-benzyloxy- / V-r3-chloro-4- (4-methyl-f1.4ldiazepan-1 -vπ- phenyl-propionic acid amide

1.58 g (3.06 mmol) (2ft) -3-benzyloxy-2-Boc-amino-Λ / - [(3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) phenyI] 19 ml (114 mmol) of 6 molar hydrochloric acid are added to propionic acid amide in 6 ml of dioxane and the mixture is then stirred for 30 minutes at room temperature, after which ethyl acetate and water are added and the mixture is extracted with ethyl acetate and the aqueous phase is made alkaline with ammonia solution and extracted with ethyl acetate, the combined organic phases are dried over sodium sulfate and evaporated completely, yield: 930 mg (73%)

R _f value: 0.34 (silica gel; dichloromethane / methanol = 4: 1) C ₂₂ H ₂₉ CIN ₄ 0 ₂ (416.94) mass spectrum: (M + H) ⁺ = 417/419 (chlorine isotopes)

(e) Λ / -ff1 f?) - 2-Benzyloxy-1- (3-chloro-4- (4-methyl-π .4ldiazepan-1-yl) - phenylcarbamovπ-ethvπ-5-chloro-thiophene-2- carboxylic acid amide prepared analogously to Example 1c from 5-chloro-thiophene-2-carboxylic acid and (2fi) -2- Amino-3-benzyloxy-Λ / - [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) -phenyl] - propionic acid amide with TBTU and NMM in DMF. Yield: 65% R _t value: 2.93 min C ₂₇ H ₃₀ CI ₂ N ₄ O ₃ S * CF ₃ COOH (675.55 / 561.53) Mass spectrum: (M + H) ⁺ = 560/562/564 (chlorine isotopes)

The following connections were made analogously:

The following connections can be made analogously:

(1) 5-Bromo-thiophene-2-carboxylic acid / V - {(1 f?) - 1 - [3-chloro-4- (pyrazolidin-1-yl) - phenylcarbamoyl] -2-methoxy-ethyl} - amide, (2) 5-bromo-thiophene-2-carboxylic acid N - {(1 ft) -1- [3-chloro-4- (tetrahydropyridazin-1-yl) phenylcarbamoyl] -2-methoxy-ethyl} - amide,

(3) 5-bromo-thiophene-2-carboxylic acid Λ- {1- [3-chloro-4- (2-oxopiperazin-4-yl) phenylcarbamoyl] ethyl} amide,

(4) 5-bromo-thiophene-2-carboxylic acid Λ / - {1- [3-chloro-4- (tetrahydro-pyridazin-3-one-1-yl) -phenylcarbamoyl] ethyl} amide,

(5) 5-chloro-thiophene-2-carboxylic acid Λ / - {(1 r?) - 1 - [3-methyl-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl ] -3-methylsulfanyl-propyl} amide,

(6) 5-chloro-thiophene-2-carboxylic acid Λ / - {1 - [3-methyl-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl] -1-phenyl- methyl} -amide, (7) 5-chloro-thiophene-2-carboxylic acid Λ / - {1 - [3-methyl-4- (4-methyl- [1, 4] diazepan-1-yl) -phenylcarbamoyl] -1 - [pyridin-3-yl] methyl} amide,

(8) 5-chloro-thiophene-2-carboxylic acid Λ / - {1 - [3-methyl-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl] -2- [imidazole -4-yl] ethyl} amide,

(9) 5-Chlorothiophene-2-carboxylic acid / V- {1 - [3-methyl-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl] -3- (dimethylaminocarbonyl ) -propyl} - amide,

Example 2

5-chloro-thiophene-2-carboxylic acid Λ / - {1 - [3-bromo-4- (4-methyl-piperazin-1-yl) - phenylcarbamoyl] ethyl} -amide

Prepared analogously to Example 1c from 2 - [(5-chloro-thiophene-2-carbonyl) amino] - propionic acid and 3-bromo-4- (4-methyl-piperazin-1-yl) aniline with TBTU and TEA in DMF.

Yield: 44%

R _f value: 0.31 (silica gel; dichloromethane / methanol = 9: 1) Cι ₉ H ₂₂ BrCIN ₄ 0 ₂ S (485.83)

Mass spectrum: (M + H) ⁺ = 485/487/489 (bromine and chlorine isotopes)

Example 3

5-chloro-thiophene-2-carboxylic acid Λ / - {(1 f?) - 1 - [3-chloro-4- (4-methyl- [1, 4] diazepan-1 • yl) -phenylcarbamoyl] -2 hydroxy-ethyl} amide

200 mg (0.30 mmol) 5-chloro-thiophene-2-carboxylic acid / V - {(1 f?) - 2-benzyloxy-1 - [3-chloro-4- (4-methyl- [1, 4] diazepane In 1.65 ml of TFA, 445 mg (3.0 mmol) of pentamethylbenzene are added to -1-yl) -phenylcarbamoyl] -ethyl} -amide and trifluoroacetate and the mixture is heated to 50 ° C. for 9.5 hours with stirring and stirred at room temperature for 60 hours. The mixture is evaporated, taken up in acetonitrile, acidified with TFA and purified by HPLC. Yield: 62 mg (36%) R _t value: 2.37 min

C ₂₀ H ₂ CI ₂ N ₄ θ ₃ S * CF ₃ COOH (585.42 / 471.40) mass spectrum: (M + H) ⁺ = 472/474/476 (chlorine isotopes)

Example 7

5-Bromo-thiophene-2-carboxylic acid Λ- {1-methyl-1- [3-trifluoromethyl-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbarnoyl] ethyl} amide

(a) 2-f (5-bromo-thiophene-2-carbonyl) amino1-2-methyl-propionic acid ferf-butyl ester

Prepared analogously to Example 1c from 5-bromo-thiophene-2-carboxylic acid and 2-amino-2-methyl-propionic acid-finished butyl ester with TBTU and TEA in DMF. Yield: 80%

R _f value: 0.85 (silica gel; petroleum ether / ethyl acetate = 1: 1)

Mass spectrum: (M + H) ⁺ = 348/350 (bromine isotopes)

(b) 2-F (5-bromo-thiophene-2-carbonyl) amino1-2-methyl-propionic acid 31.0 g (89.0 mmol) 2 - [(5-bromo-thiophene-2-carbonyl) amino] -2 -methyl-propionic acid te / t-butyl ester in 125 ml dichloromethane with 45 ml

Trifluoroacetic acid stirred for 18 h at room temperature, then heated to reflux for 1 h, a further 10 ml of trifluoroacetic acid was added and heated to reflux for a further 2 h. After that i. Vak. concentrated, the residue taken up twice in toloule and completely concentrated. Yield: 24.7 g (95%)

R _f value: 0.30 (silica gel; petroleum ether / ethyl acetate = 1: 1 + 1% acetic acid)

C ₉ H ₁₀ BrNO ₃ S (292.15)

Mass spectrum: (M + H) ⁺ = 292/294 (bromine isotopes)

(c) 3-Trifluoromethyl-4- (4-methyl-H, 4ldiazepan-1-yl) -1-nitro-benzene

Prepared analogously to example 1a from 4-fluoro-3-trifluoro-1-nitro-benzene and 1-methyl-

[1, 4] diazepan with potassium carbonate in DMF.

Yield: 45%

RrValue: 0.20 (silica gel; dichloromethane / methanol = 95: 5) C _l3 H ₁₆ F ₃ N ₃ 0 ₂ (303.28) Mass spectrum: (M + H) ⁺ = 304

(d) 3-trifluoromethyl-4- (4-methyl-π .41diazepan-1-yl) aniline 520 mg (1.72 mmol) 3-trifluoromethyl-4- (4-methyl- [1, 4] diazepan-1- yl) -1-nitrobenzene are mixed in 10 ml of methanol with 60 mg of 20% palladium-carbon and hydrogenated in a Parr apparatus at room temperature for 3.5 h at 50 psi hydrogen pressure. The palladium-carbon is then filtered off and the filtrate i. Vak. concentrated. The residue is reacted without further purification. Yield: 402 mg (86%) Cι ₃ H ₁₈ F ₃ N ₃ (273.30) mass spectrum: (M + H) ⁺ = 274 (e) 5-bromo-thiophene-2-carboxylic acid / V- (1-methyl-1- [3-trifluoromethyl-4 - (4-methyl-π, 41diazepan-1-yl) -phenyl-carbamoyl ^" l-ethyl) -amide Prepared analogously to Example 1c from 2 - [(5-bromo-thiophene-2-carbonyl) -amino] -2- methyl propionic acid and 3-trifluoromethyl-4- (4-methyl- [1, 4] diazepan-1-yl) aniline with TBTU and NMM in DMF. Yield: 25% C ₂₂ H ₂₆ BrF ₃ N ₄ 0 ₂ S ^* CF ₃ COOH (547.39 / 661.46) mass spectrum: (M + H) ⁺ = 547/549 (bromine isotopes) The following compound was prepared analogously:

The following connections can be made analogously:

(1) 5-bromo-thiophene-2-carboxylic acid Λ / - {1 - [3-chloro-4- (pyrazolidin-1-yl) - phenylcarbamoyl] - 1-methyl l-ethyl} -amide, (2) 5-chloro-thiophene-2-carboxylic acid Λ / - {1 - [3-methyl-4- (pyrazolidin-1-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide, (3) 5-bromo- thiophene-2-carboxylic acid / V- {1 - [3-chloro-4- (tetrahydropyridazin-1 - yl) phenylcarbamoyl] -1-methyl-ethyl} -amide, (4) 5-chloro-thiophene-2 -carboxylic acid- V- {1 - [3-methyl-4- (tetrahydropyridazin-1 - yl) -phenylcarbamoyl] -1-methyl-ethyl} -amide, (5) 5-bromo-thiophene-2-carboxylic acid- V- {1 - [3-bromo-4- (4-methyl- [1, 4] diazepan-1-yl) -phenylcarbamoyl] -1-methyl-ethyl} -amide, (6) 5-bromo-thiophene-2- carboxylic acid Λ / - {1- [3-trifluoromethoxy-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl] -1-methyl-ethyl} -amide, (7) 5-bromo -thiophene-2-carboxylic acid Λ / - {1-methyl- [3-methyl-4- (2,5-dimethyl-pyrrolidin-1-yl) phenylcarbamoyl] ethyl} amide, (8) 5-bromo -thiophene-2-carboxylic acid / V- {1- [3-methyl-4- (2,6-dimethylpiperidin-1-yl) phenylcarbamoyl] cyclopentyl} amide, (9) 5-bromo-thiop hen-2-carboxylic acid Λ / - {4- [3-methyl-4- (2,6-dimethyl-piperidin-1-yl) phenylcarbamoyl] tetrahydropyran-4-yl} amide, (10) 5- Bromothiophene-2-carboxylic acid Λ / - {1-methyl-4- [3-methyl-4- (2,6-dimethyl-morpholin-4-yl) phenylcarbamoyl] piperazin-4-yl} -amide , (11) 5-Bromo-thiophene-2-carboxylic acid V- {3- [3-chloro-4- (2,2-dimethyl-pyrrolidin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yI} - amide,

Example 8

5-bromo-thiophene-2-carboxylic acid Λ / - {1 - [3-chloro-4- (morpholin-4-yl) - phenyIcarbamoyl] -1-methyl-ethyl} -amide

206 mg (0.71 mmol) of 2 - [(5-bromo-thiophene-2-carbonyI) amino] -2-methyl-propionic acid together with 295 mg (0.78 mmol) of HATU in 3.0 ml of DMF are stirred at room temperature with 155 μl (1.41 mmol) NMM added and stirred for 45 min. 150 mg of 3-chloro-4- (morpholin-4-yl) aniline are then added and the mixture is heated at 85 ° C. for 3 h. After stirring at room temperature for 16 h, the mixture is sat on ice with sat. Poured sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are with 0.5 molar potassium hydrogen sulfate solution and sat. Washed sodium chloride solution, dried over magnesium sulfate and i. Vak. completely evaporated. The residue is triturated in diethyl ether, filtered off and dried at room temperature. Yield: 235 mg (68%) R _f value: 0.20 (silica gel; dichloromethane / methanol = 9: 1) CigHaiBrCINaOaS (486.81) mass spectrum: (M + H) ⁺ = 486/488/490 (bromine and chlorine isotopes)

The following connections were made analogously:

The following compounds can be prepared analogously: 1) 5-chloro-thiophene-2-carboxylic acid Λ / - {1 - [3-methyl-4- (morpholin-4-yl) - phenylcarbamoyl] -1-methyl-ethyl} - amide, 2) 5-bromo-thiophene-2-carboxylic acid / V - {(1?) - 1 - [3-tfhlor-4- (morpholin-4-yr) - phenylcarbamoyl] -2-methoxy-ethyl} - amide, 3) 5-bromo-thiophene-2-carboxylic acid / V- {1 - [3-chloro-4 - ([1, 2] oxazinan-2-yi) - phenylcarbamoyl] -1-methyl-ethyl} - amide, 4) 5-chloro-thiophene-2-carboxylic acid / V- {1 - [3-methyl-4 - ([1, 2] oxazinan-2-yl) -

10 phenylcarbamoyl] -1-methyl-ethyl} -amide, 5) 5-bromo-thiophene-2-carboxylic acid Λ / - {(1?) - 1- [3-chloro-4 - ([1, 2] oxazinan -2-yl) -phenylcarbamoyl] -2-methoxy-ethyl} -amide, 6) 5-bromo-thiophene-2-carboxylic acid Λ / - {1 - [3-chloro-4 - ([1, 2] oxazepane -2-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide, 15 7) 5-chloro-thiophene-2-carboxylic acid Λ / - {1 - [3-methyl-4 - ([1, 2] oxazepan-2-yl) - phenylcarbamoyl] -1-methyl-ethyl} -amide, 8) 5-bromo-thiophene-2-carboxylic acid / V - {(1 R) -1- [3-chloro-4- ( [1, 2] oxazepan-2-yl) -phenylcarbamoyi] -2-methoxy-ethyl} -amide,

, 20 Example 10

5-chloro-thiophene-2-carboxylic acid Λ / - {1- [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) phenylcarbamoyl] ethyl} amide

(a) 2-r (5-chloro-thiophene-2-carbonyl) amino1-propionic acid methyl ester

Prepared analogously to Example 1c from 5-chloro-thiophene-2-carboxylic acid and 2-

Amino propionic acid methyl ester with TBTU and NMM in THF.

Yield: 81%

Rf value: 0.63 (silica gel; petroleum ether / ethyl acetate = 1: 1)

Mass spectrum: (M + H) ⁺ = 248/250 (chlorine isotopes)

(b) 2-r (5-chloro-thiophene-2-carbonyl) amino1-propionic acid

3.80 g (15.3 mmol) of methyl 2 - [(5-chloro-thiophene-2-carbonyl) amino] propionate are stirred in 15.5 ml of 1 molar sodium hydroxide solution and 15 ml of ethanol for 4 h at room temperature. Then i. Vak. concentrated, the residue mixed with ice water and extracted twice with diethyl ether. The aqueous phase is poured onto ice with acetic acid, the precipitate formed is filtered off, washed with water and dried at 60.degree. Yield: 2.90 g (81%) R _f value: 0.05-0.35 (silica gel; petroleum ether / ethyl acetate = 1: 2) C ₈ H ₈ CIN0 ₃ S (233.67)

(c) 5-Chloro-thiophene-2-carboxylic acid Λ / - (1-f3-chloro-4- (4-methyl-f1.4ldiazepan-1-vD-phenyl-carbamoyl-1-ethyl) -amide

Prepared analogously to Example 1c from 2 - [(5-chloro-thiophene-2-carbonyl) amino] - propionic acid and 3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) aniline with TBTU and

NMM to DMF.

Yield: 9%

R _t value: 4.08 min

C ₂₀ H ₂₄ CI ₂ NO ₂ S * CF ₃ COOH (569.43 / 455.36) mass spectrum: (M + H) ⁺ = 455/457/459 (chlorine isotopes) Example 17

5-chloro-thiophene-2-carboxylic acid Λ / - {4- [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) - phenylcarbamoyl] -tetrahydropyran-4-yl} - amide

(a) 4-Boc-Amino-Λ / -r3-chloro-4- (4-methyl-ri, 41diazepan-1-yl) -phenyl1-tetrahvdropyran-4-carboxylic acid amide

Prepared analogously to Example 8 from 4-Boc-amino-tetrahydropyran-4-carboxylic acid and 3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) aniline with HATU and NMM in DMF. Yield: 40% R _t value: 2.31 min C ₂₃ H ₃₅ CIN ₄ O ₄ (467.00)

Mass spectrum: (M + H) ⁺ = 467/469 (chlorine isotopes)

(b) 4-Amino- / V-r3-chloro-4- (4-methyl-H, 4ldiazepan-1 -vD-phenvIl- tetrahvdropyran-4-carboxylic acid amide Manufactured analogously to Example 1d from 4-Boc-Amino-Λ / - [3-chloro-4- (4-methyl-

[1, 4] diazepan-1-yl) phenyl] tetrahydropyran-4-carboxylic acid amide with hydrochloric acid in dioxane.

Yield: quant.

R _t value: 1.72 min C ₁₈ H ₂₇ CIN ₄ O ₂ * 3 HCI (476.27 / 366.89)

(c) 5-chloro-thiophene-2-carboxylic acid / V- (1- [3-chloro-4- (4-methyl- [1.41diazepan- 1-vD-phenyl-carbamoyl1-tetrahvdropyran-4-yl) - amide

Prepared analogously to Example 1c from 5-chloro-thiophene-2-carboxylic acid and 4- Amino-Λ / - [3-chloro-4- (4-methyl- [1,4] diazepan-1-yl) phenyl] tetrahydropyran-4-carboxylic acid amide with TBTU and NMM in DMF. Yield: 2% R _t value: 2.45 min C ₂₃ H ₂₈ CI ₂ N ₄ θ ₃ S * CF ₃ COOH (625.49 / 511.42) Mass spectrum: (M + H) ⁺ = 511/513 (chlorine isotopes)

The following connections were made analogously:

Example 21

5-Bromo-thiophene-2-carboxylic acid / V- {1 - [4- (4-methyl- [1, 4] diazepan-1-yl) - phenylcarbamoyl) -1-methyl-ethyl} -amide

(a) 4- (2.5-Dimethyl-pyrrolidin-1-yl) -1-nitro-benzene Prepared analogously to Example 1a from 4-fluoro-1-nitro-benzene and 2,5-dimethyl-pyrrolidine with potassium carbonate in DMSO. Yield: 58% Cι ₂ H ₁₆ N ₂ 0 ₂ (220.27) mass spectrum: (M + H) ⁺ = 221

(b) 4- (2,5-Dimethyl-pyrrolidin-1-yl) aniline

250 mg (1.14 mmol) 4- (2,5-dimethyl-pyrrolidin-1-yl) -1-nitro-benzene are concentrated in 10 ml methanol with 150 mg 10% palladium-carbon and 450 μl. Hydrochloric acid added and hydrogenated in a Parr apparatus at room temperature for 1.5 h at 50 psi hydrogen pressure. The palladium-carbon is then filtered off and the filtrate i. Vak. concentrated. The residue is directly implemented without further purification.

Yield: 250 mg (50%). ,

Cι ₂ H ₁₈ N ₂ ^* 2 HCI (263.21 / 190.29) mass spectrum: (M + H) ⁺ = 191

(c) 2-Boc-Amino-Λ / -r4- (2.5-dimethyl-pyrrolidin-1-yl) -phenvn-2-methyl-propionic acid amide Prepared analogously to Example 1c from 2-Boc-amino-isobutyric acid and 4- (2,5-Dimethyl-pyrrolidin-1-yl) aniline with TBTU and NMM in DMF. Yield: 75% Rt value: 0.60 (Alox; dichloromethane / methanol = 95: 5) C ₂ ιH ₃₃ N ₃ O ₃ (375.51) mass spectrum: (M + H) ⁺ = 376

(d) 2-Amino-A / -r4- (2,5-dimethyl-pyrrolidin-1-vπ-phenvn-2-methyl-propionic acid amide Prepared analogously to Example 1d from 2-Boc-Amino- / V- [4 - (2,5-dimethyl-pyrrolidin-1-yl) -phenyl] -2-methyl-propionic acid with hydrochloric acid in dioxane. Yield: quant. R _t value: 0.10 (Alox; dichloromethane / methanol = 9: 1) C ₁ 6H ₂ 5N3O * 2 HCI (348.31 / 275.39)

(e) 5-Bromo-thiophene-2-carboxylic acid A / -π - (4-f2.5-dimethyl-pyrrolidin-1-yl) - phenylcarbamovP-1-methyl-ethyl-amide Prepared analogously to Example 1c from 5- Bromothiophene-2-carboxylic acid and 2-amino-Λ / - [4- (2,5-dimethyl-pyrrolidin-1-yl) phenyl] -2-methyl-propionic acid amide with TBTU and NMM in DMF. Yield: 54% R _t value: 2.51 min C ₂₁ H ₂₆ BrN ₃ 0 ₂ S * CF ₃ COOH (578.44 / 464.38) Mass spectrum: (M + H) ⁺ = 464/466 (bromine isotopes)

The following connection was established analogously:

Example 23 5-bromo-thiophene-2-carboxylic acid Λ / - {1- [3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl) - phenylcarbamoyl] -cyclopent-1-yl} - amide

(a) 1 - [(5-Bromo-thiophene-2-carbonyl) amino1-cvclopentyl-1-carboxylic acid, methyl ester

576 mg (2.78 mmol) of 5-bromo-thiophene-2-carboxylic acid in 5 ml of dichloromethane are mixed with 5 ml of thionyl chloride and heated to reflux for 2 hours. Then the mixture i. Vak. concentrated, mixed with toluene and evaporated completely. The residue is added dropwise in 5 ml of dichloromethane to a mixture of 500 mg (2.78 mmol) of 1-amino-cyclopentyl-1-carboxylic acid methyl ester and 1.94 ml (13.9 mmol) of TEA in 5 ml of dichloromethane and then at room temperature for 4 h touched. The

The reaction mixture is shaken out twice with water, the aqueous phases are back-extracted with dichloromethane and the combined organic phases are dried over magnesium sulfate and evaporated down completely. Yield: 800 mg (87%) R _f value: 0.91 (silica gel; dichloromethane / methanol = 9: 1) C ₁₂ Hι BrNO ₃ S (332.22) mass spectrum: (M + H) ⁺ = 332/334 (bromine isotopes)

(b) 1-r (5-bromo-thiophene-2-carbonyl) -amino1-cvclopentyl-1-carboxylic acid Prepared analogously to Example 10b from 1 - [(5-bromo-thiophene-2-carbonyl) -amino] - cyclopentyl- 1-carboxylic acid methyl ester with 1 molar sodium hydroxide solution in methanol.

Yield: 52%

R _f value: 0.31 (silica gel; dichloromethane / methanol = 9: 1)

CnH ₁₂ BrNO ₃ S (318.19) Mass spectrum: (M + H) ⁺ = 318/320 (bromine isotopes)

(c) 5-Bromo-thiophene-2-carboxylic acid Λ / - (1- [3-chloro-4- (4-methyl-f1, 41diazepan-1 -vQ-phenvI-carbamovIl-cvclopent-l -vD-amide Prepared analogously to Example 8 from 1 - [(5-bromo-thiophene-2-carbonyl) amino] - cyclopentyl-1-carboxylic acid and 3-chloro-4- (4-methyl- [1, 4] diazepan-1-yl ) -aniline with HATU and NMM in DMF.Yield: 27%

Rt value: 0.29 (silica gel; dichloromethane / methanol = 9: 1) C ₂₃ H ₂₈ BrCIN ₄ O ₂ S (539.92)

Mass spectrum: (M + H) ⁺ = 539/541/543 (bromine and chlorine isotopes)

Example 24

5-chlorothiophene-2-carboxylic acid / V- {1- [4- (4-methyl-piperazin-1-yl) phenylcarbamoyl) -1-methyl-ethyl} -amide

(a) 2- (5-chloro-thiophene-2-vπ-4,4-dimethyl-4H-oxazol-5-one

1.00 g (4.04 mmol) of 2 - ([5-chloro-thiophene-2-carbonyl] amino) isobutyric acid are heated in 30 ml of acetic anhydride at 85 ° C. for 1 h and then evaporated completely. Yield: 927 mg (quant.) C ₉ H ₈ N0 ₂ S (229.68)

Mass spectrum: (M + H) ⁺ = 229/231 (chlorine isotopes)

(b) 4- (2,5-Dimethyl-pyrrolidin-1-yl) aniline

200 μl of a 0.05 molar solution of 2- (5-chloro-thiophen-2-yl) -4,4-dimethyl-4H-oxazol-5-one in a solvent mixture of toluene and glacial acetic acid 9: 1 200 μl of a 0.05 molar solution of 4- (4-methyl-piperazin-1-yl) aniline in DMF are mixed with 5% DIPEA and heated to 80 ° C. for 16 h. The mixture is then left open for 7 days, then filtered through basic aluminum oxide and washed with DMF / methanol 9: 1. Then i. Vak. evaporated. Yield: 5.1 mg (quant.) R _t value: 3.18 min C ₂₀ H ₂₅ CIN ₄ O ₂ S (420.96) Mass spectrum: (M + H) ⁺ = 421/423 (chlorine isotopes)

The following connection was established analogously:

Example 27

5-Bromo-thiophene-2-carboxylic acid Λ / - {1-methyl-1- [3-chloro-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl) ethyl} amide

(a) Λ / -Boc-Λ / -Methyl-hvdrazine 4.47 ml (82.3 mmol) of methylhydrazine become a mixture of 17.07 g (78.23 mmol) pyrocarbonate di-fer.-butyl ester in 75 ml of methanol was added dropwise with stirring at room temperature, heated to reflux for 2.5 hours and then i. Vak. concentrated. The residue is directly implemented without further purification. Yield: 10.50 g (92%) C ₆ HN ₂ 0 ₂ (146.19) mass spectrum: (M + H) ⁺ = 147

(b) / V-Boc-Λ - (2-chloro-4-nitro-phenyl) - / V-methyl-hvdrazine 2.30 g (13.1 mmol) of 3-chloro-4-fluoro-1-nitro-benzene are combined with 4.50 g (26.2 mmol) Λ / -Boc-V-methyl-hydrazine and 7.30 g (52.8 mmol) potassium carbonate in 25 ml DMF for 3 days at room temperature, then for 4 h at 90 ° C and then for 16 h at room temperature. After concentration of the reaction mixture i. Vak. is mixed with a mixture of water / ethyl acetate 1: 1, adjusted to pH 4 with 0.5 normal potassium hydrogen sulfate solution and extracted with ethyl acetate. The combined organic phases are half-saturated with. and sat. Washed sodium chloride solution, dried over magnesium sulfate and i. Vac concentrated. The residue is mixed with cyclohexane and triturated. After filtering, the product is washed with cyclohexane and dried at 55 ° C.

Yield: 1.41 g (36%)

RrValue: 0.38 (silica gel; cyclohexane / ethyl acetate = 8: 2)

Cι ₂ H ₁₆ CIN ₃ O ₄ (301.73)

Mass spectrum: (M + H) ⁺ = 301/303 (chlorine isotopes)

(c) Λ / -Boc- '- (4-bromo-butyl) -Λ / - (2-chloro-4-nitro-phenyl) -Λ / -methyl-hvdrazine 350 mg (1.16 mmol) Λ / -Boc- / V- (2-chloro-4-nitro-phenyl) -Λ / -methyl-hydrazine together with 350 μl (2.93 mmol) of 1,4-dibromobutane in 7.5 ml DMF in a Schlenck tube under nitrogen atmosphere and cooling 50.6 mg (1.16 mmol) of 55% sodium hydride, dispersed in paraffin oil, are added in an ice bath. After cooling for 10 min in an ice bath, stirring for 30 min at room temperature and heating to 75 ° C. for 1 h, the reaction mixture is evaporated down i. Vak. completely concentrated and the residue was mixed twice with toluene and dichloromethane and completely evaporated. The residue is directly implemented without further purification.

Yield: 900 mg (approx. 53%, contaminated)

R _r value: 0.69 (silica gel; cyclohexane / ethyl acetate = 6: 4 + 0.5% concentrated ammonia solution)

Cι ₆ H ₂₃ BrCIN ₃ 0 ₄ (436.73)

(d) 3-Chloro-4- (2-methyl-tetrahvdropyridazin-1-yl) -1-nitro-benzene

890 mg (approx. 0.71 mmol) / V-Boc- / V '- (4-bromo-butyl) - / V- (2-chloro-4-nitro-phenyl) -iV- methyl-hydrazine (product obtained above) 1.50 ml (19.6 mmol) of TFA are added in 10 ml of dichloromethane at room temperature with stirring and then stirred for 90 min at room temperature. After narrowing i. Vak. the residue is taken up 3 times in dichloromethane and evaporated completely. The residue is then taken up in 10 ml of acetone, 490 mg (3.55 mmol) of potassium carbonate are added and the mixture is stirred at room temperature for 15 h. After filtering, the filtrate is i. Vak. concentrated and the residue purified by chromatography on silica gel (eluent gradient: cyclohexane / ethyl acetate = 9: 1 -> 8: 2). Yield: 180 mg (quant.) R _f value: 0.48 (silica gel; cyclohexane / ethyl acetate = 8: 2) CιιHι ₄ CIN ₃ 0 ₂ (255.70) mass spectrum: (M + H) ⁺ = 255/257 (chlorine isotopes)

(e) 3-Chloro-4- (2-methyl-tetrahydropyridazin-1-yl) aniline Prepared analogously to Example 1b from 3-chloro-4- (2-methyl-tetrahydropyridazin-1-yl) -1 -nitro-benzene by hydrogenation with hydrogen and Raney nickel in

Ethyl acetate.

Yield: 63% (contaminated)

Rt value: 0.71 (RP-8; 5% sodium chloride solution / methanol = 2: 3 CnHiβCINa ^* 2 HCl (298.64 / 225.72)

Mass spectrum: (M + H) ⁺ = 225/227 (chlorine isotopes)

(f) 5-bromo-thiophene-2-carboxylic acid Λ / - (1 -methyl-1-f3-chloro-4- (2-methyl- tetrahvdropyridazin-1-yl) -phenylcarbamoyll-ethyl} -amide Manufactured analogously to Example 8 from 3-chloro-4- (2-methyl-tetrahydropyridazin-1-yl) aniline and 2 - [(5-bromo-thiophene-2- carbonyl) amino] isobutyric acid with HATU and NMM in NMP. Yield: 38% (HPLC) R _t value: 3.25 min C ₂₀ H ₂ BrCIN ₄ O ₂ S (499.85) Mass spectrum: (M + H) ⁺ = 499/501/503 (bromine and chlorine isotopes)

The following connections can be made analogously:

(1) 5-chlorothiophene-2-carboxylic acid / V- {1 - [3-methyl-4- (2-methyltetrahydropyridazin-1-yl) phenylcarbamoyl] -1-methylethyl} amide,

(2) 5-bromo-thiophene-2-carboxylic acid / V - {(1β) -1 - [3-chloro-4- (2-methyltetrahydropyridazin-1-yl) -phenylcarbamoyl] -2-methoxy- ethyl} amide,

(3) 5-bromo-thiophene-2-carboxylic acid / V- {3- [3-methyl-4- (2-methyltetrahydropyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} - amide,

(4) 5-chloro-thiophene-2-carboxylic acid Λ / - {3- [3-methyl-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} - amide, (5) 5-chloro-thiophene-2-carboxylic acid / V- {2- [4- (2-methyl-tetrahydro-pyridazin-1-yl) phenylcarbamoyl] bicyclo [2.2.1] hept-2 yl} amide,

(6) 5-chloro-thiophene-2-carboxylic acid Λ / - {3- [3-chloro-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} - amide,

(7) 5-chloro-thiophene-2-carboxylic acid Λ / - {3- [3-bromo-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} - amide,

(8) 5-chloro-thiophene-2-carboxylic acid Λ / - {3- [3-fluoro-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} - amide,

(9) 5-chloro-thiophene-2-carboxylic acid Λ / - {3- [3-trifluoromethyl-4- (2-methyltetrahydro-pyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} - amide, (10) 5-chloro-thiophene-2-carboxylic acid - / - {3- [4- (2-methyl-tetrahydro-pyridazin-1-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} amide, (11) 5-chloro-thiophene-2-carboxylic acid - / - {2- [3-methyl-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl] bicyclo [2.2.1] hept -2-yl} -amide, (12) 5-chloro-thiophene-2-carboxylic acid - / - {2- [3-methyl-4- (2-methyl-tetrahydropyridazin-1-yl) phenylcarbamoyl3-7-oxa-bicyclo [2.2. 1] hept-2-yl} -amide,

(13) 5-Chlorothiophene-2-carboxylic acid onsäure / - {3- [3-methyl-4 - ([2-methyl- [1, 2] diazepan-1-yl) phenylcarbamoyl] tetrahydrofuran-3 yl} amide,

(14) 5-chloro-thiophene-2-carboxylic acid / V- {3- [3-methyl-4- (5-methyl- [1, 4,5] oxadiazepan-4-yl) phenylcarbamoyl] tetrahydrofuran 3-yl} -amide,

(15) 5-Bromo-thiophene-2-carboxylic acid Λ / - {3- [4- (5-methyl- [1, 4,5] oxadiazepan-4-yl) phenylcarbamoyl] tetrahydrofuran-3-yl} amide,

The following examples describe the preparation of pharmaceutical use forms which contain any compound of the general formula I as active ingredient:

Example I

Dry ampoule with 75 mg active ingredient per 10 ml

Composition:

Active ingredient 75.0 mg mannitol 50.0 mg water for injections ad 10.0 ml

production:

Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for injections.

Example II

Dry ampoule with 35 mα active ingredient per 2 ml Composition:

Active ingredient 35.0 mg mannitol 100.0 mg water for injections ad 2.0 ml

production:

Example III

Tablet with 50 mg of active ingredient

Composition:

(1) Active ingredient 50.0 mg

(2) milk sugar 98.0 mg

(3) Corn starch 50.0 mg

(4) Polyvinylpyrrolidone 15.0 mg

(5) Magnesium stearate 2.0 mo 215.0 mg

production:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplane with a facet on both sides and a notch on one side.

Tablet diameter: 9 mm.

Example IV Tablet with 350 mα active ingredient

Composition:

(1) Active ingredient 350.0 mg

(2) milk sugar 136.0 mg

(3) corn starch 80.0 mg

(4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg 600.0 mg

production:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with a facet on both sides and a partial notch on one side. Tablet diameter: 12 mm.

Example V

Capsules with 50 mg of active ingredient

Composition:

(1) Active ingredient 50.0 mg

(2) Corn starch dried 58.0 mg

(3) Milk sugar powdered 50.0 mg

(4) Magnesium stearate 2.0 mg 160.0 mg

production:

(1) is triturated with (3). This trituration is the mixture of (2) and (4) added with intensive mixing.

This powder mixture is filled into size 3 hard gelatine capsules on a capsule filling machine.

Example VI

Capsules with 350 mg of active ingredient

Composition:

(1) Active ingredient 350.0 mg

(2) Corn starch dried 46.0 mg

(3) Milk sugar powdered 30.0 mg

(4) Magnesium stearate 4.0 mg 430.0 mg

production:

(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.

This powder mixture is filled into size 0 hard gelatin capsules on a capsule filling machine.

Example VII

Suppositories with 100 mg of active ingredient

1 suppository contains: active ingredient 100.0 mg

Polyethylene glycol (MW 1500) 600.0 mg Polyethylene glycol (MG 6000) 460.0 mg Polyethylene sorbitan monostearate 840.0 mg 2000.0 mg

production:

The polyethylene glycol is melted together with polyethylene sorbitan monostearate. The milled active substance is homogeneously dispersed in the melt at 40 ° C. It is cooled to 38 ° C and poured into weakly pre-cooled suppository molds.

Claims

claims

1. Substituted thiophene-2-carboxamides of the general formula

characterized in that

A is a radical of the general formula

means

in the

m is the number 1 or 2,

R ^8a each independently of one another is a hydrogen or fluorine atom or a C 5 alkyl, hydroxy, hydroxy C _1-5 alkyl, C ₁ alkoxy, 5 alkoxy d 5 alkyl 5 , Amino-, Cι _-5 -alkylamino-, di- (d _-5 -alkyl) -amino-, amino-Cι _-5 -alkyl-, C _1-5 -Alkylamino-d _-5 -alkyl-, Di- ( d- ₅ -alkyl) -amino-d _-5 -alkyl-, aminocarbonyl-, -Cι _-5 -alkylaminocarbonyl-, di- (Cι _-5 -alkyl) -aminocarbonyl- or Ci.s-alkylcarbonylamino group, with the above Said substituted 5- to 7-membered radicals A, the heteroatoms F, O or N optionally introduced with R ^8a as substituents are not separated by exactly one carbon atom from a heteroatom from the group N, O, S, and two substituents R ^8a on the same or different carbon atoms can represent a C _-5 alkylene group,

R _D 8b each independently of one another represents a hydrogen atom or a d- ₅ alkyl group,

X ^{1 represents} an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8c group,

R ^8c each independently represents a hydrogen atom, a Ci-s-alkyl, d- ₅ alkylcarbonyl, Cι_ ₅ alkyloxycarbonyl or Cι _-5 alkylsulfonyl group,

X ^{2 is} an oxygen atom or an -NR ^8b group, X ^{3 is} an oxygen or sulfur atom, an -NR ^8c group,

X ^{4 is} a carbonyl or sulfonyl group,

X ^{5 is} an oxygen atom, an -NR ⁸ - or methylene group,

X ^{6 is} an oxygen or sulfur atom or an -NR ^8c group,

X ^{7 represents} a methylene or carbonyl group,

R ^{1 is} a hydrogen, fluorine, chlorine, bromine or iodine atom, a C ₃ alkyl or C ₃ alkoxy group, the hydrogen atoms of the C ₃ alkyl or C ₃ alkoxy group optionally entirely or can be partially replaced by fluorine atoms, a C ₂ . ₃ denotes alkenyl, C _2-3 alkynyl, nitrile, nitro or amino group,

R ^{2 represents} a hydrogen or halogen atom or a C _{3 -3} alkyl group,

R ^{3 represents} a hydrogen atom or a Cι _-3 alkyl group,

R ⁴ and R ^{5 are} each independently a hydrogen atom, a C ₂ -6 alkenyl or C _2-6 alkynyl group, a straight-chain or branched Cι. ₆ -alkyl group, the hydrogen atoms of the straight-chain or branched Cι. ₆ -alkyl group may optionally be wholly or partly replaced by fluorine atoms, and which may optionally be replaced by a C ₃ - ₅ cycloalkyl group, a nitrile, hydroxyl, a Cι- ₅ alkyloxy group, the hydrogen atoms of the Cι- ₅ alkyloxy group optionally being completely or can be partially replaced by fluorine atoms, an allyloxy, propargyloxy, benzyloxy, C ₅ alkylcarbonyloxy, C ₅ alkyloxycarbonyloxy, Carboxy-C-5-alkyloxy, Ci-s-alkyloxycarbonyl-Ci-s-alkyloxy, mercapto, Cι _-5 alkylsulfanyl, Cι _-5 alkylsulfonyl, carboxy, Cι-5-alkyloxycarbonyl, aminocarbonyl -, Ci-s-Alkylaminocarbonyl-, di- (Cι _-5 -alkyl) -aminocarbonyl-, C ₃ -6-cycloalkyleniminocarbonyl-, aminosulfonyl-, C1-5-AI-kylaminosulfonyl-, di- (Cι-5-alkyl ) -aminosulfonyl-, C _3-6 -cycloalkyleniminosulfonyl-, amino-, d _-5 -alkylamino-, di- (Cι- ₅ -alkyl) -amino-, Cι- ₅ -alkylcarbonylamino-, d _-5 -alkyl- sulfonylamino -, Λ / - (Cι- ₅ alkylsulfonyl) -C _-5 alkylamino or C ₃ - ₆ cycloalkylcarbonylamino group may be substituted,

a carboxy, aminocarbonyl, Cι _-5 -alkylammocarbonyl, C3-6-cycloalkylaminocarbonyl, di- (Cι _-5 -alkyl) aminocarbonyl, Ci-s-alkoxycarbonyl, C _4-6 -cycloalkyleniminocarbonyl group,

a phenyl, heteroaryl, phenyl -C ₅ alkyl or heteroaryl

Cι- ₅ alkyl group which is optionally monosubstituted in the phenyl or heteroaryl moiety to trisubstituted by identical or different substituents selected from the group consisting of halogen atoms, C - ₅ alkyl, di (Cι _-5 alkyl) amino, Hydroxy, d _-5 alkyloxy, mono-, di- or trifluoromethoxy, carboxy and Ci.s-alkyloxycarbonyl groups can be substituted,

a 3- to 7-membered cycloalkyl, cycloalkylenimino, cycloalkyl

Cι-5-alkyl or cycloalkylenimino-Cι.3-alkyl group, in which in 4- to 7-membered cycles in the cyclic part a methylene group optionally by an -N (R ^8o ) group, an oxygen or sulfur atom or a - S (O) - or -S (0) ₂ - group can be replaced, or in the case of 4- to 7-membered cycles in the cyclic part, two adjacent methylene groups together, if appropriate, by a -C (0) N (R ^8b ) - or -S (0) ₂ N (R ⁸ ) group may be replaced, or in which, in the case of 6- to 7-membered cycles in the cyclic part, three adjacent methylene groups together, if appropriate, by , a substituted -OC (0) N (R ^8b ) - or -N (R ^8b ) C (O) N (R ^8b ) - or -N (R ^8b ) S (O) ₂ N (R ^8b ) group with the proviso that a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-d- ₅ -alkyl or cycloalkylenimino-Cι- ₃ -alkyl group, as defined above, in which two heteroatoms from the group oxygen and Nitrogen are separated from one another by exactly one optionally substituted -CH ₂ group, is excluded, a 3- to 7-membered cycloalkyl-, cycloalkylenimino-, cycloalkyl-Cι _-5 -alkyl- or cycloalkylenimino-Cι- ₃ - as defined above alkyl group on one or two -CH ₂ - groups can each be substituted by one or two -C _-3 alkyl groups, means, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C ₃ - ₈ cycloalkyl or C - ₈ cycloalkenyl group, one C ₃ .s-cycloalkyl or C ₄ - ₈ cycloalkenyl group on one single carbon atom can be substituted by a C _2-5 alkylene group or at the same time on two different carbon atoms by a Cι _-4 alkylene group to form a corresponding spirocycle or a bridged bicyclus, one of the methylene groups of a C _-8 cycloalkyl or Cs -s Cycloalkenyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above can be replaced by an oxygen or sulfur atom or an -N (R ^8c ) -, or a carbonyl, sulfinyl or sulfonyl group, and / or

two directly adjacent methylene groups of a C. ₈ -cycloalkyl group together can be replaced by a -C (0) N (R ^8b ) -, - C (0) 0- or -S (0) ₂ N (R ^8b ) group, and / or

three directly adjacent methylene groups of a Cβ-β-cycloalkyl group together by a -OC (0) N (R ^8b ) ~, - N (R ^8b ) C (O) N (R ^8b ) - or -N (R ^8b ) S ( 0) ₂ N (R ^8b ) group can be replaced,

where 1 to 3 carbon atoms of a C3-s-cycloalkyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above, optionally independently of one another, in each case by one or two fluorine atoms or one or two identical or different C 5 alkyl, nitrile -

Hydroxy, Cι _-5 -alkyloxy-, d _-5 alkylcarbonyloxy, carboxy-d _-5 - alkyl-, Cι- ₅ alkyloxycarbonyl-Cι-5-alkyl, Cι-5-alkylsulfanyl, Cι-5- Alkylsulfonyl-, carboxy-, Cι- ₅ -alkyloxycarbonyl-, aminocarbonyl-, Cι-5-alkylaminocarbonyl-, di- (d _-5 -alkyl) - aminocarbonyl-, C3-6-cycloalkyleniminocarbonyl-, aminosulfonyl-,

Ci.s-Alkylaminosulfonyl-, Di- (Cι-5-alkyl) -aminosulfonyl-, C ₃ -6-Cycloalkyleniminosulfonyl-, Amino-, Cι- ₅ -Alkylamino-, Di- (Cι _-5 -alkyl) -amino- , d _-5 -alkylcarbonylamino-, d _-5 -alkylsulfonylamino-, Λ / - (Cι _-5 -alkylsulfonyl) -Cι _-5 -alkylamino- or C ₃ - ₆ "cycloalkylcarbonylamino groups can be substituted,

where 1 to 2 carbon atoms of a C ₃ -8-cycloalkenyl group, optionally independently of one another, each by a C1-5 Alkyl, nitrile, carboxy-C _1-5 alkyl, Cι _-5 -alkyloxycarbonyl-Cι _-5 -alkyl-, carboxy-, d _-5 -alkyloxycarbonyl-, aminocarbonyl, Cι- ₅ -alkylaminocarbonyl-, Di - (d- ₅ -alkyl) -aminocarbonyl-, C _3-6 -cycloalkyleniminocarbonyl-, aminosulfonyl-, Cι- ₅ -alkylaminosulfonyl-, di- (Cι _-5 -alkyl) -aminosulfonyl-,

C ₃ - ₆ -Cycloalkyleniminosulfonylgruppen may be substituted,

and 1 to 2 carbon atoms of a C ₄ - ₈ cycloalkenyl group, which are not bound by a double bond to another carbon atom, optionally independently of one another by one or two fluorine atoms or a hydroxy, C ₅ alkyloxy, Ci.s-alkylcarbonyloxy -, d _-5 -Alkylsulfanyl-, Cι _-5 -alkylsulfonyl-, amino-, Ci.s-alkylamino-, di- (d- ₅ -alkyl) -amino-, Cι- ₅ -alkylcarbonylamino-, Cι- ₅ - Alkylsulfonylamino-, Λ / - (Cι _-5 -alkylsulfonyl) -Cι _-5 -alkylamino- or

C3- ₆ -Cycloalkylcarbonylaminogruppen may be substituted,

with the proviso that such a C ₃ - ₈ cycloalkyl or C3-s-cycloalkenyl group formed together from R ⁴ and R ⁵ or a corresponding spirocycle or a corresponding bridged bicyclus as described above, in which two heteroatoms in the Cycles from the group oxygen and nitrogen are separated from one another by exactly one optionally substituted -CH ₂ group, and / or in which one or both methylene groups of the cycle, which are directly connected to the carbon atom, on which the radicals R ⁴ and R ⁵ are attached, are replaced by a heteroatom from the group oxygen, nitrogen and sulfur, and / or in which a substituent attached to the cyclic group, which is characterized in that a hetero atom from the group oxygen, nitrogen, sulfur and halogen atom is bonded directly to the cyclic group, from another hetero atom from the group oxygen, nitrogen and sulfur, with the exception of the sulfone group, by exactly one, optionally substituted , Methylene group is separated, and / or in which two oxygen atoms are directly connected to one another, and / or in which a hetero atom from the group consisting of oxygen, nitrogen and sulfur is connected directly to a carbon atom which is connected to a further carbon atom by a double bond, and / or which contains a cycle with three ring members, one or more of which corresponds to the group oxygen or sulfur atom or -N (R ^8c ) group, is excluded,

R ^{6 represents} a hydrogen, fluorine, chlorine, bromine or iodine atom, a nitrite group, a C ₃ alkyl group, or a C ₃ alkoxy group, the hydrogen atoms of the C ₃ alkyl or d _-3 Alkoxy group can optionally be completely or partially replaced by fluorine atoms,

R ^{7 is,} independently of one another, a C _-3 alkyl, where the hydrogen atoms can optionally be replaced in whole or in part by fluorine atoms, hydroxy, d- ₃ alkyloxy, where the hydrogen atoms can be replaced in whole or in part by fluorine atoms, amino , d- ₃ -alkylamino-, di- (Cι _-3 -alkyl) -amino-, C _3-6 -cycloalkylenimino-, carboxy-, Nitrile, d- ₃ -alkoxycarbonyl, aminocarbonyl, C ι _-3 -alkylaminocarbonyl or a di- (Cι _-3 -alkyl) -aminocarbonyl group, unless otherwise mentioned, below that mentioned in the definitions above The expression “heteroaryl group” is to be understood as a monocyclic 5- or 6-membered heteroaryl group, the 6-membered heteroaryl group having one, two or three nitrogen atoms and the 5-membered heteroaryl group, optionally with a C ₃ -C ₃ -alkyl, phenyl or phenyl group -Cι- ₃ -alkyl group-substituted imino group, an oxygen or sulfur atom or one optionally substituted by a Cι _-3 alkyl, phenyl, amino-C _2. ₃ alkyl, C _{-3 -3} alkylamino C _2-3 - alkyl, di (Cι _-3 alkyl) amino C _2-3 alkyl, a C ₃ - ₆ - cycloalkylenimino d ₃ alkyl or phenyl C ₃ alkyl substituted imino group or an oxygen - Or sulfur atom and in addition a nitrogen atom or an optionally by a .d-3-alkyl or phenyl -CC _-3- alkyl group substituted imino group and two or three nitrogen atoms, and also to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms, optionally by a fluorine, chlorine or bromine atom, a d- ₃ -alkyl, hydroxy, Cι _{- 3} -Alkyloxygruppe, amino, -C-3-alkylamino, di- (d _-3 -alkyl) - amino or C _3-6 cycloalkyleneimino substituted phenyl ring can be fused and the bond via a nitrogen atom or via a carbon atom of the heterocyclic Part or a fused phenyl ring takes place, Unless otherwise stated, the term "halogen atom" mentioned above in the definitions means an atom from the group fluorine, chlorine, bromine and iodine,

2. Substituted thiophene-2-carboxamides of the general formula I according to claim 1, characterized in that

A is a radical of the general formula

means in the

m is the number 1 or 2,

R ^8a each independently of one another is a hydrogen or fluorine atom or a C 3 alkyl, hydroxy, hydroxy C ₃ alkyl, C ₃ alkoxy, d ₃ alkoxy d ₃ alkyl ₃ , Amino, C _-3 alkylamino, di (d _-3 alkyl) amino, amino C _{3 -3} alkyl, Ci-s-alkylamino-Ci.s-alkyl, di (Cι ₃ -alkyl) -amino-d- ₃ -alkyl group, where in the above-mentioned substituted 5- to 7-membered radicals A, the heteroatoms F, O or N optionally introduced with R ^8a as substituents are not replaced by exactly one carbon atom of one Heteroatoms from the group N, O, S are separated, and two substituents R ^8a on the same or different carbon atoms form a Cι. ₅ -alkylene group can represent

R ^{8b represents} a hydrogen atom or a C _-3 alkyl group,

X ^{1 represents} an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8c group,

R ^8c each independently of one another a hydrogen atom, a Cι. ₃ -alkyl-, Cι- ₃ alkylcarbonyl, or a Cι- ₄ alkyloxycarbonyl group,

X ^{3 is} an oxygen atom or an -NR ^8c group,

X ^{4 represents} a carbonyl group,

R ^{1 represents} a fluorine, chlorine, bromine or iodine atom, a methyl or a methoxy group, where the hydrogen atoms of the methyl or methoxy group can optionally be completely or partially replaced by fluorine atoms, R ^{2 represents} a hydrogen or fluorine atom,

R ^{3 represents} a hydrogen atom,

R ^{4 is} a straight-chain or branched C _1-4 alkyl group, where the hydrogen atoms may optionally be replaced in whole or in part by fluorine atoms, and which may optionally be replaced by a hydroxy, a C 3 alkyloxy group, the hydrogen atoms of the C _{3 -3} alkyloxy group can be wholly or partly replaced by fluorine atoms, a benzyloxy, C _-3 alkylcarbonyloxy, C -3 alkyloxycarbonyl, aminocarbonyl, C _{3 -3} alkylaminocarbonyl, di (C ₃ alkyl) aminocarbonyl, C _3- 6-Cycloalkyleniminocarbonyl-, aminosulphonyl, d _-3 -AI- kylaminosulfonyl-, di- ₍₃ Cι- alkyl) -aminosulfonyl-, C ₃ - ₆ -Cycloalkyleniminosulfonyl-, amino, alkylamino d _-3 , Di- (Cι _-3 alkyl) - amino, d _-3 alkylcarbonylamino or Cι _-3 alkylsulfonylamino group may be substituted, a heteroaryl -CC _-2 alkyl or C-linked heteroaryl group, the heteroaryl group being selected from the group consisting of pyrrolyl, oxazolyl, imidazolyl, furanyl, thiophenyl, thiazolyl, 1, 2,3-T riazolyl, 1, 2,4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl and pyrazinyl, and which in the heteroaryl part are optionally selected one to two times by identical or different substituents selected from the group consisting of halogen atoms, Cι. ₃ -Alkyl-, hydroxy-, C _1-3 -alkyioxy-, mono-, di- and trifluoromethoxy groups can be substituted,

R ^{5 is} a hydrogen atom, a straight-chain or branched d _-4 -alkyl group, the hydrogen atoms optionally being able to be replaced in whole or in part by fluorine atoms, and optionally by a d- ₃ -alkyloxy group, the hydrogen atoms being the d-3-alkyloxy group can optionally be wholly or partly replaced by fluorine atoms, can be substituted, or d R ⁵ together with the carbon atom to which they are attached is a C _3-7 cycloalkyl or C _-7 cycloalkenyl group form, the C _3-7 cycloalkyl or C _4-7 cycloalkenyl group on a single carbon atom by a C _2-5 -A! kylengruppe or simultaneously on two different carbon atoms by a Cι _-4 alkylene group to form a corresponding spirocyclic or a bridged bicyclic system may be substituted, wherein one of the methylene groups of a C _4-7 cycloalkyl or C ₄ -7 cycloalkenyl or one, a corresponding spirocyclic or a corresponding bridged bicyclic by an oxygen or sulfur atom as described above or a sulfonyl or -N (R ^8c ) group can be replaced, and / or two directly adjacent methylene groups of a C _4-8 cycloalkyl group together by a -C (0) N (R ^8b ) - or - C (0) O group can be replaced, where 1 to 2 carbon atoms of a C _3-7 cycloalkyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above, optionally independently of one another, by ad _-3 -alkyl -, Hydroxy-, d- ₃ -alkyloxy-, di- (Cι- ₃ -alkyl) -amino group can be substituted, with the proviso that such, together from R ⁴ and R ⁵ formed C _3-7 cycloalkyl or C _-7 cycloalkenyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above, in which a methylene group of the cycle, which are directly connected to the carbon atom on which the radicals R ⁴ and R ^{5 are} connected, are replaced by a hetero atom from the group oxygen, nitrogen and sulfur, and / or in which a substituent bound to the cyclic group, which is characterized in that a hetero atom from the group oxygen and nitrogen is directly attached the cyclic group is bonded, is separated from another hetero atom from the group oxygen, nitrogen and sulfur, with the exception of the sulfone group, by exactly one, optionally substituted, methylene group, and / or in which a hetero atom from the group oxygen, nitrogen and sulfur is directly connected to a carbon atom which is connected to a further carbon atom by a double bond, and / or which contains a cycle with three ring members, one or more of which corresponds to the group oxygen or sulfur atom or -N (R ^8c ) group, is excluded,

R ^{6 represents} a chlorine or bromine atom,

Unless otherwise stated, the term "halogen atom" mentioned above in the definitions means an atom from the group fluorine, chlorine, bromine and iodine, where the alkyl and alkoxy groups contained in the definitions mentioned above, which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched and the alkyl groups in the aforementioned dialkylated radicals, for example the dialkylamino groups, are the same or different could be,

3. Substituted thiophene-2-carboxamides of the general formula I according to claim 1 or 2, characterized in that

A is a radical of the general formula

, or means

in the

m is the number 1 or 2, R ^8a each independently of one another is a hydrogen or fluorine atom or ad _-3 alkyl, hydroxy, hydroxy d _-3 alkyl, C ₃ alkoxy, d ₃ alkoxy C ₃ alkyl ₃ , Amino-, Cι _-3 -alkylamino-, di- (d _-3 -alkyl) -amino-, amino-Cι _-3 -alkyl-, Cι- ₃ -alkylamino-Cι _-3 -alkyl-, Di- (Cι _-3 ~ alkyl) -amino-d _-3 -alkyl group, where in the above-mentioned substituted 5- to 7-membered radicals A, the heteroatoms F, O or N optionally introduced with R ^8a as substituents are not replaced by exactly one carbon atom of one Heteroatoms are separated from the group N, O, S,

R ^{8b represents} a hydrogen atom or ad _-3 alkyl group,

X ^{1 represents} an oxygen atom or a -CH ₂ -, -CHR ^8a - or -NR ^8c group,

R ^{8c is} a hydrogen atom, a Cι _-3 alkyl, d. ₃ -Alkylcarbonyl-, or a Cι- ₄ alkyloxycarbonyl group,

X ^{3 represents} an oxygen atom or an -NR ^8c group,

R ^{2 represents} a hydrogen or fluorine atom,

R ^{3 represents} a hydrogen atom,

R ^{4 is} a methyl group which can optionally be substituted by a hydroxy, methoxy, benzyloxy, methoxycarbonyl or pyridin-4-yl group, or a furan-2-yl, 1-methyl-pyrazin-3-yl, Phenyl, pyridin-3-yl or pyrazin-2-yl group, R ^{5 represents} a hydrogen atom or a methyl group, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C _3-6 cycloalkyl or C _5-6 cycloalkenyl group, the C _3-6 cycloalkyl or C _5-6 cycloalkenyl group being attached a single carbon atom can be substituted by a C _2-4 alkylene group or at the same time on two different carbon atoms by a d- ₃ alkylene group to form a corresponding spirocycle or a bridged bicyclus, one of the methylene groups of a C _4-6 cycloalkyI- or C5-6 cycloalkenyl group or a corresponding spirocycle or a corresponding bridged bicyclus as described above can be replaced by an oxygen atom or an -N (R ^8c ) group, with the proviso that such a group, together from R ⁴ and R ⁵ formed C ₃ - ₆ cycloalkyl or C _5-6 cycloalkenyl group or a as described above, a corresponding spirocyclic or a corresponding bridged bicyclic system, in which a methylene group of the cycle, the are directly connected to the carbon atom to which the radicals R ⁴ and R ^{5 are} attached, are replaced by a hetero atom from the group oxygen and nitrogen, and / or in which a hetero atom from the group oxygen and nitrogen is connected directly to a carbon atom which is connected to a further carbon atom by a double bond, and / or which contains a cycle with three ring members, one or more of which corresponds to the group oxygen atom or -N (R ^8c ) group, is excluded,

R ^{6 represents} a chlorine or bromine atom

4. Substituted thiophene-2-carboxamides of the general formula I according to one or more of claims 1 to 3, characterized in that R ⁴ and R ^{5 is} not hydrogen.

5. Substituted thiophene-2-carboxamides of the general formula I according to one or more of claims 1 to 4, characterized in that R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclic group.

6. Substituted thiophene-2-carboxamides of the general formula I according to one or more of claims 1 to 5, characterized in that R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclic group, in which cyclic group, a methylene group is replaced by an oxygen atom or an N (R ^8c ) group.

7. Substituted thiophene-2-carboxamides of the general formula I according to one or more of claims 1 to 6, characterized in that R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclic group

represents.

8. Substituted thiophene-2-carboxamides of the general formula I according to one or more of claims 1 to 6, characterized in that R ⁴ and R ⁵ together with the carbon atom to which they are attached form a bridged bicyclic group

represents.

9. Substituted thiophene-2-carboxamides of the general formula I according to one or more of claims 1 to 8, characterized in that the radical A is the group means.

10. Substituted thiophene-2-carboxamides of the general formula I according to one or more of claims 1 to 8, characterized in that the radical A is the group

means.

11. Substituted thiophene-2-carboxamides of the general formula I according to one or more of claims 1 to 10, characterized in that R ^{6 is} a bromine atom.

12. Substituted thiophene-2-carboxamides of the general formula I according to one or more of claims 1 to 10, characterized in that R ^{6 represents} a chlorine atom.

13. Substituted thiophene-2-carboxamides of the general formula I according to one or more of claims 1 to 11, characterized in that R ^{1 represents} a fluorine, chlorine or bromine atom or a methyl or trifluoromethyl group.

14. Substituted thiophene-2-carboxamides of the general formula I according to one or more of claims 1 to 12, characterized in that R ^{1 represents} a hydrogen atom.

15. Physiologically acceptable salts of the compounds according to Claims 1 to 14.

16. Medicament containing a compound according to at least one of claims 1 to 14 or a physiologically acceptable salt according to claim 15 in addition to optionally one or more inert carriers and / or diluents.

17. Use of a compound according to at least one of claims 1 to 14 or a physiologically tolerable salt according to claim 15 for the manufacture of a medicament with an inhibitory effect on factor Xa and / or an inhibitory effect on related serine proteases.

18. A method for producing a medicament according to claim 15, characterized in that a compound according to at least one of claims 1 to 14 or a physiologically tolerable salt according to claim 15 is incorporated into one or more inert carriers and / or diluents in a non-chemical way.

19. A process for the preparation of the compounds according to claims 1 to 14, characterized in that

(a) a compound of the general formula

in which A, R ¹ , R ² and R ^{3 are} as defined in claim 1, with a compound of the general formula in which R ⁴ and R ^{5 are} as defined in claim 1, Z ^{6 represents} a protective group and Q represents a hydroxy, Cι _-4 alkoxy or an acyloxy group or a halogen atom, in an acylation step and subsequent cleavage of the protective group Z ⁶ to a compound the general formula

in which A, R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined in claim 1, and the compound of the general formula (XIV) is then reacted in an acylation step with a compound of the general formula

in which R ^{6 is} as defined in claim 1 and Q represents a hydroxy or -CC _-4 alkoxy group, a halogen atom or an acyloxy group, is converted to a thiophene-2-carboxamide of the general formula (I), or

(b) a compound of the general formula

in which R ⁴ and R ^{5 are} as defined in claim 1 and Z ^{8 represents} a protective group, with a compound of the general formula

in which R ^{6 is} as defined in claim 1 and Q represents a hydroxy or C ₄ alkoxy group, a halogen atom or an acyloxy group, in an acylation step and subsequent cleavage of the protective group Z ⁸ to a compound of the general formula

in which R ⁴ , R ⁵ and R ^{6 are} as defined in claim 1 and Q represents a hydroxy or Cι- ₄ alkoxy group, a halogen atom or an acyloxy group, and the compound of the general formula (XVII) is then reacted in a further one Acylation step with a compound of the general formula

in which A, R ¹ , R ² and R ^{3 are} as defined in claim 1, is converted to a thiophene-2-carboxamide of the general formula (I).