EP1910345A1

EP1910345A1 - Substituted amides, their preparation and their use as pharmaceuticals

Info

Publication number: EP1910345A1
Application number: EP06764178A
Authority: EP
Inventors: Kai Gerlach; Henning Priepke; Roland Pfau; Wolfgang Wienen; Annette Schuler-Metz; Georg Dahmann
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: 2005-07-19
Filing date: 2006-07-17
Publication date: 2008-04-16
Also published as: JP2009501760A; TW200740798A; WO2007009963A1; AR055201A1; US20070032473A1; CA2615447A1

Abstract

The present invention provides new substituted amides of the general formula (I) in which D, L, M, W and B are as defined in the description, their tautomers, their enantiomers, their diastereomers, mixtures thereof and salts thereof, particularly their physiologically acceptable salts with organic or inorganic acids or bases, which have valuable properties. The compounds act as inhibitors of factor Xa.

Description

- -

Substituted amides, their preparation and their use as pharmaceuticals

The present invention relates to novel substituted amides of the general formula (I)

their tautomers, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable 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 acceptable salts with inorganic or organic acids or bases, and their stereoisomers have valuable pharmacological properties, in particular an antithrombotic Effect and a factor Xa-inhibiting effect.

The present application relates to novel compounds of the above general formula (I), their preparation, the medicaments 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 - -

represents a substituted bicyclic ring system of the formula (II)

by doing

Each of K ¹ and K ⁴ independently represents a -CH ₂ -, -CHR ^7a -, -CR ^7b R ^7c - or a -C (O) group, wherein

R ^7a / R ^7b / R ^7c each independently represents a fluorine atom, a hydroxy, Ci- ₅ alkoxy, amino, Ci- ₅ alkylamino, di- (Ci- _5-alkyl) amino, C ₃ - ₅ -Cycloalkylenimino-, Ci- ₅ alkylcarbonylamino group, a Ci- ₅ alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-Ci ₅ alkyl, Ci-s-alkoxy-Ci-s-alkyl- .

Amino-d- _5- alkyl, ds-alkylamino-ds-alkyl, di- (Ci _-5- alkyl) -amino-Ci _-5- alkyl, C ^ -cycloalkylenimino-ds-alkyl, carboxy-Co -5-alkyl-, ds-alkoxycarbonyl-Co-s-alkyl, aminocarbonyl-C _0- 5 alkyl, ds-alkylaminocarbonyl-Co-s-alkyl, di (Ci _-5 alkyl) - aminocarbonyl Co- _5- alkyl or d- _7- cycloalkyleneiminocarbonyl

Co- ₅ -alkyl group means, wherein not simultaneously both R ^7b / R ^7c can be bonded via a heteroatom to the ring carbon atom, except -C (R ^7b R ^7c ) - corresponds to a -CF ₂ - group, or

two radicals R ^7b / R ^7c together with the ring carbon atom represent a 3-, 4-, 5-, 6- or 7-membered saturated carbocycle or a cyclopentene, cyclohexene, oxetane, azetidine, - -

Thietane, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran, piperidine, pentamethylenesulphide,

Hexamethyleneimine, 1, 3-dioxolane, 1, 4-dioxane,

Hexahydropyridazine, piperazine, thiomorpholine, morpholine, 2-imidazolidinone, 2-oxazolidinone, tetrahydro-2 (1 H) -pyrimidinone or [1, 3] oxazinan-2-one ring, wherein the Methylene groups may be substituted by 1 or 2 Ci _-3 - alkyl or -CF ₃ groups, and / or its methylene groups, unless they are attached to a

Heteroatom are bonded, may be substituted by 1-2 fluorine atoms, and / or in which a -CH ₂ group in addition to an N-atom may be replaced by a -C (O) - group and / or its imino groups in each case by a Ci _-3 alkyl or

Ci _-3 alkylcarbonyl group can be substituted and / or in which the sulfur atom can be oxidized to a sulfoxide or sulfone group,

Each of K ² and K ³ independently represents a -CH ₂ -, -CHR ^8a -, -CR ^8b R ^8c - or a -C (O) group, wherein

R ^8a / R ^8b / R ^8c each independently represent a Ci ₅ alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-Ci _-5 - alkyl, Ci-s-alkoxy-ds-alkyl, amino -ds-alkyl-, d- ₅ -alkyl-amino-C-ι- ₅ -alkyl-, di- (Ci- ₅ -alkyl) -amino-Ci- ₅ -alkyl-, C _4-7 -cyclo-alkylenimino -C-ι- ₅ alkyl, carboxy-d- ₅ alkyl, d- ₅ -Alkoxycarbo- nyl-Ci ₅ alkyl, aminocarbonyl-Ci- ₅ alkyl, Ci- ₅ -Alkylaminocar- - -

bonyl-Ci ₅ alkyl, di (Ci _-5 alkyl) aminocarbonyl-Ci _-5 alkyl or C ₄ -7-Cycloalkyleniminocarbonyl-Ci _-5 alkyl group means,

or two radicals R ^8b / R ^8c together with the ring carbon atom, a 3-, 4-, 5-, 6- or 7-membered saturated carbocycle or a cyclopentene, cyclohexene, oxetane, azetidine, thietane, tetrahydrofuran, pyrrolidine -, tetrahydrothiophene, tetrahydropyran, piperidine, pentamethylene sulfide, hexamethyleneimine, hexahydropyridazine, tetrahydro-2 (1 H) -pyrimidinone or [1, 3] oxazinan-2-one ring can form, wherein the Methylene groups by 1 or 2 d- ₃ -

Alkyl or -CF ₃ groups may be substituted, and / or its methylene groups, unless they are attached to a

Heteroatom are attached may be substituted by 1 or 2 fluorine atoms, and / or wherein a -CH ₂ - group may be replaced in addition to a nitrogen atom by a -CO- group and / or the imino groups in each case by a Ci- ₃ alkyl or d- _3- alkylcarbonyl group may be substituted and / or wherein the sulfur atom to a sulfoxide or

Sulfone group can be oxidized, with the proviso that a heteroatom introduced by R ^8b or R ^8c not by only one

Carbon atom of X may be separated in formula I, and

in total in formula (II) a maximum of four radicals selected from R ^7a , R ^7b , R ^7c ,

R ^8a , R ^8b and R ^8c may be present, - -

X represents an oxygen or sulfur atom, a sulfene, sulfone or an -N (R ¹ ) group, in which

R ¹ is a hydrogen atom or a hydroxy, Ci- ₃ alkoxy, amino, _d-3 alkylamino, di- (Ci ₃ alkyl) amino, d- ₅ alkyl, C _{_3-5} Alkenyl-CH ₂ -,

C _3-5 alkynyl CH ₂ , Cs-e-cycloalkyl, C _4-6 cycloalkenyl, oxetan-3-yl,

Tetrahydrofuran-3-yl, benzyl, ds-alkylcarbonyl, trifluoromethylcarbonyl, Cs-β-cycloalkylcarbonyl, Ci _-5- alkylsulfonyl, C _3-6 -cycloalkylsulfonyl, aminocarbonyl, ds-alkylaminocarbonyl -, di (Ci- ₅ -AL- alkyl) aminocarbonyl, Ci _-5 alkyloxycarbonyl- or C _4-7 cycloalkyl eniminocarbonylgruppe,

wherein the methylene and methyl groups present in the above-mentioned groups may additionally be substituted by a Ci _-3 alkyl, carboxy, Ci _-5 -Alkylcarboxycarbonylgruppe, or by a hydroxy, Ci _-5 - alkoxy, amino, Ci ₅ alkylamino, Ci- ₅ dialkylamino, or C _4- 7-cycloalkyleneimino group may be substituted, the methylene or methyl groups are not directly provided to a hetero atom from the group O, N or S are bound,

and / or one to three hydrogen atoms may be replaced by fluorine atoms, provided that the methylene or methyl groups are not bonded directly to a heteroatom from the group O, N or S,

A ^{1 represents} an oxygen or sulfur atom, a -C (R ¹⁰ ) = N, -N = C (R ¹⁰ ) -, or -C (R ¹⁰ ) = C (R ¹¹ ) group,

A ^{2 is} either a nitrogen atom or an = C (R ¹² ) group,

wherein R ¹⁰ , R ¹¹ and R ^{12 are} each independently - -

is a hydrogen, fluorine, chlorine, bromine or iodine atom, or a Ci ₅ alkyl, -CF _3, C ₂ - ₅ alkenyl, C ₂ - ₅ alkynyl, cyano, carboxy, C _-5 alkoxycarbonyl, hydroxy, Ci _-3 alkoxy, CF ₃ O, CHF ₂ O, CH ₂ FO, amino, Ci- ₅ alkylamino, di- (Ci- ₅ alkyl) mean amino or C 1-4 cycloalkyleneimino group,

represents a substituted ring system of the formula (IIa) or (IIb),

by doing

R ³ is a hydrogen atom or a Ci _-3 alkyl group,

R ⁴ and R ^{5 are} each independently

a hydrogen atom, a hydroxy group, an -OR ⁹ group, a C _2-6 alkenyl or C _2-6 alkynyl group,

a linear or branched C ₆ alkyl group wherein the hydrogen atoms of the straight-chain or branched d-β-alkyl group may optionally be substituted by fluorine atoms entirely or partially, and wherein the straight or branched Ci _-6 alkyl group optionally substituted by a C _3-5 cycloalkyl, nitrile, hydroxy, Ci _-5 alkyloxy group, allyloxy, propargyloxy, benzyloxy, Ci- ₅ alkylcarbonyloxy, Ci- ₅ -Alkyloxycarbonyloxy-, carboxy- Ci- alkyloxy _5, Ci- s-alkyloxycarbonyl-Ci-s-alkyloxy, mercapto, - -

Ci _-5 alkylsulphanyl, Ci _-5 alkylsulfonyl, carboxy, Ci _-5 -Al kyloxy- carbonyl, aminocarbonyl, ds-alkylaminocarbonyl, di- (Ci _-5 -AL- alkyl) aminocarbonyl, Cs-β-Cycloalkyleniminocarbonyl-, sulfonyl amino, Ci- ₅ alkylaminosulfonyl, di- (Ci- _5-alkyl) -aminosulfonyl-, Cs-β-Cycloalkyleniminosulfonyl-, amino, ds-alkylamino, di-

(Ci- ₅ -alkyl) amino, Ci- ₅ alkylcarbonylamino, d- ₅ alkylsulfonylamino, A / ds-AlkylsulfonyO-Ci-s-alkylamino or C _3-6 -Cycloalkylcarbonylaminogruppe substituted may be, wherein the hydrogen atoms of the Ci _-5 alkyloxy group may optionally be substituted by fluorine atoms entirely or partially, and wherein membered 7 in the 6- to cycles of C ₃ - ₆ -

Cycloalkyleniminocarbonylgruppe in the cyclic part a

Methylene group in the 4-position of a 6- or 7-membered Cycloalkyleniminogruppe by an oxygen or

Sulfur atom, may be replaced by a carbonyl, sulfinyl, sulfonyl or --NR ^8c group, and additionally a methylene group adjacent to an aforementioned - NR ^8c group may be replaced by a carbonyl group,

a phenyl or heteroaryl group which is optionally substituted in the phenyl or heteroaryl moiety to trisubstituted by identical or different substituents selected from the group consisting of halogen atoms, Ci- ₅ alkyl, di (Ci _-5 alkyl) amino may be hydroxy, Ci _-5 -alkyloxy, mono-, di- or trifluoromethoxy, carboxy and Ci- ₅ alkyloxy carbonyl substituted,

a phenyl-Ci ₅ alkyl or heteroaryl-Ci- ₅ alkyl group, in the phenyl or heteroaryl moiety may optionally be mono- to trisubstituted by identical or different substituents selected from the group consisting of halogen atoms, - -

CI ₅ alkyl, di (Ci _-5 alkyl) amino, hydroxy, Ci _-5 -alkyloxy, mono-, di- or trifluoromethoxy, carboxy and Ci- ₅ alkyloxy carbonyl groups substituted may optionally be in the Ci- ₅ -alkyl part by a hydroxy or a d- ₅ -alkyl- oxygruppe, wherein the hydrogen atoms of the Ci- ₅ -alkyloxy group may optionally be wholly or partially replaced by fluorine atoms, an allyloxy , propargyloxy, benzyloxy, d- ₅ alkylcarbonyloxy, d- ₅ -Alkyloxycarbonyloxy-, carboxy- Ci- ₅ alkyloxy or ds-alkyloxycarbonyl-d-alkyloxy group may be substituted,

a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-d- _5- alkyl or cycloalkyleneimino-ds-alkyl group, in which at 4- to 7-membered cycles in the cyclic part of a methylene group optionally substituted by an -N (R ^8c ) group, a

Oxygen or sulfur atom, or an -S (O) - or -S (O) 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 (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 substituted by a -OC (O) 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, cycloalkyl-d- _5- alkyl or cycloalkyleneimino-ci ₃ -alkyl group as defined above, in which two heteroatoms from the group consisting of oxygen and nitrogen by exactly - -

an optionally substituted -CH ₂ group are separated from each other, is excluded,

wherein a composition as defined above, 3- to 7-membered cycloalkyl, Cycloalkylenimino-, cycloalkyl-d-alkyl or cycloalkylene imino-Ci- ₃ alkyl group at one or two -CH ₂ groups in each case by one or two Ci _-3 With the proviso that R ⁴ and R ⁵ can not be simultaneously defined as hydroxy or -OR ⁹ groups, and wherein

R ⁹ is a straight or branched C ₆ alkyl group wherein the hydrogen atoms of the straight-chain or branched comparable Ci _-6 alkyl group may optionally be wholly or partly replaced by fluorine atoms, and wherein the straight or branched Ci _-6 alkyl group optionally by a C _3-5 cycloalkyl group, hydroxy, Ci- _oxy-5 alkyloxy, allyloxy, propargyloxy, benzyl, Ci- ₅ alkylcarbonyloxy, Ci -Alkyloxycarbonyloxy- _5,

Carboxy-Ci- ₅ -alkyloxy, Ci-s-alkyloxycarbonyl-Ci-s-alkyl-oxy, carboxy, Ci- ₅ -alkyloxycarbonyl, aminocarbonyl, Ci _-5- alkylaminocarbonyl, di (Ci _-5 -alkyl) -aminocarbonyl, Cs-β-cycloalkyleniminocarbonyl, amino, ds-alkylamino, di- (Ci _-5- alkyl) -amino, ds-alkylcarbonylamino,

Ci- ₅ alkylsulfonylamino, Λ / - (Ci _-5 alkylsulfonyl) -C _-5 alkyl amino or Cs-β-cycloalkylcarbonylamino group may be substituted, wherein the hydrogen atoms of the Ci ₅ alkyloxy optionally be wholly or partly replaced by Fluorine atoms can be replaced, and wherein in the 6- to 7-membered cycles of C _3-6 - - -

Cycloalkyleniminocarbonylgruppe in the cyclic part of a methylene group in the 4-position of a 6- or 7-membered Cycloalkyleniminogruppe by an oxygen or sulfur atom, by a carbonyl, sulfinyl,

5 sulfonyl or -NR ^8c - group may be replaced, and in addition a methylene group adjacent to an aforementioned -NR ^8c - group may be replaced by a carbonyl group, with the proviso that the replacement of

10 hydrogen atoms of the first carbon atom of the straight-chain or branched C ₆ alkyl group is excluded by substituents from the group of oxygen, sulfur or nitrogen,

15 is a phenyl, heteroaryl, phenyl-Ci _-5- alkyl- or heteroaryl-d- _5- alkyl group which in the phenyl or heteroaryl optionally one to three times by identical or different substituents selected from the group consisting

20 from halogen atoms, Ci- ₅ alkyl, di- (Ci- _5-alkyl) -amino,

Hydroxy, Ci- ₅ -alkyloxy, mono-, di- or trifluoro-methoxy, carboxy and Ci- ₅ -Alkyloxycarbonylgruppen may be substituted,

25 is a 3- to 7-membered cycloalkyl, cycloalkyl-Ci _-5- alkyl- or cycloalkylenimino-C _2-3 alkyl group, in which at 4- to 7-membered cycles in the cyclic part, a methylene group optionally substituted by an -N ( R ^8c ) group, an oxygen or sulfur atom

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

with the proviso that a 3- to 7-membered cycloalkyl, cycloalkyl-Ci- ₅ -alkyl or cycloalkyleneimino-C ₂ - ₃ -alkyl group as defined above in which two heteroatoms from the group oxygen and

Nitrogen are separated by exactly one optionally substituted -CH ₂ - group, is excluded,

wherein a 3- to 7-membered one as defined above

Cycloalkyl, cycloalkyl-Ci- ₅ -alkyl- or cycloalkylene-imino-C ₂ - ₃ -alkyl group may be substituted on one or two -CH ₂ - groups by one or two Ci _-3 alkyl groups, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C ₃ - ₈ cycloalkenyl group form - ₈ cycloalkyl or C ₃

wherein one of the methylene groups of a C ₄ -S-CyClOaI- kylgruppe by an oxygen or sulfur atom or - -

a -N (R ^8c ), carbonyl, sulfinyl or sulfonyl group may be replaced, and / or

two directly adjacent methylene groups one

May be replaced by a -C (O) N (R ^8b ) - or -S (O) ₂ N (R ^8b ) - group and / or. 5 C ₄ - ₈ -Cycloalkyl group together

three directly adjacent methylene groups of a C _6-8 -cycloalkyl group together by a -OC (O) N (R ^8b ) -, -

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

wherein 1 to 3 carbon atoms of a C ₃ - ₈ cycloalkyl group optionally independently of each other by a

15 or two identical or different halogen atoms, or C ₅ alkyl, nitrile, hydroxy, Ci _-5 alkyloxy, _d-5 alkyl carbonyloxy, carboxy-Ci _-5 alkyl, d- ₅ alkyloxycarbonyl- ₅ d- alkyl, Ci _-5 alkylsulphanyl, Ci _-5 alkylsulfonyl, carboxy, Ci- ₅ alkyloxycarbonyl, aminocarbonyl, d- alkylamino ₅

20 carbonyl, di- (Ci- _5-alkyl) aminocarbonyl, C ₃ - ₆ cycloalkylene iminocarbonyl-, aminosulfonyl, d- ₅ alkylaminosulfonyl, di- (Ci- _5-alkyl) -aminosulfonyl-, C ₃ - ₆ nyl- -Cycloalkyleniminosulfo-, amino, d- ₅ alkylamino, di- (Ci- _5-alkyl) -amino, Ci-5-alkylcarbonylamino, Ci _-5 alkylsulfonylamino, Λ / - (d-5

25 alkylsulfonyl) -Ci _-5- alkylamino or C _3-6 -cycloalkylcarbonyl-amino groups may be substituted,

wherein 1 to 2 carbon atoms of a C _{_3-8} -Cycloalken- yl group optionally substituted independently by

30 each represents a d-5-alkyl, nitrile, carboxy-d-5-alkyl, d-5

Alkyloxycarbonyl-d-5-alkyl, carboxy, Ci-5-Alkyloxycarbo- nyl-, aminocarbonyl, d- ₅ alkylaminocarbonyl, di (Ci _-5 -AL- - -

alkyl) aminocarbonyl, Cs-β-Cycloalkyleniminocarbonyl-, amino nosulfonyl-, Ci- ₅ alkylaminosulfonyl, di- (Ci- _5-alkyl) amino-sulfonyl or Cs-β-Cycloalkyleniminosulfonylgruppe may be substituted, 5 and 1 to 2 carbon atoms of a C 1-8 cycloalkenyl group, which are not bound by a double bond to another carbon atom, optionally independently of each other by a fluorine atom or a

10 hydroxy, Ci _-5 -alkyloxy-, ds-alkylcarbonyloxy, Ci _-5 alkyl sulfanyl, _d-5 alkylsulfonyl, amino, ds-alkylamino, di- (Ci- _5-alkyl) - amino, Ci- ₅ -alkylcarbonylamino-, d- ₅ -Alkylsul- fonylamino-, Λ / - (Ci- ₅ alkylsulfonyl) -ci- ₅ alkylamino or Cs-β-cycloalkylcarbonylamino group may be substituted

15,

with the proviso that such a C _3-8 -cycloalkyl or C _3-8 -cycloalkenyl group formed together from R ⁴ and R ⁵ ,

20 in the two heteroatoms in the cycle from the group

Oxygen and nitrogen are separated by exactly one optionally substituted -CH ₂ - group, and / or

25 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

30 in the bonded to the cyclic group substituent, which is characterized in that a - -

Heteroatom from the group oxygen, nitrogen, sulfur and halogen atom is bonded directly to the cyclic group, is separated from another heteroatom 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, is excluded,

M represents a -CH ₂ -, -CHR ³ -, -CR ³ R ³ - group or a bond,

W represents an oxygen or sulfur atom,

B represents a thiophene ring according to formula (IM),

which is bonded via the 2-position to the carbonyl group in formula (I) and which is substituted in the 5-position by R ² and optionally additionally by R ⁶ , wherein

R ^{2 is} a fluorine, chlorine, bromine or iodine atom, or a methoxy, Ci _-2 -

Alkyl or ethynyl group means

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

Ci _-2 alkyl or amino group means - -

Unless otherwise stated, the term "heteroaryl group" mentioned above in the definitions refers to a monocyclic 5- or 6-membered heteroaryl group, wherein

the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and

the 5-membered heteroaryl group optionally substituted by a Ci _-3 alkyl imino group, an oxygen or sulfur atom, or

an optionally substituted by a Ci _-3 alkyl group imino group, or an oxygen or sulfur atom and additionally a nitrogen atom, or

an optionally, contains by a Ci _-3 alkyl substituted imino group and two or three nitrogen atoms,

and in addition to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms optionally substituted by a fluorine, chlorine or bromine atom, a C ₃ alkyl, hydroxy, Ci- ₃ alkyloxy, amino, Ci- ₃ alkylamino , Di- (ci- _3- alkyl) -amino or C _3-6 -cycloalkyleneimino group may be fused to a substituted phenyl ring,

and the bond is 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 consisting of fluorine, chlorine, bromine and iodine, - -

wherein the alkyl, alkenyl, alkynyl and alkoxy groups having more than two carbon atoms contained in the above-mentioned definitions, unless otherwise mentioned, may be straight-chain or branched and the alkyl groups in the above-mentioned dialkylated groups, for example, the dialkylamino groups , same or different,

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

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

Examples of monocyclic heteroaryl groups are the pyridyl, Λ / -oxypyridyl, 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 [αf] isothiazolyl, benzooxazolyl, , Benzo [c] isoxazolyl, benzo [αφsoxazolyl, 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 / oxyquinolinyl, isoquinolinyl, quinazolinyl, Λ / Oxyquinazolinyl, quinoxalinyl, phthalazinyl, indolyl, isoindolyl or 1-oxa-2,3-diaza-indenyl group.

Examples of the above-mentioned in the definitions d- ₆ alkyl groups - -

are the methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, ferf-butyl, 1-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 above-mentioned in the definitions Ci _-5 -Alkyloxygruppen are the methyloxy, ethyloxy, 1-propyloxy, 2-propyl-oxy, n-butyloxy, sec-butyloxy, ferf-butyloxy, 1 - Pentyloxy, 2-pentyloxy, 3-pentyloxy or neo-pentyloxy group.

Examples of the above-mentioned in the definitions of C ₂ - ₅ alkenyl groups are ethenyl, 1-propen-1-yl, 2-propen-1-yl, 1-butene-1-yl, 2-butene 1-yl, 3-buten-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-ene -2-yl, but-2-en-2-yl, but-1-en-3-yl, 2-methyl-prop-2-en-1-yl, pent-1-ene-2 -yl, pent-2-en-2-yl, pent-3-en-2-yl, pent-4-en-2-yl, pent-1-en-3-yl, pentyl 2-en-3-yl, 2-methylbut-1-en-1-yl, 2-methylbut-2-en-1-yl, 2-methylbut-3-ene-1 -yl or 2-ethyl-prop-2-en-1-yl group,

Examples of the above-mentioned in the definitions of C ₂ - ₅ alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1-butyn-1-yl, 1-butyn-3-yl, 2-butyn 1-yl, 3-butyn-1-yl, 1-pentyne-1-yl, 1-pentyne-3-yl, 1-pentyne-4-yl, 2-pentyne-1-yl , 2-Pentin-3-yl, 3-pentyne-1-yl, 4-pentyne-1-yl, 2-methyl-1-butyne-4-yl, 3-methyl-1-butyne-1 -yl or 3-methyl-1-butyn-3-yl group.

A second embodiment of the present invention includes those

Compounds of the general formula (I) in which

D represents a substituted bicyclic ring system of the formula (II)

(H). - -

by doing

_R 7a _{/ R} 7b _{/ R} 7c each independently represents a fluorine atom, a hydroxy, d- ₅ alkoxy group, a C ₅ alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-Ci ₅ alkyl , C ₁ . _5- alkoxy-C ₁ . ₅ - alkyl group, where not both R ^7b / R ^7c can be bonded via a heteroatom to the ring carbon atom at the same time, except -C (R ^7b R ^7c ) - corresponds to a -CF ₂ - group, or

two R ^7b / R ^7c together with the ring carbon may form a 3-, 4-, 5-, 6- or 7-membered saturated carbocycle or a cyclopentene, cyclohexene, oxetane, tetrahydrofuran, tetrahydropyran ring, wherein its methylene groups by 1 or 2 C ₁ . ₃ -alkyl or -CF ₃ groups may be substituted, and / or its methylene groups, if they are not bonded to a heteroatom, may be substituted by 1-2 fluorine atoms, and / or in which a -CH ₂ - group in addition to a N atom may be replaced by a -C (O) group,

K ² and K ³ - -

each independently represents a -CH ₂ -, -CHR ^8a -, -CR ^8b R ^8c - or a -C (O) group, wherein

_R 8a _{/ R} 8b _{/ R} 8c each independently represent a Ci ₅ alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-d- ₅ - alkyl, Ci _-5 alkoxy-Ci _-5 alkyl group means .

or two R ^8b / R ^8c together with the ring carbon may form a 3-, 4-, 5-, 6- or 7-membered saturated carbocycle or a cyclopentene, cyclohexene, oxetane, tetrahydrofuran, tetrahydropyran ring, wherein its methylene groups may be substituted by 1 or 2 d- ₃ - alkyl or -CF ₃ groups, and / or its methylene groups, if they are not bonded to a heteroatom, may be substituted by 1 or 2 fluorine atoms, and / or at in which a -CH ₂ - group may be replaced by a -C (O) group in addition to a nitrogen atom,

with the proviso that a heteroatom introduced by R ^8b or R ^{8c may} not be separated by only one carbon atom of X in Formula I, and

in total in formula (II) a maximum of four radicals selected from R ^7a , R ^7b , R ^7c , R ^8a , R ^8b and R ^8c may be present,

X represents an oxygen or sulfur atom, a sulfene, sulfone or an -N (R ¹ ) group, in which - -

R ¹ is a hydrogen atom or a hydroxy, Ci- ₃ alkoxy, amino, _d-3 alkylamino, di- (Ci ₃ alkyl) amino, Ci- ₅ alkyl, C _{_3-5} Alkenyl CH ₂ , C _3-5 alkynyl CH ₂ , Cs-e-cycloalkyl, C _4-6 cycloalkenyl, oxetan-3-yl, tetrahydrofuran-3-yl, benzyl, d- ₅ alkylcarbonyl, trifluoromethyl carbonyl, Cs-β-cycloalkylcarbonyl, Ci- ₅ alkylsulfonyl, C ₃ - ₆ kylsulfonyl- -Cycloal-, aminocarbonyl, ds-alkylaminocarbonyl, di- (Ci- ₅ alkyl) - aminocarbonyl, d- ₅ -alkyloxycarbonyl or C _4-7 -cycloalkylene-iminocarbonyl group,

wherein the methylene and methyl groups present in the above-mentioned groups may additionally ₅ -Alkylcarboxycarbonylgruppe by a Ci- ₃ alkyl, carboxy, Ci- be substituted or by a hydroxy, ds- alkoxy, amino, Ci- ₅ - Alkylamino, Ci- ₅ -dialkylamino or

C ₄ -7-Cycloalkyleniminogruppe can be substituted if the methylene or methyl groups are not directly bonded to a heteroatom from the group O, N or S,

A ^{2 is} either a nitrogen atom or an = C (R ¹² ) group,

wherein R ¹⁰ , R ¹¹ and R ^{12 are} each independently

a hydrogen, fluorine, chlorine, bromine or iodine atom, or a - -

d- _C5 alkyl, -CF _3, C _2-5 alkenyl, C _2-5 alkynyl, cyano, carboxy, Ci- ₅ alkoxycarbonyl, hydroxy, Ci _-3 alkoxy, CF ₃ O, CHF, CH ₂ FO, amino, Ci- ₅ alkylamino, di- (Ci- _5-alkyl) amino or C ^ -Cycloalkylenimino- group ₂ O-,

represents a substituted ring system of the formula (IIa) or (IIb),

by doing

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

R ⁴ and R ^{5 are} each independently

a straight or branched _Ci-6-alkyl group wherein the hydrogen atoms of the straight-chain or branched

Ci- ₆ alkyl group may optionally be wholly or partly replaced by fluorine atoms, and wherein the straight-chain or branched C ₆ alkyl group optionally substituted by a C _3-5 cycloalkyl, nitrile, hydroxy, Ci- ₅ alkyloxy group, allyloxy , Propargyloxy, benzyloxy,

Ci _-5 alkylcarbonyloxy, ds-alkyloxycarbonyloxy, carboxy Ci- alkyloxy _5, Ci-s-alkoxycarbonyl-d-alkyloxy, mercapto, Ci- ₅ alkylsulphanyl, Ci- ₅ alkylsulfonyl, carboxy -, carbonyl Ci- ₅ alkyloxy, aminocarbonyl, Ci-s-alkylaminocarbonyl, di- (Ci- ₅ -AL- - -

alkyl) aminocarbonyl, Cs-β-Cycloalkyleniminocarbonyl-, Aminosul- fonyl-, Ci- ₅ alkylaminosulfonyl, di- (Ci- _5-alkyl) -aminosulfonyl-, Cs-β-Cycloalkyleniminosulfonyl-, amino, Ci _5- Alkylamino-, di- (Ci- ₅ -alkyl) -amino, Ci-s-alkylcarbonylamino, d- ₅ -Alkylsulfonylamino-, Λ / - (Ci- ₅ -alkylsulfonyl) -Ci- ₅ -alkylamino - or C ₃ - ₆ -Cy- cloalkylcarbonylaminogruppe may be substituted, wherein the hydrogen atoms of the Ci _-5 alkyloxy group may optionally be substituted by fluorine atoms entirely or partially, and wherein membered 7 in the 6- to cycles of C ₃ - ₆ -

Cycloalkyleniminocarbonylgruppe in the cyclic portion of a methylene group in the 4-position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulfur atom, by a carbonyl, sulfinyl, sulfonyl or --NR ^8c group, and additionally one

Methylene group adjacent to an aforementioned - NR ^8c group may be replaced by a carbonyl group,

a phenyl or heteroaryl group which is optionally substituted 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 (Ci _-5 alkyl) amino , Hydroxy, Ci _-5- alkyloxy, mono-, di- or trifluoromethoxy, carboxy and ds-alkyl oxycarbonyl groups may be substituted,

a phenyl-Ci _-5 alkyl, or heteroaryl-Ci _-5 alkyl, 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,

CI ₅ alkyl, di- (Ci- _5-alkyl) amino, hydroxy, Ci- ₅ -alkyloxy, mono-, di- or trifluoromethoxy, carboxy and Ci- ₅ -alkyloxy- - -

carbonyl groups may be substituted, and which optionally in the Ci- ₅ -alkyl part by a hydroxy or a Ci- ₅ -alkyloxy, wherein the hydrogen atoms of the Ci- ₅ -alkyloxy may optionally be wholly or partially replaced by fluorine atoms, an allyloxy , Propargyloxy,

Alkyloxy benzyloxy, Ci- ₅ alkylcarbonyloxy, Ci- ₅ -Alkyloxycarbonyloxy-, carboxy-d- _5, or a Ci _-5 alkyloxycarbonyl- Ci- ₅ alkyloxy group may be substituted,

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

Ci- ₅ -alkyl- or cycloalkylenimino-ci- _3- alkyl group, in which at 4- to 7-membered cycles in the cyclic part a

Methylene optionally by a -N (R ^8c ) group

Oxygen or sulfur atom, or a -S (O) or -S (O) ₂ - group may be replaced, or

with the proviso that a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-ds-alkyl or cycloalkyleneimino-cis-alkyl group as defined above, in which two heteroatoms selected from the group consisting of oxygen and nitrogen by exactly one optionally substituted - CH ₂ group are separated from each other, is excluded, - -

wherein a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-ds-alkyl or cycloalkylenimino-ci ₃ -alkyl group as defined above is substituted on one or two -CH ₂ groups by one or two d- _3, respectively With the proviso that R ⁴ and R ⁵ can not be simultaneously defined as hydroxy or -OR ⁹ groups, and wherein

R ⁹ is a straight or branched C ₆ alkyl group wherein the hydrogen atoms of the straight-chain or branched C ₆ alkyl group may optionally be wholly or partly replaced by fluorine atoms, and wherein the straight or branched

Ci _-6 alkyl group optionally alkyl group by a C _3-5 -cycloalkyl, hydroxy, Ci _-5 alkyloxy, allyloxy, propargyloxy, benzyloxy, Ci _-5 alkylcarbonyloxy, Ci -Alkyloxycarbonyloxy- _5, Carboxy-Ci- ₅ -alkyloxy, Ci-s-Al-kyloxycarbonyl-Ci- ₅ -alkyloxy, carboxy, Ci- ₅ -Alkyloxycar- bonyl-, aminocarbonyl, Ci- ₅ -alkylaminocarbonyl, di (Ci - ₅ alkyl) aminocarbonyl, C ₃ - ₆ -Cycloalkyleniminocarbo- nyl-, amino, ds-alkylamino, di- (Ci- _5-alkyl) -amino, Ci- ₅ -alkylcarbonylamino-, Ci- ₅ Alkylsulfonylamino-, A / ^ Ci-s-alkylsulfonyO-Ci-s-alkylamino or C _3-6 -cycloalkylcarbonylaminogruppe may be substituted, wherein the hydrogen atoms of the Ci _-5- alkyloxy may optionally be wholly or partly replaced by fluorine atoms , and wherein in the 6- to 7-membered cycles the C ₃ - ₆ -

Cycloalkyleniminocarbonylgruppe in the cyclic part of a methylene group in the 4-position of a 6- or 7- - -

may be replaced by an oxygen or sulfur atom, by a carbonyl, sulfinyl, sulfonyl or -NR ^8c - group and additionally adjacent to a methylene group

May be replaced by a carbonyl group, with the proviso that the replacement of hydrogen atoms of the first carbon atom of the straight-chain or branched Ci _-6 alkyl group - 5 to a above-mentioned -NR ^8c

10 by substituents from the group oxygen,

Sulfur or nitrogen is excluded,

a phenyl, heteroaryl, phenyl-Ci ₅ alkyl or heteroaryl-C-ι- ₅ alkyl group,

15 in the phenyl or heteroaryl optionally one to three times by the same or different substituents selected from the group consisting of halogen atoms, Ci _-5- alkyl, di (Ci _-5- alkyl) -amino-, hydroxy-, Ci- _5- alkyloxy, mono-, di- or trifluoromethylene

20 thoxy-, carboxy and Ci- ₅ -Alkyloxycarbonylgruppen may be substituted,

a 3- to 7-membered cycloalkyl, cycloalkyl-Ci _-5- alkyl- or cycloalkylenimino-C _2-3 -alkyl group,

25 in the case of 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 (O) ₂ - group can be replaced, or

30 in the at 4- to 7-membered cycles in the cyclic part two adjacent methylene together - -

optionally substituted by a -C (O) N (R ^8b ) or -S (O) ₂ N (R ^8b ) group, or

with the proviso that a 3- to 7-membered cycloalkyl, cycloalkyl-Ci- ₅ -alkyl or cycloalkyleneimino-C ₂ - ₃ -alkyl group as defined above, in which two heteroatoms from the group oxygen and nitrogen by exactly one optionally substituted -CH ₂ - group are separated from each other, is excluded,

where a 3- to 7-membered cycloalkyl, cycloalkyl-Ci- ₅ -alkyl or cycloalkylene-imino-C ₂ - ₃ -alkyl group as defined above is present at one or two -CH ₂ -

Groups may be substituted by one or two d- ₃ alkyl groups, 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 one of the methylene groups of a C ₄ -S-CyClOaI kyl- group by an oxygen or sulfur atom or a

-N (R ^8c ), carbonyl, sulfinyl or sulfonyl group may be replaced, and / or - -

two directly adjacent methylene groups of a _d-8 -cycloalkyl alkyl group together by a -C (O) N (R ^8b) - or - S (O) ₂ N (R ^8b) - group can be replaced, and / or 5 three directly adjacent methylene groups of a Cβ-β-cycloalkyl group together by a -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,

10 wherein from 1 to 3 carbon atoms of a C _{_3-8} cycloalkyl group optionally substituted independently from each other by one or two identical or different halogen atoms, or C ₅ alkyl, nitrile, hydroxy, Ci _-5 -alkyloxy-, d- ₅ alkyl

15 carbonyloxy, carboxy-Ci _-5 alkyl, d- d- alkyloxycarbonyl- ₅ ₅ alkyl, Ci _-5 alkylsulphanyl, Ci _-5 alkylsulfonyl, carboxy, Ci- ₅ -alkyloxycarbonyl, aminocarbonyl, d- ₅ alkylamino, carbonyl-di (Ci _-5 alkyl) aminocarbonyl, C _3-6 cycloalkylene iminocarbonyl-, aminosulfonyl, d- ₅ alkylaminosulfonyl,

20 di- (Ci- _5-alkyl) -aminosulfonyl-, C ₃ - ₆ nyl- -Cycloalkyleniminosulfo-, amino, d- ₅ alkylamino, di- (Ci- _5-alkyl) -amino, Ci-5 Alkylcarbonylamino, Ci-5-alkylsulfonylamino, Λ / (d-5-alkylsulfonyl) -Ci _-5- alkylamino or C _3-6 -cycloalkylcarbonyl-amino groups may be substituted,

25 wherein from 1 to 2 carbon atoms of a C _{_3-8} cycloalkenyl group optionally substituted independently by a respective d-5-alkyl, nitrile, carboxy-d-5-alkyl, d-5- alkyloxycarbonyl-d-5-alkyl , Carboxy, Ci-5-Alkyloxycarbo-

30 nyl, aminocarbonyl, d-5-alkylaminocarbonyl, di-

(d-5-alkyl) aminocarbonyl, C 3-6 Cycloalkyleniminocarbo- nyl-, aminosulphonyl, Ci ₅ alkylaminosulfonyl, di- (d- ₅ -AL- - -

alkyl) -aminosulfonyl- or C ₃ - Group ₆ -Cycloalkyleniminosulfonyl- may be substituted,

and 1 to 2 carbon atoms of a C 1-5 cycloalkenyl group which are not replaced by a double bond to another

Carbon atom are attached, optionally substituted independently by a fluorine atom or a hydroxy, Ci _-5 alkyloxy-, Ci _-5 alkylcarbonyloxy, Ci _-5 alkyl sulfanyl, _d-5 alkylsulfonyl, amino, ds- Alkylamino, di-

Substituted 10 (Ci _-5- alkyl) amino, ds-alkylcarbonylamino, Ci _-5- alkylsulfonylamino, Λ / (Ci- ₅ -alkylsulfonyl) -Ci- ₅ -alkylamino or Cs-β-Cycloalkylcarbonylaminogruppe could be,

15 with the proviso that such, together from R ⁴ and

R ⁵ formed C _3-8 -cycloalkyl or C _3-8 -cycloalkenyl group,

in the two heteroatoms in the cycle from the group oxygen and nitrogen by exactly one

20 optionally substituted -CH ₂ - group are separated from each other, and / or

in the one or both methylene groups of the cycle, which are directly connected to the carbon atom, to the

25, the radicals R ⁴ and R ^{5 are} attached by a

Heteroatom from the group oxygen, nitrogen and sulfur are replaced, and / or

in which one bound to the cyclic group

30 substituent, which is characterized in that a

Heteroatom from the group oxygen, nitrogen, sulfur and halogen directly to the cyclic - -

Group is separated from another heteroatom 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, is excluded,

M represents a -CH ₂ -, -CHR ³ -, -CR ³ R ³ - group or a bond,

W represents an oxygen or sulfur atom,

B represents a thiophene ring according to formula (IM),

R ^{2 is} a fluorine, chlorine, bromine or iodine atom, or a methoxy, Ci _-2 - alkyl or ethynyl group,

R ⁶ represents a hydrogen, fluorine, chlorine, bromine or iodine atom, or a Ci _-2 alkyl or amino group, - -

the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and

an optionally substituted by a Ci _-3 alkyl group

Imino group and two or three nitrogen atoms,

A third embodiment of the present invention includes those

Compounds of the general formula (I) in which

D represents a substituted bicyclic ring system of the formula (II)

by doing

_R 7a _{/ R} 7b _{/ R} 7c each independently represents a fluorine atom, a hydroxy, Ci- ₅ alkoxy group, - -

a Ci _-5- alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-Ci _-5- alkyl, Ci _-5 -alkoxy-Ci _-5 - alkyl group, wherein not simultaneously both radicals R ^7b / R ^7c may be bonded via a heteroatom to the ring carbon atom, except -C (R ^7b R ^7c ) - corresponds to a -CF ₂ -

Group, or

two radicals R ^7b / R ^7c together with the ring carbon atom can form a 3-, 4-, 5-, 6- or 7-membered saturated carbocycle or a cyclopentene, cyclohexene, oxetane, tetrahydrofuran, tetrahydropyran ring , Whose methylene groups may be substituted by 1 or 2 d- ₃ - alkyl or -CF ₃ groups, and / or its methylene groups, if they are not bonded to a heteroatom, may be substituted by 1-2 fluorine atoms, and / or in which a -CH ₂ - group may be replaced by a -C (O) group in addition to an N atom,

_R 8a _{/ R} 8b _{/ R} 8c each independently represent a Ci ₅ alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-d- ₅ - alkyl, Ci-s-alkoxy-Ci-s-alkyl group .

or two radicals R ^8b / R ^8c together with the ring carbon atom is a 3-, 4-, 5-, 6- or 7-membered - -

form saturated carbocycle or a cyclopentene, cyclohexene, oxetane, tetrahydrofuran, tetrahydropyran ring, wherein the methylene groups may be substituted by 1 or 2 Ci _-3 - alkyl or -CF ₃ groups, and / or its methylene groups, unless you agree

Heteroatom, which may be substituted by 1 or 2 fluorine atoms, and / or in which a -CH ₂ - group in addition to a nitrogen atom may be replaced by a -C (O) - group,

with the proviso that a heteroatom introduced by R ^8b or R ^8c may not be removed by only one carbon atom of X in formula I, and

X represents an -N (R ¹ ) group in the

R ¹ is a hydrogen atom or a Ci _-5 alkyl, C _3-S -alkenyl-CH ₂ -, C _3-5 alkynyl-CH ₂ -, C _3-6 cycloalkyl, C _4-6 cycloalkenyl group means

wherein the methylene and methyl groups present in the above-mentioned groups may additionally be substituted by a Ci _-3 alkyl, carboxy, Ci-s-Alkylcarboxycarbonylgruppe, or by a hydroxy, d- ₅ - alkoxy, amino, Ci ₅ -alkylamino, Ci- ₅ -dialkylamino or

C ₄ -7-Cycloalkyleniminogruppe can be substituted provided that the methylene or methyl groups are not directly attached to a - -

Heteroatom from the group O, N or S are bonded,

and / or one to three hydrogen atoms may be replaced by fluorine atoms, provided that the methylene or methyl groups are not directly attached to a heteroatom from the

Group O, N or S are bonded,

A ^{1 is} a sulfur atom, a -C (R ¹⁰ ) = N-, -N = C (R ¹⁰ ) -, or -

C (R ¹⁰ ) = C (R ¹¹ ) - group means

A ^{2 is} either a nitrogen atom or an = C (R ¹² ) group,

wherein R ¹⁰ , R ¹¹ and R ^{12 are} each independently

a hydrogen, fluorine, chlorine, bromine, or a Ci _-5 alkyl, -

CF _3, cyano, carboxy, Ci _-5 alkoxycarbonyl, hydroxy, Ci _-3 - alkoxy, CF ₃ O, CHF ₂ O, CH ₂ FO group,

represents a substituted ring system of the formula (IIa),

by doing

R ^{3 represents} a hydrogen atom,

R ⁴ and R ^{5 are} each independently

a hydrogen atom, a hydroxy group, an -OR ⁹ group, - -

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

a linear or branched C ₆ alkyl group wherein the hydrogen atoms of the straight-chain or branched C-ι- ₆ alkyl group, optionally completely or partially by

Fluorine atoms can be replaced, and wherein the straight or branched Ci _-6 alkyl group optionally substituted by a Cs-s-cycloalkyl, nitrile, hydroxy, d- ₅ alkyloxy, allyloxy, propargyloxy, benzyloxy, Ci- ₅ Alkylcarbonyloxy, d- _5- alkyloxycarbonyloxy, carboxy

Ci- ₅ alkyloxy, alkyloxycarbonyl d- _{5-ds-alkyloxy,} mercapto, Ci- ₅ alkylsulphanyl, Ci- ₅ alkylsulfonyl, carboxy d-, ₅ alkyloxy carbonyl, aminocarbonyl, d- ₅ alkylaminocarbonyl, di- (d- ₅ -AL- alkyl) aminocarbonyl, Cs-β-Cycloalkyleniminocarbonyl-, fonyl- Aminosul-, Ci- ₅ alkylaminosulfonyl, di (Ci _-5 alkyl) -aminosulfonyl-,

Cs-β-cycloalkyleneiminosulfonyl, amino, d- _5- alkylamino, di (Ci _-5- alkyl) amino, d- _5- alkylcarbonylamino, d- _5- alkylsulfonylamino, Λ / ( Ci _-5- alkylsulfonyl) -Ci _-5- alkylamino or Cs-β-Cycloalkylcarbonylaminogruppe may be substituted, wherein the hydrogen atoms of the d-5-alkyloxy may optionally be wholly or partially replaced by fluorine atoms, and wherein in the 6-7 -gliedrigen cycles of C _3-6 -

Cycloalkyleniminocarbonylgruppe in the cyclic part of a methylene group in the 4-position of a 6- or 7-membered

Cycloalkyleneimino group may be replaced by an oxygen or sulfur atom, by a carbonyl, sulphinyl, sulphonyl or -NR ^8c group, and additionally a methylene group adjacent to an abovementioned - NR ^8c group may be replaced by a carbonyl group,

a phenyl or heteroaryl group, - -

optionally in the phenyl or heteroaryl optionally one to three times by identical or different substituents selected from the group consisting of halogen atoms, Ci- ₅ alkyl, di- (Ci- ₅ -alkyl) amino, hydroxy, Ci- ₅ Alkyloxy, mono-, di- or trifluoromethoxy, carboxy and d- _5- alkyloxycarbonyl groups may be substituted,

a phenyl-Ci _-5 alkyl, or heteroaryl-Ci _-5 alkyl group which in the phenyl or heteroaryl optionally Ci- mono- to trisubstituted by identical or different substituents selected from the group consisting of halogen atoms, ₅ alkyl, di - (Ci- ₅ -alkyl) amino, hydroxy, Ci- ₅ -alkyloxy, mono-, di- or trifluoromethoxy, carboxy and Ci- ₅ -alkyloxycarbonyl may be substituted, and optionally in Ci- ₅ Alkyl part by a hydroxy or a d- ₅ alkyloxy, wherein the hydrogen atoms of the Ci- ₅ alkyloxy may optionally be wholly or partially replaced by fluorine atoms, an allyloxy, Propargyloxy-, benzyloxy, Ci- ₅ -Alkylcarbonyloxy -, Ci- ₅ -Alkyloxycarbonyloxy-, carboxy-Ci ₅ alkyloxy or d- Ci ₅ alkyloxycarbonyl- ₅ alkyloxy group may be substituted,

a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-d- _5- alkyl or cycloalkyleneimino-ds-alkyl group, in which at 4- to 7-membered cycles in the cyclic part a

Methylene group may optionally be replaced by a -N (R ^8c ) group, an oxygen or sulfur atom, or an -S (O) or -S (O) ₂ - group, or

in the case of 4- to 7-membered cycles in the cyclic part, two adjacent methylene groups together optionally be replaced by a -C (O) N (R ^8b ) or -S (O) ₂ N (R ^8b ) group - -

can, or

in the case of 6- to 7-membered cycles in the cyclic part, three adjacent methylene groups together optionally substituted by a -OC (O) 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, cycloalkyl-Ci _-5- alkyl or cycloalkylenimino-ds-alkyl group as defined above, in the two

Heteroatoms from the group oxygen and nitrogen by exactly one optionally substituted -CH ₂ group are separated from each other, is excluded,

where a 3- to 7-membered cycloalkyl, as defined above,

Cycloalkylenimino-, cycloalkyl-Ci- ₅ alkyl or cycloalkylene imino-Ci _-3 alkyl group at one or two -CH ₂ groups in each case by one or two Ci _-3 alkyl groups may be substituted, with the proviso that R ⁴ and R ⁵ can not be simultaneously defined as hydroxy or -OR ⁹ groups, and wherein

R ⁹ is a straight or branched _Ci-6-alkyl group wherein the hydrogen atoms of the straight-chain or branched Ci can _-6 alkyl group optionally wholly or partly be replaced by fluorine atoms, and wherein the straight-chain or branched C ₆ alkyl group optionally substituted by a C ₃ - ₅ -Cy- cloalkylgruppe, hydroxy, Ci- ₅ alkyloxy, allyloxy, product pargyloxy-, benzyloxy, Ci- ₅ alkylcarbonyloxy, _d-5 alkyl oxycarbonyloxy, carboxy-Ci _-5 - alkyloxy, Ci _-5 -alkyloxy- - -

carbonyl-Ci _-5 alkyloxy, carboxyl, d- ₅ alkyloxycarbonyl, aminocarbonyl, Ci- ₅ alkylaminocarbonyl, di- (Ci- _5-alkyl) - aminocarbonyl, Cs-β-Cycloalkyleniminocarbonyl-, amino -, Ci- ₅ alkylamino, di- (Ci- _5-alkyl) -amino, ds-Alkylcarbo-

5 nylamino-, Ci- ₅ alkylsulfonylamino, Λ / - (Ci- ₅ alkylsulfonyl) -

CI ₅ alkylamino or C ₃ - ₆ -Cycloalkylcarbonylamino- group may be substituted, wherein the hydrogen atoms of the Ci _-5 alkyloxy group may optionally be substituted by fluorine atoms 10 completely or partially, and wherein membered 7 in the 6- to Cyclen the C ₃ - ₆ - Cycloalkyleniminocarbonylgruppe in the cyclic moiety a methylene group in the 4-position of a 6- or 7-membered cycloalkyleneimino group by a

15 oxygen or sulfur atom, by a carbonyl,

Sulfinyl, sulfonyl or -NR ^8c - group may be replaced, and in addition a methylene group adjacent to an aforementioned -NR ^8c - group may be replaced by a carbonyl group,

20 with the proviso that the replacement of

Hydrogen atoms of the first carbon atom of the straight-chain or branched d-β-alkyl group are excluded by substituents from the group consisting of oxygen, sulfur or nitrogen,

25 is a phenyl, heteroaryl, phenyl-Ci- ₅ -alkyl or

Heteroaryl-Ci _-5- alkyl group which in the phenyl or heteroaryl optionally one to three times by the same or different

30 substituents selected from the group consisting of halogen atoms, Ci- ₅ alkyl, di- (Ci- _5-alkyl) amino, hydroxy, Ci- ₅ -alkyloxy, mono-, di- or trifluoromethanesulfonic - -

thoxy, carboxy and Ci _-5- alkyloxycarbonyl may be substituted,

a 3 to 7-membered cycloalkyl, cycloalkyl-d- _5- alkyl-5 or cycloalkyleneimino-C ₂ - ₃ -alkyl group in which, in the case of 4- to 7-membered cyclic compounds in the cyclic part, a methylene group is optionally substituted by -N ( R ^8c ) group, an oxygen or sulfur atom or an -S (O) or -S (O) ₂ - group may be replaced, 10 or

in the case of 4- to 7-membered cyclic compounds in the cyclic part, two adjacent methylene groups together may optionally be replaced by a -C (O) N (R ^8b ) or - 15 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 substituted by a -OC (O) N (R ^8b ) -20 or -N (R ^8b ) C (O) N (R ^8b ) - or

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

with the proviso that a 3- to 7-membered cycloalkyl, cycloalkyl-Ci _-5- alkyl or as defined above

25 Cycloalkylenimino-C ^ alkyl group, in the two

Heteroatoms from the group oxygen and nitrogen are separated by exactly one optionally substituted -CH ₂ - group, is excluded,

30 wherein a 3- to 7-membered cycloalkyl, cycloalkyl-Ci _-5- alkyl or cycloalkylene as defined above - -

_imino-C2-C3 alkyl group at one or two -CH ₂ - groups in each case by one or two Ci _-3 alkyl groups may be substituted,

M represents a -CH ₂ -, -CHR ³ -, -CR ³ R ³ - group or a bond,

W represents an oxygen or sulfur atom,

B represents a thiophene ring according to formula (IM),

R ^{6 represents} a hydrogen atom,

the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and

the 5-membered heteroaryl group optionally substituted by a Ci _-3 alkyl imino group, an oxygen or sulfur atom, or - -

and also to the aforementioned monocyclic

Heteroaryl groups via two adjacent carbon atoms, optionally substituted by a fluorine, chlorine or bromine atom, a C _1-3 -alkyl, hydroxy, C _1-3 -alkyloxy, amino, C _1-3 -alkylamino, di (C _1-3 alkyl) - amino or C ₃ - ₆ -Cycloalkyleniminogruppe substituted phenyl ring can be fused,

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

and wherein the hydrogen atoms in the above-mentioned - -

Methyl or ethyl groups, unless otherwise stated, may be wholly or partly replaced by fluorine atoms,

A fourth embodiment of the present invention includes those

Compounds of the general formula (I) in which

D represents a substituted bicyclic ring system of the formula (II)

by doing

_R 7a _{/ R} 7b _{/ R} 7c each independently represents a fluorine atom, a hydroxy, Ci- ₅ alkoxy group, a C ₅ alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-Ci ₅ alkyl , C ₁ . _5- alkoxy-C ₁ . ₅ - alkyl group, where not both R ^7b / R ^7c can be bonded via a heteroatom to the ring carbon atom at the same time, except -C (R ^7b R ^7c ) - corresponds to a -CF ₂ - group, or

two radicals R ^7b / R ^7c together with the ring carbon atom - -

may form a 3-, 4-, 5-, 6- or 7-membered saturated carbocycle, or a cyclopentene, cyclohexene, oxetane, tetrahydrofuran, tetrahydropyran ring, wherein the methylene groups by 1 or 2 Ci _-3 - alkyl - or -CF ₃ groups may be substituted, and / or its methylene groups, unless they are attached to a

Heteroatom are bonded, may be substituted by 1-2 fluorine atoms, and / or in which a -CH ₂ - group may be replaced by a -C (O) - group in addition to an N atom,

_R 8a _{/ R} 8b _{/ R} 8c each independently represent a Ci ₅ alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-d- ₅ - alkyl, Cis-Cis-alkoxy-alkyl group;

or two radicals R ^8b / R ^8c together with the

Ring carbon atom can form a 3-, 4-, 5-, 6- or 7-membered saturated carbocycle or a cyclopentene, cyclohexene, oxetane, tetrahydrofuran, tetrahydropyran ring, wherein the methylene groups by 1 or 2 Ci _-3 - Alkyl or -CF ₃ groups may be substituted, and / or its methylene groups, unless they are attached to a

Heteroatom are bonded, may be substituted by 1 or 2 fluorine atoms, and / or - -

in which a -CH ₂ - group may be replaced by a -C (O) group in addition to a nitrogen atom,

with the proviso that a heteroatom introduced by R ^8b or R ^{8c is} not substituted by only one

Carbon atom of X may be separated in formula I, and

X represents an -N (R ¹ ) group in the

R ¹ is a hydrogen atom or a Ci- ₅ alkyl, C ₃ - ₅ alkenyl-CH ₂ -, C _3-5 alkynyl-CH ₂ -, Cs-β-cycloalkyl, C _4-6 cycloalkenyl group means,

wherein the methylene and methyl groups present in the above-mentioned groups may additionally ₅ -Alkylcarboxycarbonylgruppe by a Ci- ₃ alkyl, carboxy, Ci- be substituted or by a hydroxy, d- ₅ -

Alkoxy, amino, Ci- ₅ alkylamino, dialkylamino ₅ Ci or _C4 -7-cycloalkyleneimino group may be substituted provided that the methylene or methyl groups are not directly bound to a heteroatom from the group O, N or S,

A ^{1 represents} a sulfur atom, a -C (R ¹⁰ ) = N-, -N = C (R ¹⁰ ) -, or - C (R ¹⁰ ) = C (R ¹¹ ) group, - -

A ^{2 is} either a nitrogen atom or an = C (R ¹² ) group,

wherein R ¹⁰ , R ¹¹ and R ^{12 are} each independently

a hydrogen, fluorine, chlorine, bromine, or a d- ₅ alkyl, - CF ₃ , cyano, carboxy, Ci _-5 alkoxycarbonyl, hydroxy, Ci _-3 - alkoxy, CF ₃ O. Mean, CHF ₂ O, CH ₂ FO group,

represents a substituted ring system of the formula (IIa),

by doing

R ^{3 represents} a hydrogen atom,

R ^{4 is} a hydrogen atom, a straight-chain or branched C _1-4

Alkyl group, wherein the hydrogen atoms of the straight-chain or branched

Ci- ₄ alkyl group may optionally be wholly or partly replaced by fluorine atoms and which may be optionally substituted by a Ci _-3 alkoxy group, wherein the hydrogen atoms of the Ci _-3 alkoxy group may be replaced by fluorine atoms entirely or partially, means

R ^{5 is} a hydrogen atom, a hydroxy group, an -OR ⁹ group, - -

a C _2-4 alkenyl or C _2-4 alkynyl group,

a straight or branched C ₄ alkyl group, wherein the hydrogen atoms of the straight-chain or branched C ₄ alkyl group, optionally completely or partially by

Optionally substituted by a C _3-5 -cycloalkyl, nitrile, hydroxy, d- _5- alkyloxy, allyloxy, propargyloxy, benzyloxy, or C 1 -C ₄ -alkyl group may be replaced, and wherein the straight-chain or branched _5- alkylcarbonyloxy, Ci _-5- alkyloxycarbonyloxy, carboxy

Ci- ₅ alkyloxy, alkyloxycarbonyl d- _{5-ds-alkyloxy,} mercapto, Ci- ₅ alkylsulphanyl, Ci- ₅ alkylsulfonyl, carboxy d-, ₅ alkyloxy carbonyl, aminocarbonyl, CI ₅ alkylaminocarbonyl, di (d- ₅ -AL- alkyl) aminocarbonyl, Cs-β-Cycloalkyleniminocarbonyl-, fonyl- Aminosul-, CI ₅ alkylaminosulfonyl, di (Ci _-5 alkyl) -aminosulfonyl-,

Cs-β-cycloalkyleneiminosulfonyl, amino, d- _5- alkylamino, di (Ci _-5- alkyl) -amino, d- ₅ -alkylcarbonylamino, d- ₅ -alkylsulfonylamino-, Λ / - ( d- _5- alkylsulfonyl) -d- _5- alkylamino or C _3-6 -cycloalkylcarbonylamino group may be substituted, wherein the hydrogen atoms of the d-5-alkyloxy may optionally be wholly or partly replaced by fluorine atoms, and wherein in the 6 - to 7-membered cyclic groups of the C _3-6 -

a phenyl or heteroaryl group, - -

and where

R ⁹ is a straight or branched Ci _-4 alkyl group, wherein the hydrogen atoms of the straight-chain or branched Ci- to _C4 alkyl group optionally wholly or partly be replaced by fluorine atoms, and wherein the straight or branched C-ι- ₄ alkyl group optionally substituted by a C ₃ - ₅ -

Cycloalkyl, hydroxy, Ci- ₅ alkyloxy, allyloxy, propargyloxy, benzyloxy, Ci _-5 alkylcarbonyloxy, - -

Ci _-5 -Alkyloxycarbonyloxy-, carboxy-d- alkyloxy _5, Ci _-5 -Al- kyloxycarbonyl-Ci _-5 alkyloxy, carboxy, Ci _-5 -Al kyloxy- carbonyl, aminocarbonyl, Ci-s alkylaminocarbonyl, di- (Ci- _5-alkyl) aminocarbonyl, C ₃ - ₆ -Cycloalkyleniminocarbo-

5 nyl-, amino, Ci- ₅ alkylamino, di- (Ci- _5-alkyl) -amino,

Ci ₅ alkylcarbonylamino, alkylsulfonylamino Ci _5,

^ (Ci-s-alkylsulfonyO-Ci-ö-alkylamino or C _3-6 cycloalkyl-kylcarbonylaminogruppe may be substituted, wherein the hydrogen atoms of the Ci _-5 -Alkyloxygruppe

10 may be wholly or partially replaced by fluorine atoms, and wherein in the 6- to 7-membered cycles of C ₃ - ₆ - Cycloalkyleniminocarbonylgruppe in the cyclic part of a methylene group in the 4-position of a 6- or 7-

15-membered Cycloalkyleniminogruppe by a

Oxygen or sulfur atom, may be replaced by a carbonyl, sulfinyl, sulfonyl or -NR ^8c group, and additionally a methylene group adjacent to an aforementioned -NR ^8c group may be replaced by a carbonyl group, with the proviso that the replacement by hydrogen atoms of the first carbon atom of the straight-chain or branched Ci _-6 alkyl group is excluded by substituents from the group of oxygen, sulfur or nitrogen 25,

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

Heteroaryl-C-ι- ₅ alkyl group which is optionally monosubstituted in the phenyl or heteroaryl moiety

30 to threefold by the same or different

Substituents selected from the group consisting of halogen atoms, Ci _-5- alkyl, di (Ci _-5- alkyl) -amino, - -

Methoxy- hydroxy, Ci- ₅ -alkyloxy, mono-, di- or trifluoro, carboxy and Ci may be substituted _-5 -Alkyloxycarbonylgruppen,

M represents a -CH ₂ - group or a bond,

W represents an oxygen atom,

B represents a thiophene ring according to formula (IM),

R ^{6 represents} a hydrogen atom,

the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and

and also to the aforementioned monocyclic

Heteroaryl groups via two adjacent carbon atoms, a (optionally substituted by a fluorine, chlorine or bromine atom, a C ₃ alkyl, hydroxy, Ci- ₃ alkyloxy, amino, Ci- ₃ alkylamino, di- Ci ₃ alkyl) -amino or Cs-β-cycloalkyleneimino group may be fused to substituted phenyl ring,

and wherein the hydrogen atoms in the above-mentioned - -

A fifth embodiment of the present invention includes those

Compounds of the general formula (I) in which

D represents a substituted bicyclic ring system of the formula (II)

by doing

_R 7a _{/ R} 7b _{/ R} 7c each independently represents a Ci ₂ alkyl group which may be substituted by 1-3 fluorine atoms, means

K ² and K ³ each represents a -CH ₂ - group

X represents an -N (R ¹ ) group in the

R ¹ is a hydrogen atom or a Ci _-5 alkyl or C _3-4 cyclo- alkyl group, - -

the methylene and methyl groups in the abovementioned groups may additionally be substituted by a hydroxyl group, provided that the methylene or methyl groups are not bonded directly to a heteroatom from the group O, N or S,

A ^{1 represents} a sulfur atom or -C (R ¹⁰ ) = C (R ¹¹ ) group,

A ^{2 is} either a nitrogen atom or an = C (R ¹² ) group,

wherein R ¹⁰ , R ¹¹ and R ^{12 are} each independently

a hydrogen, fluorine or chlorine atom, or a Ci _-5 alkyl, - CF ₃ , methoxy, CF ₃ O, CHF ₂ O, CH ₂ FO group mean

represents a substituted ring system of the formula (IIa),

by doing

R ^{3 represents} a hydrogen atom,

R ^{4 represents} a hydrogen atom, - -

R ⁵ is a hydrogen atom, a C _{_2-4} alkenyl or C _{_2-4} alkynyl group,

a straight-chain or branched C 1-4 -alkyl group, where the hydrogen atoms are straight-chain or branched

Ci-4-alkyl group may optionally be substituted by fluorine atoms entirely or partially, and wherein the straight or branched Ci _-4 alkyl group optionally substituted by a hydroxy, Ci _-5 alkyloxy group or a di (Ci _-5 alkyl) aminocarbonyl may be substituted, wherein the hydrogen atoms of the Ci ₅ alkyloxy group may optionally be substituted by fluorine atoms entirely or partially,

a phenyl-Ci _-3 alkyl, or heteroaryl-Ci _-3 alkyl,

M represents a -CH ₂ - group or a bond,

W represents an oxygen atom,

B represents a thiophene ring according to formula (IM),

R ^{2 represents} a chlorine or bromine atom, or an ethynyl group, - -

R ^{6 represents} a hydrogen atom,

the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and

the 5-membered heteroaryl group optionally substituted by a a Ci _-3 alkyl

Imino group, an oxygen or sulfur atom, or

wherein the alkyl, alkenyl, alkynyl and alkoxy groups having more than two carbon atoms contained in the above-mentioned definitions, unless otherwise mentioned, may be straight-chain or branched and the alkyl groups in the above-mentioned dialkylated - -

Radicals, for example the dialkylamino groups, may be identical or different,

A sixth embodiment of the present invention comprises those compounds of general formula (I) corresponding to embodiments 1, 2, 3, 4 or 5, wherein D represents a substituted bicyclic ring system of formula (II)

by doing

K ² and K ³ each represents a -CH ₂ - group - -

X represents an -N (R ¹ ) group in the

R ^{1 is} a hydrogen atom or a C ₅ -alkyl or O ₃ . ₄ - cycloalkyl group means

A ^{1 represents} a sulfur atom

A ^{2 represents} a nitrogen atom.

A seventh embodiment of the present invention includes those compounds of general formula (I) corresponding to embodiments 1, 2, 3, 4 or 5, wherein D represents a substituted bicyclic ring system of formula (II)

n that

K ¹ and K ⁴ - -

each independently represents a -CH ₂ -, -CHR ^7a -, -CR ^7b R ^7c - or a -C (O) group, wherein

K ² and K ³ each represents a -CH ₂ - group

X represents an -N (R ¹ ) group in the

R ¹ is a hydrogen atom or a Ci- ₅ alkyl or C ₃ - ₄ - cycloalkyl group,

A ^{1 represents} a -C (R ¹⁰ ) = C (R ¹¹ ) group,

A ² denotes an = C (R ¹² ) group,

wherein R ¹⁰ , R ¹¹ and R ^{12 are} each independently - -

is a hydrogen, fluorine or chlorine atom, or a Ci _-5 alkyl, -CF ₃ , methoxy, CF ₃ O, CHF ₂ O, CH ₂ FO group.

An eighth embodiment of the present invention includes those compounds of general formula (I) according to embodiments 1, 2, 3, 4, 5, 6 or 7, in which

M represents a bond.

Examples which may be mentioned are the following preferred compounds of the general formula (I), both as their tautomers, their enantiomers, their diastereomers, their mixtures and their salts:

(1) (f) - 5-Bromo-thiophene-2-carboxylic acid [1- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) - 5-oxo-pyrrolidin-3-yl] -amide

(2) (f) - 5-Chloro-thiophene-2-carboxylic acid [1- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) - 5-oxo-pyrrolidin-3-yl] -amide

(3) (f) - 5-ethynyl-thiophene-2-carboxylic acid [1- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) - 5-oxo-pyrrolidin-3-yl] -amide

(4) (f?) - 2- {4 - [(5-Bromo-thiophene-2-carbonyl) -amino] -2-oxo-pyrrolidin-1-yl}-4,5,7,8-tetrahydro- thiazolo [4,5-d] azepine-6-carboxylic acid tert-butyl ester

(5) (f) - 5-Chloro-thiophene-2-carboxylic acid [1- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) - 5-oxo-pyrrolidin-3-yl] -amide

(6) 5-chloro-thiophene-2-carboxylic acid - [(3f?, 4f?) - 1- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepine-7 yl) -5-oxo-4-propyl-pyrrolidin-3-yl] -amide

(7) 5-Bromo-thiophene-2-carboxylic acid - [(3f?, 4f?) - 1- (3-methyl-2,3,4,5-tetrahydro-) - -

1 H-benzo [d] azepin-7-yl) -5-oxo-4-propylpyrrolidin-3-yl] -amide

(8) 5-Bromo-thiophene-2-carboxylic acid - [(3f?, 4f?) - 4-methoxymethyl-1- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) -5-oxo-4-propylpyrrolidin-3-yl] -amide

(9) 5-Chloro-thiophene-2-carboxylic acid - [(3f?, 4f?) - 4- (2-methoxy-ethyl) -1- (3-methyl-2,3,4,5-tetrahydro-1 H-benzo [d] azepin-7-yl) -5-oxopyrrolidin-3-yl] amide

(10) 5-Chloro-thiophene-2-carboxylic acid - [(3f?, 4f?) - 4-butyl-1 - (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) -5-oxo-pyrrolidin-3-yl] -amide

(11) 5-Bromo-thiophene-2-carboxylic acid - [(3f?, 4f?) - 4-butyl-1 - (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) -5-oxo-pyrrolidin-3-yl] -amide

(12) 5-Chloro-thiophene-2-carboxylic acid - [(3f?, 4f?) - 4-ethyl-1- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) -5-oxo-pyrrolidin-3-yl] -amide

(13) 5-Bromo-thiophene-2-carboxylic acid - [(3f?, 4f?) - 4-ethyl-1- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) -5-oxo-pyrrolidin-3-yl] -amide

(14) (RJ-δ-chloro-thiophene-carboxylic acid t δ-oxo-1-α, ε-δ-tetrahydro-1 H-benzo [d] azepin-7-yl) -pyrrolidin-7-yl] - amide

(15) (f) - 5-Bromo-thiophene-2-carboxylic acid [5-oxo-1 - (5,6,7,8-tetrahydro-4H-thiazolo [4,5d] azepin-2-yl) -pyrrolidin-3-yl] -amide

(16) (f) - 5-Chloro-thiophene-2-carboxylic acid [1- (3-isopropyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) - 5-oxo-pyrrolidin-3-yl] -amide

(17) (f) - 5-Bromo-thiophene-2-carboxylic acid [1- (6-methyl-5,6,7,8-tetrahydro-4H- - -

thiazolo [4,5-d] azepin-2-yl) -5-oxo-pyrrolidin-3-yl] -amide

(18) (f) - 5-Chloro-thiophene-2-carboxylic acid [1- (3-ethyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) - 5-oxo-pyrrolidin-3-yl] -amide

(19) 5-Chloro-thiophene-2-carboxylic acid - [(3f?, 4f?) - 1- (6-methyl-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d] azepine -2-yl) -5-oxo-4-propyl-pyrrolidin-3-yl] -amide

(20) 5-Bromo-thiophene-2-carboxylic acid - [(3f?, 4f?) - 1- (6-methyl-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d] azepine -2-yl) -5-oxo-4-propyl-pyrrolidin-3-yl] -amide

(21) 5-Ethynyl-thiophene-2-carboxylic acid - [(3f?, 4f?) - 1- (6-methyl-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d] azepine -2-yl) -5-oxo-4-propylpyrrolidin-3-yl] amide

(22) 5-Bromo-thiophene-2-carboxylic acid [1- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) -5-oxo-pyrrolidine -3-ylmethyl] -amide

(23) δ-Chlorothiophene-thiocarboxylic acid ti - (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) -5-oxo-pyrrolidine-3 ylmethyl] -amide

(24) 5-Chloro-thiophene-2-thiocarboxylic acid [1- (1,1,3-trimethyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) -5 oxo-pyrrolidin-3-ylmethyl] -amide.

The invention also relates to physiologically acceptable salts of the compounds according to the previously defined embodiments and examples.

The invention also relates to medicaments containing a compound or a physiologically acceptable salt of a compound according to the previously defined embodiments and examples, optionally together with one or more inert carriers and / or diluents. - -

The invention also provides the use of a compound or a physiologically acceptable salt of a compound according to the above-defined embodiments and examples, for the preparation of a medicament having an inhibitory effect on factor Xa and / or an inhibitory effect on related serine proteases.

The invention also provides a process for the preparation of a medicament, which comprises incorporating by non-chemical means a compound or a physiologically acceptable salt of a compound according to the previously defined embodiments and examples into one or more inert carriers and / or diluents.

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) The preparation of a compound of general formula (I)

in the A ¹ and A ² , K ¹ to K ⁴ , X, L, M and R ¹ to R ^{6 are defined} as mentioned in Embodiment 1 and optionally on existing amino, hydroxy, carboxy or thiol groups by common protecting groups such as those described in TW Greene, PGM Wuts can be protected in "Protective Groups in Organic Synthesis" and their protecting groups can be cleaved in the literature, is described in the embodiments or can be carried out for example according to one of the following Schemes 1 and 2: - -

Scheme 1

i) lactone opening

PG = protective group

(IV) (V) of the amino group ii

iv) acylation with

the

Alternatively, compounds of the general formula (Ia) can also be prepared by analogous ring opening of the lactone of the general formula (Va)

(Va) (Va)

and subsequent ring closure are converted to the corresponding pyrrolidinones (Ia). - -

Scheme 2

iv) acylation with

the

In Schemes 1 and 2 mean

Q is a hydroxy or Ci _-4 -Al koxygruppe, a halogen atom or a

Alkoxycarbonyloxy or acyloxy group and

PG is a protective amine group known from the literature, for example a tert-butoxycarbonyl, benzyloxycarbonyl or a trifluoroacetyl group.

The reaction stages i) -x) described in Schemes 1 and 2 can be carried out in the manner described in the examples or according to conditions known from the literature, for example as follows: - -

i) ring opening of the lactone (V) with the amine (IV)

The amine of the general formula (IV) is reacted with an organoaluminum compound such as trimethylaluminum, triethylaluminum, tripropylaluminum, triisobutylaluminum, tributylaluminum, triphenylaluminum in a solvent or solvent mixture such as dichloromethane, toluene, xylene, benzene, hexane, cyclohexane, heptane, tetrahydrofuran at a temperature of -100 to 100 ⁰ C, but preferably between -80 and 80 ⁰ C, activated and reacted with the lactone of the general formula (V) or (Va).

ii) ring closure to pyrrolidinone

The lactamization may conveniently be carried out under Mitsunubo conditions in an inert solvent or solvent mixture such as tetrahydrofuran, dioxane, benzene, toluene, xylene, acetonitrile in the presence of phosphines such as triphenylphosphine, tributylphosphine with dialkyl azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, di (tert .-Butyl) azodicarboxylate, for example at a temperature of -50 to 200 ⁰ C, but preferably between -20 and 150 ⁰ C, are performed.

iii) or v) removal of a protective group in Scheme 1 and Scheme 2:

The optional subsequent cleavage of a protective moiety used is carried out, for example hydrolytically in an aqueous solvent, for example 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 metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether cleavage, for. B. in the presence of iodotrimethylsilane, at temperatures between 0 and 100 ⁰ C, preferably at temperatures between 10 and 50 ⁰ C.

The cleavage of a benzyl, methoxybenzyl or Benzyloxycarbonylrestes - -

However, for example, hydrogenolytically, for example 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 5O ⁰ C. , but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 1 to 5 bar.

The cleavage of a protective group can also according to the T.W. Greene, P.G.M. Wuts in "Protective Groups in Organic Synthesis" described procedures.

iv) Acylation of an amine (VIII) or (XII) with an optionally activated carboxylic acid (V)

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, caustic soda or sulfolane optionally in the presence of an inorganic or organic base at temperatures between -20 and 200 ⁰ C, but preferably at temperatures between -10 and 16O ⁰ C, performed.

However, the acylation may also be carried out with the free acid optionally 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,

Λ /./ V-dicyclohexylcarbodiimide / camphorsulfonic acid, Λ /, / V-dicyclohexylcarbodiimide / Λ / -hydroxysuccinimide or 1-hydroxybenzotriazole, Λ / ./ V-carbonyldiimidazole, O- (benzotriazol-1-yl) -Λ /, Λ /, Λ / \ Λmetramethyluronium tetrafluoroborate / Λ / -methylmorpholine, O- (benzotriazol-1-yl) -Λ /, Λ /, Λ / ^I , Λmetramethyl-uronium - -

tetrafluoroborate / Λ / ethyldiisopropylamine, O-pentafluorophenyl-Λ /, Λ /, Λ / ', Λ / -tetramethyluronium hexafluorophosphate / triethylamine, Λ /./ V-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, at temperatures between -20 and 200 ⁰ C, but preferably at temperatures between -10 and 16O ⁰ C, are performed.

vi) Tandem Michael addition lactamization with itaconic acid

The tandem Michael addition-lactamization is conveniently carried out at a temperature from 50 to 250 ⁰ C, but preferably at 80-200 ⁰ C, in the absence or presence of a solvent or solvent mixture such as water, ethanol, propanol, butanol, toluene, xylene, Chlorobenzene, tetralin, diphenyl ether, carried out with itaconic acid.

viii) esterification and Grignard reaction

An optionally subsequent substitution with radicals R ³ is prepared by blocking the carboxylic acid function by esterification by literature methods and reaction with Grignard compounds of the type R ³ -Mg -Br or R ³ -Mg-CI in an inert solvent such as diethyl ether or tetrahydrofuran at temperatures of -100 ⁰ C to +100 ⁰ C; but preferably between -8O ⁰ C and + 8O ⁰ C. This tertiary alcohols of the general formula (Xl) are formed.

vii) Reduction of the carboxylic acid to the primary alcohol of the general formula (XI)

The reduction of the carboxylic acid function can by known literature methods by esterification or other activation (eg by conversion to an active ester or carbonyl chloride) and subsequent reduction with a borohydride such as sodium or lithium borohydride in a solvent or solvent mixture of such as methanol, - -

Water, tetrahydrofuran, diethyl ether at temperatures between -100 ⁰ C and + 100 ⁰ C, but preferably between -8O ⁰ C and + 100 ⁰ C are performed.

ix) conversion of the hydroxy compound of the general formula (XI) into a primary amine

The conversion of the alcohol function into an amine succeeds in a two-stage process by activation according to Mitsunobu analogous to ii). By reaction with phthalimide and subsequent release of the amine with hydrazine or methylamine, the amine of the general formula (XII) is obtained.

Alternatively, the hydroxy function may also be converted to a leaving group such as mesylate, tosylate, iodide, or the like, as known in the literature. By subsequent nucleophilic substitution with a compound, for example from the group lithium. Sodium, potassium azide, sodium, potassium phthalimide, 4-methoxybenzylamine, benzylamine, 2,4-dimethoxybenzylamine, dibenzylamine, potassium or sodium cyanide, and then reduction of the so introduced nitrogen-containing group by standard methods gives the amines of the general formula (XII).

Other methods of amide coupling are described in, for example, P.D. Bailey, I.D. Collier, K.M. Morgan in "Comprehensive Functional Group Interconversion", Vol. 5, page 257ff., Pergamon 1995 or also in Houben-Weyl Supplement 22, Thieme Verlag, 2003 and the literature cited therein.

x) Reaction with Lawesson Reagent to the Corresponding Thio-Amide The conversion of the carbonyl group can be carried out by literature methods by reaction, for example with the Lawesson reagent in an inert solvent or solvent mixture such as toluene, benzene, chlorobenzene at temperatures between -100 ⁰ C and +100 ⁰ C, but preferably between -8O ⁰ C and + 100 ⁰ C are performed. - -

(b) The building blocks of the general formula

in which A ¹ , A ² , K ¹ , K ² , K ³ , K ⁴ and X are defined as mentioned in embodiment 1, and optionally on existing amino, hydroxy, carboxy or thiol groups by common protecting groups such as those in TW Greene, PGM Wuts can be protected in Protective Groups in Organic Synthesis described and their protecting groups in the literature known in the course of the synthesis sequence to compounds of formula (I) are known from the literature or their synthesis is described in the embodiments or they can be synthesized, for example, by synthesis methods known from the literature or analogously to synthesis methods known from the literature, for example DE 4429079, US Pat.

Bobowski et al., J. Heterocyclic Chem. 16, 1525, 1979 or in P.D., US Pat. No. 4,990,369, DE3515864, US5175157, DE1921861, WO85 / 00808 and G. Bobowski et al. Johnson et al., Bioorg. Med. Chem. Lett 2003, 4197.

For example, a compound of the general formula (IV) wherein A ¹ , A ² , K ¹ , K ² , K ³ , K ⁴ and X are defined as mentioned in Embodiment 1 may be used

Reduction of the nitro group of a compound of the general formula (XII) - -

in which A ¹ , A ² , K ¹ , K ² , K ³ , K ⁴ and X are defined as mentioned in embodiment 1, are prepared:

The reduction of the nitro group is, for example, conveniently 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 reducing agent, conveniently 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, diisobutylaluminum hydride, conveniently in a solvent or solvent mixture such as water, methanol, ethanol, isopropanol, pentane, hexane, cyclohexane, heptane, Ben zol, toluene, xylene, ethyl acetate, methyl propionate, glycol, glycol dimethyl ether, diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, Λ / -methylpyrrolidinone, or Λ / -ethyl-diisopropylamine, Λ / -Ci- ₅ -alkylmorpholine, Λ / -Ci- ₅ - Alkylpiperidine, Λ / -Ci- ₅ alkylpyrrolidine, triethylamine, pyridine, for example, at temperatures between -30 and 25O ⁰ C, but preferably between 0 and 15O ⁰ C performed.

(c) The building blocks of the general formula - -

in which R ² -R ^{6 are defined} as mentioned in embodiment 1, and wherein

PG represents a protecting group of the amino group, and optionally on existing amino, hydroxy, carboxy or thiol groups by common protecting groups such as those in T.W. Greene, P.G.M. Wuts in "Protective

Groups in Organic Synthesis "can be protected and their protecting groups in literature known to be cleaved in the course of the synthesis sequence to compounds of formula (I) are known from the literature or their synthesis is described in the

Embodiments described or they can be prepared for example by literature synthesis methods or by the following methods:

1) Reduction and subsequent lactonization of a compound of the general formula - -

wherein PG represents a protecting group of the amino function, which can be subsequently cleaved by literature methods, and R ³ to R ^{5 are defined} as mentioned in the first embodiment:

The reduction to the intermediate hydroxy acid is conveniently carried out, for example, in a solvent or solvent mixture such as tetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, pentane, hexane, cyclohexane, heptane, benzene, toluene or xylene with complex hydrides such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, for example Temperatures between -80 and 250 ⁰ C, but preferably carried out between -30 and 150 ⁰ C.

The subsequent lactonization of the intermediate is conveniently carried out, for example, in a solvent or solvent mixture such as benzene, chlorobenzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane in the presence of a catalyst such as para-toluenesulfonic acid, camphorsulfonic acid or acidic ion exchanger optionally in the presence of Desiccant such as sodium sulfate, magnesium sulfate or molecular sieves, for example at temperatures between -30 and 250 ⁰ C, but preferably between temperatures of 0 and 200 ⁰ C performed. For example, this reaction can be carried out as described by GJ McGarvey, JM Williams, R.

N. Hiner, Y. Matsubara, T. Oh J. Am. Chem. Soc. 1986, 708, 4943-4952. - -

2) (Sequential) alkylation of a compound of the general formula

wherein R ^{3 is defined} as mentioned in the first embodiment and Z ^{10 represents} a protective group of the amino function, which can be cleaved subsequently by literature methods, but also an acyl group of the formula

O

in which B is defined as in the first embodiment,

with a compound of the general formula

T-7 ¹¹ ^TZ (XV),

in which the group T is the group R ⁴ or R ⁵ defined in the first embodiment, with the proviso that T can not denote the group OR ⁹ , and Z ^{11 is} a nucleofugic group, for example an iodine, bromine or chlorine atom or a tosylate, triflate or mesylate group, represents:

The alkylation can be repeated with a same or different alkylating agent of formula (XV) to give α, α-disubstituted lactones of compound (V) or (Va).

The alkylations may, for example, be analogous to A. El Hadri, A. Ahbouabdellah, U. Thomet, R. Baur, R. Furtmuller, E. Sigel, W. Sieghart, RH Dodd, J. Med. - -

Chem. 2002, 45, 2824-2831.

In the reactions described above, optionally present reactive groups such as hydroxyl, carboxy, amino, alkylamino or imino groups can be protected during the reaction by conventional protecting groups, which are cleaved again after the reaction. For example, the protective group for a hydroxy group is the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, fe / t-butyl, trityl, benzyl or tetrahydropyranyl group,

as protecting groups for a carboxyl group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group and

as a protecting group for an amino, alkylamino or imino group, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, fe / t-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group additionally the phthalyl group,

as a protective group for an ethynyl group, the trimethylsilyl, diphenylmethylsilyl, tert.Butyldimethylsilyl- or a 1-hydroxy-1-methyl-ethyl group into consideration.

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

The optional subsequent cleavage of a protective moiety used is carried out, for example hydrolytically in an aqueous solvent, for example 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 metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether cleavage, for. B. in the presence of iodotrimethylsilane, at temperatures between 0 and 100 ⁰ C, preferably at - -

Temperatures between 10 and 5O ⁰ C.

However, cleavage of a benzyl, methoxybenzyl or benzyloxycarbonyl radical is for example effected 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

Hydrochloric acid at temperatures between 0 and 5O ⁰ C, but preferably at

Room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 1 to 5 bar.

The removal of a methoxybenzyl group can also be carried out in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 5O ⁰ C, but preferably at room temperature.

The removal of a methoxy group is advantageously carried out in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between -35 and -25 ⁰ C.

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

The cleavage of a Fe / t-butyl or Fe / t-Butoxycarbonylrestes is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid optionally using a solvent such as methylene chloride, dioxane or ether.

The cleavage of a Phthalylrestes preferably takes place 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 5O ⁰ C. - -

Cleavage of an allyloxycarbonyl radical is accomplished 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

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 (I) 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 7O ⁰ C.

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

Thus, for example, the compounds of the general formula (I) which are obtained in racemates can be converted into their optical systems by methods known per se (see Allinger NL and ENeI EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) Antipodes and compounds of general formula (I) with at least two asymmetric carbon atoms due to their physicochemical differences according to methods known per se, eg by chromatography and / or fractional crystallization, into their diastereomers, which, if they are obtained 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 reacting with a, with the racemic compound salts or derivatives such as esters or amides forming optically active substance, in particular acids and their activated derivatives or alcohols, and Separation of the thus obtained diastereomeric salt mixture or derivative, for example due to different solubilities, wherein from the pure diastereomeric salts or derivatives, the free antipodes by - -

Exposure of suitable agents can be released. Particularly common optically active acids are e.g. the D and L forms of tartaric or dibenzoyltartaric, di-o-toluenoic, malic, mandelic, camphorsulfonic, glutamic, aspartic or quinic acids. As optically active alcohol, for example, (+) - or (-) - menthol and as an optically active acyl radical in amides, for example, the (+) - or (-) - Menthyloxycarbonylrest into consideration.

Furthermore, the compounds of the formula (I) obtained can be converted into their salts, in particular for the pharmaceutical application, into their physiologically tolerated salts with inorganic or organic acids. As acids for this example, hydrochloric acid,

Hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid,

Fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid into consideration.

In addition, the novel compounds of the formula (I) thus obtained, if they contain a carboxy group, can optionally subsequently be converted into their salts with inorganic or organic bases, in particular for the pharmaceutical application into their physiologically tolerated salts. Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

As already mentioned, 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 effect, which is preferably based on a thrombin or factor Xa-influencing action, for example, on a thrombin-inhibiting or factor Xa-inhibiting effect, on an aPTT-prolonging effect and on an inhibitory effect on related serine proteases such. As urokinase, factor - -

VIIa, Factor IX, Factor Xl and Factor XII.

The compounds listed in the Experimental section were tested for their effect on the inhibition of Factor Xa as follows:

Methodology:

Enzyme kinetic measurement with chromogenic substrate. The amount of p-nitroaniline (pNA) released by the human factor Xa from the colorless chromogenic substrate is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used. The inhibition of the enzyme activity by the test substance (based on the solvent control) is determined at various test substance concentrations and from this the IC _{50 is} calculated as the concentration which inhibits the factor Xa used by 50%.

Material:

Tris (hydroxymethyl) aminomethane buffer (10mmol) and sodium chloride (150mmol), pH 8.0 plus 1mg / ml Human Albumin Fraction V, protease free

Factor Xa (Calbiochem), Specific Activity: 217 IU / mg, final concentration: 7 IU / ml per reaction

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

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 ⁰ C. After adding 25 μl of S 2765 working solution (2.82 mmol / L) - -

the sample in the photometer (SpectraMax 250) at 405 nm for 600 seconds at 37 ⁰ C measured.

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 at Y = 50% inhibition.

All compounds tested showed IC 50 values less than 100 μmol / L.

The compounds according to the invention are generally well tolerated.

Because of their pharmacological properties, the novel compounds and their physiologically acceptable salts are suitable for the prevention and treatment of venous and arterial thrombotic disorders, such as the prevention and treatment of deep vein thrombosis, the prevention of reocclusion after bypass surgery or angioplasty (PT C) A), as well as the occlusion in peripheral arterial diseases, as well as prevention and treatment of pulmonary embolism, disseminated intravascular coagulation and severe sepsis, the prevention and prophylaxis of DVT in patients with exacerbation of COPD, the treatment of ulcerative colitis, prophylaxis and treatment - -

Coronary thrombosis, prophylaxis of stroke and prevention of occlusion of shunts.

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

Due to their pharmacological properties, the new compounds and their physiologically acceptable salts are also suitable for the treatment of Alzheimer's and Parkinson ^'s disease. A rational for this, for example, results from the following findings, from which one can conclude that Thrombinhemmer or factor Xa inhibitors, by inhibiting the thrombin formation or activity, could be valuable drugs in the treatment of Alzheimer's and Parkinson ^'s disease. Clinical and experimental studies suggest that neurotoxic mechanisms, such as inflammation associated with the activation of proteases of the coagulation cascade, are involved in the death of neurons due to brain trauma. Several studies indicate involvement of thrombin in neurodegenerative processes such as stroke, repeated bypass surgery or traumatic brain injury. An increased thrombin activity could be detected for example even days after peripheral nerve injury. It could be further shown that thrombin has a neurite retraction, as well as glial proliferation, and apoptosis in primary cultures of - -

Neurons and neuroblastoma cells (for review see: Neurobiol Aging 2004, 25 (6), 783-793). In addition, various in vitro studies on brains of patients with Alzheimer's disease indicate that thrombin plays a role in the pathogenesis of this disease (Neurosci., Leu., 1992, 146, 152-54). An accumulation of immunoreactive thrombin could be detected in neurite plaques in brains of Alzheimer's patients. In vitro, thrombin has also been shown to play a role in the regulation and stimulation of amyloid precursor protein (APP) production, as well as in the cleavage of the APP into fragments detected in the amyloid plaques in the brains of Alzheimer's disease patients can. Furthermore, it has been shown that thrombin-induced microglial activation in vivo leads to the degeneration of nigral dopaminergic neurons. These findings suggest that microglial activation, triggered by endogenous substance (s) such as thrombin, is involved in the neuropathological process of cell death of dopaminergic neurons, as found in patients with Parkinson ^'s disease (J. Neurosci., 2003, 23 , 5877-86).

The dose required to achieve a corresponding effect is expediently when intravenously administered 0.01 to 3 mg / kg, preferably 0.03 to 1.0 mg / kg, and oral administration 0.03 to 30 mg / kg, preferably 0.1 to 10 mg / kg, each 1 to 4 times a day.

For this purpose, the compounds of the formula (I) 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, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,

Citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol,

Carboxymethylcellulose or fatty substances such as hard fat or their suitable mixtures, in common pharmaceutical preparations such as tablets, - -

Make dragees, capsules, powders, suspensions or suppositories.

The novel compounds and their physiologically acceptable salts can be used therapeutically in combination with acetylsalicylic acid, with inhibitors of platelet aggregation such as fibrinogen receptor antagonists (eg abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of the coagulation system and their recombinant analogues (eg protein C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (eg clopidogrel, ticlopidine), with P ₂ T receptor antagonists (eg cangrelor) or with combined thromboxane

Receptor antagonists / synthetase inhibitors (e.g., Terbogrel).

Experimental part

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

Melting points, IR, UV, ¹ H-NMR and / or mass spectra are generally present for the compounds prepared. Unless otherwise stated, Rr values were determined using GC-finished DC plates Kieselgel 60 F ₂₅₄ (E. Merck, Darmstadt, Article No. 1.05714) with no chamber saturation. The Rr values determined under the name Alox were determined using TLC plates alumina 60 F2 ₅ 4 (E. Merck, Darmstadt, Article No. 1,05713) without chamber saturation. The Rr values determined under the designation Reversed-Phase-8 were determined using GC-finished precast plates RP-8 F ₂₅ 4 _s (E. Merck, Darmstadt, Article No. 1.15684) without chamber saturation. The ratios indicated for the flow agents relate to volume units of the respective solvents. For chromatographic purifications, silica gel from Millipore (MATREX ™, 35-70 μm) was used. If further information on the configuration is missing, it remains unclear whether it is pure stereoisomers or enantiomeric - -

/ Diastereomer mixtures.

The test descriptions use the following abbreviations:

Boc fe / t-butoxycarbonyl

DCC Λ /, Λ / -dicyclohexylcarbodiimide

DIPEA Λ / ethyl diisopropylamine

DMSO dimethylsulfoxide DMF Λ /, Λ / -dimethylformamide

DPPA diphenylphosphoryl azide sat. saturated i. Vak. concentrated in vacuo. Concentrates NMM Λ / methyl morpholine

NMP Λ / -methylpyrrolidin-2-one o Ortho

PfTU O-pentafluorophenyl-Λ /, Λ /, Λ / ', Λ / -tetramethyluronium hexafluorophosphate PPA propanephosphonic acid anhydride quant. quantitatively

R _f retention factor

R _t retention time rac. Racemic TBTU O- (benzotriazol-1-yl) -Λ /, Λ /, W. Λ -metramethyluronium tetrafluoroborate

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran tert. Tertiary Σ yield over all the analogous steps described

The HPLC data for Examples 3, 20 and 23 were among the following - -

Conditions generated:

Waters ZMD, Alliance 2695 HPLC, Waters 2700 autosampler, Waters 996 diode array detector The mobile phase used was: 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 column as the stationary phase Varian Microsorb 100 served Cis 3 microns, 4.6 mm x 50 mm, batch no 2,231,108 (column temperature: constant at 25 ⁰ C)..

The diode array detection took place in the wavelength range 210-300 nm.

The HPLC data for all other examples were generated under the following conditions:

Waters ZMD, Alliance 2695 HPLC, Waters 2700 Autosampler, Waters 2996

Diode array detector

As mobile phase was used:

A: Water with 0.10% TFA

B: acetonitrile with 0.10% TFA

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

0.0 95 5 1.00 - -

0.1 95 5 1.00

3.1 2 98 1.00

4.5 2 98 1.00

5.0 95 5 1.00

As a stationary phase, a column XTerra®, MS served Cis 2.5 micron, 4.6 mm x 30 mm (column temperature: constant at 25 ⁰ C).

The diode array detection took place in the wavelength range 210-300 nm.

example 1

(f?) - 5-Bromo-thiophene-2-carboxylic acid [1- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) -5-oxo -pyrrolidin-3-yl] -amide (mono-trifluoroacetate salt)

(a) (f?) - (2-Hydroxy-1-r (3-methyl-2,3,4,5-tetrahydro-1H-benzodlazepine-7-ylcarbamovD-methyl-ethyl-benzoic acid benzyl ester

2.00 g (7.74 mmol) of 7-amino-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo [c /] azepine are dissolved in 8 ml of dichloromethane and treated at room temperature with 4.1 ml (8.2 mmol) of trimethylaluminum Solution (2M in toluene). After 15 minutes, 1.82 g (7.74 mmol) of (f?) - (5-oxo-tetrahydrofuran-3-yl) -carbamic acid benzyl ester are added and the mixture is stirred for 16 hours at room temperature. It is then acidified with 2N hydrochloric acid, diluted with water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated to dryness. The crude product thus obtained is purified by chromatography on silica gel (eluent: dichloromethane / methanol 9: 1). You get a white one - -

Solid.

Yield: 1.44 g (38%)

R f value: 00:27 (silica gel; dichloromethane / methanol = 95: 5) C ₂₄ H ₂₆ F ₃ N ₃ O ₅ (493.48) Mass spectrum: (M + H) ⁺ = 494

(b) (ff) - (5-Oxo-1-r3- (2.2.2-trifluoro-acetyl-2.3.4.5-tetrahydro-1H-benzodlazepine-7-yl-pyrrolidin-3-yl) -carbamic acid benzyl ester

1.44 g (2.92 mmol) of (f?) - {2-hydroxy-1 - [(3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-ylcarbamoyl) -methyl] ethyl} -carbamic acid benzyl ester are dissolved in 4 ml of THF. While cooling with ice, a mixture of 740 mg (3.2 mmol) of di-tert-butylazodicarboxylate and 800 μl (3.2 mmol) of tributylphosphine in 3 ml of THF is added. The mixture is warmed slowly to room temperature and stirred for 16 hours. The mixture is then concentrated to dryness. The residue is purified by reversed-phase chromatography. Yield: 545 mg (39%) R _t : 3.21 min C ₂₄ H ₂₄ F ₃ N ₃ O ₄ (475.46) Mass spectrum: (M + H) ⁺ = 476

(c) (f?) - r5-Oxo-1- (2,3,4,5-tetrahydro-1H-benzodiazepin-7-yl) -pyrrolidin-3-yl-carbamic acid benzyl ester

500 mg (1.1 mmol) of (f?) - {5-oxo-1- [3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl] -pyrrolidin-3-yl} -carbaminsäurebenzylester are dissolved in a mixture of 10 ml of methanol and 5 ml of water, treated with 620 mg (4.5 mmol) of potassium carbonate and stirred for 4.5 hours at room temperature. The mixture is concentrated on a rotary evaporator to dryness. The residue is diluted with water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated i.vak. concentrated to dryness. This gives a white solid. - -

Yield: 360 mg (90%) Rt value: 2.25 min C ₂₂ H ₂₅ N ₃ O ₃ (379.45) Mass spectrum: (M + H) ⁺ = 380

(d) (f?) - ri- (3-methyl-2,3,4,5-tetrahydro-1H-benzodiazepine-7-vn-5-oxo-pyrrolidin-3-yl-carbamic acid benzyl ester

320 mg (0.84 mmol) of (f?) - [5-oxo-1- (2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) -pyrrolidin-3-yl] - Benzyl carbamate are suspended in 2 ml of methanol and acidified with glacial acetic acid (pH = 6). 120 μl (1.6 mmol) of an aqueous formaldehyde solution (37% strength) are added and the mixture is stirred at room temperature for 30 minutes. Subsequently, 340 mg (1.6 mmol) of sodium triacetoxyborohydride are added. After an hour, the mixture is on sat. Sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic Pahsen are dried over sodium sulfate and i. Vak. concentrated to dryness. This gives a white solid.

Yield: 320 mg (96%) Rt value: 2.25 min C ₂₃ H ₂₇ N ₃ O ₃ (393.48) Mass spectrum: (M + H) ⁺ = 394

(e) (f) - 4-Amino-1- (3-methyl-2,3,4,5-tetrahydro-1H-benzodiazepin-7-yl-pyrrolidin-2-one

320 mg (0.8 mmol) of (f?) - [1- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) -5-oxo-pyrrolidine-3 -yl] -carbaminsäurebenzylester are dissolved in a mixture of 10 ml of methanol and 6 ml of tetrahydrofuran, treated with 100 mg of palladium on carbon and hydrogenated in a Parr apparatus at 1 bar hydrogen pressure at room temperature for 45 minutes. The mixture is filtered off from the catalyst and on a rotary evaporator for - -

Dry concentrated.

Yield: 210 mg (quantitative)

Rr value: 0.05 (silica gel, dichloromethane / methanol 90:10)

C ₁₅ H ₂₁ N ₃ O (259.35)

Mass spectrum: (M + H) ⁺ = 260

(f) (f?) - 5-Bromo-thiophene-2-carboxylic acid π- (3-methyl-2,3,4,5-tetrahydro-1H-benzodiazepin-7-yl) -5-oxo-pyrrolidin-3-yl amide (mono-trifluoroacetate salt)

72 mg (0.35 mmol) of 5-bromo-thiophene-2-carboxylic acid are mixed in 1.5 ml of DMF with 120 μl (1.1 mmol) of NMM and 113 mg (0.35 mmol) of TBTU and then under nitrogen atmosphere at room temperature for 30 minutes touched. Then, 92 mg (0.35 mmol) of (f?) - 4-amino-1- (3-methyl-2, 3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl] -pyrrolidine are added. 2-on in 0.5 ml of DMF dissolved and stirred for 16 hours at room temperature, then the reaction mixture is acidified with trifluoroacetic acid and purified by reversed-phase chromatography Yield: 86 mg (44%) R _t : 2.34 min C ₂₀ H ₂₂ BrN ₃ O ₂ S (448.39) Mass spectrum: (M + H) ⁺ = 448/450 (bromine isotopes)

The following compounds were prepared analogously:

- -

Example 3

5-Chloro-thiophene-2-carboxylic acid - [(3f, 4f) -1- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) - 5-oxo-4-propylpyrrolidin-3-yl] -amide (mono-trifluoroacetate salt)

- -

(a) N- (2.3.4.5-tetrahydro-1H-benzodiazepin-7-yl) -acetamide

15.6 g (61.4 mmol) of 7-amino-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo [c /] azepine are dissolved in 50 ml of glacial acetic acid, with 8.7 ml (92 mmol)

Added acetic anhydride and stirred for 16 hours at room temperature.

Then the mixture is poured onto water, filtered the precipitated

Remove solids and rinse thoroughly with water.

The somewhat moist solid is dissolved in a mixture of 400 ml of methanol, 100 ml of water and 50 ml of tetrahydrofuran, with 30 g (215 mmol).

Added potassium carbonate and stirred at room temperature for one hour.

Subsequently, the organic solvents are removed on a rotary evaporator; the aqueous residue is diluted with 100 ml of water and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. This gives a yellow-orange oil.

Yield: 9 g (74%)

Rr value: 0.12 (silica gel, dichloromethane / methanol 90:10) Mass spectrum: (M + H) ⁺ = 205

(b) N- (3-methyl-2.3.4.5-tetrahydro-1H-benzodiazepin-7-yl) -acetamide

Preparation analogous to Example 1 d of N- (2,3,4,5-tetrahydro-1 H-benzo [d] azepine-7-yl) acetamide by reductive alkylation with formaldehyde solution.

Yield: 91%

Rr value: 0.35 (silica gel, dichloromethane / methanol 70:30)

Mass spectrum: (M + H) ⁺ = 219

(c) 3-methyl-2,3,4,5-tetrahydro-1H-benzodiazepin-7-ylamine (as bis-hydrochloride salt) - -

2.75 g (12.6 mmol) of N- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepine-7-yl) -acetamide are dissolved in 20 ml of semiconc. Hydrochloric acid and irradiated for 45 minutes in a microwave oven at 260 watts. It is then evaporated to dryness. It gives slightly reddish, glassy solid. Yield: 91%

Rr value: 0.09 (silica gel, dichloromethane / methanol 70:30) Mass spectrum: (M + H) ⁺ = 177

(d) r (3f?, 4f?) - 4-allyl-5-oxo-tetrahydrofuran furan-3-ylcarbamic acid benzyl ester

2.72 ml (19.4 mmol) of diisopropylamine are initially charged in 30 ml of THF and, while cooling with ice, 12 ml (19.2 mmol) of an n-butyllithium solution in hexane (1.6M) are added. The mixture is stirred for 10 minutes at ^{0 0} C, then cooled to -78 ⁰ C and a solution of 2 g (8.5 mmol) (f?) - (5-oxo-tetrahydrofuran-3-yl) - carbaminsäurebenzylester in 10 ml THF too. The mixture is stirred for one hour at -78 ^0C. Subsequently 2.86 ml (33 mmol) of allyl bromide are added dropwise and the mixture is heated over one hour to -6O ⁰ C. There are then 5 ml sat. Ammonium chloride solution was added and warmed to room temperature. Add water and extract three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated to dryness. The residue is taken up in DMF, acidified with TFA and purified by reversed-phase chromatography. Yield: 820 mg (35%) R _t : 2.70 min Mass spectrum: (MH) ^" = 276

(e) {(1R, 2R) -λ-Hydroxymethyl-2- (3-methyl-2,3,4,5-tetrambda-1H-benzordlazepin-7-ylcarbamoyl) -pent-4-enyl) -carbamic acid benzyl ester - -

Preparation analogous to Example 1a from 3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-ylamine dihydrochloride and [(3f?, 4f?) - 4-allyl-5 oxo-tetrahydrofuran-3-yl] -carbamic acid benzyl ester with trimethylaluminum in dichloromethane. The purification is carried out by means of reversed-phase chromatography. Yield: 50% R _t : 4.04 min C ₂₆ H ₃₃ N ₃ O ₄ (451.56) Mass spectrum: (M + H) ⁺ = 451

(f) ((3f? .4f?) - 4-allyl-1- (3-methyl-2.3.4.5-tetrahvdro-1H-benzodlazepine-7-vn-)

5-oxo-pyrrolidin-3-yl) -carbamic acid benzyl ester (as mono-hydrochloride

salt)

Preparation analogous to Example 1 b from {(7f?, 2f?) - 1-hydroxymethyl-2- (3-methyl-2,3,4,5-tert-hydro-1H-benzo [d] azepin-7-ylcarbamoyl) - pent-4-enyl} -carbamic acid benzyl ester with di-tert-butylazodicarboxylate and tributylphosphine in THF. The purification is carried out by means of reversed-phase chromatography. The residue is dissolved in 1 N hydrochloric acid and extracted three times with ethyl acetate. The aqueous phase is freeze-dried.

A colorless solid is obtained. Yield: 21% (purity 50%) R _t value: 4.04 min Mass spectrum: (M + H) ⁺ = 434

(g) (3R4f?) _"4-Amino-1- (3-methyl-2,3,4,5-tetrahydro-1 H-benzordlazepin-7-yl) -3-propyl-pyrrolidin-2-one (as the bis-Hvdrochlorid- Salt)

Preparation analogous to Example 1 e from {(3f?, 4f?) - 4-allyl-1- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) - 5-oxo-pyrrolidin-3-yl} -carbamic acid benzyl ester hydrochloride. - -

Yield: 35% (purity 50%) R _t value: 3.02 min Mass spectrum: (M + H) ⁺ = 302

(h) 5-Chloro-thiophene-2-carboxylic acid r (3f? .4f?) - 1- (3-methyl-2.3.4.5-tetrahydro-1H-benzodiazepin-7-yl) -5-oxo-4 -propyl-pyrrolidin-3-yl-amide (as a mono-trifluoroacetate salt)

Preparation analogous to Example 1 f (3f, 4f) -4-amino-1- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) 3-propylpyrrolidin-2-one dihydrochloride and 5-chlorothiophene-2-carboxylic acid with TBTU and NMM.

The reaction mixture is concentrated, taken up with diethyl ether / isopropanol and treated with ethereal hydrochloric acid solution. The precipitate is washed twice with diethyl ether, then taken up in a water / trifluoroacetic acid / acetonitrile mixture and purified by reversed-phase chromatography. Yield: 79% R _t value: 4.59 min C ₂₃ H ₂₈ CIN ₃ O ₂ S (446.02)

Mass spectrum: (M + H) ⁺ = 446/448 (chloroisotopes)

The following compounds were prepared analogously:

- -

Example 6

(R) -5-Chloro-thiophene-2-carboxylic acid [5-oxo-1 - (2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) -pyrrolidine-7 yl] -amide

(a) (ffl-δ-chloro-thiophene-carboxylic acid-rδ-oxo-I ^ .S ^ .δ-tetrahydro-1H-benzodiazepin-7-yl) -pyrrolidin-7-yl-amide

Prepared analogously to Example 1c from (f?) - 5-chloro-thiophene-2-carboxylic acid {5-oxo-1- [3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro -1 H-benzo [d] azepin-7-yl] -pyrrolidin-3-yl} -amide. A colorless solid is obtained. - -

Yield: 221 mg (78%) R _t : 2.37 min. Ci ₉ H ₂₀ CIN ₃ O ₂ S (389.90)

Mass spectrum: (M + H) ⁺ = 390/392 (chloroisotopes)

Example 7

(f?) - 5-bromo-thiophene-2-carboxylic acid [5-oxo-1 - (5,6,7,8-tetrahydro-4H-thiazolo [4,5d] azepin-2-yl) - pyrrolidin-3-yl] -amide (mono-trifluoroacetate salt)

(a) (f) - 5-Bromo-thiophene-2-carboxylic acid r5-oxo-1 - (5.6.7.8-tetrahydro-4H-thiazolor4.5dlazepin-2-yl) -pyrrolidin-3-yl-amide ( mono-trifluoroacetate salt)

50 mg (92 μmol) (f?) - 2- {4 - [(5-Bromo-thiophene-2-carbonyl) -amino] -2-oxo-pyrrolinedin-1-yl} -4,5,7 Tert-Butyl 8-tetrahydro-thiazolo [4,5-d] azepine-6-carboxylate are dissolved in a mixture of 0.5 ml of dichloromethane and 0.25 ml

Trifluoroacetic acid and stirred at room temperature for one hour. The mixture is then concentrated to dryness, dissolved in water and lyophilized.

A colorless solid is obtained.

Yield: 44 mg (85%)

R _t value: 2.37 min Ci ₆ H ₁₇ BrN ₄ O ₂ S ₂ (441.37)

Mass spectrum: (M + H) ⁺ = 441/443 (bromine isotopes)

Example 8 (f?) - 5-chloro-thiophene-2-carboxylic acid [1- (3-ethyl-2,3,4,5-tetrahydro-1H- - -

benzo [d] azepin-7-yl) -5-oxo-pyrrolidin-3-yl] -amide

(a) (ffl-δ-Chloro-thiophene-Z-carboxylic acid π-O-ethyI-Z.a ^ .δ-tetrahydro-1H-benzo-diazepin-7-yl) -5-oxo-pyrrolidin-3-yl-amide

100 mg (256 μmol) (f?) Of 5-chloro-thiophene-2-carboxylic acid [5-oxo-1 - (2,3,4,5-tetrahydro-1H-benzo [d] azepine-7 yl) -pyrrolidin-7-yl] -amide are dissolved in a mixture of 1.5 ml of THF and 1 ml of DMF and cooled to ⁰ ° C. 36 .mu.l (256 .mu.mol) of triethylamine and then 23 .mu.l (282 .mu.mol) of ethyl iodide are added dropwise and the mixture is stirred at room temperature for 18 hours. Then the mixture is added to the

Dry concentrated.

A yellowish solid is obtained. Yield: 101 mg (95%)

R _t value: 2.36 min

C21 H ₂₄ CIN ₃ O ₂ S (417.95)

Mass spectrum: (MH) ^" = 416/418 (chloroisotopes)

The following compounds were prepared analogously:

- -

Example 13 5-Bromo-thiophene-2-carboxylic acid [1- (3-methyl-2,3,4,5-tetrahydro-1H- - -

benzo [d] azepin-7-yl) -5-oxopyrrolidin-3-ylmethyl] -amide (mono-trifluoroacetate salt)

(a) 1- (3-Methyl-2,3,4,5-tetrahydro-1H-benzodiazepin-7-yl) -5-oxo-pyrrolidine-3-carboxylic acid (mono-trifluoroacetate salt)

895 mg (3.59 mmol) of 3-methyl-2,3,4,5-tetrahydrobenzo [d] azepin-7-ylamine-bis-hydrochloride are suspended in 3 ml of DCM and admixed with 0.61 ml (3.59 mmol) of diisopropylethylamine. The mixture is stirred for five minutes and then 701 mg (5.39 mmol) of itaconic acid are added. This mixture is heated with stirring to 5O ⁰ C until the solvent is evaporated, and then fused at 14O ⁰ C for 4.5 hours. The melt is then cooled, dissolved in a mixture of water and trifluoroacetic acid and purified by chromatography by RP-HPLC. A colorless solid is obtained. Yield: 764 mg (53%) R _t : 1.71 min Mass spectrum: (M + H) ⁺ = 289

(b) 4-Hydroxymethyl-1- (3-methyl-2.3.4.5-tetrahydro-benzodiazepin-7-yl) -pyrrolidin-2-one (mono-trifluoroacetate salt)

500 mg (1.24 mmol) of 1- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) -5-oxo-pyrrolidine-3-carboxylic acid monotrifluoroacetate are suspended in 20 ml THF and treated at ^{0 0} C with 9 ml (9 mmol) borane-THF complex (1 M in THF). The mixture is stirred for 20 hours at RT and the solvent is distilled off. Of the - -

Residue is suspended in water and trifluoroacetic acid and stirred until homogeneous. Subsequently, the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The residue is purified by chromatography by RP-HPLC. This gives a colorless oil. Yield: 80 mg (17%) R _t : 1.60 min Mass spectrum: (M + H) ⁺ = 275

(c) Methanesulfonic acid 1- (3-methyl-2-.3,4,5-tetrahydrobenzordlazepin-7-yl) -5-oxo-pyrrolidin-3-ylmethyl ester

79 mg (203 μmol) of 4-hydroxymethyl-1- (3-methyl-2,3,4,5-tetrahydrobenzo [d] azepin-7-yl) -pyrrolidin-2-one-mono-trifluoroacetate are dissolved in Dissolved 10 ml of DCM and treated with 150 ul (1, 1 mmol) of triethylamine. It is cooled to ⁰ ° C., admixed with 50 μl (646 μmol) of methanesulfonyl chloride and stirred at RT for five hours. The solution is combined with water and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The methanesulfonate is obtained as crude product (66 mg, orange oil). R _t value: 1.90 min Mass spectrum: (M + H) ⁺ = 353

(d) 4-Azidomethyl-1- (3-methyl-2.3.4.5-tetrahydro-1H-benzodiazepin-7-yl) -pyrrolidin-2-one

66 mg of methanesulfonic acid 1 - (3-methyl-2-, 3,4,5-tetrahydrobenzo [d] azepin-7-yl) -5-oxopyrrolidin-3-ylmethyl ester are dissolved as crude product in 5 ml of DMF and added with 40 mg (615 .mu.mol) of sodium azide. The mixture is stirred for 20 hours at 5O ⁰ C and the solvent is distilled under slight vacuum on a rotary evaporator - -

from. The residue is taken up in ethyl acetate and washed with a mixture of sat. Sodium bicarbonate solution and sat. Washed saline solution. The aqueous phase is reextracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The azide is obtained as crude product (56 mg, orange oil). R _t value: 2.08 min Mass spectrum: (M + H) ⁺ = 300

(e) 5-Bromo-thiophene-2-carboxylic acid tri- (3-methyl-2.3.4.5-tetrahydro-1H-benzo-diazepin-7-yl) -5-oxo-pyrrolidin-3-yl-methvH-amide (mono trifluoroacetate salt)

56 mg of 4-azidomethyl-1- (3-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) -pyrrolidin-2-one are as crude product analogous to Example 1 e in Hydrogenated methanol.

The amine thus obtained (crude product, 25 mg, colorless oil) is dissolved in DMF and reacted analogously to Example 1 f with 5-bromothiophene-2-carboxylic acid, TBTU and NMM. The purification is carried out by chromatography using RP-HPLC.

A colorless solid is obtained. Yield: 8.4% (starting from 4-hydroxymethyl-1- (3-methyl-2, 3,4,5-tetrahydrobenzo [d] azepin-7-yl) -pyrrolidin-2-one (mono-trifluoroacetate salt ))

R _t value: 2.35 min

C _2I H ₂₄ BrN ₃ O ₂ S (462.41)

Mass spectrum: (M + H) ⁺ = 462/464 (bromine isotopes)

Example 15

(f?) - 5-Chloro-thiophene-2-thiocarboxylic acid [1- (3-ethyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yl) -5-thioxo -pyrrolidin-3-ylmethyl] -amide (mono-trifluoroacetate salt) - -

(a) 1- (3-Methyl-2,3,4,5-tetrahydro-1H-benzodiazepin-7-yl) -5-oxo-pyrrolidine

3-carboxylic acid (mono-trifluoroacetate salt)

60 mg (144 μmol) of (f) - 5-chloro-thiophene-2-carboxylic acid [1- (3-ethyl-2,3,4,5-tetrahydro-1H-benzo [d] azepine-7 yl) -5-oxo-pyrrolidin-3-yl] -amide are in 2 ml

Dissolved dioxane and added 116 mg (288 μmol) of Lawesson's reagent. The mixture is stirred for two hours under reflux. The mixture is then cooled and freed of volatiles in vacuo. The residue is dissolved in a mixture of water and trifluoroacetic acid and purified by means of

RP-HPLC purified by chromatography.

Yield: 67 mg (81%)

R _t value: 2.85 min

Mass spectrum: (M + H) ⁺ = 450/452 (chloroisotopes)

Example A

Dry ampoule containing 75 mg of active ingredient per 10 ml

Composition:

Active substance 75.0 mg Mannitol 50.0 mg

Water for injections ad 10.0 ml

production:

Active substance and mannitol are dissolved in water. After bottling is freeze-dried. The solution for the ready-to-use solution is with - -

Water for injections.

Example B

Dry ampoule containing 35 mg of active ingredient per 2 ml

Composition:

Active substance 35.0 mg Mannitol 100.0 mg

Water for injections ad 2.0 ml

production:

Active substance and mannitol are dissolved in water. After bottling is freeze-dried.

The solution to the ready-to-use solution is water for injections.

Example C

Tablet with 50 mg active ingredient

Composition:

(1) Active ingredient 50.0 mg

(2) lactose 98.0 mg

(3) Cornstarch 50.0 mg

(4) polyvinylpyrrolidone 15.0 mg

(5) Magnesium stearate 2.0 mg 215.0 mg

production: - -

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are admixed with (5). From this mixture tablets are pressed, biplan with double-sided facet and one-sided part notch. Diameter of the tablets: 9 mm.

Example D

Tablet with 350 mg active ingredient

Composition:

(1) Active ingredient 350.0 mg

(2) lactose 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). The dried granules are admixed with (5). From this mixture tablets are pressed, biplan with double-sided facet and one-sided part notch. Diameter of the tablets: 12 mm.

Example E

Capsules with 50 mg active ingredient

Composition: - -

(1) Active ingredient 50.0 mg

(2) corn starch dried 58.0 mg

(3) lactose powdered 50.0 mg

(4) magnesium stearate 2.0 mq

160.0 mg

production:

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

This powder mixture is filled in a capsule filling machine in hard gelatin capsule size 3.

Example F

Capsules with 350 mα active ingredient

Composition:

(1) Active ingredient 350.0 mg

(2) corn starch dried 46.0 mg

(3) lactose powdered 30.0 mg

(4) magnesium stearate 4.0 mq

430.0 mg

production:

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

Example G

Suppositories containing 100 mg of active ingredient

1 suppository contains:

Active ingredient 100.0 mg

Polyethylene glycol (M.G. 1500) 600.0 mg

Polyethylene glycol (M.G. 6000) 460.0 mg

Polyethylene sorbitan monostearate 840.0 mg 2000.0 mg

production:

The polyethylene glycol is melted together with polyethylene sorbitan monostearate. At 4O ⁰ C the ground active substance is homogeneously dispersed in the melt. It is cooled to 38 ⁰ C and poured into slightly pre-cooled suppository molds.

Claims

- Patent claims

1. Compounds of the general formula (I)

in which

D represents a substituted bicyclic ring system of the formula (II)

by doing

_R 7a _{/ R} 7b _{/ R} 7c each independently represents a fluorine atom, a hydroxy, d- ₅ alkoxy, amino, Ci _-5 alkylamino, di (Ci _-5 alkyl) amino,

C _3-5 -Cycloalkylenimino-, Ci _-5 alkylcarbonylamino group, a Ci _-5 alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-Ci _-5 alkyl, Ci _-5 alkoxy-Ci _-5 alkyl, amino-C-ι- ₅ alkyl, cis-cis-alkyl-alkylamino, di- (Ci- _5-alkyl) - alkyl- amino-Ci- _5, C ^ Ci--Cycloalkylenimino s-alkyl, carboxy

Co- _5- alkyl, Ci-s-alkoxycarbonyl-Co-s-alkyl, aminocarbonyl-Co- ₅ - alkyl, Ci-s-alkylaminocarbonyl-co-s-alkyl, di (Ci- ₅ -alkyl ) - - -

aminocarbonyl-Co- _5- alkyl- or C 1-4 -cycloalkyleneiminocarbonyl-

Co- _5- alkyl group means, where not both R ^7b / R ^7c can be bonded simultaneously via a heteroatom to the ring carbon atom, except -C (R ^7b R ^7c ) - corresponds to a -CF ₂ -

Group, or

two radicals R ^7b / R ^7c together with the ring carbon atom represent a 3-, 4-, 5-, 6- or 7-membered saturated carbocycle or a cyclopentene, cyclohexene, oxetane, azetidine,

Hexamethyleneimine, 1, 3-dioxolane, 1, 4-dioxane,

K ² and K ^{3 are} each independently of one another -CH ₂ -, -CHR ^8a -, -CR ^8b R ^8c - - -

or a -C (O) group, where

_R 8a _{/ R} 8b _{/ R} 8c each independently represent a C-ι- ₅ alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-ds-alkyl, Ci-s-alkoxy-Ci-s-alkyl- , Amino-Ci- _5- alkyl, d- _5- alkyl-amino-Ci _-5- alkyl, di (Ci _-5- alkyl) -amino-Ci _-5- alkyl, C _4-7 -cyclo - alkyleneimino-Ci _-5 alkyl, carboxy-Ci _-5 alkyl, Ci _-5 -Al koxycarbo- nyl-Ci ₅ alkyl, aminocarbonyl-ds-alkyl, Ci _-5 -Alkylaminocar- bonyl- d-5-alkyl, di (d _-5- alkyl) aminocarbonyl-d _-5- alkyl or dy-cycloalkyleniminocarbonyl-Ci-s-alkyl group,

or two radicals R ^8b / R ^8c together with the

Ring carbon atom, a 3-, 4-, 5-, 6- or 7-membered saturated carbocycle or a cyclopentene, cyclohexene,

Oxetane, azetidine, thietane, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran, piperidine, pentamethylene sulfide, hexamethyleneimine, hexahydropyridazine, tetrahydro-2 (1H) -pyrimidinone or [1, 3 ] Can form oxazinan-2-one ring, with its methylene groups being replaced by 1 or 2 d- ₃ -

Alkyl- or -CF ₃ may be substituted groups, and / or its methylene groups, if they are not bonded to a heteroatom, may be substituted by 1 or 2 fluorine atoms, and / or in which a -CH ₂ - group in addition to a nitrogen atom a -CO- group may be replaced and / or the imino groups ₃ alkylcarbonyl group may be substituted by a Ci- ₃ alkyl or C and / or wherein the sulfur atom to a sulfoxide or - -

Carbon atom of X may be separated in formula I, and

R ¹ is a hydrogen atom or a hydroxy, Ci- ₃ alkoxy, amino, C-ι- ₃ alkylamino, di- (Ci ₃ alkyl) amino, d- ₅ alkyl, C ₃ _5- alkenyl-CH ₂ -, C _3-5 -alkynyl-CH ₂ -, Cs-e-cycloalkyl-, C _4-6 -cycloalkenyl-, oxetan-3-yl-,

Tetrahydrofuran-3-yl, benzyl, ds-alkylcarbonyl, trifluoromethylcarbonyl, Cs-β-cycloalkylcarbonyl, Ci _-5- alkylsulfonyl, C _3-6 -cycloalkylsulfonyl, aminocarbonyl, Ci- ₅ alkylaminocarbonyl, di (Ci- ₅ -AL- alkyl) aminocarbonyl, Ci- ₅ alkyloxycarbonyl- or C ₄ - ₇ cycloalkyl eniminocarbonylgruppe means

wherein the methylene and methyl groups present in the above-mentioned groups may additionally _-5 -Alkylcarboxycarbonylgruppe by a Ci _-3 alkyl, carboxy, Ci be substituted or by a hydroxy, Ci _-5 -

Alkoxy, amino, Ci- ₅ alkylamino, Ci- ₅ dialkylamino, or C _4- 7-cycloalkyleneimino group may be substituted, the methylene or methyl groups are not directly provided to a hetero atom from the group O, N or S are bound .

and / or one to three hydrogen atoms may be replaced by fluorine atoms, provided that the methylene or - -

Methyl groups are not bonded directly to a heteroatom from the group O, N or S,

A ^{2 is} either a nitrogen atom or an = C (R ¹² ) group,

wherein R ¹⁰ , R ¹¹ and R ^{12 are} each independently

is a hydrogen, fluorine, chlorine, bromine or iodine atom, or a C ₅ -alkyl, -CF _3, C _2-5 alkenyl, C _2-5 alkynyl, cyano, carboxy, C _-5 alkoxycarbonyl, hydroxy, Ci _-3 alkoxy, CF ₃ O, CHF ₂ O, CH ₂ FO, amino, Ci- ₅ alkylamino, di- (Ci- ₅ alkyl) mean amino or C 1-4 cycloalkyleneimino group,

represents a substituted ring system of the formula (IIa) or (IIb),

by doing

R ³ is a hydrogen atom or a Ci _-3 alkyl group,

R ⁴ and R ^{5 are} each independently

a hydrogen atom, a hydroxy group, an -OR ⁹ group, a C _2-6 alkenyl or C _2-6 alkynyl group, - -

a linear or branched C ₆ alkyl group wherein the hydrogen atoms of the straight-chain or branched C ₆ alkyl group optionally may be replaced by fluorine atoms entirely or partially, and wherein the straight-chain or branched C ₆ alkyl group optionally substituted by a C _{_3-5} cycloalkyl, nitrile, hydroxy, d- ₅ alkyloxy, allyloxy, propargyloxy, benzyloxy, Ci- ₅ alkylcarbonyloxy, d- ₅ -Alkyloxycarbonyloxy-, carboxy- Ci- ₅ alkyloxy, d- ₅ alkyloxycarbonyl-d-alkyloxy, mercapto, d- ₅ alkylsulphanyl, Ci _-5 alkylsulfonyl, carboxy, d- ₅ alkyloxy carbonyl, aminocarbonyl, d-5-alkylaminocarbonyl, di- (d-5-al kyl) aminocarbonyl, Cs-β-Cycloalkyleniminocarbonyl-, amino sulfonyl, Ci- ₅ alkylaminosulfonyl, di- (Ci- _5-alkyl) -aminosulfonyl-, Cs-β-Cycloalkyleniminosulfonyl -, amino, d-5-alkylamino, di- (Ci _-5- alkyl) -amino, d- ₅ -alkylcarbonylamino, d- ₅ -alkylsulfonylamino, Λ / - (d- ₅ -alkylsulfonyl ) -d- _5- alkylamino or C _3-6 -cyclo oalkylcarbonylamino group may be substituted, wherein the hydrogen atoms of the d _-5- alkyloxy may optionally be wholly or partially replaced by fluorine atoms, and wherein in the 6- to 7-membered cycles of C ₃ - ₆ - Cycloalkyleniminocarbonylgruppe in the cyclic part of a methylene group in 4- Position of a 6- or 7-membered cycloalkyleneimino group by an oxygen or sulfur atom, by a carbonyl, sulfinyl, sulfonyl or

-NR ^8c group may be replaced, and in addition, a methylene group adjacent to an aforementioned - NR ^8c group may be replaced by a carbonyl group,

a phenyl or heteroaryl group which in the phenyl or heteroaryl optionally 1 to 3 times by identical or different substituents - -

selected from the group consisting of halogen atoms, d- ₅ alkyl, di (Ci _-5- alkyl) amino, hydroxy, Ci _-5 alkyloxy, mono-, di- or trifluoromethoxy, carboxy and Ci- ₅ alkyloxy carbonyl groups may be substituted,

a phenyl-Ci ₅ alkyl or heteroaryl-Ci- ₅ alkyl group, in the phenyl or heteroaryl moiety optionally Ci- mono- to trisubstituted by identical or different substituents selected from the group consisting of halogen atoms, ₅ alkyl, di - (Ci _-5- alkyl) -amino, hydroxy, Ci _-5- alkyloxy, mono-, di- or trifluoromethoxy, carboxy and Ci- ₅ alkyloxy-carbonyl groups may be substituted, and optionally in Ci - _5- alkyl part by a hydroxy or a d- ₅ -alkyl- oxygruppe, wherein the hydrogen atoms of the Ci- ₅ -alkyloxy may optionally be wholly or partially replaced by fluorine atoms, an allyloxy, propargyloxy, benzyloxy, Ci - ₅ alkylcarbonyloxy, d- ₅ -Alkyloxycarbonyloxy-, carboxy- Ci- ₅ alkyloxy or ds-alkyloxycarbonyl-d-alkyloxy group may be substituted,

a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-d- _5- alkyl or cycloalkyleneimino-ci ₃ -alkyl group, in which at 4- to 7-membered cycles in the cyclic portion of a methylene group optionally substituted by an -N (R ^8c ) group, an oxygen or sulfur atom, or an -S (O) - or -S (O) 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 (O) ₂ N (R ^8b ) group, or - -

with the proviso that a composition as defined above, 3- to 7-membered cycloalkyl, Cycloalkylenimino-, cycloalkyl-Ci alkyl or Cycloalkylenimino _-5-Ci _-3 alkyl, in which two hetero-atoms selected from among oxygen and nitrogen are separated by exactly one optionally substituted --CH ₂ - group, is excluded,

where a 3- to 7-membered cycloalkyl, as defined above,

R ⁹ is a straight or branched C ₆ alkyl group wherein the hydrogen atoms may be replaced of linear or branched d- _C6 alkyl group optionally fully or partly by fluorine atoms, and wherein the straight or branched Ci _-6 alkyl group optionally by a C _3-5 cycloalkyl group, hydroxy, Ci- ₅ alkyloxy, allyloxy, propargyloxy, benzyl oxy, Ci ₅ alkylcarbonyloxy, Ci- ₅ -Alkyloxycarbonyloxy-, carboxy-Ci ₅ - alkyloxy-, Ci-s-alkoxycarbonyl-Ci-s-alkyl- oxy, carboxy, Ci- ₅ alkyloxycarbonyl, aminocarbonyl, Ci _-5 alkylaminocarbonyl, di (Ci _-5 alkyl) aminocarbonyl . - -

C ₃ - ₆ -Cycloalkyleniminocarbonyl-, amino, ds-alkylamines no-, di (Ci _-5 alkyl) amino, ds-alkylcarbonylamino, Ci- ₅ alkylsulfonylamino, Λ / - (Ci- ₅ alkylsulfonyl) amino -ci- ₅ alkyl or C ₃ - ₆ -Cycloalkylcarbonylaminogruppe 5 may be substituted, wherein the hydrogen atoms of the Ci ₅ alkyloxy group may optionally be substituted by fluorine atoms entirely or partially, and wherein the 6- to 7-membered cycles of C _3-6 -

10 Cycloalkyleniminocarbonylgruppe in the cyclic portion of a methylene group in the 4-position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulfur atom, by a carbonyl, sulfinyl, sulfonyl or -NR ^8c - group, and

In addition, a methylene group adjacent to an aforementioned -NR ^8c group may be replaced by a carbonyl group, provided that the replacement of hydrogen atoms of the first carbon atom of the

20 straight-chain or branched d-β-alkyl group is excluded by substituents from the group oxygen, sulfur or nitrogen,

a phenyl, heteroaryl, phenyl-Ci _-5- alkyl or heteroaryl

25 aryl-Ci- ₅ -alkyl group which in the phenyl or heteroaryl optionally one to three times by identical or different substituents selected from the group consisting of halogen atoms, Ci- ₅ alkyl, di (Ci- ₅ -alkyl) - amino,

30 hydroxy, Ci- methoxy- ₅ -alkyloxy, mono-, di- or trifluoro, carboxy and Ci- ₅ -Alkyloxycarbonylgruppen may be substituted, - -

a 3- to 7-membered cycloalkyl, cycloalkyl-Ci _-5- alkyl- or cycloalkyleneimino-C ₂ - ₃ -alkyl group, in which at 4 to 7-membered cycles in the cyclic part 5, a methylene group optionally by a

-N (R ^8c ) group, an oxygen or sulfur atom or an -S (O) or -S (O) ₂ - group may be replaced, or

In the case of 4- to 7-membered cyclic compounds 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 ⁸¹³ ) group, or

15 in the case of 6- to 7-membered cycles in the cyclic part, three adjacent methylene groups together optionally substituted by a -OC (O) N (R ^8b ) - or -N (R ^8b ) C (O) N (R ^8b ) - or -N (R ^8b ) S (O) ₂ N (R ^8b ) - group may be replaced with the proviso that a 3- to 7-membered cycloalkyl, cycloalkyl-Ci- ₅ -alkyl as defined above or cycloalkylenimino-C _2-3 -alkyl group in which two heteroatoms from the group oxygen and

25 nitrogen are separated by exactly one optionally substituted -CH ₂ - group, is excluded,

wherein a 3- to 7-membered one as defined above

30 cycloalkyl, cycloalkyl-Ci- ₅ -alkyl- or cycloalkylene-imino-C _2-3 -alkyl group on one or two -CH ₂ - groups by one or two Ci _-3 alkyl groups - -

may be substituted or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a Cs-s-cycloalkyl or C ₃ - ₈ cycloalkenyl group form,

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

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

three directly adjacent methylene groups of a C _6-8 cycloalkyl group together through a -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,

wherein 1 to 3 carbon atoms, a _C3 - ₈ cycloalkyl group is optionally substituted independently from each other by one or two identical or different halogen atoms, or C ₅ alkyl, nitrile, hydroxy, Ci _-5 alkyloxy-, Ci _-5 - alkyl carbonyloxy, carboxy-Ci _-5 alkyl, Ci _-5 alkyloxycarbonyl- ₅ d- alkyl, Ci _-5 alkylsulphanyl, Ci _-5 alkylsulfonyl, carboxy, Ci- ₅ alkyloxycarbonyl- , aminocarbonyl, ds-alkylamino carbonyl, di- (Ci- _5-alkyl) aminocarbonyl, C ₃ - ₆ cycloalkylene iminocarbonyl-, aminosulfonyl, Ci- ₅ alkylaminosulfonyl,

Di- (Ci- _5-alkyl) -aminosulfonyl-, C ₃ - ₆ nyl- -Cycloalkyleniminosulfo-, amino, ds-alkylamino, di- (Ci- _5-alkyl) -amino, - -

Ci _-5- Alkylcarbonylamino-, d- ₅ -alkylsulfonylamino, / V- (Ci _-5 - alkylsulfonyl) -Ci _-5- alkylamino or C _3-6 -cycloalkylcarbonyl- amino groups may be substituted,

5 wherein 1 to 2 carbon atoms of a C _{_3-8} -Cycloalken- yl group optionally substituted independently from each other by a Ci _-5 alkyl, nitrile, carboxy-Ci _-5 alkyl, Ci _-5 - alkyloxycarbonyl-Ci _-5 alkyl , carboxy, Ci _-5 -Al kyloxycarbo- nyl-, aminocarbonyl, ds-alkylaminocarbonyl, di- (Ci _-5 -AL-

10-kyl) -aminocarbonyl, Cs-β-cycloalkyleneiminocarbonyl, aminosulfonyl, ds-alkylaminosulfonyl, di (Ci- ₅ -alkyl) -aminosulfonyl or Cs-β-cycloalkyleniminosulfonyl group,

Group 15 and 1 to 2 carbon atoms of a ds-cycloalkenyl, which are not bound by a double bond to a different carbon atom, optionally substituted independently by a fluorine atom or a hydroxy, Ci- ₅ alkyloxy-, Ci- ₅ alkylcarbonyloxy, Ci- ₅ -alkyl-

20 sulfanyl, d-5-alkylsulfonyl, amino, d-5-alkylamino, di-

(d-5-alkyl) amino, Ci-5-Alkylcarbonylamino-, Ci-5-Alkylsul- fonylamino, Λ / - (d-5-alkylsulfonyl) -d-5-alkylamino or Cs-β-Cycloalkylcarbonylaminogruppe can be substituted

in the two heteroatoms in the cycle from the group

30 oxygen and nitrogen are separated by exactly one optionally substituted -CH ₂ - group, and / or - -

in the 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, by a heteroatom 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 heteroatom from the group oxygen, nitrogen,

Sulfur and halogen atom is bonded directly to the cyclic group, is separated from another heteroatom 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, is excluded,

M represents a -CH ₂ -, -CHR ³ -, -CR ³ R ³ - group or a bond,

W represents an oxygen or sulfur atom,

B represents a thiophene ring according to formula (IM),

which is bonded via the 2-position to the carbonyl group in formula (I) - -

and which is substituted in the 5-position by R ² and optionally additionally by R ⁶ , wherein

R ^{2 represents} a fluorine, chlorine, bromine or iodine atom, or a methoxy, d-2-alkyl or ethynyl group,

R ^{6 represents} a hydrogen, fluorine, chlorine, bromine or iodine atom, or a d-2-alkyl or amino group,

the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and

an optionally substituted by a Ci _-3 alkyl group

Imino group, or an oxygen or sulfur atom and additionally a nitrogen atom, or

optionally substituted by a Ci _-3 alkyl imino group and containing two or three nitrogen atoms,

and also to the aforementioned monocyclic

Heteroaryl groups, optionally substituted by a fluorine, chlorine or bromine atom, a C-ι- ₃ alkyl via two adjacent carbon atoms

Hydroxy, Ci- ₃ alkyloxy, amino, Ci- ₃ alkylamino, di (Ci- ₃ alkyl) - - -

amino- or Cs-β-cycloalkyleneimino group may be fused to substituted phenyl ring,

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

D represents a substituted bicyclic ring system of the formula (II)

(H). - -

by doing

K ² and K ³ - -

A ^{2 is} either a nitrogen atom or an = C (R ¹² ) group,

wherein R ¹⁰ , R ¹¹ and R ^{12 are} each independently

a hydrogen, fluorine, chlorine, bromine or iodine atom, or a - -

CI ₅ alkyl, -CF _3, C _2-5 alkenyl, C _2-5 alkynyl, cyano, carboxy, Ci- ₅ alkoxycarbonyl, hydroxy, Ci _-3 alkoxy, CF ₃ O, CHF, CH ₂ FO, amino, Ci- ₅ alkylamino, di- (Ci- _5-alkyl) amino or C ^ -Cycloalkylenimino- group ₂ O-,

represents a substituted ring system of the formula (IIa) or (IIb),

by doing

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

R ⁴ and R ^{5 are} each independently

a straight or branched _Ci-6-alkyl group wherein the hydrogen atoms of the straight-chain or branched d-β-alkyl group may optionally be wholly or partly replaced by fluorine atoms, and wherein the straight-chain or branched C ₆ alkyl group optionally substituted by a C _3-5 cycloalkyl, nitrile, hydroxy, Ci ₅ alkyloxy, allyloxy, propargyloxy, benzyloxy,

Ci _-5 alkylcarbonyloxy, d- ₅ -Alkyloxycarbonyloxy-, carboxy- Ci- ₅ alkyloxy, ds-alkyloxycarbonyl-ds-alkyloxy, mercapto, Ci- ₅ alkylsulphanyl, Ci- ₅ alkylsulfonyl, carboxy -, carbonyl Ci- ₅ alkyloxy, aminocarbonyl, Ci- ₅ alkylaminocarbonyl, di- (Ci- ₅ -AL- - -

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

Methylene optionally by a -N (R ^8c ) group

Oxygen or sulfur atom, or a -S (O) or -S (O) ₂ - group may be replaced, or

10 by substituents from the group oxygen,

Sulfur or nitrogen is excluded,

a phenyl, heteroaryl, phenyl-Ci ₅ alkyl or heteroaryl-C-ι- ₅ alkyl group,

20 thoxy-, carboxy and Ci- ₅ -Alkyloxycarbonylgruppen may be substituted,

Groups may be substituted by one or two d- ₃ alkyl groups, or

-N (R ^8c ), carbonyl, sulfinyl or sulfonyl group may be replaced, and / or - -

15 carbonyloxy, carboxy-Ci _-5 alkyl, d- d- alkyloxycarbonyl- ₅ ₅ alkyl, Ci _-5 alkylsulphanyl, Ci _-5 alkylsulfonyl, carboxy, Ci- ₅ -alkyloxycarbonyl, aminocarbonyl, d- ₅ -alkylamino carbonyl, di (Ci _-5 alkyl) aminocarbonyl, C _3-6 cycloalkylene iminocarbonyl-, aminosulfonyl, Ci- ₅ alkylaminosulfonyl,

25 wherein from 1 to 2 carbon atoms of a C _{_3-8} cycloalkenyl group optionally substituted independently from each other by a C ₅ alkyl, nitrile, carboxy-d- ₅ alkyl, d- ₅ - alkyloxycarbonyl-d-5-alkyl , Carboxy, d-5-alkyloxycarbo-

30 nyl-, aminocarbonyl, Ci- ₅ alkylaminocarbonyl, di-

(Ci- _5-alkyl) aminocarbonyl, C ₃ - ₆ -Cycloalkyleniminocarbo- nyl-, aminosulfonyl, d-5-alkylaminosulphonyl, di- (Ci-5-al - -

15 with the proviso that such, together from R ⁴ and

R ⁵ formed C _3-8 -cycloalkyl or C _3-8 -cycloalkenyl group,

25, the radicals R ⁴ and R ^{5 are} attached by a

Heteroatom from the group oxygen, nitrogen and sulfur are replaced, and / or

in which one bound to the cyclic group

30 substituent, which is characterized in that a

in which two oxygen atoms are directly connected, is excluded,

M represents a -CH ₂ -, -CHR ³ -, -CR ³ R ³ - group or a bond,

W represents an oxygen or sulfur atom,

B represents a thiophene ring according to formula (IM),

the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and

an optionally substituted by a Ci _-3 alkyl group

Imino group and two or three nitrogen atoms,

3. Compounds of general formula (I) according to claim 1 or 2, in which

D represents a substituted bicyclic ring system of the formula (II)

by doing

_R 7a _{/ R} 7b _{/ R} 7c - -

each independently a fluorine atom, a hydroxy, d- ₅ alkoxy, a d- ₅ alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-Ci- ₅ -alkyl-, C ₁ . _5- alkoxy-C ₁ . ₅ - alkyl group, where not both R ^7b / R ^7c can be bonded via a heteroatom to the ring carbon atom at the same time, except -C (R ^7b R ^7c ) - corresponds to a -CF ₂ - group, or

two radicals R ^7b / R ^7c together with the ring carbon atom can form a 3-, 4-, 5-, 6- or 7-membered saturated carbocycle or a cyclopentene, cyclohexene, oxetane, tetrahydrofuran, tetrahydropyran ring where the methylene groups are replaced by 1 or 2 C ₁ . ₃ -

Alkyl or -CF ₃ groups may be substituted, and / or the methylene groups, if they are not bonded to a heteroatom, may be substituted by 1-2 fluorine atoms, and / or in which a -CH ₂ - group in addition to an N- Atom may be replaced by a -C (O) group,

_R 8a _{/ R} 8b _{/ R} 8c each independently represent a Ci ₅ alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-Ci- ₅ - means alkyl, Ci-s-alkoxy-Ci-s-alkyl group . - -

or two R ^8b / R ^8c together with the ring carbon may form a 3-, 4-, 5-, 6- or 7-membered saturated carbocycle or a cyclopentene, cyclohexene, oxetane, tetrahydrofuran, tetrahydropyran ring, where the methylene groups are replaced by 1 or 2 Ci _-3 -

Alkyl- or -CF ₃ may be substituted groups, and / or its methylene groups, if they are not bonded to a heteroatom, may be substituted by 1 or 2 fluorine atoms, and / or in which a -CH ₂ - group in addition to a nitrogen atom a -C (O) group may be replaced,

Carbon atom of X may be removed in formula I, and

R ^8a , R ^8b and R ^8c may be present,

X represents an -N (R ¹ ) group in the

R ¹ is a hydrogen atom or a Ci _-5 alkyl, C _3-S -alkenyl-CH ₂ -,

C _3-5 -alkynyl-CH ₂ -, C _3-6 -cycloalkyl, C _4-6 -cycloalkenyl group,

wherein the methylene and methyl groups present in the above-mentioned groups may additionally be substituted by a Ci _-3 alkyl, carboxy, Ci-s-Alkylcarboxycarbonylgruppe, or by a hydroxy, d- ₅ - alkoxy, amino, Ci ₅ -alkylamino, Ci- ₅ -dialkylamino or - -

C4-7-Cycloalkyleniminogruppe can be substituted if the methylene or methyl groups are not directly bonded to a heteroatom from the group O, N or S,

A ^{1 is} a sulfur atom, a -C (R ¹⁰ ) = N-, -N = C (R ¹⁰ ) -, or -

C (R ¹⁰ ) = C (R ¹¹ ) - group means

A ^{2 is} either a nitrogen atom or an = C (R ¹² ) group,

wherein R ¹⁰ , R ¹¹ and R ^{12 are} each independently

a hydrogen, fluorine, chlorine, bromine, or a Ci _-5 alkyl, - CF ₃ , cyano, carboxy, Ci _-5 alkoxycarbonyl, hydroxy, Ci _-3 - alkoxy, CF ₃ O. Mean, CHF ₂ O, CH ₂ FO group,

represents a substituted ring system of the formula (IIa),

by doing

R ^{3 represents} a hydrogen atom,

R ⁴ and R ^{5 are} each independently - -

a hydrogen atom, a hydroxy group, an -OR ⁹ group, a C ₂ - ₆ alkenyl or C ₂ - ₆ alkynyl group,

a linear or branched C ₆ alkyl group wherein the hydrogen atoms of the straight-chain or branched Ci _-6 alkyl group may optionally be wholly or partly replaced by fluorine atoms, and wherein the straight or branched Ci _-6 alkyl group optionally substituted by a C _3-5 Cycloalkyl, nitrile, hydroxy,

Ci- ₅ alkyloxy, allyloxy, propargyloxy, benzyloxy, Ci- ₅ alkylcarbonyloxy, CI ₅ -Alkyloxycarbonyloxy-, carboxy- Ci- alkyloxy _5, Ci-s-alkoxycarbonyl-Ci-s-alkyloxy- , mercapto, Ci- ₅ alkylsulphanyl, Ci- ₅ alkylsulfonyl, carboxy, Ci- _carbonyl-5 alkyloxy, aminocarbonyl, Ci _-5 alkylaminocarbonyl, di (Ci _-5 alkyl -AL- ) aminocarbonyl, Cs-β-Cycloalkyleniminocarbonyl-, fonyl- Aminosul-, Ci- ₅ alkylaminosulfonyl, di (Ci _-5 alkyl) -aminosulfonyl-, Cs-β-Cycloalkyleniminosulfonyl-, amino, Ci- ₅ alkylamino, di- (Ci- _5-alkyl) -amino, Ci- ₅ -alkylcarbonylamino-, d- ₅ alkyl sulfonylamino, Λ / - (Ci- ₅ alkylsulfonyl) alkylamino -ci- ₅ or

Cs-β-Cycloalkylcarbonylaminogruppe may be substituted, wherein the hydrogen atoms of the Ci- ₅ -alkyloxy may optionally be wholly or partially replaced by fluorine atoms, and wherein in the 6- to 7-membered cycles of C _3-6 -

Methylene group adjacent to an aforementioned - NR ^8c group may be replaced by a carbonyl group, - -

a phenyl or heteroaryl group which, in the phenyl or heteroaryl moiety, is optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of halogen atoms,

CI ₅ alkyl, di- (Ci- _5-alkyl) amino, hydroxy, Ci- ₅ -alkyloxy, mono-, di- or trifluoromethoxy, carboxy- and d- ₅ -Alkyloxycarbonylgruppen may be substituted .

a phenyl-Ci _-5 alkyl, or heteroaryl-Ci _-5 alkyl group which in the phenyl or heteroaryl optionally Ci- mono- to trisubstituted by identical or different substituents selected from the group consisting of halogen atoms, ₅ alkyl, di - (Ci- _5-alkyl) amino, hydroxy, Ci- ₅ -alkyloxy, mono-, di- or trifluoromethoxy, carboxy- and

Cis- _5- Alkyloxycarbonylgruppen may be substituted, and optionally in the Ci- ₅ -alkyl part by a hydroxy or a Ci- ₅ -alkyloxy, wherein the hydrogen atoms of the Ci- ₅ -alkyloxy may optionally be wholly or partially replaced by fluorine atoms , an allyloxy, propargyloxy,

Benzyloxy, Ci- ₅ alkylcarbonyloxy, Ci- ₅ -Alkyloxycarbonyloxy-, carboxy-Ci ₅ alkyloxy or Ci- ₅ alkyloxycarbonyl C-ι- ₅ alkyloxy group may be substituted,

Methylene optionally by a -N (R ^8c ) group

Oxygen or sulfur atom, or a -S (O) or -S (O) ₂ - group may be replaced, or

in the case of 4- to 7-membered cycles in the cyclic part two - -

optionally adjacent methylene groups may optionally be replaced by a -C (O) N (R ^8b ) or -S (O) ₂ N (R ^8b ) group, or

with the proviso that a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-d- _5- alkyl or cycloalkyleneimino-ci ₃ -alkyl group as defined above, in which two heteroatoms from the group oxygen and nitrogen by exactly an optionally substituted -CH ₂ group are separated from each other, is excluded,

wherein a composition as defined above, 3- to 7-membered cycloalkyl, Cycloalkylenimino-, cycloalkyl-Ci- ₅ alkyl or cycloalkylene imino-C-ι- ₃ alkyl group at one or two -CH ₂ groups by one or in each case two d- _C3 alkyl groups may be substituted, with the proviso that R ⁴ and R ⁵ hydroxy -OR ⁹ groups may be the same as or not defined, and wherein

R ⁹ is a straight or branched _Ci-6-alkyl group wherein the hydrogen atoms of the straight-chain or branched d-β-alkyl group may optionally be substituted by fluorine atoms entirely or partially, and wherein the straight or branched

Ci- ₆ alkyl group optionally substituted by a C ₃ - ₅ cloalkylgruppe -Cy-, hydroxy, Ci _-5 alkyloxy, allyloxy, pro - -

pargyloxy-, benzyloxy, ds-alkylcarbonyloxy, Ci oxycarbonyloxy _-5 alkyl, carboxy-d- ₅ alkyloxy, Ci _-5 -Al kyloxy- carbonyl-Ci ₅ alkyloxy, carboxy, Ci- _5- alkyloxycarbonyl, aminocarbonyl, Ci-s-alkylaminocarbonyl, di- (Ci- ₅ -alkyl) -

5 aminocarbonyl, Cs-β-cycloalkyleneiminocarbonyl, amino,

C-ι- ₅ alkylamino, di- (Ci- _5-alkyl) -amino, Ci- nylamino- ₅ -Alkylcarbo-, ds-alkylsulfonylamino, Λ / - (Ci- ₅ alkylsulfonyl) - Ci- ₅ alkylamino or C _3-6 cycloalkylcarbonylamino group may be substituted,

10 wherein the hydrogen atoms of the Ci _-5- alkyloxy may optionally be wholly or partially replaced by fluorine atoms, and wherein in the 6- to 7-membered cycles of C ₃ - ₆ - Cycloalkyleniminocarbonylgruppe in the cyclic part

15 a methylene group in the 4-position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulfur atom, by a carbonyl, sulfinyl, sulfonyl or -NR ^8c group, and additionally adjacent to a methylene group

20 to a previously mentioned -NR ^8c - group may be replaced by a carbonyl group, with the proviso that the replacement of hydrogen atoms of the first carbon atom of the straight-chain or branched Ci _-6 alkyl group

25 by substituents from the group oxygen,

Sulfur or nitrogen is excluded,

a phenyl, heteroaryl, phenyl-Ci ₅ alkyl or heteroaryl-C-ι- ₅ alkyl group,

30 in the phenyl or heteroaryl optionally one to three times by identical or different substituents selected from the group consisting - -

, Ci, di (Ci _-5 alkyl) amino, Ci- thoxy- ₅ -alkyloxy, mono-, di- or trifluoromethanesulfonic from halogen atoms _-5 alkyl hydroxy, carboxy and Ci- ₅ 5 is a 3- to 7-membered cycloalkyl, cycloalkyl-d- _5- alkyl or cycloalkyleneimino-C _2-3 -alkyl group in which at 4- to 7-membered cycles in the cyclic part of a methylene group optionally by a

10 -N (R ^8c ) group, an oxygen or sulfur atom or an -S (O) or -S (O) ₂ - group may be replaced, or

in the case of 4- to 7-membered cycles in the cyclic part

15 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 the 6- to 7-membered cycles in the cyclic part

20 three adjacent methylene groups together optionally substituted by a -OC (O) 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, cycloalkyl-Ci _-5- alkyl- or cycloalkylenimino-C _2-3 -alkyl group as defined above, in which two heteroatoms from the group oxygen and nitrogen by exactly one possibly

30 substituted -CH ₂ - group are separated from each other, is excluded, - -

wherein a composition as defined above, 3- to 7-membered cycloalkyl, cycloalkyl-ds-alkyl or cycloalkylene _imino-C2-C3 alkyl group at one or two -CH ₂ - groups in each case by one or two C ₃ alkyl substituted can be,

M represents a -CH ₂ -, -CHR ³ -, -CR ³ R ³ - group or a bond,

W represents an oxygen or sulfur atom,

B represents a thiophene ring according to formula (IM),

R ^{6 represents} a hydrogen atom,

the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and

the 5-membered heteroaryl group - -

an optionally substituted by a Ci _-3 alkyl group imino group, an oxygen or sulfur atom, or

an optionally substituted by a Ci _-3 alkyl group imino group, or an oxygen or sulfur atom and additionally

Nitrogen atom, or

and in addition to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms optionally substituted by a fluorine, chlorine or bromine atom, a C ₃ alkyl, hydroxy, Ci _-3 alkyloxy, amino, Ci _-3 alkylamino , di (Ci _-3 alkyl) - amino or Cs-β-cycloalkyleneimino substituted phenyl ring can be fused,

wherein the alkyl, alkenyl, alkynyl and alkoxy groups having more than two carbon atoms contained in the above-mentioned definitions, unless otherwise mentioned, may be straight-chain or branched and the alkyl groups in the above-mentioned dialkylated groups, for example, the dialkylamino groups , same or different, - -

4. Compounds of general formula (I) according to one of claims 1 to 3, in which

D represents a substituted bicyclic ring system of the formula (II)

by doing

_R 7a _{/ R} 7b _{/ R} 7c each independently represent a fluorine atom, a hydroxy,

CI ₅ alkoxy group, a Ci _-5 alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-Ci _-5 alkyl, Ci _-5-Al koxy-Ci _-5 - alkyl group, wherein not simultaneously both radicals R ^7b / R ^7c may be bonded via a heteroatom to the ring carbon atom, except -C (R ^7b R ^7c ) - corresponds to a -CF ₂ - - -

Group, or

two radicals R ^7b / R ^7c together with the ring carbon atom represent a 3-, 4-, 5-, 6- or 7-membered saturated carbocycle or a cyclopentene, cyclohexene, oxetane,

Tetrahydrofuran, tetrahydropyran ring, with its methylene groups being replaced by 1 or 2 Ci ₃ -

R ^8a / R ^8b / R ^8c each independently represent a Ci ₅ alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-d- ₅ - alkyl, Ci _-5 alkoxy-Ci _-5 alkyl group means .

or two radicals R ^8b / R ^8c together with the

Ring carbon atom can form a 3-, 4-, 5-, 6- or 7-membered saturated carbocycle or a cyclopentene, cyclohexene, oxetane, tetrahydrofuran, tetrahydropyran ring, wherein the methylene groups by 1 or 2 Ci _-3 -

Alkyl or -CF ₃ groups may be substituted, and / or - -

whose methylene groups, if they are not bonded to a heteroatom, may be substituted by 1 or 2 fluorine atoms, and / or in which a -CH ₂ - group may be replaced by a -C (O) group in addition to a nitrogen atom,

X represents an -N (R ¹ ) group in the

R ¹ is a hydrogen atom or a Ci _-5 alkyl, _C3-5 alkenyl-CH ₂ -, C _3-5 alkynyl-CH ₂ -, Cs-β-cycloalkyl, C _4-6 cycloalkenyl group means,

wherein the methylene and methyl groups present in the above-mentioned groups may additionally be substituted by a Ci- ₃ alkyl, carboxy, Ci- ₅ -Alkylcarboxycarbonylgruppe, or by a hydroxy, Ci _-5 - alkoxy, amino, Ci _5- Alkylamino-, Ci- ₅ -dialkylamino or C ₄ -7-Cycloalkyleniminogruppe can be substituted if the methylene or methyl groups are not directly bonded to a heteroatom from the group O, N or S,

and / or one to three hydrogen atoms may be replaced by fluorine atoms, provided that the methylene or

Methyl groups are not bonded directly to a heteroatom from the group O, N or S, - -

A ^{1 represents} a sulfur atom, a -C (R ¹⁰ ) = N-, -N = C (R ¹⁰ ) -, or - C (R ¹⁰ ) = C (R ¹¹ ) group,

A ^{2 is} either a nitrogen atom or an = C (R ¹² ) group,

wherein R ¹⁰ , R ¹¹ and R ^{12 are} each independently

a hydrogen, fluorine, chlorine, bromine atom, or a Ci _-5- alkyl, - CF ₃ , cyano, carboxy, Ci _-5- alkoxycarbonyl, hydroxy, Ci _-3 -

Alkoxy, CF ₃ O, CHF ₂ O, CH ₂ FO group mean

represents a substituted ring system of the formula (IIa),

by doing

R ^{3 represents} a hydrogen atom,

R ⁴ is a hydrogen atom, a straight or branched Ci _-4 - its alkyl group, the hydrogen atoms of the straight-chain or branched C ₄ alkyl group may optionally be substituted by fluorine atoms entirely or partially, and optionally substituted by a Ci _-3 alkoxy substituted, can, while the hydrogen atoms of the C may be replaced by fluorine atoms _-3 alkoxy entirely or partially, - -

means

a hydrogen atom, a hydroxy group, a -OR ⁹ group, a C _{_2-4} alkenyl or C _{_2-4} alkynyl group,

a straight or branched C ₄ alkyl group, wherein the hydrogen atoms of the straight-chain or branched Ci can, _-4 alkyl group, optionally completely or partly be replaced by fluorine atoms and wherein the straight or branched Ci _-4 alkyl group optionally substituted by a C _{_3-5} cycloalkyl, nitrile, hydroxy, Ci- ₅ alkyloxy, allyloxy, propargyloxy, benzyloxy, Ci- ₅ alkylcarbonyloxy, Ci- ₅ -Alkyloxycarbonyloxy-, carboxy- Ci- alkyloxy _5, Ci- s-alkyloxycarbonyl-Ci-s-alkyloxy, mercapto, Ci _-5- alkylsulfanyl, Ci _-5- alkylsulfonyl, carboxy, Ci _-5- al kyloxycarbonyl, aminocarbonyl, ds-alkylaminocarbonyl, di (Ci _-5- al-kyl) -aminocarbonyl, Cs-β-Cycloalkyleniminocarbonyl-, aminosulphonyl, Ci- ₅ -alkylaminosulphonyl, di- (Ci _-5- alkyl) -aminosulphonyl, Cs-β- Cycloalkyleniminosulfonyl-, amino, ds-alkylamino, di- (Ci- _5-alkyl) -amino, Ci- ₅ -alkylcarbonylamino-, d- ₅ -Alkylsulfo- nylamino-, Λ / - (Ci- ₅ alkylsulfonyl) -ci- ₅ alkylamino or C ₃ - ₆ -Cy- cloalkylcarbonylaminogruppe may be substituted, wherein the hydrogen atoms of the Ci _-5 alkyloxy group may optionally be substituted by fluorine atoms entirely or partially, and wherein membered 7 in the 6- to cycles of C _3-6 - Cycloalkyleniminocarbonylgruppe in the cyclic Part of a methylene group in the 4-position of a 6- or 7-membered cycloalkyleneimino group by an oxygen or sulfur atom, by a carbonyl, sulfinyl, sulfonyl or

-NR ^8c group can be replaced, and additionally a methylene group adjacent to one mentioned above - - -

NR ^8c group may be replaced by a carbonyl group,

a phenyl or heteroaryl group which is optionally substituted 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 (Ci _-5 alkyl) amino , hydroxy, Ci _-5 -alkyloxy, mono-, di- or trifluoromethoxy, carboxy- and C-ι- may be substituted ₅ -Alkyloxycarbonylgruppen,

a phenyl-Ci ₅ alkyl or heteroaryl-Ci- ₅ alkyl group, in the phenyl or heteroaryl moiety optionally Ci mono- to trisubstituted by identical or different substituents selected from the group consisting of halogen atoms, _-5 alkyl, di (Ci _-5- alkyl) -amino, hydroxy, Ci _-5- alkyloxy-,

Mono-, di- or trifluoromethoxy, carboxy and Ci- ₅ -Alkyloxycarbonylgruppen may be substituted, and optionally in the _Ci-5 alkyl part, by a hydroxy or Ci ₅ -alkyloxy group wherein the hydrogen atoms of the Ci ₅ alkyloxy optionally complete or in part

Be replaced by fluoro atoms, an allyloxy, propargyloxy, benzyloxy, Ci- ₅ -Alkylcarbonyloxy-, Ci- ₅ -Alkyloxycarbonyloxy-, carboxy-Ci _-5 -alkyloxy-, or a Ci _-5 -alkyloxycarbonyl- C-ι- ₅ -alkyloxy group may be substituted,

and where

R ⁹ is a straight or branched C ₄ alkyl group, wherein the hydrogen atoms of the straight-chain or branched C ₄ alkyl group may optionally be wholly or partly replaced by fluorine atoms, and wherein the straight or branched - -

Ci- ₄ alkyl group optionally substituted by a C _3-5 -, C kyloxy- cycloalkyl, hydroxy _-5-Al, allyloxy, propargyloxy, benzyloxy, Ci- ₅ alkylcarbonyloxy, CI ₅ -Alkyloxycarbonyloxy-, carboxy -Ci- ₅ -alkyloxy, Ci-s-AI-

5 kyloxycarbonyl-Ci- ₅ alkyloxy, carboxy, Ci- _carbonyl-5 alkyloxy, aminocarbonyl, Ci- ₅ alkylaminocarbonyl, di (Ci _-5 alkyl) aminocarbonyl, C _3-6 - Cycloalkyleniminocarbo- nyl-, amino, Ci- ₅ alkylamino, di- (Ci- _5-alkyl) -amino, Ci- ₅ -alkylcarbonylamino-, Ci- ₅ alkylsulfonylamino,

10 A / ^ Ci-ö-alkylsulfonyO-Ci-s-alkylamino or C _3-6 -cycloalkyl-kylcarbonylaminogruppe may be substituted, wherein the hydrogen atoms of the Ci- ₅ -alkyloxy group may optionally be wholly or partly replaced by fluorine atoms,

15 and wherein in the 6- to 7-membered cycles of C _3-O -

Cycloalkyleniminocarbonylgruppe in the cyclic part of a methylene group in the 4-position of a 6- or 7-membered cycloalkylene imino group by an oxygen or sulfur atom, by a carbonyl,

20 sulfinyl, sulfonyl or -NR ^8c - group may be replaced, and additionally a methylene group adjacent to an aforementioned -NR ^8c - group may be replaced by a carbonyl group, with the proviso that the replacement of

25 hydrogen atoms of the first carbon atom of the straight-chain or branched Ci _-6 alkyl group is excluded by substituents from the group of oxygen, sulfur or nitrogen,

30 is a phenyl, heteroaryl, phenyl-d- _5- alkyl or

Heteroaryl-C-ι- 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, Ci- ₅ alkyl, di- (Ci- _5-alkyl) amino, hydroxy, Ci- ₅ -alkyloxy, mono-, di- or trifluoro- methoxy, carboxy and Ci- ₅ -Alkyloxycarbonylgruppen may be substituted,

M represents a -CH ₂ - group or a bond,

W represents an oxygen atom,

B represents a thiophene ring according to formula (IM),

R ^{2 is} a fluorine, chlorine, bromine or iodine atom, or a methoxy, Ci _-2 -

Alkyl or ethynyl group means

R ^{6 represents} a hydrogen atom,

the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and - -

an optionally substituted by a Ci _-3 alkyl group

Imino group, or an oxygen or sulfur atom and additionally a nitrogen atom, or

and in addition to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms optionally substituted by a fluorine, chlorine or bromine atom, a C ₃ alkyl,

Hydroxy, Ci _-3 alkyloxy, amino, Ci _-3 alkylamino, di- (Ci _-3 alkyl) - amino or Cs-β-cycloalkyleneimino substituted phenyl ring can be fused,

wherein the alkyl, contained in the above-mentioned definitions,

Alkenyl, alkynyl and alkoxy groups having more than two carbon atoms, unless mentioned otherwise, may be straight-chain or branched and the alkyl groups in the above dialkylated - -

Radicals, for example the dialkylamino groups, may be identical or different,

5. Compounds of general formula (I) according to one of claims 1 to 4, in which

D represents a substituted bicyclic ring system of the formula (II)

by doing

K ² and K ³ each represents a -CH ₂ - group - -

X represents an -N (R ¹ ) group in the

R ¹ is a hydrogen atom or a Ci- ₅ alkyl or C _3-4 cyclo- alkyl group,

A ^{1 represents} a sulfur atom or -C (R ¹⁰ ) = C (R ¹¹ ) group,

A ^{2 is} either a nitrogen atom or an = C (R ¹² ) group,

wherein R ¹⁰ , R ¹¹ and R ^{12 are} each independently

represents a substituted ring system of the formula (IIa),

(IIa) - -

by doing

R ^{3 represents} a hydrogen atom,

R ^{4 represents} a hydrogen atom,

R ⁵ is a hydrogen atom, a C _{_2-4} alkenyl or C _{_2-4} alkynyl group,

a straight or branched Ci _-4 alkyl group, wherein the hydrogen atoms of the straight-chain or branched

Ci- ₄ alkyl group may optionally be substituted by fluorine atoms entirely or partially, and wherein the straight-chain or branched C ₄ alkyl group optionally substituted by a hydroxy, Ci- ₅ alkyloxy group or a di (Ci _-5 alkyl) aminocarbonyl may be substituted, wherein the hydrogen atoms of the Ci _-5 alkyloxy may optionally be wholly or partially replaced by fluorine atoms,

a phenyl-D- _3- alkyl or heteroaryl-C-ι- _3- alkyl group,

M represents a -CH ₂ - group or a bond,

W represents an oxygen atom,

B represents a thiophene ring according to formula (IM),

which is bonded via the 2-position to the carbonyl group in formula (I) - -

R ^{2 represents} a chlorine or bromine atom, or an ethynyl group,

R ^{6 represents} a hydrogen atom,

the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and

the 5-membered heteroaryl group optionally substituted by a a Ci _-3 alkyl

Imino group, an oxygen or sulfur atom, or

6. Compounds of general formula (I) according to one of claims 1 to 5, in which

D represents a substituted bicyclic ring system of the formula (II)

by doing

_R 7a _{/ R} 7b _{/ R} 7c - -

each independently represents a Ci ₂ alkyl group which may be substituted by 1-3 fluorine atoms, means

K ² and K ³ each represents a -CH ₂ - group

X represents an -N (R ¹ ) group in the

R ¹ is a hydrogen atom or a Ci _-5 alkyl or C _3-4 - cycloalkyl group,

wherein the methylene and methyl groups in the above-mentioned groups may additionally be substituted by a hydroxy group, provided that the methylene or methyl groups are not directly attached to a

Heteroatom from the group O, N or S are bonded,

Group O, N or S are bonded,

A ^{1 represents} a sulfur atom

A ^{2 represents} a nitrogen atom,

7. Compounds of general formula (I) according to one of claims 1 to 6, in which - -

represents a substituted bicyclic ring system of the formula (II)

by doing

R ^7a / R ^7b / R ^7c each independently represents a Ci ₂ alkyl group which may be substituted by 1-3 fluorine atoms, means

K ² and K ³ each represents a -CH ₂ - group

X represents an -N (R ¹ ) group in the

R ¹ is a hydrogen atom or a Ci _-5 alkyl or C _3-4 - cycloalkyl group,

Heteroatom from the group O, N or S are bonded,

Methyl groups are not bonded directly to a heteroatom from the group O, N or S,

A ^{1 represents} a -C (R ¹⁰ ) = C (R ¹¹ ) group,

A ² denotes an = C (R ¹² ) group,

wherein R ¹⁰ , R ¹¹ and R ^{12 are} each independently

a hydrogen, fluorine or chlorine atom, or a Ci _-5 alkyl, -CF ₃ ,

Mean methoxy, CF ₃ O, CHF ₂ O, CH ₂ FO group,

8. Compounds of general formula (I) according to one of claims 1 to 7, in which

M represents a bond,

9. Physiologically acceptable salts of the compounds according to any one of claims 1 to 8.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a physiologically acceptable salt according to claim 9, optionally together with one or more inert carriers and / or diluents.

11. Use of a compound according to at least one of claims 1 - -

to 8 or a physiologically acceptable salt according to claim 9 for the preparation of a medicament having an inhibitory effect on factor Xa and / or an inhibitory effect on related serine proteases.

12. A process for the preparation of a medicament according to claim 10, characterized in that a compound according to at least one of claims 1 to 8 or a physiologically acceptable salt according to claim 9 is incorporated into one or more inert carriers and / or diluents by non-chemical means.