CARBOXYLIC ACID AMIDES AS FACTOR XA INHIBITORS

The present invention relates to new substituted carboxylic acid amides of general formula

the tautomers, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable properties.

The compounds of the above general formula I as well as the tautomers, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, and the stereoisomers thereof, have valuable pharmacological properties, particularly an antithrombotic activity and a factor Xa-inhibiting activity.

The present application thus relates to the new compounds of the above general formula (I), the preparation thereof, the pharmaceutical compositions containing the pharmacologically effective compounds, the preparation and use thereof.

In the above general formula in a first embodiment

D denotes a substituted bicyclic ring system of formula (Ma), (Mb) or (lie)

or

or

wherein

K ¹ and K ⁴ each independently of one another denote a bond, a -CH ₂ , -CHR ^2a , -CR ^2b R ^2c or a -C(O) group, and wherein

_R 2a _/R 2b _/R 2c each independently of one another denote a fluorine atom, a hydroxy, Ci _-5 -alkyloxy, amino, Ci _-5 -alkylamino, di-(Ci _-5 -alkyl)- amino, Cs-s-cycloalkyleneimino, 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-alkyloxy-Ci-s-alkyl, amino-Ci _-5 -alkyl, Ci-s-alkylamino-Ci-s-alkyl, di-(Ci- ₅ -alkyl)-amino-Ci- ₅ -alkyl, C _4-7 - cycloalkyleneimino-Ci- ₅ -alkyl, carboxy-Co- ₅ -alkyl, Ci _-5 - alkyloxycarbonyl-Co- ₅ -alkyl, aminocarbonyl-Co- ₅ -alkyl,

Ci-s-alkylaminocarbonyl-Co-s-alkyl, di-(Ci _-5 -alkyl)-annirιocarbonyl- Co- ₅ -alkyl or a C _4-7 -cycloalkyleneinninocarbonyl-Co- ₅ -alkyl group, wherein the two groups R ^2b /R ^2c may not simultaneously be bound to the cyclic carbon atom via a hetero atom, except where -C(R ^2b R ^2c )- corresponds to a -CF ₂ group, or

R ^2a denotes a fluorine-, chlorine-, bromine-, methyl-, methoxy-, amino- or nitro-substituted phenyl or monocyclic heteroaryl group, or

two groups R ^2b /R ^2c together with the cyclic carbon atom may form a 3-, 4-, 5-, 6- or 7-membered saturated carbocyclic group or a cyclopentene, cyclohexene, oxetane, azetidine, thietane, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran, piperidine, pentamethylenesulphide, hexamethyleneimine, 1 ,3- dioxolan, 1 ,4-dioxane, hexahydropyridazine, piperazine, thiomorpholine, morpholine, 2-imidazolidinone, 2-oxazolidinone, tetrahydro-2(1 H)-pyhmidinone or [1 ,3]oxazinan-2-one ring, while the methylene groups thereof may be substituted by 1 -2 Ci- ₃ -alkyl or CF ₃ - groups, and/or the methylene groups thereof, if they are not bound to a heteroatom, may be substituted by 1-2 fluorine atoms, and/or wherein a -CH ₂ group, besides an N atom, may be replaced by a -CO group, and/or the imino groups thereof may be substituted in each case by a Ci- ₃ -alkyl or Ci- ₃ -alkylcarbonyl group, and/or wherein the sulphur atom may be oxidised to form a sulphoxide or sulphone group,

K ² and K ³ each independently of one another denote a -CH ₂ , -CHR ^6a , -CR ^6b R ^6c or a -C(O) group, wherein

_R 6a _/R 6b _/R 6c each independently of one another denote a Ci _-5 -alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-Ci _-5 - alkyl, Ci-s-alkyloxy-Ci-s-alkyl, amino-Ci _-5 -alkyl, Ci _-5 -alkylamino- Ci- ₅ -alkyl, di-(Ci- ₅ -alkyl)-amino-Ci- ₅ -alkyl, C _4-7 -cycloalkyleneimino-

C 1 -5-a I ky I , ca rboxy-Co-5-a I ky I , C i _-5 -a I ky loxyca rbony I -C _0- 5-a I ky I , aminocarbonyl-Co- ₅ -alkyl, Ci-s-alkylaminocarbonyl-Co-s-alkyl, di- (Ci- ₅ -alkyl)-aminocarbonyl-Co- ₅ -alkyl or a C _4-7 - cycloalkyleneiminocarbonyl-Co- ₅ -alkyl group,

or two groups R ^6b /R ^6c together with the cyclic carbon atom may form a 3-, 4-, 5-, 6- or 7-membered saturated carbocyclic group or a cyclopentene, cyclohexene, oxetane, azetidine, thietane, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran, piperidine, pentamethylenesulphide, hexamethyleneimine, hexahydropyridazine, tetrahydro-2(1 H)-pyhmidinone, [1 ,3]oxazinan-2-one ring, while the methylene groups thereof may be substituted by

1 -2 Ci- ₃ -alkyl or CF ₃ groups, and/or the methylene groups thereof, if they are not bound to a heteroatom, may be substituted by 1-2 fluorine atoms, and/or wherein a -CH ₂ group, besides a nitrogen atom, may be replaced by a -CO group, and/or the imino groups thereof may be substituted in each case by a Ci- ₃ -alkyl or Ci- ₃ -alkylcarbonyl group, and/or wherein the sulphur atom may be oxidised to form a sulphoxide or sulphone group, with the proviso that a heteroatom introduced by R ^6b or R ^6c may not be only one carbon atom away from X in formula

(I), and

n formula (Ma) or (Mb) or (lie) a maximum of four groups selected

from among R ^2a , R ^2b , R ^2c , R ^6a , R ^6b and R ^6c may be present, and

X denotes an oxygen or sulphur atom, a CF ₂ , sulphene, sulphone or an NR ¹ group, wherein

R ¹ denotes a hydrogen atom or a hydroxy, Ci _-3 -alkyloxy, amino, Ci-3-alkylamino, di-(Ci _-3 -alkyl)-amino, a Ci _-5 -alkyl, C2-5-alkenyl-CH ₂ , C2-5-alkynyl-CH ₂ , Cs-β-cycloalkyl, C _4- 6- cycloalkenyl, oxetan-3-yl, tetrahydrofuran-3-yl, benzyl, Ci _-5 - alkyl-carbonyl, thfluoromethylcarbonyl, C ₃ - ₆ -cycloalkyl- carbonyl, Ci _-5 -alkyl-sulphonyl, Cs-β-cycloalkyl-sulphonyl, aminocarbonyl, Ci- ₅ -alkylaminocarbonyl, di-(Ci _-5 -alkyl)- aminocarbonyl, Ci _-5 -alkyloxycarbonyl, C _4-7 - cycloalkyleneiminocarbonyl group, while the methylene and methyl groups present in the groups mentioned above may additionally be substituted by a Ci-salkyl, carboxy, Ci _-5 -alkoxycarbonyl group, or by a hydroxy, Ci _-5 -alkyloxy, amino, Ci _-5 - alkylamino, Ci _-5 -dialkylamino or C _4-7 - cycloalkyleneimino group, provided that the methylene or methyl groups are not bound directly to a heteroatom selected from among O, N and S, and/or one to three hydrogen atoms may be replaced by fluorine atoms, provided that the methylene or methyl groups are not bound directly to a heteroatom selected from among O, N and S,

and wherein

A ¹ denotes either N or CR ¹⁰ ,

A denotes either N or CR 11

A ³ denotes either N or CR ¹² ,

A ⁴ denotes either N or CR ¹² ,

A ⁵ denotes NH, sulphur or oxygen,

while R ¹⁰ , R ¹¹ and R ¹² each independently of one another denote

a hydrogen, fluorine, chlorine, bromine or iodine atom, or a phenyl, Ci-5-alkyl, CF ₃ , C2-5 -alkenyl, C2-5-alkynyl, a cyano, carboxy, Ci _-5 - alkyloxycarbonyl, hydroxy, Ci-3-alkyloxy, CF ₃ O, CHF ₂ O, CH ₂ FO, amino, Ci _-5 -alkylamino, di-(Ci _-5 -alkyl)-amino or C _4-7 - cycloalkyleneimino group, and

R ³ denotes a hydrogen atom, a C _2-3 -alkenyl or C _2-3 -alkynyl group or a straight- chain or branched Ci-6-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a nitrile, hydroxy, a Ci _-5 -alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, an allyloxy, propargyloxy, benzyloxy, Ci _-5 -alkylcarbonyloxy, Ci-5-alkyloxycarbonyloxy, carboxy-Ci _-3 -alkyl- oxy, Ci-s-alkyloxycarbonyl-Ci-s-alkyloxy, Ci-s-alkyloxycarbonylamino, mercapto, Ci- ₃ -alkylsulphanyl, Ci _-3 -alkylsulphinyl, Ci _-3 -alkylsulphonyl, Ci-ralkylcarbonylamino-Ci-s-alkylsulphanyl, Ci _-3 -alkylcarbonylamino- Ci- ₃ -alkylsulphinyl, Ci-s-alkylcarbonylamino-Ci-s-alkylsulphonyl, carboxy, Ci- ₃ -alkyloxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl, benzyloxycarbonyl, aminocarbonyl, Ci- ₃ -alkylaminocarbonyl, di-(Ci- ₃ -alkyl)- aminocarbonyl, C ₃ - ₆ -cycloalkyleneiminocarbonyl, aminosulphonyl, Ci-3-alkylaminosulphonyl, di-(Ci _-3 -alkyl)-aminosulphonyl, C3-6- cycloalkyleneiminosulphonyl, amino, Ci-3-alkylamino, di-(Ci-3-alkyl)-amino, Ci-5-alkylcarbonylamino, Ci _-3 -alkylsulphonylamino, λ/-(Ci _-3 -alkylsulphonyl)- Ci-3-alkylamino, Cs-β-cycloalkylcarbonylamino, aminocarbonylamino, Ci-3-alkylaminocarbonylamino, di-(Ci-3-alkyl)-aminocarbonylamino, a 4- to 7- membered cycloalkyleneiminocarbonylamino, benzyloxycarbonylamino,

phenylcarbonylamino or guanidino group,

a carboxy, aminocarbonyl, Ci _-4 -alkylaminocarbonyl, C ₃ - ₆ -cycloalkylamino- carbonyl, di-(Ci _-3 -alkyl)-anninocarbonyl, Ci _-4 -alkoxycarbonyl, C _4-6 - cycloalkyleneiminocarbonyl group,

a phenyl or heteroaryl, phenylcarbonyl-Ci- ₃ -alkyl, phenyl-Ci _-3 -alkyl or heteroaryl- Ci-3-alkyl group which is optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorine or bromine atoms, Ci-3-alkyl, amino, Ci-3-alkylamino, di-(Ci-3-alkyl)-amino, hydroxy, Ci _-4 -alkyloxy, mono-, di- or thfluoromethoxy, benzyloxy, carboxy-Ci-3-alkyloxy, Ci-3-alkyloxycarbonyl- Ci-3-alkyloxy, aminocarbonyl-Ci-3-alkyloxy, Ci _-3 -alkylaminocarbonyl- Ci-3-alkyloxy, di-(Ci-3-alkyl)-aminocarbonyl-Ci-3-alkyloxy, a 4- to 7-membered cycloalkyleneiminocarbonyl-Ci-3-alkoxy, carboxy, Ci _-3 -alkyloxycarbonyl or Ci-3-alkyloxycarbonylamino group,

a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-Ci-3-alkyl or cycloalkyleneimino-Ci-s-alkyl group wherein in the cyclic moiety a methylene group may be replaced by an -NH group optionally substituted by a Ci-3-alkyl or Ci- ₃ -alkylcarbonyl group or an oxygen atom and wherein additionally a methylene group adjacent to the -NH, -N(Ci _-3 -alkylcarbonyl) or -N(Ci _-3 -alkyl) group may be replaced in each case by a carbonyl or sulphonyl group, with the proviso that a cycloalkyleneimino group as hereinbefore defined wherein two nitrogen atoms are separated from each other by precisely one -CH ₂ group is excluded,

R ⁴ denotes a hydrogen atom or a Ci- ₃ -alkyl group or

R ³ and R ⁴ together with the carbon atom to which they are bound denote a C-3-7- cycloalkyl group, while

one of the methylene groups of the C3 _-7 -cycloalkyl group may be replaced by an imino, Ci-3-alkylimino, acylimino or sulphonylimino group,

R ⁵ denotes a hydrogen atom or a Ci- ₃ -alkyl group,

B denotes a group of formula

wherein

n denotes the number 1 or 2,

R ⁷ denotes a hydrogen atom or a Ci- ₃ -alkyl, hydroxy, Ci _-5 -alkyloxycarbonyl, carboxy-Ci- ₃ -alkyl, Ci-s-alkyloxycarbonyl-Ci-s-alkyl, amino or Ci- ₃ -alkylamino group and

R ⁸ independently of one another denote a hydrogen, fluorine, chlorine, bromine or iodine atom, a Ci- ₃ -alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C ₂ - ₃ -alkenyl or C ₂ - ₃ -alkynyl, a hydroxy, Ci-3-alkoxy, thfluoromethoxy, amino, nitro or nitrile group,

while, unless stated otherwise, by the term "heteroaryl group" mentioned in the definitions hereinbefore is meant a monocyclic 5- or 6-membered heteroaryl group, while

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

the 5-membered heteroaryl group contains an imino group optionally substituted by a Ci- ₃ -alkyl, phenyl or phenyl-Ci- ₃ -alkyl group, an oxygen or sulphur atom or

an imino group optionally substituted by a Ci-3-alkyl, phenyl, amino- C ₂ - ₃ -alkyl, Ci- ₃ -alkylamino-C ₂ - ₃ -alkyl, di-(Ci- ₃ -alkyl)-amino-C ₂ - ₃ -alkyl, a 4- to 7-mennbered cycloalkyleneinnino-Ci-s-alkyl or phenyl-Ci- ₃ -alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or

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

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

and the bond is effected via a nitrogen atom or a carbon atom of the heterocyclic moiety or a fused-on phenyl ring,

while the alkyl and alkoxy groups which have more than two carbon atoms, contained in the foregoing definitions, unless stated otherwise, may be straight- chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different,

and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms,

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.

Examples of monocyclic heteroaryl groups are the pyridyl, /V-oxy-pyhdyl, 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]thazolyl, 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[c/] isothiazolyl, benzoxazolyl, benzo[c]isoxazolyl, benzo[c/]- isoxazolyl, benzo[1 ,2,5]oxadiazolyl, benzo[1 ,2,5]thiadiazolyl, benzo[1 ,2,3]thia- diazolyl, benzo[c/][1 ,2,3]triazinyl, benzo[1 ,2,4]triazinyl, benzotriazolyl, cinnolinyl, quinolinyl, /V-oxy-quinolinyl, isoquinolinyl, quinazolinyl, /V-oxy-quinazolinyl, quinoxalinyl, phthalazinyl, indolyl, isoindolyl or 1 -oxa-2,3-diaza-indenyl group.

Examples of the Ci-s-alkyl groups mentioned hereinbefore in the definitions are the methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, sec-butyl, te/t-butyl, 1 -pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1 -hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1 -octyl, 2-octyl, 3-octyl or 4-octyl group.

Examples of the Ci-s-alkyloxy groups mentioned hereinbefore in the definitions are the methyloxy, ethyloxy, 1 -propyloxy, 2-propyloxy, n-butyloxy, sec-butyloxy, te/t-butyloxy, 1 -pentyloxy, 2-pentyloxy, 3-pentyloxy, neo-pentyloxy, 1 -hexyloxy, 2-hexyloxy, 3-hexyloxy, 1 -heptyloxy, 2-heptyloxy, 3-heptyloxy, 4-heptyloxy, 1 -octyloxy, 2-octyloxy, 3-octyloxy or 4-octyloxy group.

By a group which can be converted in vivo into a carboxy group is meant, for example, a carboxy group esterified with an alcohol wherein the alcohol moiety is preferably a Ci-6-alkanol, a phenyl-Ci-3-alkanol, a Cs-g-cycloalkanol, a C _5-7 - cycloalkenol, a C3 _-5 -alkenol, a phenyl-C3 _-5 -alkenol, a C3 _-5 -alkynol or phenyl- C3 _-5 -alkynol, with the proviso that no bond to the oxygen atom starts from a carbon atom that carries a double or triple bond, a C ₃ -8-cycloalkyl-Ci-3-alkanol or an alcohol of formula

R ¹³ -CO-O-(R ¹⁴ CR ¹⁵ )-OH,

wherein

R ¹³ denotes a Ci-s-alkyl, C _5-7 -cycloalkyl, phenyl or phenyl-Ci- ₃ -alkyl group,

R ¹⁴ denotes a hydrogen atom, a Ci _-3 -alkyl, C _5-7 -cycloalkyl or phenyl group and

R ¹⁵ denotes a hydrogen atom or a Ci _-3 -alkyl group.

Examples of preferred groups that can be cleaved from a carboxy group in vivo include a Ci-6-alkoxy group such as the methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy or cyclohexyloxy group or a phenyl-Ci-3-alkoxy group such as the benzyloxy group.

Those compounds of general formula I wherein R ³ contains a group that can be converted into a carboxy group in vivo are prodrugs for those compounds of general formula I wherein R ³ contains a carboxy group.

A 2nd embodiment of the present invention includes those compounds of general formula I, wherein D and B are defined as described in embodiment 1 , and wherein

R ³ denotes a C ₂ - ₃ -alkenyl or C ₂ - ₃ -alkynyl group or a straight-chain or branched Ci- ₆ -alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a nitrile, hydroxy, a Ci-5-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, an allyloxy, propargyloxy, benzyloxy, Ci _-5 -alkyl- carbonyloxy, Ci _-5 -alkyloxycarbonyloxy, carboxy-Ci-3-alkyloxy, Ci _-5 -alkyloxy- carbonyl-Ci-3-alkyloxy, Ci-s-alkyloxycarbonylamino, mercapto, Ci- ₃ -alkylsulphanyl, Ci _-3 -alkylsulphinyl, Ci _-3 -alkylsulphonyl, Ci-s-alkylcarbonylamino-Ci-s-alkylsulphanyl, Ci _-3 -alkylcarbonylamino- Ci- ₃ -alkylsulphinyl, Ci-s-alkylcarbonylamino-Ci-s-alkylsulphonyl, carboxy, Ci- ₃ -alkyloxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl, benzyloxycarbonyl, aminocarbonyl, Ci- ₃ -alkylaminocarbonyl, di-(Ci- ₃ -alkyl)-

aminocarbonyl, C ₃ - ₆ -cycloalkyleneinninocarbonyl, aminosulphonyl, Ci- ₃ -alkylanninosulphonyl, di-(Ci- ₃ -alkyl)-anninosulphonyl, C- ₃ - ₆ - cycloalkyleneiminosulphonyl, amino, Ci-3-alkylannino, di-(Ci-3-alkyl)-annino, Ci-5-alkylcarbonylannino, Ci _-3 -alkylsulphonylannino, λ/-(Ci _-3 -alkylsulphonyl)- Ci-3-alkylannino, Cs-e-cycloalkylcarbonylamino, aminocarbonylamino,

Ci-3-alkylaminocarbonylannino, di-(Ci-3-alkyl)-anninocarbonylannino, a 4- to 7- membered cycloalkyleneiminocarbonylamino, benzyloxycarbonylamino, phenylcarbonylamino or guanidino group,

a carboxy, aminocarbonyl, Ci _-4 -alkylaminocarbonyl, C ₃ - ₆ -cycloalkylamino- carbonyl, di-(Ci- ₃ -alkyl)-aminocarbonyl, Ci _-4 -alkoxycarbonyl, C _4-6 - cycloalkyleneiminocarbonyl group,

a phenyl or heteroaryl, phenylcarbonyl-Ci- ₃ -alkyl, phenyl-Ci _-3 -alkyl or heteroaryl- Ci-3-alkyl group which is optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorine or bromine atoms, Ci-3-alkyl, amino, Ci-3-alkylannino, di-(Ci-3-alkyl)-amino, hydroxy, Ci _-4 -alkyloxy, mono-, di- or trifluoromethoxy, benzyloxy, carboxy-Ci-3-alkyloxy, Ci-3-alkyloxycarbonyl- Ci-3-alkyloxy, aminocarbonyl-Ci-3-alkyloxy, Ci-3-alkylaminocarbonyl- Ci-3-alkyloxy, di-(Ci-3-alkyl)-aminocarbonyl-Ci-3-alkyloxy, a 4- to 7-membered cycloalkyleneiminocarbonyl-Ci-3-alkoxy, carboxy, Ci _-3 -alkyloxycarbonyl or Ci-3-alkyloxycarbonylamino group,

a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-Ci-3-alkyl or cycloalkyleneimino-Ci-s-alkyl group wherein in the cyclic moiety a methylene group may be replaced by an -NH group optionally substituted by a Ci-3-alkyl or Ci- ₃ -alkylcarbonyl group or an oxygen atom and wherein additionally a methylene group adjacent to a -NH, -N(Ci _-3 -alkylcarbonyl) or -N(Ci _-3 -alkyl) group benachbarte may be replaced in each case by a carbonyl or sulphonyl group, with the proviso that a cycloalkyleneimino group as hereinbefore defined wherein two nitrogen atoms are separated from one another by precisely one -CH ₂ group is excluded,

R ⁴ denotes a hydrogen atom or a Ci- ₃ -alkyl group,

R ⁵ denotes a hydrogen atom or a Ci- ₃ -alkyl group,

while, unless stated otherwise, by the term "heteroaryl group" mentioned in the definitions hereinbefore is meant 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 contains an imino group optionally substituted by a Ci- ₃ -alkyl, phenyl or phenyl-Ci _-3 -alkyl group, an oxygen or sulphur atom or

an imino group optionally substituted by a Ci-3-alkyl, phenyl, amino- C ₂ - ₃ -alkyl, Ci- ₃ -alkylamino-C ₂ - ₃ -alkyl, di-(Ci- ₃ -alkyl)-amino-C ₂ - ₃ -alkyl, a 4- to 7-membered cycloalkyleneimino-Ci-s-alkyl or phenyl-Ci- ₃ -alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or

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

and moreover a phenyl ring optionally substituted by a fluorine, chlorine or bromine atom, a Ci-3-alkyl, hydroxy, Ci-3-alkyloxy group, amino,

Ci-3-alkylamino, di-(Ci-3-alkyl)-amino or C3-6-cycloalkyleneimino group may be fused to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms

and the bond is effected via a nitrogen atom or a carbon atom of the heterocyclic moiety or a fused-on phenyl ring,

while the alkyl and alkoxy groups which have more than two carbon atoms, contained in the foregoing definitions, may unless stated otherwise be straight- chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different,

and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms,

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.

A 3rd embodiment of the present invention includes those compounds of general formula I, wherein

D denotes a substituted bicyclic ring system of formula (Ma) or (Mb)

or

wherein

K ¹ and K ⁴ each independently of one another denote a bond, a -CH ₂ , -CHR ^2a , -CR ^2b R ^2c or a -C(O) group, and wherein

_R 2a _/R 2b _/R 2c each independently of one another denote a fluorine atom, a hydroxy, Ci _-5 -alkyloxy, a Ci _-5 -alkyl group, wherein the two groups R ^2b /R ^2c may not simultaneously be bound to the cyclic carbon atom via a hetero atom, except where -C(R ^2b R ^2c )- corresponds to a -CF ₂ group, or

two groups R ^2b /R ^2c together with the cyclic carbon atom may form a 3-membered carbocyclic group,

with the proviso that K ¹ and K ⁴ simultaneously represent a bond, is excluded,

K ² and K ³ each independently of one another denote a -CH ₂ , -CHR ^6a , -CR ^6b R ^6c or a -C(O)- group, wherein

_R 6a _/R 6b _/R 6c each independently of one another denote a Ci _-5 -alkyl group, and/or two groups R ^6b /R ^6c together with the cyclic carbon atom may form a 3-membered saturated carbocyclic group

and

in all, in formulae (Ma) or (Mb) a maximum of four groups selected from R ^2a , R ^2b , R ^2c , R ^6a , R ^6b and R ^6c may be present, and

X denotes an oxygen or sulphur atom, a -CF ₂ - or a NR ¹ group, wherein

R ¹ denotes a hydrogen atom or a hydroxy, Ci-3-alkyloxy,

amino, Ci-3-alkylannino, di-(Ci-3-alkyl)-annino, a Ci _-5 -alkyl, C2-5-alkenyl-CH ₂ , C2-5-alkynyl-CH ₂ or a C3-6-cycloalkyl group,

and wherein

A ¹ denotes either N or CR ¹⁰ ,

A ² denotes either N or CR ¹¹ ,

A ³ denotes either N or CR ¹² ,

A ⁴ denotes either N or CR ¹² ,

A denotes NH, sulphur or oxygen,

while R ¹⁰ , R ¹¹ and R ¹² each independently of one another represent

a hydrogen, fluorine, chlorine, bromine or iodine atom, or a Ci _-5 - alkyl, CF ₃ , a cyano, carboxy, Ci _-5 -alkyloxycarbonyl, hydroxy, Ci _-3 - alkyloxy, CF ₃ O, CHF ₂ O, CH ₂ FO, amino, Ci _-5 -alkylamino, di-(Ci _-5 - alkyl)-amino or C _4-7 -cycloalkyleneimino group, and

R ³ denotes a straight-chain or branched Ci- ₆ -alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a nitrile, hydroxy, benzyloxy, a Ci _-5 -alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, an allyloxy, Ci _-5 -alkylcarbonyloxy, Ci-5-alkyloxycarbonyloxy, carboxy- Ci _-3 -alkyloxy, Ci-s-alkyloxycarbonyl-Ci-s-alkyloxy, Ci-s-alkyloxycarbonylamino, Ci- ₃ -alkylsulphanyl, Ci _-3 -alkylsulphonyl, carboxy, Ci _-3 -alkyloxycarbonyl, Ci-s-alkylaminocarbonyl, di-(Ci _-3 -alkyl)-aminocarbonyl, C _3-6 - cycloalkyleneiminocarbonyl, aminocarbonylamino, Ci-s-alkylaminocarbonylamino or di-(Ci _-3 -alkyl)-aminocarbonylamino group,

an aminocarbonyl, Ci _-4 -alkylaminocarbonyl, C ₃ - ₆ -cycloalkylaminocarbonyl or di- (Ci- ₃ -alkyl)-aminocarbonyl group,

a phenyl or heteroaryl, phenyl-Ci _-3 -alkyl or heteroaryl-Ci _-3 -alkyl group which is optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorine or bromine atoms, Ci-3-alkyl, amino, Ci-3-alkylamino, di-(Ci-3-alkyl)-amino, hydroxy, Ci _-4 -alkyloxy, mono-, di- or trifluoromethoxy, carboxy, or Ci- ₃ -alkyloxycarbonyl group,

a 3- to 7-membered cycloalkyl group wherein in the cyclic moiety a methylene group may be replaced by an -NH group optionally substituted by a Ci-3-alkyl or Ci- ₃ -alkylcarbonyl group or an oxygen atom,

R ⁴ denotes a hydrogen atom,

R ⁵ denotes a hydrogen atom,

B denotes a group of formula

wherein

n denotes the number 1 ,

R ⁷ denotes a hydrogen atom and

R ⁸ denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a methyl, C2-3-alkynyl, or methoxy group, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms,

while, unless stated otherwise, by the term "heteroaryl group" mentioned in the definitions hereinbefore is meant 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 contains an imino group optionally substituted by a Ci- ₃ -alkyl group, an oxygen or sulphur atom or

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

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

and the bond is effected through a nitrogen atom or through a carbon atom,

while the alkyl and alkoxy groups which have more than two carbon atoms, contained in the foregoing definitions, may unless stated otherwise be straight- chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different,

and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms,

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.

A 4th embodiment of the present invention includes those compounds of embodiments 1 , 2 or 3, wherein

denotes a substituted bicyclic ring system of formula (Ma) or (Mb)

or

wherein K ¹ , K ² , K ³ , K ⁴ are defined as described in embodiments 1 , 2 or 3 and wherein

X denotes an NR ¹ group, wherein

R ¹ denotes a hydrogen atom or a Ci _-5 -alkyl, allyl or cyclopropyl group, and

A ¹ denotes CR ¹⁰ ,

A ² denotes CR ¹¹ ,

A ³ denotes CR ¹² ,

A ⁴ denotes either N or CR ¹² ,

A ⁵ denotes sulphur,

while R ¹⁰ , R ¹¹ and R ¹² each independently of one another represent

a hydrogen, fluorine or chlorine atom, or a methyl, CF ₃ , hydroxy, methoxy, CF ₃ O, CHF ₂ O, CH ₂ FO group, and

R ³ denotes a straight-chain or branched Ci _-4 -alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a Ci _-4 -alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a benzyloxy, a Ci _-3 -alkylsulphanyl, Ci _-3 -alkylsulphonyl, carboxy or Ci _-3 -alkyloxycarbonyl group,

a phenyl or heteroaryl, phenyl-Ci _-3 -alkyl or heteroaryl-Ci _-3 -alkyl group which is optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorine or bromine atoms, Ci _-3 -alkyl, Ci _-4 -alkyloxy, mono-, di- or thfluoromethoxy, carboxy, or Ci _-3 -alkyloxycarbonyl group,

R ⁴ denotes a hydrogen atom,

R ⁵ denotes a hydrogen atom and

B denotes a group of formula

wherein

n denotes the number 1 ,

R ⁷ denotes a hydrogen atom and

R ⁸ denotes a chlorine or bromine atom or the ethynyl group,

while, unless stated otherwise, by the term "heteroaryl group" mentioned in the definitions hereinbefore is meant 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 contains an imino group optionally substituted by a Ci- ₃ -alkyl group, an oxygen or sulphur atom or

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

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

and the bond is effected through a nitrogen atom or through a carbon atom,

while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may unless stated otherwise be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different,

and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms,

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.

A 5th embodiment of the present invention includes those compounds of embodiments 1 , 2, 3 or 4, wherein

D denotes a substituted bicyclic ring system of formula

wherein

K ¹ denotes a -CH ₂ , -CHR ^2a or a -CR ^2b R ^2c group, and

2a ₃ 2b _D 2c

K ⁴ denotes a bond, a -CH ₂ , -CHR ^za or a -CR ^ZD R ^ZC group, while

R ^2a denotes a Ci _-5 -alkyl group and

R ^2b /R ^2c each independently of one another denote a hydroxy, Ci-5-alkyloxy or a Ci _-5 -alkyl group, wherein the two groups R ^2b /R ^2c may not simultaneously be bound to the cyclic carbon atom through an oxygen atom, and K ² and K ³ each independently of one another denote a -CH ₂ , -CHR ^6a , or a _ _CR ^6b _R ^6c _groupj wherein

_R 6a _/R 6b _/R 6c each independently of one another denote a Ci _-5 -alkyl group, and

in all in formulae (Me) or (Mf) a maximum of four groups selected from R 2a , R ^2b , R ^2c , R ^6a , R ^6b and R ^6c may be present, and

R ¹ denotes a hydrogen atom or a Ci-3-alkyl, allyl or cyclopropyl group, and wherein

A ¹ denotes CR ¹⁰ ,

k denotes CR 11

A ³ denotes CR ¹² ,

A ⁴ denotes either N or CR ¹² ,

while R ¹⁰ , R ¹¹ and R ¹² each independently of one another represent

a hydrogen, fluorine or chlorine atom, or a methyl, CF ₃ , hydroxy, methoxy, CF ₃ O, CHF ₂ O, CH ₂ FO group, and

R ³ denotes a straight-chain or branched Ci _-4 -alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a Ci _-4 -alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a benzyloxy, a Ci _-3 -alkylsulphanyl, Ci _-3 -alkylsulphonyl, carboxy or Ci _-3 -alkyloxycarbonyl group,

a furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyhdinyl-Ci _-2 -alkyl or imidazolyl-Ci- ₂ -alkyl group which may optionally be substituted in the heteroaryl moiety by one or two Ci _-3 -alkyl groups, Ci _-3 -alkyloxy groups, carboxy or Ci _-3 - alkyloxycarbonyl groups, and

R ⁴ denotes a hydrogen atom,

R ⁵ denotes a hydrogen atom and

B denotes a group of formula

wherein

n denotes the number 1 ,

R ⁷ denotes a hydrogen atom and

R ⁸ denotes a chlorine or bromine atom or an ethynyl group,

while, unless stated otherwise, by the term "heteroaryl group" mentioned in the definitions hereinbefore is meant 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 contains an imino group optionally substituted by a Ci- ₃ -alkyl group, an oxygen or sulphur atom or

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

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

and the bond is effected through a nitrogen atom or through a carbon atom,

while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may unless stated otherwise be straight-chain or

branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different,

and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms,

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.

A 6th embodiment of the present invention includes those compounds of embodiments 1 , 2, 3, 4 or 5, wherein

D denotes a substituted bicyclic ring system of formula

wherein

K ¹ denotes a -CH ₂ , -CHR ^2a or a -CR ^2b R ^2c group, and

K ⁴ denotes a bond, a -CH ₂ , -CHR ^2a or a -CR ^2b R ^2c group, while

R ^2a denotes a Ci _-5 -alkyl group and R ^2b /R ^2c each independently of one another denote a hydroxy, Ci _-5 - alkyloxy or a Ci _-5 -alkyl group, wherein the two groups R ^2b /R ^2c may not simultaneously be bound to the cyclic carbon atom via an oxygen atom, and K ² and K ³ each independently of one another denote a -CH ₂ , -CHR ^6a or a

_ _CR 6b _R 6c _{g rou pj wh j|e}

_R 6a _/R 6b _/R 6c each independently of one another denote a Ci _-5 -alkyl group, and

in all, in formula (Mf) there may be a maximum of four groups selected from R ^2a , R ^2b , R ^2c , R ^6a , R ^6b and R ^6c , and

R ¹ denotes a hydrogen atom or a Ci-3-alkyl or cyclopropyl group, and wherein

A ⁴ denotes either N or CR ¹² ,

wherein R ¹²

denotes a hydrogen or fluorine atom.

A 7th embodiment of the present invention includes those compounds of general formula (I) corresponding to embodiments 1 , 2, 3, 4, 5 or 6, wherein

B denotes the group

wherein

R ⁸ denotes a chlorine, bromine atom or a ethynyl group.

An 8th embodiment of the present invention includes those compounds of general formula I corresponding to embodiments 1 , 2, 3, 4, 5, 6 or 7, wherein the group R ⁸ denotes a chlorine atom.

A 9th embodiment of the present invention comprises the following compounds:

6-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3d]azepine-2-carb oxylic acid-[(1 R)-1 - (5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-amide

(I S^RJ-e-methyl-δ.ej.δ-tetrahydro^H-thieno^.S-dlazepine^-car boxylic acid- [1 -(6-chloro-1 H-benzimidazol-2-yl)-2-hydroxy-propyl]-amide

(R)-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-2-c arboxylic acid-[1-(5- ethynyl-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-amide

(RJ-e-methyl-δ.ej.δ-tetrahydro^H-thiazoloK.δ-dlazepine ^-carboxylic acid-ti- (5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-amide

(8RS)-8-methoxy-6-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3 -d]azepine-2- carboxylic acid [(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-amide

(4RS)-4,6-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]aze pine-2-carboxylic acid[(1 R)- 1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-amide

(8RS)-6,8-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]aze pine-2-carboxylic acid[(1 R)- 1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-amide

(4RS)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3 -d]azepine-2- carboxylic acid-[(1 R)- 1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-amide

and the salts thereof.

Within the scope of the present application, the terms "isomers",

"stereoisomers", "diastereomers", "enantiomers", "chiral", "racemate" or "racemic mixture" are to be understood as follows. Compounds with the same generic formula that differ in the nature or arrangement of the bonding of their

atoms or their connectivity or the spatial arrangement of the atoms in the molecule are known as isomers. Isomers which, while having the same type and manner of connectivity between their atoms, differ in the spatial arrangement of the atoms in the molecule and are not congruent are referred to as "stereoisomers". Stereoisomers that do not behave as an image and mirror image to each other are known as "diastereomers", and stereoisomers that behave as an image and mirror image to each other are known as "enantiomers". If there is an asymmetric centre or atom present (also known as a stereocentre or chiral centre), for example at a carbon atom substituted by four different substituents, the molecule is of a "chiral" nature and a pair of enantiomers is possible. An enantiomer may be characterised by the absolute configuration of its stereocentre. The absolute configuration is described using the descriptors (R) and (S), which are determined by applying the sequence rules according to Cahn, lngold and Prelog , or by describing the rotation of the plane of polarised light on interaction with the molecule which is termed dextrorotatory or levorotatory (i.e. with (+) or (-) as descriptor, accordingly). A chiral compound may be present either as an individual enantiomer or as a mixture of the corresponding enantiomers. A mixture that contains equal amounts of both enantiomers of a compound is termed a "racemate" or "racemic mixture".

According to the invention the compounds of general formula (I) are obtained by methods known per se, for example by the following methods:

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

wherein D, B and R ³ to R ⁵ are defined as described in embodiment 1 , and which may optionally be protected at any amino, hydroxy,

carboxy or thiol groups durch common protective groups such as for example those described in T.W. Greene, P. G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999, and the protective groups of which may be cleaved by methods known from the literature, is described in the examples or may be carried out for example according to the following formula scheme 1 or analogously to the methods of synthesis described in WO2005/082895.

Scheme 1

(III) Ia)

D. .Q i) acylation with

O (IV)

(Ib)

optional cleaving of a i) protective group

compound of general formula (I) wherein

Q denotes a leaving group or a group which may be converted in-situ into a leaving group, such as for example a halogen atom, a hydroxy, Ci _-4 -alkyloxy, alkyloxycarbonyloxy, 4-pentafluorophenyloxy,

nitrophenyloxy, a trichloromethyl or acyloxy group or together with the carbonyl group denotes an alkali carboxylate group, and PG denotes a protective group for the amino function known from the literature, such as for example a tert.-butoxycarbonyl, benzyloxycarbonyl or a trifluoroacetyl group.

The reaction steps i) and ii) shown in Scheme 1 may be carried out in the manner described in the Examples or according to the conditions known from the literature, for example as follows:

i) by acylating an amine (Ilia) with an optionally activated carboxylic acid (IV):

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, dimethylsulphoxide, sodium hydroxide solution or sulpholane, 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 100 ⁰ C.

The acylation may however 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 ethyl-1 - ethoxy-1 ,2-dihydroquinoline-1 -carboxylate, isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, propanephosphonic acid cycloanhydride, λ/./V-dicyclohexylcarbodiimide, λ/./V-dicyclohexylcarbodiimide/camphorsulphonic acid,

A/,/V-dicyclohexylcarbodiinnide/A/-hyclroxysuccininnide or 1 -hydroxy-benzotriazole, λ/./V-carbonyldiimidazole, O-(benzotriazol-1 -yl)-/V,/V,λλ/V-tetramethyl-uronium tetrafluoroborate/W-methylmorpholine, O-(benzotriazol-1 -yl)- 5 A/./V./V./V-tetrannethyl-uroniunn tetrafluoroborate//V- ethyldiisopropylamine, O-(7-azabenzotriazol-1 -yl)- /V,/V,/V',/V'-tetramethyluronium-hexafluorophosphate//V- methylnnorpholine, O-pentafluorophenyl-λ/,λ/,λ/',λ/'- tetramethyluronium-hexafluorophosphate/triethylamine,

10 λ/./V-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, optionally with the addition of an auxiliary base such as sodium hydroxide solution, caesium, potassium or sodium carbonate or hydrogen carbonate or an amine base such as pyridine, thethylamine, N-

15 methylmorpholine or diisopropylethylamine, at temperatures between -20 and 200 ⁰ C, but preferably at temperatures between -10 and 160 ⁰ C.

Other methods of amide coupling are described for example

20 in P. D. Bailey, I. D. Collier, K.M. Morgan in "Comprehensive

Functional Group Interconversions", Vol. 5, page 257ff., Pergamon 1995, or in the Houben-Weyl Supplementary Volume 22, published by Thieme, 2003, and the literature cited therein.

25 ii) Cleaving a protective group

Any protecting group used may optionally subsequently be cleaved for example by hydrolysis in an aqueous solvent,

30 e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium

hydroxide, sodium hydroxide or potassium hydroxide or by ether splitting, e.g. in the presence of iodothmethylsilane, at temperatures between 0 and 100 ⁰ C, preferably at temperatures between 10 and 50 ⁰ C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved hydrogenolytically, for example, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, preferably, however, 1 to 5 bar.

However, a protective group may also be cleaved by the methods described by T.W. Greene, P. G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999.

(b) In order to prepare compounds of general formula

, (Ml)

wherein R ³ to R ⁵ are as hereinbefore defined and Z ¹ denotes the hydrogen atom or a protective group and B' denotes a group of formula

wherein R ⁷ and R ⁸ are as hereinbefore defined:

cyclising a compound of general formula

optionally formed in the reaction mixture, wherein

R ³ to R ⁵ , R ⁷ and R ⁸ are as hereinbefore defined and Z ¹ denotes the hydrogen atom or a protective group, and any protective group present is subsequently cleaved.

The cyclisation is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycoldimethylether, sulpholane, dimethylformamide or tetraline, dimethylsulphoxide, methylene chloride, chloroform, tetrachloromethane, for example at temperatures between 0 and 250 ⁰ C, but preferably between 20 and 100 ⁰ C, optionally in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, sulphuryl chloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid, acetic anhydride, λ/.λ/'-dicyclohexylcarbodiimide or optionally also in the presence of a

base such as potassiumethoxide or potassium-te/t.-butoxide. However, the cyclisation may also be carried out without a solvent and/or condensing agent.

Compounds of general formula (Vl) may be prepared by acylation of compounds of general formula

wherein n, R ⁷ and R ⁸ are as hereinbefore defined, with compounds of general formula

wherein R ³ , R ⁴ and R ⁵ are as hereinbefore defined, Q denotes a halogen atom or a hydroxy, Ci _-4 -alkoxy or Ci _-4 -acyloxy group and Z ¹ denotes a protective group, according to methods described in (e).

(c) In order to prepare a compound of general formula

wherein R ³ to R ⁵ are as hereinbefore defined, Z ¹ denotes the hydrogen atom or a protective group, for example a Ci _-5 -alkyloxycarbonyl or benzyloxycarbonyl group, and B' denotes a group of formula

wherein R ⁷ and R ⁸ are as hereinbefore defined:

i) transition metal-catalysed coupling and cyclisation of a compound of general formula

wherein R ³ denotes a phenyl or heteroaryl group and R ⁴ denotes a hydrogen atom and R ⁵ is as hereinbefore defined, with a compound of general formula

wherein R ⁸ is as hereinbefore defined and Z ¹ denotes a protective group, for example an acetyl or methylsulphonyl group, after which the protective group is cleaved.

The reaction sequence is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycoldimethylether, sulpholane, dimethylformamide,

/V-methylpyrrolidinone, tetraline, dimethylsulphoxide, methylene chloride, chloroform or tetrachloromethane, for example at temperatures between 0 and 250 ⁰ C, but preferably between 20 and 120 ⁰ C, conveniently in the presence of transition metal catalysts such as bis-(triphenylphosphine)-palladium(ll)- chloride, bis-(thcyclohexylphosphin)-palladium(ll)-chlohd, bis-(triethylphosphin)- palladium(ll)-chloride or bis-(tri-o-tolylphosphine)-palladium(ll)-chloride and optionally in the presence of a transition metal catalyst such as copper(l)-iodide, copper(l)-bromide or copper(l)-acetate and conveniently in the presence of a base such as tetramethylguanidine, tetramethylethylenediamine or N,N'- dimethylethylenediamine and optionally using an inert gas atmosphere (for example nitrogen or argon).

ii) Alkylation and subsequent reductive amination of a compound of general formula

wherein R ⁷ and R ⁸ are as hereinbefore defined and Y denotes a halogen atom, a Ci _-4 -alkoxy, Ci _-4 -alkoxyamino or a λ/-Ci _-4 -alkoxy-λ/-Ci _-4 -alkyl- amino group, with a compound of general formula

R ⁴ - M , (XIII)

wherein R ⁴ is as hereinbefore defined and M denotes a metal, such as for example lithium, sodium or potassium, or a metal such as for example magnesium, cadmium, copper or zinc, with a suitable counter-ion, such as for example chloride, bromide or iodide, or also a combination of two metals, such as for example magnesium and copper, lithium and copper or zinc and copper, with suitable counter-ions, such as for example cyanide, chloride, bromide or iodide, and a grouping containing

combinations thereof, and subsequent reductive amination of the compounds thus obtained.

The alkylation is conveniently carried out in a solvent or mixture of solvents such as benzene, chlorobenzene, toluene, xylene, glycoldimethylether, diethyleneglycoldimethylether, sulpholane, dimethylformamide, N- methylpyrrolidinone, tetraline, dimethylsulphoxide, methylene chloride, chloroform, tetrachloromethane, diethyl ether, te/t-butyl-methyl-ether or tetrahydrofuran, for example, at temperatures between -100 and +100 ⁰ C, but preferably between -100 and 30 ⁰ C, with alkylating reagents such as Grignard reagents, organolithium reagents, Gilman or Knochel cuprates, which may be prepared using methods known from the literature, optionally using an inert gas atmosphere (nitrogen or argon). The subsequent reductive amination of the ketones formed after alkylation is carried out by reacting, for example, with ammonia, hydroxylamine, alkoxylamines, primary amines, hydroxyl-alkylamines or alkoxy-alkylamines followed or accompanied by reduction for example with hydride donors such as sodium borohydride, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminium hydride in a solvent or mixture of solvents such as ethanol, isopropanol, benzene, toluene, pyridine, ethyleneglycoldimethylether, diethyleneglycoldimethylether, /V-alkylmorpholine, diethyl ether, te/t-butyl-methylether, tetrahydrofuran, hexane or cyclohexane or by hydrogenation, optionally under pressure and conveniently in the presence of a catalyst such as Raney nickel, palladium, palladium charcoal, platinum or platinum oxide, in a solvent or mixture of solvents such as ethyl acetate, ethanol, isopropanol, benzene, toluene, pyridine, ethyleneglycoldimethylether, diethyleneglycoldimethylether, /V-Ci _-5 - alkylmorpholine, diethyl ether, te/t-butyl-methylether, tetrahydrofuran, hexane or cyclohexane.

(d) In order to prepare a compound of general formula

wherein R ³ to R ⁵ are as hereinbefore defined, Z ¹ denotes the hydrogen atom or a protective group, for example a Ci _-5 -alkyloxycarbonyl or benzyloxycarbonyl group, and B' denotes a group of formula

wherein R is as hereinbefore defined:

coupling and subsequent cyclisation of a compound of general formula

wherein n and R are as hereinbefore defined, with a compound of general formula

. (XVi)

wherein R ³ to R ⁵ are as hereinbefore defined, Z ¹ denotes a protective group, for example a Ci _-5 -alkyloxycarbonyl or benzyloxycarbonyl group, and Z ⁴ denotes a nucleofugic leaving group, for example a chlorine, bromine or iodine atom, a tosylate, triflate or mesylate group, the protective group Z ¹ then being cleaved using methods known from the literature.

The reaction sequence is conveniently carried out in a solvent or mixture of solvents such as water, ethanol, isopropanol, benzene, chlorobenzene, toluene, xylene, glycol, glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide, /V-methylpyrrolidinone, tetraline, dimethylsulphoxide, sulpholane, methylene chloride, chloroform, tetrachloromethane or /V-ethyl- diisopropylamine, λ/-Ci _-5 -alkylnnorpholine, /V-Ci _-5 -alkylpipehdine, /V-Ci-5-alkylpyrrolidine, thethylamine, pyridine, for example at temperatures between -30 and 250 ⁰ C, but preferably between 0 and 150 ⁰ C, optionally conveniently in the presence of bases such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium-te/t.-butoxide, sodium ethoxide, potassium hexamethyldisilazane, sodium hydride or lithium diiso- propylamide.

(e) The components of general formula

wherein Q denotes a hydroxy or alkyloxy group or together with the carbonyl group denotes an alkali metal carboxylate group, and wherein D is defined as in embodiment 1 , and which may optionally be protected at any amino, hydroxy, carboxy or thiol groups present by common protective groups such as for example those described in T.W. Greene, P. G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999, and the protective groups of which may be cleaved by methods

known from the literature, in the course of the synthesis sequence, to form compounds of formula (I), are known from the literature, or their synthesis is described in the Examples, or they may be prepared for example using methods of synthesis known in the literature or analogously to methods of synthesis known in the literature such as for example in DE3105858, JP04046139 bzw. in N. Haginoya et al. J. Med. Chem. 2004, 47(21 ), 5167, S. Komoriya et al. Bioorg. Med. Chem. 2006, 14, 1309, Ortar et al. Tetrahedron Lett. 1986, 3931 or in J. M. Herbert et al., Tetrahedron. Lett 1998, 2421.

For example, a compound of general formula (IV), wherein D is defined as mentioned in embodiment 1 , may be prepared as follows by palladium-mediated carboxylation in alcohols or water from compounds of general formula (XVII)

wherein L ³ denotes a leaving group or a group that can be converted in-situ into a leaving group such as for example a halogen atom or a thfluoromethanesulphonate, and wherein A ¹ , A ² , A ³ , K ¹ , K ² , K ³ , K ⁴ and X are defined as in embodiment 1.

The introduction of an ester group from compounds of general formula

(XVII) is conveniently carried out for example with an alcohol by catalytic carbonylation with carbon monoxide, for example under a pressure of between 0.5 and 100 bar, but preferably between 1 and 50 bar, conveniently in the presence of a catalyst such as for example palladium(ll)acetate, tetrakis(triphenylphosphine)palladium(0) or

dichlorobis(triphenylphosphine)palladiunn(ll), conveniently in a solvent or mixture of solvents such as water, methanol, ethanol, isopropanol, butanol, pentane, hexane, cyclohexane, heptane, benzene, toluene, xylene, ethyl acetate, methylpropionate, glycol, glycoldimethylether, diethyleneglycoldimethylether, dioxane, tetrahydrofuran, for example at temperatures between -30 and 250 ⁰ C, but preferably between 0 and 150 ⁰ C.

(f) In order to prepare a compound of general formula (III), (VII), (Xl), (XII) or (XV), wherein B and R ³ to R ⁷ are as hereinbefore defined and R ⁸ denotes a C2-3-alkynyl group which is linked via the carbon atom to the aromatic group that simultaneously carries the triple bond, from a corresponding compound wherein R ⁸ denotes a bromine or iodine atom or the triflate, boric acid or boric acid ester group:

transition metal-catalysed coupling reaction of a compound of general formula

(XVIII),

wherein Z ⁵ denotes the hydrogen atom, the methyl group or a protective group such as for example a trimethylsilyl, te/t-butyl-dimethylsilyl, te/t-butyl- diphenylsilyl or thisopropyl group, which can then be cleaved, with a compound of general formula (III), (VII), (Xl), (XII) or (XV), wherein B and R ³ to R ⁷ are as hereinbefore defined and R ⁸ denotes a bromine or iodine atom or the triflate, boric acid or boric acid ester group.

The reaction is preferably carried out in a solvent or mixture of solvents such as acetonitrile, diethyl ether, tetrahydrofuran, dioxane, water or dimethylformamide or a mixture of solvents in the presence of a palladium catalyst such as for example bis(thphenylphosphine)-palladium(ll)choride, palladium(ll)-[1 ,1 '-bis- (diphenylphosphino)ferrocene]-chloride or tetrakis-(triphenylphosphine)-

palladium(O) in the presence of a base such as triethylamine, /V-isopropyl- diethylamine, λ/,λ/-diisopropyl-ethylannine, potassium-te/t-butoxide, sodium carbonate or caesium carbonate, optionally in the presence of ligands such as triphenylphosphine, th-o-tolylphosphine, tri-te/t-butylphosphine, 1 ,3-bis- (diphenylphosphino)-propane, 2,2'-bis-(diphenylphosphino)-1 ,1 '-dinaphthyl, 1 ,1 '-bis-(diphenylphosphino)-ferrocene, Xantphos and optionally in the presence of a transition metal compound such as a copper halide such as for example copper(l)iodide and at temperatures between 20 and 120 ⁰ C, preferably at temperatures between 20 and 90 ⁰ C, under an argon or nitrogen atmosphere (cf. also K. Sonogashira, Comprehensive Organic Synthesis, Vol. 3, page 52ff., Pergamon Press, Oxford 1991 ).

Any silyl protective group present, such as for example trimethylsilyl, is preferably cleaved in a solvent or mixture of solvents such as water, methanol, ethanol, isopropanol, acetone, dioxane, tetrahydrofuran or dimethylformamide in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methoxide. Fluoride reagents such as for example tetrabutylammonium fluoride, lithium fluoride or potassium fluoride, optionally with the addition of a complexing agent such as 18-crown-6-ether, are also suitable for cleaving in organic solvents such as for example diethyl ether, tetrahydrofuran, dimethylformamide or dichloromethane.

In the reactions described above any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.

For example, a suitable protecting group for a hydroxy group may be the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert. butyl, trityl, benzyl or tetrahydropyranyl group.

Suitable protecting groups for a carboxyl group might be the trimethylsilyl, methyl, ethyl, tert. butyl, benzyl or tetrahydropyranyl group.

Suitable protecting groups for an amino, alkylamino or imino group might be the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, the phthalyl group.

Other protective groups which may be used and their cleaving are described in T.W. Greene, P. G. M. Wuts, "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999.

Any protective group used may optionally subsequently be cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether splitting, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100 ⁰ C, preferably at temperatures between 10 and 50 ⁰ C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved hydrogenolytically, for example, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, preferably, however, 1 to 5 bar.

A methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cerium(IV)ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures of between 0 and 50 ⁰ C, but preferably at ambient temperature.

A methoxy group is expediently cleaved in the presence of boron thbromide in a

solvent such as methylene chloride at temperatures between -35 and -25°C.

A 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisol.

A te/t.butyl or te/t.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.

A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50 ⁰ C.

An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis-(thphenylphosphine)-palladium(0), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1 ,3-dimedone at temperatures between 0 and 100 ⁰ C, preferably at ambient temperature and under an inert gas, or by treating with a catalytic amount of tris-(thphenylphosphine)-rhodium(l)chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1 ,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70°C.

Compounds of general formulae (III), wherein the group B' is represented by a group of general formula (V), and (Vl) may be prepared for example analogously to K. Maekawa, J. Ohtani, Agr. Biol. Chem. 1976, 40, 791-799.

Moreover the compounds of general formula (I) obtained may be resolved into their enantiomers and/or diastereomers.

Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and ENeI E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971 )

into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomehc mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides may be a (+)- or (-)-menthyloxycarbonyl, for example.

Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Moreover, if the new compounds of formula I contain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine,

diethanolamine and triethanolamine.

As already mentioned, the compounds of general formula I as well as the tautomers, the enantiomers, the diastereomers and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an antithrombotic activity, which is preferably based on an effect on thrombin or factor Xa, for example on a thrombin-inhibiting or factor Xa-inhibiting activity, on a prolonging effect on the aPTT time and on an inhibiting effect on related serine proteases such as e.g. urokinase, factor Vila, factor IX, factor Xl and factor XII.

The compounds listed in the experimental section may be investigated for their effect on the inhibition of factor Xa as follows:

Method:

Enzyme-kinetic measurement with chromogenic substrate. The quantity of p- nitroaniline (pNA) released from the colourless chromogenic substrate by human factor Xa is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used. The inhibition of the enzyme activity by the test substance (in relation to the solvent control) is determined at various concentrations of test substance and from this the IC ₅ O is calculated, as the concentration which inhibits the factor Xa used by 50 %.

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

Factor Xa (Calbiochem), spec, activity: 217 IU/mg, final concentration: 7 IU/ml for each reaction mixture

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

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

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

Evaluation:

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

2. Determining the % inhibition based on the solvent control.

3. Plotting a dosage/activity curve (% inhibition vs substance concentration).

4. Determining the IC ₅ O by interpolating the X-value (substance concentration) of the dosage/activity curve at Y = 50 % inhibition.

All the compounds tested had an IC ₅ O value of less than 100 μmol/L.

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

In view of their pharmacological properties the new compounds and the physiologically acceptable salts thereof are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as for example the prevention and treatment of deep leg vein thrombosis, thrombophlebitis, for preventing reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases, and for preventing and treating pulmonary embolism, disseminated intravascular coagulation and severe sepsis, for preventing and treating DVT in patients with exacerbation of COPD,

for treating ulcerative colitis, for treating and preventing coronary thrombosis, for preventing stroke and the occlusion of shunts.

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

The compounds specified may also be used as anticoagulants in connection with the preparation, storage, fractionation or use of whole blood or in invasive therapies, e.g. for coating prostheses, artificial heart valves and catheters for reducing the risk of thrombosis.

In view of their pharmacological properties the new compounds and the physiologically acceptable salts thereof are also suitable for treating Alzheimer's and Parkinson ^' s disease. One rationale for this can be seen for example in the following findings, from which it can be concluded that thrombin inhibitors or factor Xa inhibitors, by inhibiting thrombin formation or activity, could be valuable drugs for treating Alzheimer's and Parkinson ^' s disease. Clinical and experimental studies indicate that neurotoxic mechanisms, for example the inflammation that accompanies the activation of proteases of the clotting cascade, are involved in the dying off of neurones following brain damage. Various studies indicate an involvement of thrombin in neurodegenerative processes, e.g. following a stroke, repeated bypass operations or traumatic brain injury. An increased thrombin activity was able to be detected for example some days after peripoheral nerve damage. It was also shown that thrombin causes neurite retraction and glia proliferation, and apoptosis in primary

cultures of neurones and neuroblastoma cells (for an overview see: Neurobiol. Aging, 2004, 25(6), 783-793). In addition, various in vitro studies on the brains of patients with Alzheimer's disease indicate that thrombin plays a part in the pathogenesis of this disease (Neurosci. Lett., 1992, 146, 152-54). An accumulation of immunoreactive thrombin has been detected in neurite plaques in the brains of Alzheimer's patients. It was demonstrated in vitro that thrombin also plays a part in the regulation and stimulation of the production of Amyloid Precursor Protein (APP) as well as in the cleaving of APP into fragments which can be detected in the amyloid plaques in the brains of Alzheimer's patients. It has also been shown that thrombin-induced microglial activation in vivo leads to the degeneration of nigral dopaminergic neurones. These findings lead one to conclude that microglial activation, triggered by endogenous substance(s) such as thrombin, for example, are involved in the neuropathological process of the cell death of dopaminergic neurones, such as occurs in patients with Parkinson's disease (J. Neurosci., 2003, 23, 5877-86).

The new compounds and the physiologically acceptable salts thereof can also be used for the prevention and treatment of arterial vascular diseases in combination therapy with lipid-lowering active substances such as HMG-CoA reductase inhibitors and vasodilators, particularly ACE inhibitors, angiotensin Il antagonists, renin inhibitors, β-receptor antagonists, α-receptor antagonists, diuretics, Ca-channel blockers, or stimulators of soluble guanylate cyclase.

By increasing the antithrombotic activity the new compounds and the physiologically acceptable salts thereof can also be used in combination therapy with other anticoagulants such as, for example, unfractionated heparin, low-molecular heparin, fondaparinux or direct thrombin inhibitors, for example recombinant hirudine or "active-site" thrombin inhibitors.

The new compounds and the physiologically acceptable salts thereof may be used therapeutically in conjunction with acetylsalicylic acid, with inhibitors of platelet aggregation such as fibrinogen receptor antagonists (e.g. abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of

the clotting system and the recombinant analogues thereof (e.g. Protein C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (e.g. clopidogrel, prasugrel, ticlopidine), with P ₂ T receptor antagonists (e.g. cangrelor) or with combined thromboxane receptor antagonists/synthetase inhibitors (e.g. terbogrel).

The dosage required to achieve such an effect is appropriately 0.01 to 3 mg/kg, preferably 0.03 to 1.0 mg/kg by intravenous route, and 0.03 to 30 mg/kg, preferably 0.1 to 10 mg/kg by oral route, in each case administered 1 to 4 times a day.

For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.

The new compounds and the physiologically acceptable salts thereof may be used therapeutically in conjunction with acetylsalicylic acid, with inhibitors of platelet aggregation such as fibrinogen receptor antagonists (e.g. abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of the clotting system and the recombinant analogues thereof (e.g. Protein C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (e.g. clopidogrel, ticlopidine), with P ₂ T receptor antagonists (e.g. cangrelor) or with combined thromboxane receptor antagonists/synthetase inhibitors (e.g. terbogrel).

Experimental section

The following Examples are intended to illustrate the invention, without restricting its scope.

As a rule, melting points, IR, UV, ¹ H-NMR and/or mass spectra have been obtained for the compounds prepared. Unless otherwise stated, Rf values were obtained using ready-made silica gel 60 F ₂ S ₄ TLC plates (E. Merck, Darmstadt, Item no. 1.05714) without chamber saturation. The R _f values obtained under the name Alox were determined using ready-made aluminium oxide 60 F ₂ S ₄ TLC plates (E. Merck, Darmstadt, Item no. 1.05713) without chamber saturation. The Rf values obtained under the name Reversed-phase-8 were determined using ready-made RP-8 F ₂₅₄₈ TLC plates (E. Merck, Darmstadt, Item no. 1.15684) without chamber saturation. The ratios given for the eluants refer to units by volume of the solvents in question. Chromatographic purification was done using silica gel supplied by Messrs Millipore (MATREX™, 35-70 μm). If the configuration is not specified in detail, it is unclear whether the compound in question is a pure stereoisomer or a mixture of enantiomer and diastereomer.

The following abbreviations are used in the test descriptions:

Boc te/t.-butoxycarbonyl

DIPEA /V-ethyl-diisopropylamine

DMSO dimethylsulphoxide

DMF N, N-ύ imethylformam ide

EE ethyl acetate sat. saturated h hour(s) i. vac. in vacuo cone. concentrated

NMM /V-methyl-morpholine

NMP /V-methyl-pyrrolidin-2-one

O ortho

PE petroleum ether

PfTU O-pentafluorophenyl-/V,/V,/V',/V4etramethyluronium hexafluorophosphate

PPA propanephosphonic acid cycloanhydride quant. quantitative

Rf retention factor

Rt retention time rac. racemic

TBTU O-(benzotriazol-1 -yl)-λ/,λ/,/V\/V-tetranrιethyluror tetrafluoroborate

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran tert. tertiary ∑ yield over all the steps carried out analogously

Method A:

Waters Alliance 2695, PDA detector 2996. The mobile phase used was: A: water with 0.1 % HCOOH

B: acetonitrile with 0.1 % HCOOH

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

0.00 95 5 1 .60

4.50 10 90 1 .60

The stationary phase used was a YMC-Pack ODS-AQ column, 3 μm, 4.6 mm x 75 mm.

Method B:

Waters Alliance 2695, Waters Micromass ZQ mass spectrometer with diode array detector 2996.

The mobile phase used was:

A: water with O.13% TFA B: acetonitrile

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

0.00 95 5 3.50

0.18 95 5 3.50

2.00 2 98 3.50

2.20 2 98 3.50

2.30 95 5 3.50

2.50 95 5 3.50

2.60 95 5 0.10

The stationary phase used was a Varian MS 100 C18 column, 3 μm, 4.6 mm x 30 mm.

The diode array detection was carried out within the wavelength range 210-380 nm.

Method D:

Waters Alliance 2695, Waters Micromass ZQ mass spectrometer with diode array detector 2996. The mobile phase used was:

A: water with 0.13% trifluoroacetic acid B: acetonitrile

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

0.00 100 0 5.00

0.08 100 0 5.00

1.70 0 100 5.00

1.75 0 100 5.00

1.80 100 0 5.00

1.85 100 0 5.00

1.90 100 0 0.10

The stationary phase used was a Varian Polaris C18, 3 μm, 4.6 mm x 30 mm.

The diode array detection was carried out within the wavelength range 210-380 nm.

Method E:

Waters Alliance 2695, Waters Micromass ZQ mass spectrometer with diode array detector 2996.

The mobile phase used was:

A: water with 0.1 % ammonia B: acetonitrile

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

0.00 95 5 4.00

0.01 95 5 4.00

0.89 2 98 4.00

0.90 2 98 4.00

0.95 95 5 4.00

1.05 95 5 4.00

1.10 95 5 0.50

The stationary phase used was a column Waters Xbridge C18, 3.5 μm, 4.6 mm x 20 mm.

The diode array detection was carried out within the wavelength range 210-380 nm.

Method F:

Waters Alliance 2790 HPLC, Waters ZMD mass spectrometer with diode array detector 996. The mobile phase used was:

A: water with 0.1 % trifluoroacetic acid

B: acetonitrile with 0.1 % trifluoroacetic acid

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

0.00 95 5 1 .00

0.10 95 5 1 .00

5.10 2 98 1 .00

6.50 2 98 1 .00

7.00 95 5 1 .00

The stationary phase used was a Waters XTerra C18 MS column, 3.5 μm, 4.6 mm x 50 mm.

The diode array detection was carried out within the wavelength range 210-500 nm.

Method G: Agilent HP 1100, Agilent mass spectrometer HP 1100 Series MSD. The mobile phase used was:

A: water with 0.1 % trifluoroacetic acid

B: acetonitrile with 0.1 % trifluoroacetic acid

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

0.00 95 5 5.00

0.25 95 5 100. 00

0.50 95 5 100. 00

4.00 5 95 100. 00

4.75 5 95 100. 00

5.00 95 5 100. 00

6.00 95 5 100. 00

The stationary phase used was a column Waters SunFire C18 OBD, 10 μm, 30 mm x 100 mm.

Method H:

Agilent HP 1100, Agilent mass spectrometer HP 1100 LC/MSD SL.

The mobile phase used was:

A: water with 0.1 % ammonia

B: acetonitrile with 0.1 % ammonia

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

0.00 95 5 5.00

0.50 95 5 50.00

1.00 95 5 50.00

8.00 5 95 50.00

9.50 5 95 50.00

9.70 95 5 50.00

The stationary phase used was a Waters XBridge Prep C18 OBD column, 5 μm, 30 mm x 100 mm.

Method I:

Waters Alliance 2695, Waters Micromass ZQ mass spectrometer with diode array detector 2996. The mobile phase used was: A: water with 0.13% ammonia

B: acetonitrile time in min %A %B flow rate in ml/min

0.00 95 5 5.00

0.01 95 5 5.00 1 1 ..8800 2 2 9 988 5.00

1 .90 2 98 5.00

2.00 95 5 5.00

2.10 95 5 5.00

2.15 95 5 0.50 The stationary phase used was a Varian Pursuit XRS 5 C18 column, 3 μm, 4.6 mm x 30 mm.

The diode array detection was carried out within the wavelength range 210-380 nm.

Example 1

(f?)-3-methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepine-7-carboxylic acid-[1 -(5- chloro-1 H-benzimidazol-2-yl)-2-nnethoxy-ethyl]-annide

(a) 1 -(3-acetyl-2,3,4,5-tetrahydro-1 H-benzord1azepin-7-yl)-ethanone 22.2 g (166.4 mmol) aluminium trichloride are added in small amounts to 50 ml of dichloroethane. 6.2 ml (87.2 mmol) acetyl chloride are then added dropwise while cooling with ice. Then a solution of 15 g (79 mmol) 1 -(1 ,2,4, 5-tetrahydro- benzo[d]azepin-3-yl)-ethanone in 35 ml of dichloroethane is slowly added dropwise at 15-20 ⁰ C. The reaction mixture is stirred for two hours at RT and then poured onto a mixture of 20 ml 6N hydrochloric acid and ice. The aqueous phase is extracted three times with DCM and the combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The residue is triturated with diethyl ether and dried. Ci ₄ Hi ₇ NO ₂ (231.29) Mass spectrum: (M+H) ⁺ = 232

Rf value: 0.09 (silica gel; petroleum ether/ethyl acetate = 3:7)

(b) 3-acetyl-2,3,4,5-tetrahvdro-1 H-benzord1azepine-7-carboxylic acid 16.8 g (72.5 mmol) 1 -(3-acetyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepin-7-yl)- ethanone are suspended in 460 ml 2.5 N sodium hydroxide solution. Then 14.5 ml (282 mmol) bromine are slowly added dropwise. The reaction mixture is stirred for one hour at RT and then filtered to remove the insoluble matter. The filtrate is extracted twice with tert.-butylmethylether, then acidified with cone, hydrochloric acid and mixed with some sodium disulphite solution. The

precipitate is filtered off, washed with water and dried at 45°C.

Ci ₃ Hi ₅ NO ₃ (233.26)

Rf value: 0.15 (RP-8; toluene/1 ,4-dioxane/methanol/ammonia = 20:50:20:5)

(c) 2,3,4,5-tetrahvdro-1 H-benzord1azepine-7-carboxylic acid (as hydrochloride salt)

16.7 g (71.4 mmol) S-acetyl^SAδ-tetrahydro-I H-benzotdlazepine^-carboxylic acid are suspended in 130 ml 6 N hydrochloric acid and refluxed for five days. Then the mixture is cooled and the precipitate is filtered off. It is washed twice with acetone and diethyl ether and dried. CiiHi ₃ N0 ₂ x HCI (191.23) Mass spectrum: (M+H) ⁺ = 192 Rf value: 0.66 (RP-8; MeOH/5% NaCI solution 6:4)

(d) 3-methyl-2,3,4,5-tetrahydro-1 H-benzo[d1azepine-7-carboxylic acid (as hydrochloride salt)

11.6 g (51.0 mmol) 2,3,4,5-tetrahydro-1 H-benzo[d]azepine-7-carboxylic acid (as hydrochloride salt) are dissolved in 19.3 ml formic acid, carefully mixed successively with 5.4 ml (102 mmol) sodium hydroxide solution (50% in water) and 15.2 ml (204 mmol) formalin (37% in water) and stirred for four hours at 70 ⁰ C. Then the mixture is evaporated down and the residue is acidified with cone, hydrochloric acid. This mixture is evaporated down again and then mixed with 30 ml of water while cooling with ice. The precipitate is filtered off, washed with a little cold water and dried. Ci ₂ Hi ₅ NO ₂ x HCI (205.26)

Mass spectrum: (M+H) ⁺ = 206

Rf value: 0.70 (RP-8; MeOH/5% NaCI solution 6:4)

(e) /V-(2-amino-4-chloro-phenyl)-/V-Boc-(S)-O-methyl-serinamide and N'-(2- amino-5-chloro-phenyl)-λ/-Boc-(S)-O-methyl-sehnamide

30.0 g (137 mmol) λ/-Boc-(S)-O-methyl-sehne together with 21.9 g (154 mmol) 4-chloro-1 ,2-phenylendiamine are dissolved in 658 ml THF, and 43.9 ml (316 mmol) triethylamine and 103 ml (173 mmol) of a 50 % solution of PPA in ethyl

acetate are added with stirring in the ice bath. After 15 minutes stirring in the ice bath the mixture is heated to ambient temperature, poured into water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with sat. sodium carbonate solution and water, dried on sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluant-gradient: dichloromethane/methanol = 30:1 -> 9:1 ). Ci ₅ H ₂₂ CIN ₃ O ₄ (343.81 )

Mass spectrum: (M-H) ^" = 342/344 (chlorine isotopes) Rf value: 0.80 (silica gel; dichloromethane/methanol = 9:1 )

(f) ( ^• /f?)-λ/-Boc-1 -(5-chloro-1 /-/-benzimidazol-2-yl)-2-methoxy-ethylamine 26.01 g (75.65 mmol) of the mixture obtained in Example 21 b are dissolved in 1500 ml of toluene, and 20.8 ml (364 mmol) acetic acid and 10.0 g molecular sieve, 4A, are added. The reaction mixture is stirred for 5 hours at 60 ⁰ C. The reaction mixture is filtered, washed with ethyl acetate and the organic phase is washed with semi-sat, sodium hydrogen carbonate solution, dried on sodium sulphate and evaporated down i. vac. The residue is stirred with diethyl ether and the crystals formed are suction filtered. The filtrate is evaporated down i. vac. and the residue is purified by three lots of chromatography on silica gel (eluant-gradient: dichloromethane/methanol 80:1 -> 50:1 ). Ci ₅ H ₂₀ CIN ₃ O ₃ (325.79)

Mass spectrum: (M+H) ⁺ = 326/328 (chlorine isotopes) Rf value: 0.29 (silica gel; dichloromethane/methanol = 30:1 )

(g) (1 f?)-1 -(5-chloro-1 /-/-benzimidazol-1 -yl)-2-methoxy-ethylamine 0.5O g (1.54 mmol) (1 R)-/V-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy- ethylamine in 1.5 ml dichloromethane are combined with 1.54 ml (20.0 mmol) TFA and the mixture is stirred for 2 h at ambient temperature. Then the mixture is poured into sat. sodium hydrogen carbonate solution and after thorough mixing the aqueous phase is extracted with dichloromethane and ethyl acetate. The combined organic phases are dried on sodium sulphate and purified by

chromatography on silica gel (eluant: dichloromethane/methanol = 9:1 + 1 % cone, ammonia solution).

Mass spectrum: (M-H) ^" = 224/226 (chlorine isotopes) Rf value: 0.40 (silica gel, dichloromethane/methanol 9:1 + 1 % cone, ammonia solution)

(h) (R)-3-methyl-2,3,4,5-tetrahvdro-1 H-benzo[d1azepine-7-carboxylic acid-[1 - (5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethvH-amide 0.1 g (532 μmol) 3-methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepine-7-carboxylic acid (as hydrochloride salt) are dissolved in 5 ml DMF and combined with 0.2 g (585 μmol) TBTU and 0.3 ml (1.6 mmol) DIPEA. The mixture is stirred for 15 minutes, then 0.1 g (532 μmol) (1 R)-1-(5-chloro-1 H-benzimidazol-1 -yl)-2- methoxy-ethylamine are added and the mixture is stirred for 16 hours at RT. Then the reaction mixture is evaporated down and combined with ethyl acetate. The organic phase is washed successively with water, sat. sodium hydrogen carbonate solution, twice with water and saturated sodium chloride solution and dried on sodium sulphate, filtered and concentrated i. vac. C ₂₂ H ₂₅ CIN ₄ O ₂ (412.91 ) Mass spectrum: (M+H) ⁺ = 413/415 (chlorine isotopes)

Rf value: 0.80 (silica gel; dichloromethane/methanol/ammonia = 80:20:2)

The following compounds were prepared analogously:

N°. Structural formula Mass peak(s) Rf value or R _t

Name

2-methyl-1 ,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid-[1 -(5- chloro-1 H-benzinnidazol-2-yl)-3-nnethoxy-propyl]]-annide (as the formate salt)

Example 14

(3R)-2,3-dimethyl-1 ,2,3,4-tetraahydro-isoquinoline-6-carboxylic acid-[(1 R)-1 -(5- chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-amide (as the bis-trifluoroacetate salt)

(a) (S.q,R)-2-methyl-propane-2-sulphinic acid-r2-(5-bromo-2-cvano-phenyl)-1- methyl-ethyli-amide

6.0 ml (42.8 mmol) diisopropylamine are dissolved in 80 ml THF, slowly combined with 26.7 ml (42.8 mmol) butyllithium solution (1.6 M in n-hexane) at 0 ⁰ C, stirred for 30 min. Then this solution is cooled to -78°C and a solution of 4.0 g (20.4 mmol) 4-bromo-2-methyl-benzonithle in 15 ml THF is slowly added dropwise. The mixture is stirred for 70 minutes at -78°C and then a solution of 1.5 g (10.2 mmol) (Ss)-ethylidene-N-tert.-butyl-sulphinamide (prepared analogously to J. Ellman et al. J. Org. Chem. 2001 , 66, 8772 from acetaldehyde and (Ss)-tert.-butylsulphinamide) in 15 ml THF is added dropwise thereto. The mixture is stirred for 2.5 hours at -70 to -65°C. The reaction mixture is combined with 5 ml sat. ammonium chloride solution and after thawing it is mixed with water and ethyl acetate. The aqueous phase is extracted three times with ethyl acetate, the combined organic phases are dried on sodium sulphate and

evaporated to dryness i. vac. The residue is purified by column chromatography on silica gel (eluant DCM/MeOH 100:3) Rt value: 1.45 min (Method B) Mass spectrum: (M+H) ⁺ = 343/345 (bromine isotopes)

(b) (R)-2-(2-amino-propyl)-4-bromo-benzonitrile (as hydrochloride salt)

830 mg (2.4 mmol) (Ss,R)-2-methyl-propane-2-sulphinic acid-[2-(5-bromo-2- cyano-phenyl)-1 -methyl-ethyl]-amide are dissolved in 10 ml of ethanolic hydrochloric acid (40%) and stirred for 3 hours at 60 ⁰ C and then for 16 hours at

RT. Then the reaction mixture is evaporated to dryness.

Rt value: 0.97 min (Method B)

Ci ₀ HnBrN ₂ x HCI (239.12) Mass spectrum: (M+H) ⁺ = 239/241 (bromine isotopes)

(c) (R)-6-bromo-3-methyl-3,4-dihydro-2H-isoquinolin-1 -one

480 mg (1.7 mmol) (R)-2-(2-amino-propyl)-4-bromo-benzonitrile (as hydrochloride salt) are dissolved in 5 ml 10 N sodium hydroxide solution and stirred for 16 hours at 80 ⁰ C. Then the reaction mixture is acidified with hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The residue is purified by RP-HPLC. Rt value: 1.31 min (Method B)

CioHioBrNO (240.10)

Mass spectrum: (M+H) ⁺ = 240/242 (bromine isotopes)

(d) (R)-6-bromo-2,3-dimethyl-3,4-dihydro-2H-isoquinolin-1 -one

426 mg (1.7 mmol) (R)-6-bromo-3-methyl-3,4-dihydro-2H-isoquinolin-1 -one are dissolved in 3 ml DMF and at 0°C combined with 80 mg (2 mmol) sodium hydride (60% in mineral oil dispersion). After 10 minutes 122 μl (1.9 mmol) methyl iodide are added dropwise, and the mixture is stirred for 16 hours at RT.

Then the reaction mixture is mixed with water and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The residue is purified by flash chromatography on silica gel (eluant DCM/MeOH 20:1 ). Rt value: 1.40 min (Method B) Mass spectrum: (M+H) ⁺ = 254/256 (bromine isotopes)

(e) methyl (R)-2,3-dimethyl-1 -oxo-1 ,2,3,4-tetrahydroisoquinoline-6- carboxylate

In an inertised autoclave 100 mg (394 μmol) (R)-6-bromo-2,3-dimethyl-3,4- dihydro-2H-isoquinolin-1 -one are dissolved in a mixture of 20 ml MeOH and 5 ml DMF and combined with 20 mg (89 μmol) palladium(ll)-acetate, 70 mg (86 μmol) 1 ,1 '-bis-(diphenylphospino)-ferrocene-dichloropalladium(ll) complex with DCM and with 110 μl (08. mmol) TEA. Then 2 bar carbon monoxide pressure are applied and the mixture is shaken for 16 hours. Then the same amount of palladium(ll)-acetate and 1 ,1 '-bis-(diphenylphosphino)-ferrocene- dichloropalladium(ll) complex with DCM is added twice more and in each case the mixture is shaken for a further 24 hours at the same temperature. The mixture is left to cool and filtered to remove the catalyst mixture. The filtrate is evaporated down i. vac. The residue thus obtained is purified by flash chromatography on silica gel (eluant PE/EE 1 :1 ). The fractions containing the product are combined and concentrated i. vac. The crude product is purified by RP-HPLC.

Rt value: 1.22 min (Method B)

Ci ₃ Hi ₅ NO ₃ (233.26)

Mass spectrum: (M+H) ⁺ = 234

(f) methyl (R)-2,3-dimethyl-1 ,2,3,4-tetrahvdroisoquinoline-6-carboxylate

60 mg (257 μmol) methyl (R)-2,3-dimethyl-1-oxo-1 ,2,3,4-tetrahydroisoquinoline- 6-carboxylate are dissolved in 2 ml THF under an argon atmosphere and 100 μl (542 μmol) diphenylsilan are added at RT. Then 20 mg (21 μmol)

carbonylhydridotris(triphenylphosphine)rhodium(l) are added and the mixture is stirred for two hours. A further 50 μl diphenylsilane and 10 mg carbonylhydridotris(triphenylphosphine)rhodium(l) are added and the mixture is stirred for a further 2.5 hours. Then the reaction mixture is evaporated down i. vac. and purified by flash chromatography on silica gel (eluant DCM/MeOH 95:5).

Rt value: 0.93 min (Method B) Ci ₃ Hi ₇ NO ₂ (219.28) Mass spectrum: (M+H) ⁺ = 220

(g) (R)-2,3-dimethyl-1 ,2,3,4-tetrahvdroisoquinoline-6-carboxylic acid (as the hydrochloride salt)

44 mg (201 μmol) methyl (R)-2,3-dimethyl-1 ,2,3,4-tetrahydroisoquinoline-6- carboxylate are dissolved in 2 ml 6 N hydrochloric acid and stirred for one day at 6O ⁰ C. Then the reaction mixture is concentrated i. vac. and lyophilised.

Rt value: 0.62 min (Method B)

Ci ₂ Hi ₅ NO ₂ x HCI (205.26)

Mass spectrum: (M+H) ⁺ = 206

(h) (3f?)-2,3-dimethyl-1 ,2,3,4-tetrahvdro-isoquinoline-6-carboxylic acid-fd f?)- 1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl1-amide (as the bis- trifluoroacetate salt)

25 mg (103 μmol) 2-methyl-1 ,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (as the hydrochloride) are dissolved in 0.5 ml DMF, combined with 33 μl (300 μmol)

NMM and 39 mg (103 μmol) HATU and stirred for five minutes at RT. Then 23 mg (102 μmol) (1 R)-1-(5-chloro-1 H-benzimidazol-1 -yl)-2-methoxy-ethylamine are added and the mixture is stirred for 16 hours. Then the mixture is poured onto 1 N sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated to dryness i. vac. The residue is purified by RP-HPLC.

Rt value: 0.96 min (Method B)

C ₂₂ H ₂₅ CIN ₄ O ₂ x 2 CF ₃ CO ₂ H (412.92)

Mass spectrum: (M+H) ⁺ = 413/415 (chlorine isotopes)

The following compound was prepared analogously:

Example 16

2,4-dimethyl-1 ,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid-[(1 R)-1 -(5-chloro- 1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-amide (as the bis-trifluoroacetate salt)

(a) 3-(2-amino-1 -methyl-ethyl)-benzoic acid (as the hydrochloride salt) 14.5 g (82.8 mmol) 3-(cyano-methyl-methyl)-benzoic acid are dissolved in a mixture of 200 ml THF and 140 ml of water, combined with 1.5 g palladium/charcoal and 82.7 ml (165.3 mmol) 2N hydrochloric acid and hydrogenated for four hours at 3 bar hydrogen and RT. Then the mixture is filtered to remove the catalyst and concentrated to dryness i. vac. Rt value: 0.81 min (Method B) C ₁₀ H ₁₃ NO ₂ x HCI (179.22)

Mass spectrum: (M+H) ⁺ = 180

(b) methyl 3-(2-amino-1 -methyl -ethyl )-benzoate

17.2 g (63.9 mmol, 80% purity) 3-(2-amino-1-methyl-ethyl)-benzoic acid (as the hydrochloride salt) are dissolved in 100 ml of methanol and combined with 9 ml (124 mmol) thionyl chloride while cooling with an ice bath. The cooling bath is removed and the mixture is refluxed for three hours. Then the reaction mixture is evaporated to dryness i. vac. and combined with 2N sodium hydroxide solution and ethyl acetate. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. Rt value: 0.91 min (Method B) C _H H _I5 NO ₂ (193.24) Mass spectrum: (M+H) ⁺ = 194

(c) methyl 3-ri -methyl-2-(2,2,2-thfluoro-acetylamino)-ethyl1-benzoate

6.7 g (34.8 mmol) methyl 3-(2-amino-1 -methyl-ethyl)-benzoate are dissolved in 70 ml DCM and combined successively with 9.6 ml (69.1 mmol) TEA and 4.9 ml (35.3 mmol) trifluoroacetic anhydride while cooling with an ice bath. The mixture is stirred for one hour at ice bath temperature and then the volume of the mixture is reduced by half. Then 50 ml of water are added and the phases are separated using a phase separation cartridge. The organic phase is washed once with sat. sodium chloride solution and then evaporated down i. vac. Rt value: 1.52 min (Method B) Ci ₃ Hi ₄ F ₃ NO ₃ (289.25) Mass spectrum: (M+H) ⁺ = 290

(d) methyl 4-methyl-2-(2,2,2-trifluoro-acetyl)-1 ,2,3,4-tetrahvdro-isoquinoline- 6-carboxylate

9.0 g (31.1 mmol) methyl 3-[1 -methyl-2-(2,2,2-trifluoro-acetylamino)-ethyl]- benzoate are dissolved in 27 ml glacial acetic acid and combined with 18 ml cone sulphuric acid while cooling with an ice bath. The mixture is stirred for 10

minutes, then 1 .8 g paraformaldehyde are added and the mixture is stirred for two hours at RT and for 16 hours at 50 ⁰ C. Then the reaction mixture is poured onto a mixture of ice and water, and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The residue is purified by RP-HPLC. Rt value: 1 .56 min (Method B) Ci ₄ Hi ₄ F ₃ NO ₃ (301 .26) Mass spectrum: (M+NH ₄ ) ⁺ = 319

(e) 2,4-dimethyl-1 ,2,3,4-tetrahvdro-isoquinoline-6-carboxylic acid

(as the trifluoroacetate salt)

1 .4 g (4.5 mmol) methyl 4-methyl-2-(2,2,2-thfluoro-acetyl)-1 ,2,3,4-tetrahydro- isoquinoline-6-carboxylate are dissolved in 15 ml THF, combined with 4.5 ml (17.9 mmol) 4 N sodium hydroxide solution and stirred for 1 .5 days at 40 ⁰ C and for two days at RT. The reaction mixture is evaporated down i. vac. and suspended in 3.4 ml (90.1 mmol) formic acid. 1 .3 ml (18.0 mmol) formalin solution (37% in water) is added and the mixture is heated for 26 hours to 70°C. Then the mixture is evaporated down i. vac. and purified by RP-HPLC. Rt value: 1 .56 min (Method B) Ci ₂ Hi ₅ NO ₂ x CF ₃ CO ₂ H (205.26)

Mass spectrum: (M+H) ⁺ = 206

(f) 2,4-dimethyl-1 ,2,3,4-tetrahvdro-isoquinoline-6-carboxylic acid-[(1 f?)-1 -(5- chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl1-amide (as the bis-trifluoroacetate salt)

Prepared analogously to Example 14 h from 2,4-dimethyl-1 ,2,3,4-tetrahydro- isoquinoline-6-carboxylic acid (as the trifluoroacetate salt) and (1 R)-1 -(5-chloro-

1 H-benzimidazol-1 -yl)-2-methoxy-ethylamine.

Rt value: 0.99 min (Method B) C ₂₂ H ₂₅ CIN ₄ O ₂ x CF ₃ CO ₂ H (412.92)

Mass spectrum: (M+H) ⁺ = 413/415 (chlorine isotopes)

Example 17

2,3-dimethyl-1 ,2,3,4-tetrahydro-isoquinoline-7-carboxylic acid-[(1 R)-1 -(5-chloro- 1 H-benzimidazol-2-yl)-2-nnethoxy-ethyl]-annide (as the formate salt)

Prepared analogously to the synthesis sequence Example 16 b-f starting from methyl 4-(2-amino-propyl)-benzoate (as the hydrochloride salt). Rt value: 2.40 min (Method A) C ₂₂ H ₂₅ CIN ₄ O ₂ x HCO ₂ H (412.92) Mass spectrum: (M+H) ⁺ = 413/415 (chlorine isotopes)

Example 18

(rac)-2-Methyl-2,3-dihydro-1 H-isoindole-5-carboxylic acid-[1-(5-bromo-1 H- benzimidazol-2-yl)-2-methoxy-ethyl]-amide (as the trifluoroacetate salt)

(a) methyl 2,3-dihvdro-1 H-isoindole-5-carboxylate

Prepared analogously to Example 16 b from 2,3-dihydro-1 H-isoindole-5- carboxylic acid (as the hydrochloride salt; prepared analogously to EP 0 528

369).

Rt value: 0.49 min (Method D)

CioHiiNO ₂ (177.20)

Mass spectrum: (M+H) ⁺ = 178

(b) methyl 2-methyl-2,3-dihvdro-1 H-isoindole-5-carboxylate

1.2 g (6.6 mmol) methyl 2,3-dihydro-1 H-isoindole-5-carboxylate are dissolved in 5 ml formic acid, combined with 2 ml formalin solution (37% solution in water), heated to 70 ⁰ C for 3.5 hours and stirred for 16 hours at RT. The reaction mixture is evaporated down i. vac. and combined with 0.1 N sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. Rt value: 0.60 min (Method E) CiiHi ₃ NO ₂ (191.23) Mass spectrum: (M+H) ⁺ = 192

(c) 2-methyl-2,3-dihvdro-1 H-isoindole-5-carboxylic acid (as the hydrochloride salt)

Prepared analogously to Example 14 g from methyl 2-methyl-2,3-dihydro-1 H- isoindole-5-carboxylate. Rt value: 0.25 min (Method B) C10H11NO2 x HCI (177.20) Mass spectrum: (M+H) ⁺ = 178

(d) 2-methyl-2,3-dihvdro-1 H-isoindole-5-carboxylic acid-[1 -(5-bromo-1 H- benzimidazol-2-yl)-2-methoxy-ethyl1-amide (as the trifluoroacetate salt)

Prepared analogously to Example 14 h from 2-methyl-2,3-dihydro-1 H- isoindole-5-carboxylic acid (as the hydrochloride salt) and 1 -(5-bromo-1 H- benzimidazol-1 -yl)-2-methoxy-ethylamine (as the bis-trifluoroacetate salt).

Rt value: 0.99 min (Method B)

C ₂₀ H ₂ IBrN ₄ O ₂ x CF ₃ CO ₂ H (429.32)

Mass spectrum: (M+H) ⁺ = 429/431 (bromine isotopes)

Example 19

6-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3d]azepine-2-carboxy lic acid-[(1 R)-1 ^■ (5-chloro-1 H-benzimidazol-2-yl)-2-nnethoxy-ethyl]-annide (as the bis- trifluoroacetate salt)

(a) methyl 5,6,7,8-tetrahydro-4H-thieno[2,3-d1azepine-2-carboxylate (as the hydrochloride)

Prepared analogously to DE 3105858 from methyl 6-(3-chloro-benzyl)-5, 6,7,8- tetrahydro-4H-thieno[2,3-d]azepine-2-carboxylate. Rt value: 0.85 min (Method B) C10H13NO2S x HCI (211.28) Mass spectrum: (M+H) ⁺ = 212

(b) methyl 6-methyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1azepine-2- carboxylate

Prepared analogously to Example 18 b from methyl 5,6,7,8-tetrahydro-4H- thieno[2,3-d]azepine-2-carboxylate (as the hydrochloride). Rt value: 0.64 min (Method E) ) Mass spectrum: (M+H) ⁺ = 226

(c) 6-methyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1azepine-2-carbox ylic acid

(as the hydrochloride)

Prepared analogously to Example 14 g from methyl 5,6,7,8-tetrahydro-4H- thieno[2,3-d]azepine-2-carboxylate (as the hydrochloride). Yield: quantitative

Rt value: 0.52 min (Method B)

C10H13NO2S x HCI (211.28)

Mass spectrum: (M+H) ⁺ = 212

(d) 6-methyl-5,6,7,8-tetrahvdro-4H-thienor2,3d1azepine-2-carboxy lic acid- [(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethvH-amide (as the bis-trifluoroacetate salt)

Prepared analogously to Example 14 h from 6-methyl-5,6,7,8-tetrahydro-4H- thieno[2,3-d]azepine-2-carboxylic acid (as the hydrochloride) and (1 R)-1-(5- chloro-1 H-benzimidazol-1 -yl)-2-methoxy-ethylamine.

Rt value: 1.01 min (Method B)

C ₂₀ H ₂₃ CIN ₄ O ₂ S x 2 CF ₃ CO ₂ H (418.95)

Mass spectrum: (M+H) ⁺ = 419/421 (chlorine isotopes)

The following compounds were prepared analogously:

Example 20

(3RS)-6-methyl-3-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3d ]azepine-2- carboxylic acid-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-nnethoxy-ethyl]-annide (as the trifluoroacetate salt)

(a) 1 -benzyl-5-chloro-2,3,6,7-tetrahydro-1 H-azepine-4-carbaldehyde (as the hydrochloride salt)

65 ml (800 mmol) DMF are slowly combined with 77 ml (839 mmol) phosphorus oxychloride at 8-18°C. 84 ml of DCM and then 50 g (200 mmol) 1 -benzyl- azepan-4-one (as the hydrochloride salt) are added thereto. The mixture is stirred for 16 hours at RT and then poured onto 300 ml ice water. The organic phase is separated off and the aqueous phase is extracted three times with DCM. The combined organic phases are dried on magnesium sulphate, filtered and evaporated down i. vac. The residue is rinsed with a little acetone and dried. Rt value: 1.62 min (Method G) Ci ₄ Hi ₆ CINO x HCI (249.74)

Mass spectrum: (M+H) ⁺ = 250

(b) (rac)-d -benzyl-δ-chloro^, 3,6, 7-tetrahvdro-1 H-azepin-4-yl)-phenyl- methanol (as the hydrochloride salt) 35 ml (105 mmol) phenylmagnesium bromide solution (3 M in THF) are dissolved in 100 ml diethyl ether and slowly combined with a solution of 10 g (35 mmol) i -benzyl-δ-chloro^.S.θJ-tetrahydro-I H-azepine^-carbaldehyde (as the hydrochloride salt) in 80 ml diethyl ether. The reaction mixture is refluxed for two hours. Then 110 ml 4 M hydrochloric acid is added dropwise and the mixture is stirred for 45 minutes. The precipitate formed is filtered off, washed with diethyl ether, 1 M hydrochloric acid and water and dried. Rt value: 1.90 min (Method G) C ₂₀ H ₂₂ CINO x HCI (327.85) Mass spectrum: (M+H) ⁺ = 328/320 (chlorine isotopes)

(c) (rac)-d -benzyl-5-chloro-2, 3,6, 7-tetrahydro-1 H-azepin-4-yl)-phenyl- methanone

A mixture of 10 g (27 mmol) (me)- (1 -benzyl-5-chloro-2,3,6,7-tetrahydro-1 H- azepin-4-yl)-phenyl-methanol (as the hydrochloride salt) in 100 ml DCM is added dropwise at RT to a mixture of 13 g (61 mmol) pyridinium chlorochromate in 100 ml DCM and the mixture is stirred for 16 hours.

Saturated sodium carbonate solution is added thereto, the mixture is stirred for two hours and filtered to remove any undissolved matter. The residue is washed with DCM. The aqueous phase is extracted three times with DCM. The combined organic phases are dried on magnesium sulphate, filtered and evaporated down i. vac.

Rt value: 1.94 min (Method G)

C ₂₀ H ₂ OCINO (325.83)

Mass spectrum: (M+H) ⁺ = 326/328 (chlorine isotopes)

(d) (rac)- ethyl 6-benzyl-3-phenyl-5,6,7,8-tetrahvdro-4H-thieno[2,3d1azepine- 2-carboxylate

2.1 g (30.7 mmol) sodium ethoxide are added to a mixture of 5.O g (13.3 mmol)

(rac)- (1 -benzyl-5-chloro-2,3,6,7-tetrahydro-1 H-azepin-4-yl)-phenyl-methanone and 1.9 ml (16.9 mmol) ethyl mercaptoacetate in 50 ml of ethanol. The mixture is stirred for two hours at RT and then evaporated down i. vac. The residue is purified by RP-HPLC. Rt value: 2.09 min (Method H) C ₂₄ H ₂₅ NO ₂ S (391.53) Mass spectrum: (M+H) ⁺ = 392

(e) (rac)- ethyl 3-phenyl-5,6,7,8-tetrahvdro-4H-thienor2,3d1azepine-2- carboxylate (as the hydrochloride salt)

Prepared analogously to Example 19 a from (rac)- ethyl 6-benzyl-3-phenyl- 5,6,7,8-tetrahydro-4H-thieno[2,3d]azepine-2-carboxylate. Rt value: 1.88 min (Method G) Ci ₇ H ₂₀ NO ₂ S x HCI (301.41 ) Mass spectrum: (M+H) ⁺ = 302

(f) (rac)- ethyl 6-methyl-3-phenyl-5,6,7,8-tetrahvdro-4H-thienor2,3d1azepine- 2-carboxylate

200 mg (664 μmol) {rac)- ethyl 3-phenyl-5,6,7,8-tetrahydro-4H- thieno[2,3d]azepine-2-carboxylate (as the hydrochloride salt) are dissolved in methanol and filtered through an Alox column. The solution thus obtained is evaporated down i. vac. and dissolved in 4 ml formalin solution (37% in water) and hydrogenated with 3 bar hydrogen through palladium/charcoal at RT for 7 hours. The catalyst is filtered off and evaporated down i. vac. The residue is purified by RP-HPLC. The product thus obtained is again dissolved in methanol and filtered through an Alox column and evaporated down again i. vac. Rt value: 1.89 min (Method G) Ci ₈ H ₂ iNO ₂ S (315.43) Mass spectrum: (M+H) ⁺ = 316

(g) (rac)-6-methyl-3-phenyl-5,6,7,8-tetrahvdro-4H-thienor2,3d1az epine-2- carboxylic acid

170 mg (539 μmol) {rac)- ethyl 6-methyl-3-phenyl-5,6,7,8-tetrahydro-4H-

thieno[2,3d]azepine-2-carboxylate are dissolved in 10 ml of ethanol and combined with 1.6 ml (1.6 mmol) 1 N sodium hydroxide solution. The reaction mixture is stirred for four hours at 70 ⁰ C and then evaporated down i. vac. The residue is purified by RP-HPLC. Rt value: 1.60 min (Method G) Ci ₆ Hi ₇ NO ₂ S (287.38) Mass spectrum: (M+H) ⁺ = 288

(h) (3f?S)-6-methyl-3-phenyl-5,6,7,8-tetrahvdro-4H-thienor2,3d1a zepine-2- carboxylic acid-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl1- amide (as the trifluoroacetate salt)

Prepared analogously to Example 14 h from (rac)-6-methyl-3-phenyl-5, 6,7,8- tetrahydro-4H-thieno[2,3d]azepine-2-carboxylic acid and (R)-1-(5-chloro-1 H- benzimidazol-1 -yl)-2-methoxy-ethylamine. Rt value: 1.80 min (Method G)

C ₂₆ H ₂₇ CIN ₄ O ₂ S x CF ₃ CO ₂ H (495.05)

Mass spectrum: (M+H) ⁺ = 495/497 (chlorine isotopes)

Example 21 (f?)-5-methyl-4,5,6,7-tetrahvdro-thienor3,2-cipyridine-2-car boxylic acid-n-(5- chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl1-amide (as the trifluoroacetate salt ) Chiral

(a) tert. butyl 4-chloro-5-formyl-3,6-dihvdro-2H-pyhdine-1-carboxylate

Prepared analogously to Example 20 a from tert. butyl 4-oxo-piperidine-1- carboxylate.

Rf value: 0.45 (silica gel, PE/EE 8:2)

CiiHi ₆ CINO ₃ (245.70)

Mass spectrum:(M+H) ⁺ = 246/248 (chlorine isotopes)

(b) 5-tert-butyl-2-ethyl 6,7-dihvdro-4H-thienor3,2-cipyπdine-2,5-dicarboxylate

2.2 g (50% purity, 4.5 mmol) tert. butyl 4-chloro-5-formyl-3,6-dihydro-2H- pyridine-1-carboxylate are dissolved in 20 ml DCM and then combined with a mixture of 1.8 ml ( 16.0 mmol) ethyl mercapto-acetate and 2.79 ml (19.9 mmol) triethylamine. The reaction mixture is refluxed for 2.5 hours. It is then cooled to RT and mixed with water. The organic phase is separated off, dried on sodium sulphate, filtered and evaporated down i.vaα. The residue is purified by flash chromatography on silica gel (eluant: cyclohexane/ethyl acetate 8:2). Rt- Value: 1.71 min ( Method B)

Mass spectrum: (M+H) ⁺ = 312

(c) ethyl 4,5,6,7-tetrahvdro-thieno[3,2-cipyridine-2-carboxylate

615 mg (1 mmol) 5-tert-buty I -2-ethyl 6,7-dihydro-4H-thieno[3,2-c]pyhdine-2,5- dicarboxylate are dissolved in a mixture of 2 ml DCM and 2 ml TFA and stirred for 30 minutes. Then the reaction mixture is neutralised with triethylamine and evaporated down i.vaα. Rt- Value: 0.89 min ( Method B)

Mass spectrum: (M+H) ⁺ = 212

(d) ethyl 5-methyl-4,5,6,7-tetrahvdro-thieno[3,2-cipyridine-2-carboxyl ate (as the trifluoroacetate salt)

Prepared analogously to Example 18 b from ethyl 4,5,6,7-tetrahydro-thieno[3,2- c]pyridine-2-carboxylate.

Rt- Value: 0.90 min ( Method B)

CH HI ₅ NO ₂ S x C ₂ HF ₃ O ₂ (339.33) Mass spectrum: (M+H) ⁺ = 226

(e) 5-methyl-4,5,6,7-tetrahvdro-thienor3,2-cipyπdine-2-carboxyl ic acid

120 mg (0.35 mmol) ethyl 5-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-2- carboxylate (as the trifluoroacetate salt) are dissolved in 1 ml MeOH, combined with 700 μl (1.77 mmol) 8% lithium hydroxide solution and stirred for three hours at RT. The reaction mixture is then neutralised with 4N hydrochloric acid and evaporated down i.vaα.

Rt- Value: 0.29 min ( Method B)

C ₉ HnNO ₂ S (197.26)

Mass spectrum: (M+H) ⁺ = 198

(f) (^-δ-methyl^.δ.ey-tetrahvdro-thienors^-cipyridine^-carboxy lic acid-[1 -(5- chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethvH-amide ( as the trifluoroacetate )

Prepared analogously to Example 14 h from 5-methyl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine-2-carboxylic acid. Rt- Value: 1.02 min ( Method B)

C _I9 H _2I CIN ₄ O ₂ S X C ₂ HF ₃ O ₂ = (518.94)

Mass spectrum: (M+H) ⁺ = 405/407 (chlorine isotopes)

Example 22

(f?)-6-methyl-4,5,6,7-tetrahvdro-thienor2,3-cipyhdine-2-c arboxylic acidri -(5- chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethvH-amide ( as the trifluoroacetate )

Chiral

(a) methyl 6-methyl-4,5,6,7-tetrahvdro-thienor2,3-cipyridine-2-carboxyl ate (as the trifluoroacetate salt)

496 mg (2.1 mmol) 2-bromo-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (prepared analogously to EP 0314154 from 6-methyl-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine) are dissolved in 10 ml THF and cooled to -78°C. Then 2 ml (3.2 mmol) n-butyllithium solution (1.6 M in n-hexane) are slowly added dropwise. The reaction mixture is stirred for 30 minutes at -78°C and then combined with 1.0 ml (12.9 mmol) methyl chloroformate. The mixture is stirred for five minutes at -78°C, heated to RT and the mixture is evaporated down i. vac. The residue is purified by RP-HPLC. Rt value: 0.79 min (Method B) C10H13NO2S x CF ₃ CO ₂ H (211.28) Mass spectrum: (M+H) ⁺ = 212

(b) 6-methyl-4,5,6,7-tetrahvdro-thienor2,3-cipyridine-2-carboxyl ic acid (as the hydrochloride salt)

Prepared analogously to Example 21 e from methyl 6-methyl-4, 5,6,7- tetrahydro-thieno[2,3-c]pyridine-2-carboxylate (as the trifluoroacetate salt).

Rt value: 0.22 min (Method B)

C ₉ HnNO ₂ S x HCI (197.26)

Mass spectrum: (M+H) ⁺ = 198

(c) (f?)-6-methyl-4,5,6,7-tetrahvdro-thienor2,3-cipyhdine-2-carb oxylic acid[1 - (5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethvH-amide (as the trifluoroacetate salt)

Prepared analogously to Example 14 h from 6-methyl-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine-2-carboxylic acid (as the hydrochloride salt). Rt value: 0.88 min (Method B) Ci ₉ H ₂ iCIN ₄ O ₂ S x CF ₃ CO ₂ H = (518.94)

Mass spectrum: (M+H) ⁺ = 405/407 (chlorine isotopes)

The following compounds were prepared analogously:

Example 25

(R^δ-methyl^.δ.Gy-tetrahvdro-thiazolorδλ-cipyridine^- carboxylic acid-[1 -(5- chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl1-amide ( as the trifluoroacetate salt)

Chiral

Prepared analogously to 14 h from (R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2- methoxy-ethylamine and 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2- carboxylic acid (Heterocycles, 63, 2004, 1555-1562).

Rt value: 1.0 min (Method B)

Ci ₈ H ₂₀ CLN ₅ O ₂ S x 2CF ₃ CO ₂ H = (633.95)

Mass spectrum: (M+H) ⁺ = 406/408 (chlorine isotopes)

Example 26

Ethyl (f?)-2-[1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethylcarbamoyl1-6,7- dihvdro-4H-thieno[3,2-cipyridin-5-carboxylate (as the trifluoroacetate salt)

Chiral

a) 5-ethyl 6,7-dihvdro-4H-thieno[3,2-cipyhdine-2,5-dicarboxylate

1.00 g (4.18 mmol) ethyl 2-formyl-6,7-dihydro-4H-thieno[3,2-c]pyhdine-5- carboxylate are combined with 23 ml tert.-butanol and 1.44 g (25 mmol) of isobutylene weighed out in the freezer. Then 17 ml of an aqueous solution of 3.77 g (31 mmol) sodium hydrogen phosphate and 3.78 g (41 mmol) sodium chlorite are added and the mixture is stirred for 2 h. The reaction mixture is made basic with NaOH and extracted with ethyl acetate. Then the aqueous

phase is acidified with HCI and extracted with ethyl acetate. The combined ethyl acetate fractions are dried on sodium sulphate, concentrated and the residue is purified by flash chromatography on silica gel (eluant mixture dichloromethane:methanol 95:5 to 8:2). Rt value: 1.23 min (Method B) C _H H _{I 3} NO ₄ S (255.29) Mass spectrum:(M+H) ⁺ = 256

(b) ethyl (f?)-2-[1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethylcarbamovH- 6,7-dihvdro-4H-thieno[3,2-cipyhdin-5-carboxylate (as the trifluoroacetate salt)

Prepared analogously to Example 14 h from (R)-1 -(5-chloro-1 H-benzimidazol- 2-yl)-2-methoxy-ethylamine and 5-ethyl 6,7-dihydro-4H-thieno[3,2-c]pyhdine- 2,5-dicarboxylate. Rt value: 1.2 min (Method B)

C _2I H ₂₃ CIN ₄ O ₄ S X CF ₃ CO ₂ H (576.97)

Mass spectrum:(M+H) ⁺ = 463/465 (chlorine isotopes)

Example 28

(4f?S)-4,5-dimethyl-4,5,6,7-tetrahvdro-thiazolor5,4-cipyr idine-2-carboxylic acid[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl1-amide

Prepared analogously to 14 h from (R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2- methoxy-ethylamine and (rac)-4,5-dimethyl-4,5,6,7-tetrahydro-thiazolo[5,4-

c]pyridine-2-carboxylic acid (as the hydrochloride salt) (Prepared analogously to WO2004059728). Rt value: 0.94 min (Method B) Ci ₉ H ₂₂ CIN ₅ O ₂ S (419.93) Mass spectrum: (M +H) ⁺ = 420/422 (chlorine isotopes)

Example 29

(f?)-6-methyl-5,6,7,8-tetrahvdro-4H-thiazolor4,5-d1azepin e-2-carboxylic acid-ri- (5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl1-amide

Prepared analogously to 14 h from (R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2- methoxy-ethylamine and 6-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5- d]azepine-2-carboxylic acid ( as the hydrochloride salt) (Prepared analogously to WO2004058715).

Rt value: 0.90 min (Method B)

Ci ₉ H ₂₂ CIN ₅ O ₂ S (419.93)

Mass spectrum:(M+H) ⁺ = 420/422 (chlorine isotopes)

Example 38

(7RS)-6,7-dimethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridi ne-2-carboxylic acid [(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-amide

(a) 67-dimethyl-4,5-dihvdro-thieno[2,3-cipyridinium iodide

A mixture of 4.64 g (31 mmol) 7-methyl-4,5-dihydro-thieno[2,3-c]pyridine (prepared analogously to J.Am.Chem.Soc, 1951 , 1257), 8.0 ml (128 mmol) methyl iodide and 20 ml of ethyl acetate is stirred for 15 min. The precipitate formed is suction filtered, washed with ethyl acetate and dried in vacuo. Rt value: 0.47 min (Method B) C ₉ Hi ₂ NS x I (293.169) Mass spectrum: (M-I) ⁺ = 166

(b) (rac)-6,7-dimethyl-4,5,6,7-tetrahvdro-thienor2,3-cipyridine

A mixture of 7.2 g (24 mmol) 6,7-dimethyl-4,5-dihydro-thieno[2,3-c]pyridinium iodide and 80 ml of methanol is combined batchwise with 1.87 g (49 mmol) sodium borohydride while cooling with an ice bath. The mixture is stirred for 1.5 hours, concentrated, combined with sat. NaHCO3 solution and extracted three times with methylene chloride. The combined organic phases are dried on sodium sulphate, filtered and concentrated i.vaα.

Rt value: 0.66 min (Method B) C ₉ Hi ₃ NS (167.272)

Mass spectrum: (M+H) ⁺ = 168

(c) (rac)-2-bromo-6,7-dimethyl-4,5,6,7-tetrahydro-thienor2,3-cip yhdine (as the hvdrobromide salt)

A mixture of 4.0 g (24 mmol) (rac)-6,7-dimethyl-4,5,6,7-tetrahydro-thieno[2,3- c]pyridin and 25 ml of water is mixed batchwise with a mixture of 2.23 ml bromine and 6.7 g potassium bromide in 15 ml of water while cooling with an ice bath. After 30 min methylene chloride is added; the aqueous phase is separated off and the organic phase is concentrated. The crude product is reacted further, without any further purification. Rt value: 0.94 min (Method B) C ₉ Hi ₃ BrNS x HBr (246.168)

Mass spectrum:(M+H) ⁺ = 246/248

(d) methyl (rac)-6,7-dinnethyl-4,5,6,7-tetrahvdro-thienor2,3-cipyπdine -2- carboxylate

A mixture of 2.0 g (6.1 mmol) (rac)-2-bromo-6,7-dimethyl-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine (as hydrobromide salt), 2.0 g (24 mmol) sodium acetate and 100 ml of methanol is combined with 15 mg (0.067 mmol) palladium acetate, 150 mg (0.27 mmol) 1 ,1 '-bis(diphenylphosphino)ferrocene and 2.6 ml (18 mmol) triethylamine and carbonylated for 3.5 h at 80 ⁰ C under 5 bar of CO atmosphere. Then it is filtered off, concentrated, mixed with sat. NaHCO3 solution and methylene chloride and the resulting emulsion is filtered through CeI ite. The aqueous phase is separated off and extracted 2x with methylene chloride and the combined organic phases are dried with Na2SO ₄ and concentrated. The crude product is reacted further, without any further purification.

Rt value: 0.84 min (Method B) C _H H _I5 NO ₂ S (225.308) Mass spectrum:(M+H) ⁺ = 226

(e) (7f?S)-6,7-dimethyl-4,5,6,7-tetrahvdro-thienor2,3-cipyridine -2-carboxylic acid-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethvH-amide

(rac)-Methyl 6,7-dimethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-2-carb oxylate is saponified analogously to Example 21 e with lithium hydroxide and then reacted analogously to Example 14 h with (R)-1 -(5-chloro-1 H-benzimidazol-2- yl)-2-methoxy-ethylamine to form the title compound.

Rt value: 0.97 min (Method B)

C ₂₀ H ₂₃ CIN ₄ O ₂ S = (418.94) Mass spectrum:(M+H) ⁺ = 419/421 (chlorine isotopes)

The following compounds were prepared analogously:

Example 40

(8f?S)-8-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thienor2, 3-d1azepine-2- carboxylic acid [(1 R)- 1 -(5-chloro-1 H-benzimidazol-2-yl)-2-nnethoxy-ethyl1-annide (as the trifluoroacetate)

Chiral

(a) ethyl (rac)-8-hydroxy-4,5,7,8-tetrahydro-thieno[2,3-d1azepine-6- carboxylate

500 mg (2.1 mmol) ethyl 8-oxo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6- carboxylate (prepared analogously to US 2006/0003990) are dissolved in 5 ml of ethanol and combined with 390 mg (10.3 mmol) sodium borohydride. The reaction mixture is then decomposed with dilute hydrochloric acid solution. Then water is added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac.

Rt value: 1.19 min (Method B) C _H H _I5 NO ₃ S (241.31 ) Mass spectrum: M+ = 241

(b) ethyl (rac)- 8-methoxy-4,5,7,8-tetrahvdro-thieno[2,3-d1azepine-6- carboxylate

370 mg (1.53 mmol) {rac)- ethyl 8-hydroxy-4,5,7,8-tetrahydro-thieno[2,3- d]azepine-6-carboxylate are dissolved in 5 ml THF, cooled to -57°C and combined with 1.84 ml (1.84 mmol) LiHMDS (1 M in n-hexane). The reaction mixture is heated to RT and then combined with 150 μl (2.41 mmol) methyl iodide. The reaction mixture is decomposed by the addition of ethanol and evaporated down. The residue thus obtained is purified by flash chromatography on silica gel (eluant: cyclohexane/ EE 8:2). Rf value: 0.39 (silica gel, PE/EE 8:2) Ci ₂ Hi ₇ NO ₃ S (255.33) Mass spectrum:(M+ Na) ⁺ = 278

(c) (rac)-8-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1 azepine

30 mg (0.79 mmol) lithium aluminum hydride are placed in 2.4 ml THF and slowly combined with a solution of 31 mg (0.12 mmol) (rac)- ethyl 8-methoxy- 4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylate in 1.4 ml THF at RT. The mixture is stirred at RT until the development of gas ceases and is then refluxed for 1.5 hours. Then the mixture is cooled in the ice/water bath and mixed with sat. sodium sulphate solution. The reaction mixture is combined with sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i.vaα. Rt value: 0.84 min (Method B) Mass spectrum:(M+H) ⁺ = 198

(d) (rac)-2-bromo-8-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thien or2,3- diazepine

117 mg (0.6 mmol) (rac)-8-methoxy-6-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3- d]azepine are placed in a mixture of 1.5 ml glacial acetic acid and 1.5 ml chloroform and combined with 106 mg (0.6 mmol) N-bromosuccinimide. The mixture is stirred for three hours at RT, then 20 mg N-bromosuccinimide are added and the mixture is stirred for a further hour at RT. Then the mixture is mixed with water and extracted twice with ethyl acetate. The extract is discarded. The aqueous phase is made alkaline and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate and evaporated down i.vaα. Rt value: 1.01 min (Method B) Ci ₀ Hi ₄ BrNOS (276.19) Mass spectrum:(M+H) ⁺ = 276/278 (bromine isotopes)

(e) methyl (rac)- 8-methoxy-6-methyl-5.67.8-tetrahvdro-4H-thienor2.3- diazepine-2-carboxylate

In an inertised autoclave 137 mg (0.5 mmol) (rac)-2-bromo-8-methoxy-6-methyl- 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine in a mixture of 0.27 μmol 1 ,1 '-bis- (diphenylphosphino)-ferrocene-dichloropalladium(ll) complex are combined with DCM and with 500 μl (3.6 mmol) TEA. Then 5 bar carbon monoxide pressure are applied and the mixture is shaken for 4 hours at 80 ⁰ C. The mixture is left to cool and filtered to remove the catalyst mixture. The filtrate is evaporated down i. vac. The residue thus obtained is dissolved in EE, combined with 1 N HCI and extracted twice with EE. The aqueous phase is made basic with 2N NaOH while being cooled and extracted twice with EE. The organic phase is dried on sodium sulphate and evaporated down. Rt value: 0.9 min (Method B) Ci ₂ Hi ₇ NO ₃ S (255.33) Mass spectrum:(M+H) ⁺ = 256

(f) (rac)-8-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1 azepine-2- carboxylic acid

Prepared analogously to Example 21 e from (rac)-methyl 8-methoxy-6-methyl- 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-2-carboxylate. Rt value: 0.58 min (Method B) C _H H _I5 NO ₃ S (241.31 )

(g) (8f?S)-8-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d 1azepine-2- carboxylic acid [(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethvH-amide (as the trifluoroacetate)

Prepared analogously to Example 14 h from (rac)-8-methoxy-6-methyl-5, 6,7,8- tetrahydro-4H-thieno[2,3-d]azepine-2-carboxylic acid and (R)-1-(5-chloro-1 H- benzimidazol-2-yl)-2-methoxy-ethylamine. Rt value: 1.03 min (Method B) C21 H ₂ SiCIN ₄ O ₃ S x C ₂ HF ₃ O ₂ (562.99) Mass spectrum:(M+H) ⁺ = 449/451 (chlorine isotopes)

Example 41

(4f?S)-4,6-dimethyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1az epine-2-carboxylic acid[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl1-amide

Chiral

(a) (rac)-4,6-dimethyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1azepin e

Prepared analogously to Example 40 c from (rac)-ethyl-4-methyl-4, 5,7,8- tetrahydro-thieno[2,3-d]azepine-6-carboxylate (prepared analogously to US 2006/003990). Rt value: 0.88 min (Method B) Mass spectrum:(M+H) ⁺ = 182

(b) (rac)-2-bromo-4,6-dimethyl-5,6,7,8-tetrahvdro-4H-thienor2,3- d1azepine

Prepared analogously to Example 40 d from (rac)-4,6-dimethyl-5, 6,7,8- tetrahydro-4H-thieno[2,3-d]azepine.

Rt value: 1.08 min (Method B) Mass spectrum:(M+H) ⁺ = 260/262 (bromine isotopes)

(c) methyl (rac)-4,6-dimethyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1azepin e-2- carboxylate

Prepared analogously to 40 e from (rac)-2-bromo-4,6-dimethyl-5, 6,7,8- tetrahydro-4H-thieno[2,3-d]azepine. Purification by flash chromatography on silica gel, (eluant: DCM/MeOH 95:5).

Rt value: 0.88 min (Method B)

Ci ₂ Hi ₇ NO ₂ S (239.33) Mass spectrum:(M+H) ⁺ = 240

(d) (rac)-4,6-dimethyl-5,6,7,8-tetrahydro-4H-thienor2,3-d1azepin e-2-carboxylic acid

Prepared analogously to Example 21 e from methyl (rac)-4,6-dimethyl-5, 6,7,8- tetrahydro-4H-thieno[2,3-d]azepine-2-carboxylate. Rt value: 0.66 min (Method B) C11H15NO2S (225.31 )

(e) (4f?S)-4,6-dimethyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1azepi ne-2-carboxylic acid [(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethvH-annide

Prepared analogously to 14 h from (rac)-4,6-dimethyl-5,6,7,8-tetrahydro-4H- thieno[2,3-d]azepine-2-carboxylic acid and (R)-1 -(5-chloro-1 H-benzimidazol-2- yl)-2-methoxy-ethylamine.

Rt value: 0.96 min (Method B)

C _2I H ₂₅ CIN ₄ O ₂ S (432.97)

Mass spectrum: (M +H) ⁺ = 432/434 (chlorine isotopes)

Example 42

(8f?S)-6,8-dimethyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1az epine-2-carboxylic acid[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl1-amide

Chiral

(a) (rac)-6,8-dimethyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1azepin e

Prepared analogously to Example 40 c from ethyl (rac)-2-bromo-8-methyl-

4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylate (prepared analogously to

US 2006/003990).

Rt value: 0.88 min (Method B)

Mass spectrum:(M+H) ⁺ = 182

(b) (rac)-2-bromo-6,8-dimethyl-5,6,7,8-tetrahvdro-4H-thienor2,3- d1azepine

Prepared analogously to Example 40 d from (rac)-6,8-dimethyl-5, 6,7,8- tetrahydro-4H-thieno[2,3-d]azepine. Rt value: 1.12 min (Method B) Mass spectrum:(M+H) ⁺ = 260/262 (bromine isotopes)

(c) methyl (rac)-6,8-dimethyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1azepin e-2- carboxylate

Prepared analogously to 40 e from (rac)-2-bromo-6,8-dimethyl-5, 6,7,8- tetrahydro-4H-thieno[2,3-d]azepine. Purification by flash chromatography on silica gel, (eluant: DCM/MeOH 95:5). Rt value: 0.9 min (Method B) Ci ₂ Hi ₇ NO ₂ S (239.33) Mass spectrum:(M+H) ⁺ = 240

(d) (rac)-6,8-dimethyl-5,6,7,8-tetrahydro-4H-thienor2,3-d1azepin e-2-carboxylic acid

Prepared analogously to Example 21 e from methyl (rac)-6,8-dimethyl-5, 6,7,8- tetrahydro-4H-thieno[2,3-d]azepine-2-carboxylate. Rt value: 0.66 min (Method B) )

(e) (8f?S)-6,8-dimethyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1azepi ne-2- carboxylic acid [(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl1-amide

Prepared analogously to 14 h from (rac)-6,8-dimethyl-5,6,7,8-tetrahydro-4H- thieno[2,3-d]azepine-2-carboxylic acid and (1R)-1 -(5-chloro-1 H-benzimidazol-2- yl)-2-methoxy-ethylamine. Rt value: 0.96 min (Method B)

C _2I H ₂₅ CIN ₄ O ₂ S (432.97)

Mass spectrum: (M +H) ⁺ = 433/435 (chlorine isotopes)

Example 44

(5f?S)-5.6-dimethyl-4,5,6,7-tetrahvdro-thienor2,3-cipyrid ine-2-carboxylic acid [(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl1-amide

(a) 2-(2-nitro-propenyl)-thiophene

5.0 g (44.6 mmol) 3-formylthiophene are dissolved together with 8.9 ml (124.8 mmol) nitroethane, 5.3 ml (53.5 mmol) butylamine in 25.1 ml glacial acetic acid

(454.7 mmol) and heated to 80 ⁰ C. After two hours the mixture is cooled and the precipitate formed is suction filtered and washed with plenty of water. The crude product thus obtained is dissolved in ethyl acetate, dried on sodium sulphate and evaporated down i.vaα.

Rt value: 1.48 min (Method B)

C ₇ H ₇ NO ₂ S (169.20) Mass spectrum: (M+H) ⁺ = 170

(b) 1 -methyl-2-thiophen-2-yl-ethylamine

A solution of 3.7 g (21.9 mmol) 2-(2-nitro-propenyl)-thiophene in 50 ml THF is added dropwise to a suspension of 4.1 g (109.3 mmol) lithium aluminium hydride in 150 ml THF. After the addition has ended the mixture is refluxed. After 1.5 hours it is cooled to RT and stirred for another 16 hours. Then the mixture is slowly combined with 10 ml sat. sodium sulphate solution and filtered

through Celite. The filtrate thus obtained is evaporated down i. vac. Rt value: 0.52 min (Method E) C ₇ HnNS (141.23) Mass spectrum:(M+H) ⁺ = 142

(c) N-(1 -methyl-2-thiphen-2-yl-ethyl)-formamide

A solution of 5.9 g (33.4 mmol) 1 -methyl-2-thiophen-2-yl-ethylamine in 34.8 ml (417.7 mmol) ethyl formate is refluxed for 16 hours. Then the mixture is cooled and evaporated to dryness i.vaα. Rt value: 1.00 min (Method B) C ₈ HnNOS (169.25) Mass spectrum:(M+H) ⁺ = 170

(d) 5-methyl-4,5-dihvdro-thieno[2,3-c1-pyridine

A solution of 6.6 g (33.1 mmol) N-(1 -methyl-2-thiphen-2-yl-ethyl)-formamide in 200 ml acetonitrile is cooled in the ice bath and slowly combined with a solution of 6.1 ml (66.3 mmol) phosphorus oxychloride in 50 ml acetonitrile. The mixture is stirred first of all for a further three hours in the ice bath and then for 16 hours at RT. Then the mixture is poured onto 200 ml of water, made alkaline with 9 g solid sodium hydroxide and extracted three times with ethyl acetate. The combined organic phases are combined with activated charcoal and sodium sulphate, filtered and evaporated down i.vaα. Rt value: 0.84 min (Method I) C ₈ H ₉ NS (151.23) Mass spectrum:(M+H) ⁺ = 152

(e) 5.6-dimethyl-4,5-dihvdro-thieno[2,3-cipyridinium iodide

A solution of 4.0 g (26.5 mmol) 5-methyl-4,5-dihydro-thieno[2,3-c]-pyridine in 250 ml acetonitrile is combined at RT with 16.5 ml (264.5 mmol) methyl iodide and stirred for 30 min. The precipitate formed is filtered off and washed with

acetonitrile.

Rt value: 0.29 min (Method E) C ₉ Hi ₂ NSI (293.17) Mass spectrum: (M) ⁺ = 166

(f) (rac)-5.6-dinnethyl-4,5,6,7-tetrahvdro-thienor2,3-cipyπdine (as the trifluoroacetate salt)

A mixture of 3.4 g (9.3 mmol) 5,6-dimethyl-4,5-dihydro-thieno[2,3-c]pyridinium iodide in 30 ml of methanol is combined batchwise with 709 mg (18.6 mmol) sodiumborohydride at ice bath temperature. The reaction mixture is slowly heated to RT and stirred for 16 hours. Then the mixture is cooled again and combined with 5 ml hydrochloric acid in dioxane (4N). The mixture is evaporated down i.vac. and purified by preparative HPLC (eluant water/acetonitrile/TFA).

Rt value: 0.69 min (Method B) C ₉ H ₁₃ NS x CF ₃ CO ₂ H (167.27) Mass spectrum: (M) ⁺ = 168

(g) (rac)-2-bromo-5,6-dimethyl-4,5,6,7-tetrahydro-thienor2,3-cip yhdine

1.0 g (3.6 mmol) (rac)-5,6-dimethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (as the trifluoroacetate salt) are dissolved in 60 ml of water and combined with a solution of 1.0 g (8.5 mmol) potassium bromide and 182 μl (3.6 mmol) bromine in 20 ml of water at ice bath temperature. The mixture is stirred for a further 2.5 hours in the ice bath and then extracted twice with 100 ml ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, then dried on sodium sulphate and evaporated down i.vac. The crude product thus obtained is purified by chromatography on silica gel (eluant DCM/methanol 50:1 ).

Rt value: 0.99 min (Method B)

Mass spectrum: (M+H) ⁺ = 246/248 (bromine isotopes)

(h) methyl (rac)-5,6-dimethyl-4,5,67-tetrahvdro-thieno[2,3-cipyridine-2 - carboxylate

Prepared analogously to Example 40 c from (rac)-2-bromo-4-5,6-dimethyl- 4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine. Rt value: 0.63 min (Method E) C _H H _I5 NO ₂ S (225.31 ) Mass spectrum: (M+H) ⁺ = 226

(i) (rac)-5,6-dimethyl-4,5,6,7-tetrahvdro-thienor2,3-cipyridine- 2-carboxylic acid

Prepared analogously to Example 21 e from methyl (rac)-5,6-dimethyl-4, 5,6,7- tetrahydro-thieno[2,3-c]pyridine-2-carboxylate. Rt value: 0.32 min (Method B) Mass spectrum:(M+H) ⁺ = 212

G) (5f?S)-5,6-dimethyl-4,5,6,7-tetrahvdro-thienor2,3-cipyridine -2-carboxylic acid [(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl1-amide

Prepared analogously to Example 14 h from (rac)-5,6-dimethyl-4, 5,6,7- tetrahydro-thieno[2,3-c]pyridine-2-carboxylic acid and (R)-1 -(5-chloro-1 H- benzimidazol-2-yl)-2-methoxy-ethylamine. Rt value: 0.63 min (Method E) C ₂₀ H ₂₃ CIN ₄ O ₂ S (418.94) Mass spectrum:(M+H) ⁺ = 419/421 (chlorine isotopes)

Example 45

(4f?S)-4-methoxy-6-nnethyl-4,5,6,7-tetrahvdro-thienor2,3- cipyridine-2-carboxylic acid [(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethvH-amide

(a) ethyl r(thiophen-2-ylnnethyl)-annine1-acetate

10 g (88.4 mmol) C-thiophen-2-yl-methylannine are dissolved in 450 ml DCM and 18.6 ml (88.4 mmol) ethyl-glyoxylat in toluene (47%) and 535 μl (9.4 mmol) cone, acetic acid are added. The reaction mixture is stirred for 10 min at RT and then a total of 24 g (113 mmol) sodium triacetoxyborohydride are added batchwise and the mixture is stirred for 1.5 h at RT. The reaction solution is evaporated down i. vac.

Rt value: 0.78 min (Method B)

C ₉ Hi ₃ NO ₂ S (199.27)

Mass spectrum:(M+H) ⁺ = 200

(b) ethyl (ethoxycarbonyl-thiophen-2-ylmethyl-amine)-acetate

17.7 g (71 mmol) ethyl [(thiophen-2-ylmethyl)-amine]-acetate are dissolved in 250ml THF and 250 ml of water. 22.5 g (268 mmol) sodium hydrogen carbonate are added batchwise and then 11.2 ml (118 mmol) chloroethyl formate are added dropwise. The reaction mixture is stirred for 1.5 h at RT. Then ethyl acetate is added and the phases are separated. The aqueous phase is

extracted twice with ethyl acetate. The organic phases are combined, dried on sodium sulphate and evaporated down i.vaα. The residue thus obtained is purified by flash chromatography on silica gel (eluant: cyclohexane/ethyl acetate 8:2). Rt value: 1.48 min (Method B) Ci ₂ Hi ₇ NO ₄ S (271.33) Mass spectrum:(M+H) ⁺ = 272

(c) (ethoxycarbonyl-thiophen-2-ylmethyl-amine)-acetic acid

13.9 g (51.3 mmol) ethyl (ethoxycarbonyl-thiophen-2-ylmethyl-amine)-acetate are dissolved in 170 ml of ethanol, combined with 170 ml (170 mmol) 1 N NaOH and stirred for 40 min at RT. The reaction mixture is concentrated, the residue is acidified with cone. HCI to pH = 1 and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate and evaporated down i. vac. Rt value: 1.20 min (Method B) Ci ₀ Hi ₃ NO ₄ S (243.28) Mass spectrum:(M+H) ⁺ = 244

(d) ethyl chlorocarbonylmethyl-thiophen-2-ylmethyl-carbamate

12.0 g (49.1 mmol) (ethoxycarbonyl-thiophen-2-ylmethyl-amine)-acetic acid are dissolved in 250 ml DCM and one drop of DMF. Then 6.8 ml (78 mmol) oxalyl chloride are added and the mixture is stirred for 12 hours at RT. Then the reaction mixture is evaporated down i.vaα.

(e) ethyl 4-oxo-4,7-dihvdro-5H-thieno[2,3-cipyridine-6-carboxylate

12.9 g (70% purity, 34.4 mmol) ethyl chlorocarbonylmethyl-thiophen-2-ylmethyl- carbamate are dissolved in 350 ml 1 ,2-dichloroethane and 10.1 g (74.3 mmol) aluminium trichloride are added batchwise. The mixture is stirred for two hours

at RT. Then the reaction mixture is poured onto ice water and extracted three times with 1 ,2-dichloroethane. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i.vaα. The residue thus obtained is purified by flash chromatography on silica gel (eluant: cyclohexane/ethyl acetate 7:3). Rt value: 1.2 min (Method B) C ₁₀ H ₁₁ NO ₃ S (225.27) Mass spectrum:(M+H) ⁺ = 226

(f) ethyl (rac)-4-hvdroxy-4,7-dihydro-5H-thienor2,3-cipyridine-6-carbo xylate

Prepared analogously to Example 40 a from ethyl 4-oxo-4,7-dihydro-5H- thieno[2,3-c]pyridine-6-carboxylate. Rt value: 1.08 min (Method B)

Mass spectrum:(M+H) ⁺ = 228

(g) ethyl (rac)-4-methoxy-4,7-dihydro-5H-thienor2,3-cipyridine-6-carbo xylate

495 mg (2.18 mmol) ethyl (rac)-4-hydroxy-4,7-dihydro-5H-thieno[2,3-c]pyridine- 6-carboxylate are dissolved in 5 ml THF and combined batchwise with 180 mg (4.5 mmol) sodium hydride. The mixture is stirred for 15 min at RT and then 200 μl (3.2 mmol) methyl iodide are added. The reaction mixture is stirred for twelve hours at RT gerϋhrt, poured onto ice water and extracted three times with ethyl acetate. The organic phases are combined, dried on sodium sulphate, filtered off and evaporated down i.vaα. Rt value: 1.28 min (Method B) ) Mass spectrum:(M+H) ⁺ = 242

(h) (rac)-4-methoxy-6-methyl-4,5,6,7-tetrahvdro-thieno[2,3-cipyh dine

Prepared analogously to Example 40 c from ethyl (rac)-4-methoxy-4,7-dihydro-

5H-thieno[2,3-c]pyridine-6-carboxylate. Rt value: 0.4 min (Method B) C ₉ Hi ₃ NOS (183.27) Mass spectrum: (M +H) ⁺ = 184

(i) (rac)-2-bromo-4-methoxy-6-methyl-4,5,6,7-tetrahvdro-thieno[2 ,3-cipyridine

310 mg (1.7 mmol) (rac)-4-methoxy-6-methyl-4,5,6,7-tetrahydro-thieno[2,3- c]pyridine are combined with 10 ml of water and 5 ml THF, cooled in the ice bath, and a solution of 100 μl (1.95 mmol) bromine and 480 mg (4 mmol) potassium bromide in 10 ml of water is added dropwise. The reaction mixture is stirred for 10 min in the ice bath, heated to RT and stirred for two hours. Then the same amount again of bromine and potassium bromide is added and the mixture is stirred for a further hour at RT. DCM is added and the phases are separated using a phase separation cartridge. The organic phase is evaporated down i. vac. The residue thus obtained is purified by flash chromatography on silica gel (eluant: petroleum ether/ethyl acetate 8:2). Rt value: 0.74min (Method B) C ₉ Hi ₂ BrNOS (262.17) Mass spectrum:(M+H) ⁺ = 262/264 (bromine isotopes)

(j) methyl (rac)-4-methoxy-6-methyl-4,5,6,7-tetrahvdro-thieno[2,3-cipyr idine-2- carboxylate

Prepared analogously to Example 40 e from (rac)-2-bromo-4-methoxy-6- methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine.

Rt value: 0.78min (Method B) )

Mass spectrum:(M+H) ⁺ = 242

(k) (rac)-4-methoxy-6-methyl-4,5,6,7-tetrahvdro-thieno[2,3-cipyr idine-2- carboxylic acid

Prepared analogously to Example 21 e from methyl (rac)-4-methoxy-6-methyl- 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-2-carboxylate. Rt value: 0.24min (Method B) Mass spectrum:(M+H) ⁺ = 228

(I) (4f?S)-4-methoxy-6-methyl-4,5,6,7-tetrahvdro-thienor2,3-cipy ridine-2- carboxylic acid-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethvH-amide

Prepared analogously to 14 h from (rac)-4-methoxy-6-methyl-4, 5,6,7- tetrahydro-thieno[2,3-c]pyridine-2-carboxylic acid and (R)-1 -(5-chloro-1 H- benzimidazol-2-yl)-2-methoxy-ethylamine.

Rt value: 0.62min (Method E)

C ₂₀ H ₂₃ CIN ₄ O ₃ S (434.94) Mass spectrum:(M+H) ⁺ = 435/437 (chlorine isotopes)

Example 47

(4f?S)-4-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thienor2, 3-d1azepine-2- carboxylic acid-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl1-amide

(a) (rac)-4-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thieno[2,3-d1 azepine

Prepared analogously to Example 40 c from ethyl (rac)-4-methoxy-4, 5,7,8- tetrahydro-thieno[2,3-d]azepine-6-carboxylate (prepared analogously to US 2006/0003990).

Rt value: 0.97 min (Method B)

Mass spectrum: (M +H) ⁺ = 198

(b) (rac)-2-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thien or2,3- diazepine

Prepared analogously to Example 40 d from (rac)-4-methoxy-6-methyl-5, 6,7,8- tetrahydro-4H-thieno[2,3-d]azepine. Rt value: 1.04 min (Method B) Ci ₀ Hi ₄ BrNOS (276.19) Mass spectrum:(M+H) ⁺ = 276/278 (bromine isotopes)

(c) methyl (rac)-4-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thienor2,3- diazepine-2-carboxylate

Prepared analogously to Example 40 e from (rac)-2-bromo-4-methoxy-6- methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine. Rt value: 0.87 min (Method B) Ci ₂ Hi ₇ NO ₃ S (255.33)

Mass spectrum:(M+H) ⁺ = 256

(d) (rac)-4-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1 azepine-2- carboxylic acid

Prepared analogously to Example 21 e from methyl (rac)-4-methoxy-6-methyl- 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-2-carboxylate. Rt value: 0.55 min (Method B) ) Mass spectrum:(M+H) ⁺ = 242

(e) (4f?S)-4-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d 1azepine-2- carboxylic acid-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl1-amide

Prepared analogously to Example 14 h from (rac)-4-methoxy-6-methyl-5, 6,7,8- tetrahydro-4H-thieno[2,3-d]azepine-2-carboxylic acid and (R)-1-(5-chloro-1 H- benzimidazol-2-yl)-2-methoxy-ethylamine. Rt value: 0.63 min (Method E) C _2I iH ₂₅ CIN ₄ O ₃ S (448.97) Mass spectrum:(M+H) ⁺ = 449/451 (chlorine isotopes)

Example 48

(f?)-5-methyl-4,5,6,7-tetrahvdro-pyrazolo[1 ,5-aipyrazine-2-carboxylic acid-[1 -(5- chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl1-amide

(a) δ-benzyl-2-ethyl 6,7-dihvdro-4H-pyrazolo[1 ,5-aipyrazin-2,5-dicarboxylate

Prepared analogously to A. M. Venkatesan et al., J. Med. Chem. 2006, 49, 4623 starting from 1 -benzyl piperazine-1 ,3-dicarboxylate. Rt value: 1.41 min (Method B) Ci ₇ Hi ₉ N ₃ O ₄ (329.35)

Mass spectrum:(M+H) ⁺ = 330

(b) 2-ethyl 4,5,6,7-tetrahvdro-pyrazolo[1 ,5-aipyrazine-2-carboxylate

200.0 mg (0.7 mmol) 5-benzyl-2-ethyl 6,7-dihydro-4H-pyrazolo[1 ,5-a]pyrazin- 2,5-dicarboxylate are dissolved in 20 ml of methanol, combined with 100 mg palladium/charcoal 10% and hydrogenated at 3 bar hydrogen pressure and RT for 1.5 hours. Then the catalyst is filtered off and the filtrate is evaporated down i.vaα.

Rt value: 0.49 min (Method B)

C ₉ Hi ₃ N ₃ O ₂ (195.22)

Mass spectrum: (M+H) ⁺ = 196

(c) 2-ethyl 5-methyl-4,5,6,7-tetrahvdro-pyrazolo[1 ,5-aipyrazine-2-carboxylate (as the trifluoroacetate salt)

130 mg (0.57 mmol) 2-ethyl 4,5,6,7-tetrahydro-pyrazolo[1 ,5-a]pyrazine-2- carboxylate, 250 μl (3.34 mmol) formalin solution (37% in water) and 1 ml (26.5 mmol) formic acid are combined and stirred for 3h at 70 ⁰ C. The reaction mixture is evaporated down i.vac. and the residue is purified by preparative HPLC. Rt value: 0.56 min (Method B) C10H15N3O2 x CF ₃ CO ₂ H (323.27) Mass spectrum: (M+H) ⁺ = 210

(d) 5-methyl-4,5,6,7-tetrahvdro-pyrazolo[1 ,5-aipyrazine-2-carboxylic acid

Prepared analogously to Example 21 e starting from 2-ethyl 5-methyl-4, 5,6,7- tetrahydro-pyrazolo[1 ,5-a]pyrazine-2-carboxylate (as the trifluoroacetate salt) Rt value: 0.1 min (Method E) C ₈ HnN ₃ O ₂ (181.19) Mass spectrum: (M+H) ⁺ = 182

(e) (f?)-5-methyl-4,5,6,7-tetrahvdro-pyrazoloπ ,5-aipyrazine-2-carboxylic acid-π -fδ-chloro-I H-benzimidazol^-vD^-methoxy-ethyli-amide

Prepared analogously to Example 14h starting from 5-methyl-4, 5,6,7- tetrahydro-pyrazolo[1 ,5-a]pyrazine-2-carboxylic acid and (R)-I -(5-chloro-1 H- benzimidazol-2-yl)-2-methoxy-ethylamine. Rt value: 0.89 min (Method B) Ci ₈ H ₂ ICIN ₆ O ₂ (388.85) Mass spectrum: (M+H) ⁺ = 389/391 (chlorine isotopes)

Example 49

(/^-Z-methyl-ey.δ.g-tetrahvdro-δH-imidazoH ^-aiH λIdiazepine^-carboxylic acid-ri -(5-chloro-1 H-benzinnidazol-2-yl)-2-ιinethoxy-ethyl1-annide

(a) benzyl 5-oxo-H ,41diazepine-1 -carboxylate

4.8 g (42.0 mmol) [1 ,4]diazepin-5-one are dissolved in 60 ml DCM and combined successively with 11.0 ml (83.9 mmol) thethylamine and 6.8 ml (46.2 mmol) benzyl chloroformate at ice bath temperature. The mixture is heated to RT and three hours at this temperature. Then the mixture is concentrated and mixed with water. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i.vaα. The crude product is by column chromatography on silica gel (eluant DCM/MeOH 95:5 -> 90:10). Rt value: 1.06 min (Method B) Ci ₃ Hi ₆ N ₂ O ₃ (248.28)

Mass spectrum: (M+H) ⁺ = 249

(b) benzyl 5-imino-[1 ,41diazepine-1-carboxylate

1.0 g (4.0 mmol) benzyl 5-oxo-[1 ,4]diazepine-1 -carboxylate are suspended in 1.0 ml (10.6 mmol) dimethylsulphate, stirred at 90 ⁰ C for two hours and after cooling dissolved in 10 ml (20 mmol) ammonia solution (2N in methanol). The mixture is stirred for 3.5 hours at RT and then evaporated to dryness. Rt value: 1.02 min (Method B)

Ci ₃ Hi ₇ N ₃ O ₂ (247.29)

Mass spectrum: (M+H) ⁺ = 248

(c) benzyl 2-formyl-5,6,8,9-tetrahvdro-iιinidazo[1 ,2-aiH ,41diazepine-7- carboxylate

1.0 g (4.0 mmol) benzyl 5-imino-[1 ,4]diazepine-1 -carboxylate are dissolved in 3 ml of ethanol and combined with 2.8 ml (8.1 mmol) sodium methoxide solution (30% in methanol). A solution of 843 mg (4.4 mmol) 2-bromo-3-isopropoxy- propenal in 3 ml of ethanol is added and once the addition has ended the mixture is refluxed for 1.5 hours. Then the mixture is concentrated, the residue is dissolved in 6 ml chloroform and 560 μl (4.0 mmol) triethylamine are added. The reaction mixture is refluxed for 16 hours, then cooled, evaporated down and purified by flash chromatography on silica gel (eluant DCM/methanol 20:1 ). A still impure product fraction is obtained which is purified by preparative HPLC (eluant water/acetonitrile/conc. ammonia). Rt value: 0.63 min (Method E) Ci ₆ Hi ₇ N ₃ O ₃ (299.32) Mass spectrum: (M+H) ⁺ = 300

(d) ammonium-5,6,8,9-tetrahvdro-imidazori ,2-aiπ ,41diazepine-7-carboxylate benzyl-2-carboxylate

107.0 mg (0.36 mmol) benzyl 2-formyl-5,6,8,9-tetrahydro-imidazo[1 ,2- a][1 ,4]diazepine-7-carboxylate are dissolved in 1 ml DMSO and combined with a solution of 85 mg (0.55 mmol) sodium dihydrogen sulphate-dihydrate in 0.5 ml of water and cooled in the ice bath. 160 mg (1.4 mmol) sodium chlorate are dissolved in 0.5 ml of water and slowly added dropwise to the educt solution.

The mixture is stirred for 30 min and filtered to remove insoluble matter. The filtrate is purified by preparative HPLC (water/acetonitrile/conc. ammonia).

Rt value: 0.41 min (Method E)

Ci ₆ Hi ₇ N ₃ O ₄ x NH ₃ (315.33)

Mass spectrum: (M+H) ⁺ = 316

(e) 7-benzyl-2-methyl 5,6,8,9-tetrahvdro-innidazo[1 ,2-aiH ,41diazepine-2,7- dicarboxylate

68.0 mg (0.21 mmol) ammonium-5,6,8,9-tetrahydro-imidazo[1 ,2- a][1 ,4]diazepine-7-carboxylate benzyl-2-carboxylate are dissolved in 1.5 ml of methanol and combined with 40 μl (0.6 mmol) thionyl chloride in the ice bath. The ice bath is taken away and after 30 minutes the mixture is refluxed for one day. A further 100 μl thionyl chloride are added twice more and the mixture is heated for another day. Then the reaction mixture is concentrated i.vac. and further reacted as the crude product. Rt value: 1.15 min (Method B) Ci ₇ Hi ₉ N ₃ O ₄ (329.35)

(f) methyl 6,7,8,9-tetrahvdro-5H-imidazo[1 ,2-aiH ,41diazepine-2-carboxylate

Prepared analogously to Example 48 b from 7-benzyl-2-methyl 5,6,8,9- tetrahydro-imidazo[1 ,2-a][1 ,4]diazepine-2.7-dicarboxylate. Rt value: 0.36 min (Method E) C ₉ Hi ₃ N ₃ O ₂ (195.22)

Mass spectrum: (M+H) ⁺ = 196

(g) methyl 7-methyl-6,7,8,9-tetrahvdro-5H-imidazo[1 ,2-aiH ,41diazepine-2- carboxylate (as the trifluoroacetate salt)

Prepared analogously to Example 48 c from methyl 6,7,8,9-tetrahydro-5H- imidazo[1 ,2-a][1 ,4]diazepine-2-carboxylate. Rt value: 0.2 min (Method B) C10H15N3O2 x C ₂ HF ₃ O ₂ (323.27) Mass spectrum: (M+H) ⁺ = 210

(h) 7-methyl-6,7,8,9-tetrahvdro-5H-imidazori ,2-aiπ ,41diazepine-2-carboxylic acid

Prepared analogously to Example 21 e from methyl 7-methyl-6, 7,8,9- tetrahydro-5H-imidazo[1 ,2-a][1 ,4]diazepine-2-carboxylate (as the trifluoroacetate salt). Rt value: 0.16min (Method B) C ₉ Hi ₃ N ₃ O ₂ (195.22) Mass spectrum:(M+H) ⁺ = 196

(i) (f?)-7-methyl-6,7,8,9-tetrahvdro-5H-imidazori ,2-aiπ ,41diazepine-2- carboxylic acid-[1 -(5-chloro-1 H-benzoimidazol-2-yl)-2-methoxy-ethvH-amide

Prepared analogously to Example 14 h from 7-methyl-6,7,8,9-tetrahydro-5H- imidazo[1 ,2-a][1 ,4]diazepine-2-carboxylic acid and (R)-1 -(5-chloro-1 H- benzoimidazol-2-yl)-2-methoxy-ethylamine. Rt value: 0.88min (Method B) Ci ₉ H ₂₃ CIN ₆ O ₂ (402.88) Mass spectrum: (M+H) ⁺ = 403/405 (chlorine isotopes)

Example 52

7-methoxymethyl-6-methyl-4,5,6,7-tetrahvdro-thienor2,3-ci pyridine-2-carboxylic acid [1 -(5-chloro-1 H-benzoimidazol-2-yl)-2-methoxy-ethvH-amide

(a) 2-methoxy-λ/-(2-thiophen-3-yl -ethyl Vacetamide

10.0 g (78.6 mmol) 2-thiophen-3-yl-ethylamine are dissolved in 120 ml THF and combined successively with 7.9 ml (86.5 mmol) methoxyacetic acid chloride and a solution of 21.9 ml (157.2 mmol) thethylamine in 30 ml THF at -10 ⁰ C. The

mixture is heated to RT and stirred for one hour. Then it is acidified with 2N hydrochloric acid and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i.vaα. Rt value: 1.01 min (Method B) C ₉ Hi ₃ NO ₂ S (199.27) Mass spectrum: (M+H) ⁺ = 200

(b) 7-methoxymethyl-4,5-dihvdro-thieno[2,3-cipyridine

15.6 g (78.3 mmol) 2-methoxy-λ/-(2-thiophen-3-yl-ethyl)-acetamide are dissolved in 350 ml chloroform and while cooling with an ice bath combined with 35.8 ml (391.4 mmol) phosphorus oxychlohde. The ice bath is taken away and the mixture is refluxed for 5 hours. Then the reaction mixture is carefully added to 600 ml warm sodium hydroxide solution (4N) and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i.vaα. The crude product is purified by flash chromatography on silica gel (eluant DCM/methanol 98:2 -> 95:5). Rt value: 0.59 min (Method B) C ₉ HnNOS (181.26) Mass spectrum: (M+H) ⁺ = 182

(c) 7-methoxymethyl-4,5,6,7-tetrahvdro-thienor2,3-cipyridine

1.0 g (5.5 mmol) 7-methoxymethyl-4,5-dihydro-thieno[2,3-c]pyhdine are dissolved in 10 ml of methanol and combined batchwise with 0.4 g (11.0 mmol) sodiumborohydride while cooling with an ice bath. The ice bath is taken away and the mixture is stirred at RT for two hours. Then the reaction mixture is evaporated down and reacted further as the crude product. Rt value: 0.75 min (Method B) C ₉ Hi ₃ NOS (183.27) Mass spectrum: (M+H) ⁺ = 184

(d) 7-methoxynnethyl-6-nnethyl-4,5,6,7-tetrahvdro-thienor2,3-cip yπdine

Prepared analogously to 48 c from 7-methoxymethyl-4,5,6,7-tetrahydro- thieno[2,3-c]pyridine.

Rt value: 0.78 min (Method B)

Mass spectrum: (M +H) ⁺ = 198

(e) 2-bromo-7-methoxymethyl-6-methyl-4,5,6,7-tetrahvdro-thienor2 ,3-cipyridine

Prepared analogously to Example 45 i from 7-methoxymethyl-6-methyl-4, 5,6,7- tetrahydro-thieno[2,3-c]pyhdine. Rt value: 1.04 min (Method B) Ci ₀ Hi ₄ BrNOS (276.19)

Mass spectrum:(M+H) ⁺ = 276/278 (bromine isotopes)

(f) methyl 7-methoxymethyl-6-methyl-4,5,6,7-tetrahydro-thienor2,3-cipyh dine-2- carboxylate

Prepared analogously to Example 40 e from 2-bromo-7-methoxymethyl-6- methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine.

Rt value: 0.87 min (Method B)

Ci ₂ Hi ₇ NO ₃ S (255.33) Mass spectrum:(M+H) ⁺ = 256

(g) 7-methoxymethyl-6-methyl-4,5,6,7-tetrahvdro-thieno[2,3-cipyr idine-2- carboxylic acid

Prepared analogously to Example 21 e from methyl 7-methoxymethyl-6-methyl- 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-2-carboxylate. Rt value: 0.58 min (Method B) C11H15NO3S (241.31 )

Mass spectrum: (M +H) ⁺ = 242

(h) 7-methoxymethyl-6-methyl-4,5,6,7-tetrahvdro-thieno[2,3-cipyr idine-2- carboxylic acid [1 -(5-chloro-1 H-benzoimidazol-2-yl)-2-methoxy-ethvH- amide

Prepared analogously to Example 14 h from 7-methoxymethyl-6-methyl- 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-2-carboxylic acid and 1-(5-chloro-1 H- benzoimidazol-2-yl)-2-methoxy-ethylamine. Rt value: 0.99 min (Method B) C _2I H ₂₅ CIN ₄ O ₃ S (448.97) Mass spectrum:(M+H) ⁺ = 449/451 (chlorine isotopes)

Example 53 (4f?)-4-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1 azepine-2- carboxylic acid[(1 f?)-1 -(5-chloro-1 H-benzoimidazol-2-yl)-2-methoxy-ethyl1-amide

(a) ethyl (/?)-4-hvdroxy-4,5,7,8-tetrahvdro-thieno[2,3-d1azepine-6-car boxylate

1.1 g (4.6 mmol) ethyl 4-oxo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6- carboxylate (prepared analogously to US 2006/003990) are dissolved in 13 ml DCM and combined with 0.55 ml (0.55 mmol) (R)-2-methyl-CBS- oxazaborolidine (1 M in toluene). The reaction mixture is cooled to -25°C. 5.7 ml (11.5 mmol) borane-dimethylsulphide complex (2 M in THF) dissolved in 18 ml DCM are slowly added dropwise (temp. < -20 ⁰ C). The reaction mixture is then left to stand for two days at -18°C, then decomposed with sat. ammonium

chloride solution and extracted three times with DCM. The combined organic phases are dried on sodium sulphate, filtered and evaporated down. The residue thus obtained is purified by flash chromatography on silica gel (eluant:

DCM/MeOH 95:5). Rt value: 1.15 min (Method B)

C _H H _I5 NO ₃ S (241.31 )

Mass spectrum:(M-H ₂ O+H) ⁺ = 224

A conventional HPLC system with a DAICEL AD-H 250 mm x 4.6 mm chiral column with a particle size of 5 μm is used to determine the enantiomeric excess. Elution is carried out using ethanol + 13 % diethylamine mixture as the liquid phase with a flow rate of 6 ml/min. The following retention times are obtained accordingly for the enantiomers:

(R)-enantiomer (main isomer):

Rt value: 3.29 min (S)-enantiomer:

Rt value: 3.02 min

An enantiomeric excess of 81 % in favour of the desired (R)-enantiomer is determined. The stereochemical attribution is carried out analogously to methods known from the literature for the reagent.

(b) ethyl (/?)-4-methoxy-4,57,8-tetrahvdro-thieno[2,3-d1azepine-6-carb oxylate

Prepared analogously to Example 45 g from ethyl (R)-4-hydroxy-4, 5,7,8- tetrahydro-thieno[2,3-d]azepine-6-carboxylate. Rt value: 1.40 min (Method B) Ci ₂ Hi ₇ NO ₃ S (255.33) Mass spectrum:(M-MeOH+H) ⁺ = 223

(c) (f?)-4-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1a zepine

Prepared analogously to Example 40 c from ethyl (R)-4-methoxy-4, 5,7,8- tetrahydro-thieno[2,3-d]azepine-6-carboxylate.

Rt value: 0.78 min (Method B)

CioHi ₅ NOS (197.30)

Mass spectrum: (M +H) ⁺ = 198

(d) (f?)-2-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thieno r2,3-d1azepine

Prepared analogously to Example 40 d from (R)-4-methoxy-6-methyl-5, 6,7,8- tetrahydro-4H-thieno[2,3-d]azepine. Rt value: 1.03 min (Method B) Ci ₀ Hi ₄ BrNOS (276.19) Mass spectrum:(M+H) ⁺ = 276/278 (bromine isotopes)

(e) methyl (/?)-4-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thieno[2,3-d1a zepine- 2-carboxylate

Prepared analogously to Example 40 e from (R)-2-bromo-4-methoxy-6-methyl-

5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine.

Rt value: 0.86 min (Method B)

Ci ₂ Hi ₇ NO ₃ S (255.33)

Mass spectrum:(M+H) ⁺ = 256

(f) (f?)-4-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1a zepine-2- carboxylic acid

Prepared analogously to Example 21 e from methyl (R)-4-methoxy-6-methyl- 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-2-carboxylate. Rt value: 0.45 min (Method B) ) Mass spectrum:(M+H) ⁺ = 242

(g) (4f?)-4-methoxy-6-methyl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1 azepine-2- carboxylic acid-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl1-amide

Prepared analogously to Example 14 h from (R)-4-methoxy-6-methyl-5,6,7,8-

tetrahydro-4H-thieno[2,3-d]azepine-2-carboxylic acid and (R)-1-(5-chloro-1 H- benzimidazol-2-yl)-2-methoxy-ethylamine. Rt value: 0.63 min (Method E) C _2I H ₂₅ CIN ₄ O ₃ S (448.97) Mass spectrum: (M +H) ⁺ = 449/451 chlorine isotopes

Example 54

(f?)-6-methyl-5,6,7,8-tetrahydro-4H-1 ,6,8a-thaza-azulene-2-carboxylic acid-[1 - (5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethvH-amide (as the trifluoroacetate salt)

Chiral

(a) 6-benzyl-2-ethyl 4,5,7,8-tetrahvdro-1 ,6,8a-triaza-azulene-2,6-dicarboxylate Prepared analogously to Example 48 a. Rt value: 1.45 min (Method B) Ci ₈ H ₂ iN ₃ O ₄ (343.38) Mass spectrum:(M+H) ⁺ = 344

(b) ethyl 5,6,7,8-tetrahvdro-4H-1 ,6,8a-thaza-azulene-2-carboxylate

Prepared analogously to Example 48 b from 6-benzyl-2-ethyl 4,5,7,8- tetrahydro-1 ,6,8a-triaza-azulene-2,6-dicarboxylate. Rt value: 0.73 min (Method B) Ci ₀ Hi ₅ N ₃ O ₂ (209.25) Mass spectrum:(M+H) ⁺ = 210

(c) ethyl 6-methyl-5,67,8-tetrahvdro-4H-1 ,6,8a-triaza-azulene-2-carboxylate (as the trifluoroacetate salt)

Prepared analogously to Example 48 c from ethyl 5,6,7,8-tetrahydro-4H-1 ,6,8a- triaza-azulene-2-carboxylate. Rt value: 0.73 min (Method B) CnHi ₇ N ₃ O ₂ x C ₂ HF ₃ O ₂ (337.30) Mass spectrum:(M+H) ⁺ = 224

(d) G-methyl-δ.Gy.δ-tetrahvdro^H-I .G.δa-triaza-azulene^-carboxylic acid (as the trifluoroacetate salt)

Prepared analogously to Example 21 e from ethyl 6-methyl-5,6,7,8-tetrahydro- 4H-1 ,6,8a-thaza-azulene-2-carboxylate (as the trifluoroacetate salt). Rt value: 0.12 min (Method E) C ₉ Hi ₃ N ₃ O ₂ x C ₂ HF ₃ O ₂ (309.24) Mass spectrum:(M+H) ⁺ = 196

(e) (^-G-methyl-δ.Gy.δ-tetrahvdro^H-I .G.δa-triaza-azulene^-carboxylic acid- [1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethvH-amide (as the trifluoroacetate salt)

Prepared analogously to Example 14 h from 6-methyl-5,6,7,8-tetrahydro-4H- 1 ,6,8a-thaza-azulene-2-carboxylic acid (as the trifluoroacetate salt) and (R)-1-

(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethylamine.

Rt value: 1.07 min (Method E)

Ci ₉ H ₂₃ CIN ₆ O ₂ x C ₂ HF ₃ O ₂ (516.90)

Mass spectrum:(M+H) ⁺ = 403/405 (chlorine isotopes)