CA2666177A1 - Acylaminoimidazoles and acylaminothiazoles - Google Patents

Abstract

The invention relates to acyl aminoimidazoles and acyl aminothiazoles, to a method for producing same and to the use thereof for producing medicaments for the treatment and/or prevention of diseases, in particular cardiovascular diseases, preferably thromboembolic diseases.

Description

BHC 06 1 167-Foreign Countries GH/2008-10-15 Acylaminoimidazoles and acylaminothiazoles The invention relates to acylaminoimidazoles and acylaminothiazoles and to processes for their preparation, and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular disorders, preferably thromboembolic disorders.

Blood coagulation is a protective mechanism of the organism which helps to "sea]" defects in the wall of the blood vessels quickly and reliably. Thus, loss of blood can be avoided or kept to a minimum. Haemostasis after injury of the blood vessels is effected mainly by the coagulation system in which an enzymatic cascade of complex reactions of plasma proteins is triggered.
Numerous blood coagulation factors are involved in this process, each of which factors converts, on activation, the respectively next inactive precursor into its active form.
At the end of the cascade comes the conversion of soluble fibrinogen into insoluble fibrin, resulting in the formation of a blood clot. In blood coagulation, traditionally the intrinsic and the extrinsic system, which end in a joint reaction path, are distinguished. Here, the active enzyme factor Xa is formed from the proenzyme factor X. The activated serine protease Xa cleaves prothrombin to thrombin. The resulting thrombin, in turn, cleaves fibrinogen to fibrin. Subsequent crosslinking of the fibrin monomers causes formation of blood clots and thus haemostasis.

In addition, via proteolytic activation of platelet receptors, thrombin is a potent trigger of platelet aggregation, which also makes a major contribution to haemostasis. Further functions of thrombin which contribute to blood coagulation are the stabilization of the fibrin clot via activation of factor XIII, potentiation of the coagulation reaction via activation of cofactors V
and VIII and inhibition of fibrinolysis via activation of procarboxypeptidase B (syn. TAFI). Finally, by proteolytic activation of protein C, thrombin can counteract excessive activity of the coagulation cascade and thus overshooting haemostasis (thrombosis).

Haemostasis is subject to a complex regulatory mechanism. Uncontrolled activation of the coagulant system or defective inhibition of the activation processes may cause formation of local thrombi or embolisms in vessels (arteries, veins, lymph vessels) or in heart cavities. This may lead to serious thromboembolic disorders. In addition, in the case of consumption coagulopathy, hypercoagulability may - systemically - result in disseminated intravascular coagulation.
Thromboembolic complications furthermore occur in microangiopathic hemolytic anemias, extracorporeal blood circulation, such as haemodialysis, and also in connection with prosthetic heart valves.

Thromboembolic disorders are the most frequent cause of morbidity and mortality in most industrialized countries [Heart Disease: A Textbook of Cardiovascular Medicine, Eugene BHC 06 1 167-Foreign Countries Braunwald, 5th edition, 1997, W.B. Saunders Company, Philadelphia].

The anticoagulants, i.e. substances for inhibiting or preventing blood coagulation, which are known from the prior art, have various, often grave disadvantages.
Accordingly, in practice, an efficient treatment or prophylaxis of thromboembolic disorders is very difficult and unsatisfactory (D.A. Lane, et al, Directing Thrombin. Blood 106, 2605-2612, 2005; D.
Gustafsson, et al., Nature Reviews Drug Discovery, 3, 649-659, 2004; L. Wallentin, et al., The Lancet 362, 789-797, 2003).
In the therapy and prophylaxis of thromboembolic disorders, use is firstly made of heparin, which is administered parenterally or subcutaneously. Owing to more favorable pharmacokinetic properties, preference is nowadays more and more given to low-molecular-weight heparin;
however, even with low-molecular-weight heparin, it is not possible to avoid the known disadvantages described below, which are involved in heparin therapy. Thus, heparin is ineffective when administered orally and has a relatively short half-life. Since heparin inhibits a plurality of factors of the blood coagulation cascade at the same time, the action is non-selective. Moreover, there is a high risk of bleeding; in particular, brain hemorrhages and gastrointestinal bleeding may occur, which may result in thrombopenia, drug-induced alopecia or osteoporosis [Pschyrembel, Klinisches Worterbuch, 257th edition, 1994, Walter de Gruyter Verlag, page 610, entry "Heparin";
Rompp Lexikon Chemie, Version 1.5, 1998, Georg Thieme Verlag Stuttgart, entry "Heparin"].

A second class of anticoagulants are the vitamin K antagonists. These include, for example, 1,3-indanediones, and especially compounds such as warfarin, phenprocoumon, dicumarol and other coumarin derivatives which inhibit the synthesis of various products of certain vitamin K-dependent coagulation factors in the liver in a non-selective manner. Owing to the mechanism of action, however, the onset of the action is very slow (latency to the onset of action 36 to 48 hours).
It is possible to administer the compounds orally; however, owing to the high risk of bleeding and the narrow therapeutic index, a time-consuming individual adjustment and monitoring of the patient are required [J. Hirsh, J. Dalen, D.R. Anderson et al., "Oral anticoagulants: Mechanism of action, clinical effectiveness, and optimal therapeutic range" Chest 2001, 119, 8S-21S; J. Ansel], J. Hirsh, J. Dalen et al., "Managing oral anticoagulant therapy" Chest 2001, 119, 22S-38S;
P.S. Wells, A.M. Holbrook, N.R. Crowther et al., "Interactions of warfarin with drugs and food"
Ann. Intern. Med. 1994, 121, 676-683]. Other side effects such as gastrointestinal problems, hair loss and skin necroses have also been described.

However, during the course of many cardiovascular disorders and metabolic disorders, owing to systemic factors, such as, for example hyperlipidemia, diabetes or sinoking, owing to changes in blood flow with stases, such as, for example, in the case of atrial fibrillation, or owing to BHC 06 1 167-Foreign Countries pathological changes of the walls of the vessels, for example endothelial dysfunction or atherosclerosis, there is an increased tendency of coagulation activation and platelet activation.
This unwanted and excessive haemoastsis may, by formation of fibrin- and platelet-rich thrombi, result in thromboembolic disorders and thrombotic complications with life-threatening states.

Novel approaches toward oral anticoagulants are in various phases of clinical development or clinical use; however, they have also shown disadvantages, such as, for example, highly variable bioavailability, liver damage and bleeding complications.

Accordingly, it is an object of the present invention to provide novel compounds as thrombin inhibitors for the treatment of cardiovascular disorders, in particular thromboembolic disorders, in humans and animals, which compounds have a wide therapeutic spectrum.

4 describes structurally similar imidazole derivatives and their use for the treatment of neurodegenerative and neurological disorders, such as, for example, Alzheimer's disease. WO 02/053161 describes the use of imidazole and thiazole derivatives for the treatment of fibrotic disorders.

The invention provides compounds of the formula R H N
~ YI\ X
H Rs Ra O N~ (1), z R
in which X represents NH or S, R' represents phenyl or 5- or 6-membered heteroaryl, where phenyl and heteroaryl may be substituted by I to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C,-C4-alkyl, CI-C4-alkoxy, C,-C4-alkylamino, C,-C4-alkylthio and C,-C4-alkylcarbonyl, R2 represents phenyl or 5- or 6-membered heteroaryl, where phenyl and heteroaryl may be substituted by I to 3 substituents, where the BHC 06 1 167-Foreign Countries substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, CI-C4-alkyl, CI-C4-alkoxy, Cl-C4-alkylamino, Cl-C4-alkylthio and C,-C4-alkylcarbonyl, R3 represents hydrogen or methyl, R4 represents CI-C6-alkyl, Cz-C6-alkenyl or C3-C6-cycloalkyl, where alkyl and alkenyl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C,-C4-alkoxy, C,-C4-alkylamino and C3-C6-cycloalkyl, or R' and R4 are linked to one another and, together with the atoms to which they are attached, form a pyrrolidine ring or a 1,3-thiazolidine ring, where the pyrrolidine ring and the l,3-thiazolidine ring may be substituted by 1 or 2 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, Ci-C4-alkyl, C2-C4-alkenyl, C,-Cq-alkoxy and C,-C4-alkylamino, R5 represents hydrogen, halogen, hydroxyl, amino, CI-C6-alkyl, CI-C6-alkoxy, alkylamino, Cl-C6-alkylcarbonyloxy, C,-C6-alkylcarbonylamino or 5- to 7-membered heterocyclyl, where alkyl and alkylamino may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, amino, hydroxycarbonyl, CI-C6-alkylamino, Cl-C4-alkoxycarbonyl and 5- to 7-membered heterocyclyl, where heterocyclyl for its part may be substituted by I to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C,-C4-alkyl, CI-C4-alkoxy, Cl-C4-alkylamino, CI-C4-alkylthio, Ci-C4-alkylcarbonyl, Cl-C4-alkoxycarbonyl, Cl-C4-alkylcarbonyl-amino, C,-C4-alkylaminocarbonyl, C,-C4-alkoxycarbonylamino and C,-C4-alkyl-carbonyloxy, 3 0 and BHC 06 1 167-Forei ng Countries where heterocyclyl may be substituted by I to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, CI-C4-alkyl, CI-Ca-alkoxy, C-C4-alkylamino, CI-C4-alkylthio, CI-alkylcarbonyl, Cl-C4-alkoxycarbonyl, Cl-C4-alkylcarbonylamino, Cl-C4-alkylamino-carbonyl, CI -C4-alkoxycarbonyl amino and Cl-C4-alkylcarbonyloxy, or R4 and R5 are linked to one another and, together with the atoms to which they are attached, form a pyrrolidinone ring, where the pyrrolidinone ring may be substituted by 1 or 2 substituents, where the substituents independently of one another are selected from the group consisting of hydroxyl, amino, CI-C4-alkyl, C,-C4-alkoxy and Cl-C4-alkylamino, R 6 represents phenyl, 5- or 6-membered heteroaryl or 5- to 7-membered heterocyclyl, where phenyl and heteroaryl may be substituted by I to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, ainino, cyano, nitro, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, Ci-C4-alkyl, CI-C4-alkoxy, C,-C4-alkylamino, alkylthio, Cl-C4-alkylcarbonyl, Cl-C4-alkoxycarbonyl, Ci-C4-alkylcarbonylamino, CI-C4-alkylaminocarbonyl, C,-Ca-alkoxycarbonylamino, C,-C4-alkylcarbonyloxy, C2-C4-alkylsulfonyl and C,-C4-alkylsulfinyl, and where heterocyclyl may be substituted by I to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, CI-C4-alkyl, CI-C4-alkoxy, Cl-C4-alkylamino, Cl-C4-alkylthio, C-alkylcarbonyl, Cl-C4-alkoxycarbonyl, C,-C4-alkylcarbonylamino, CX4-alkylamino-carbonyl, Ci-C4-alkoxycarbonylamino and C,-C4-alkylcarbonyloxy, or R5 and R6 are linked to one another and, together with the carbon atom to which they are attached, form a group of the formula BHC 06 1 167-Foreign Countries R ' R O ~

O
where * indicates the carbon atom to which R5 and R6 are attached, and R' and R8 are linked to one another and, together with the carbon atom to which they are attached, form a cyclopentane ring or cyclohexane ring, where the cyclopentane ring and the cyclohexane ring may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, CI-C4-alkyl, Cl-C4-alkoxy and Cl-C4-alkylamino, and where R' and R5 are not both linked to R4 and where Ra and R6 are not both linked to R5, and their salts, their solvates and the solvates of their salts.

Compounds according to the invention are the compounds of the formula (1) and their salts, solvates and solvates of the salts, and the compounds, comprised by formula (1), mentioned below as embodiments and their salts, solvates and solvates of the salts if the compounds, comprised by formula (1), mentioned below are not already salts, solvates and solvates of the salts.

Depending on their structure, the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). Accordingly, the invention comprises the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and/or diastereomers, it is possible to isolate the stereo i somerical ly uniform components in a known manner.

If the compounds according to the invention can be present in tautomeric forms, the present invention comprises all tautomeric forms.

In the context of the present invention, preferred salts are physiologically acceptable salts of the BHC 06 1 167-Foreign Countries compounds according to the invention. The invention also comprises salts which for their part are not suitable for pharmaceutical applications, but which can be used, for example, for isolating or purifying the compounds according to the invention.

Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium salts and potassium salts), alkaline earth metal salts (for example calcium salts and magnesium salts) and ammonium salts, derived from ammonia or organic amines having I to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.

In the context of the invention, solvates are those forms of the compounds according to the invention which, in solid or liquid state, form a complex by coordination with solvent molecules.
Hydrates are a specific form of the solvates where the coordination is with water.

Moreover, the present invention also comprises prodrugs of the compounds according to the invention. The term "prodrugs" includes compounds which for their part may be biologically active or inactive but which, during the time they spend in the body, are converted into compounds according to the invention (for example metabolically or hydrolytically).

In the context of the present invention, unless specified differently, the substituents have the following meanings:

Alkyl per se and "alk" and "alkyl" in alkoxy, alkylamino, alkylthio, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylaminocarbonyl, alkylsulfonyl alkylsulfinyl, alkoxycarbonyl and alkoxycarbon lamino represents a straight-chain or branched alkyl radical having I to 6, preferably I to 4, carbon atoms, by way of example and by way of preference methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl and n-hexyl.

Alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms.

BHC 06 1 167-Foreign Countries Preference is given to a straight-chain or branched alkenyl radical having 2 to 4, particularly preferably 2 or 3, carbon atoms. The following radicals may be mentioned by way of example and by way of preference: vinyl, allyl, n-prop-l-en-l-yl and n-but-2-en-1-yl.

By way of example and by way of preference, alkoxy represents methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

Al , lamino represents an alkylamino radical having one or two alkyl substituents (selected independently of one another), by way of example and by way of preference methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino. CI-C;-Alkylamino represents, for example, a monoalkylamino radical having I to 3 carbon atoms or represents a dialkylamino radical having in each case I to 3 carbon atoms per alkyl substituent.

By way of example and by way of preference, alkylthio represents methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.

By way of example and by way of preference, alkylcarbonyl represents methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl and tert-butylcarbonyl.

By way of example and by way of preference, alkylcarbonylamino represents methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino and tert-butylcarbonylamino.

By way of example and by way of preference, alkylcarbonyloxy represents methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy and tert-butylcarbonyloxy.

AlkylaminocarboVl represents an alkylaminocarbonyl radical having one or two alkyl substituents (selected independently of one another), by way of example and by way of preference methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl, N-isopropyl-N-n-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylaminocarbonyl and N-n-hexyl-N-methylaminocarbonyl. Ci-C3-Alkylaminocarbonyl represents, for example, a monoalkylaminocarbonyl radical having I to 3 carbon atoms or represents a dialkylaminocarbonyl radical having in each case I to 3 carbon atoms per alkyl substituent.

BHC 06 1 167 Foreign Countries By way of example and by way of preference, alkylsulfonyl represents methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl and tert-butylsulfonyl.

By way of example and by way of preference, alkylsulfinyl represents methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl and tert-butylsulfinyl.

By way of example and by way of preference, alkoxycarbonyl represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

By way of example and by way of preference, alkoxycarbonylamino represents methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino and n-hexoxycarbonyl-amino.

Cycloa11~ represents a monocyclic cycloalkyl group having generally 3 to 6, preferably 3, 5 or 6, carbon atoms, by way of example and by way of preference, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl may be mentioned for cycloalkyl.

Heterocyclyl represents a monocyclic heterocyclic radical having generally 5 to 7, preferably 5 or 6, ring atoms and up to 3, preferably up to 2, heteroatoms and/or hetero groups from the group consisting of N, 0, S, SO, SO2, where a nitrogen atom may also form an N-oxide. The heterocyclyl radicals can be saturated or partially unsaturated. Preference is given to 5-or 6- membered monocyclic saturated heterocyclyl radicals having up to 2 heteroatoms from the group consisting of 0, N and S, by way of example and by way of preference pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, thiopyranyl, morpholin-l-yl, morpholin-2-yl, morpholin-3-yl, perhydroazepinyl, piperazin- l -yl and piperazin-2-yl.

Heteroaryl represents an aromatic monocyclic radical having 5 or 6 ring atoms and up to 4, preferably up to 2, heteroatoms from the group consisting of S, 0 and N, where a nitrogen atom may also form an N-oxide, by way of example and by way of preference thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl.
Halogen represents fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

If radicals in the compounds of the formula (I), their salts, their solvates or the solvates of their salts are substituted, the radicals can, unless specified otherwise, be mono-or polysubstituted by identical or different substituents. Substitution with up to three identical or different substituents is ~ BHC 06 1 167-Foreign Countries preferred. Very particular preference is given to substitution with one substituent.
Preference is given to the compounds of the formula (1) in which X represents NH or S, R' represents phenyl, pyridyl or pyrimidyl, where phenyl, pyridyl and pyrimidyl may be substituted by I to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, CI-C4-alkyl, Cl-C4-alkoxy, Cl-C4-alkylamino, Ci-C4-alkylthio and CX4-alkylcarbonyl, R2 represents phenyl, thienyl, furyl, thiazolyl, oxazolyl or imidazolyl, where phenyl, thienyl, fury], thiazolyl, oxazolyl and imidazolyl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, cyano, trifluoromethyl, C,-C4-alkyl and C,-C4-alkoxy, R3 represents hydrogen, R4 represents C,-C6-alkyl or C3-C6-cycloalkyl, where alkyl may be substituted with I to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C,-C4-alkoxy, C,-C4-alkylamino and C3-C6-cycloalkyl, or R3 and R4 are linked to one another and, together with the atoms to which they are attached, form a pyrrolidine ring, where the pyrrolidine ring may be substituted by I or 2 substituents, where the substituents independently of one another are selected from the group consisting of Ci-C4-alkyl and Cl-C4-alkoxy, R5 represents hydrogen, halogen, hydroxyl, amino, CX6-alkyl, Cl-C6-alkoxy, C1-alkylamino, Ci-C6-alkylcarbonyloxy, Ci-C6-alkylcarbonylamino, morpholinyl, thiomorpholinyl or 4-(CI-C4-alkyl)piperazinyl, where alkyl and alkylamino may be substituted by a substituent, where the substituent is = ' BHC 06 1 167-Foreign Countries selected from the group consisting of hydroxyl, amino, hydroxycarbonyl, CI-C6-alkylamino, Cl-C4-alkoxycarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl, where pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl for their part may be substituted by I or 2 substituents, where the substituents independently of one another are selected from the group consisting of C,-C4-alkyl and C-C4-alkoxy, or R4 and RS are linked to one another and, together with the atoms to which they are attached, form a pyrrolidinone ring, where the pyrrolidinone ring may be substituted by I or 2 substituents, where the substituents independently of one another are selected from the group consisting of CI-C4-alkyl, R6 represents phenyl, tetrahydrofuranyl, pyranyl, piperidinyl or thiopyranyl, where phenyl may be substituted by I to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C,-C4-alkyl, CI-C4-alkoxy, CI-C4-alkylcarbonylamino, C-C4-alkylaminocarbonyl and Cl-C4-alkoxycarbonylamino, and where tetrahydrofuranyl, pyranyl, piperidinyl and thiopyranyl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, oxo, hydroxycarbonyl, aminocarbonyl, Ci-C4-alkyl, CI-C4-alkoxy, Cl-C4-alkylcarbonylamino, Cl-C4-alkylamino-carbonyl and Cl-C4-alkoxycarbonylamino, or R5 and R6 are linked to one another and, together with the carbon atom to which they are attached, form a group of the formula = BHC 06 1 167-Foreign Countries R ' R O *

O
where * indicates the carbon atom to which RS and R6 are attached, and R' and R 8 are linked to one another and, together with the carbon atom to which they are attached, form a cyclohexane ring, and where R' and RS are not both linked to R4 and where R4 and R6 are not both linked to R5, and their salts, their solvates and the solvates of their salts.

Preference is also given to compounds of the formula (1) in which X represents NH or S, RI represents phenyl or pyridyl, where phenyl and pyridyl may be substituted by I or 2 substituents, where the substituents independently of one another are selected from the group consisting of halogen and methoxy, R 2 represents phenyl or thienyl, where phenyl and thienyl may be substituted by I or 2 substituents, where the substituents independently of one another are selected from the group consisting of fluorine, chlorine and bromine, R' represents hydrogen, R4 represents isopropyl, or = ' BHC 06 1 167-Foreign Countries R3 and R4 are linked to one another and, together with the atoms to which they are attached, form a pyrrolidine ring, where the pyrrolidine ring may be substituted by I or 2 methyl substituents, R5 represents hydrogen, Ci-C4-alkyl or Ci-C4-alkoxy, where alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, hydroxycarbonyl and C,-C4-alkoxycarbonyl, or R4 and R5 are linked to one another and, together with the atoms to which they are attached, form a pyrrolidinone ring, where the pyrrolidinone ring may be substituted by I or 2 methyl substituents, R6 represents phenyl or 4-pyranyl, where phenyl may be substituted by I to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl and C,-C4-alkoxy, or R5 and R6 are linked to one another and, together with the carbon atom to which they are attached, form a group of the formula R7 R$
O

O
where * indicates the carbon atom to which RS and R6 are attached, and R' and R8 are linked to one another and, together with the carbon atom to which they are attached, form a cyclohexane ring, and = ~ BHC 06 1 167-Foreign Countries where R' and R5 are not both linked to R4 and where R4 and R6 are not both linked to R5, and their salts, their solvates and the solvates of their salts.

Preference is also given to compounds of the formula (I), in which X
represents NH.

Preference is also given to compounds of the formula (I), in which R' represents phenyl, where phenyl may be substituted by a fluorine substituent.

Preference is also given to compounds of the formula (I), in which R2 represents phenyl or thienyl, where phenyl and thienyl may be substituted by a fluorine or chlorine substituent.

Particular preference is also given to compounds of the formula (I), in which R2 represents thienyl, where thienyl may be substituted by a fluorine substituent.

Very particular preference is also given to compounds of the formula (1), in which R2 represents 5-fluoro-2-thienyl or 5-chloro-2-thienyl.

Very particular preference is also given to compounds of the formula (1), in which R2 represents 5-fl uoro-2-thienyl.

Preference is also given to compounds of the formula (I), in which R3 represents hydrogen.
Preference is also given to compounds of the formula (1), in which RQ
represents isopropyl.
Preference is also given to compounds of the formula (I), in which RS
represents hydrogen or C,-C4-alkyl, where alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl and hydroxycarbonyl.

Preference is also given to compounds of the formula (I), in which R6 represents phenyl, where phenyl may be substituted by I to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl and CI-C4-alkoxy.

Particular preference is also given to compounds of the formula (1), in which R6 represents phenyl, where phenyl may be substituted by 2 methoxy substituents or one methoxy substituent and one chlorine substituent.

Very particular preference is also given to compounds of the formula (1), in which R6 represents 3,4-dimethoxyphenyl or 3-chloro-4-methoxyphenyl.

BHC 06 1 167-Foreign Countries The invention furthermore provides a process for preparing the compounds of the formula (I), where according to process [A] a compound of the formula H H
N
HN /
R (II), 4 0 N ~ X

R

in which X, R', RZ, R3 and R4 have the meaning given above, is reacted with a compound of the formula O

Y' H R5 (III), in which R5 and R6 have the meaning given above and Y' represents halogen, preferably chlorine, bromine or iodine, or hydroxyl, or [B] a compound of the formula R' /
X (IV
N~

RZ
in which X, R' and R2 have the meaning given above, BHC 06 1 167-Foreign Countries is reacted with a compound of the formula N 1~ /
H 5 1 4 \V)~
R R O
in which R3, R4, RS and R6 have the meaning given above and Y2 represents halogen, preferably chlorine, bromine oder iodine, or hydroxyl.

The reaction according to process [A] and process [B] is, if Y' or Y2 is halogen, generally carried out in inert solvents, in the presence of a base, preferably in a temperature range of from 0 C to 40 C at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons, such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents, such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile; preference is given to tetrahydrofuran or methylene chloride.

Bases are, for example, alkali metal carbonates, such as cesium carbonate, sodium carbonate or potassium carbonate, or sodium methoxide or potassium methoxide, or sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or amides, such as sodium amide, lithium bis(trimethylsilyl)amide or lithium diisopropylamide, or other bases, such as sodium hydride, DBU, triethylamine or diisopropylethylamine; preference is given to diisopropylethylamine.

The reaction according to the process [A] and process [B] is, if Y' or Y2 is hydroxyl, generally carried out in inert solvents, in the presence of dehydrating agents, if appropriate in the presence of a base, preferably in a temperature range of from 0 C to room temperature at atmospheric pressure.

Suitable dehydrating agents are here, for example, carbodiimides, such as, for example, N,N'-diethyl-, N,N'-dipropyl-, N,N'-di isopropyl-, N,N'-dicyclohexylcarbodiimide, N-(3-dimethylamino-isopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) (if appropriate in the presence of pentafluorophenol (PFP)), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide), or carbonyl compounds, such as carbonyldiimidazole, or 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compounds, such as 2-ethoxy-I-ethoxycarbonyl-l,2-dihydroquinoline, or BHC 06 1 167-Foreign Countries propanephosphonic anhydride, or isobutyl chloroformate, or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride or benzotriazolyloxytri(dimethylamino)phosphonium hexafluorophosphate, or O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol- l -yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), or mixtures of these, with bases. The condensation is preferably carried out using HOBt and EDC.

Bases are, for example, alkali metal carbonates, such as, for example, sodium carbonate or potassium carbonate or sodium bicarbonate or potassium bicarbonate, or organic bases, such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine. The condensation is preferably carried out using diisopropylethylamine.

Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane or trichloromethane, hydrocarbons, such as benzene, nitromethane, dioxane, dimethylformamide, ] 5 acetonitrile or hexamethylphosphoric triamide. It is also possible to use mixtures of the solvents.
Particular preference is given to dichloromethane or dimethylformamide.

The compounds of the formula (111) are known or can be synthesized by known processes from the appropriate starting materials.

The compounds of the formula (IV) are known or can be synthesized by known processes from the appropriate starting materials. The preparation of the aminoimidazoles is as described, for example, by Cook, et a]. J. Chem. Soc., 1949, 1074-1076 and Bador, et a]. J.
Chem. Soc., 1950, 2775-2780.

The compounds of the formula (V) are known or can be synthesized by known processes from the appropriate starting materials. Use is made, inter alia, of peptide couplings and alkylations.

The compounds of the formula (II) are known or can be prepared by reacting compounds of the formula R3 R' H H

y X (VI ), O <

R

BHC 06 1 167-Foreign Countries in which X, R', R2 and R3 have the meaning given above, and Y3 represents halogen, preferably iodine, bromine or chlorine, with compounds of the formula H2N-RQ (VII), in which R4 has the meaning given above.

The reaction is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range of from 0 C to 40 C at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons, such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents, such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile; preference is given to tetrahydrofuran or methylene chloride.

Bases are, for example, alkali metal carbonates, such as cesium carbonate, sodium carbonate, or potassium carbonate, or sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or amides, such as sodium amide, lithium bis(trimethylsilyl)amide or lithium diisopropylamide, or other bases, such as sodium hydride, DBU, triethylamine or diisopropylethylamine; preference is given to diisopropylethylamine.

The compounds of the formula (VII) are known or can be synthesized by known processes from the appropriate starting materials.

The compounds of the formula (VI) are known or can be prepared by reacting compounds of the formula (IV) with compounds of the formula F-I y 4 (VIII), in which BHC 06 1 167-Foreign Countries R3 has the meaning given above, Y3 represents halogen, preferably iodine, bromine or chlorine, and Y4 represents halogen, preferably iodine or bromine, or hydroxyl.
The reaction is carried out according to process [A].

The compounds of the formula (VIII) are known or can be synthesized by known processes from the appropriate starting materials.

Alternatively to the process described above, the amines (1I) can also be prepared by reductive amination of the primary amines using a suitable ketone or aldehyde. Here, the primary amines are obtained by acylation of the aminoimidazoles (IV), where the primary amine function is protected during the acylation with a suitable protective group, such as, for example, a Boc group, which is removed after the reaction under reaction conditions known to the person skilled in the art. Here, preferred acylating agents are the N-protected amino acids, which are activated using a coupling agent.

The preparation of the starting materials and the compounds of the formula (I) can be illustrated by the synthesis scheme below.

Scheme:

BHC 06 1 167-Foreign Countries R R
x +~ 1+J R ~~
FOr?C = NH: R
NH HN a HN o z~
R S R3XNHQ R3 TNH, CNH H H
I ~ R ~~aH2 ~

Rz Rz Rz R1 r/~ iy R1 ~11 _~ R1 ~IN'~ ~1 ~IIV

NHz HN O HN O
FOrX = S:

R3 H1(3 R3 H XNH
x Suzuki Ri , R' 0 0..-CH, x Br x / R 2 J
R'~, R'~--~ ~\ ~~
Br NHBoo HN 0 ------~~~~ ~
R' O R 5 R N H
R. Re The compounds according to the invention have an unforeseeable useful pharmacological and pharmacokinetic activity spectrum. They are compounds which have an effect on the proteolytic activity of the serin protease thrombin. The compounds according to the invention inhibit the enzymatic cleavage of substrates which play an important role in the activation of coagulation and the aggregation of platelets.

Accordingly, they are suitable for use as medicaments for the treatment and/or prophylaxis of diseases in humans and animals.

The present invention furthermore provides the use of the compounds according to the invention for the treatment and/or prophylaxis of disorders, preferably thromboembolic disorders andlor thromboembolic complications.

The "thromboembolic diseases" within the meaning of the present invention in particular include diseases such as acute coronary syndrome (ACS), myocardial infarct with ST
segment elevation (STEMI) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusions and restenoses after coronary interventions such as angioplasty, stent implantation or aortocoronary bypass, peripheral arterial occlusive diseases, pulmonary BHC 06 1 167-Foreign Countries embolisms, venous thromboses, in particular deep vein thromboses and renal vein thromboses, transitory ischemic attacks, and thrombotic and thromboembolic cerebral stroke.

The compounds according to the invention are therefore also suitable for the prevention and treatment of cardiogenic thromboembolisms, such as, for example, cerebral ischemias, stroke and systemic thromboembolisms and ischemias in patients with acute, intermittent or persistent cardiac arrhythmias, such as, for example, atrial fibrillation, and those who are subject to cardioversion, furthermore in the case of patients with heart valve diseases or with artificial heart valves.
Moreover, the compounds according to the invention are suitable for the treatment of disseminated intravasal clotting (DIC).

Thromboembolic complications furthermore occur in microangiopathic hemolytic anemias, extracorporeal blood circulations, such as hemodialysis, and heart valve prostheses.

Moreover, the compounds according to the invention are also suitable for influencing wound healing, for the prophylaxis and/or treatment of atherosclerotic vascular diseases and inflammatory diseases such as rheumatic diseases of the locomotor system, coronary heart diseases, heart failure, hypertension, inflammatory disorders, such as, for example, asthma, inflammatory pulmonary disorders, glomerular nephritis and inflammatory disorders of the intestine, moreover also for the prophylaxis and/or treatment of Alzheimer's disease. Moreover, the compounds according to the invention can be employed for the inhibition of tumor growth and of metastasis formation, in microangiopathies, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular diseases, and for the prevention and treatment of thromboembolic complications, such as, for example, venous thromboembolisms, in tumor patients, in particular those who are subjected to relatively large surgical interventions or chemo-or radiotherapy.

The compounds according to the invention can moreover be employed for the prevention of coagulation ex vivo, e.g. for the preservation of blood and plasma products, for the cleaning/pretreatment of catheters and other medical aids and equipment, for the coating of artificial surfaces of medical aids and equipment employed in vivo or ex vivo or in biological samples which contain blood platelets.

The present invention further relates to the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases, in particular of the aforementioned diseases.

The present invention furthermore relates to the use of the compounds according to the invention for the production of a medicament for the treatment and/or prophylaxis of diseases, in particular of the aforementioned diseases.

~. ' BHC 06 1 167-Foreign Countries The present invention furthermore relates to a process for the treatment and/or prophylaxis of diseases, in particular of the aforementioned diseases, using a therapeutically effective amount of compound according to the invention.

The present invention furthermore relates to medicaments comprising a compound according to the invention and one or more other active substances, in particular for the treatment and/or prophylaxis of the aforementioned diseases. Suitable combination active substances which may be mentioned by way of example and preferably are:

= lipid-lowering agents, in particular HMG-CoA-(3-hydroxy-3-methylglutaryl-coenzyme A)-reductase inhibitors;

= coronary therapeutics/vasodilators, in particular ACE (angiotensin converting enzyme) inhibitors; All (angiotensin II) receptor antagonists; beta-adrenoceptor antagonists; alpha-l-adrenoceptor antagonists; diuretics; calcium channel blockers; substances which bring about an increase in cyclic guanosine monophosphate (cGMP), such as, for example, stimulators of soluble guanylate cyclase;

= plasminogen activators (thrombolytics/fibrinolytics) and thrombolysis/fibrinolysis-increasing compounds such as inhibitors of the plasminogen activator inhibitor (PAl inhibitors) or inhibitors of the thrombin-activated fibrinolysis inhibitor (TAFI inhibitors);

= substances having anticoagulatory activity (anticoagulants);

= substances inhibiting platelet aggregation (platelet aggregation inhibitors, thrombocyte aggregation inhibitors);

= and fibrinogen receptor antagonists (glycoprotein Ilb/IIIa antagonists);
= antiarrhythmics;

= chemotherapeutics for malignant tumors, such as antimetabolites, alkylating zytostatics, topoisomerase inhibitors, mitose inhibitors and zytostatically active antibiotics, hormones, hormone antagonists, other zytostatics (antibodies, kinase inhibitors, zytokine).

The invention furthermore relates to a method for the prevention of blood coagulation in vitro, in particular in blood preserves or biological samples containing blood platelets, which method is characterized in that an anticoagulatory effective amount of the compound according to the invention is added.

BHC 06 1 167-Foreign Countries The compounds according to the invention can act systemically and/or locally.
For this purpose, they can be administered in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For oral administration, administration forms functioning according to the prior art, releasing the compounds according to the invention rapidly and/or in modified form, which contain the compounds according to the invention in crystalline and/or amorphized and/or dissolved form, such as, for example, tablets (noncoated or coated tablets, for example with enteric coatings or coatings which dissolve with a delay or are insoluble, which control the release of the compound according to the invention), tablets disintegrating rapidly in the oral cavity or films/wafers, films/lyophilizates, capsules (for example hard or soft gelatin capsules), coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions are suitable.

Parenteral administration can take place with circumvention of an absorption step (e.g.
intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or with intervention of an absorption (e.g. intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). For parenteral administration, suitable administration forms are, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

Preference is given to oral administration.

For the other administration routes, for example, inhalation pharmaceutical forms (inter alia powder inhalers, nebulizers), nose drops, solutions or sprays; tablets to be administered lingually, sublingually or buccally, films/wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, dusting powders, implants or stents are suitable.

The compounds according to the invention can be converted to the administration forms mentioned. This can take place in a manner known per se by mixing with inert, nontoxic, pharmaceutically suitable excipients. These excipients include, inter alia, vehicles (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecylsulfate, polyoxysorbitan BHC 06 1 167-Foreign Countries oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants such as, for example, ascorbic acid), colorants (e.g.
inorganic pigments such as, for example, iron oxides) and taste and/or odor corrigents.

The present invention furthermore relates to medicaments comprising at least one compound according to the invention, preferably together with one or more inert non-toxic pharmaceutically suitable auxiliaries, and to their use for the purposes mentioned above.

In general, it has proven advantageous in the case of parenteral administration to administer amounts of approximately 5 to 250 mg every 24 hours to achieve effective results. In the case of oral administration, the dose is approximately 5 to 100 mg every 24 hours.

In spite of this, it may optionally be necessary to depart from the amounts mentioned, namely depending on body weight, route of administration, individual behavior toward the medicament, type of preparation and time or interval at which administration takes place.

The percentages in the tests and examples below are, unless indicated otherwise, percentages by weight; parts are parts by weight, solvent ratios, dilution ratios and concentrations of liquid/liquid solutions are in each case based on volume. The term "w/v" means "weight/volume". Thus, for example, "10% w/v" means: 100 ml of solution or suspension comprise 10 g of substance.

BHC 06 1 167-Foreign Countries A) Examples Abbreviations:
abs. absolute Boc tert-butoxycarbonyl CDC13 deuterochloroform COz carbon dioxide d day DIEA N,N-diisopropylethylamine DMAP 4-N,N-dimethylaminopyridine DMF dimethylformamide DMSO dimethyl sulfoxide of theory of theory EDC N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide x HCI
eq. equivalent ESI electrospray ionization (in MS) sat. saturated H hour HOBt l-hydroxy-1 H-benzotriazole x H20 HPLC high-pressure, high-performance liquid chromatography conc. concentrated LC-MS liquid chromatography-coupled mass spectrometry min. minutes MS mass spectrometry MW molecular weight [g/mol]
NMR nuclear magnetic resonance spectroscopy PyBOP 1-benzotriazolyloxytripyrrolidinophosphonium hexafluorophosphate Rf retention index (in TLC) RP-HPLC reversed-phase HPLC
RT room temperature Rr retention time (in HPLC) TFA trifluoroacetic acid THF tetrahydrofuran BHC 06 1 167-Foreign Countries HPLC methods:

Method 1: Instrument: HP 1100 with DAD detection; column: Kromasil RP-18, 60 mm x 2 mm, 3.5 pm; mobile phase A: 5 ml of perchloric acid/I of water, mobile phase B:
acetonitrile; gradient:
0 min 2%B, 0.5 min 2%B, 4.5 min 90%B, 6.5 min 90%B, 6.7 min 2%B, 7.5 min 2%B;
flow rate:
0.75 ml/min; oven: 30 C; UV detection: 210 nm.

Method 2: Instrument: HP 1100 with DAD detection; column: Kromasil RP-18, 60 mm x 2 mm, 3.5 pm; mobile phase A: 5 ml of perchloric acid/I of water, mobile phase B:
acetonitrile; gradient:
0 min 2%B, 0.5 min 2%B, 4.5 min 90%B, 9 min 90%B, 9.2 min 2%B, 10 min 2%B;
flow rate:
0.75 ml/min; oven: 30 C; UV detection: 210 nm.

LC-MS methods:

Method 1: MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance 2795;
column: Phenomenex Synergi 2p hydro-RP Mercury 20 mm x 4 mm; mobile phase A: 1 1 of water + 0.5 ml of 50% strength formic acid, mobile phase B: 1 1 of acetonitrile +
0.5 ml of 50% strength formic acid; gradient: 0.0 min 90%A 4 2.5 min 30%A 4 3.0 min 5%A 4 4.5 min 5%A; flow rate: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50 C; UV
detection: 210 nm.
Method 2: Instrument: Micromass Platform LCZ with HPLC Agilent series 1100;
column:
Thermo Hypersil GOLD 3 20 mm x 4 mm; mobile phase A: 1 1 of water + 0.5 ml of 50% formic acid, mobile phase B: 1 1 of acetonitrile + 0.5 ml of 50% strength formic acid; gradient: 0.0 min 100%A -> 0.2 min 100%A 4 2.9 min 30%A 4 3.1 min ] 0%A 4 5.5 min 10%A; flow rate:
0.0 min I ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50 C; UV detection:
208-400 nm.
Method 3: Instrument: Micromass Quattro LCZ with HPLC Agilent series 1100;
column:
Phenomenex Gemini 3 30 mm x 3.00 mm; mobile phase A: 1 1 of water + 0.5 ml of 50% strength formic acid, mobile phase B: 1 1 of acetonitrile + 0.5 ml of 50% strength formic acid; gradient:
0.0 min 90%A 4 2.5 min 30%A 4 3.0 min 5%A -> 4.5 min 5%A; flow rate: 0.0 min I
ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50 C; UV detection: 208-400 nm.

GC-MS methods:

Method 1: Instrument: Micromass GCT, GC6890; column: Restek RTX-35, 15 m x 200 pm x 0.33 m; constant flow of helium: 0.88 mI/min; oven: 70 C; inlet: 250 C;
gradient: 70 C, C/min -> 3 l0 C (maintained for 3 min).

BHC 06 1 167-Foreign Countries Starting materials Example IA

Benzyl benzcarbimidothioate hydrobromide NH x HBr I \ S I \

A solution of 10 g (72.8 mmol) of thiobenzamide and 12.5 g (72.8 mmol) of benzyl bromide in 300 ml of dioxane is heated at 100 C for 48 h. The solvent is evaporated under reduced pressure to one fifth of the original amount. The mixture is allowed to cool, and the precipitated solid is filtered off. The solid is washed with a little dioxane and diethyl ether and dried under reduced pressure. This gives 13.1 g (58% of theory) of crystals.

HPLC (method 1): R, = 3.89 min MS (DClpos): m/z = 228 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 11.5 (b, 2H), 7.9 (d, 2H), 7.8 (t, IH), 7.65 (t, 2H), 7.55 (d, 2H), 7.4 (m, 3H), 4.7 (s, 2H).

Example 2A

2,5-Diphenyl-1 H-imidazol-4-amine NHZ
N
H

300 mg (0.97 mmol) of benzyl benzcarbimidothioate hydrobromide and 128 mg (0.97 mmol) of amino(phenyl)acetonitrile are dissolved in 20 ml of chloroform and heated at 70 C for 16 h. The mixture is allowed to cool and diluted with water and saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is purified by preparative HPLC using a gradient of acetonitrile and water. The product-containing fractions are concentrated BHC 06 1 167-Foreign Countries to dryness under reduced pressure. This gives 116 mg (51 % of theory) of product.
HPLC (method 1): Rr= 3.56 min MS (DClpos): m/z = 236 (M+H)+

'H-NMR (400 MHz, DMSO-db): 8 11.8 (s, 1H), 7.1-8.0 (m, I OH), 4.7 (s, 2H).
Example 3A

2-Chloro-N-(2,5-diphenyl-1 H-imidazol-4-yl)acetamide ~CI
O
NH
H

375 mg (1.59 mmol) of 2,5-diphenyl-lH-imidazol-4-amine are dissolved in 5 ml of 1,2-dichloroethane, and 333 l (2.39 mmol) of triethylamine and 234 mg (2.1 mmol) of chloroacetyl chloride are added. The mixture is stirred at room temperature for 15 min and at 45 C
for a further 16 h and then diluted with dichloromethane and water. Saturated sodium bicarbonate solution is added until the mixture gives a basic reaction, and the phases are separated. The organic phase is dried with sodium sulfate, filtered and concentrated to dryness under reduced pressure.
The residue is chromatographed by HPLC using a gradient of acetonitrile and water, and the product-containing fractions are combined and concentrated to dryness under reduced pressure.
This gives 372 mg (75% of theory) of product.

HPLC (method 1): R, 3.56 min MS (DClpos): m/z = 312 (M+H)+

'H-NMR (400 MHz, DMSO-d6): S= 12.6 (s, 1H), 10.0 (s, 1H), 7.2-8.1 (m, 10 H), 4.25 (s, 2H).
Example 4A

N-(2,5-Diphenyl-1 H-imidazol-4-yl)-N2-isopropylglycinamide BHC 06 1 167-Foreign Countries = -29->_CH3 N
OH
NH

365 mg (1.17 mmol) of 2-chloro-N-(2,5-diphenyl-lH-imidazol-4-yl)acetamide are dissolved in ml of acetonitrile, and 559 mg (9.37 mmol) of isopropylamine are added. After the addition has ended, the mixture is stirred at room temperature for a further 16 h, and the reaction solution is 5 then diluted with dichloromethane, extracted twice with water and dried over sodium sulfate. The organic phase is concentrated to dryness under reduced pressure, and the residue is chromatographed by HPLC, using a gradient of acetonitrile and water. The product-containing fractions are combined and evaporated to dryness under reduced pressure. This gives 326 mg (83%
of theory) of product.

HPLC (method 1): R, = 3.29 min MS (DClpos): m/z = 335 (M+H)+

'H-NMR (400 MHz, DM SO-d6): 8= 12.5 (s, 1H), 9.6 (b, IH), 7.2-8.1 (m, 10 H), 3.3 (m, 2H), 2.8 (m, I H), 1.0 (d, 6H).

Example 5A

Benzyl 4-fluorobenzcarbimidothioate hydrochloride NH x HCI
I \ g I \
F /

2 g (16.5 mmol) of 4-fluorobenzonitrile and 3.5 g (28.1 mmol) of benzyl mercaptan are dissolved in 10 ml of anhydrous dioxane and cooled to 0 C. Hydrogen chloride gas is introduced for 40 min, and the mixture is stirred at room temperature for a further 16 h. 50 ml of diethyl ether are added to the solution, and the precipitated crystals are filtered off and dried under reduced pressure. This gives 1.3 g (28% of theory) of crystals.

. BHC 06 1 167-Foreign Countries HPLC (method 1): R, = 3.94 min MS (DClpos): m/z = 246 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6= 12.0 (b, 1H), 8.0 (m, 2H), 7.3-7.6 (m, 7H), 4.6 (s, 2H).
Example 6A

Benzyl-5-fluorothiophene-2-carbimidothioate hydrochloride NH x HCI
S ~ g I \
F \
/
8 g (59.5 mmol) of 5-fluorothiophene-2-carbonitrile and 12.5 g (101.2 mmol) of benzyl mercaptan are dissolved in 80 ml of anhydrous dioxane and cooled to 0 C. Hydrogen chloride gas is introduced for 40 min, and the mixture is kept at room temperature for a further 3 days. 300 ml of diethyl ether are added to the solution, and the precipitated crystals are filtered off and dried under reduced pressure. This gives 16 g (95% of theory) of crystals.

HPLC (method 1): R, = 3.91 min MS (DCIpos): m/z = 252 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 10.5 (b, 1 H), 7.9 (b, IH), 7.5 (d, 2H), 7.3-7.45 (m, 3H), 7.1 (s, 1 H), 4.6 (s, 2H).

Example 7A
Amino(phenyl)acetonitrile N

NH

c 4 g(23.7 mmol) of alpha-cyanobenzylamine are dissolved in 100 ml of dichloromethane and extracted twice with 15 ml of saturated sodium bicarbonate solution. The mixture is washed with saturated sodium chloride solution, and the organic phase is dried over sodium sulfate, filtered and BHC 06 1 167-Foreign Countries evaporated to dryness under reduced pressure. This gives 2.75 g (98% of theory) of crystals.
LC-MS (method 2): R, = 1.53 min 'H-NMR (400 MHz, DMSO-d6): 6= 7.2-7.6 (m, 5H), 5.0 (s, I H), 2.8 (s, 2H).
Example 8A

Amino(6-chloropyridin-3-yl)acetonitrile N

, CI
2.9 g (44.2 nnnol) of potassium cyanide in 60 ml of aqueous ammonia, and 3.8 g (70.6 mmol) of ammonium chloride are added. A solution of 5 g(353 mmol) of 6-chloronicotinaldehyde in 30 ml of methanol is added dropwise to the suspension over a period of one hour. The mixture is stirred for another 16 h and then diluted with dichloromethane. The phases are separated, and the aqueous phase is extracted two more times with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue is chromatographed on silica gel using a gradient of dichloromethane and methanol, and the product-containing fractions are combined and concentrated to dryness under reduced pressure. This gives 1.3 g (19% of theory) of product.

LC-MS (method 1): R, = 0.66 min 'H-NMR (400 MHz, DMSO-d6): 8= 8.85 (s, IH), 8.2 (m, 2H), 7.6-7.8 (m, 2H).
Example 9A

Bromo(4-methoxyphenyl)acetonitrile H3C - Br O
CN
2.9 g (16.3 mmol) of N-bromosuccinimide and 0.223 mg (1.36 mmol) of a,a-azoisobutyronitrile are initially charged in 10 ml of carbon tetrachloride, and 2.0 g(13.59 mmol) of 4-methoxybenzyl BHC 06 1 167-Foreign Countries cyanide are added. After 3 hours of boiling under reflux, the solvent is removed under reduced pressure in vacuo, and the residue is purified by flash chromatography. The product fractions are combined and the solvent is removed. This gives 2.53 g (82% of theory) of the desired product.
HPLC (method 1): R, = 3.47 min MS (DCI(NH3)): m/z = 243.1 (M+NH4)+

'H-NMR (400 MHz, DMSO-d6): S= 7.53 (d, J= 7.53 Hz, 2H), 7.04 (d, J= 8.8 Hz, 2H), 6.57 (s, 1 H), 3.80 (s, 3H).

Example IOA

Methyl 2-bromo-5 -phenyl-l,3-thi azol-4-carboxylate O
H3li/~I O 'Ir Br s 5.0 g (21.3 mmol) of methyl 2-amino-5-phenyl-l,3-thiazol-4-carboxylate are dissolved in 50 ml of dry acetonitrile, and 7.15 g (32.0 mmol) of copper(II) bromide are added. At room temperature, 3.8 ml (3.30 g, 32.0 mmol) of tert-butyl nitrite are added dropwise. After the addition, the mixture is stirred until the evolution of gas has ceased. Water and dichloromethane are then added, the solution is acidified with aqueous 12N hydrochloric acid, further dichloromethane is added and the organic phase is separated off and dried over magnesium sulfate. After filtration, the solvent is removed and the residue is dried under reduced pressure. This gives 5.95 g(83%
of theory) of the desired product.

HPLC (method 1): Rr= 4.50 min MS (DCI(NH3)): m/z = 314.9 (M+NH4)+

'H-NMR (400 MHz, DMSO-d6): 6 = 7.57-7.42 (m, 5H), 3.71 (s, 3 H).

BHC 06 1 167-Foreign Countries ~~

Example 11A

2-Bromo-5-phenyl-1,3-thiazol-4-carboxylic acid O
HO NBr S
5.99 g (20.1 mmol) of methyl 2-bromo-5-phenyl-l,3-thiazol-4-carboxylate are dissolved in 36 ml of tetrahydrofuran, and 30 ml of an aqueous 1M lithium hydroxide solution are added. The reaction solution is stirred at room temperature for 2 h and then acidified with aqueous hydrochloric acid and diluted with aqueous saturated ammonium chloride solution. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness on a rotary evaporator.
Without further purification, 5.5 g (96% of theory) of the desired product are obtained.

HPLC (method 1): Rr= 3.40 min MS (DCI(NH3)): mfz = 300.9 (M+NH4)+

'H-NMR (400 MHz, DMSO-d6): 8= 13.2 (br s, 1 H), 7.56-7.41 (m, 5H).
Example 12A

Tert-butyl(2-bromo-5-phenyl-l,3-thiazol-4-yl)carbamate H3CL x O
O-<
NH
l-' Br S
I
Under argon and at room temperature, 4.59 ml (5.86 g, 21.29 mmol) of diphenyl phosphoryl azide are added dropwise to a solution of 5.5 g (19.36 mmol) of 2-bromo-5-phenyl-1,3-thiazol-4-BHC 06 1 167-Foreign Countries carboxylic acid and 2.97 ml (2.16 g, 21.29 mmol) of triethylamine in 48 ml of dry 1,2-dimethoxyethane and 19.1 ml (14.81 g, 199.77 mmol) of tert-butanol. After the addition, the reaction mixture is stirred at an oil bath temperature of 90 C overnight.
After cooling, aqueous saturated sodium bicarbonate solution is added, and the aqueous solution is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness using a rotary evaporator. The residue is purified by flash chromatography, and the product fractions are combined and evaporated to dryness using a rotary evaporator.
Drying under high vacuum gives 3.58 g (52% of theory) of the desired product.

HPLC (method 1): R,= 4.82 min MS (ES+): m/z = 355 and 357 (M+H)+

'H-NMR (500 MHz, DMSO-d6): 8= 9.24 (s, 1H), 7.59-7.22 (m, 5H), 1.31 (s, 9H).
Example 13A

Tert-butyl (2,5-diphenyl-l,3-thiazol-4-yl)carbamate O~CH3 NH

S
800 mg (2.25 mmol) of tert-butyl (2-bromo-5-phenyl-l,3-thiazol-4-yl)carbamate and 660 mg (5.41 mmol) of phenylboronic acid are dissolved in 20.3 ml of dry N,N-dimethylformamide, and 2.48 ml of aqueous 2M sodium carbonate solution are added. The solution is degassed by passing through a stream of argon for 15 minutes. 164.77 mg (0.23 mmol) of 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (1:1 complex with dichloromethane) are then added, and the reaction is stirred under an atmosphere of argon at an oil bath temperature of 95 C overnight. The reaction solution is filtered off through Celite , and the filter cake is washed with ethyl acetate. The solvent is removed under reduced pressure with gentle warming, and the residue is purified by preparative HPLC. The product fractions are combined, the solvent is removed and the residue is dried under reduced pressure. This gives 296 mg (27% of theory) of the desired product.

BHC 06 1 167-Foreign Countries HPLC (method 2): R,= 5.24 min MS (DCI(NH3)): m/z = 353.1 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 9.20 (s, IH), 7.97-7.87 (m, 2H), 7.64-7.32 (m, 8H), 1.31 (s, 9H).

Example 14A
2,5-Diphenyl-l,3-thiazol-4-amine w s 296 mg (0.84 mmol) of tert-butyl (2,5-diphenyl-l,3-thiazol-4-yl)carbamate are dissolved in 20 ml of a 4N solution of hydrogen chloride in dioxane and stirred at room temperature for 2 h. Using aqueous potassium hydroxide solution, the reaction mixture is made basic, and it is washed with aqueous saturated sodium carbonate solution. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure with gentle warming using a rotary evaporator. Without further purification, 189 mg (89% of theory) of the desired product are obtained.

HPLC (method 2): Rr 4.87 min MS (DCI(NH3)): m/z = 253 (M+H)+
Example 15A

5-(4-Methoxyphenyl)-2-phenyl-1,3-thiazol-4-amine HzN
H3C s 1 ~
O i 500 mg (2.21 mmol) of bromo(4-methoxyphenyl)acetonitrile are dissolved in 10 ml of dichloromethane, and 303.44 mg (2.21 mmol) of thiobenzamide are added. The mixture is stirred at reflux overnight. After cooling, the precipitated solid is filtered off with suction and dried under BHC 06 1 167-Foreign Countries high vacuum. This gives 548 mg (76% of theory) of product.
HPLC (method 1): Rr= 4.64 min MS (DCI(NH3)): m/z = 283.3 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 7.86 (d, J= 6.6 Hz, 2H), 7.54-7.41 (m, 5H), 7.02 (d, J= 7.02 Hz, 2H), 4.74 (br s, 2H), 3.79 (s, 3H).

The aminoimidazoles of the table below are prepared analogously to Example 2A.
Example Structure Characterization MS (ESIpos): m/z = 272 (M+H)+
N HZ
N HPLC (method 1): R, = 3.71 min.
/
16A ~\ H F 'H-NMR (400 MHz, DMSO-d6): S= 11.5 (b, F i IH), 8.0 (m, 2H), 7.7 (m, 2H), 7.1-7.4 (m, 4H), 5.0 (b, 2H).

MS (ESlpos): m/z = 260 (M+H)+

N HPLC (method 1): Rt = 3.57 min.
F
17A H 'H-NMR (400 MHz, DMSO-d6): S= 12.0 (s, 1 H), 7.6 (b, 2H), 7.2-7.4 (m, 3H), 7.1 (m, 1 H), 6.7 (s, 1 H), 4.8 (b, 2H).

LC-MS (method 2): Rt = 2.75 min NHZ
N MS (ES[pos): m/z = 295 (M+H)+
F
18A CI 'H-NMR (400 MHz, DMSO d6): S= 11.5 (b, N I H), 8.65 (d, 1 H), 8.0 (dd, 1 H), 7.5 (d, 1 H), 7.3 (s, 1 H), 6.75 (b, I H).

BHC 06 1 167-Foreign Countries The chloroacetylaminoimidazoles of the table below are prepared analogously to example 3A.
Example Structure Characterization MS (ESIpos): m/z = 348 (M+H)+
H_~--CI
N HPLC (method 1): R, = 3.70 min.
~ \ 0 19A ~~ N 'H-NMR (400 MHz, DMSO-d6): 6= 10.3 (b, F ~ H F 1H), 8.1 (m, 2H), 7.7 (m, 2H), 7.25-7.45 (m, 4H), 4.2(s, 2H).

MS (ESlpos): m/z = 336 (M+H)+
H~CI
N HPLC (method 1): R, = 3.58 min.

~

H 'H-NMR (400 1V1Hz, DMSO-d6): S 12.75 (s, 1 H), 10. 1 (s, 1 H), 7.2-7.9 (m, 6H), 6.7 (s, IH), 4.25 (b, 2H).

MS (ESipos): m/z = 371 (M+H)+
H_~-CI
N HPLC (method 1): Rr = 3.68 min.

21A F es H 1 / 'H-NMR (400 MHz, DMSO-d6): 6= 12.9 (b, N CI 1 H), 10.2 (b, 1 H), 8.6 (s, 1 H), 8.0 (d, 1 H), 7.3-7.6 (m, 2H), 6.8 (s, 1H), 4.2 (s, 2H).

BHC 06 1 167-Foreign Countries The chloroacetylaminoimidazoles of the table below are prepared analogously to example 4A.
Example Structure Characterization H3C MS (ESlpos): m/z = 371 (M+H)+
~CH3 H~N HPLC (method 1): R, = 3.42 min.
N H
22A N 0 'H-NMR (400 MHz, DMSO-d6): S= 12.5 (s, H l H), 9.5 (b, 1 H), 8.05 (t, 2H), 7.6-7.8 (m, F
F ~ 2H), 7.1-7.4 (m, 4H), 6.0 (b, 1H), 3.2-3.4 (b, 2H), 2.7 (m, 1 H), 1.0 (d, 6H).

H C MS (ESIpos): m/z = 359 (M+H)+
3 >--CH3 H... CH HPLC (method 1): Rt = 3.34 min.
N
23A S N 0 'H-NMR (400 MHz, DMSO-d6): S= 12.7 (s, H 1 H), 9.6 (s, 1 H), 7.2-7.8 (m, 6H), 6.8 (s, 1 H), 3.8 (b, 2H), 2.8 (m, 1H), 1.0 (d, 6H).

MS (ESlpos): m/z = 394 (M+H)+

>-CH3 HPLC (method 1): R, = 3.49 min.
H N
N H
24A N 0 'H-NMR (400 MHz, DMSO-d6): 8= 13.0 (b, F S l H), 8.6 (b, 1 H), 8.0 (d, 1 H), 7.55 (d, 1 H), H Ci 7.3 (s, 1 H), 6.8 (m, 1 H), 3.2-3.4 (b, 2H), 2.7 N
(m, I H), 1.0 (d, 6H).

BHC 06 1 167-Foreign Countries Example 25A

Tert-butyl (2R)-2-{[2-(5-fluoro-2-thienyl)-5-phenyl-lH-imidazol-4-yl]carbamoyl}pyrrolidine-1-carboxylate O
N p C>-~
NH
N
F S /
H
250 mg (0.96 mmol) of 2-(5-fluoro-2-thienyl)-5-phenyl-lH-imidazol-4-amine and 208 mg (0.96 mmol) of 1-(tert-butoxycarbonyl)-D-proline are dissolved in 5 ml of N,N-dimethylformamide, and 441 [t] of diisopropylethylamine and 550 mg (1.45 mmol) of N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate are added. The reaction mixture is stirred at room temperature for 4 days and then chromatographed using preparative HPLC and a gradient of acetonitrile and water. The product-containing fractions are combined and concentrated to dryness under reduced pressure. This gives 284 mg (65% of theory) of product.

MS (ESlpos): m/z = 457 (M+H)+
HPLC (method 1): R, = 4.20 min.

'H-NMR (400 MHz, DMSO-d6): 8= 12.6 (s, 1 H), 9.7 (d, 1 H), 7.2-7.8 (m, 6H), 6.8 (b, 1 H), 4.2 (m, 1 H), 3.3 (m, 2H), 2.2 (m, 2H), 1.8 (m, 2H) 1.3-1.5 (m, 9H).

Example 26A

Tert-butyl (4S)-4-{ [2-(5-fluoro-2-thienyl)-5-phenyl-I H-imidazol-4-yl]carbamoyl}-1,3-thiazolidin-3-carboxylate BHC 06 1 167-Foreign Countries = -40-H3c H 3C__CH3 C) N O
S "~~
NH
N
F S
H
50 mg (0.19 mmol) of 2-(5-fluoro-2-thienyl)-5-phenyl-lH-imidazol-4-amine and 45 mg (0.19 mmol) of (R)-N-(t-butylcarbonyl)thiazolidine-4-carboxylic acid are dissolved in 5 ml of dichloromethane, and 101 l of diisopropylethylamine and 50 mg (0.29 mmol) of benzotriazol-l-yloxytrispyrrolidinophosphonium hexafluorophosphate are added. The reaction mixture is stirred under reflux for 16 h and then concentrated and chromatographed using preparative HPLC and a gradient of acetonitrile and water. The product-containing fractions are combined and concentrated to dryness under reduced pressure. This gives 61 mg (67% of theory) of product.

MS (ESIpos): m/z = 458 (M+H)+
LC-MS (method 1): R, = 2.20 min.

'H-NMR (400 MHz, DMSO-d6): 8= 12.7 (s, 1 H), 9.8 (b, 1 H), 7.2-7.8 (m, 6H), 6.8 (b, 1 H), 4.2 (m, 1 H), 3.3 (m, 2H), 2.2 (m, 2H), 1.8 (m, 2H) 1.3-1.5 (m, 9H).

Example 27A

Tert-butyl N-[2-(5-fluoro-2-thienyl)-5-phenyl-1 H-imidazol-4-yl]-D-prolinamide H
N p NH
N
S
H 1 ~

270 mg of tert-butyl 2-{[2-(5-fluoro-2-thienyl)-5-phenyl-lH-imidazol-4-yl]carbamoyl}pyrrolidine-1-carboxylate are dissolved in 15 ml of dichloromethane, and 680 l (8.8 mmol) of trifluoroacetic BHC 06 1 167-Foreign Countries acid are added. After 16 h, the reaction solution is diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue is purified chromatographically using HPLC and a gradient of acetonitrile and water, the product fractions are combined and concentrated to dryness under reduced pressure. This gives 154 mg (73% of theory) of product.
MS (ESIpos): m/z = 357 (M+H)+

HPLC (method 1): Rr = 3.35 min.

'H-NMR (400 MHz, DM SO-d6): S= 12.7 (s, 1H), 9.6 (s, IH), 7.0-7.8 (m, 7H), 6.8 (s, 1H), 3.7 (m, 1 H), 1.6-3.0 (m, 6H).

Example 28A
2-Chloro-N-(2,5-diphenyl-l,3-thiazol-4-yl)acetamide cl H

S
O N

268.1 mg (1.06 mmol) of 2,5-diphenyl-l,3-thiazol-4-amine are dissolved in dry dichloromethane and cooled to 0 C. 119 l (156 mg, 1.38 mmol) of chloroacetyl chloride are added dropwise, and the mixture is stirred at room temperature overnight. Saturated aqueous ammonium chloride solution is added to the mixture, the aqueous phase is extracted twice with ethyl acetate and the combined organic phases are dried over sodium sulfate. After filtration, the solvent is removed under reduced pressure. Without further work-up, 242 mg (47% of theory) of the desired product are obtained.

HPLC (method 1): R,= 4.65 min MS (DCI(NH3)): m/z = 3 29 (M+H)+

, BHC 06 1 167-Foreign Countries Example 29A

N-(2,5-Diphenyl-1,3-thiazol-4-yl)-N2-isopropylglycinamide H
HN y S
N

HC CH

242 mg (0.74 mmol) of 2-chloro-N-(2,5-diphenyl-1,3-thiazol-4-yl)acetamide are dissolved in dry dichloromethane, and 314 l (218.1 mg, 3.69 mmol) of isopropylamine are added.
The reaction solution is stirred at 45 C overnight, and aqueous saturated sodium carbonate solution is then added. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure with gentle heating. The residue is purified by preparative HPLC. The isolated product fractions are combined and evaporated to dryness. This gives 89 mg (34% of theory) of the desired product.

LC-MS (method 3): R,= 1.44 min; MS (ES+): m/z= 352.1 (M+H)+
Example 30A

Ethyl 2-(3,4-dimethoxyphenyl)pent-4-enoate H3C~~ 0 \,-,CH3 Under an atmosphere of argon, 5.00 g(22.30 mmol) of ethyl (3,4-dimethoxyphenyl)acetate are dissolved in dry tetrahydrofuran and cooled to -78 C. Over a period of 30 min, 28.98 ml (5.32 g, 28.98 mmol) of a 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran are added = BHC 06 1 167-Foreign Countries dropwise. By occasional addition of dry tetrahydrofuran, the suspension is kept stirrable. The suspension is stirred at -78 C for 1 h, and 2.89 ml (4.05 g, 33.44 mmol) of 3-bromoprop-l-ene are then added dropwise. The reaction solution is stirred at -20 C for 2 h, and aqueous saturated ammonium chloride solution, water and a hexane/diethyl ether mixture are then added. The aqueous phase is extracted twice with a hexane/diethyl ether mixture. The combined organic phases are washed with water and aqueous saturated sodium chloride solution.
After drying, the solvent is removed on a rotary evaporator. Without further work-up, 6.33 g (64% of theory) of the desired product are obtained.

HPLC (method 1): R, = 4.61 min MS (DCI(NH3)): m/z = 282 (M+NH4)+

'H-NMR (400 MHz, DMSO-d6): S= 6.94-6.68 (m, 3H), 5.78-5.43 (m, IH), 5.11-4.92 (m, 2H), 4.14-3.95 (m, 2H), 3.78-3.67 (m, 6H), 3.67-3.58 (m, 1H), 2.75-2.32 (m, 2H), 1.17-1.05 (m, 3H).
Example 31A

Ethyl 2-(3,4-dimethoxyphenyl)-4-oxobutanoate H

H3\i\O \ / O\~liH3 H3C~_0 6.33 g(23.95 mmol) of ethyl 2-(3,4-dimethoxyphenyl)pent-4-enoate are dissolved in 67 ml of dry dichloromethane and cooled to -78 C. Ozone is passed through the solution until the starting material has been consumed. Oxygen is then passed through the solution, and 7.03 ml of dimethyl sulfide are added. The reaction mixture is allowed to warm to room temperature overnight and evaporated to dryness under reduced pressure in vacuo using a rotary evaporator. The residue is purified by flash chromatography. The product fractions are combined and evaporated to dryness using a rotary evaporator. This gives 1.48 g(23% of theory) of the desired product.

GC-MS (method 1): Rt = 6.83 min; MS (El): m/z = 266 (M)+
Example 32A

BHC 06 1 167-Foreign Countries Methyl [3-(3,4-dimethoxyphenyl)-2-oxopyrrolidin-1-yl]acetate --~r CH3 A little at a time, 2.85 g (43.56 mmol) of zinc are added to a solution, cooled to 0 C, of 1.16 g (4.36 mmol) of ethyl 2-(3,4-dimethoxyphenyl)-4-oxobutanoate and 601.6mg (4.79 mmol) of methyl glycinate hydrochloride in 32.5 ml of glacial acetic acid. The mixture is boiled under reflux for 4 h, and the solution is then allowed to cool. Chloroform is added, the mixture is filtered and the filter cake is washed with ethanol/chloroform (1:1). With gentle heating, the filtrate is concentrated under reduced pressure using a rotary evaporator. The residue is dissolved in ethyl acetate, and the insoluble particles are filtered off. The filtrate is concentrated to dryness with gentle heating under reduced pressure using a rotary evaporator, and the residue is purified by flash chromatography. This gives 900 mg (26% of theory) of the desired product.

HPLC (method 1): Rr= 3.49 min MS (ES+): m/z = 294 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6= 6.93-6.72 (m, 3H), 4.12 (dd, J= 23.0, 17.6 Hz, 2H), 3.76-3.70 (m, 6H), 3.68 (s, 3H), 3.63-3.40 (m, 3H), 2.50-1.93 (m, 2H, partially obscured by the DMSO
signal).

Example 33A
[3-(3,4-Dimethoxyphenyl)-2-oxopyrrolidin-1-yl]acetic acid H3C0 ~ \ N OH
~
- O
O

912.1 mg (3.11 mmol) of methyl [3-(3,4-dimethoxyphenyl)-2-oxopyrrolidin-l-yl]acetate are dissolved in 15 ml of tetrahydrofuran, and 15 ml of an aqueous IN lithium hydroxide solution are added. The reaction mixture is stirred at room temperature for 3 h and acidified with aqueous 6N

BHC 06 1 167-Foreign Countries hydrochloric acid, aqueous saturated ammonium chloride solution is added and the mixture is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and, under reduced pressure and with gentle heating, evaporated to dryness using a rotary evaporator.
Without further work-up, 637 mg (73 l0 of theory) of the desired product are obtained.

HPLC (method 1): Rt= 3.23 min MS (DCI(NH3)): m/z = 297.1 (M+NH4)+

'H-NMR (400 MHz, DMSO-d6): 8= 12.87 (br s, lH), 6.92-6.72 (m, 3H), 4.00 (dd, J= 29.1, 17.6 Hz, 2H), 3.77-3.68 (m, 6H), 3.62-3.38 (m, 3H), 2.49-1.89 (partially obscured by the DMSO signal, m, 2H).

Example 34A

Ethyl N-[(3,4-dimethoxyphenyl)acetyl]-N-isopropylglycinate u ~ I O~/CH3 O O N
~

5.00 g (27.52 mmol) of ethyl N-isopropylglycinate hydrochloride are dissolved in 100 ml of dry dichloromethane, and 8.44 ml (6.13 g, 60.55 mmol) of triethylamine and catalytic amounts of DMAP are added. At 0 C, 5.91 g(27:52 mmol) of 3,4-dimethoxyphenylacetyl chloride are added, and the reaction mixture is allowed to warm to room temperature. The mixture is stirred at room temperature for another I h. More dichloromethane is then added, and the reaction is stopped by addition of 20 ml of a IN aqueous sodium bicarbonate solution. The organic phase is separated off and washed with IN aqueous sodium hydroxide solution, aqueous IN hydrochloric acid solution and water. After drying over magnesium sulfate, the solvent is removed and the residue is purified by flash chromatography. The product fractions are combined and evaporated to dryness using a rotary evaporator. This gives 5.18 g(58% of theory) of the desired product.

HPLC (method 1): R, = 4.00 min MS (DCl(NH3)): m/z 324.3 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6 = 6.95-6.61 (m, 3H), 4.24-3.96 (m, 3H), 3.87 (s, 2H), 3.78-3.61 BHC 06 1 167-Foreign Countries (m, 8H), 1.26-1.09 (m, 3H), 0.99 (d, J= 6.9 Hz, 6H).
Example 35A

N-[(3,4-Dimethoxyphenyl)acetyl]-N-isopropylglycine O O
I OH
O

CH3 H C'J" CHO

5.18 g (16.02 mmol) of ethyl N-[(3,4-dimethoxyphenyl)acetyl]-N-isopropylglycinate are dissolved in 72 ml of tetrahydrofuran, and 72 ml of an aqueous 1N lithium hydroxide solution are added. The mixture is stirred at room temperature overnight and then acidified with concentrated aqueous hydrochloric acid solution. The aqueous phase is extracted repeatedly with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated to dryness.
Without further work-up, 4.23 g(89% of theory) of the desired product are obtained.

HPLC (method 1): R, = 3.46 min MS (ES+): m/z = 296 (M+H)+

'H-NMR (400 MHz, DMSO-d6): S= 12.36 (br s, IH), 6.95-6.62 (m, 3H), 4.72-3.95 (m, 2H), 3.85-3.63 (m, 9H), 1.04-0.94 (m, 6H).

Example 36A
I -lodoacetone O
I

4.34 ml (5.00 g, 54.04 mmol) of chloroacetone are dissolved in 10 ml of acetone, and 9.87 g (59.44 mmol) of potassium iodide are added. After 1.5 h of stirring at room temperature, the solid is filtered off with suction and washed with acetone. The mother liquor is concentrated to dryness with gentle heating and under a slight vacuum using a rotary evaporator. The residue is reacted further without further purification.

BHC 06 1 167-Foreign Countries GC-MS (method 1): R, = 2.07 min; MS (El+): m/z = 184.0 (M)+
'H-NMR (400 MHz, DMSO-d6): 8= 4.03 (s, 2H), 2.30 (s, 3H).
Example 37A

2-(E/Z)-1-iodoacetone O-benzyl oxime I\ ~I
CH

8.375 g (45.52 mmol) of 1-iodoacetone and 5.61 g (45.52 mmol) of O-benzylhydroxylamine are dissolved in methanol/water (45 ml/14 ml) and stirred at room temperature for 1 h. The solvent is concentrated under reduced pressure, using a rotary evaporator, to a volunle of 15 ml, and dichloromethane and water are added. The aqueous phase is extracted three times with dichloromethane, and the organic phases are combined. After drying over sodium sulfate, the solvent is removed and the residue is purified by flash chromatography. This gives 8.88 g (65% of theory) of the desired product.

HPLC (method 1): R, = 4.85 and 4.95 min MS (ES+): m/z = 290 (M+H)+

'H-NMR (400 MHz, DMSO-d6, isomer mixture): 6= 7.42-7.42 (m, IOH), 5.10 (s, 2H), 5.06 (s, 2H), 4.00 (s, 2H), 3.90 (s, 2H), 1.95 (s, 3H), 1.93 (s, 3H).

Example 38A

Ethyl 4-(E/Z)-4-[(benzyloxy)imino]-2-(3,4-dimethoxyphenyl)pentanoate BHC 06 1 167-Foreign Countries N ~0 0 ~ OcH3 Ii 0 40, I

Under an atmosphere of argon, 4.50 ml (0.96 g, 8.99 mmol) of a 2M solution of lithium diisopropylamide in tetrahydrofuran are added dropwise to a solution, cooled to -78 C, of 1.55 mg (6.92 mmol) of ethyl 3,4-dimethoxyphenylacetate in 40 ml of dry tetrahydrofuran. The solution is allowed to warm to room temperature and then once more cooled to -78 C. A
solution of 2.00 g (6.92 mmol) of 2-(EJZ)-1-iodoacetone O-benzyl oxime in 9 ml of dry tetrahydrofuran is added dropwise, and the mixture is once more allowed to warm to room temperature and stirred under reflux for I h. The solvent is then removed, and the residue is purified by flash chromatography.
The product fractions are combined and dried under reduced pressure. This gives 2.10 g (65% of theory) of the desired product.

HPLC (method 1): R,= 4.87 and 4.97 min MS (DCI(NH3)): m/z = 386 (M+H)+

'H-NMR (400 MHz, DMSO-d6, isomer mixture): 8= 7.39-7.22 (m, 5H), 6.92-6.65 (m, 3H), 5.01-4.91 (m, 2H), 4.12-3.82 (m, 3H), 3.74-3.63 (m, 6H), 2.99-2.76 (m, I H), 2.56-2.44 (m, I H, obscured by the DMSO signal), 1.83-1.59 (m, 3H), 1.16-1.04 (m, 3H).

Example 39A

3 -(3,4-Di methoxyphenyl)-5-methylpyrro I idin-2-one H3 0 ~ 0 ' ~ NH

500 mg (1.30 mmol) of ethyl-4-(EfZ)-4-[(benzyloxy)imino]-2-(3,4-dimethoxyphenyl)pentanoate BHC 06 1 167-Foreign Countries are dissolved in 300 ml of methanol, and 1.52 g of a 50% strength Raney nickel suspension in water are added. The reaction suspension is hydrogenated at 2.5 bar and room temperature overnight. The catalyst is removed by filtration through Celite , and the solution is evaporated to dryness. The residue is separated by preparative HPLC, and the product fractions are combined.
Drying under high vacuum gives 204 mg (67% of theory) of the desired product.
HPLC (method 1): R,= 3.37 min MS (DCI(NH3)): m/z = 236 (M+H)+

'H-NMR (400 MHz, DMSO-d6): S= 7.83 (s, 1 H), 6.91-6.69 (m, 3H), 3.75-3.69 (m, 6H), 3.67-3.46 (m, 2H), 2.60-2.45 (m, l H obscured by the DMSO signal), 2.28-1.98 (m, l H), 1.17 (t, J= 5.9 Hz, 3H).

Example 40A

tert-Butyl [3-(3,4-dimethoxyphenyl)-5-methyl-2-oxopyrrolidin-l-yl]acetate H3 ~ ~ O

I ~ N O

k OH~

Under an atmosphere of argon, 289.0 mg (1.23 mmol) of 3-(3,4-dimethoxyphenyl)-methylpyrrolidin-2-one are dissolved in dry 1-methyl-2-pyrrolidinone, and 58.95 mg (1.47 mmol) of a 60% strength sodium hydride suspension are added. After 10 min of stirring at room temperature, 362.75 l (479.19 mg, 2.46 mmol) of tert-butyl bromoacetate are added. A strongly exothermic reaction sets in. After a further 20 min at room temperature, the reaction is quenched with water, and the reaction mixture is separated without further work-up by preparative HPLC.
The product fractions are combined, and the solvent is removed under reduced pressure with gentle heating. This gives 147 mg (34% of theory) of the desired product.

HPLC (method 1): R, = 4.27 min MS (ES+): m/z = 350.0 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 6.92-6.71 (m, 3H), 4.15-3.99 (m, IH), 3.89-3.54 (m, 9H), 2.68-1.51 (m, 2H), 1.42 (s, 9H), 1.25-1.15 (m, 3 H).

= BHC 06 l] 67-Foreign Countries Example 41A

3-(3,4-Dimethoxyphenyl)-5-methyl-2-oxopyrrolidin-l-yl]acetic acid O O
O OH
N~

270 mg (0.77 mmol) of tert-butyl [3-(3,4-dimethoxyphenyl)-5-methyl-2-oxopyrrolidin-l-yl]acetate are dissolved in 7.5 ml of a 4M solution of hydrogen chloride in dioxane/water and stirred at room temperature for 1.5 h. The solution is concentrated to dryness under reduced pressure with gentle warming using a rotary evaporator, and the residue is dissolved in 2 ml of water and 10 ml of ethyl acetate. The solution is stirred vigorously for 5 min. The solution is dried on an EXtrelut -NT3 column, and the column is repeatedly washed with ethyl acetate. The solution is concentrated under reduced pressure in vacuo and with gentle heating using a rotary evaporator. Without further work-up, 205 mg (78% of theory) of product are obtained.

HPLC (method 1): Rr= 3.41 min MS (ES-): m/z - 292.1 (M-H)_ 'H-NMR (400 MHz, DMSO-d6): S= 12.71 (br s, I H), 6.94-6.68 (m, 3H), 4.24-3.43 (m, IOH), 2.70-1.49 (m, 2H), 1.30-1.]2 (m,3H).

Example 42A

4-tert-Butyl ] -ethyl 2-(3,4-dimethoxyphenyl)succinate O
H3CO P O/_~CH3 Under an atmosphere of argon, 28.98 m] (10.63 g, 57.97 mmol) of a 2M solution of sodium BHC 06 1 167-Foreign Countries hexamethylenedisilazane in tetrahydrofuran are added dropwise to a solution, cooled to -78 C, of 10.0 g (44.59 mmol) of ethyl (3,4-dimethoxyphenyl)acetate in 50 ml of dry tetrahydrofuran. To avoid solidification of the reaction solution, a further 30 ml of dry tetrahydrofuran are added. The reaction mixture is stirred at -78 C for I h, and 9.88 ml (13.05 g, 66.89 mmol) of tert-butyl bromoacetate are then added. The solution is stirred at -20 C for 2 h and then warmed to room temperature overnight. A saturated aqueous ammonium chloride solution, water and a 1:1 mixture of hexane:diethyl ether are then added. The aqueous phase is extracted twice with 1:1 hexane/diethyl ether. The combined organic phases are washed successively with water and aqueous saturated sodium chloride solution, dried, filtered and then evaporated to dryness under reduced pressure using a rotary evaporator. The residue is separated by flash chromatography. The product fractions are combined, the solvent is removed and the residue is dried under high vacuum.
This gives 13.7 g(73% of theory) of the desired product.

HPLC (method 1): Rr 4.72 min MS (DCI(NH3)): m/z = 356 (M+NH4)+

'H-NMR (400 MHz, DMSO-d6): 8= 6.92-6.73 (m, 3H), 4.11-3.97 (m, 2H), 3.92-3.84 (m, IH), 3.73 (s, 3H), 3.72 (s, 3H), 2.98-2.87 (m, IH), 2.59-2.51 (m, IH, obscured by the DMSO signal), 1.37 (s, 9H), 1.13 (t, J= 7.1 Hz, 3H).

Example 43A
4-tert-Butoxy-2-(3,4-dimethoxyphenyl)-4-oxobutanoic acid O

p p OH
O O

H3C-x 4.0 g(11.82 mmol) of 4-tert-butyl I-ethyl 2-(3,4-dimethoxyphenyl)succinate are dissolved in 2.1 ml of methanol, and a solution of 82.92 mg (1.48 mmol) of potassium hydroxide in 2.1 ml of water is added. The reaction mixture is stirred at room temperature overnight and then carefully neutralized using a IN aqueous hydrochloric acid solution and diluted with an aqueous saturated ammonium chloride solution. The aqueous phase is extracted twice with ethyl acetate. The BHC 06 1 167-Foreign Countries combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness using a rotary evaporator. Without further work-up, 376 mg (quantitative yield) of the desired product are obtained.

MS (DCI(NH3)): m/z = 328 (M+NH4)+

'H-NMR (400 MHz, DMSO-d6): S= 12.31 (br s, 1H), 6.95-6.73 (m, 3H), 3.86-3.76 (m, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 3.00-3.82 (m, 1 H), 2.57-2.45 (m, 1 H, obscured by the DMSO signal), 1.36 (s, 9H).

Example 44A

Ethyl 2-(3,4-dimethoxyphenyl)-3-hydroxypropanoate H3C p~oH
O
H3C-O O \-CH3 4.0 g (13.4 mmol) of ethyl (3,4-dimethoxyphenyl)acetate and 422 mg (13.4 mmol) of aqueous formaldehyde are dissolved in 13 ml of dimethylsulfonamide. 262 mg (0.77 mmol) of sodium ethoxide are added as a 20 percent by weight strength solution in ethanol.
After 30 min, acetic acid is added until the mixture is acidic, and the mixture is purified by preparative HPLC using a gradient of acetonitrile and water. The product fractions are combined and evaporated to dryness under reduced pressure. This gives 1.9 g (56% of theory) of product.

'H-NMR (400 MHz, DMSO-d6): S= 6.9 (m, 2H), 6.8 (m, 1H), 5.0 (t, IH), 4.1 (m, 2H), 3.9 (m, 1 H), 3.7 (d, 6H), 3.6 (m, l H), 3.55 (m, l H), 1.2 (t, 3H).

Example 45A

2-(3,4-Dimethoxyphenyl)-3-hydroxypropanoic acid O
OH

300 mg (1.18 mmol) of ethyl 2-(3,4-dimethoxyphenyl)-3-hydroxypropanoate are dissolved in 2 ml of a mixture of acetone and water, and 34 mg (1.42 mmol) of lithium hydroxide are added. The BHC 06 1 167-Foreign Countries mixture is stirred at 50 C for I h, and another 8 mg (0.33 mmol) of lithium hydroxide are then added. After a further hour at 50 C, the reaction mixture is diluted with ethyl acetate and acidified with dilute hydrochloric acid until it gives an acidic reaction. The organic phase is washed two more times with dilute hydrochloric acid and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is purified by preparative HPLC using a gradient of acetonitrile and water. The product fractions are combined and concentrated to dryness under reduced pressure. This gives 131 mg (49% of theory) of product.

MS (ESlpos): m/z = 244 (M+NH4)+
HPLC (method 1): Rt = 2.83 min.

'H-NMR (400 MHz, DMSO-d6): 6= 12.3 (b, 1 H), 6.9 (m, 2H), 6.8 (m, 1 H), 4.6 (b, I H), 3.9 (t 1 H), 3.7 (d, 6H), 3.5 (m, 2H).

Example 46A
4-{[tert-Buty](dimethyl)silyl]oxy}-2-(3,4-dimethoxyphenyl)butanoic acid i H3 CH3 O-SI~CH3 H3 ~ P CH3 CH3 OH

500 mg (2.55 mmol) of (3,4-dimethoxyphenyl)acetic acid are dissolved in 25 m]
of anhydrous tetrahydrofuran and cooled to -78 C. At this temperature, 1.17 g(6.37 mmol) of sodium hexamethylenedisilazane are added as a I M solution in tetrahydrofuran over a period of 10 min.
After the addition has ended, 670 mg (2.8 mmol) of 2-(bromoethoxy)-tert-butyldimethylsilane are added and the mixture is stirred at this temperature for a further 30 min, before cooling is removed.
After a further 16 h, the reaction mixture is diluted with ethyl acetate and acidified with five percent strength potassium bisulfate solution until it gives an acidic reaction. The organic phase is washed two more times with five percent strength potassium bisulfate solution and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is purified by preparative HPLC using a gradient of acetonitrile and water. The product fractions are combined and concentrated to dryness under reduced pressure. This gives 361 mg (40% of theory) of product.

' BHC 06 l 167-Foreign Countries MS (ESlpos): m/z = 355 (M+H)+

HPLC (method 1): R, = 4.95 min.

'H-NMR (400 MHz, DMSO-d6): S= 12.2 (b, 1 H), 6.9 (d, I H), 6.8 (m, 2H), 3.7 (s, 6H), 3.5 (m, 3H), 2.6 (s, 6H), 2.2 (m, I H), 1.8 (m, I H), 0.9 (s, 9H).

Example 47A
2-(3,4-Dimethoxyphenyl)pent-4-enoic acid CHZ
H3C ~ ~
O
- OH

5.0 g (25.5 mmol) of (3,4-dimethoxyphenyl)acetic acid are dissolved in 250 ml of anhydrous tetrahydrofuran and cooled to -78 C. At this temperature, 11.7 g (63.7 mmol) of sodium hexamethylenedisilazane, as a I M solution in tetrahydrofuran, are added over a period of 10 min.
After the addition has ended, 3.4 g (28.0 mmol) of allyl bromide are added and the mixture is stirred at this temperature for a further 30 min, before cooling is removed.
After a further 16 h, the reaction mixture is diluted with ethyl acetate and acidified with five percent strength potassium bisulfate solution until it gives an acidic reaction. The organic phase is washed two more times with five percent strength potassium bisulfate solution and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure.
The residue is purified by preparative HPLC using a gradient of acetonitrile and water. The product fractions are combined and concentrated to dryness under reduced pressure. This gives 4.7 g(78 /a of theory) of product.

MS (ESlpos): m/z = 254 (M+NH4)+
HPLC (method 1): Rr = 3.85 min.

'H-NMR (400 MHz, DMSO-db): S= 12.2 (b, l H), 6.9 (m, 2H), 6.8 (m, 1 H), 5.7 (m, 1 H), 5.0 (m, 2H), 3.7 (d, 6H), 3.5 (t, 1 H), 2.7 (m, I H), 2.4 (m, I H).

Example 48A

S-(2,4-Dimethoxybenzyl) 5-chlorothiophene-2-carbothioate BHC 06 1 167-Foreign Countries S
CI S

O

20 g(123.0 mmol) of 5-chlorothiophene-2-carboxylic acid, 20.6 g(123.0 mmol) of 2,4-dimethoxybenzylamine, 25.9 g(135.3 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.75 g (6.15 mmol) of DMAP and 20.7 g (135.3 mmol) of HOBt are dissolved in 250 ml of anhydrous THF, and the mixture is stirred at RT overnight. After removal of the solvents under reduced pressure, the residue is taken up in methylene chloride and the mixture is extracted twice with water and once with saturated sodium chloride solution. The organic phases are dried over sodium sulfate and filtered, and the solvent is removed under reduced pressure. Purification by flash column chromatography on silica gel (methylene chloride) gives 33.7 g (87% of theory) of the product.

LC-MS (method 3): m/z = 312.2 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6= 8.9 (t, I H), 7.7 (d, 1 H), 7.2 (d, 1 H), 7.1 (d, 1 H), 6.6 (d, l H), 6.5 (dd, 1H), 4.3 (d, 2H), 3.8 (s, 3H), 3.7 (s, 3H).

Example 49A

5-Chloro-N-(2,4-dimethoxybenzyl)thiophene-2-carbothioamide S N
CI \ I H

O

28.7 g (92.0 mmol) of Example 48A are dissolved in 450 ml of toluene. 20.5 g (50.6 mmol) of Lawesson reagent are then added, and the solution is stirred at 90 C for 3 h.
Two purifications by flash column chromatography on silica gel (cyclohexane/toluene 1:1) give 21.1 g (70% of theory) of the product.

HPLC (method 1): Rt= 4.95 min BHC 06 1 167-Foreiv-n Countries 'H-NMR (400 MHz, DMSO-d6): 8= 10.5 (t, 1 H), 7.7 (d, 1 H), 7.2 (d, 1 H), 7.1 (d, 1 H), 6.6 (d, 1 H), 6.5 (dd, I H), 4.8 (d, 2H), 3.8 (s, 3H), 3.8 (s, 3H).

Example 50A

5-Chl orothi ophene-2-carbothioami de S
S
CI NHZ

21.1 g(64.3 mmol) of Example 49A and 34.7 g (321.3 mmol) of methoxybenzene are dissolved in a mixture of trifluoroacetic acid/methylene chloride (1:5), and the mixture is stirred at RT
overnight. The solvents are removed under reduced pressure, and diethyl ether and pentane are added to the residue. The precipitated solid is filtered off and recrystallized from ethyl acetate, and the crude product is, after removal of the solvent, purified by flash column chromatography on silica gel (cyclohexane/ethyl acetate 2:1). This gives 9.7 g (85% of theory) of the product.

HPLC (method 1): R,= 3.88 min MS (DClpos): m/z= 178 (M+H)+

`H-NMR (400 MHz, DMSO-db): S= 9.8 (s, I H), 9.5 (s, I H), 7.6 (d, I H), 7.2 (d, I H).
Example 51A

S-Benzyl 5-chlorothiophene-2-carbimidothioate hydrobromide H-Br NH

S S I \
CI
/
4.0 g(22.5 mmol) of Example 50A and 4.0 g(23.6 mmol) of benzyl bromide are dissolved in 100 ml of dioxane, and the mixture is stirred at 100 C for 4 h. The reaction mixture is then diluted with a little acetonitrile and cooled to 0 C, and the solid is filtered off with suction. Removal of the remaining solvent under reduced pressure gives 2.7 g (29% of theory, purity 85%) of the product.
The mother liquor is also triturated with acetonitrile, and the solid is filtered off with suction and dried under reduced pressure. This gives 2.8 g (25% of theory, purity 69%) of the product.

BHC 06 1 167-Foreign Countries HPLC (method 1): RT=4.03 min MS (DClpos): m/z = 270 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6= 10.5 (d, I H), 7.1-7.6 (m, 7H), 4.3 (d, 1 H).
The aminoimidazole of the table below is prepared analogously to Example 2A.
Example Structure Characterization MS (ESlpos): m/z = 276 (M+H)+

52A S N HPLC (method 1): Rt = 3.69 min.
CI
H IH-NMR (400 MHz, DMSO-d6): 6= 12.0 (d, 1 H), 7.0-8.3 (m, 7H), 4.9 (d, 2H).

Example 53A

(2R)-I -tert-Butyl 2-methyl 5 -methoxypyrrol i d ine- 1,2-di carboxyl ate 0 ~
H3C~"0..,, O
~ CH3 H3C)---CH3 8.20 g(35.8 mmol) of Boc-D-proline methyl ester are dissolved in 70 ml of methanol, 1.00 g (3.3 mmol) of tetraethylammonium para-toluenesulfonate is added and the mixture is, in a jacketed electrochemical cell with argon as protective gas, cooled to 5 C
using a circulation cryostat. The cell is provided with two graphite electrodes (dimensions about 1.0 x 1.0 x 0.25 cm) which are positioned at a distance to one another of about 2 cm. For 20 h, a constant current of about 250 mA (about 5F/mol) is passed through these electrodes. The reaction solution is introduced into 500 ml of diethyl ether, whereupon the conducting salt precipitates as an oil and can be removed. The organic phase is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. This gives 9.00 g (97% of theory) of crude product which is used without further purification in the next step.

BHC 06 1 167-Foreign Countries GC-MS (method 1): R,= 5.05 min; m/z= 158 (M-Boc+H)+.

'H-NMR (400 MHz, DMSO-d6): 6= 4.15-4.02 (m, 3H), 3.87-3.76 (m, IH), 2.30-2.20 (m, IH), 2.06-1.90 (m, IH), 1.90-1.76 (m, IH), 1.42-1.30 (m, 9H), 1.21-0.95 (m, 6H).

Example 54A

(2R,5S)-1-tert-Butyl2-methyl5-methylpyrrolidine-1,2-dicarboxylate I`. ==,,, O~
H3C N/ ~ CH3 0 X'0 0 H3C-~-CH3 H 3 c In an apparatus which has been dried by heating, under an atmosphere of argon, 12.62 g (61.4 mmol) of copper bromide/dimethyl sulfide complex are initially charged in 225 ml of absolute diethyl ether, and the mixture is cooled to -50 C. 38.0 ml of methyllithium (60.8 mmol, 1.6 molar solution diethyl ether) are then added dropwise. The mixture is stirred at -45 C to -35 C
for 30 min, and 9.75 ml (92.1 mmol) of boron trifluoride diethyl etherate are then added dropwise.
The mixture is stirred at -45 C for a further 15 min, and 9.00 g (34.7 mmol) of (2R)-1-tert-butyl 2-methyl 5-methoxypyrrolidine-1,2-dicarboxylate are then added dropwise. The reaction solution is slowly thawed overnight. 60 ml of conc. ammonia solution are added, and the reaction mixture is stirred for a further 30 min. The reaction mixture is filtered through Kieselgur, the filter cake is washed with dichloromethane and the phases of the combined filtrates are separated. The organic phase is dried over sodium sulfate and concentrated. The product is separated on silica gel using cyclohexane/ethyl acetate 6/1. This gives 5.3 g (62% of theory) of considerably diastereomerically enriched (dr ~ 9:1) product.

LC-MS (method 2): Rr= 3.51 min; m/z = 144 (M-Boc+H)+

'H-NMR (400 MHz, DMSO-d6): 6= 4.22-4.15 (m, I H), 4.02-3.87 (rn, I H), 3.67-3.58 (m, 3 H), 2.36-2.19 (m, I H), 2.05-1.88 (m, I H), 1.87-1.75 (m, I H), 1.57-1.45 (m, I
H), 1.44-1.29 (m, 9 H), 1.13-1.06 (m, 3 H) Example 55A

(2R,5S)-1-(tert-butoxycarbonyl)-5-methylproline BHC 06 1 167-Foreign Countries ~ OH
H 3 c O Z'_0 0 H3C)-CH3 H3c In 40 ml of water/dioxane (1/1), 2.72 g (64.7 mmol) of lithium hydroxide monohydrate are added to 5.25 g (21.6 mmol) of (2R,5S)-1-tert-butyl 2-methyl 5-methylpyrrolidine-1,2-dicarboxylate, and the mixture is stirred overnight. The reaction mixture is concentrated under reduced pressure, and 50 ml of saturated ammonium chloride solution are added. The pH is carefully adjusted to 2-3 using dilute hydrochloric acid, and the mixture is extracted three times with in each case 50 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Evaporation gives 4.50 g (89%
of theory) of (2R,5S)-l-(tert-butoxycarbonyl)-5-methylproline in a diastereomer ratio of dr = 9:1.

LC-MS (method 2): R, = 3.06 min; m/z = 228.0 (M-H)+.

'H-NMR (400 MHz, DMSO-d6): 8= 4.23-4.14 (m, I H), 4.03-3.86 (m, I H), 3.35-3.31 (s, I H), 2.37-2.18 (m, I H), 2.04-1.90 (m, I H), 1.87-1.74 (m, I H), 1.58-1.46 (m, I
H), 1.43-1.28 (m, 9 H), 1.13-1.07 (m, 3 H).

Example 56A

tert-Butyl-(2R,5S)-2-{[2-(5-chloro-2-thienyl)-5-phenyl-lH-imidazol-4-yl]carbamoyl}-5-methylpyrrol idi ne-l-carboxy late H
H3C N ~~'r N N
~O O N
~+ O
H3li`` ~
/y`\CH3 H 3 c c.i 424 mg (1.85 mmol) of Example 55A, 704 mg (1.85 mmol) of HATU and 1.2 ml (6.73 mmol) of BHC 06 1 167-Foreign Countries N,N-diisopropylethylamine are added to a solution of 464 mg (1.68 mmol) of Example 52A in 8 ml of DMF. The mixture is then stirred at room temperature overnight. For work-up, the reaction mixture is separated directly by preparative HPLC using a gradient of acetonitrile and water. The product-containing fractions are combined and, after removal of the solvents under reduced pressure, are once more purified by preparative HPLC. Removal of the solvents from the product-containing fractions on a rotary evaporator gives 612 mg (75% of theory) of the product.

MS (ESlpos): m/z = 487 (M+H)+
HPLC (method 1): R, = 4.49 min.

'H-NMR (400 MHz, DMSO-d6): 6= 12.8-12.6 (m, 1 H), 9.6-10.0 (dd, l H), 7.1-7.8 (m, 7H), 4.2-4.4 (m, 1H), 3.8-4.0 (m, lH), 1.4-2.4 (m, 3 H), 1.1-1.4 (m, 13H).

BHC 06 1 167-Foreign Countries Exemplary embodiments Example 1 N2-[(3,4-Dimethoxyphenyl)acetyl]-N-(2,5-diphenyl-1 H-imidazol-4-yl)-N~-isopropylglycinamide CH3 I ~
~
o 0 H

3C~p NN ~ NH
p N-)0- H

40 mg (0.19 mmol) of 3,4-dimethoxyphenylacetic acid, 2.42 mg (0.018 mmol) of 1H-benzotriazol-1-ole and 38mg (0.19 mmol) of N-[2-(dimethylamino)ethyl]-N'-isopropylcarbodiimide as coupling agent are added to a solution of 60 mg (0.18 mmol) of N-(2,5-diphenyl-lH-imidazol-4-yl)-N2-isopropylglycinamide in 2.5 ml of DMF. The mixture is then stirred at room temperature overnight. For work-up, the reaction mixture is separated directly by preparative HPLC using a gradient of acetonitrile and water. The product-containing fractions are combined and evaporated to dryness under reduced pressure. This gives 84 mg (88% of theory) of the product.

MS (ESIpos): m/z = 513 (M+H)+
HPLC (method 1): R, = 4.06 min.

'H-NMR (400 MHz, DMSO-d6): 8= 12.4-12.6 (d, 1H), 9.6-9.8 (d, 1H), 6.6-8.1 (m, 13H), 4.7 (m, l H), 3.5-4.3 (m, I OH), 1.1 (m, 6H).

The examples of the table below are prepared analogously to Example I using the suitable amine and the suitable carboxylic acid. Also suitable for use as coupling agents are N-[(dimethylamino)(3 H-[ 1,2,3 ]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-methanaminium hexafluorophosphate (HATU) or (1H-benzotriazol-1-yloxy)(tripyrrolidin-l-yl)phosphonium hexafluorophosphate (PyBOP).

BHC 06 1 167-Foreign Countries Example Structure Characterization MS (ESipos): m/z = 567 (M+H)+
O
HsC ~ 0 H HPLC (method 1): R, = 4.00 min.

2 H3C' 0 NN ~ NH 'H-NMR (400 MHz, DMSO-d6): S=
H3C 3C~CH3 0 N\ 12.6-12.8 (m, IH), 9.7-9.9 (m, IH), S 7.6-7.8 (m, 2H), 7.2-7.5 (m, 4H), 6.7-7.0 (m, 4H), 3.9-5.1 (m, 4H), 3.7 (m, F 6H), 3.3 (s, 3H), 0.8-1.1 (m, 6H).

MS (ESipos): m/z = 523 (M+H)+

I
O /
I O HPLC (method 1): R, = 3.99 min.

3 HO \ N / NH 'H-NMR (400 MHz, DMSO-d6): 8=
12.6-12.8 (m, IH), 9.5-9.9 (m, 1 H), 8.8-9.0 (m, 1 H), 7.6-7.8 (m, 2H), 7.2-7.4 7.4 (m, 4H), 6.5-6.9 (m, 4H), 3.3-4.7 F (m, 8H), 1.0 (m, 6H).

MS (ESIpos): m/z = 537 (M+H)+
"0 a j H HPLC (method 1): Rt = 4.03 min.
HsC ) 4 H3C~0 N~N ~ NH 'H-NMR (400 MHz, DMSO-d6): 8=
H3C~CH~ N 12.6-12.8 (m, 1H), 9.6-9.9 (m, 1H), S 7.6-7.8 (m, 2H), 7.2-7.4 (m, 4H), 6.5-6.9 (m, 4H), 3.6-4.8 (m, 11 H), 1.0 F (m, 6H).

MS (ESIpos): m/z = 549 (M+H)+
H3 C-O \/ HPLC (method 1): R, = 4.11 min.
H C N ``~' N
3\0 / NH 'H-NMR (400 MHz, DMSO-d6): 8=
0 O N~ 12.6-12.8 (m, IH), 9.6-9.9 (m, IH), H3C S 7.5-7.8 (m, 2H), 7.2-7.4 (m, 4H), 6.7-6.9 (m, 4H), 4.5 (m, 1H), 3.1-3.9 (m, F 9H), 1.7-2.2 (m, 4H), 1.2-1.4 (3H).

BHC 06 1 167-Foreign Countries Example Structure Characterization H MS (ESIpos): m/z = 527 (M+H)+
~ 3 O ~ HPLC (method 1): R, = 4.16 min.

6 H3C, 0 N~N NH 'H-NMR (400 MHz, DMSO-d6): S=
12.4-12.7 (m, 1 H), 9.6-9.9 (m, I H), CH b CH ~ N
7.6-8.1 (m, 4H), 7.2-7.5 (m, 6H), 6.7-6.9 (m, 3H), 3.4-4.8 (m, IOH), 0.6-1.4 (m, 9H).

MS (ESlpos): m/z = 539 (M+H)+
O H HPLC (method 1): R, = 4.23 min.
N
7 O N NH 'H-NMR (400 MHz, DMSO-d6): S=
H3C CH ~ N 12.6-12.8 (m, 1 H), 9.6-9.9 (m, 1 H), 7.2-7.9 (m, 6H), 6.8 (b, 1 H), 3.6-4.7 (m, 4H), 2.9 (m, 1 H), 0.8-2.0 (m, F 17H).

Ci MS (ESlpos): m/z = 602 (M+H)+

/ HPLC (method 1): R, = 4.09 min.

8 / I O H 'H-NMR (400 MHz, DMSO-d6): S=
O N NH 12.7-13.1 (m, IH), 10.0 ] 0.2 (m, CH3 H3C~ 3C~CH 3 N` IH), 8.6-8.9 (m, IH), 7.9-8.2 (m, IH), 7.3-7.6 (m, 2H), 6.8-7.0 (m, 4H), 3.6-5.1 (m, IOH), 3.4 (s, 3H), F
0.8-1.0 (m, 6H).

CI MS (ESipos): mlz = 572 (M+H)+

HPLC (method 1): R, = 4.07 min.
O
9 H 'H-NMR (400 MHz, DMSO-d6): 8=
O N NH 12.8 13.1 (m, I H), 9.9-10.2 (m, 1 H), ~
CH3 H3C CH 0 N 8.6-8.9 (m, 1 H), 7.9-8.2 (m, 1 H), 7.3-S 7.6 (m, 2H), 6.7-6.9 (m, 4H), 3.6-4.8 (in, I I H), 1.0 (m, 6H).
F

BHC 06 1 167-Foreign Countries Example Structure Characterization MS (ESIpos): m/z = 527 (M+H)+
~
H3C~0 0 HPLC (method 1): R, = 4.21 min.
H
H3C' O NN / NH 'H-NMR (400 MHz, DMSO-d6): 6=
12.4-12.7 (m, 1 H), 9.6-9.9 (m, 1 H), CH3~ CH~ N
6.7-8.2 (m, 13H), 3.6-4.8 (m, lOH), 0.6-1.4 (m, 9H).

~ MS (ESIpos): m/z = 525 (M+H)+
F ~ 0 H ~
~ HPLC (method 1): Rt = 4.27 min.

11 / N~N " NH 'H-NMR (400 MHz, DMSO-d6): 6=
.~O '~' 0 N
H3C H3C CH3 12.4-12.7 (b, IH), 9.6-9.8 (b, IH), 5 6.9-7.8 (m, IOH), 6.75 (b, 1H), 3.8-5.8 (m, 4H), 3.8 (s, 3H), 0.8-1.1 (m, F 6H).

~ MS (ESIpos): m/z = 535 (M+H)+
H3 C- O N HPLC (method 1): R, = 3.97 min.
~
12 H3C`0\ I N rKNH 'H-NMR (400 MHz, DMSO-d6): 8=
N~
O 0 12.6-12.8 (m, 1 H), 9.7-10.0 (m, I H), S 6.7-7.8 (m, IOH), 4.5 (m, IH), 3.5-3.8 (m, l OH), 1.8-2.4 (m, 4H).
F
CH3 / MS (ESipos): m/z = 543 (M+H)+
O HPLC (method 1): R, = 3.98 min.

13 H3C' 0 N~N / NH 'H-NMR (400 MHz, DMSO-d6): 6=
C~CHO N` 12.4-12.8 (m, IH), 9.6-10.0 (m, 1H), H C'~3 3 6.8-8.1 (m, 13H), 3.3-5.2 (m, 13H), 0.8-1.2 (m, 6H).

BHC 06 1 167-Foreign Countries Example Structure Characterization F MS (ESIpos): m/z = 579 (M+H)`
HPLC (method 1): R, = 4.09 min.
H3C~0 O

14 H H 'H-NMR (400 MHz, DMSO-d6): S=
3C~ O N~ i 0 N NH 12.5-13.8 (m, IH), 9.8-10.0 (m, 1H), H3C H3C CH3 6.8-8.2 (m, I 1 H), 3.2-5.2 (m, 13H), 0.8-1.2 (m, 6H).

F
~ MS (ESlpos): m/z = 537 (M+H)+
H ~/ HPLC (method 1): R, = 4.08 min.
N

15 N ~ NH 'H-NMR (400 MHz, DMSO-d6): 8=
O 0 0 N 12.6-12.8 (m, IH), 9.8-10.0 (m, IH), .O S 7.2-7.8 (m, 9H), 6.8 (m, 1 H), 4.5 (m, 1H), 1.2-3.8 (m, 17H).
F

F MS (ESipos): m/z = 549 (M+H)+
/ HPLC (method 1): R, = 4.11 min.
H3C~0 \ O

16 H3C\ ~/ N 'H-NMR (400 MHz, DMSO-d6): 6=
O N ~
0 N NH 12.4-12.8 (m, 1 H), 9.6-10.0 (m, l H), H3C CH3 6.6-8.2 (m, I 1 H), 3.3-4.7 (m, l I H), 1.0-1.2 (m, 6H).

F
~ MS (ESIpos): m/z = 485 (M+H)+
O O ~/ HPLC (method 1): R, = 3.72 min.
H

17 ~~ N Y NH 'H-NMR (400 MHz, DMSO-d6): 6=
H3C CH 0 N~ 12.6-12.8 (m, l H), 9.5-9.8 (m, l H), S 7.2-7.8 (m, 6H), 6.8 (m, 1 H), 3.2-4.8 (m, 7H), 0.8-2.7 (m, 13H).
F

BHC 06 1 167-Foreign Countries Example Structure Characterization MS (ESlpos): m/z = 501 (M+H)+
F ~ O H
~ HPLC (method 1): R, = 4.26 min.

18 / N,~,-yN / NH 'H-NMR (400 MHz, DMSO-d6): 6=
12.4-12.8 (m, I H), 9.6-9.8 (m, 1 H), H C'~3 C~CH3 0 N

7.1-8.1 (m, 14H), 3.1-5.2 (m, 7H), 0.8-1.2 (m, 6H).

MS (ESipos): m/z = 545 (M+H)+
CI
0 HPLC (method 1): R, = 4.56 min.
H

19 CI N.,-yN NH 'H-NMR (400 MHz, DMSO-d6): 6=

12.6-12.8 (m, 1 H), 9.6-9.8 (m, 1 H), 6.7-7.8 (m, IOH), 3.2-4.8 (m, 5H), S
0.8-1.2 (m, 6H).
F

MS (ESlpos): m/z = 541 (M+H)+

O / O HPLC (method 1): R, = 434 min.
H

20 CI N / NH 'H-NMR (400 MHz, DMSO-d6): 8=
H C'J~' CH 0 N 12.6-12.8 (m, 1 H), 9.6-9.8 (m, 1 H), 6.7-7.8 (m, IOH), 3.2-4.8 (m, 8H), s 0.8-1.2 (m, 6H).
F

MS (ESipos): m/z = 571 (M+H)+

O / 0 HPLC (inethod 1): R, = 4.33 min.
H

21 CI N~N / NH 'H-NMR (400 MHz, DMSO-d6): 6=
H C' 3C~CH3 0 N 12.6-12.8 (m, 1 H), 9.6-9.8 (m, 1 H), 6.7-7.8 (m, IOH), 3.2-5.2 (m, IOH), s 0.8-1.2 (m, 6H).
F

BHC 06 1 167-Foreign Countries Example 22 N-{2-[(2,5-Diphenyl-l,3-thiazol-4-yl)amino]-2-oxoethyl }-N-isopropyl-2-oxo-1-oxaspiro[4.5]decane-4-carboxamide O H
N
O N y S
O N

O
50mg (0.14 mmol) of N-(2,5-diphenyl-l,3-thiazol-4-yl)-N2-isopropylglycinamide, 39.5 mg (0.20 mmol) of 2-oxo-l-oxaspiro[4.5]decane-4-carboxylic acid and 79.3 pl (58.84 mg, 0.46 mmol) of diisopropylethylamine are dissolved in dry N,N-dimethylformamide. 75.73 mg (0.20 mmol) of HATU are added, and the mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and acetonitrile and purified by preparative HPLC. The product fractions are combined and evaporated to dryness. This gives 26 mg (34% of theory) of the desired product.
HPLC (method 2): Rr= 4.93 min MS (ES+): m!z = 532 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6= 10.48-10.11 (m, 1H), 8.00-7.26 (m, IOH), 4.69-3.53 (m, 3H), 3.00-2.55 (m, 2H), 2.35-0.81 (m, 17H).

Example 23 NZ-[(), ,4-Dimethoxyphenyl)acetyl]-N-(2,5-diphenyl-1,3-thiazol-4-yl)-NZ-isopropylglycinamide = BHC 06 1 167-Foreign Countries ~ H3 H ~'~K N

I
O y II S
UH3 O N ~
H3li vHg / \

40 mg (0.11 mmol) of N-(2,5-diphenyl-1,3-thiazol-4-yl)-N2-isopropylglycinamide, 31.3 mg (0.16 mmol) of (3,4-dimethoxyphenyl)acetic acid and 63.4 1 (47.07 mg, 0.36 mmol) of diisopropylethylamine are dissolved in dry N,N-dimethylformamide. 60.58 mg (0.16 mmol) of HATU are added, and the mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and acetonitrile and purified by preparative HPLC. The product fractions are combined and evaporated to dryness. This gives 41 mg (69% of theory) of the desired product.
HPLC (method 2): Rt= 4.78 min MS (ES+): m/z = 530 (M+H)+

'H-NMR (400 MHz, DMSO-d6): S= 10.44-10.06 (m, 1H), 8.00-6.55 (m, liH), 4.70-3.85 (m, 3H), 3.78- 3.52 (m, 8H), 1.11-0.86 (m, 6H).

Example 24 2-[3-(3,4-Dimethoxyphenyl)-2-oxopyrrolidin-l-yl]-N-[2-(5-fluoro-2-thienyl)-4-phenyl-1 H-imidazol-5-yl]acetamide ~ I
\
O
H N N / 'N
N
O H
O

F

BHC 06 1 167-Foreign Countries 100mg (0.36 mmol) of [3-(3,4-dimethoxyphenyl)-2-oxopyrrolidin-l-yl]acetic acid, 111.4mg (0.43 mmol) of 2-(5-fluoro-2-thienyl)-4-phenyl-lH-imidazol-5-amine and 187.0 l (138.83 mg, 1.07 mmol) of diisopropylethylamine are dissolved in dry dichloromethane.
279.49 mg (0.54 mmol) of PyBOP are added, and the mixture is stirred at a bath temperature of 65 C
overnight. After cooling, the reaction mixture is concentrated using a rotary evaporator, dissolved using water and acetonitrile and purified by preparative HPLC. The product fractions are combined and evaporated to dryness. For further work-up, the product is purified a second time by preparative HPLC. This gives 62 mg (33% of theory) of the desired product.

HPLC (method 2): Rr= 3.91 min MS (ES+): m/z = 521 (M+H)+

'H-NMR (400 MHz, DMSO-d6): S= 12.94-12.62 (m, IH), 10.19-9.75 (m, 1H), 7.78-6.66 (m, lOH), 4.28-4.00 (m, 2H), 3.80-3.41 ( m, 9H), 2.48-1.91 (m, 2H partially obscured by the DMSO
signal).

Example 25 (4S)-3-[(3,4-Dimethoxyphenyl)acetyl]-N-[2-(5-fluoro-2-thienyl)-5-phenyl-1 H-imidazol-4-yl]-1,3-thiazolidin-4-carboxamide iH$ S

H O / "".. r N Y?N I N

H3C~ ~ O N
O O

S

F
At 0 C, 1 ml of trifluoroacetic acid is added to a solution of 61 mg (0.13 mmol) of tert-butyl (4S)-4-{[2-(5-fluoro-2-thienyl)-5-phenyl-1 H-imidazol-4-yl]carbamoyl}-1,3-thiazolidine-3-carboxylate in I ml of dichloromethane. The mixture is stirred at RT for 18 hours and evaporated to dryness.
2.5 ml of DMF are then added, followed by 28 mg (0.14 mmol) of 3,4-dimethoxyphenylacetic acid, 1 12 pl of diisopropylethylamine and 54 mg (0.14 mmol) of N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate.

BHC 06 1 167-Foreign Countries The reaction mixture is stirred at room temperature for 18 hours and then chromatographed by preparative HPLC using a gradient of acetonitrile and water. The product-containing fractions are combined and evaporated to dryness under reduced pressure. This gives 56 mg (78% of theory) of product.

MS (ESIpos): m/z = 553 (M+H)+
HPLC (method 1): Rr= 1.96 min.

'H-NMR (400 MHz, DMSO-d6): 8= 12.6-12.8 (m, IH), 9.8-10.1 (m, 1H), 6.7-7.8 (m, IOH), 4.3-5.2 (m, 3H), 3.5-3.9 (m, 8H), 3.0-3.5 (m, 2H).

Example 26 Nz-[(3,4-Dimethoxyphenyl)acetyl]-N2-isopropyl-N-[5-(4-methoxyphenyl)-2-phenyl-1,3-thiazol-4-yl]glycinamide O"CH3 ~ I 0 H

O \ N-y N ~ S CH3 H CCHO N

A solution of 75 mg (0.27 mmol) of 5-(4-methoxyphenyl)-2-phenyl-l,3-thiazol-4-amine, 94.13 mg (0.32 mmol) of N-[(3,4-dimethoxyphenyl)acetyl]-N-isopropylglycine, 207.34 mg (0.40 mmol) of PyBOP and 138.8 l (103.0 mg, 0.80 mmol) of diisopropylethylamine in 3 m] of dry dichloromethane is stirred at an oil bath temperature of 65 C overnight. After cooling, the residue is dissolved in acetonitrile/water and separated by preparative HPLC. The product fractions are combined and evaporated to dryness under reduced pressure with gentle heating using a rotary evaporator. This gives 39 mg (25% of theory) of the desired product.

HPLC (method 1): R2= 4.62 min MS (ES+): m/z = 560 (M+H)+

= BHC 06 1 167-Foreign Countries 'H-NMR (400 MHz, DMSO-d6): 8= 10.35-9.93 (m, IH), 7.99-6.55 (m, 12H), 4.70-3.58 (m, 14H), 1.11-0.88 (m, 6H).

Example 27 2-[3-(3,4-Dimethoxyphenyl)-5-methyl-2-oxopyrrolidin-l-yl]-N-[2-(5-fluoro-2-thienyl)-4-phenyl-1 H-imidazol-5-yl]acetamide / I
\
O
H3CO / \ N N / IN
N

O CH3 CH3 S ~

F
100mg (0.34 mmol) of 3-(3,4-dimethoxyphenyl)-5-methyl-2-oxopyrrolidin-l-yl]acetic acid and 106.08 mg (0.41 mmol) of 2-(5-fluoro-2-thienyl)-4-phenyl-1 H-imidazol-5-amine are dissolved in dry dichloromethane, and 178.15 l (132.19 mg, 1.02 mmol) of N,N-diisopropylethylamine and 266.12 mg (0.51 mmol) of PyBOP are added. The mixture is stirred at an oil bath temperature of 65 C overnight and then concentrated to dryness using a rotary evaporator. The residue is coevaporated with toluene and then purified by preparative HPLC. The product fractions are combined and concentrated to dryness using a rotary evaporator. Drying under high vacuum gives 43 mg (24% of theory) of the desired product.

HPLC (method 1): R, = 3.94 min MS (ES+): m/z = 535 (M+H)+

'H-NMR (400 MHz, DMSO-d6): S= 12.96-12.60 (m, 1 H), 10.23-9.68 (m, I H), 7.90-6.59 (m, I OH), 4.48-3.48 (m, I OH), 2.41-2.73 (m, IH), 2.27-1.98 (m, 1H), 1.68-1.07 (m, 3H).

Example 28 tert-Butyl 3-(3,4-dimethoxyphenyl)-4-[(2-{[2-(5-fluoro-2-thienyl)-4-phenyl-lH-imidazol-5-yl]amino } -2-oxoethyl)(isopropyl)am ino] -4-oxobutanoate BHC 06 1 167-Foreign Countries ~ I
\

O H
N N N
N
O 0 H3C CH~ H ~

H3li 0 H3C_ - F

250.0 mg (0.70 mmol) of N-[2-(5-fluoro-2-thienyl)-5-phenyl-lH-imidazol-4-yl]-isopropylglycinamide are dissolved in dry N,N-dimethylformamide, and 238.1 mg (0.77 mmol) of 4-tert-butoxy-2-(3,4-dimethoxyphenyl)-4-oxobutanoic acid, 371.28 mg (0.98 mmol) of HATU and 388.8 l (288.46 mg, 2.23 mmol) of N,N-diisopropylethylamine are added. The reaction mixture is stirred at room temperature overnight. The solution is diluted with acetonitrile and water and purified by preparative HPLC. The product fractions are combined, and the solvent is removed.
The residue is dried under high vacuum. This gives 367 mg (79% of theory) of the desired product.
HPLC (method 1): R, = 4.48 m i n MS (ES+): m/z = 651 (M+H)+

'H-NMR (400 MHz, DMSO-d6): S= 12.85-12.53 (m, 1H), 9.83-9.45 (m, 1H), 7.88-6.67 (m, 10 H), 4.63 -3.57 (m, 8H), 3.52 (s, 2H), 2.92-2.68 (m, 1H), 2.58-2.39 (m, 1H), 1.41-0.58 (m, 15H).
Example 29 3-(3,4-Dimethoxyphenyl)-4-[(2-{ [2-(5-fluoro-2-thienyl)-4-phenyl-1 H-imidazol-5-yl]amino}-2-oxoethyl)(isopropyl)amino]-4-oxobutanoic acid BHC 06 1 167-Foreign Countries ~ I

N N N
N
O O
CH O H3C CH3 H _ OH S /
F
314 mg (0.48 mmol) of tert-butyl-3-(3,4-dimethoxyphenyl)-4-[(2-{ [2-(5-fluoro-2-thienyl)-4-phenyl-lH-imidazol-5-yl]amino}-2-oxoethyl)(isopropyl)amino]-4-oxobutanoate are dissolved in 20 ml of a 4N solution of hydrogen chloride in dioxane, and the mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and with gentle heating, and the residue is separated by preparative HPLC. The product fractions are combined and concentrated to dryness using a rotary evaporator. This gives 121.2 mg (42% of theory) of the desired product.

HPLC (method 1): R, = 3.91 min MS (ES+): m/z = 595 (M+H)+

'H-NMR (400 MHz, DMSO-d6): S= 12.90-12.52 (m, IH), 12.21-11.93 (br s, IH), 9.86-9.45 (m, IH), 7.90-6.68 (m, IOH), 4.67-4.26 (1H), 4.26-3.53 (m, 7H), 3.52-3.38 (s, 2H), 3.02-2.75 (m, 1H), 2.60-2.35 (m, 1H), 1.26-0.58 (m, 6H).

Example 30 2-(3,4-Dimethoxyphenyl)-N-(2-{[2-(5-fluoro-2-thienyl)-4-phenyl-lH-imidazol-5-yl]amino}-2-oxoethyl)-4-hydroxy-N-i sopropylbutanamide BHC 06 1 167-Foreign Countries i H3 ~
Q
O
H
O N N N

OH
S

F
54mg (0.15 mmol) of 4-{[tert-butyl(dimethyl)silyl]oxy}-2-(3,4-dimethoxyphenyl)butanoic acid are added to a solution of 50 mg (0.14 mmol) of N-(2,5-diphenyl-1 H-imidazol-4-yl)-N2-isopropylglycinamide in 2 ml of DMF, 30 l (0.17 mmol) of diisopropylethylamine and 80 mg of PyBOP are added and the mixture is stirred at room temperature overnight. The solution is diluted with dichloromethane and washed twice with five percent strength of potassium bisulfate solution, dried over sodium sulfate, filtered and concentrated to 2 ml under reduced pressure. 0.3 ml of trifluoroacetic acid is added to the residue, and after a further 5 inin the mixture is diluted with dichloromethane. The organic phase is washed with 1N aqueous sodium hydroxide solution and saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. For work-up, the reaction mixture is separated directly by preparative HPLC using a gradient of acetonitrile and water. The product-containing fractions are combined and evaporated to dryness under reduced pressure. This gives 12 mg (15% of theory) of the product.

MS (ESlpos): m/z = 581 (M+H)+
HPLC (method 1): Rr = 3.90 min.

'H-NMR (400 MHz, DMSO-d6): 8= 12.6-12.9 (m, 1 H), 9.6-9.8 (m, 1 H), 6.7-7.9 (m, I 1 H), 0.8-4.6 (m, 20H).

Example 31 2-(3,4-Dimethoxyphenyl)-N-(2-{ [2-(5-fluoro-2-thienyl)-4-phenyl-1 H-imidazol-5-yl]amino}-2-oxoethyl)-3-hydroxy-N-isopropylpropanamide BHC 06 1 167-Foreign Countries /
CH

O
H
O N~N N

S

F
56 mg (0.25 mmol) of 2-(3,4-dimethoxyphenyl)-3-hydroxypropanoic acid are added to a solution of 80 mg (0.25 mmol) of N-(2,5-diphenyl-lH-imidazol-4-yl)-N2-isopropylglycinamide in 2 ml of DMF, 50 l (0.28 mmol) of diisopropylethylamine and 128 mg (0.25 mmol) of PyBOP are added and the mixture is stirred at room temperature overnight. For work-up, the reaction mixture is separated directly by preparative HPLC using a gradient of acetonitrile and water. The product-containing fractions are combined and evaporated to dryness under reduced pressure. This gives 19 mg (13% of theory) of the product.

MS (ESlpos): m/z = 567 (M+H)+
HPLC (method 1): Rr = 3.88 min.

'H-NMR (400 MHz, DMSO-d6): 6= 12.6-12.9 (m, IH), 9.6-9.8 (m, 1H), 6.7-7.9 (m, I IH), 0.8-4.6 (m, 18H).

Example 32 N-(2,5-Diphenyl-1 H-imidazol-4-yl)-N2-isopropyl-N2 -(tetrahydro-2H-pyran-4-ylacetyl)glycinamide /
O O
H
N ~ NH
O N-H

BHC 06 1 167-Foreign Countries 28 mg (0.2 mmol) of tetrahydro-2H-pyran-4-yl-acetic acid are added to a solution of 60 mg (0.18 mmol) of N-(2,5-diphenyl-1 H-imidazol-4-yl)-N2-isopropylglycinamide in 2.5 ml of DMF.
2.4 mg (0.02 mmol) of hydroxybenzotriazole and 38 mg (0.2 mmol) of EDC are added, and the mixture is stirred at room temperature overnight. For work-up, the reaction mixture is separated directly by preparative HPLC using a gradient of acetonitrile and water. The product-containing fractions are combined and evaporated to dryness under reduced pressure. This gives 64 mg (75%
of theory) of the product.

MS (ESlpos): m/z = 461 (M+H)+
HPLC (method 1): R, = 3.81 min.

'H-NMR (400 MHz, DMSO-d6): 8= 12.4-12.8 (m, 1H), 9.6-9.8 (m, IH), 7.2-8.2 (m, I OH), 3.7-4.7 (m, 5H), 3.3 (s, 2H), 0.9-2.4 ( m, 13H).

The examples of the table below are prepared analogously to Example 25 using the appropriate BOC-protected amine 56A and the appropriate carboxylic acid.

Example Structure Characterization MS (ESIpos): m/z = 565 (M+H)+
H C H / HPLC (method 1): Rt = 4.22 min.
3 N/' N
NH
33 0 0 N 'H-NMR (400 MHz, DMSO-d6): 6=
~ 12.6-12.8 (m, I H), 9.7-10.3 (m, 1 H), H'o, o \~ S 6.7-7.9 (m, l OH), 4.4-4.7 (m, 1 H), ci 4.1-4.3 (m, l H), 3.2-3.8 (m, 8H), 1.5-2.4 (m, 4H), 1.1-1.3 (m, 3H).

\ MS (ESIpos): m/z = 595 (M+H)+
~
H ~ HPLC (method 1): Rt = 4.06 min.
H3C~ I N /
34 H3c-O N- NH 'H-NMR (400 MHz, DMSO-d6): 6=
o 12.6-12.9 (m, 1H), 9.8-I0.3 (m, IH), o S 6.6-7.9 (rn, IOH), 2.9-5.0 (m, 12H), H3 c C, 2.2-2.4 (m, I H), 1.8-2.1 (m, 2H), 1.4-H3o-o 1.6 (m, 1 H), 1.0-1.3 (m, 3 H).

BHC 06 1 167-Foreign Countries B) Evaluation of the physiololZical activity The suitability of the compounds according to the invention for treating thromboembolic disorders can be demonstrated using the following assay systems:

In vitro enzyme assay Measurement of the thrombin inhibition To determine the thrombin inhibition of the substances listed above, a biochemical test system is used in which the conversion of a thrombin substrate is used for determining the enzymatic activity of human thrombin. Here, thrombin cleaves aminomethylcoumarin, which is measured fluorescently, from the peptic substrate. The determination is carried out in microtiter plates.

Substances to be tested are dissolved in various concentrations in dimethyl sulfoxide and incubated for 15 min with human thrombin (0.06 nmol/1 dissolved in 50 mmol/1 of Tris buffer [C,C,C-tris(hydroxymethyl)aminomethane], 100 mmol/1 of NaCI, 0.1 % BSA [bovine serum albumin], pH 7.4) at 22 C. The substrate (5 mol/1 Boc-Asp(OBzl)-Pro-Arg-AMC from Bachem) is then added. After 30 min of incubation, the sample is excited at a wavelength of 360 nm and the emission is measured at 460 nm. The measured emissions of the test batches with test substance are compared to the control batches without test substance (only dimethyl sulfoxide instead of test substance in dimethyl sulfoxide) and the IC50 values are calculated from the concentration/activity relationships. Representative activity data from this test are listed in table A below:

Table A

Example No. IC50 InMI

21 0.7 30 2.4 31 3.1 33 0.33 BHC 06 1 167-Foreign Countries Determination of the selectivity To demonstrate the selectivity of the substances with respect to thrombin inhibition, the test substances are examined for their inhibition of other human serin proteases, such as factor Xa, factor Xla, trypsin and plasmin. To determine the enzymatic activity of factor Xa (1.3 nmol/1 from Kordia), factor XIa (0.4 nmol/l from Kordia), trypsin (83 mU/ml from Sigma) and plasmin (0.1 g/ml from Kordia), these enzymes are dissolved (50 mmol/1 of Tris buffer [C,C,C-tris(hydroxymethyl)aminomethane], 100 mmol/1 of NaCI, 0.1% BSA [bovine serum albumin], 5 mmol/1 of calcium chloride, pH 7.4) and incubated for 15 min with test substance in various concentrations in dimethyl sulfoxide and also with dimethyl sulfoxide without test substance. The enzymatic reaction is then started by addition of the appropriate substrates (5 pmol/1 of Boc-Ile-Glu-Gly-Arg-AMC from Bachem for factor Xa and trypsin, 5 pmol/1 of Boc-Glu(OBzl)-Ala-Arg-AMC from Bachem for factor Xla, 50 pmol/1 of MeOSuc-Ala-Phe-Lys-AMC from Bachem for plasmin). After an incubation time of 30 min at 22 C, fluorescence is measured (excitation:
360 nm, emission: 460 nm). The measured emissions of the test batches with test substance are compared to the control batches without test substance (only dimethyl sulfoxide instead of test substance in dimethyl sulfoxide), and the ICso values are calculated from the concentration/activity relationships.

Thrombin plasma assay In a 96-well flat-bottom plate, 20 l of substance dilution (in water) are mixed with 20 l of ecarin (ecarin reagent, from Sigma E-0504, final concentration 20 mU/ml, final concentration in the well 20 mU) in Ca buffer (200 mM Hepes + 560 mM NaCl + 10 mM CaC12 + 0.4% PEG). To the first 3 upper wells A1-A3, only Ca buffer is added; these samples serve as non-stimulated controls.
Furthermore, 20 ] of fluorogenic thrombin substrate (from Bachem 1-1 120, final concentration in the well 50 M) and 20 1 of citrate plasma (from Octapharma) are added to each well, and the mixtures are homogenized well. The plate is read in a Spectra fluor plus reader having a 360 nm excitation filter and a 465 nm emission filter every minute over a period of 20 min. The IC50 value is determined after about 12 minutes when 70% of the maximum value is reached.

Thrombin generation assay (thrombolZram) The effect of the test substances on the thrombogram (Thrombin Generation Assay according to Hemker) is determined in vitro in human plasma (Octaplas from Octapharma).

In the thrombin generation assay according to Hemker, the activity of thrombin in coagulating plasma is determined by measuring the fluorescent cleavage products of the substrate 1-1140 BHC 06 1 167-Foreign Countries (Z-Gly-Gly-Arg-AMC, Bachem). The reactions are carried out in the presence of varying concentrations of test substance or the corresponding solvents. To start the reaction, reagents from Thrombinoscope (PPP reagent: 30 pM recombinant tissue factor, 24 M
phospholipids in HEPES) are used. Moreover, a thrombin calibrator from Thrombinoscope is used whose amidolytic activity is required for calculating the thrombin activity in a sample containing an unknown amount of thrombin. The test is carried out according to the specifications of the manufacturer (Thrombionscope BV): 4 l of test substance or of the solvent, 76 l of plasma and 20 I of PPP
reagent or thrombin calibrator are incubated at 37 C for 5 min. After addition of 20 l of 2.5 mM
thrombin substrate in 20 mM hepes, 60 mg/ml of BSA, 102 mM of CaC12, the thrombin generation is measured every 20 s over a period of 120 min. Measurement is carried out using a fluorometer (fluoroskan Ascent) from Thermo Electron fitted with a 390/460 nm filter pair and a dispenser.
Using the Thrombinoscope software, the thrombogram is calculated and represented graphically.
What is calculated are the following parameters: lag time, time to peak, peak, ETP (endogenous thrombin potential) and start tail.

Determination of the anticoalzulatory activity The anticoagulatory activity of the test substances is determined in vitro in human plasma, rabbit plasma and rat plasma. To this end, blood is drawn off in a mixing ratio of sodium citrate/blood of 1/9 using a 0.11 molar sodium citrate solution as receiver. Immediately after the blood has been drawn off, it is mixed thoroughly and centrifuged at about 4000 g for 15 minutes. The supernatant is pipetted off.

The prothrombin time (PT, synonyms: thromboplastin time, quick test) is determined in the presence of varying concentrations of test substance or the corresponding solvent using a commercial test kit (Neoplastin from Boehringer Mannheim or Hemoliance RecombiPlastin from Instrumentation Laboratory). The test compounds are incubated with the plasma at 37 C for 3 minutes. Coagulation is then started by addition of thromboplastin, and the time when coagulation occurs is determined. The concentration of test substance which effected a doubling of the prothrombin time is detetermined.

The thrombin time (TT) is determined in the presence of varying concentrations of test substance or the corresponding solvent using a commercial test kit (Thrombin Reagent from Roche). The test compounds are incubated with the plasma at 37 C for 3 minutes. Coagulation is then started by addition of the thrombin reagent, and the time when coagulation occurs is determined. The concentration of test substance which effects a doubling of the thrombin time is determined.

BHC 06 1 167-Foreign Countries The activated partial thromboplastin time (APTT) is determined in the presence of varying concentrations of test substance or the corresponding solvent using a commercial test kit (PTT
reagent from Roche). The test compounds are incubated with the plasma and the PTT reagent (Cephalin, Kaolin) at 37 C for 3 minutes. Coagulation is then started by addition of 25 mM CaClz, and the time when coagulation occurs is determined. The concentration of test substance which effects a doubling of the APTT is determined.

Thromboelastography (thromboelastogram) The thromboelastography is carried out with the aid of the thromboelastograph ROTEM from Pentapharm and its accessories, cup and pin. The measurement is carried out in whole blood drawn off beforehand into sodium citrate monovettes from Sarstedt. The blood in the monovettes is kept in motion using a shaker and preincubated at 37 C for 30 min. For the measurement, 20 l of CaC12 solution from a 200 mM stock solution (diluted with 0.9% NaCI) are initially charged into the cups (final concentration 12.5 mM). 3.2 l of substance or solvent are added. The measurement is started by addition of 300 l of whole blood. After the addition, using the tip of the pipette, the mixture is briefly drawn into the pipette and released again without generating air bubbles. The measurement is carried out over a period of 2.5 hours or stopped when fibrinolysis sets in. For evaluation, the following parameters are determined: CT(clotting time/[sec.]), CFT (clotting formation time/[sec.]), MCF (maximum clot firmness/[mm]) and the alpha angle [
]. The measurement points are determined every 3 seconds and represented graphically, with the y axis for MCF [mm] and the x axis for time [sec.].

Arteriovenous shunt and hemorrhage model (combi-model rat) Fasting male rats (strain: HSD CPB:WU) having a weight of 300-350 g are anesthetized using Inactin (150-180 mg/kg). Thrombin formation is initiated in an arteriovenous shunt in accordance with the method described by Christopher N. Berry et al., Br. J. Pharmacol.
(1994), 1 13, 1209-1214. To this end, the left jugular vein and the right carotid artery are exposed. The two vessels are connected by an extracorporeal shunt using a polyethylene tube (PE
60) of a length of 10 cm. In the middle, this polyethylene tube is attached to a further polyethylene tube (PE 160) of a length of 3 cm which contains a roughened nylon thread arranged in the form of a loop, to form a thrombogenic surface. The extracorporeal circulation is maintained for 15 minutes. The shunt is then removed and the nylon thread with the thrombus is weighed immediately.
The weight of the nylon thread on its own is determined before the experiment has started.

To determine the bleeding time, immediately after opening of the shunt circulation, the tip of the tail of the rats is docked by 3 mm using a razor blade. The tail is then placed into physiological BHC 06 1 167-Foreign Countries saline kept at a temperature of 37 C, and the bleeding from the cut is observed over a period of 15 minutes. What is determined are the time until bleeding ceases for at least 30 seconds (initial bleeding time), total bleeding time over a period of 15 minutes (cumulative bleeding time) and the quantitative blood loss via photometric determination of the collected hemoglobin.

Before the extracorporeal circulation is set up and the tip of the tail is docked, the test substances are administered to the animals while awake either intravenously via the contralateral jugular vein as a single bolus or as a bolus with subsequent continuous infusion or orally using a pharyngeal tube.

BHC 06 1 167-Foreign Countries C) Exemplary embodiments of pharmaceutical compositions The compounds according to the invention can be converted into pharmaceutical preparations in the following ways:

Tablet:
Composition:

100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch, mg of polyvinylpyrrolidone (PVP 25) (from BASF, Germany) and 2 mg of magnesium stearate.
Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

Preparation:
10 The mixture of the compound of Example 1, lactose and starch is granulated with a 5% strength solution (m/m) of PVP in water. The granules are dried and then mixed with the magnesium stearate for 5 minutes. This mixture is compressed using a conventional tablet press (see above for format of the tablet).

Oral suspension:
Composition:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum) (from FMC, USA) and 99 g of water 10 ml of oral suspension are equivalent to a single dose of 100 mg of the compound according to the invention.

Preparation:

The Rhodigel is suspended in ethanol, and the compound of Example I is added to the suspension.
The water is added while stirring. The mixture is stirred for about 6 h until the swelling of the Rhodigel is complete.

BHC 06 1 167-Foreign Countries Solution for intravenous administration:

Composition:
I mg of the compound of Example 1, 15 g of polyethylene glycol 400 and 250 g of water for injection.

Preparation:

The compound of Example I is dissolved together with polyethylene glycol 400 in the water with stirring. The solution is sterilized by filtration (pore diameter 0.22 pm) and dispensed under aseptic conditions into heat-sterilized infusion bottles. The latter are closed with infusion stoppers and trimmed caps.

Claims (10)

1. A compound of the formula in which X represents NH or S, R1 represents phenyl or 5- or 6-membered heteroaryl, where phenyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-alkyl, C1-C4-alkoxy, C1-C4-alkylamino, C1-C4-alkylthio and C1-C4-alkylcarbonyl, R2 represents phenyl or 5- or 6-membered heteroaryl, where phenyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-alkyl, C1-C4-alkoxy, C1-C4-alkylamino, C1-C4-alkylthio and C1-C4-alkylcarbonyl, R3 represents hydrogen or methyl, R4 represents C1-C6-alkyl, C2-C6-alkenyl or C3-C6-cycloalkyl, where alkyl and alkenyl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C1-C4-alkoxy, C1-C4-alkylamino and C3-C6-cycloalkyl, or R3 and R4 are linked to one another and, together with the atoms to which they are attached, form a pyrrolidine ring or a 1,3-thiazolidine ring, where the pyrrolidine ring and the 1,3-thiazolidine ring may be substituted by 1 or

2 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, C1-C4-alkyl, C2-C4-alkenyl, C1-C4-alkoxy and C1-C4-alkylamino, R5 represents hydrogen, halogen, hydroxyl, amino, C1-C6-alkyl, C1-C6-alkoxy, alkylamino, C1-C6-alkylcarbonyloxy, C1-C6-alkylcarbonylamino or 5- to 7-membered heterocyclyl, where alkyl and alkylamino may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, amino, hydroxycarbonyl, C1-C6-alkylamino, C1-C4-alkoxycarbonyl and 5- to 7-membered heterocyclyl, where heterocyclyl for its part may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylamino, C1-C4-alkylthio, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkylcarbonylamino, C1-C4-alkylaminocarbonyl, C1-C4-alkoxycarbonylamino and C1-C4-alkyl-carbonyloxy, and where heterocyclyl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylamino, C1-C4-alkylthio, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkyl-carbonylamino, C1-C4-alkylaminocarbonyl, C1-C4-alkoxycarbonylamino and C1-C4-alkylcarbonyloxy, or R4 and R5 are linked to one another and, together with the atoms to which they are attached, form a pyrrolidinone ring, where the pyrrolidinone ring may be substituted by 1 or 2 substituents, where the substituents independently of one another are selected from the group consisting of hydroxyl, amino, C1-C4-alkyl, C1-C4-alkoxy and C1-C4-alkylamino, R6 represents phenyl, 5- or 6-membered heteroaryl or 5- to 7-membered heterocyclyl, where phenyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylamino, C1-C4-alkylthio, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkylcarbonyl-amino, C1-C4-alkylaminocarbonyl, C1-C4-alkoxycarbonylamino, C1-C4-alkylcarbonyloxy, C1-C4-alkylsulfonyl and C1-C4-alkylsulfinyl, and where heterocyclyl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylamino, C1-C4-alkylthio, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkyl-carbonylamino, C1-C4-alkylaminocarbonyl, C1-C4-alkoxycarbonylamino and C1-C4-alkylcarbonyloxy, or R5 and R6 are linked to one another and, together with the carbon atom to which they are attached, form a group of the formula where * indicates the carbon atom to which R5 and R6 are attached, and R7 and R8 are linked to one another and, together with the carbon atom to which they are attached, form a cyclopentane ring or cyclohexane ring, where the cyclopentane ring and the cyclohexane ring may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, C1-C4-alkyl, C1-C4-alkoxy and C1-C4-alkylamino, and where R3 and R5 are not both linked to R4 and where R4 and R6 are not both linked to R5, or one of its salts, its solvates or the solvates of its salts.

2. The compound as claimed in claim 1, characterized in that X represents NH or S, R1 represents phenyl, pyridyl or pyrimidyl, where phenyl, pyridyl and pyrimidyl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylamino, C1-C4-alkylthio and C1-C4-alkylcarbonyl, R2 represents phenyl, thienyl, furyl, thiazolyl, oxazolyl or imidazolyl, where phenyl, thienyl, furyl, thiazolyl, oxazolyl and imidazolyl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, cyano, trifluoromethyl, C1-C4-alkyl and C1-C4-alkoxy, R3 represents hydrogen, R4 represents C1-C6-alkyl or C3-C6-cycloalkyl, where alkyl may be substituted with 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C1-C4-alkoxy, C1-C4-alkylamino and C3-C6-cycloalkyl, or R3 and R4 are linked to one another and, together with the atoms to which they are attached, form a pyrrolidine ring, where the pyrrolidine ring may be substituted by 1 or 2 substituents, where the substituents independently of one another are selected from the group consisting of C1-C4-alkyl and C1-C4-alkoxy, R5 represents hydrogen, halogen, hydroxyl, amino, C1-C6-alkyl, C1-C6-alkoxy, alkylamino, C1-C6-alkylcarbonyloxy, C1-C6-alkylcarbonylamino, morpholinyl, thiomorpholinyl or 4-(C1-C4-alkyl)piperazinyl, where alkyl and alkylamino may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, amino, hydroxycarbonyl, C1-C6-alkylamino, C1-C4-alkoxycarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl, where pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl for their part may be substituted by 1 or 2 substituents, where the substituents independently of one another are selected from the group consisting of C1-C4-alkyl and C1-C4-alkoxy, or R4 and R5 are linked to one another and, together with the atoms to which they are attached, form a pyrrolidinone ring, where the pyrrolidinone ring may be substituted by 1 or 2 substituents, where the substituents independently of one another are selected from the group consisting of C1-C4-alkyl, R6 represents phenyl, tetrahydrofuranyl, pyranyl, piperidinyl or thiopyranyl, where phenyl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylcarbonylamino, C1-C4-alkylaminocarbonyl and C1-C4-alkoxycarbonylamino, and where tetrahydrofuranyl, pyranyl, piperidinyl and thiopyranyl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl, amino, cyano, oxo, hydroxycarbonyl, aminocarbonyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkyl-carbonylamino, C1-C4-alkylaminocarbonyl and C1-C4-alkoxycarbonylamino, or R5 and R6 are linked to one another and, together with the carbon atom to which they are attached, form a group of the formula where * indicates the carbon atom to which R5 and R6 are attached, and R7 and R8 are linked to one another and, together with the carbon atom to which they are attached, form a cyclohexane ring, and where R3 and R5 are not both linked to R4 and where R4 and R6 are not both linked to R5, or one of its salts, its solvates or the solvates of its salts.

3. The compound as claimed in claim 1 or 2, characterized in that X represents NH or S, R1 represents phenyl or pyridyl, where phenyl and pyridyl may be substituted by 1 or 2 substituents, where the substituents independently of one another are selected from the group consisting of halogen and methoxy, R2 represents phenyl or thienyl, where phenyl and thienyl may be substituted by 1 or 2 substituents, where the substituents independently of one another are selected from the group consisting of fluorine, chlorine and bromine, R3 represents hydrogen, R4 represents isopropyl, or R3 and R4 are linked to one another and, together with the atoms to which they are attached, form a pyrrolidine ring, where the pyrrolidine ring may be substituted by 1 or 2 methyl substituents, R5 represents hydrogen, C1-C4-alkyl or C1-C4-alkoxy, where alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, hydroxycarbonyl and C1-C4-alkoxycarbonyl, or R4 and R5 are linked to one another and, together with the atoms to which they are attached, form a pyrrolidinone ring, where the pyrrolidinone ring may be substituted by 1 or 2 methyl substituents, R6 represents phenyl or 4-pyranyl, where phenyl may be substituted by 1 to 3 substituents, where the substituents independently of one another are selected from the group consisting of halogen, hydroxyl and C1-C4-alkoxy, or R5 and R6 are linked to one another and, together with the carbon atom to which they are attached, form a group of the formula where * indicates the carbon atom to which R5 and R6 are attached, and R7 and R8 are linked to one another and, together with the carbon atom to which they are attached, form a cyclohexane ring, and where R3 and R5 are not both linked to R4 and where R4 and R6 are not both linked to R5, or one of its salts, its solvates or the solvates of its salts.

4. A process for preparing a compound of the formula (I) as claimed in claim 1, characterized in that according to process [A] a compound of the formula in which X, R1, R2, R3 and R4 have the meaning given in claim 1, is reacted with a compound of the formula in which R5 and R6 have the meaning given in claim 1 and Y1 represents halogen, preferably chlorine, bromine or iodine, or hydroxyl, or [B] a compound of the formula in which X, R1 and R2 have the meaning given in claim 1, is reacted with a compound of the formula in which R3 R4, R5 and R6 have the meaning given in claim 1, and Y2 represents halogen, preferably chlorine, bromine oder iodine, or hydroxyl.

5. The compound as claimed in any of claims 1 to 3 for the treatment and/or prophylaxis of diseases.

6. The use of a compound as claimed in any of claims 1 to 3 for preparing a medicament for the treatment and/or prophylaxis of diseases.

7. The use of a compound as claimed in any of claims 1 to 3 for preparing a medicament for the treatment and/or prophylaxis of thromboembolic disorders.

8. A medicament, comprising a compound as claimed in any of claims 1 to 3 in combination with an inert non-toxic pharmaceutically acceptable auxiliary.

9. The medicament as claimed in claim 8 for the treatment and/or prophylaxis of cardiovascular disorders.

10. A method for treating cardiovascular disorders in humans and animals by administering a therapeutically effective amount of at least one compound as claimed in any of claims 1 to 3, a medicament as claimed in claim 8 or a medicament obtained as claimed in claim 6 or 7.