EP1802594A1 - Novel oxadiazinone derivatives and use thereof as ppar-alpha modulators - Google Patents

Abstract

The invention relates to novel 1,3,4-oxadiazine-5-on derivatives of general formula (I), methods for the production thereof, the use thereof for treating and/or preventing diseases, and the use thereof for producing medicaments used for the treatment and/or prevention of diseases, preferably cardiovascular diseases, especially dyslipidemia and arteriosclerosis.

Description

NEW OXADIAZINONE DERIVATIVES AND THEIR USE AS PPAR ALPHA MODULATORS

The present application relates to novel l, 3,4-oxadiazin-5-one derivatives, processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of Diseases, preferably for the treatment and / or prevention of cardiovascular diseases, in particular of dyslipidaemias and arteriosclerosis.

Despite multiple therapeutic successes, cardiovascular disease remains a serious public health problem. While the treatment with statins by inhibiting HMG-CoA reductase very successfully reduces both the plasma concentrations of LDL-cholesterol (LDL-C) and the mortality of high-risk patients, today convincing treatment strategies for the therapy of patients with unfavorable HDL are lacking. C / LDL-C ratio or hyper-triglyceridemia.

In addition to niacin, fibrates are the only therapy option for patients in these risk groups. They lower elevated triglycerides by 20-50%, decrease LDL-C by 10-15%, change the LDL particle size from low-density atherogenic LDL to normal dense and less athero ¬ gene LDL and increase the HDL concentration by 10-15%.

Fibrates act as weak agonists of the peroxisome proliferator-activated receptor (PPAR) alpha (Nature 1990, 347. 645-50). PPAR-alpha is a nuclear receptor that regulates the expression of target genes by binding to DNA sequences in the promoter region of these genes [also called PPAR response elements (PPRE)]. PPREs have been identified in a number of genes that encode proteins that regulate lipid metabolism. PPAR-alpha is highly expressed in the liver and its activation leads, inter alia, to decreased VLDL production / secretion and reduced apolipoprotein CIH (ApoCEDQ synthesis), in contrast to the synthesis of apolipoprotein Al (ApoAl).

A disadvantage of hitherto approved fibrates is their only weak interaction with the receptor (EC ₅₀ in the μM range), which in turn leads to the relatively low pharmacological effects described above.

It is an object of the present invention to provide novel compounds which can be used as PPAR-alpha modulators for the treatment and / or prevention of, in particular, cardiovascular diseases. PPAR-alpha agonists with l, 2,4-triazol-3-one partial structure are described in WO 02/38553. l, 3,4-oxadiazol-2-one derivatives as PPAR-alpha agonists are disclosed in WO 03/043997.

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

in which

Y and Z are each independently O or S,

m is the number 0, 1 or 2,

n is the number 1 or 2,

R ^{1 is} (C ₆ -C 10) -aryl or 5- to 10-membered heteroaryl, which are each up to four times, identical or different, with substituents selected from the group halogen, nitro, cyano, (C ₁ -C ₆ ) - Alkyl, which in turn may be substituted by hydroxy, (C ₃ -C ₈ ) - cycloalkyl, phenyl, hydroxy, (Ci-C ₆ ) alkoxy, trifluoromethyl, trifluoromethoxy, amino, mono- and di- (C ₁ -C ₆ ) -alkylamino, R ⁸ -C (O) -NH-, R ⁹ -C (O) -, R ¹⁰ R ¹¹ NC (O) -NH- and R ¹² R ¹³ NC (O) - may be substituted, wherein

R ⁸ is hydrogen, (C _{r C6)} alkyl, (C ₃ -C ₈₎ -cycloalkyl, phenyl or (C ₁ -Q) -alkoxy means

R ⁹ is hydrogen, (dC ₆₎ alkyl, (C ₃ -C ₈₎ -cycloalkyl, phenyl, hydroxy or (C ₁ -C ₆₎ - alkoxy

and

R ¹⁰ , R ¹¹ , R ¹² and R ^{13 are} identical or different and independently of one another are hydrogen, (C ₁ -C 6) -alkyl, C ₃ -C ₈ -cycloalkyl or phenyl,

R ² is hydrogen, (C ₆ -C ₁₀₎ -aryl, (C _{r C6)} alkyl, (C ₂ -C ₆₎ alkenyl or (C ₂ -C ₆₎ alkynyl is, wherein alkyl, alkenyl, and Alkynyl each with trifluoromethyl, (C _r C ₆ ) alkoxy, trifluoro- methoxy, fluoro, cyano, (Co-Qo) -ATyI or 5- or 6-membered heteroaryl may be substituted, wherein said aryl and heteroaryl groups in turn each up to three times, same or different, having substituents selected from the series halogen, nitro, cyano, (C _{r C6)} alkyl, hydroxy, (Ci-C ₆₎ alkoxy, trifluoromethyl and Trifluormeth- oxy can be substituted,

R ³ and R ⁴ are the same or different and are each independently hydrogen, (Ci-C ₆₎ - alkyl, (C ₂ -C 6) alkenyl, (dC ₆₎ alkoxy, trifluoromethyl, trifluoromethoxy or halogen,

R ⁵ and R ^{6 are} identical or different and independently of one another represent hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy or phenoxy or together with the carbon atom to which they are bonded form a (C ₃ -C ₈ ) -cycloalkyl ring,

and

R ^{7 is} a group of the formula -NHR ¹⁴ or -OR ¹⁵ , wherein

R ^{14 is} hydrogen, (C _r C ₆ ) -alkyl or (C _r C ₆ ) -alkylsulfonyl

and

R ^{15 is} hydrogen or is a hydrolyzable group which can be converted into the corresponding carboxylic acid,

and their salts, solvates and solvates of the salts.

In the context of the invention, in the definition of R ^15, a hydrolyzable group means a group which, especially in the body, leads to a conversion of the -C (O) OR ^{15 group} into the corresponding carboxylic acid (R ¹⁵ = hydrogen). Such groups are exemplary and vor¬ preferably benzyl, (C _r C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, each optionally mono- or polysubstituted, identical or different, with halogen, hydroxy, amino, (Ci -C ₆ ) alkoxy, carboxyl, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylammo or (C ₁ -C ₆ ) alkanoyloxy, or in particular (C ₁ -C ₄ ) -alkyl, which may be one - or multiply, identically or differently, with halogen, hydroxyl, amino, (C 1 -C ₄ ) -alkoxy, carboxyl, (C 1 -C ₄ ) -alkoxycarbonyl, (C 1 -C ₆ -alkoxycarbonylamino or (C 1 -C ₄ ) Alkanoyloxy is substituted.

Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts encompassed by formula (I) and those of the formula (I), to- following compounds mentioned as exemplary embodiments and their salts, solvates and solvates of the salts, as far as the compounds encompassed by formula (T) below are not already salts, solvates and solvates of the salts.

Depending on their structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

Salts in the context of the present invention are physiologically acceptable salts of the invention. preferred compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic 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 and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms. 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 and N-methylpiperidine.

Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention. In addition, the present invention also includes prodrugs of the compounds according to the invention. The term "prodrugs" includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:

(C ₁ -Cs) -AlkVl and TC ₁ -Cd) -AlkVl in the context of the invention are a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms. Preferred is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethyl-propyl, n-pentyl and n-hexyl.

In the context of the invention, (C ₂ -C 15) -alkenyl and (C 1 -C 4) -alkenyl are a straight-chain or branched alkenyl radical having 2 to 6 or 2 to 4 carbon atoms, preferably a straight-chain or branched alkenyl radical having 2 By way of example and by way of preference, mention may be made of vinyl, AHyI, isopropenyl, n-but-2-en-1-yl and 2-methyl-2-propen-1-yl.

(C ₂ -Cg) -AlkJnVl and (C ₂ -Cd) -AlkJnVl in the context of the invention represent a straight-chain or branched alkynyl radical having 2 to 6 or 2 to 4 carbon atoms. Preference is given to a straight-chain or branched alkynyl radical having 2 to 4 carbon atoms. Examples which may be mentioned are: ethynyl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-yn-1-yl.

in the context of the invention are a monocyclic cycloalkyl group having 3 to 8 or 3 to 6 carbon atoms. Preference is given to a cycloalkyl radical having 3 to 6 carbon atoms. Examples which may be mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohepryl.

(Cfi-Cin) -aryl is in the context of the invention an aromatic radical having preferably 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

in the context of the invention for a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. By way of example and preference may be mentioned: methoxy, ethoxy, n-propoxy, isopropoxy and tert-butoxy.

(Cr-C ₈ VAlkoxycarbonyl and (Ci-CiVAlkoxycarbonyl are in the context of the invention a straight-chain or branched alkoxy radical having from 1 to 6 or 1 to 4 carbon atoms, the above a carbonyl group is linked. Preference is given to a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms in the alkoxy group. Examples which may be mentioned by way of example include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

(G-CfiVAlkylsulfonyl ^'is in the context of the invention a straight-chain or branched alkylsulphonyl radical having 1 to 6 carbon atoms is preferably mentioned a straight or ver¬-chain alkylsulfonyl group having 1 to 4 carbon atoms, Examples which may preferably be:.., Methylsulfonyl, ethylsulfonyl , n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl and tert-butylsulfonyl.

in the context of the invention are an amino group having a straight-chain or branched alkyl substituent which has 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

in the context of the invention are an amino group having two identical or different straight-chain or branched alkyl substituents which have in each case 1 to 6 or 1 to 4 carbon atoms. Straight-chain or branched dialkylamino radicals having in each case 1 to 4 carbon atoms are preferred. Examples which may be mentioned are: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

in the context of the invention are an amino group having a straight-chain or branched alkoxycarbonyl substituent which has 1 to 6 or 1 to 4 carbon atoms in the alkoxy radical and is linked via the carbonyl group to the nitrogen atom. Preference is given to an alkoxycarbonylamino radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino and tert-butoxycarbonylamino.

fC _r Cfi) alkanoyloxy and ((ZVCaVAlkanoyloxy the invention for a straight-chain or branched alkyl radical within the framework of 1 to 6 or 1 to 4 carbon atoms, which in the

1 position carries a double-bonded oxygen atom and in the 1-position over another

Oxygen atom is linked. Preferred is an alkanoyloxy radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy and n-hexanoyloxy.

5- to 10-membered heteroaryl is in the context of the invention for a mono- or optionally bicyclic aromatic heterocycle (heteroaromatic) with up to four identical or different heteroatoms from the series N, O and / or S, via a Ring carbon atom or optionally linked via a ring nitrogen atom of the heteroaromatic. Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, Benzothiazolyl, benzotriazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinazolinyl, quinoxalinyl. Preference is given to monocyclic 5- or 6-membered heteroaryl radicals having up to three heteroatoms from the series N, O and / or S such as furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl , Pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl.

Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.

If radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of one another for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.

Preferred in the context of the present invention are compounds of the formula (T) in which

Y stands for O,

Z stands for S,

m is the number 0, 1 or 2,

n is the number 1 or 2,

R ^{1 is} phenyl or 5- or 6-membered heteroaryl, which are each up to four times, identical or different, with substituents selected from the group halogen, nitro, cyano,

(C ₁ -C ₄ ) -alkyl, which in turn may be substituted by hydroxy, (C ₃ -C ₆ ) -cycloalkyl, phenyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, trifluoromethyl, trifluoromethoxy, arnino, mono- and Di- (C _r C ₄₎ alkylamino, R ⁸ -C (O) -NH-, R ⁹ -C (O) -, R ¹⁰ R ¹¹ NC (O) -NH-, and R ¹² R ¹³ NC (O ) - substituted in which

R ⁸ is hydrogen, (C, -C ₄₎ alkyl, (C ₃ -C ₆₎ -cycloalkyl, phenyl or (C _r C ₄₎ alkoxy means,

R ⁹ is hydrogen, (C _{r C4)} alkyl, (C ₃ -C ₆₎ -cycloalkyl, phenyl, hydroxy or (C ₁ -C ₄₎ -

Alkoxy means

and

R ^10, R ^11, R ¹² and R ¹³ are identical or different and independently material Wasser¬, (C _{r C4)} alkyl, (C ₃ -C ₆₎ -cycloalkyl or phenyl,

R ^{2 is} hydrogen, phenyl, (C ₁ -C ₄ ) -alkyl, (C ₂ -C ₄ ) -alkenyl or (C ₂ -C ₄ ) -alkynyl, in which alkyl, alkenyl and alkynyl are each reacted with trifluoromethyl, fluorine, Cyano, (C _r C ₄ ) alkoxy, phenyl or 5- or 6-membered heteroaryl may be substituted, wherein all said phenyl and heteroaryl groups in turn each up to three times, same or different, having substituents selected from the group halogen , nitro, cyano, (C ₁ -C ₄₎ - alkyl, hydroxy, (Ci-C ₄₎ alkoxy, trifluoromethyl and trifluoromethoxy,

R ³ and R ⁴ are identical or different and are independently hydrogen, (C ₁ -C ₄₎ - alkyl, (C _{r C4)} alkoxy, trifluoromethyl, trifluoromethoxy or halogen,

R ⁵ and R ^{6 are} identical or different and independently of one another are hydrogen, methyl, ethyl, methoxy, ethoxy or phenoxy or together with the carbon atom to which they are attached form a (C ₃ -C ₆ ) -cycloalkyl ring,

and

R ^{7 is} a group of the formula -NHR ¹⁴ or -OR ¹⁵ , wherein

R ^{14 is} hydrogen or (C _r C ₄ ) alkyl

and

R ^{15 is} hydrogen or is a hydrolyzable group which can be converted into the corresponding carboxylic acid,

and their salts, solvates and solvates of the salts. Particularly preferred in the context of the present invention are compounds of the formula (I) in which

Y stands for O,

Z stands for S,

m is the number 0 or 1,

n is the number 1 or 2,

R ^{1 is} phenyl or pyridyl, which in each case may be monosubstituted or disubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, nitro, methyl, methoxy, trifluoromethyl and trifluoromethoxy,

R ^{2 is} hydrogen, propargyl or (C _r C ₄ ) -alkyl which may be substituted by fluorine, cyano, (C 1 -C ₄ ) -alkoxy, phenyl, furyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl can, where phenyl and all said heteroaromatic rings in turn each one or two times, same or different, selected from substituents aus¬ selected from the series fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy substituted could be,

R ³ and R ^{4 are} identical or different and independently of one another represent hydrogen, methyl, methoxy, fluorine or chlorine,

R ⁵ and R ^{6 are the} same or different and represent hydrogen or methyl,

and

R ^{7 is} -OH, -NH ₂ or -NHCH ₃ ,

and their salts, solvates and solvates of the salts.

Of particular importance are compounds of the formula (I-A)

in which

R ¹ , R ² , m and n each have the meanings given above.

The residue definitions given in detail in the respective combinations or preferred combinations of residues are also replaced by residue definitions of other combinations, regardless of the particular combinations of the residues indicated.

Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.

The invention further provides a process for the preparation of the compounds of the formula (T) or (I-A) according to the invention, which comprises reacting compounds of the formula (TT)

in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z each have the meanings given above

and

T ^{1 is} (C ¹ -C ₄ ) -alkyl, preferably tert-butyl, or is benzyl,

first in an inert solvent in the presence of a base with a compound of the formula (TTT)

in which n has the meaning given above and

T ^{2 is} (C 1 -C ₄ ) -alkyl, preferably methyl or ethyl,

and Q ^{1 represents} a suitable leaving group such as, for example, halogen, mesylate, tosylate or triflate,

to compounds of the formula (IV)

in which n, T ¹ , T ² , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are each as defined above,

subsequently reacted under suitable reaction conditions selectively to carboxylic acids of the formula (V)

in SAVE, T ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are each as defined above,

hydrolyzed, then in an inert solvent in the presence of a condensing agent and a base with a compound of formula (VI)

R- (CH ₂ ) -N-NH ₂ (VI),

in which R ¹ and m each have the meanings given above,

in compounds of the formula (VIT)

in which m, n, T, R ¹ , R ² , R ³ , R, R, R and Z are each as defined above, then converted with chloroacetyl chloride in the presence of a base with cyclization to give compounds of the formula (IB)

in which m, n, T, R, R, R, R ₃ R ₅ R and Z each have the meanings given above,

subsequently, by basic or acidic hydrolysis or in the case where T ^{1 is} benzyl, also hydrogenolytically in carboxylic acids of the formula (IC)

in which m, n, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are each as defined above,

then, if appropriate, are converted into the compounds of the formula (I) by methods known from the literature for the esterification or amidation

and optionally reacting the compounds of the formula (I) with the corresponding (i) solvents and / or (ii) bases or acids to their solvates, salts and / or solvates of the salts.

Compounds of the formula (I-D)

in which m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and Z each have the meanings given above, can also be prepared by reacting compounds of formula (H) in an inert solvent in the presence of a base with a compound of the formula (VHI)

in which m and R ¹ each have the meanings given above, and

is a suitable leaving group such as halogen,

to compounds of the formula (I-E)

in which m, T fl, r R> 1, T R> 2, τ R> 3, τ R> 4, R τ j 5, τ R> 6 and Z are each as defined above,

subsequently, by basic or acidic hydrolysis or in the case where T ^{1 is} benzyl, also hydrogenolytically in carboxylic acids of the formula (IF)

in which m, R, R, R, R, R, R and Z are each as defined above,

überfuhrt and optionally subsequently reacted by literature methods for esterification or amidation to the compounds of formula (I-D).

The compounds of the formula (II) and their preparation are described in WO 02/28821 or can be prepared in analogy to the processes described therein. Compounds of Formula (H) in which Z is S can also be prepared by reacting compounds of the formula (IX)

in which R ³ and R ⁴ each have the meanings given above,

first in an inert solvent with sodium sulfide in compounds of the formula (X)

in which R and R each have the meanings given above,

then, with or without interim isolation, react with a compound of formula (XI)

in which T ¹ , R ⁵ and R ⁶ each have the meanings given above

and

Q ^{3 represents} a suitable leaving group such as, for example, halogen, mesylate, tosylate or triflate,

to compounds of the formula (XH)

in which T ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ each have the meanings given above,

then with a suitable reducing agent, preferably borane or borane complexes (e.g., diethylaniline, dimethylsulfide or tetrahydrofuran complexes) or also with sodium borohydride in combination with aluminum chloride, to give compounds of formula (H-A).

in which T, R, R, R and R each have the meanings given above,

and, if appropriate, finally in the presence of a base with a compound of the formula (XIII)

R ² -Q ⁴ (XHI),

in which

R ^{2 * has} the abovementioned meaning of R ² , but does not stand for hydrogen,

and

Q ^{4 represents} a suitable leaving group such as, for example, halogen, mesylate, tosylate or triflate,

implements.

The compounds of the formula (VTB) can be prepared by reacting compounds of the formula (VI) in an inert solvent in the presence of a base with two equivalents of a compound of the formula (XTV)

in which Q ^{2 has} the meaning given above,

implements.

Inert solvents for process steps (II) + (ST) → (TV), (S) + (YTJT) → (IE) and (UA) + (XST) -> (S) are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane , Tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate , Acetone, dimethylformamide, dimethyl sulfoxide, N, N'-dimethylpropyl enurea (DMPU), N-methylpyrrolidone (ΝMP), pyridine or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to tetrahydrofuran and dimethylformamide.

Suitable bases for the process steps (H) + (III) → (TV), (H) + (Vm) -> (IE) and (HA) + (XJTX) → (II) are the usual inorganic or organic bases. These include, preferably, alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, alkali metal hydrides such as sodium hydride, amides such as sodium amide, lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, pyridine, 1 , 5-diazabicyclo [4.3.0] non-5-ene (USN), 1,4-diazabicyclo [2.2.2] octane (DABCO ^®) or 1,8-diazabicyclo [5.4.0] - undec-7- en (DBU). Preference is given to N, N-diisopropylethylamine, triethylamine, potassium carbonate or cesium carbonate.

The base is used in these process steps in each case in an amount of 1 to 5 mol, preferably in an amount of 1 to 2.5 mol, based on 1 mol of the compound of formula (TT) I (HA) or its hydrochloride. In some cases, it has proven advantageous to carry out the reaction in the presence of an alkylation catalyst such as, for example, tetra-N-butylammonium bromide or iodide. The reaction is generally carried out in a temperature range of 0 ⁰ C to +150 ⁰ C, preferably +20 ⁰ C to +100 ⁰ C. The reaction can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar ). Generally, one works at normal pressure.

The hydrolysis of the carboxylic acid esters in process steps (IV) - »(V), (IB) -» (IC) and (IE) -> ■ (IF) is carried out by customary methods by treating the esters in bases with inert solvents, wherein the initially formed salts are converted by treatment with acid into the free carboxylic acids. In the case of the tert-butyl ester ester cleavage is preferably carried out with acids.

Suitable inert solvents for the hydrolysis of the carboxylic acid esters are water or the organic solvents customary for ester cleavage. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, acetonitrile, dichloromethane, dimethylformamide or dimethyl sulfoxide. It is also possible to use mixtures of said solvents. In the case of a basic ester hydrolysis, preference is given to using mixtures of water with dioxane, tetrahydrofuran, methanol and / or ethanol. In the case of the reaction with trifluoroacetic acid, preference is given to using dichloromethane and, in the case of the reaction with hydrogen chloride, preferably tetrahydrofuran, diethyl ether, dioxane or water.

Suitable bases for the ester hydrolysis are the customary inorganic bases. These include preferably alkali or alkaline earth hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Particular preference is given to using sodium hydroxide or lithium hydroxide.

Suitable acids for the ester cleavage are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrobromic / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water. Hydrogen chloride or trifluoroacetic acid are preferred in the case of the tert-butyl esters and hydrochloric acid in the case of the methyl esters.

The ester cleavage is generally carried out in a temperature range from -20 ⁰ C to + 100 ⁰ C, preferably from 0 ⁰ C to + 5O ⁰ C. The reaction can be carried out at normal, elevated or at reduced pressure (eg from 0.5 to 5 bar ). In general, one works at normal pressure. The process steps (IC) → (T), (IF) → (ID) and (V) + (VI) → (VE) are carried out by literature methods for the esterification or amidation (amide formation) of carboxylic acids durch¬ ,

Inert solvents for these process steps are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane , Trichlor- ethylene or chlorobenzene, or other solvents such as ethyl acetate, pyridine, dimethyl sulfoxide, dimethylformamide, N, N-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝMP), acetonitrile or acetone. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to dichloromethane, tetrahydrofuran, dimethylformamide or mixtures of these solvents.

Suitable condensing agents for esterification or amide formation in process steps (IC) → (J), (IF) → (ID) or (V) + (VI) → (VJI) are, for example, carbodiimides such as N, N'-diethyl 'NN'-dipropyl, NN'-diisopropyl, N, N'-dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), or phosgene derivatives such as N, N' 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 1-ethoxycarbonyl-1,2-dihydroquinoline, or isobutyl chloroformate, propanephosphonic acid anhydride, diethyl cyanophosphonate, bis (2-oxo-3-oxazolidinyl) -phosphoryl chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, benzotriazole 1-yloxy-tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), 2- (2 oxo-l- (2H) -pyridyl ) -l, l, 3,3-tetramethyl-uronium tetrafluoroborate (TPTU), <9- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (ΗATU) or 0 - (lH-6-chlorobenzotriazol-1-yl) -1,3,3-tetramethyluronium tetrafluoroborate (TCTU), optionally in combination with other auxiliaries such as 1-hydroxybenzotriazole (ΗOBt) or Ν-hydroxysuccinimide (ΗOSu), as well as as bases alkali metal carbonates, eg Sodium or potassium carbonate or bicarbonate, or organic bases such as trialkylamines, e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine or N, N-diisopropylethylamine. Preference is given to using ΗATU or TCTU in combination with N, N-diisopropylethylamine.

The process steps (IC) → (I), (IF) → (ID) and (V) + (VI) → (VJI) are generally in a temperature range from -20 ⁰ C to + 60 ⁰ C, preferably -10 ⁰ C to +40 ⁰ C, performed. The reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.

In process step (VIT) - »(IB), the reaction of the compound of formula (Vü) with chloroacetyl chloride is preferably carried out in DMF at 0 ⁰ C to + 3O ⁰ C or in chloroform at +20 ⁰ C to +70 ⁰ C. The cyclisation of the intermediate so obtained is carried out in the presence of a base, preferably potassium carbonate, in DMF or an alcoholic solvent, especially ethanol, at elevated temperature, in particular in a temperature range of +50 ⁰ C to +80 ⁰ C.

Process step (VT) + (XIV) - »(VIH) is preferably carried out using N, N-diisopropylethylamine as base in at least three molar ratios, based on the compound of formula (VI), in DMF in a temperature range of + 20 ⁰ C to +80 ⁰ C performed.

The compounds of the formulas (IH), (VI), (IX), (XI), (XIH) and (XIV) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature.

The preparation of the compounds according to the invention can be illustrated by the following synthesis schemes:

Scheme 1

[a): coupling reaction by means of HATU or TCTU and DIEA in THF or DMF; b): 1. chloroacetyl chloride in DMF or chloroform, 2. potassium carbonate in DMF or ethanol, 70 ^° C.; c): chlorine-hydrogen in dioxane]. Scheme 2

[a): N-alkylation using triethylamine in DMF (X = halogen); b): DIEA in DMF; c): N-alkylation using triethylamine, DIEA and TBAI in THF; d): hydrogen chloride in dioxane].

Scheme 3

[a): N-alkylation using triethylamine and DIEA in THF; b): N-alkylation using triethylamine, DIEA and TBAI in THF (X = halogen); c): hydrogen chloride in dioxane].

The compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

The compounds according to the invention are highly effective PPAR-alpha modulators and are suitable as such, in particular for the treatment of cardiovascular diseases. These include dyslipidaemias (hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, combined hyperlipidemias), arteriosclerosis and metabolic disorders (metabolic syndrome, non-msulin-dependent diabetes, insulin-dependent diabetes, hyperinsulinemia, Glucose intolerance, obesity, obesity and diabetic sequelae such as retinopathy, nephropathy and neuropathy). Other independent risk factors for cardiovascular diseases that can be treated by the compounds of the present invention are hypertension, ischemia, myocardial infarction, increased levels of fibrinogen and low density LDL, as well as elevated levels of plasminogen activator inhibitors 1 (PAI-I). In addition, the compounds of the invention can also be used for the treatment or prophylaxis of cancer, diseases of the central nervous system (stroke, Alzheimer's disease, dementia), immune diseases (Crohn's disease, ulcerative colitis) as well as kidney diseases, thyroid diseases, Leberfϊbrose, psoriasis and osteoporosis become.

The effectiveness of the compounds of the invention can be e.g. in vitro by the transactivation assay described in the Examples section.

The efficacy of the compounds according to the invention in vivo can be determined e.g. Check by the tests described in the example section.

Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using Ver use of an effective amount of at least one of the compounds of the invention.

The compounds of the invention may be used alone or as needed in combination with other agents. Another object of the present invention are medicaments, containing at least one compound of the invention and at least one or more further active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases. Examples of suitable combination active ingredients are: lipid modulators (CETP inhibitors, inhibitors of HMG-CoA reductase, inhibitors of HMG-CoA reductase expression, squalene synthesis inhibitors, ACAT inhibitors, cholesterol absorption inhibitors , Bile acid absorption inhibitors, MTP inhibitors, fibrates, niacin, lipase inhibitors, PPAR-γ and / or PPAR-δ agonists), blood pressure depressants (calcium antagonists, angiotensin II receptor antagonists), circulation-promoting agents (Antiplatelet agents, anticoagulants) as well as antidiabetics, antioxidants, thyroid hormones and / or thyroid mimetics, aldose reductase inhibitors and anorectics.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

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

For the oral administration are according to the prior art working, the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), tablets or wafers rapidly breaking down in the oral cavity, films / lyophilisates, capsules (for example Hart - or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For other routes of administration are, for example inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules , aqueous suspensions (lotions, shake mixtures), lipophilic Suspensions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.

Preference is given to oral or parenteral administration, in particular oral administration.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), Stabilizers (eg antioxidants such as ascorbic acid, for example), dyes (eg inorganic pigments such as iron oxides) and flavor and / or odoriferous.

In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight, in order to achieve effective results. When administered orally, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg Körper¬ weight.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to make do with less than the aforementioned Mindest¬ amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The following exemplary embodiments illustrate the invention. The invention is not limited to the examples.

The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume. A. Examples

Abkürzuneen:

Section. absolutely

DCI direct chemical ionization (in MS)

DIEA N _j N-diisopropylethylamine

DMF dimethylformamide

DMSO dimethyl sulfoxide d. Th. Of theory (in yield) eq. Equivalent (s)

EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

ESI electrospray ionization (in MS)

EtOAc ethyl acetate h hour (s)

HATU O- (7-azabenzotriazole-1-yl) -N, N, N ', N-tetramethyluronium hexafluorophosphate

HOBt 1-Hydroxy-lH-benzotriazole hydrate

HPLC high pressure, high performance liquid chromatography

LC / MS liquid chromatography-coupled mass spectroscopy min minute (s)

MS mass spectroscopy

MTBE methyl tert. butyl ether

NMP N-methylpyrrolidinone

NMR nuclear magnetic resonance spectroscopy

RT room temperature

Retention time (by HPLC) sbr broad singlet (by NMR)

TBAI Tetra-N-butylammonium iodide

TCTU O- (1H-6-chlorobenzotriazol-1-yl) -1,3,3-tetramethyluronium tetrafluoroborate

THF tetrahydrofuran

UV ultraviolet spectroscopy

* unexpected multiplicity of signals, eg. Caused by random isochromes (in NMR) LC / MS and HPLC methods:

Method 1 (LC / MS ^:

Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A - »2.5 min 30% A -> 3.0 min 5% A → 4.5 min 5% A; Flow: 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 (LCMS):

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A → 3.0 min 5% A - »4.5 min 5% A; Flow: 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 3 (LCMS):

Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A → 3.0 min 5% A -> 4.5 min 5% A; Flow: 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 4 (LCMS):

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 5O ⁰ C; UV detection: 208-400 nm. Starting Compounds and Intermediates:

Example IA

2 - [(4- {[(2-Furylmethyl) (2-ethoxy-2-oxoethyl) -amino] -methyl} -phenyl) thio] -2-methyl-propionic acid tert -butyl ester

3.00 g of 2 - [(4- {[(2-Fιιiylmethyl) amino] methyl} phenyl) thio] -2-methyl-propionic acid-iert. Butyl ester hydrochloride (7.46 mmol) [WO 02/28821, Example H-3] are suspended in 30 ml of DMF and with 4.86 g of cesium carbonate (14.91 mmol) and 1.25 g ethyl bromoacetate (7.46 mmol) ver¬ sets. The reaction mixture is stirred overnight at room temperature. 100 ml of water are added and the mixture is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate and the solvent is removed on a rotary evaporator. The residue is purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 1). There are obtained 1.87 g (56% of theory) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.26 (t, J = 7.2, 3H), 1.41 (s, 9H), 1.43 (s, 6H), 3.32 (s, 2H), 3.80 (s, 2H), 3.84 (s, 2H), 4.16 (q, J = 7.2, 2H), 6.19-6.20 (m, IH), 6.31 (dd, J = 3.0, J = 1.9, IH), 7.32- 7.35 (m , 2H) ₅ 7.38 (dd, J = 1.9, J = 0.8, IH), 7.44-7.47 (m, 2H).

LC / MS (Method 2): R _t = 3.06 min .; MS (ESIpos): m / z = 448 [M + H] ⁺ . Example 2A

N- {4 - [(2-tert-Butoxy-1, 1-dimethyl-2-oxoethyl) thio] benzyl} -N- (2-furylmethyl) glycine

1.00 g of the compound from Example IA (2.23 mmol) are dissolved in 7 ml of dioxane / water (2: 1) and admixed with 3.37 ml of 1N sodium hydroxide solution (3.37 mmol). The reaction mixture is stirred for 16 h at room temperature. It is acidified to pH 2 with 2N hydrochloric acid and the mixture is extracted three times with dichloromethane. The combined organic phases are dried with sodium sulfate and concentrated on a rotary evaporator. 0.832 g (89% of theory) of the title compound are obtained.

LC / MS (Method 1): R _t = 2.18 min .; MS (ESIpos): m / z = 420 [M + H] ⁺ .

¹ H-NMR (400 MHz, CDCl _3): δ [ppm] = 1:42 (s, 9H) 1.44 (s, 6H), 3:32 (s, 2H), 3.76 (s, 2H), 3.77 (s, 2H ), 6.26-6.27 (m, IH), 6.36 (m, IH), 7.26-7.28 (m, 2H), 7.43-7.44 (m, IH), 7.49-7.51 (m, 2H).

Example 3A

tert -Butyl 2 - [(4 - {[2- [2- (2,4-dimethylphenyl) hydrazino] -2-oxoethyl} (2-furylmethyl) amino] -methyl} phenyl) thio] -2- methylpropanoate

1.00 g of the compound from Example 2A (2.38 mmol) are dissolved in 20 ml of THF and admixed with 997 mg of TCTU (2.80 mmol), 0.81 ml of DIEA (4.67 mmol) and 403 mg of 2,4-dimethylphenylhydrazine (2.34 mmol). It is stirred overnight at RT. The mixture is concentrated, the residue in Water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried with sodium sulfate and the solvent is distilled off under reduced pressure. The mixture is then purified by chromatography (silica gel, cyclohexane / ethyl acetate 1: 1). 1.01 g (purity: 90% according to LC / MS, 72% of theory) of the title compound are obtained. The substance is reacted further without further purification steps.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.34 (s, 9H), 1.38 (s, 6H), 2.12 (s, 3H), 2.15 (s, 3H), 3.18 (s, 2H ), 3.73 (s, 2H), 3.76 (s, 2H), 6.36 (d, IH), 6.42-6.51 (m, 2H), 6.72-6.89 (m, 3H), 7.45 (s *, 4H), 7.63 (dd, IH), 9.60 (s, IH).

LC / MS (Method 2): R _t = 2.96 min .; MS (ESIpos): m / z = 538 [M + H] ⁺ .

Example 4A

tert-butyl 2 - [(4 - {[{[4- (2,4-dimethylphenyl) -5-oxo-5,6-dihydro-4H-l, 3,4-oxadiazine-2-yl] methyl} - (2-furylmethyl) amino] methyl} phenyl) thio] -2-methylpropanoate

1.00 g of the compound from Example 3 A (1.67 mmol) are dissolved in 20 ml of abs. DMF solved. Subsequently, 227 mg of chloroacetyl chloride (0.16 ml, 2.01 mmol) as a solution in 5 ml of abs. DMF was added dropwise over 30 min. After a reaction time of 30 minutes at RT, 578 mg of potassium carbonate (4.18 mmol) are added and the mixture is stirred at 70 ^° C. overnight. The solvent is distilled off in vacuo, the residue taken up in water and extracted with ethyl acetate. After drying with sodium sulfate, the solvent is distilled off and the residue is purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). 70 mg (25% of theory) of the title compound are obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.33 (s, 9H), 1.36 (s, 6H), 2.08 (s, 3H), 2.30 (s, 3H) ₃ 3.27 (s , 2H), 3.72 (s, 2H), 3.74 (s, 2H), 4.75 (s, 2H), 6.31 (d, IH), 6.41 (dd, IH), 7.04-7.14 (m, 3H), 7.36 ( d, 2H), 7.42 (d, 2H), 7.6 (m, IH). MS (ESIpos): m / z = 578 [M + H] ⁺ . Example 5A

tert-Butyl-2 - ({4 - [((2-fluoromethyl) {2- [2- (2-phenyl) thio) -2-methylpropanoate

1.00 g of the compound of Example 2A (2.38 mmol), 378 mg of 2-tolylhydrazole hydrochloride (2.38 mmol), 387 mg of HOBt (2.86 mmol) and 913 mg of EDCI (4.77 mmol) are dissolved in 5 ml of DMF. Subsequently, 0.26 ml of 4-methylmorpholine (2.38 mmol) are added dropwise with ice-cooling. It is stirred overnight at RT. The batch is added to cooled 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried with sodium sulfate and the solvent distilled off under reduced pressure. The mixture is then purified by column chromatography (silica gel, dichloromethane - »dichloromethane / isopropanol 10: 1). 900 mg (purity: 80% according to LCMS, 58% of theory) of the title compound are obtained. The substance is reacted further without further purification steps.

LC / MS (Method 3): R _t = 3.11 min .; MS (ESIpos): m / z = 524 [M + H] ⁺ .

Example 6A

/ E7L-butyl-2 - ({4 - [((2-furylmethyl) {[4- (2-methylphenyl) -5-oxo-5,6-dihydro-4H-l, 3,4-oxadiazin-2- yl] methyl} amino) methyl] phenyl} thio) -2-methylpropanoate

300 mg of the compound from Example 5A (0.47 mmol) are dissolved in 10 ml of chloroform, admixed with 116 mg of chloroacetyl chloride (0.08 ml, 1.03 mmol) and heated at reflux overnight. The solvent is then distilled off, the residue taken up in 10 ml of ethanol, mixed with 285 mg of potassium carbonate (2.06 mmol) and stirred overnight at reflux temperature. The solvent is distilled off in vacuo, the residue taken up in water and extracted with ethyl acetate. After drying with sodium sulfate, the solvent is distilled off under reduced pressure and the residue is purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20: 80-> 95: 5). 36 mg (12% of theory) of the title compound are obtained.

LC / MS (Method 4): R _t = 3.26 min .; MS (ESIpos): m / z = 564 [M + H] ⁺ .

Example 7A

tert-Buyl-2 - ({4 - [((2-furylmethyl) {2- [2- (3-methylphenyl) hydrazino] -2-oxoethyl} amino) methyl] phenyl} thio) -2-methylpropanoate

1.06 g of the compound of Example 2A (2.52 mmol), 400 mg of 3-tolylhydrazine hydrochloride (2.52 mmol), 408 mg of HOBt (3.03 mmol) and 966 mg of EDCI (5.04 mmol) are dissolved in 5 ml of DMF. Then, with ice cooling, 0.28 ml of 4-methylmorpholine (2.52 mmol) are added dropwise. It is stirred overnight at RT. The batch is added to cooled 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried with sodium sulfate and the solvent distilled off under reduced pressure. The mixture is then purified by column chromatography (silica gel, dichloromethane - »dichloromethane / isopropanol 20: 1). 489 mg (58% of theory) of the title compound are obtained.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.34 (s, 9H), 1.37 (s, 6H), 2.16 (s, 3H), 3.16 (s, 2H), 3.72 (s, 2H ), 3.75 (s, 2H), 6.35 (d, IH), 6.42-6.55 (m, 4H), 6.98 (t, IH), 7.45 (s *, 4H), 7.58-7.66 (m, 2H), 9.58 (s, IH).

LC / MS (Method 1): R _t = 3.07 min .; MS (ESIpos): m / z = 524 [M + H] ⁺ . Example 8A

ter /.- butyl 2 - ({4 - [((2-nαrylmethyl) {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-l, 3,4-oxadiazm-2 - yl] methyl} amino) methyl] phenyl} thio) -2-methylpropanoate

200 mg of the compound from Example 7A (0.29 mmol) are dissolved in 10 ml of chloroform, admixed with 86 mg of chloroacetyl chloride (0.06 ml, 0.76 mmol) and heated at reflux overnight. The solvent is then distilled off, the residue taken up in 10 ml of ethanol, treated with 211 mg of potassium carbonate (1.53 mmol) and stirred overnight at reflux temperature. The solvent is distilled off in vacuo, the residue taken up in water and extracted with ethyl acetate. After drying with sodium sulfate, the solvent is distilled off and the residue is purified by preparative HPLC (eluent: acetone / water with 0.1% formic acid, gradient 20:80 -> 95: 5). 40 mg (19% of theory) of the title compound are obtained.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.33 (s, 9H), 1.36 (s, 6H), 2.33 (s, 3H), 3.76 (s, 2H), 3.77 (s, 2H ), 4.74 (s, 2H), 6.34 (d, IH), 6.42 (dd, IH), 7.09 (d, IH), 7.31-7.48 (m, 7H), 7.62 (m, IH).

LC / MS (Method 4): R _t = 3.34 min .; MS (ESIpos): m / z = 564 [M + H] ⁺ .

Example 9A

tert -Butyl 2 - ({4 - [((2-furylmethyl) {2- [2- (4-methylphenyl) hydrazino] -2-oxoethyl} amino) methyl] phenyl} thio) -2-methylpropanoate

1.00 g of the compound of Example 2A (2.38 mmol), 378 mg of 4-tolylhydrazine hydrochloride (2.38 mmol), 387 mg of HOBt (2.86 mmol) and 913 mg of EDCI (4.77 mmol) are dissolved in 5 ml of DMF. Subsequently, 0.26 ml of 4-methylmorpholine (2.38 mmol) are added dropwise with ice-cooling. It is stirred overnight at RT. The batch is added to cooled 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried with sodium sulfate and the solvent distilled off under reduced pressure. The mixture is then purified by column chromatography (silica gel, dichloromethane -> dichloromethane / isopropanol 20: 1). 500 mg (40% of theory, purity 75%) of the title compound are obtained.

LC / MS (Method 3): R _t = 3.08 min .; MS (ESIpos): m / z = 524 [M + H] ⁺ .

Example IQA

iert.-butyl-2 - ({4 - [((2-furylmethyl) {[4- (4-methylphenyl) -5-oxo-5,6-dihydro-4H-l, 3,4-oxadiazm-2- yl] methyl} amino) methyl] phenyl} thio) -2-methylpropanoate

200 mg of the compound from Example 9A (0.29 mmol) are dissolved in 10 ml of chloroform, treated with 64 mg of chloroacetyl chloride (0.05 ml, 0.57 mmol) and heated under reflux overnight. The solvent is then distilled off, the residue taken up in 10 ml of ethanol, treated with 158 mg of potassium carbonate (1.15 mmol) and stirred overnight at reflux temperature. The solvent is distilled off in vacuo, the residue taken up in water and washed with Extracted ethyl acetate. After drying with sodium sulfate, the solvent is distilled off and the residue is purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 -> 95: 5). 11 mg (6.4% of theory) of the title compound are obtained.

LC / MS (Method 4): R ₁ = 3.33 min. ^" MS (ESIpos): m / z = 564 [M + H] ⁺ .

Example IIA

2- (4-Cyanophenylsulfanyl) -2-methyl-propionic acid ter-butyl ester /.-

In a 26 liter kettle, 2473 g (19.01 mol) of sodium sulfo (hydrous) are suspended in 14.4 liters of NMP. Then 5.1 liters of the solvent are distilled off again at 125-13O ⁰ C and 110 mbar. At an internal temperature of 130-140 ° C is then added dropwise within one hour, a solution of 2110 g (15.33 mol) of 4-chlorobenzonitrile in 3.84 liters of NMP. The temperature is raised to 155-160 ⁰ C and it is stirred for 6 h. At 40-45 ⁰ C 3761 g (16.86 mol) bromoisobutyric acid te / 1-butyl ester are added within 45 min. Thereafter, 13.0 liters of the solvent are distilled off at 97 ⁰ C and 24 mbar, the batch is cooled to 90 ⁰ C, and 5.8 liters of methylcyclohexane are added. It is cooled to 15-20 ⁰ C, mixed with 7.70 liters of water and 288 g of diatomaceous earth and stirred for 15 min at 20 ⁰ C after. The mixture is then filtered through a porcelain chute with a Seitz filter plate (K800), the filtrate is transferred to a 40 liter separating pear and the phases are separated. The organic phase (9.1 liters) is stirred twice each with 5.8 liters of water and the organic phase concentrated on a rotary evaporator at 55- 60 ⁰ C / 1 mbar. The residue obtained is 3788 g (89% of theory) of an oil which solidifies on storage at room temperature (purity 93% by GC). The residue is used without further purification in the next step.

¹ H-NMR (500 MHz, DMSOd ₆ ): δ = 1.37 (s, 9H), 1.45 (s, 6H), 7.60 (d, 2H), 7.85 (d, 2H).

Example 12A

2- [4- (aminomethyl) phenylsulfanyl] -2-methyl-propionic acid tert-butyl ester hydrochloride

x HCl

In a 26 liter kettle is added to a solution of 3000 g (10.74 mol) of 2- (4-cyanophenylsulfanyl) -2-methyl-propionic acid fer / -butyl ester (Example I IA) in 5.5 liters of THF at 72 ° C, a solution of 2627 g (16.11 mol) of borane-N, N-diethylaniline complex added dropwise within 2 h. The mixture is stirred for 1 h at 72 ° C, then cooled to RT and added within 1 h 2.33 liters of methanol. Then it is mixed with 5.81 liters of 6 M hydrochloric acid and stirred overnight at RT. It is transferred to a 40 liter separating pear and the kettle is rinsed with 3.88 liters of water and 7.75 liters of methylcyclohexane. The organic phase is stirred twice with 3.8 liters of water. The combined aqueous phases are stirred with 3.88 liters of methylcyclohexane and then adjusted to pH 10.5 with concentrated sodium hydroxide solution (consumption: 2.5 liters). The aqueous-oily phase is stirred twice with 3.88 liters of methylcyclohexane and the combined organic phases are washed with 5.81 liters of water. The organic phase (14.5 liters) is concentrated on a rotary evaporator at 75 ° C / 45 mbar. This gives 4.45 kg of a crude solution containing the desired product in admixture with diethylaniline.

This crude solution is combined with a previous batch of the same size and the diethylaniline is largely distilled off in two steps on a thin film evaporator (1st distillation: product feed 458 g / h, feed temperature 80-85 ⁰ C, pressure 2.7 mbar, head temperature 67 ° C, bottom temperature 37 ° C, 2nd distillation: identical conditions at 1.0 mbar). The distillation residue (3664 g) is taken up in an enamel kettle in 7.8 liters of MTBE and treated dropwise within 20 min with a 5-6 molar solution of hydrogen chloride in isopropanol. The internal temperature rises to 47 ° C. The suspension is cooled to RT and stirred for 2 h. It is sucked off via a Seitz filter plate and washed four times with 2.6 liter MTBE each time. The moist product (5.33 kg) is dried in vacuo at 40 ⁰ C and nitrogen blanketing to constant mass. 2780 g (41% of theory) of the title compound are obtained as white crystals for the two combined batches.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ - 1.39 (m, 15H), 4.04 (s, 2H), 7.49 (m, 4H), 8.48 (sbr, 3H).

MS (DCI / NH ₃ ): m / z = 282 [M + H] ⁺ , 299 [M ^ -NH ₄ J ⁺ . Example 13A

tert-butyl 2 - [(4 - {[(2-methoxyethyl) amino] methyl} phenyl) thio] -2-methylpropanoate

5.00 g of the compound from Example 12A (15.73 mmol) are initially charged in 15 ml of DMF and at RT with 1.97 g of 2-bromoethyl methyl ether (14.16 mmol) and 5.48 ml of triethylamine (39.32 mmol) ver¬ sets. It is stirred overnight at RT and then concentrated on a rotary evaporator. The residue is treated with water, extracted twice with ethyl acetate, dried with sodium sulfate and the solvent is distilled off under reduced pressure. The purification is carried out by flash chromatography on silica gel (eluent: dichloromethane / isopropanol 5: 1). There are obtained 2.56 g (48% of theory) of the title compound.

LC / MS (method 2): R ₁ = 1.49 min .; MS (ESIpos): m / z = 340 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.38 (s *, 15H), 3.09 (t, 2H), 3.30 (s, 3H), 3.58 (t, 2H), 4.18 ( s, 2H), 7.51 (s *, 4H), 8.92 (sbr, IH).

Example 14A

2- (chloromethyl) -4- (3-methylphenyl) -4H-l, -one 3,4-oxadiazine-5 (6H)

2.46 g of 3-methylphenylhydrazine (20.14 mmol) and 1 g of molecular sieve (4A) are dissolved in 30 ml of abs. DMF submitted. Subsequently, 1.60 ml of chloroacetyl chloride (20.14 mmol) as a solution in 10 ml of abs. DMF was added dropwise over a period of 30 min. After complete implementation (con- control via analytical HPLC), another equivalent of chloroacetyl chloride is added and 3.51 ml DlEA (20.14 mmol) as a solution in 10 ml abs. DMF slowly added dropwise over about 30 min. After renewed HPLC control, another 7.01 ml of DIEA (40.27 mmol) are added. The mixture is then stirred at 70 ⁰ C overnight. After cooling, the solvent is distilled off under reduced pressure, the residue taken up in water and extracted three times with ethyl acetate. It is washed with water, dried with sodium sulfate and then the solvent removed on a rotary evaporator. The purification is carried out by flash chromatography on silica gel (eluent: cyclohexane / ethyl acetate 5: 1). 3.11 g (63% of theory) of the title compound are obtained.

LC / MS (Method 4): R _t = 2.24 min .; MS (ESIpos): m / z = 239 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 2.33 (s, 3H), 4.40 (s, 2H), 4.90 (s, 2H), 7.12 (m, IH), 7.29-7.36 (m , 3H).

Example 15A

tert-butyl 2 - ({4 - [((2-methoxyethyl) {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-l, 3,4-oxadiazine] yl] methyl} amino) methyl] phenyl} thio) -2-methylpropanoate

150 mg of the compound from Example 13A (0.44 mmol), 116 mg of the compound from Example 14A (0.49 mmol), 0.15 ml of triethylamine (1.10 mmol) and 33 mg of TBAI (0.09 mmol) are dissolved in 3 ml of TΗF and overnight at 100 ⁰ C reacted in a pressure-resistant vessel. The solvent is then removed under reduced pressure and the residue is taken up in water. After twice extraction with ethyl acetate is dried with sodium sulfate and the solvent was removed on a rotary evaporator. The purification is carried out by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). 116 mg (48% of theory) of the title compound are obtained.

LC / MS (Method 2): R _t = 2.87 min .; MS (ESIpos): m / z = 542 [M + Η] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.34 (s, 9H), 1.36 (s, 6H), 2.33 (s, 3H), 2.76 (t, 2H), 3.21 (s , 3H), 3.39 (s, 2H), 3.44 (t, 2H), 3.80 (s, 2H), 4.76 (s, 2H), 7.09 (d, IH), 7.25-7.45 (m, 7H).

Example 16A

te ^ .- butyl-2-methyl-2 - ({4 - [({[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-l, 3,4-oxadiazin-2- yl] - methyl} amino) methyl] phenyl} thio) propanoate

1.31 g of the compound from Example 12A (4.11 mmol) are initially charged in 20 ml of TΗF and admixed with 0.72 ml of DEEA (4.11 mmol). After stirring for five minutes, 1.00 g of the compound from Example 14A (4.11 mmol), 0.86 ml of triethylamine (6.16 mmol) and 0.30 g of TBAI (0.82 mmol) are added and the reaction mixture is stirred overnight at RT. The mixture is then concentrated on a rotary evaporator and the residue is taken up in water. After extracting twice with ethyl acetate, it is dried with sodium sulfate and the solvent is distilled off under reduced pressure. The purification is carried out by flash chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 1). 350 mg (18% of theory) of the title compound are obtained.

LC / MS (Method 2): R _t = 1.78 min .; MS (ESIpos): m / z = 484 [M + Η] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.35 (s *, 15H), 2.33 (s, 3H), 2.68 (sbr, IH), 3.35 (s, 2H), 3.79 ( s, 2H), 4.76 (s, 2H), 7.09 (d, IH), 7.29 (t, IH), 7.33-7.43 (m, 6H).

Example 17A

^ Rt-butyl-2-methyl-2 - ({4 - [(methyl {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-l, 3,4-oxadiazine-2 - yl] methyl} amino) methyl] phenyl} thio) propanoate

135 mg of the compound from Example 16A (0.28 mmol), 0.02 ml of methyl iodide (0.33 mmol), 0.10 ml of triethylamine (0.70 mmol) and 0.05 ml of DlEA (0.28 mmol) are dissolved in 4 ml of THF and stored in a pressure-resistant vessel overnight at 100 ⁰ C implemented. The reaction mixture is concentrated on a rotary evaporator and the residue taken up in water. After two extractions with ethyl acetate, the mixture is dried using sodium sulfate and the solvent is distilled off under reduced pressure. The purification is carried out by means of preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). 73 mg (51% of theory) of the title compound are obtained.

LC / MS (method 2): R ₄ = 2.32 min .; MS (ESIpos): m / z = 498 [MH-H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.34 (s, 9H), 1.36 (s, 6H), 2.26 (s, 3H), 2.33 (s, 3H), 3.28 (s, 2H ), 3.66 (s, 2H), 4.80 (s, 2H), 7.09 (d, IH), 7.24-7.38 (m, 5H), 7.42 (d, 2H).

Example 18A

2- (chloromethyl) -4- (3-chlorophenyl) -4H-l, -one 3,4-oxadiazine-5 (6H)

13.00 g of 3-chlorophenylhydrazine (91.17 mmol) and 5 g of molecular sieve (4A) are dissolved in 200 ml of abs. DMF submitted. Then 7.26 ml of chloroacetyl chloride (91.17 mmol) as a solution in 100 ml of abs. DMF was added dropwise over a period of 30 min. After complete reaction (control by means of analytical HPLC), another equivalent of chloroacetyl chloride is added and 15.88 ml of DIEA (91.17 mmol) as a solution in 100 ml of abs. DMF slowly added dropwise over about 30 min. After renewed ΗPLC control, another 31.76 ml of DIEA (182.34 mmol) are added. The mixture is then stirred at 70 ⁰ C overnight. After cooling, the solvent is distilled off under reduced pressure, the residue taken up in water and extracted three times with ethyl acetate. It is washed with water, dried with sodium sulfate and then the solvent removed on a rotary evaporator. The purification is carried out by flash chromatography on silica gel (eluent: cyclohexane / ethyl acetate 5: 1). There are obtained 10.00 g (42% of theory) of the title compound. LC / MS (Method 2): R _t = 2.16 min .; MS (ESIpos): m / z = 259 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 4.43 (s, 2H), 4.92 (s, 2H), 7.37 (d, IH), 7.47 (t, IH), 7.59 (i.e. , IH), 7.67 (t, IH).

Example 19A

^ Rt-butyl-2 - ({4 - [((2-methoxyethyl) {[4- (3-chlorophenyl) -5-oxo-5,6-dihydro-4H-l, 3,4-oxadiazine-2 - yl] methyl} amino) methyl] phenyl} thio) -2-methylpropanoate

250 mg of the compound from Example 13A (0.74 mmol), 209 mg of the compound from Example 18A (0.81 mmol), 0.26 ml of triethylamine (1.84 mmol) and 54 mg of TBAI (0.15 mmol) are dissolved in 3 ml of THF and overnight 100 ° C reacted in a pressure-resistant vessel. The solvent is then removed under reduced pressure and the residue is taken up in water. After twice extraction with ethyl acetate is dried with sodium sulfate and the solvent was removed on a rotary evaporator. The purification is carried out by means of preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 → 95: 5). 276 mg (67% of theory) of the title compound are obtained.

LC / MS (Method 1): R _t = 3.17 min .; MS (ESIpos): m / z = 562 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.33 (s, 9H), 1.35 (s, 6H), 2.77 (t, 2H), 3.21 (s, 3H), 3.41 (s, 2H ), 3.45 (t, 2H), 3.81 (s, 2H), 4.79 (s, 2H), 7.31-7.50 (m, 6H), 7.61 (m, IH), 7.68 (t, IH).

Example 2OA

tert. Butyl 2 - [(4- {[(cyanomethyl) amino] methyl} phenyl) thio] -2-methylpropanoate

5.00 g of the compound from Example 12A (15.73 mmol) are initially charged in 50 ml of DMF and admixed at RT with 1.89 g of bromoacetonitrile (15.73 mmol) and 5.48 ml of triethylamine (39.32 mmol). It is stirred overnight at RT and then concentrated on a rotary evaporator. The residue is treated with water, extracted twice with ethyl acetate, dried with sodium sulfate and the solvent is distilled off under reduced pressure. The purification is carried out by flash chromatography on silica gel (eluent: cyclohexane / ethyl acetate 7: 3). There are obtained 4.55 g (90% of theory) of the title compound.

LC / MS (Method 1): R _t = 2.55 min .; MS (ESIpos): m / z = 641 [2M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.36 (s *, 15H), 3.09 (dt, IH), 3.58 (d, 2H), 3.77 (d, 2H), 7.34 (d, 2H), 7.42 (d, 2H).

Example 21A

tert -Butyl 2 - ({4 - [((cyanomethyl) {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1, 3,4-oxadiazin-2-yl] methyl} amino) methyl] phenyl} thio) -2-methylpropanoate

150 mg of the compound from Example 2OA (0.47 mmol), 134 mg of the compound from Example 14A (0.33 mmol), 0.16 ml of triethylamine (1.17 mmol) and 35 mg of TBAI (0.09 mmol) are dissolved in 4 ml of THF and in a pressure-resistant vessel reacted overnight at 100 ⁰ C. The reaction mixture is concentrated on a rotary evaporator and the residue is taken up in water. After extracting twice with ethyl acetate, it is dried with sodium sulfate and the solvent is distilled off under reduced pressure. The purification is carried out by means of preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). There are obtained 70 mg (29% of theory) of the title compound.

LCMS (Method 4): R ₁ = 3.10 min .; MS (ESIpos): m / z = 523 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.34 (s, 9H), 1.37 (s, 6H), 2.33 (s, 3H), 3.40 (s, 2H), 3.82 (s *, 4H) ₅ 4.79 (s, 2H), 7.10 (d, IH), 7.27-7.41 (m, 5H), 7.45 (d, 2H).

Example 22A

tert. Butyl 2-methyl-2- ({4 - [(prop-2-yn-1-ylamino) methyl] phenyl} thio) propanoate

5.00 g of the compound from Example 12A (15.73 mmol) are initially charged in 50 ml of DMF and treated at RT with 1.87 g of propargyl bromide (15.73 mmol) and 5.48 ml of triethylamine (39.32 mmol). It is stirred overnight at RT and then concentrated on a rotary evaporator. The residue is admixed with water, extracted twice with ethyl acetate, dried with sodium sulfate and the solvent is distilled off under reduced pressure. The purification is carried out by flash chromatography on silica gel (eluent: cyclohexane / ethyl acetate 6: 4). There are obtained 1.70 g (34% of theory) of the title compound.

LC / MS (Method 4): R _t = 1.84 min .; MS (ESIpos): m / z = 320 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.35 (s *, 15H), 2.56 (br.s, IH), 3.09 (t, IH), 3.26 (d, 2H), 3.75 ( s, 2H), 7.33 (d, 2H), 7.40 (d, 2H).

Example 23A

tert. Butyl 2-methyl-2 - [(4- {[{4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] - methyl} (prop-2-in-l-yl) amino] methyl} phenyl) thio] propanoate

134 mg of the compound from Example 22A (0.42 mmol), 120 mg of the compound from Example 14A (0.50 mmol), 0.18 ml DlEA (1.05 mmol) and 31 mg TBAI (0.08 mmol) are dissolved in 2 ml THF and placed in a pressure-resistant vessel reacted overnight at 100 ° C. The reaction mixture is concentrated on a rotary evaporator and the residue taken up in water. After extraction twice with ethyl acetate, it is dried with sodium sulfate and the solvent is distilled off under reduced pressure. The purification is carried out by means of preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). 193 mg (88% of theory) of the title compound are obtained.

LC / MS (Method 1): R _t = 3.24 min .; MS (ESIpos): m / z = 522 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.34 (s, 9H), 1.36 (s, 6H), 2.33 (s, 3H), 3.28 (t, IH), 3.37 (s, 2H ), 3.41 (d, 2H), 3.76 (s, 2H), 4.78 (s, 2H), 7.09 (d, IH), 7.25-7.40 (m, 5H), 7.43 (d, 2H).

Example 24A

tot.-butyl-2 - ({4 - [((2-fluoroethyl) {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-l, 3,4-oxadiazm-2- yl] methyl} amino) methyl] phenyl} thio) -2-methylpropanoate

100 mg of the compound from Example 16A (0.21 mmol), 40 mg 1-bromo-2-fluoroethane (0.31 mmol),

0.09 ml of DIEA (0.52 mmol) and 13 mg of TBAI (0.04 mmol) are dissolved in 1 ml of THF and reacted in a pressure-resistant vessel at 100 ^° C. overnight. The reaction mixture is concentrated on a rotary evaporator and the residue is taken up in water. After two ex-works Traction with ethyl acetate is dried with sodium sulfate and the solvent is distilled off under reduced pressure. The purification is carried out by means of preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). 87 mg (79% of theory) of the title compound are obtained.

LC / MS (Method 4): R _t = 3.19 min .; MS (ESIpos): m / z = 530 [M + H] ⁺ .

Example 25A

2- (chloromethyl) -4- [-4- (trifluoromethyl) phenyl] -4H-l, -one 3,4-oxadiazine-5 (6H)

1.55 g of 4-trifluoromethylphenylhydrazine (8.80 mmol) and 0.5 g of molecular sieve (4A) are dissolved in 20 ml of abs. DMF submitted. Then 0.7 ml of chloroacetyl chloride (8.80 mmol) as a solution in 10 ml of abs. DMF was added dropwise over a period of 30 min. After complete reaction (control over analytical HPLC), another equivalent of chloroacetyl chloride is added and 1.5 ml of DIEA (8.80 mmol) as a solution in 10 ml of abs. DMF slowly added dropwise over about 30 min. After another ΗPLC control, add another 3.0 mL of DIEA (17.60 mmol). Subsequently, the mixture is stirred overnight at 70.degree. After cooling, the solvent is distilled off at reduced pressure, the residue is taken up in water and extracted three times with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate, and then the solvent is removed on a rotary evaporator. The purification is carried out by chromatography (Biotage 4OM, eluent: cyclohexane / tert-butylmethyl ether 3: 1). There are obtained 0.54 g (20% of theory) of the title compound.

MS (ESIpos): m / z = 310 [M + N + ₄ ] ⁺ .

¹ H-NMR (400 MHz, CDCl _3): δ [ppm] = 4.19 (s, 2H), 4.83 (s, 2H), 7.66 (d, 2H), 7.82 (d, 2H). Example 26A

tert -butyl-2 - [(4 - {[(2-metiioxyethyl) ({5-oxo-4- [4-trifluoromethyl) -phenyl] -5,6-dihydro-4H-1,4-oxadiazine) 2-yl} methyl) amino] methyl} phenyl) thio] -2-methylρropanoat

597 mg of the compound from Example 13A (1.76 mmol) and 515 mg of the compound from Example 25A (1.76 mmol) are dissolved in 5.0 ml of abs. Submitted DMF and 486 mg of potassium carbonate (3.52 mmol). The mixture is stirred for one hour at 90 ^° C. The reaction mixture is mixed with water and extracted with ethyl acetate. The combined organic phases are washed four times with water and once with saturated sodium carbonate solution and dried over magnesium sulfate. The purification of the crude product obtained after removal of the solvent is carried out by chromatography (Biotage 4OM, eluent: isohexane / ethyl acetate 65:35). From the title compound, 623 mg (59% of theory) are obtained in the form of a colorless oil.

LC / MS (method 1): R _t = 3.30 min .; MS (ESIpos): m / z = 596 [M + H] ⁺ .

Example 27A

2- (chloromethyl) -4- [4- (trifluoromethoxy) phenyl] -4 H -1,4,4-oxadiazine-5 (6H) -one

1.50 g of 4-trifluoromethoxyphenylhydrazine hydrochloride (6.56 mmol) are dissolved in 60.0 ml of about 30% sodium hydroxide solution. The aqueous phase is extracted four times with ethyl acetate. The Ver- The combined organic phases are washed with water and saturated sodium chloride solution ge and dried over magnesium sulfate. The free base, which is obtained after removal of the solvent in the form of a brownish oil, is dissolved in 20.0 ml abs. DMF submitted. Then 0.5 ml of chloroacetyl chloride (6.28 mmol) as a solution in 10 ml of abs. DMF was added dropwise over a period of 30 min. After complete reaction (control by analytical HPLC), another equivalent of chloroacetyl chloride is added and 1.0 ml of DIEA (6.00 mmol) as a solution in 10 ml abs. DMF slowly added dropwise over about 30 min. After re-HPLC, add another 2.0 mL of DIEA (12.00 mmol). The mixture is then stirred at 70 ⁰ C overnight. After cooling, the solvent is distilled off under reduced pressure, the residue taken up in water and extracted three times with ethyl acetate. The combined orgasmic phases are washed with water, dried over sodium sulfate, and then the solvent is removed on a rotary evaporator. The purification is carried out by chromatography (Biotage 4OM, eluent: cyclohexane / tert-butyl methyl ether 3: 1). There are obtained 0.53 g (29% of theory) of the title compound.

LC / MS (Method 1): R _t = 2.60 min .; MS (ESIpos): m / z = 309 [MfH] ⁺ .

¹ H-NMR (400 MHz, CDCl _3): δ [ppm] = 4.17 (s, 2H), 4.82 (s, 2H), 7.26 (d, 2H), 7.67 (d, 2H).

Example 28A

/ert.-Butyl-2-[(4-{[(2-methoxyethyl)({5-oxo-4-[4-(trifluormethoxy)phenyl]-5,6-dihydro-4H-l,3,4- oxadiazine-2-yl} methyl) amino] methyl} phenyl) thio] -2-methylpropanoate

551 mg of the compound from Example 13A (1.63 mmol) and 501 mg of the compound from Example 27A (1.63 mmol) are dissolved in 5.0 ml abs. Submitted DMF and treated with 449 mg of potassium carbonate (3.26 mmol). The batch is stirred for one hour at 90.degree. The reaction mixture is mixed with water and extracted with ethyl acetate. The combined organic phases are washed four times with water and once with saturated sodium carbonate solution and dried over magnesium sulfate. Purification of the crude product obtained after removal of the solvent. product is chromatographed (Biotage 4OM, eluent: isohexane / ethyl acetate 65:35). 371 mg (37% of theory) of the title compound are obtained in the form of a colorless oil.

LC / MS (Method 4): R _t = 3.25 min .; MS (ESIpos): m / z = 612 [M + H] ⁺ .

¹ H-NMR (400 MHz, .CDCl ₃ ): δ [ppm] = 1.43 (sbr, 15H), 2.87 (t, 2H), 3.33 (s, 3H), 3.48 (s, 2H), 3.52 (t, 2H), 3.83 (s, 2H), 4.65 (s, 2H), 7.24 (d, 2H), 7.31 (d, 2H), 7.46 (d, 2H), 7.68 (d, 2H).

Example 29A

2- (chloromethyl) -4- (4-fluorophenyl) -4H-l, -one 3,4-oxadiazine-5 (6H)

4.00 g of 4-fluorophenylhydrazine (31.71 mmol) and 2 g of molecular sieve (4A) are dissolved in 80 ml of abs. DMF submitted. Subsequently, 3.58 ml of chloroacetyl chloride (31.71 mmol) as a solution in 15 ml of abs. DMF was added dropwise over a period of 30 min. After complete reaction (control over analytical HPLC), another equivalent of chloroacetyl chloride is added and 5.52 ml of DIEA (31.17 mmol) as a solution in 15 ml of abs. DMF slowly added dropwise over about 30 min. After renewed ΗPLC control, another 11.05 ml of DIEA (63.43 mmol) are added. The mixture is subsequently stirred at 70 ^° C. overnight. After cooling, the solvent is distilled off at reduced pressure, the residue is taken up in water and extracted three times with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate, and then the solvent is removed on a rotary evaporator. The purification is carried out by flash chromatography on silica gel (eluent: cyclohexane / ethyl acetate 5: 1). There are obtained 6.5 g of the not yet ring-closed intermediate, which is then stirred again with 6.9 ml (37 mmol) of DIEA in 50 ml of DMF at 70 ⁰ C overnight. After analogous workup, 3.97 g (46% of theory) of the title compound are obtained.

LC / MS (Method 4): R _t = 2.13 min .; MS (ESIpos): m / z = 243 [M + Η] ⁺ .

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 4.2 (s, 2H), 4.85 (s, 2H), 7.1 (dd, 2H), 7.55 (m 2H). Example 30A

fe ^ .- butyl 2 - ({4 - [((2-methoxyethyl) {[4- (4-fluorophenyl) -5-oxo-5,6-dihydro-4H-l, 3,4-oxadiazine-2 - yl] methyl} amino) methyl] phenyl} thio) -2-methylpropanoate

100 mg of tert-butyl-2- (4) -{ (2-methoxyethyl) aminoethylmethyl-phenyl) thio] -2-methylpropanoate (0.29 mmol) (Example 13A), 71 mg of 2- (chloromethyl) -4- (4-fluorophenyl) -4H-l, 3,4-oxadiazm-5 (6H) -one (0.29 mmol) (Example 29A) and 82 mg of potassium carbonate are dissolved in 1 ml of DMF and at 120 ⁰ C overnight touched. The cooled batch is added to water. After extracting twice with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is removed on a rotary evaporator. The residue is purified by preparative HPLC. 28 mg (17% of theory) of the title compound are obtained.

LC / MS (Method 4): R _t = 2.97 min .; MS (ESIpos): m / z = 546 [M + Η] ⁺ .

¹ H-NMR (400 MHz, CDCl _3): δ [ppm] = 1:45 (sbr, 15H), 2.75 (sbr, 2H), 3.3 (s, 3H), 3:45 (s, 2H), 3.5 (sbr, 2H ), 3.85 (s, 2H), 4.7 (s, 2H), 7.1 (dd, 2H), 7.3 (d, 2H), 7.45 (d, 2H), 7.55 (dd, 2H).

Ausfflhrungsbeispiele:

example 1

² - [( ⁴ - {[{[4- (2,4-dimethyl-phenyl) -5-oxo-5,6-dihydro-4H-1, 3,4-oxadiazin-2-yl] -methyl} (2-furyl - methyl) amino] methyl} phenyl) thio] -2-methylpropanoic acid

100 mg of the compound from Example 4A (0.173 mmol) are combined with 5 ml of a 4 M solution of hydrogen chloride in dioxane and stirred at RT overnight. The solvent is then distilled off under reduced pressure and the remaining hydrochloride is characterized by LC / MS. 90 mg (93% of theory, purity 90%) of the hydrochloride salt are obtained.

LC / MS (Method 4): R _t = 2.69 min .; MS (ESIpos): m / z = 522 [M + Η] ⁺ (free base).

The title compound is obtained after further purification by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 → 95: 5).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.37 (s, 6H), 2.10 (s, 3H), 2.30 (s, 3H), 3.40 (s, 2H), 3.87 (s , 2H), 3.91 (s, 2H), 4.77 (s, 2H), 6.41 (m, IH), 6.44 (m, IH), 7.05-7.15 (m, 3H), 7.39 (d, 2H), 7.43 ( d, 2H), 7.66 (s, IH).

Example 2

2 - [(4 - {[{[4- (2-methylphenyl) -5-oxo-5,6-dihydro-4H-l, 3,4-oxadiazine-2-yl] methyl} (2-furylmethyl) - amino] methyl} phenyl) thio] -2-methylpropanoic acid

36 mg of the compound from Example 6A (0.064 mmol) are combined with 5 ml of a 4 M solution of hydrogen chloride in dioxane and stirred at RT overnight. Subsequently, the solvent is distilled off under reduced pressure and the remaining hydrochloride is characterized by LC / MS. 25 mg (93% of theory, purity 85%) of the hydrochloride salt are obtained.

LC / MS (Method 2): R _t = 2.38 min .; MS (ESIpos): m / z = 508 [M + H] ⁺ (free base).

The title compound is obtained after further purification by means of preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5).

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.35 (s, 6H), 2.14 (s, 3H), 3.28 (s, 2H), 3.72 (s, 2H), 3.75 (s, 2H ), 4.75 (s, 2H), 6.32 (d, IH), 6.41 (dd, IH), 7.21-7.45 (m, 8H), 7.62 (d, IH).

Example 3

2 - [(4 - {[{[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-l, 3,4-oxadiazm-2-yl] methyl} (2-furylmethyl) - amino] methyl} phenyl) thio] -2-methylpropanoic acid

900 mg of the compound from Example 8A (1.56 mmol) are mixed with 15 ml of a 4 M solution of hydrogen chloride in dioxane and stirred at 50 ^° C. for 3 h. The solvent is then distilled off under reduced pressure and the residue is purified by preparative HPLC. purified (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 -> 95: 5). 520 mg (64% of theory) of the title compound are obtained.

LC / MS (Method 2): R _t = 2.49 min .; MS (ESIpos): m / z = 508 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.37 (s, 6H), 2.33 (s, 3H), 3.43 (s, 2H), 3.87 (s, 2H), 3.89 (s, 2H ), 4.75 (s, 2H), 6.41 (d, IH), 6.45 (dd, IH), 7.10 (d, IH), 7.27-7.48 (m, 7H) 7.66 (d, IH).

Example 4

2 - [(4 - {[{[4- (4-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] methyl} (2-furylmethyl) - amino] methyl} phenyl) thio] -2-methylpropanoic acid

11 mg of the compound from Example 10A (0.020 mmol) are mixed with 3 ml of a 4 M solution of hydrogen chloride in dioxane and stirred overnight at RT. The solvent is then distilled off under reduced pressure and the remaining hydrochloride is characterized by LC / MS. 9 mg (72% of theory, purity 85%) of the hydrochloride salt are obtained.

LC / MS (Method 4): R _t = 2.69 min .; MS (ESIpos): m / z = 508 [M + Η] ⁺ (free base).

The free base is obtained after further purification by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 -> 95: 5).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.36 (s, 6H), 2.31 (s, 3H), 3.31 (s, 2H), 3.75 (s, 2H), 3.77 (s , 2H), 4.72 (s, 2H), 6.34 (s *, IH), 6.41 (s *, IH), 7.22 (d, 2H), 7.33-7.45 (m, 6H), 7.62 (s, IH), 12.59 (brs, IH). Example 5

2 - ({4 - [((2-methoxyethyl) {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] -methyl} amino) methyl] phenyl} thio) -2-methylpropanoic acid Ηydrochlorid

116 mg of the compound from Example 15A (0.21 mmol) are combined with 5 ml of a 4 M solution of hydrogen chloride in dioxane and stirred at 40 ^° C. for 3 h. Subsequently, the solvent is distilled off under reduced pressure. 115 mg (99% of theory) of the title compound are obtained.

LCMS (Method 2): R _t = 2.02 min .; MS (ESIpos): m / z = 486 [M + H] ⁺ (free base).

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.39 (s, 6H), 2.35 (s, 3H), 3.27 (s, 3H), 3.44-3.75 (m, 4H), 3.95 (sbr , 2H), 4.43 (sbr, 2H), 4.88 (s, 2H), 7.13 (d, IH), 7.28-7.42 (m, 3H), 7.44-7.53 (m, 2H), 7.54-7.66 (m, 2H ).

Example 6

2-methyl-2 - ({4 - [({[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1, 3,4-oxadiazin-2-yl] methyl} -amino ) methyl] phenyl} thio) propanoic acid Ηydrochlorid

100 of the compound from Example 16A (0:21 mmol) mg are mixed with 5 ml of a 4 M solution of hydrogen chloride in dioxane and stirred for 3 h at 4O ⁰ C. Subsequently, the solvent is distilled off under reduced pressure. 90 mg (93% of theory) of the title compound are obtained. LC / MS (Method 2): R _t = 1.51 min .; MS (ESIpos): m / z = 428 [M + H] ⁺ (free base).

¹ H-NMR (400 MHz ₅ CDCl _3): δ Qjpm] = 1:49 (s, 6H), 2:36 (s, 3H), 3.50-3.85 (m, 2H), 4.23 (sbr, 2H), 4.79 (s, 2H), 7.06 (d, IH), 7.26 (IH), 7.35-7.64 (m, 6H), 10.22 (sbr, IH).

Example 7

2-methyl-2 - ({4 - [(methyl {[4- (3-methyl-phenyl) -5-oxo-5,6-dihydro-4H-1, 3,4-oxadiazm-2-yl] -methyl} amino) methyl] phenyl} thio) propanoic acid

11.77 g of the compound from Example 17A (0.23 mmol) are introduced into 30 ml of dichloromethane and treated at 0 ⁰ C with 30 ml of trifluoroacetic acid. After one hour of stirring at RT, the mixture is concentrated and the residue taken up in 20% sodium acetate solution. It is extracted with ethyl acetate, the combined organic phases washed with water and concentrated sodium chloride solution and dried with sodium sulfate. The solvent is distilled off under reduced pressure and the residue is then dried under high vacuum. There are obtained 9.58 g (92% of theory) of the title compound.

LC / MS (Method 2): R _t = 1.58 min .; MS (ESIpos): m / z = 442 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.37 (s, 6H), 2.26 (s, 3H), 2.33 (s, 3H), 3.29 (s, 2H), 3.66 (s , 2H), 4.80 (s, 2H), 7.10 (d, IH), 7.27-7.38 (m, 5H), 7.41 (d, 2H), 12.49 (br, s, IH).

Example 8

2 - ({4 - [((2-methoxyethyl) {[4- (3-chlorophenyl) -5-oxo-5,6-dihydro-4H-l, 3,4-oxadiazine-2-yl] methyl} - amino) methyl] phenyl} thio) -2-methylpropanoic acid Ηydrochlorid

276 mg of the compound from Example 19A (0.49 mmol) are mixed with 10 ml of a 4 M solution of hydrogen chloride in dioxane and stirred at 40 ⁰ C for 3 h. Subsequently, the solvent is distilled off under reduced pressure. 249 mg (94% of theory) of the title compound are obtained.

LC / MS (Method 4): R _t = 2.33 min .; MS (ESIpos): m / z = 506 [M + H] ⁺ (free base).

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.38 (s, 6H), 3.27 (s, 3H), 3.44-3.74 (m, 4H), 3.97 (sbr, 2H), 4.42 (sbr , 2H), 4.89 (s, 2H), 7.38 (d, IH), 7.44-7.67 (m, 6H) ₅ 7.71 (t, IH).

Example 9

2 - ({4 - [((cyanomethyl) {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-l, 3,4-oxadiazin-2-yl] methyl} -amino) methyl] phenyl} thio) -2-methylpropanoic acid

70 mg of the compound from Example 21A (0.13 mmol) are mixed with 5 ml of a 4 M solution of hydrogen chloride in dioxane and stirred at 40 ⁰ C for 3 h. The solvent is then distilled off under reduced pressure and the residue is purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). 40 mg (64% of theory) of the title compound are obtained.

LC / MS (Method 1): R _t = 2.51 min .; MS (ESIpos): m / z = 467 [M + Η] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.37 (s, 6H), 2.33 (s, 3H), 3.41 (s, 2H), 3.82 (s *, 4H), 4.79 ( s, 2H), 7.10 (d, IH), 7.27-7.39 (m, 5H), 7.44 (d, 2H).

Example 10

2-methyl-2 - [(4 - {[{[4- (3-methylphenyl) -5-oxo-5,6-diliydro-4H-l, 3,4-oxadiazine-2-yl] methyl} (prop - 2-yn-1-yl) amino] methyl} phenyl) thio] propanoic acid

120 mg of the compound from Example 23A (0.23 mmol) are introduced into 3 ml of dichloromethane and treated at ^{0 0} C with 3 ml of trifluoroacetic acid. After one hour of stirring at RT, the mixture is concentrated, the residue is treated with chloroform and the solvent is distilled off again under reduced pressure. The residue is purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 → 95: 5). There are obtained 80 mg (75% of theory) of the title compound.

LC / MS (Method 4): R ₁ = 2.58 min .; MS (ESIpos): m / z = 466 [M + Η] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.36 (s, 6H), 2.33 (s, 3H), 3.28 (t, IH), 3.37 (s, 2H), 3.41 (d, 2H ), 3.75 (s, 2H), 4.77 (s, 2H), 7.09 (d, IH), 7.26-7.38 (m, 5H), 7.42 (d, 2H), 12.58 (br, s, IH).

Example 11

2 - ({4 - [((2-fluoroethyl) {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-l, 3,4-oxadiazine-2-yl] methyl} - amino) methyl] phenyl} thio) -2-methylpropanoic acid

87 mg of the compound from Example 24A (0.16 mmol) are initially charged in 3 ml of dichloromethane and admixed at 0 ^° C. with 3 ml of trifluoroacetic acid. After one hour of stirring at RT, the mixture is concentrated and the residue taken up in saturated sodium bicarbonate solution. It is extracted twice with dichloromethane, the organic phases are combined and dried with sodium sulfate. The solvent is distilled off under reduced pressure and the residue is dried under high vacuum. There are obtained 76 mg (98% of theory) of the title compound.

LC / MS (Method 2): R _t = 2.35 min .; MS (ESIpos): m / z = 474 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.36 (s, 6H), 2.33 (s, 3H), 2.94 (dt, 2H), 3.42 (s, 2H), 3.84 (s, 2H ), 4.53 (dt, 2H), 4.75 (s, 2H), 7.09 (d, IH), 7.27-7.43 (m, 7H), 12.57 (brs, IH).

Example 12

2-methyl-2 - ({4 - [(methyl {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1, 3,4-oxadiazin-2-yl] -methyl} amino) methyl] phenyl} thio) propanoic acid Ηydrochlorid

9.58 g of the compound from Example 7 (21.70 mmol) are dissolved in the necessary amount of dichloro methane and carefully mixed with 10.85 ml of a 2 M solution of hydrogen chloride in diethyl ether (21.70 mmol). The precipitated hydrochloride is filtered off and the solid washed with diethyl ether. After drying in a high vacuum, 8.87 g (86% of theory) of the title compound are obtained.

LC / MS (Method 4): R ₁ = 1.79 min .; MS (ESIpos): m / z = 442 [M + H] ⁺ . ¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.40 (s, 6H), 2.35 (s, 3H), 2.79 (sbr, 3H), 4.04 (sbr, 2H), 4.40 (sbr, IH ), 4.55 (sbr, IH), 4.91 (s, 2H), 7.13 (d, IH), 7.29-7.44 (m, 3H), 7.50 (d, 2H), 7.55-7.64 (m, 2H), 11.11 ( sbr, IH), 12.70 (sbr, IH).

Example 13

2 - [(4 - {[(2-methoxyethyl) ({5-oxo-4- [4- (trifluoromethyl) phenyl] -5,6-dihydro-4H-1, 3,4-oxadiazin-2-yl} methyl) amino] methyl} phenyl) thio] -2-methylpropionic acid

623 mg of the compound from Example 26A (1.05 mmol) are initially charged in 6 ml of dichloromethane and admixed with 3 ml of trifluoroacetic acid. After one hour of stirring at RT, the mixture is concentrated and the residue taken up in ethyl acetate. The organic phase is washed with water, 20% sodium acetate solution and saturated sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is dried under high vacuum. The crude product is purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). 72 mg (13% of theory) of the title compound are obtained in the form of a colorless oil.

LC / MS (Method 1): R _t = 2.59 min .; MS (ESIpos): m / z = 540 [M + H] ⁺ .

¹ H-NMR (400 MHz, CDCl _3): δ [ppm] = 1:51 (s, 6H), 2.90 (t, 2H) 3.33 (s, 3H), 3:50 (s, 2H), 3:54 (t, 2H ), 3.85 (s, 2H), 4.56 (s, 2H), 7.34 (d, 2H), 7.46 (d, 2H), 7.65 (d, 2H), 7.83 (d, 2H).

Example 14

2 - [(4 - {[(2-methoxyethyl) ({5-oxo-4- [4- (trifluoromethoxy) phenyl] -5,6-dihydro-4H-l, 3,4-oxadiazm-2-yl} methyl) amino] methyl} phenyl) thio] -2-methylpropionic acid

360 mg of the compound from Example 28A (0.59 mmol) are initially charged in 3.4 ml of dichloromethane and admixed with 1.7 ml of trifluoroacetic acid. After one hour of stirring at RT, the mixture is einge¬ concentrated and the residue taken up in ethyl acetate. The organic phase is washed with water, 20% sodium acetate solution and saturated sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is dried under high vacuum. The crude product is purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). 209 mg (64% of theory) of the title compound are obtained in the form of a colorless oil.

LC / MS (Method 4): R _t = 2.44 min .; MS (ESIpos): m / z = 556 [M + H] ⁺ .

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 1.51 (s, 6H), 2.89 (t, 2H), 3.33 (s, 3H), 3.48 (s, 2H), 3.53 (t, 2H ), 3.84 (s, 2H), 4.55 (s, 2H), 7.24 (d, 2H), 7.33 (d, 2H), 7.47 (d, 2H), 7.67 (d, 2H).

Example 15

2 - ({4 - [((2-methoxyethyl) {[4- (4-fluorophenyl) -5-oxo-5,6-dihydro-4H-l, 3,4-oxadiazine-2-yl] methyl} - amino) methyl] phenyl} thio)] - 2-methylpropanoic acid Ηydrochlorid

25 mg of the compound from Example 30A (0.05 mmol) are mixed in 5 ml of a 4 M solution of hydrogen chloride in dioxane and stirred overnight at room temperature. Then, the solvent is distilled off under reduced pressure and the residue is dried in vacuo. 24 mg (98% of theory) of the title compound are obtained. LC / MS (Method 2): R _t = 1.96 min .; MS (ESIpos): m / z = 490 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.4 (s, 6H), 3.25 (s, 3H), 3.4-3.75 (m, 8H), 4.85 (s, 2H), 7.3 (t, 2H), 7.45 (m, 3H), 7.6 (dd, 2H), 7.7 (m, IH).

B. Evaluation of Pharmacological Activity

The pharmacological activity of the compounds according to the invention can be demonstrated in the following assays:

1. Cellular Transactivation Assay:

a) test principle:

A cellular assay is used to identify activators of the peroxisome proliferator-activated receptor alpha (PPAR-alpha).

Since mammalian cells contain various endogenous nuclear receptors that could complicate unambiguous interpretation of the results, an established chimera system is used in which the ligand-binding domain of the human PPARα receptor is fused to the DNA binding domain of the yeast transcription factor GAL4. The resulting GAL4-PPARα chimera is co-transfected into CHO cells with a reporter construct and stably expressed.

b) Cloning:

The GAL4-PPARα expression construct contains the ligand binding domain of PPARα (amino acids 167-468), which is PCR amplified and cloned into the vector pcDNA3.1. This vector already contains the GAL4 DNA binding domain (amino acids 1-147) of the vector pFC2-dbd (Stratagene). The reporter construct, containing five copies of the GAL4 binding site upstream of a thymidine kinase promoter, expresses the firefly luciferase (Photinus pyralis) after activation and binding of GAL4-PPARα.

c) Transactivation Assay (Luciferase Reporter):

CHO (Chinese hamster ovary) cells are supplemented in DMEM / F12 medium (BioWhittaker) supplemented with 10% fetal calf serum, 1% penicillin / streptomycin (GIBCO), with a cell density of 2 × 10 ³ cells per well in one Seeded 384 well plate (Greiner). After culturing for 48 h at 37 ° C, the cells are stimulated. For this, the substances to be tested are taken up in CHO-A-SFM medium (GIBCO) supplemented with 10% fetal calf serum, 1% penicillin / streptomycin (GIBCO) and added to the cells. After a stimulation time of 24 hours, luciferase activity is measured using a video camera. The measured relative light units give a sigmoide depending on the substance concentration Stimulation curve. The EC ₅₀ values are calculated using the computer program GraphPad PRISM (Version 3.02).

The compounds according to the invention show EC ₅₀ values of 1 μM to 10 nM in this test.

2. Fibrinogen determination:

To determine the effect on the plasma fibrinogen concentration male Wistar rats or NMRI mice are treated for a period of 4-9 days by gavage or via feed admixture with the substance to be examined. Subsequently, in terminal anesthesia citrated blood is obtained by cardiac puncture. The plasma fibrinogen levels are determined by the Clauss method [A. Clauss, Acta Haematol. 17, 237-46 (1957)] by measuring the thrombin time with human fibrinogen as a standard.

3. Test description for the discovery of pharmacologically active substances, the apoprotein Al (ApoAl) and the HDL-cholesterol (HDL-C) in the serum of transgenic mice, which are transfϊziert with the human ApoAl gene ftiApoAl) increase or the serum triglvzeride Lowering (TG):

The substances to be tested for their HDL-C increasing activity in vivo are orally administered to male transgenic hApoAl mice. The animals are randomly assigned to groups with the same number of animals, usually n = 7-10, one day before the start of the experiment. Throughout the experiment, the animals have access to drinking water and food ad libitum. The substances are administered orally once a day for 7 days. For this purpose, the test substances are dissolved in a solution of Solutol HS 15 + ethanol + saline (0.9%) in the ratio 1 + 1 + 8 or in a solution of Solutol HS 15 + saline (0.9%) in the ratio 2 + 8 , The application of the dissolved substances takes place in a volume of 10 ml / kg body weight with a gavage. Animals which are treated in the same way, but only the solvent (10 ml / kg body weight) without test substance, serve as a control group.

Before the first administration of the substance, each mouse is sampled for the determination of ApoAl, serum cholesterol, HDL-C and serum triglycerides (TG) by puncture of the retro-orbital venous plexus (initial value). Subsequently, the test substance is administered to the animals for the first time with a gavage. 24 hours after the last substance application (on the 8th day after the start of treatment), each animal is again drawn by puncture of the retroorbital venous plexus to determine the same parameters. The blood samples are centrifuged and after recovery of the serum, TG, cholesterol, HDL-C and human ApoAl with a Cobas Integra 400 plus device (Cobas Integra, Fa. Roche Diagnostics GmbH, Mannheim) under Use of the respective cassettes (TRIGL, CHOL2, HDL-C and APOAT). HDL-C is purified by gel filtration and post-column derivatization with MEGA cholesterol reagent (Merck KGaA) analogously to the method of Garber et al. [J. Lipid Res. 41, 1020-1026 (2000)].

The effect of the test substances on the HDL-C, hApoAl or TG concentrations is determined by subtracting the measured value of the first blood sample (pre-value) from the measured value of the second blood sample (after treatment). The differences of all HDL-C, hApoAl or TG values of a group are averaged and compared with the average of the differences of the control group. The statistical evaluation is done with Student's t-test after checking the variances for homogeneity.

Substances which increase the HDL-C of the treated animals statistically significantly (p <0.05) by at least 20% or decrease the TG statistically significantly (p <0.05) by at least 25% compared to those of the control group are considered to be pharmacologically active ,

C. Embodiments of Pharmaceutical Compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet:

Composition:

100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

1000 of the compound of the invention, 1000 mg of ethanol mg (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water.

A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.

production:

The rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h. Orally administrable solution:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyetbylene glycol 400. A single dose of 100 mg of the compound according to the invention corresponds to 20 g of oral solution.

production:

The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring process is continued until complete dissolution of the compound according to the invention.

iv solution:

The compound of the invention is dissolved at a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

Claims

claims

1. Compound of formula (I)

in which

Y and Z are each independently O or S,

m is the number 0, 1 or 2,

n is the number 1 or 2,

R ^{1 is} (C ₆ -C ₁₀ ) -aryl or 5- to 10-membered heteroaryl, which are each up to four times, identical or different, with substituents selected from the group halogen, nitro, cyano, (C ₁ -C ₆ ) Alkyl, which in turn may be substituted by hydroxy, (C ₃ -C ₈ ) -cycloalkyl, phenyl, hydroxy, (C _r C ₆ ) alkoxy, trifluoromethyl, tri-fluoromethoxy, amino, mono- and di- (C ₁ -C ₆ ) -alkylamino, R ⁸ -C (O) -NH-, R ⁹ -C (O) -, R ¹⁰ R ¹¹ NC (O) -NH- and R ¹² R ¹³ NC (O) - be substituted can, in which

R ⁸ is hydrogen, (C _{r C6)} alkyl, (C ₃ -C ₈₎ -cycloalkyl, phenyl or (C ₁ -C ₆₎ - alkoxy,

R ^{9 is} hydrogen, (C _r C ₆ ) -alkyl, (C ₃ -C ₈ ) -cycloalkyl, phenyl, hydroxy or (C ₁ -C ₆ ) -alkoxy

and

R ^10, R ^11, R ¹² and R ¹³ are identical or different and are independently hydrogen, (C _{r C6)} alkyl, (C ₃ -C ₈₎ -cycloalkyl or phenyl,

R ^{2 is} hydrogen, (C ₆ -C ₁₀ ) aryl, (C _r C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl or (C ₂ -C ₆ ) alkynyl, wherein alkyl, alkenyl and AlMnyl in each case with trifluoromethyl, (C ₁ -C ₆ ) -alkoxy, trifluoromethoxy, fluorine, cyano, (C ₆ -C ₁₀ ) -aryl or 5- or 6-membered may be substituted by heteroaryl, where all the aryl and heteroaryl groups mentioned are each themselves up to three times, identical or different, with substituents selected from the group halogen, nitro, cyano, (C ₁ -C ₆ ) -alkyl, Hydroxy, (C ₁ -C ₆ ) -alkoxy, trifluoromethyl and trifluoromethoxy may be substituted,

R ³ and R ⁴ are identical or different and independently represent hydrogen, (Ci- _C6) alkyl, (C ₂ -C ₆₎ alkenyl, (Ci-C ₆₎ alkoxy, trifluoromethyl, trifluoromethoxy or halogen,

R ⁵ and R ^{6 are} identical or different and independently of one another represent hydrogen, (Q-C ₆ ) -alkyl, (C _r C ₆ ) -alkoxy or phenoxy or together with the carbon atom to which they are attached form a _(C3-C8) cycloalkyl ring form,

and

R ^{7 is} a group of the formula -NHR ¹⁴ or -OR ¹⁵ , wherein

R ^{14 is} hydrogen, (C _r C ₆ ) -alkyl or (C _r C ₆ ) -alkylsulfonyl

and

R ^{15 is} hydrogen or is a hydrolyzable group which can be converted to the corresponding carboxylic acid,

and their salts, solvates and solvates of the salts.

2. A compound of formula (I) according to claim 1, in which

Y stands for O,

Z stands for S,

m is the number 0, 1 or 2,

n is the number 1 or 2,

R ^{1 is} phenyl or 5- or 6-membered heteroaryl, each of which is up to four times, same or different, with substituents selected from the series

Halogen, nitro, cyano, (C _{r C4)} alkyl which may itself be substituted with hydroxy, (C ₃ -C ₆₎ -cycloalkyl, phenyl, hydroxy, (C ₁ -Q) -alkoxy, trifluoromethyl, tri- , _, fluoromethoxy, amino, mono- and di- (C ₁ -C ₄₎ alkylamino, R ⁸ -C (O) -NH-, R ⁹ -C (O) - ₃ R ¹⁰ R ¹¹ NC (O) -NH- and R ¹² R ^{13 may be} NC (O) - substituted, wherein

R ⁸ is hydrogen, (C _{r C4)} alkyl, (C ₃ -C ₆₎ -cycloalkyl, phenyl or (C ₁ -C ₄₎ - alkoxy,

R ^{9 is} hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, phenyl, hydroxy or (Q-)

C ₄ ) alkoxy

and

R ^10, R ^11, R ¹² and R ¹³ are identical or different and are independently hydrogen, (C _{r C4)} alkyl, (C ₃ -C ₆₎ -cycloalkyl or phenyl,

R ^{2 is} hydrogen, phenyl, (QC ₄ ) alkyl, (C ₂ -C ₄ ) alkenyl or (C ₂ -C ₄ ) -alkyl where alkyl, alkenyl and alkynyl are each substituted with trifluoromethyl, fluoro, cyano, ( C 1 -C ₄ ) -alkoxy, phenyl or 5- or 6-membered heteroaryl may be substituted, wherein all said phenyl and heteroaryl groups in turn each up to three times, same or different, having substituents selected from the series halogen, nitro, cyano, (C _{r C4)} alkyl, hydroxy, (C ₁ -Q) -alkoxy, trifluoro methyl and trifluoromethoxy may be substituted,

R ³ and R ^{4 are} identical or different and independently of one another represent hydrogen, (Q-Q) -alkyl, (QQ) -alkoxy, trifluoromethyl, trifluoromethoxy or halogen,

R ⁵ and R ^{6 are the} same or different and independently of one another are hydrogen, methyl, ethyl, methoxy, ethoxy or phenoxy or together with the

Carbon atom to which they are attached form a (C ₃ -C ₆ ) -cycloalkyl ring,

and

R ^{7 is} a group of the formula -NHR ¹⁴ or -OR ¹⁵ , wherein

R ^{14 is} hydrogen or (QQ) -alkyl

and

R ^{15 is} hydrogen or is a hydrolyzable group which can be converted to the corresponding carboxylic acid,

and their salts, solvates and solvates of the salts.

3. A compound of the formula (I) according to claim 1 or 2, in which

Y stands for O,

Z stands for S,

m is the number 0 or 1,

n is the number 1 or 2,

R ^{1 is} phenyl or pyridyl, which in each case may be monosubstituted or disubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, nitro, methyl, methoxy, trifluoromethyl and trifluoromethoxy,

R ^{2 is} hydrogen, propargyl or (C _r C ₄ ) alkyl, which with fluorine, cyano, (Ci-C ₄ ) alkoxy, phenyl, furyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl or

Thiadiazolyl may be substituted, wherein phenyl and all said hetero¬ aromatic rings in turn each one or two times, same or different, having substituents selected from the series fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy may be substituted,

R ³ and R ^{4 are} identical or different and independently of one another represent hydrogen, methyl, methoxy, fluorine or chlorine,

R ⁵ and R ^{6 are the} same or different and represent hydrogen or methyl,

and

R ^{7 is} -OH, -NH ₂ or -NHCH ₃ ,

and their salts, solvates and solvates of the salts.

4. Compound of formula (I-A)

(I-A),

in which

R ¹ , R ² , m and n each have the meanings given in claims 1 to 3,

and their salts, solvates and solvates of the salts.

5. A process for preparing a compound of formula (I) or (I-A) as defined in claims 1 to 4, characterized in that compounds of the formula

(Π)

in which R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z each have the meanings given in claims 1 to 4

and

T ^{1 is} (C ¹ -C 6 -alkyl, preferably tert-butyl, or is benzyl,

first in an inert solvent in the presence of a base with a compound of the formula (DI)

in which n has the meaning given in claims 1 to 4 and

T ^{2 is} (C 1 -C ₄ ) -alkyl, preferably methyl or ethyl,

and

Q ^{1 represents} a suitable leaving group such as, for example, halogen, mesylate, tosylate or triflate,

to compounds of the formula (IV)

in which n, T ¹ , T ² , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are each as defined above,

subsequently reacted under suitable reaction conditions selectively to carboxylic acids of the formula (V)

in which n, T ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are each as defined above,

hydrolyzed, then in an inert solvent in the presence of a Kondensations¬ means and a base with a compound of formula (VI)

R- (CH ₂ ) -N-NH ₂ (VI),

in which R ¹ and m each have the meanings given in claims 1 to 4,

in compounds of the formula (VIT)

in which m, n, T ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z each have the abovementioned meanings, then converted with chloroacetyl chloride in the presence of a base with cyclization to give compounds of the formula (IB)

in which m, n, T ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z each have the abovementioned meanings,

subsequently, by basic or acidic hydrolysis or in the case where T ^{1 is} benzyl, also hydrogenolytically in carboxylic acids of the formula (IC)

in which m, n, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are each as defined above,

überfuhrt and optionally then reacted by literature methods for esterification or amidation to the compounds of formula (T)

and optionally reacting the compounds of the formula (I) with the corresponding (i) solvents and / or (ii) bases or acids to give their solvates, salts and / or solvates of the salts.

6. Process for the preparation of a compound of the formula (I-D)

in which m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and Z each have the meanings given in claims 1 to 4, characterized in that compounds of the formula (II) as defined in claim 5, initially in an inert solvent in the presence of a base with a compound of formula (VJJI)

in which m and R ¹ each have the meanings given in claims 1 to 4 and

Q ^{2 represents} a suitable leaving group, for example halogen,

to compounds of the formula (I-E)

in which m, T ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are each as defined above,

followed by basic or acidic hydrolysis or in the event that T ^{1 is} for

Benzyl, also hydrogenolytically in carboxylic acids of the formula (IF)

in which m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are each as defined above,

converted and optionally then subsequently reacted by literature methods for esterification or amidation to the compounds of formula (I-D).

7. A compound as defined in any one of claims 1 to 4, for the treatment and / or prophylaxis of diseases.

8. Use of a compound as defined in any one of claims 1 to 4, for the production of a drug for the treatment and / or prevention of dyslipidaemias and arteriosclerosis.

9. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 4, in combination with an inert, non-toxic, pharmaceutically suitable excipient.

10. A medicament comprising a compound as defined in any one of claims 1 to 4, in combination with a further active ingredient selected from the group consisting of CETP inhibitors, inhibitors of HMG-CoA reductase, inhibitors of HMG-CoA

Reductase expression, squalene synthesis inhibitors, ACAT inhibitors, cholesterol absorption inhibitors, MTP inhibitors, fibrates, niacin, lipase inhibitors, PPAR-γ and / or PPAR-δ agonists, calcium antagonists, angiotensin II receptor antago - nisten, platelet aggregation inhibitors, anticoagulants, antidiabetic agents, antioxidants, thyroid hormones and / or thyroid mimetics, aldose reductase inhibitors and

Anorexics.

11. Medicament according to claim 9 or 10 for the treatment and / or prevention of dyslipidemia and arteriosclerosis.

12. A method for the treatment and / or prevention of dyslipidaemias and arteriosclerosis in humans and animals by administering an effective amount of at least one

A compound as defined in any one of claims 1 to 4 or a pharmaceutical composition as defined in any one of claims 9 to 11.