HK1136820B

HK1136820B - Substituted arylimidazolone and triazolone as inhibitors of vasopressin receptors

Info

Publication number: HK1136820B
Application number: HK10100511.8A
Authority: HK
Inventors: Heinrich Meier; Eckhard Bender; Ulf Brüggemeier; Ingo Flamme; Dagmar Karthaus; Peter Kolkhof; Daniel Meibom; Dirk Schneider; Verena Voehringer; Chantal FÜRSTNER; Jörg Keldenich; Dieter Lang; Elisabeth Pook; Carsten Schmeck
Original assignee: Bayer Intellectual Property Gmbh
Priority date: 2006-05-23
Filing date: 2007-05-21
Publication date: 2014-10-17

Description

Substituted arylimidazolones and triazolones as vasopressin receptor inhibitors

The present application relates to novel, substituted 4-arylimidazol-2-ones and 5-aryl-1, 2, 4-triazolones, to a method for the production thereof, and to the use thereof, alone or in combination, for the treatment and/or prophylaxis of diseases and for the production of medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular diseases.

The fluid content of the human body is governed by various physiological control mechanisms, the purpose of which is to keep it constant (volume homeostasis). In the present method, the volumetric filling of the vascular system and the osmolarity of the plasma are continuously recorded by means of suitable sensors (baroreceptors and osmoreceptors). The information provided by these sensors to the relevant centers in the brain regulates drinking behavior through humoral and neural signals and controls fluid excretion through the kidneys. The peptide hormone vasopressin is of great importance in this regard [ Schrier r.w., Abraham, w.t., New engl.j.med.341，577-585(1999)]。

Vasopressin is produced in the wall of the third ventricle (hypothalamus) in the supraoptic Nucleus (nucleous supraopticus) and the paraventricular Nucleus (n. paraventricular) in specialized endocrine neurons and from there is transported along its neurite into the lobe behind the pituitary (neurohypophysis). Where the hormone is released into the blood stream upon stimulation. For example, a reduction in volume stimulates an increased outflow of hormone as a result of acute blood loss, profuse sweating, prolonged thirst or diarrhea. Conversely, vasopressin secretion is inhibited by an increase in intravascular volume, for example due to increased fluid uptake.

Vasopressin exerts its effects mainly by binding to three receptors, which are classified as V1a, V1b and V2 receptors and belong to the class of G protein-coupled receptors. The V1a receptor is located primarily in cells of vascular smooth muscle tissue. Their activation produces vasoconstriction as a result of peripheral resistance and blood pressure rise. In addition to these, the V1a receptor is also detectable in the liver. The V1b receptor (also known as the V3 receptor) is detectable in the central nervous system. Along with Corticotropin Releasing Hormone (CRH), vasopressin regulates basic and stress-induced corticotropin (ACTH) secretion via the V1b receptor. The V2 receptor is located in the distal tubular epithelium and epithelium of the renal collecting duct in the kidney. Their activation renders these epithelia water-permeable. This phenomenon is due to the addition of aquaporins (specialized water channels) in the luminal membrane of epithelial cells.

The importance of vasopressin for the reabsorption of water from the urine in the kidneys is evident by the clinical phenomenon of diabetes insipidus, which is caused by hormonal deficiencies, for example due to pituitary damage. Patients suffering from this clinical picture excrete up to 20 litres of urine per 24 hours if they are not given replacement hormones. This volume corresponds to about 10% of primary urine (primary urine). Because of its great importance for water reabsorption from urine, vasopressin is also synonymously referred to as antidiuretic hormone (ADH). Logically, pharmacological inhibition of the action of the V2 receptor by vasopressin/ADH results in increased urination. However, in contrast to the action of other diuretics (thiazides and loop diuretics), the V2 receptor antagonist causes increased water excretion without substantially increasing electrolyte excretion. This means that volume homeostasis can be restored by the V2 antagonist without affecting electrolyte homeostasis in the process. Thus, drugs with V2 antagonist activity appear to be particularly suitable for the treatment of all disease states associated with body overload with water without actually increasing electrolytes. Electrolyte abnormalities important in clinical chemistry such as hyponatremia are measurable (< 135mmol/L sodium concentration); it is the most important electrolyte abnormality in hospital patients, with an annual incidence of about 5% or 250,000 in the united states alone. If the plasma sodium concentration falls below 115mmol/L, coma and death are imminent.

Hypovolemic (hypovolemic), isovolemic (euvolemic) and hypervolemic (hypervolemic) hyponatremia are distinguished depending on the following reasons. The hypervolemic form associated with edema formation is clinically important. Typical examples thereof are inappropriate ADH/vasopressin Secretion (SIAD) syndrome (e.g. after craniocerebral trauma or as a concomitant effect in carcinoma) and hypervolemic hyponatremia in liver cirrhosis, various renal diseases and cardiac insufficiency [ De Luca L. et al, am.J.Cardiol.96 (supplementary), 19L-23L (2005)]. In particular, patients with cardiac insufficiency, despite their relative hyponatremia and hypervolemia (hypervolaemia), often show elevated vasopressin levels, which are considered as a consequence of the often disturbed neurohumoral regulation in cardiac insufficiency [ Francis g.s82，1724-1729(1990)]。

Interfering with neurohormonal regulation manifests itself essentially in the rise of sympathetic tone and in the appropriate activation of the renin-angiotensin-aldosterone system. Although the inhibition of these components by beta-blockers on the one hand and by ACE inhibitors or angiotensin receptors on the other hand is now a reliable component for the pharmacological treatment of cardiac insufficiency, an increase in inappropriate secretion of vasopressin in higher cardiac insufficiency is still not adequately treated at present. In addition to the water retention regulated by the V2 receptor and the adverse hemodynamic consequences associated therewith in terms of increased load, the emptying of the left ventricle, the pressure in the pulmonary vessels and the cardiac output are also adversely affected by vasoconstriction regulated by the V1a receptor. Furthermore, on the basis of animal experimental data, the effect of promoting direct abnormal obesity in the myocardium was also attributed to vasopressin. In contrast to the volume expansion effects of the kidney, which are mediated by activation of the V2 receptor, direct effects on the myocardium are triggered by activation of the V1a receptor.

For these reasons, substances which inhibit the action of vasopressin at the V2 and/or at the V1a receptor appear to be suitable for the treatment of cardiac insufficiency. In particular, compounds having a combined activity for two vasopressin receptors (V1a and V2) should have both the desired renal impact and bloodFlow dynamics and thus provide particularly desirable properties for treating patients with cardiac insufficiency. The provision of such combination vasopressin antagonists also seems to be of interest because the reduced capacity modulated by V2 receptor blockade alone can lead to stimulation of osmoreceptors and as a result avoid further compensatory increases in vasopressin. As a result, the adverse effects of vasopressin, such as vasoconstriction and myocardial atrophy, may be further exacerbated without simultaneously blocking components of the V1a receptor [ Saghi p.26，538-543(2005)]。

The synthesis of certain imidazolinone acetamide derivatives and their antibacterial action are described in j.j.bronson et al, bioorg.med.chem.lett.13873-875 (2003). Imidazolinone alkanoic acids having pharmacological activity are described in EP 051829-A1. In WO99/54315, substituted triazolones with neuroprotective activity are disclosed, and triazolone derivatives as anti-inflammatory agents are described in WO 2006/117657. Further, in EP503548-A1 and EP 587134-A2, cyclic urea derivatives and their use for the treatment of thrombosis are claimed. Substituted imidazole-and triazolethiones as modulators of ion channels are disclosed in WO 2005/086836, WO 2005/06892 and WO 2005/097112. Triazolinthione derivatives as inhibitors of sphingomyelinase are also described in WO 02/066447.

The object of the present invention are compounds of the general formula (I)

Wherein

A represents N or C-R⁴Wherein

R⁴Meaning hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

R¹is represented by (C)₁-C₆) Alkyl radical (C)₂-C₆) Alkenyl or (C)₂-C₆) Alkynyl, each of which may be substituted one to three times, identically or differently, by radicals selected from the group consisting of halogen, cyano, Oxo (Oxo), trifluoromethyl, (C)₃-C₇) Cycloalkyl, phenyl, -OR¹⁰，-NR¹¹R¹²，-C(＝O)-OR¹³and-C (═ O) -NR¹⁴R¹⁵In which is substituted by a group of

(i)(C₃-C₇) Cycloalkyl radicals can be substituted up to two times, identically or differently by (C)₁-C₄) Alkyl, oxo, hydroxy, (C)₁-C₄) Alkoxy and/or amino substitution, and/or a pharmaceutically acceptable salt thereof,

(ii) the phenyl radical may be substituted up to three times, identically or differently, by radicals selected from the group consisting of halogen, cyano, nitro, (C)₁-C₄) Alkyl, trifluoromethyl, hydroxy, hydroxymethyl, (C)₁-C₄) Alkoxy, trifluoromethoxy, (C)₁-C₄) Alkoxymethyl, hydroxycarbonyl, (C)₁-C₄) Alkoxycarbonyl, aminocarbonyl, mono- (C)₁-C₄) Alkylaminocarbonyl and di- (C)₁-C₄) The radical of an alkylaminocarbonyl group is substituted,

(iii)R¹⁰，R¹¹，R¹²，R¹³，R¹⁴and R¹⁵Independently of one another, each independently of the others, means hydrogen, (C)₁-C₆) Alkyl or (C)₃-C₇) Cycloalkyl radicals in which

(C₁-C₆) The alkyl radicals may themselves be substituted up to two times, identically or differently, by amino, hydroxy, (C)₁-C₄) Alkoxy, hydroxycarbonyl and/or (C) ₁-C₄) The substitution of the alkoxy carbonyl group is carried out,

and

(C₃-C₇) Cycloalkyl can itself be substituted up to two times, identically or differently by (C)₁-C₄) Alkyl, oxo, hydroxy, (C)₁-C₄) Alkoxy and/or amino substitution, and/or a pharmaceutically acceptable salt thereof,

and/or

(iv)R¹¹And R¹²And R¹⁴And R¹⁵In each case in pairs with the nitrogen atom to which they are attached form a 4-to 7-membered heterocycle which may contain further heteroatoms from the group consisting of N, O and S and up to two times, identically or differently (C)₁-C₄) Alkyl, oxo, hydroxy, (C)₁-C₄) Alkoxy and/or amino substitution, and/or a pharmaceutically acceptable salt thereof,

or

R¹Is represented by (C)₃-C₇) Cycloalkyl which can be substituted up to two times, identically or differently by (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy, hydroxy, amino and/or oxo substitution,

R²represents phenyl, naphthyl, thienyl, benzothienyl, furyl or benzofuryl, each of which may be substituted one to three times, identically or differently, by a substituent selected from the group consisting of halogen, cyano, nitro, (C)₁-C₄) Alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) Alkoxy, trifluoromethoxy and phenyl,

in which the last-mentioned phenyl radical may itself be substituted up to two times, identically or differently, by radicals selected from the group consisting of halogen, cyano, nitro, (C)₁-C₄) Alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) Alkoxy, trifluoromethoxy, hydroxy- (C) ₁-C₄) -alkyl and (C)₁-C₄) Alkylthio (Alkylthio) groups,

L¹represents a compound having the formula- (CR)^5AR^5B)_mA group of (a) in which

m means the number 1, 2 or 3

And

R^5Aand R^5BIndependently of one another mean hydrogen or(C₁-C₄) Alkyl radical

Or

Two radicals R bound to the same carbon atom^5AAnd R^5BAre linked to each other and together form- (CH)₂)_n-a bridge in which

n means the number 2, 3, 4 or 5,

alternatively, when m represents the number 2 or 3,

two radicals R bound to adjacent (1, 2-or 2, 3-) or non-adjacent (1, 3-) carbon atoms^5AAnd/or R^5BAre linked to each other and together form- (CH)₂)_pA bridge therein

p means the number 1, 2, 3 or 4,

wherein, when the group-CR^5AR^5BWhen it occurs several times, R^5AAnd R^5BThe respective meanings may be the same or different in each case,

or

L¹Represents a group of the formula

L²Represents: -CR^6AR^6B-(CR^7AR^7B)_q-or-CR^6AR^6B(CR^7AR^7B) A group of-O-, in which

Meaning the binding site to the N atom of the amide group,

q means the number 0, 1 or 2

R^6AMeaning hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

R^6Bmeaning hydrogen, (C)₁-C₄) Alkyl, trifluoromethyl, (C)₃-C₆) Cycloalkyl or phenyl, which may be substituted up to two times, identically or differently by halogen, (C)₁-C₄) Alkyl and/OR trifluoromethyl substituted, OR means having the formula-C (═ O) -OR ¹⁶Or C (═ O) -NR¹⁷R¹⁸In which the radical

R¹⁶，R¹⁷And R¹⁸Independently of one another, represents hydrogen, (C)₁-C₄) Alkyl or (C)₃-C₆) Cycloalkyl radicals

Or

R¹⁷And R¹⁸Together with the nitrogen atom to which they are attached form a 4-to 6-membered heterocyclic ring which may contain further heteroatoms from the group of N, O and S and up to two times, identically or differently, (C)₁-C₄) Alkyl, hydroxy and/or (C)₁-C₄) The substitution of alkoxy groups is carried out,

or

R^6AAnd R^6BAre linked to each other and together form- (CH)₂)_rA bridge therein

r means the number 2, 3, 4 or 5

And one CH of the bridge₂The radicals may be exchanged for-O-, -S-or > N-R¹⁹Therein of which

R¹⁹Represents hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

R^7Ameaning hydrogen, fluorine, (C)₁-C₄) Alkyl or (C)₁-C₄) An alkoxy group,

R^7Bmeaning hydrogen, fluorine, (C)₁-C₄) Alkyl, hydroxy- (C)₁-C₄) Alkyl OR of the formula-OR²⁰，-NR²¹R²²，-C(＝O)-OR²³or-C (═ O) -NR²⁴R²⁵At the radical of (A) inIn

R²⁰，R²¹，R²²，R²³，R²⁴And R²⁵Independently of one another, represents hydrogen, (C)₁-C₄) Alkyl or (C)₃-C₆) Cycloalkyl radicals

Or

R²¹And R²²And R²⁴And R²⁵In each case in pairs with the nitrogen atom to which they are attached form a 4-to 6-membered heterocycle which may contain further heteroatoms from the group consisting of N, O and S and up to two times, identically or differently (C)₁-C₄) Alkyl, hydroxy and/or (C)₁-C₄) The substitution of alkoxy groups is carried out,

or

R^7AAnd R^7BTogether form an Oxo group (Oxo-Gruppe)

Or

R^7AAnd R^7BAre linked to each other and together form- (CH)₂)_sA bridge therein

s means the number 2, 3, 4 or 5

And one CH of the bridge₂The radicals may be exchanged for-O-, -S-or > N-R²⁶Therein of which

R²⁶Represents hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

wherein, when the group-CR^7AR^7BWhen it occurs several times, R^7AAnd R^7BThe respective meanings may be the same or different in each case,

or

L²Represents a group of the formula

Therein is provided with

Meaning the binding site to the N atom of the amide group,

x means the number 1, 2, 3 or 4,

in which one CH of the ring₂The radicals may be exchanged for-O-, -S-or > N-R²⁷Therein of which

R²⁷Represents hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

and

R^6Band R^7BEach of which has the meaning as described above,

R³represents phenyl, naphthyl or a 5-to 10-membered heteroaryl having up to three heteroatoms from the group of N, O and/or S, each of which may be substituted one to three times, identically or differently, by a substituent selected from the group consisting of halogen, cyano, nitro, (C)₁-C₄) Alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) Alkoxy, trifluoromethoxy, (C)₁-C₄) Alkylthio (C)₁-C₄) Alkylsulfinyl (C)₁-C₄) Alkylsulfonyl, di- (C)₁-C₄) Alkyl amino and phenyl groups, and a pharmaceutically acceptable salt thereof,

in which the last-mentioned phenyl radical may itself be substituted up to two times, identically or differently, by halogen, cyano, nitro, (C) ₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy, trifluoromethyl and/or trifluoromethoxy substituted,

or group

L²-R³Together form a group of the formula

Or

Therein is provided with

Meaning the binding site to the N atom of the amide group,

d means CH₂Or an oxygen-containing gas,

e means NH, N-CH₃The presence of oxygen, O or S,

t means the number 0 or 1,

R⁸meaning selected from halogen, cyano, nitro, (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy, trifluoromethyl and trifluoromethoxy substituents,

u means the number 0, 1 or 2,

wherein, when the substituent R⁸When occurring several times, it may mean the same or different,

and

R⁹meaning hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

and salts, solvates and solvates of salts thereof.

The compounds according to the invention are compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds of the formula mentioned below and their salts, solvates and solvates of the salts encompassed by the formula (I) and the compounds mentioned below as examples of application and their salts, solvates and solvates of the salts encompassed by the formula (I) provided that the compounds of the formula mentioned below and encompassed by the formula (I) are not already salts, solvates and solvates of the salts.

Depending on their structure, the compounds according to the invention may exist in regioisomeric forms (enantiomers, diastereomers). The present invention thus includes enantiomers or diastereomers and mixtures of each thereof. From such mixtures of enantiomers and/or diastereomers, the positionally isomeric individual components can be separated in a known manner.

The present invention includes all tautomeric forms as long as the compound according to the present invention can exist in tautomeric forms.

As salts in the context of the present invention, preference is given to physiologically harmless salts of the compounds according to the invention. Also included are salts which are not suitable per se for pharmaceutical applications but which can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically harmless salts of the compounds according to the invention include inorganic acids, acid addition salts of carboxylic and sulfonic acids, for example 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 harmless salts of the compounds according to the invention also include salts of customary bases, such as, for example and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16C atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

Those forms of the compounds according to the invention which form complexes in the solid or liquid state by coordination with solvent molecules are described in the context of the invention asSolvates. Hydrates are a special form of solvates in which coordination is made with water. Preferred hydrates in the context of the present inventionAs a solvate.

In addition, the invention also includes prodrugs of the compounds according to the invention. The term "prodrug" includes compounds which may be biologically active or inactive per se, but which are converted to the compounds according to the invention during their residence time in the body (e.g. metabolism or hydrolysis).

In the context of the present invention, unless otherwise indicated, substituents have the following meanings:

in the context of the present invention it is,(C ₁ -C ₆ ) Alkyl and (C) ₁ -C ₄ ) Alkyl radicalRepresent linear or branched alkyl groups having 1 to 6 and 1 to 4 carbon atoms, respectively. Linear or branched alkyl groups having 1 to 4 carbon atoms are preferred. For example and preferably the following can be mentioned: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.

In the context of the present invention it is,hydroxy- (C) ₁ -C ₄ ) Alkyl radicalRepresents a linear or branched alkyl group having 1 to 4 carbon atoms, which has a hydroxyl group as a substituent in the chain or in a terminal position. For example and preferably the following can be mentioned: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, 1, 1-dimethyl-2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy-2-methylpropyl, 2-hydroxy-1-methylpropyl, 2-hydroxy-2-methylpropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl and 4-hydroxybutyl.

In the context of the present invention it is,oxo radicalRepresents an oxygen atom which is bonded to a carbon atom via a double bond.

In the context of the present invention it is,(C ₂ -C ₆ ) Alkenyl and (C) ₂ -C ₄ ) Alkenyl radicalRepresents a linear or branched alkenyl group having 2 to 6 or 2 to 4 carbon atoms and a double bond, respectively. Linear or branched alkenyl groups having 2 to 4 carbon atoms are preferred. For example and preferably the following can be mentioned: vinyl, allyl, n-prop-1-en-1-yl, isopropenyl, 2-methyl-2-propen-1-yl, n-but-1-en-1-yl and n-but-2-en-1-yl.

In the context of the present invention it is,(C ₂ -C ₆ ) Alkynyl and (C) ₂ -C ₄ ) Alkynyl radicalRepresents a linear or branched alkynyl group having 2-6 and 2-4 carbon atoms and triple bonds, respectively. Linear or branched alkynyl groups having 2 to 4 carbon atoms are preferred. For example and preferably the following can be mentioned: ethynyl, n-prop-1-yn-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-yn-1-yl.

In the context of the present invention it is,(C ₁ -C ₆ ) Alkoxy and (C) ₁ -C ₄ ) Alkoxy radicalRepresent linear or branched alkoxy groups having 1 to 6 and 1 to 4 carbon atoms, respectively. Linear or branched alkoxy groups having 1 to 4 carbon atoms are preferred. For example and preferably the following can be mentioned: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.

In the context of the present invention it is,(C ₁ -C ₄ ) Alkoxy radicalCarbonyl represents a linear or branched alkoxy group having 1 to 4 carbon atoms, which is linked via a carbonyl group. For example and preferably the following can be mentioned: methoxycarbonyl, ethoxycarbonyl, n-propoxy-carbonyl, isopropoxycarbonyl, n-butoxycarbonyl and tert-butoxycarbonyl.

In the context of the present invention it is,a- (C) ₁ -C ₄ ) Alkylamino radicalRepresenting having a linear orAn amino group of a branched alkyl substituent having 1 to 4 carbon atoms. For example and preferably the following can be mentioned: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino and tert-butylamino.

In the context of the present invention it is,di- (C) ₁ -C ₄ ) Alkylamino radicalRepresents an amino group having two identical or different linear or branched alkyl substituents, each of which has from 1 to 4 carbon atoms. For example and preferably the following can be mentioned: n, N-dimethylamino, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-isopropyl-N-propylamino, N-diisopropylamino, N-butyl-N-methylamino and N-tert-butyl-N-methylamino.

In the context of the present invention it is,mono-or di- (C) ₁ -C ₄ ) Alkyl amino carbonylRepresents an amino group linked through a carbonyl group and which has in each case one linear or branched or two linear or branched identical or different alkyl substituents having in each case 1 to 4 carbon atoms. For example and preferably the following can be mentioned: methylaminocarbonyl, ethylaminocarbonyl, N-propylaminocarbonyl, isopropylaminocarbonyl, N-butylaminocarbonyl, tert-butylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-N-propylaminocarbonyl, N-N-butyl-N-methylaminocarbonyl and N-tert-butyl-N-methylaminocarbonyl.

In the context of the present invention it is,(C ₁ -C ₄ ) Alkylthio of alkylRepresents a thio group having a linear or branched alkyl substituent having from 1 to 4 carbon atoms. For example and preferably the following can be mentioned: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio and tert-butylthio.

In the context of the present invention it is,(C ₁ -C ₄ ) Alkyl sulfinylRepresents a linear or branched alkyl-sulfinyl group having 1 to 4 carbon atoms. For example and preferably the following can be mentioned: methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl and tert-butylsulfinyl.

In the context of the present invention it is,(C ₁ -C ₄ ) Alkyl sulfonyl radicalRepresents a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms. For example and preferably the following can be mentioned: methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butyl-sulfonyl and tert-butylsulfonyl.

In the context of the present invention it is,(C ₃ -C ₇ ) Cycloalkyl and (C) ₃ -C ₆ ) Cycloalkyl radicalsRepresent monocyclic saturated cycloalkyl groups having 3 to 7 and 3 to 6 carbon atoms, respectively. Cycloalkyl groups having 3 to 6 carbon atoms are preferred. For example and preferably the following can be mentioned: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In the context of the present invention it is,4 to 7-membered or 4 to 6-membered heterocyclic ringRepresents a monocyclic saturated heterocyclic ring having a total of 4 to 7 and 4 to 6 ring atoms, respectively, which heterocyclic ring contains a ring nitrogen atom, is linked through it, and may contain other ring heteroatoms from the group consisting of N, O and S. For example, the following may be mentioned: azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl and hexahydro-1, 4-diazepinyl (hexahydro-1, 4-diazepinyl). Preferably a 4 to 6-membered heterocyclic ring which may contain further ring heteroatoms from N and O in addition to the ring nitrogen atom. Pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl are particularly preferred.

In the context of the present invention it is,5 to 10-membered heteroarylRepresents a mono-or optionally bicyclic aromatic heterocycle having a total of 5 to 10 ring atoms: (Heteroaromatic) which contains up to three ring heteroatoms from N, O and/or S and is bound via a ring carbon atom or optionally via a ring nitrogen atom. For example, the following may be mentioned: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl, quinolyl, iso-quinolyl, naphthyridinyl, quinazolinyl, quinoxalinyl, phthalazinyl and pyrazolo [3, 4-b ] group ]Pyridyl (pyrazolo [3, 4-b ]]pyridinyl). Preference is given to mono-or optionally bicyclic 5-to 10-membered heteroaryl groups having up to two heteroatoms from the group consisting of N, O and/or S. Monocyclic 5-or 6-membered heteroaryl groups having up to two heteroatoms from N, O and/or S are particularly preferred, such as furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.

In the context of the present invention it is,halogen elementIncluding fluorine, chlorine, bromine and iodine. Fluorine or chlorine are preferred.

When a group is substituted in a compound according to the present invention, the group may be substituted one or more times, unless otherwise specified. In the context of the present invention, for all radicals which occur more than once, their meanings are independent of one another. Preferably by one, two or three identical or different substituents. Very particular preference is given to substitution by one substituent.

Preferred in the context of the present invention are compounds of the formula (I), wherein

A represents N or C-R⁴Therein of which

R⁴Meaning hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

R¹is represented by (C)₁-C₆) Alkyl radical, which canBy hydroxy, (C)₁-C₆) Alkoxy group, (C) ₃-C₇) Cycloalkyl or phenyl substituted, or represents (C)₃-C₇) A cycloalkyl group,

in which the cycloalkyl radicals may themselves be substituted up to two times, identically or differently by (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy, hydroxy, amino and/or oxo substitution,

and

up to three times, identically or differently, substituted by halogen, cyano, nitro, (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy, trifluoromethyl and/or trifluoromethoxy substituted,

R²represents phenyl, naphthyl, thienyl, benzothienyl, furyl or benzofuryl, each of which may be substituted up to three times, identically or differently, by halogen, cyano, nitro, (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy, trifluoromethyl, trifluoromethoxy and/or phenyl substitution,

in which the last-mentioned phenyl radical may itself be substituted up to two times, identically or differently, by halogen, cyano, nitro, (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy, trifluoromethyl and/or trifluoromethoxy substituted,

m means the number 1, 2 or 3

And

R^5Aand R^5BIndependently of one another, means hydrogen or (C)₁-C₄) Alkyl radical

Or

Two radicals R bound to the same carbon atom^5AAnd R ^5BAre linked to each other and together form- (CH)₂)_nA bridge therein

n means the number 2, 3, 4 or 5,

alternatively, when m represents the number 2 or 3,

p means the number 1, 2, 3 or 4,

or

L¹Represents a group of the formula

L²Represents: -CR^6AR^6B-(CR^7AR^7B)_q-or-CR^6AR^6B(CR^7AR^7B) -a group of-O-,

therein is provided with

Meaning the binding site to the N atom of the amide group,

q means the number 0, 1 or 2

R^6AMeaning hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

R^6Bmeaning hydrogen, (C)₁-C₄) Alkyl, trifluoromethyl, (C)₃-C₆) Cycloalkyl or phenyl, which may be up to two timesIdentically or differently substituted by halogen, (C)₁-C₄) Alkyl and/or trifluoromethyl substituted, and/or substituted,

or

r means the number 2, 3, 4 or 5,

and

R^7Aand R^7BIndependently of one another, means hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

R³Represents phenyl, naphthyl or 5-to 10-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and/or S, each of which may be substituted up to three times, identically or differently, by halogen, cyano, nitro, (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy, trifluoromethyl, trifluoromethoxy, di- (C)₁-C₄) Alkyl amino and/or phenyl substitution, and/or a salt thereof,

or group

L²-R³Together form a group of the formula

Or

Therein is provided with

Meaning the binding site to the N atom of the amide group,

d means CH₂Or an oxygen-containing gas,

e means NH, N-CH₃The presence of oxygen, O or S,

t means the number 0 or 1,

u means the number 0, 1 or 2,

and

R⁹meaning hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

and salts, solvates and solvates of salts thereof.

Also preferred in the context of the present invention are compounds of formula (I) wherein A represents N or C-R⁴Therein of which

R⁴Meaning hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

R¹is represented by (C)₁-C₆) Alkyl, which may be substituted one to three times, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, cyano, oxo, trifluoromethyl, (C)₃-C₆) CycloalkanesRadical, phenyl radical, -OR¹⁰，-NR¹¹R¹²，-C(＝O)-OR¹³and-C (═ O) -NR¹⁴R¹⁵In which is substituted by a group of

(i)(C₃-C₆) Cycloalkyl radicals can be substituted up to two times, identically or differently by (C)₁-C₄) Alkyl, oxo, hydroxy, (C)₁-C₄) Alkoxy and/or amino substitution, and/or a pharmaceutically acceptable salt thereof,

(ii) the phenyl groups can be substituted up to three times, identically or differently, by groups selected from fluorine, chlorine, cyano, (C)₁-C₄) Alkyl, trifluoromethyl, hydroxy, hydroxymethyl, (C)₁-C₄) Alkoxy, trifluoromethoxy, (C)₁-C₄) Alkoxymethyl, hydroxycarbonyl, (C)₁-C₄) Alkoxycarbonyl, aminocarbonyl, mono- (C)₁-C₄) Alkylaminocarbonyl and di- (C)₁-C₄) The radical of an alkylaminocarbonyl group is substituted,

(iii)R¹⁰，R¹¹，R¹²，R¹³，R¹⁴and R¹⁵Independently of one another, each independently of the others, means hydrogen, (C)₁-C₄) Alkyl or (C)₃-C₆) Cycloalkyl radicals, in which

(C₁-C₄) The alkyl radicals may themselves be substituted up to two times, identically or differently, by amino, hydroxy, (C)₁-C₄) Alkoxy, hydroxycarbonyl and/or (C)₁-C₄) The substitution of the alkoxy carbonyl group is carried out,

And

(C₃-C₆) Cycloalkyl can itself be substituted up to two times, identically or differently by (C)₁-C₄) Alkyl, oxo, hydroxy, (C)₁-C₄) Alkoxy and/or amino substitution, and/or a pharmaceutically acceptable salt thereof,

and/or

(iv)R¹¹And R¹²And R¹⁴And R¹⁵In each case in pairs with the nitrogen atom to which they are attached form a 4-to 6-membered heterocycle which may contain further heteroatoms from N and O and up to two times, identically or differently, (C)₁-C₄) Alkyl, oxo, hydroxy, (C)₁-C₄) Alkoxy and/or amino substitution, and/or a pharmaceutically acceptable salt thereof,

or

R¹Is represented by (C)₂-C₆) Alkenyl, which may be substituted by hydroxy, (C)₁-C₄) Alkoxy, hydroxycarbonyl and/or (C)₁-C₄) The substitution of the alkoxy carbonyl group is carried out,

or

Is represented by (C)₃-C₆) Cycloalkyl which can be substituted up to two times, identically or differently by (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy, hydroxy, amino and/or oxo substitution,

R²represents phenyl or thienyl, which may be substituted one to three times, identically or differently, by a group selected from fluorine, chlorine, cyano, (C)₁-C₄) Alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) Alkoxy, trifluoromethoxy and phenyl,

in which the last-mentioned phenyl radical may itself be substituted up to two times, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, cyano, (C1-C4) alkyl, trifluoromethyl, (C1-C4) ₁-C₄) Alkoxy and trifluoromethoxy groups, and the like,

L¹represents having the formula-CR^5AR^5BA group of (a) in which

R^5AAnd R^5BIndependently of one another, means hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

L²represents a compound having the formula-CR^6AR^6B-(CR^7AR^7B)_qA group of (a) in which

Meaning the binding site to the N atom of the amide group,

q means the number 0 or 1,

R^6Ameaning hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

R^6Bmeaning hydrogen, (C)₁-C₄) Alkyl, trifluoromethyl, (C)₃-C₆) Cycloalkyl or phenyl, which may be up to two times, identically or differently, substituted by fluorine, chlorine, (C)₁-C₄) Alkyl and/OR trifluoromethyl substituted, OR means having the formula-C (═ O) -OR¹⁶or-C (═ O) -NR¹⁷R¹⁸In which the radical

Or

R¹⁷And R¹⁸Together with the nitrogen atom to which they are attached, may form a 4-to 6-membered heterocyclic ring which may contain further heteroatoms from the N and O range and up to two times, identically or differently, (C)₁-C₄) Alkyl, hydroxy and/or (C)₁-C₄) The substitution of alkoxy groups is carried out,

or

r means the number 2, 3, 4 or 5

And one CH of the bridge₂The group can be replaced by-O-,

R^7Ameaning hydrogen, fluorine or (C)₁-C₄) An alkyl group, a carboxyl group,

R^7Bmeaning hydrogen, fluorine, (C) ₁-C₄) Alkyl, hydroxy- (C)₁-C₄) Alkyl orHaving the formula-OR²⁰，-NR²¹R²²，-C(＝O)-OR²³or-C (═ O) -NR²⁴R²⁵In which the radical

Or

R²¹And R²²And R²⁴And R²⁵Each in pairs together with the nitrogen atom to which they are attached may form a 4-to 6-membered heterocyclic ring which may contain further heteroatoms from the N and O range and up to two times, identically or differently (C)₁-C₄) Alkyl, hydroxy and/or (C)₁-C₄) The substitution of alkoxy groups is carried out,

or

R^7AAnd R^7BTogether form an Oxo group (Oxo-Gruppe)

Or

s means the number 2, 3, 4 or 5

And one CH of the bridge₂The group can be replaced by-O-,

or

L²Represents a group of the formula

Therein is provided with

Meaning the binding site to the N atom of the amide group,

x means the number 1, 2, 3 or 4,

wherein one CH2 group of the ring may be replaced by-O-,

and

R^6Band R^7BEach of which has the meaning as described above,

and

R³represents phenyl, naphthyl or a 5-to 10-membered heteroaryl having up to two heteroatoms from the group consisting of N, O and/or S, each of which may be substituted one to three times, identically or differently, by a substituent selected from the group consisting of fluorine, chlorine, cyano, (C)₁-C₄) Alkyl, trifluoromethyl, hydroxy, (C) ₁-C₄) Alkoxy, trifluoromethoxy, (C)₁-C₄) Alkylthio (C)₁-C₄) Alkylsulfonyl, di- (C)₁-C₄) Alkyl amino and phenyl groups, and a pharmaceutically acceptable salt thereof,

in which the last-mentioned phenyl radical may itself be up to two times, identically or differently, substituted by fluorine, chlorine, cyano, (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy, trifluoromethyl and/or trifluoromethoxy substituted,

and salts, solvates and solvates of salts thereof.

Particularly preferred in the context of the present invention are compounds of the formula (I) in which A represents N or C-R4, in which

R⁴Meaning hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

R¹is represented by (C)₁-C₆) Alkyl, which may be substituted by hydroxy, (C)₁-C₄) Alkoxy group, (C)₃-C₆) Cycloalkyl or phenyl substituted, or represents (C)₃-C₆) A cycloalkyl group,

in which the cycloalkyl radicals may themselves be substituted up to two times, identically or differently by (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy, hydroxy and/or amino substitution,

and

the phenyl radicals may be substituted up to two times, identically or differently, by halogen, cyano, nitro, (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy, trifluoromethyl and/or trifluoromethoxy, R²Represents phenyl, naphthyl, thienyl or benzothienyl, each of which may be substituted up to three times, identically or differently, by halogen, cyano, nitro, (C) ₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy, trifluoromethyl, trifluoromethoxy and/or phenyl substitution,

m means the number 1, 2 or 3

And

R^5Aand R^5BIndependently of one another, means hydrogen or methyl

Or

Two radicals R bound to the same carbon atom^5AAnd R^5BAre linked to each other and together form- (CH)₂)_nA bridge therein

n means the number 2, 3, 4 or 5,

alternatively, when m represents the number 2 or 3,

two radicals R bound to adjacent (1, 2-or 2, 3-) or non-adjacent (1, 3-) carbon atoms^5AAnd/or R^5BAre connected with each other and form togetherTo- (CH)₂)_pA bridge therein

p means the number 1, 2, 3 or 4,

or

L¹Represents a group of the formula

L²Represents a compound having the formula-CR^6AR^6B-(CH₂)_qA group of (a) in which

Meaning the binding site to the N atom of the amide group,

q means the number 0 or 1,

R^6AMeaning either hydrogen or a methyl group, or a mixture thereof,

R^6Bmeaning hydrogen, (C)₁-C₄) Alkyl, trifluoromethyl or (C)₃-C₆) A cycloalkyl group,

or

r means the number 2, 3, 4 or 5,

and

R³represents phenyl, naphthyl or 5-to 10-membered heteroaryl having up to two heteroatoms from the group of N, O and/or S, each of which may be substituted up to three times, identically or differently, by halogen, cyano, nitro, (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy, trifluoromethyl, trifluoromethoxy and/or phenyl substitution,

and salts, solvates and solvates of salts thereof.

Also particularly preferred in the context of the present invention are compounds of the formula (I) in which A represents N or C-R⁴Therein of which

R⁴Meaning either hydrogen or a methyl group, or a mixture thereof,

R¹is represented by (C)₁-C₆) Alkyl, which may be mono-or di-, identically or differently selected from fluoro, oxo, trifluoromethyl, (C)₃-C₆) Cycloalkyl, phenyl, -OR¹⁰，-C(＝O)-OR¹³and-C (═ O) -NR¹⁴R¹⁵In which is substituted by a group of

(i)(C₃-C₆) Cycloalkyl radicals can be substituted up to two times, identically or differently by (C)₁-C₄) Alkyl, hydroxy and/or (C)₁-C₄) The substitution of alkoxy groups is carried out,

(ii) the phenyl radicals may be substituted up to two times, identically or differently, by radicals selected from the group consisting of fluorine, chlorine, cyano, (C)₁-C₄) Alkyl, trifluoromethyl, hydroxymethyl, (C)₁-C₄) Alkoxy, hydroxycarbonyl, (C)₁-C₄) Alkoxycarbonyl, aminocarbonyl, mono- (C)₁-C₄) Alkylaminocarbonyl and di- (C)₁-C₄) The radical of an alkylaminocarbonyl group is substituted,

and

(iii)R¹⁰，R¹³，R¹⁴and R¹⁵Independently of each other when each occurs aloneUpright means hydrogen, (C)₁-C₄) Alkyl or (C)₃-C₆) Cycloalkyl radicals, in which

(C₁-C₄) The alkyl radicals may themselves be substituted up to two times, identically or differently by hydroxy, (C)₁-C₄) Alkoxy, hydroxycarbonyl and/or (C)₁-C₄) The substitution of the alkoxy carbonyl group is carried out,

and

(C₃-C₆) Cycloalkyl can itself be substituted up to two times, identically or differently by (C)₁-C₄) Alkyl, hydroxy and/or (C)₁-C₄) The substitution of alkoxy groups is carried out,

or

R¹Is represented by (C)₂-C₆) Alkenyl which may be substituted by hydroxycarbonyl and/or (C)₁-C₄) The substitution of the alkoxy carbonyl group is carried out,

or

Is represented by (C)₃-C₆) Cycloalkyl which can be substituted up to two times, identically or differently by (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy and/or hydroxy substitution, or both,

R²represents phenyl or thienyl, which may be mono-or di-substituted, identically or differently selected from fluorine, chlorine, (C) ₁-C₄) Alkyl, trifluoromethyl, (C)₁-C₄) Alkoxy and trifluoromethoxy groups, and the like,

L¹represents having the formula-CR^5AR^5BA group of (a) in which

R^5AAnd R^5BIndependently of one another, means hydrogen or methyl,

Meaning the binding site to the N atom of the amide group,

q means the number 0 or 1,

R^6Ameaning either hydrogen or a methyl group, or a mixture thereof,

R^6Bmeaning hydrogen, methyl, trifluoromethyl OR having the formula-C (═ O) -OR¹⁶or-C (═ O) -NR¹⁷R¹⁸In which the radical

Or

R¹⁷And R¹⁸Together with the nitrogen atom to which they are attached, form a 4-to 6-membered heterocyclic ring, which may contain an oxygen atom as further heteroatom,

or

r means the number 2, 3, 4 or 5

And one CH of the bridge₂The group can be replaced by-O-,

R^7Ameaning a group of hydrogen, fluorine or methyl,

R^7Bmeaning hydrogen, fluorine, methyl OR having the formula-C (═ O) -OR²³or-C (═ O) -NR²⁴R²⁵In which the radical

R²³，R²⁴And R²⁵Independently of one another, represents hydrogen, (C)₁-C₄) Alkyl or (C)₃-C₆) Cycloalkyl radicals

Or

R²⁴And R²⁵Together with the nitrogen atom to which they are attached form a 4 to 6-membered heterocyclic ring,which may contain oxygen atoms as further heteroatoms,

Or

R^7AAnd R^7BTogether form oxo

Or

s means the number 2, 3, 4 or 5

And one CH of the bridge₂The group can be replaced by-O-,

or

L²Represents a group of the formula

Therein is provided with

Meaning the binding site to the N atom of the amide group,

x means the number 1, 2, 3 or 4,

in which one CH of the ring₂The group can be replaced by-O-,

and

R^6Band R^7BEach of which has the meaning as described above,

and

R³represents phenyl, naphthyl, pyridyl, quinolyl or isoquinolyl, each of which may be mono-or di-substituted, identically or differently, by radicals selected from the group consisting of fluorine, chlorine, cyano, (C)₁-C₄) Alkyl, trifluoromethyl, (C)₁-C₄) Alkoxy, trifluoromethoxy, (C)₁-C₄) Alkyl-thio and phenyl groups,

in which the last-mentioned phenyl radicalThe radicals themselves may be substituted up to two times, identically or differently, by fluorine, chlorine, cyano, (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy, trifluoromethyl and/or trifluoromethoxy substituted,

and salts, solvates and solvates of salts thereof.

Very particular preference is given in the context of the present invention to compounds of the formula (I) in which A represents N or CH,

R¹is represented by (C)₁-C₆) Alkyl, which may be mono-or di-substituted, identically or differently selected from fluorine, oxo, hydroxy, (C) ₁-C₄) Alkoxy, trifluoromethyl, (C)₃-C₆) The radicals of cycloalkyl and phenyl are substituted,

wherein the phenyl radical itself may be substituted up to two times, identically or differently, by radicals selected from the group consisting of fluorine, chlorine, cyano, (C)₁-C₄) Alkyl, trifluoromethyl, hydroxymethyl, (C)₁-C₄) Alkoxy, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl and di- (C)₁-C₄) The radical of an alkylaminocarbonyl group is substituted,

or

R¹Is represented by (C)₂-C₄) Alkenyl or (C)₃-C₆) A cycloalkyl group,

R²represents phenyl or thienyl, which may be mono-or di-substituted, identically or differently selected from fluorine, chlorine, bromine, (C)₁-C₄) Alkyl and (C)₁-C₄) The substituent of the alkoxy group is replaced by the group,

L¹represents-CH₂-，-CH(CH₃) -or-CH₂CH₂-，

Meaning the binding site to the N atom of the amide group,

q means the number 0 or 1,

R^6Ameaning either hydrogen or a methyl group, or a mixture thereof,

R^6Bmeaning hydrogen, methyl, trifluoromethyl or have the formula-C (═ O) -NR¹⁷R¹⁸In which the radical

R¹⁷And R¹⁸Independently of one another, represents hydrogen, (C)₁-C₄) Alkyl or (C)₃-C₆) Cycloalkyl radicals

Or

or

r means the number 2, 3, 4 or 5

And one CH of the bridge₂The group can be replaced by-O-,

R^7Ameaning a group of hydrogen, fluorine or methyl,

R²³，R²⁴And R²⁵Independently of one another, hydrogen or (C)₁-C₄) Alkyl radical

Or

R²⁴And R²⁵Together with the nitrogen atom to which they are attached, form a 4-to 6-membered heterocyclic ring, which may contain an oxygen atom as further heteroatom,

or

R^7AAnd R^7BTogether form oxo

Or

s means the number 2, 3, 4 or 5

And one CH of the bridge₂The group can be replaced by-O-,

or

L²Represents a group of the formula

Wherein

Meaning the binding site to the N atom of the amide group,

x means the number 1, 2, 3 or 4

And

R^6Band R^7BEach of which has the meaning as described above,

and

R³represents phenyl or pyridyl, which may be mono-or di-substituted, identically or differently selected from fluorine, chlorine, (C)₁-C₄) Alkyl, trifluoromethyl, (C)₁-C₄) Alkoxy and trifluoromethoxy, or represents naphthyl,

and salts, solvates and solvates of salts thereof.

R¹Is represented by (C)₁-C₆) Alkyl, which may be mono-di-identicalOr are substituted by a group selected from fluorine, oxo, hydroxy, methoxy, ethoxy, trifluoromethyl, cyclopropyl and phenyl,

wherein the phenyl radical itself may be substituted up to two times, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, cyano, methyl, hydroxymethyl, methoxy, hydroxycarbonyl, aminocarbonyl and dimethylaminocarbonyl,

or

R¹Represents vinyl, allyl or cyclopropyl,

R²represents phenyl or thienyl, which may be mono-or disubstituted, identically or differently, with radicals from the group fluorine, chlorine, methyl and methoxy,

L¹represents-CH₂-，

Meaning the binding site to the N atom of the amide group,

q means the number 0 or 1,

R^6Ameaning either hydrogen or a methyl group, or a mixture thereof,

R¹⁷And R¹⁸Independently of one another, hydrogen, methyl, ethyl or cyclopropyl

Or

R¹⁷And R¹⁸Together with the nitrogen atom to which they are attached, form an azetidine, pyrrolidine, piperidine or morpholine ring,

or

R^6AAnd R^6BAre connected with each otherAnd together with the carbon atom to which they are attached form a group of formula

Or

R^7AMeaning a group of hydrogen, fluorine or methyl,

R²³，R²⁴And R²⁵Independently of one another, hydrogen, methyl or ethyl

Or

R²⁴And R²⁵Together with the nitrogen atom to which they are attached, form an azetidine, pyrrolidine, piperidine or morpholine ring,

or

R^7AAnd R^7BTogether form oxo

Or

R^7AAnd R^7BAre linked to each other and together form- (CH)₂) s bridge therein

s means the number 2, 3, 4 or 5

And one CH of the bridge₂The group can be replaced by-O-,

or

L²Represents a group of the formula

And

R³represents phenyl which is substituted, one or two times, identically or differently, by fluorine, chlorine, trifluoromethyl and/or trifluoromethoxy, or represents 1-naphthyl,

and salts, solvates and solvates of salts thereof.

Very particular preference in the context of the present invention is also given to compounds of the formula (I) in which

A represents N or CH, and the compound is represented by,

R¹is represented by (C)₁-C₄) Alkyl, 2-methoxyethyl, cyclopropyl, cyclohexylmethyl, benzyl or 1-phenylethyl,

wherein the phenyl rings in said benzyl-and 1-phenylethyl groups may be substituted by fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy,

R²Represents phenyl or thienyl, each of which is substituted, one or two times, identically or differently, by fluorine, chlorine, bromine, methyl and/or methoxy,

L¹represents-CH₂-，-CH₂CH₂-or-CH (CH)₃)-，

L²represents-CH₂-，-CH(CH₃) -or-CH (CH)₃)₂-，

And

R³represents phenyl which is substituted one or two times, identically or differently, by fluorine, chlorine, trifluoromethyl and/or trifluoromethoxy, or represents 1-naphthyl,

and salts, solvates and solvates of salts thereof.

The radical definitions stated in detail in the individual radical combinations and/or preferred combinations do not depend on the individual stated radical combinations and are also arbitrarily replaced by radical definitions of other combinations.

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

A further object of the present invention is a process for the production of the compounds according to the invention having formula (I),

it is characterized in that

[A] A compound having the following formula (II) in an inert solvent with activation of the carboxylic acid function

Wherein A, L¹，R¹And R²Each of which has the above-mentioned meaning,

coupling with Compounds of the formula (III)

R³-L²-NH₂ (III)，

Wherein L is²And R³Having the above-mentioned meaning, the optical fiber has,

or

[B] In an inert solvent in the presence of a base, a compound having the following formula (IV)

Wherein A, R¹And R ²Each of which has the above-mentioned meaning,

with a compound of the formula (V)

Wherein L is¹，L²And R³Each of which has the meaning as described above,

and

x represents a leaving group, such as halogen, mesylate or tosylate, and the resulting compounds of formula (I) are optionally converted to their solvates, salts and/or solvates of the salts with an appropriate (I) solvent and/or (ii) base or acid.

Inert solvents for process step (II) + (III) → (I) are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, ethylene 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, tetrachloromethane, 1, 2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents, such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide, N-dimethylformamide, N' -Dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). Mixtures of the said solvents can likewise be used. Preference is given to dichloromethane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or mixtures of these solvents.

Suitable condensing agents for amidation in process step (II) + (III) → (I) are, for example, carbodiimides, such as N, N '-diethyl-, N, N' -dipropyl-, N, N '-diisopropyl-, N, N' -Dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminoisopropyl) -N '-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives, such as N, N' -Carbonyldiimidazole (CDI), 1, 2-oxazolium compounds, such as 2-ethyl-5-phenyl-1, 2-oxazolium-3 sulfate or 2-tert-butyl-5-methyl-isoxazolium (isoxazolium) perchlorate, acylamino compounds, for example 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline, or isobutyl chloroformate, propanephosphonic anhydride, diethyl cyanophosphonate, bis- (2-oxo-3-oxazolidinyl) -phosphonyl chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris (pyrrolidinyl) phosphonium hexafluorophosphate (PyBOP), O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (O- (benzothizol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate) (TBTU), O- (benzotriazol-1-yl) -N, n, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) -pyridinyl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate (TPTU), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) or O- (1H-6-chlorobenzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate (TCTU), optionally in combination with further auxiliaries, for example 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and, as a base, an alkali metal carbonate, for example sodium or potassium carbonate or sodium or potassium bicarbonate, or an organic base, for example a trialkylamine, for example triethylamine, N-methylmorpholine, N-methylpiperidine or N, N-diisopropylethylamine. Preferably EDC is used in combination with HOBt or TBTU is used in combination with N, N-diisopropylethylamine.

The condensation (II) + (III) → (I) is usually carried out in the temperature range from-20 ℃ to +60 ℃ and preferably in the range from 0 ℃ to +40 ℃. The reaction can be carried out under normal pressure, increased pressure or reduced pressure (e.g.0.5 to 5 bar). The operation is generally carried out under normal pressure.

Inert solvents for process step (IV) + (V) → (I) are, for example, halogenated hydrocarbons, such as methylene chloride, chloroform, tetrachloromethane, trichloroethylene or chlorobenzene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents, such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP) or pyridine. Mixtures of the said solvents can likewise be used. Preference is given to using acetonitrile, acetone or dimethylformamide.

As base for process step (IV) + (V) → (I), customary inorganic or organic bases are suitable. These advantagesOptionally comprising alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or cesium carbonate, alkali metal alkoxides, such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or sodium tert-butoxide or potassium tert-butoxide, alkali metal hydrides, such as sodium hydride or potassium hydride, amides, such as sodium amide, lithium bis (trimethylsilyl) amide 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 (DBN), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU) or 1, 4-diazabicyclo [2.2.2]Octane (C)). Preferably, potassium carbonate or cesium carbonate is used.

For this purpose, the base is used in an amount of 1 to 5mol, preferably 1 to 2.5mol, based on 1mol of the compound of the formula (IV). The reaction is generally carried out at a temperature in the range from 0 ℃ to +100 ℃ and preferably at a temperature in the range from +20 ℃ to +80 ℃. The reaction can be carried out under normal pressure, increased pressure or reduced pressure (e.g.0.5 to 5 bar). The operation is generally carried out under normal pressure.

The production of the compounds according to the invention is illustrated by the following synthetic schemes:

scheme 1

A compound of formula (II) wherein A represents N, N may be generated by base-induced alkylation of a 5-aryl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one of formula (IVa)²-substituted compound (VIIa) and subsequent ester hydrolysis (see scheme 2):

scheme(s)2

[ Alk ═ alkyl, Hal ═ halogen ].

Alternatively, compounds having formula (VIIa) can also be prepared from the literature [ see, e.g., m.58(25)，7022-7028(1993)；E.P.Papadopoulos，J.Org.Chem.41(6)，962-965(1976)]The known N- (alkoxycarbonyl) -arylthioamides of formula (IX) are obtained by reaction with hydrazino esters of formula (VIII) and subsequent alkylation on N-4 of triazolone (Xa) (scheme 3):

Scheme 3

A compound having the formula (II) wherein A represents C-R⁴This can be achieved by reaction of an alpha-aminoketone of formula (XI) with an isocyanate of formula (XII) and subsequent ester hydrolysis (scheme 4). The compounds of formula (XI) can be synthesized as such from α -bromoketones of formula (XIV) and amino esters of formula (XV) in a manner known in the literature (scheme 5):

scheme 4

Scheme 5

Compounds of formula (IV), wherein a represents N, can be produced starting from carbohydrazides of formula (XVI) by reaction with isocyanates of formula (XII) or nitrophenylcarbamates of formula (XVII) and subsequent base-induced cyclization of the intermediate semicarbazide (XVIII) (scheme 6):

scheme 6

Compounds having formula (V) can be achieved, for example, by acylation of an amine having formula (III) with an acid chloride having formula (XIX) (scheme 7):

scheme 7

In a particular variant, the compound having formula (VIIa) or (VIIb) can optionally also be produced as follows: alternatively to R1 in the process described in scheme 2, 3, 4 or 6, a temporary Protecting Group (PG), such as allyl or 4-methoxybenzyl; after their cleavage to yield the compound of formula (X), the compound of formula (VII) can be obtained by appropriate N-alkylation (scheme 8):

Scheme 8

[ PG ═ a protecting group such as allyl or 4-methoxybenzyl ].

The analogous transformation PG → R1 can also optionally be carried out subsequently at a stage of the compounds of the formulae (IIa), (IIb) or (I):

scheme 9

The introduction and cleavage of the Protective group PG here is carried out by conventional literature methods [ see, for example, T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999 ]. The allyl groups are therefore preferably removed by formic acid in the presence of a tetrakis (triphenylphosphine) palladium (0) catalyst and an amine base such as triethylamine. Cleavage of the p-methoxybenzyl protecting group is preferably carried out by strong acids, such as trifluoroacetic acid, or by oxidative routes, such as by treatment with 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) or ammonium cerium (IV) nitrate.

The subsequent N-alkylation (X) → (VII) or (XXII) → (I) proceeds analogously to process step (IV) + (V) → (I) described before. As the inert solvent, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, toluene, tetrahydrofuran, ethylene glycol dimethyl ether or a mixture thereof is preferable. As the base, sodium hydride or potassium carbonate or cesium carbonate is preferably used. Optionally, these alkylations can advantageously be carried out with the addition of catalysts, such as lithium bromide, sodium iodide, tetra-n-butylammonium bromide or benzyltriethylammonium chloride. The reaction is generally carried out at a temperature in the range from 0 ℃ to +150 ℃ and preferably at a temperature in the range from +20 ℃ to +80 ℃.

Many of the compounds of the formulae (III), (VI), (VIII), (IX), (XII), (XIII), (XV), (XVI), (XVII) and (XIX) are commercially available, known in the literature or obtainable by generally known methods.

The compounds according to the invention have valuable pharmacological properties and can be used for the prophylaxis and/or treatment of various diseases and disease-induced states in humans and animals.

The compounds according to the invention are potent selective V1a, selective V2 and in particular bis V1a/V2 receptor antagonists which inhibit vasopressin activity in vitro and in vivo. Furthermore, the compounds according to the invention likewise act as antagonists with respect to the oxytocin receptor.

The compounds according to the invention are particularly suitable for the prophylaxis and/or treatment of cardiovascular diseases. In this connection, the following are mentioned, for example and preferably, as target indications: acute and chronic cardiac insufficiency, arterial hypertension, coronary heart disease, stable and unstable angina pectoris, myocardial ischemia, myocardial infarction, shock, arteriosclerosis, atrial and ventricular arrhythmias, transient and ischemic attacks, stroke, inflammatory cardiovascular diseases, peripheral and cardiovascular diseases, peripheral circulatory diseases, arterial pulmonary hypertension, coronary artery and peripheral arterial spasm, thrombosis, thromboembolic diseases, edema formation, such as pulmonary edema, cerebral edema, nephrogenic edema or cardiac insufficiency-related edema, and restenosis after e.g. thrombolytic therapy, Percutaneous Transluminal Angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart transplantation and bypass surgery.

In the sense of the present invention, the term cardiac insufficiency also includes more specific or related forms of disease, such as right heart insufficiency, left heart insufficiency, complete insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, heart valve defects, cardiac insufficiency with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis, pulmonary valve insufficiency, mixed heart valve defects, myocarditis (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic cardiac insufficiency, alcohol-toxic cardiomyopathy, cardiac storage disorders (kaiar spicher-erkrankung), diastolic blood supply insufficiency and systolic blood supply insufficiency.

Furthermore, the compounds according to the invention are suitable for use as diuretics for the treatment of edema and for electrolyte disorders, in particular for hypervolemic and isovolemic hyponatremia.

The compounds according to the invention are also suitable for the prophylaxis and/or treatment of polycystic kidney disease (PCKD) and the syndrome of inappropriate secretion of vasopressin (SIADH).

In addition, the compounds according to the invention can be used for the prophylaxis and/or treatment of cirrhosis of the liver, ascites, diabetes and diabetic complications, such as neuropathy and nephropathy, acute and chronic renal failure and chronic renal insufficiency.

Further, the compounds according to the invention are suitable for the prevention and/or treatment of central nervous disorders, such as anxiety states and depression, glaucoma and tumors, in particular lung tumors.

Furthermore, the compounds according to the invention can be used for the prevention and/or treatment of inflammatory diseases, asthma, chronic-obstructive airways disease (COPD), pain states, prostatic hypertrophy, incontinence, cystitis, overactive bladder, adrenal disorders, such as pheochromocytoma and adrenal stroke, intestinal disorders, such as crohn's disease and diarrhea, or menstrual disorders, such as dysmenorrhea.

A further object of the present invention is the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

A further object of the present invention is the use of a compound according to the invention for the preparation of a medicament for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

A further object of the present invention is a method for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases, by means of an effective amount of at least one compound according to the invention.

The compounds according to the invention can be used alone or, if desired, in combination with other active substances. A further object of the present invention is a pharmaceutical composition comprising at least one compound according to the invention and one or more further active substances, in particular for the treatment and/or prophylaxis of the abovementioned diseases. As binding active substances suitable for this, the following may be mentioned, for example and preferably:

organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomide or SIN-1, and inhaled NO;

diuretics, especially loop diuretics and thiazides like thiazides;

active substances which enhance contractility, such as cardiac glycosides (digoxin), and β -adrenaline and dopamine agonists, such as isoproterenol, adrenaline, noradrenaline, dopamine and dobutamine;

compounds which inhibit the degradation of cyclic guanylic acid (cGMP) and/or cyclic adenosine monophosphate (cAMP), such as Phosphodiesterase (PDE)1, 2, 3, 4 and/or 5, in particular PDE5 inhibitors, such as sildenafil, vardenafil and tadalafil, and PDE3 inhibitors, such as thalidone and milrinone;

Natriuretic peptides such as "atrial natriuretic peptide" (ANP, anaritide), "B-type natriuretic peptide" or "brain natriuretic peptide" (BNP, nesiritide), "C-type natriuretic peptide" (CNP) and diuretic (urodilatin);

calcium sensitizers, such as and preferably levosimendan;

NO-and blood-independent guanylate cyclase activators, such as, inter alia, the compounds described in WO01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO02/070462 and WO 02/070510;

NO-independent, but blood-dependent guanylate cyclase activators, such as the compounds described in particular in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;

human neutrophil elastase inhibitors (HNE), such as sevelalestat or DX-890;

compounds that inhibit signal transduction cascades, such as tyrosine kinase inhibitors, in particular sorafenib (sorafenib), imatinib, gefitinib (gefitinib) and erlotinib;

compounds which influence the metabolism of cardiac energy, such as and preferably etolimus (etomoxir), dichloroacetate, ranolazine (ranolazine) or trimethoprim;

agents having an antithrombotic effect, such as and preferably thrombocyte coagulation inhibitors, anticoagulants or profibrinolytic substances;

Hypotensive active substances, such as and preferably calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, neutral endopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha receptor blockers, beta receptor blockers, mineralocorticoid receptor antagonists and rho-kinase inhibitors; and/or

Active substances which improve fat metabolism, such as and preferably thyroid receptor agonists, cholesterol synthesis inhibitors, such as and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-a-, PPAR- γ -and/or PPAR- Δ agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric gallic acid adsorbents, gallic acid reabsorption inhibitors and lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a diuretic, such as and preferably, for example, Verbenamide (furosemide), diuretic, tolanilide, bendroflumethiazide, chlorambucil, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlorthiazide, chlorthalidone, indapamide, mefonazole sulfonamide, quinconazole, acetazolamide, oxydiphenylamide dichloride (dichlorophenamid), methazolamide, glycerol, isosorbide, mannitol, amiloride or triamcinolone.

An agent with antithrombotic action is preferably understood to be a compound from the group of inhibitors of coagulation of thrombocytes, anticoagulants or profibrinolytic substances.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombocyte coagulation inhibitor, such as and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a coagulation inhibiting factor, for example and preferably ximela-gatran, melagatran, bivalirudin or cremains (clexane).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb/IIIa antagonist, for example and preferably either ticalor or abciximab.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a factor Xa inhibitor, such as, and preferably, rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaxban, fidaxaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN 1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a Low Molecular Weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as, for example, and preferably coumarin.

By a hypotensive agent is preferably understood a compound from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, neutral endopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha receptor blockers, beta receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors and diuretics.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as and preferably nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as and preferably losartan, candesartan, valsartan, telmisartan or embusartan.

In a preferred embodiment of the present invention, the compounds according to the present invention are administered in combination with an ACE inhibitor, such as and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinapril (quinopril), perindopril or trandolapril.

In a preferred embodiment of the invention, the compounds according to the invention bind to vasopeptidase inhibitors or Neutral Endopeptidases (NEP), for example and preferably omapatrilat or AVE-7688.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist, such as and preferably bosentan, daruesentan, ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds according to the invention are combined with renin inhibitors, for example and preferably alipkiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1 receptor blocker, for example and preferably prazosin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a beta-receptor blocker, such as and preferably propranolol, atenolol, timolol, pinolol, alprenolol, oxprenolol, penbutolol, blanalol, metipranolol, nadolol, carabronolol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epamolol or bucindolol.

In a preferred embodiment of the invention, the compounds according to the invention are mixed with mineralocorticoid receptor antagonists, such as and preferably with the steroid spironolactone, eplerenone (eplerenon), canrenone or potassium canrenoate.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with rho-kinase inhibitors, such as and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.

Fat metabolism-modifying agents are preferably understood to mean compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors, such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR- α -, PPAR- γ -and/or PPAR- Δ agonists, cholesterol absorption inhibitors, polymeric gallic acid adsorbents, gallic acid reabsorption inhibitors, lipase inhibitors and lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as, and preferably, torcetrapib (CP-529414), JJT-705, BAY 60-5521, BAY 78-7499 or CETP-vaccine (Avant).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thyroid receptor agonist, for example and preferably D-thyroxine, 3, 5, 3' -triiodothyronine (T3), CGS23425 or axipirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, for example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, for example and preferably BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as and preferably avasimibe, melinamide, pactamibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor, such as and preferably impliptatide, BMS-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-gamma agonist, for example and preferably pioglitazone (pioglitazone) or rosiglitazone (rosiglitazone).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR- Δ agonist, for example with preferably GW-501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as and preferably ezetimibe, tiquinamine or pamaquine.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, e.g. and preferably orlistat.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a polybile acid adsorbent, cholestyramine, lipid lowering resin No. II, colesolvam, cholestagel or colestimid acid.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an inhibitor of gallic acid reabsorption, such as and preferably an ASBT (IBAT) inhibitor, such as AZD-7806, S-8921, AK-105, bali-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, for example and preferably gemcabene calcium (CI-1027) or niacin.

Further objects of the present invention are medicaments comprising at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmacologically suitable additives, and their use for the above mentioned purposes.

The compounds according to the invention may act systemically and/or locally. For this purpose, they can be administered in a suitable manner, for example by the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route or as a graft or stent.

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

For oral administration, administration forms which act according to the state of the art, release the compound according to the invention rapidly and/or in a modified manner, comprising the compound according to the invention in crystalline and/or amorphous and/or dissolved form, for example tablets (uncoated or, for example, sugar-coated tablets with gastric juice-resistant or delayed-dissolving or insoluble coatings which control the release of the compound according to the invention), tablets which disintegrate rapidly in the oral cavity or films/films, films/lyophilisates, capsules (for example, hard or soft gel capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions, are suitable.

Parenteral administration can be carried out omitting the absorption step (e.g., intravenous, intra-arterial, intracardiac, intraspinal or intralumbar administration) or involving absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal administration). Suitable administration forms for parenteral administration include injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For another route of administration, for example inhalation formulations (in particular powder inhalants and nebulisers), nasal drops, solutions or sprays, tablets for the tongue, sublingual or buccal tablets, films/sheets or capsules, suppositories, oral or ophthalmic formulations, vaginal capsules, aqueous suspensions (lotions, shakable mixtures), lipophilic suspensions, ointments, creams, transdermal dosage forms (e.g. plasters), creams, pastes, foams, dusting powders, implants or stents are suitable.

Oral or parenteral administration is preferred, especially oral and intravenous administration.

The compounds according to the invention can be brought into the administration form described. This can be carried out in a manner known per se by mixing with inert, non-toxic, pharmacologically suitable additives. These additives include carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g. sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants, e.g. ascorbic acid), pigments (e.g. inorganic pigments, e.g. iron oxide) and flavorants or odor improvers.

In general, it has been found to be advantageous to administer an amount of about 0.001-10mg/kg, preferably about 0.01-1mg/kg of body weight in order to achieve effective results in parenteral administration. In oral administration, the dosage is about 0.01 to 100mg/kg, preferably about 0.01 to 20mg/kg and quite particularly preferably 0.1 to 10mg/kg of body weight.

Nevertheless, it is sometimes necessary to deviate from the stated amounts, i.e. depending on the body weight, the route of administration, the individual's response to the active substance, the nature of the preparation and the time or interval over which the administration takes place. It may therefore sometimes be sufficient to cope with less than the minimum amount mentioned above, while in other cases the upper limit mentioned has to be exceeded. If taken in large quantities, it may be reasonable to divide these into several separate administrations throughout the day.

The following application examples illustrate the invention. The invention is not limited to this embodiment.

Unless otherwise indicated, the percentages stated in the following tests and examples are percentages by weight, parts are parts by weight, and information about the solvent ratio, dilution ratio and concentration of the liquid/liquid solution is each based on volume.

A.Examples

Abbreviations:

alk alkyl group

Boc tert-butoxycarbonyl

CI chemical ionization (in MS)

DCI direct chemical ionization (in MS)

DME 1, 2-dimethoxyethane

DMF dimethyl formamide

DMSO dimethyl sulfoxide

of the theory of the order (for yield)

EDC N' - (3-dimethylaminopropyl) -N-ethylcarbodiimide (hydrochloride)

EA Ethyl acetate

eq. equivalent

ESI electrospray ionization (in MS)

FMOC 9-fluorenylmethoxycarbonyl

GC/MS gas chromatography mass spectrometry online

sat, saturated

hr(s) hours

Hal halogen

HOBt 1-hydroxy-1H-benzotriazole hydrate

HPLC high pressure high performance liquid chromatography

conc. concentrated

LC/MS liquid chromatography-mass spectrometry combination

LDA lithium diisopropylamide

LiHMDS lithium hexamethyldisilazane

min(s) min

MS Mass Spectrometry

NMR nuclear magnetic resonance spectroscopy

PG protecting group

rac racemic/racemate

R_fRetention factor (in silica gel thin layer chromatography)

RT Room temperature

R_tResidence time (in HPLC)

TBTU O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate

THF tetrahydrofuran

TMOF Proformic acid trimethyl ester

UV ultraviolet spectroscopy

v/v (of solution) volume to volume ratio

LC/MS-, HPLC-and GC/MS-methods:

method 1 (HPLC): the instrument comprises the following steps: HP 1100 with DAD detection; column: kromasil100 RP-18, 60mm × 2.1mm, 3.5 μm; eluent A: 5ml HClO₄(70%)/liter water, eluent B: acetonitrile; gradient: 0min 2% B → 0.5min 2% B → 4.5min 90% B → 9min 90% B → 9.2min 2% B → 10min 2% B; flow rate: 0.75 ml/min; column temperature: 30 ℃; and (4) UV detection: 210 nm.

Method 2 (HPLC): the instrument comprises the following steps: HP 1100 with DAD detection; column: kromasil100 RP-18, 60mm × 2.1mm, 3.5 μm; eluent A: 5ml HClO₄(70%) l water, eluent B: acetonitrile; gradient: 0min 2% B → 0.5min 2% B → 4.5min 90% B → 6.5min 90% B → 6.7min 2% B → 7.5min 2% B; flow rate: 0.75 ml/min; column temperature: 30 ℃; and (4) UV detection: 210 nm.

Method 3 (LC/MS): the instrument comprises the following steps: micromass Platform LCZ with HPLC Agilent Series 1100; column: thermo Hypersil GOLD 3 μ 20mm × 4 mm; eluent A: 1l of water +0.5ml of 50% formic acid; eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 100% A → 0.2min 100% A → 2.9min 30% A → 3.1min 10% A → 5.5min 10% A; furnace: 50 ℃; flow rate: 0.8 ml/min; and (4) UV detection: 210 nm.

Method 4 (LC/MS): MS instrument type: micromass ZQ; HPLC instrument type: HP 1100 Series; UV DAD; column: phenomenex Synergi 2. mu. Hydro-RPMercury 20 mm. times.4 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min → 2.5min/3.0min/4.5min2 ml/min; furnace: 50 ℃; and (4) UV detection: 210 nm.

Method 5 (LC/MS): the instrument comprises the following steps: micromass Quattro LCZ with HPLC Agilent Series 1100; column: phenomenex Synergi 2. mu. Hydro-RPMercury 20 mm. times.4 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min → 2.5min/3.0min/4.5min2 ml/min; furnace: 50 ℃; and (4) UV detection: 208-400 nm.

Method 6 (LC/MS): and (4) an instrument MS: waters ZQ 2000; HPLC (high Performance liquid chromatography) of an instrument: agilent1100, 2-column conversion; an automatic sampler: HTC PAL; column: YMC-ODS-AQ, 50 mm. times.4.6 mm, 3.0 μm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; gradient: 0.0min 100% A → 0.2min 95% A → 1.8min 25% A → 1.9min 10% A → 2.0min 5% A → 3.2min 5% A → 3.21min 100% A → 3.35min 100% A; furnace: 40 ℃; flow rate: 3.0 ml/min; and (4) UV detection: 210 nm.

Method 7 (LC/MS): MS instrument type: micromass ZQ; HPLC instrument type: waters Alliance 2795; column: phenomenex Synergi 2. mu. Hydro-RP Mercury20mm X4 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min → 2.5min/3.0min/4.5min2 ml/min; furnace: 50 ℃; and (4) UV detection: 210 nm.

Method 8 (LC/MS): MS instrument type: micromass ZQ; HPLC instrument type: HP 1100 Series; UV DAD; column: phenomenex Gemini 3 mu 30mm x 3.00 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min → 2.5min/3.0min/4.5min2 ml/min; furnace: 50 ℃; and (4) UV detection: 210 nm.

Method 9 (preparative HPLC): the instrument comprises the following steps: abimed Gilson Pump 305/306, Manometric Module 806; column: from-Sil 120 ODS-4HE, 250mm × 30 mm; eluent: a is water, B is acetonitrile; gradient: 0.0min 30% B, 3min 30% B, 31min 95% B, 44min 95% B, 44.01min 30% B, 45min 30% B; flow rate: 50 ml/min; column temperature: RT; and (4) UV detection: 210 nm.

Method 10 (preparative HPLC): the instrument comprises the following steps: abimed Gilson Pump 305/306, Manometric Module 806; column: from-Sil 120 ODS-4HE 10 μm, 250 mm. times.20 mm; eluent: a is water, B is acetonitrile; gradient: 0.0min 10% B, 5min 10% B, 30min 95% B, 34min 95% B, 34.01min 10% B, 38min 10% B; flow rate: 25 ml/min; column temperature: RT; and (4) UV detection: 210 nm.

Method 11 (preparative HPLC): the instrument comprises the following steps: abimed Gilson Pump 305/306, Manometric Module 806; column: from-Sil 120 ODS-4HE 10 μm, 250 mm. times.20 mm; eluent: a is water, B is acetonitrile; gradient: 0.0min 10% B, 3min 10% B, 30min 95% B, 42min 95% B, 42.01min 10% B, 45min 10% B; flow rate: 50 ml/min; column temperature: RT; and (4) UV detection: 210 nm.

Method 12 (preparative HPLC): the instrument comprises the following steps: abimed Gilson Pump 305/306, Manometric Module 806; column: from-Sil 120 ODS-4HE 10 μm, 250 mm. times.40 mm; eluent: a is water, B is acetonitrile; gradient: 0.0min 10% B, 3min 10% B, 27min 98% B, 34min 98% B, 38min 10% B; flow rate: 50 ml/min; column temperature: RT; and (4) UV detection: 214 nm.

Method 13 (preparative HPLC): the instrument comprises the following steps: abimed Gilson Pump 305/306, Manometric Module 806; column: Macherey-Nagel VP 50/21 Nuclear 100-5C18 Nautilus 5 μm; eluent: a is acetonitrile, B is water + 0.1% formic acid; gradient: 0.0min 10% A, 2.00min 10% A, 6.00min 90% A, 7.00min 90% A, 7.10min 10% A, 8min 10% A; operating time: each separation was about 10 min; flow rate: 25 ml/min; column temperature: RT; and (4) UV detection: 220 nm.

Method 14 (preparative HPLC): a chiral silica phase based on the selector poly (N-methacryloyl-L-leucine-tert-butylamide); column: 680mm multiplied by 40 mm; eluent: iso-hexane/ethyl acetate 1: 1 (v/v); flow rate: 50 ml/min; temperature: 24 ℃; and (4) UV detection: 260nm. And (3) analyzing the column: 250mm × 4.6 mm; the same eluent; flow rate: 2 ml/min.

Method 15 (preparative HPLC): a chiral silica gel phase based on the selector poly (N-methacryloyl-L-leucine-dicyclopropylmethylamide); column: 250mm multiplied by 30 mm; eluent: iso-hexane/ethyl acetate 3: 7 (v/v); flow rate: 25 ml/min; temperature: 24 ℃; and (4) UV detection: 260nm. analytical column: 250mm × 4.6 mm; the same eluent; flow rate: 2 ml/min.

Method 16 (preparative HPLC): a chiral silica gel phase based on the selector poly (N-methacryloyl-D-valine-3-pentylamide); column: 250mm multiplied by 20 mm; eluent: iso-hexane/ethyl acetate 1: 3 (v/v); flow rate: 25 ml/min; temperature: 24 ℃; and (4) UV detection: 260 nm. And (3) analyzing the column: 250mm × 4.6 mm; the same eluent; flow rate: 2 ml/min.

Method 17 (LC/MS): the instrument comprises the following steps: micromass Quattro LCZ with HPLC Agilent Series 1100; column: phenomenex Onyx Monolithic C18, 100 mm. times.3 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2min 65% A → 4.5min 5% A → 6min 5% A; flow rate: 2 ml/min; furnace: 40 ℃; and (4) UV detection: 208-400 nm.

Method 18 (LC/MS): the instrument comprises the following steps: micromass Quattro LCZ with HPLC Agilent Series 1100; column: phenomenex Gemini 3 μm, 30mm × 3.00 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min → 2.5min/3.0min/4.5min 2 ml/min; furnace: 50 ℃; and (4) UV detection: 208-400 nm.

Method 19 (LC/MS): MS instrument type: waters ZQ; HPLC instrument type: waters Alliance 2795; column: phenomenex Onyx Monolithic C18, 100 mm. times.3 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2min 65% A → 4.5min 5% A → 6min 5% A; flow rate: 2 ml/min; furnace: 40 ℃; and (4) UV detection: 210 nm.

Method 20 (preparative HPLC): column: from-Sil 120 ODS-4HE, 10 μm, 250 mm. times.30 mm; eluent A: 0.1% formic acid in water, eluent B: acetonitrile; flow rate: 50 ml/min; the procedure is as follows: 10% B at 0-3min, gradient-95% B at 3-27 min; 27-34min 95% B; 34.01-38min 10% B.

Method 21 (GC/MS): the instrument comprises the following steps: micromass GCT, GC 6890; column: RestekRTX-3515 m.times.200. mu.m.times.0.33. mu.m; constant flow rate with helium: 0.88 ml/min; furnace: 70 ℃; an inlet: 250 ℃; gradient: at 70 deg.C, 30 deg.C/min (310 deg.C (3 min hold)).

Method 22 (LC/MS): MS instrument type: micromass ZQ; HPLC instrument type: waters Alliance 2795; column: phenomenex Synergi 2.5. mu.MAX-RP 100A Mercury 20mm × 4 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 0.1min 90% A → 3.0min 5% A → 4.0min 5% A → 4.01min 90% A; flow rate: 2 ml/min; furnace: 50 ℃; and (4) UV detection: 210 nm.

Method 23 (LC/MS): the instrument comprises the following steps: micromass Quattro LCZ with HPLC Agilent Series 1100; column: phenomenex Synergi 2.5 μ MAX-RP 100AMercury 20mm × 4 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 0.1min 90% A → 3.0min 5% A → 4.0min 5% A → 4.1min 90% A; flow rate: 2 ml/min; furnace: 50 ℃; and (4) UV detection: 208-400 nm.

Method 24 (LC/MS): and (4) an instrument MS: micromass TOF (LCT); HPLC (high Performance liquid chromatography) of an instrument: 2690 of water; an automatic sampler: waters 2700; column: YMC-ODS-AQ, 50 mm. times.4.6 mm, 3.0 μm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; gradient: 0.0min 100% A → 0.2min 95% A → 1.8min 25% A → 1.9min 10% A → 2.0min 5% A → 3.2min 5% A → 3.21min 100% A → 3.35min 100% A; furnace: 40 ℃; flow rate: 3.0 ml/min; and (4) UV detection: 210 nm.

Starting compounds and intermediates:

example 1A

2- [3- (trifluoromethyl) phenyl ] propan-2-amine

14.0g (56.8mmol) of anhydrous cerium (III) chloride are stirred in 60ml of tetrahydrofuran at room temperature for 2 hours under an argon atmosphere. After cooling to-50 ℃ 35.5ml of a 1.6M solution of methyllithium in diethyl ether were slowly added dropwise at this temperature and the mixture was stirred for a further 30 minutes at-50 ℃. 3.24g (18.9mmol) of 3-trifluoromethylbenzonitrile dissolved in 30ml of tetrahydrofuran are then added dropwise at-50 ℃ so that it can be warmed slowly to room temperature and then stirred overnight. For work-up, 20ml of 25% aqueous ammonia solution are added, the mixture is filtered through kieselguhr and the eluate is concentrated in vacuo. The residue was taken up in ethyl acetate and extracted twice with 1N hydrochloric acid. The combined aqueous phases were adjusted to pH12 with 1N aqueous sodium hydroxide and extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate and 3.41g (98% of theory) of the target compound remain after removal of the solvent in vacuo.

LC/MS [ method 3 ]]：R_t＝2.44min

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.39(s，6H)，2.01(br.s，2H)，7.48-7.56(m，2H)，7.78-7.85(m，1H)，7.90(s，1H).

Example 2A

2- (4-chlorobenzoyl) -N-cyclopropylsemicarbazide

4.00g (23.4mmol) of 4-chlorobenzoyl hydrazine is placed in 50ml of tetrahydrofuran under argon. 1.95g (23.4mmol) of cyclopropyl isocyanate dissolved in 50ml of tetrahydrofuran are added dropwise at 50 ℃ and the mixture is stirred further overnight at 50 ℃. The solvent was evaporated in vacuo, diethyl ether was added to the residue and the solid formed was isolated and purified by filtration and washed with diethyl ether. Thus 5.92g (about 100% of theory) of the target compound are obtained.

HPLC [ method 2 ]]：R_t＝3.69min

MS[CIpos]：m/z＝371(M+NH₄)⁺，354(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ is 0.33-0.46(m, 2H), 0.51-0.65(m, 2H), 2.44-2.52(m, 1H), 6.69(s, 1H), 7.55, 7.57(AA 'part of the AA' BB 'system, 2H), 7.88(s, 1H), 7.88, 7.90 (BB' part of the AA 'BB' system, 2H), 10.16(s, 1H).

The following compounds were obtained identically:

example 8A

2- (3-chlorobenzoyl) -N-cyclopropylsemicarbazide

430mg (2.52mmol) of 3-chlorobenzoyl hydrazine are placed in 6ml of tetrahydrofuran under argon. 209mg (2.52mmol) of cyclopropyl isocyanate dissolved in 2ml of tetrahydrofuran are added dropwise and stirring is further carried out at room temperature overnight. Concentrated and purified by stirring the residue with diethyl ether, filtered, further washed with diethyl ether and dried in vacuo. 514mg (80% of theory) of the target compound are thus obtained.

LC/MS [ method 5 ]]：R_t＝1.41min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.34-0.46(m，2H)，0.51-0.65(m，2H)，2.44-2.56(m，1H)，6.71(s，1H)，7.52(t，1H)，7.64(dd，1H)，7.83(d，1H)，7.91(d，1H)，7.92(s，1H)，10.19(s，1H).

The following compounds were obtained identically:

example 10A

2- (2-chlorobenzoyl) -N-cyclopropylsemicarbazide

10.0g (58.6mmol) of 2-chlorobenzoyl hydrazine is placed in 50ml of tetrahydrofuran under argon. 4.87g (58.6mmol) of cyclopropyl isocyanate in 50ml of tetrahydrofuran are added dropwise at 50 ℃ and the mixture is stirred further overnight at 50 ℃. After cooling to room temperature, the precipitate formed is filtered off and then washed with diethyl ether. 13.9g (93% of theory) of the target compound are thus obtained.

LC/MS [ method 7 ]]：R_t＝1.01min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.33-0.45(m，2H)，0.53-0.67(m，2H)，2.45-2.53(m，1H)，6.47(d，1H)，7.39-7.55(m，4H)，8.00(s，1H)，9.95(s，1H).

The following compounds were obtained identically:

example 14A

N-cyclopropyl-2- (2-methoxybenzoyl) -semicarbazide

To 500mg (3.01mmol) of 2-methoxybenzoyl hydrazine dissolved in 7ml of THF are added dropwise 250mg (3.01mmol) of cyclopropyl isocyanate dissolved in 3ml of THF, and the mixture is stirred at room temperature overnight. The resulting precipitate was filtered off, washed with diethyl ether and dried in vacuo. 709mg (94% of theory) of the target compound are thus obtained.

LC/MS [ method 5 ]]：R_t＝1.27min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.32-0.45(m，2H)，0.53-0.66(m，2H)，2.45-2.53(m，1H)，3.88(s，3H)，7.05(t，1H)，7.15(d，1H)，7.50(ddd，1H)，6.49(br.s，1H)，7.72(dd，1H)，7.99(d，1H)，9.62(d，1H).

The following were obtained identically:

example 15A

N-ethyl-2- (4-methoxybenzoyl) -semicarbazide

LC/MS [ method 5 ]]：R_t＝1.14min

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.00(t，3H)，3.05(dq，2H)，3.81(s，3H) 6.43(br.s, 1H), 7.00, 7.02(AA 'part of the AA' BB 'system, 2H), 7.73(s, 1H), 7.86, 7.88 (BB' part of the AA 'BB' system, 2H), 9.94(s, 1H).

Example 16A

2- (2-chlorobenzoyl) -N- (4-methoxyphenylmethyl) -semicarbazide

2.50g (14.7mmol) of 4-chlorobenzoyl hydrazine is placed in 30ml of tetrahydrofuran at room temperature. To this suspension 2.50g (15.3mmol) of 4-methoxyphenylmethyl isocyanate in 6ml of tetrahydrofuran are added dropwise rapidly with stirring. The mixture was stirred at room temperature for a further 6 hours and then allowed to stand for about 65 hours. After which 50ml of diethyl ether are added with stirring, the reaction vessel is cooled in an ice/water bath and the precipitate is filtered off, further washed with cold diethyl ether and dried in vacuo. 4.80g (98% of theory) of the target compound are thus obtained.

LC/MS [ method 5 ]]：R_t＝1.87min

¹H-NMR(400MHz，DMSO-d₆): δ — 3.72(s, 3H), 4.17(d, 2H), 6.85, 6.87(AA 'part of AA' BB 'system, 2H), 7.03(br.t, 1H), 7.18, 7.20 (BB' part of AA 'BB' system, 2H), 7.56, 7.58(AA 'part of AA' BB 'system, 2H), 7.90, 7.93 (BB' part of AA 'BB' system, 2H), 7.96(s, 1H), 10.24(s, 1H).

Example 17A

2- (4-chlorobenzoyl) -N- (3-fluorophenylmethyl) -semicarbazide

In 10ml of tetrahydrofuran, 553mg (3.24mmol) of 3-chlorobenzoyl hydrazine were placed at room temperature. To this suspension 500mg (3.31mmol) of 3-fluorophenyl methyl isocyanate dissolved in 5ml of tetrahydrofuran are rapidly added dropwise with stirring. The mixture was further stirred at room temperature overnight. The reaction mixture was treated with 50ml of diethyl ether, and the precipitate was recovered by filtration, followed by washing with diethyl ether and drying in vacuo. 965mg (92% of theory) of the target compound are thus obtained.

LC/MS [ method 8 ]]：R_t＝2.00min

¹H-NMR(400MHz，DMSO-d₆): δ ═ 4.26(d, 2H), 6.98-7.12(m, 3H), 7.20(br.s, 1H), 7.34(q, 1H), 7.56, 7.58(AA 'part of the AA' BB 'system, 2H), 7.91, 7.94 (BB' part of the AA 'BB' system, 2H), 8.08(s, 1H), 10.28(s, 1H).

Similar to the three above examples, the following were obtained:

example 32A

2- (3-bromobenzoyl) -N-isobutylsemicarbazide

5.00g (23.3mmol) of 3-bromobenzoyl hydrazine was placed in 50ml of tetrahydrofuran at room temperature. To this suspension 2.70g (27.2mmol) of isobutyl isocyanate dissolved in 10ml of tetrahydrofuran are rapidly added dropwise with stirring. The mixture was first stirred further at room temperature and then allowed to stand overnight. After addition of 100ml of diethyl ether, the precipitate formed is filtered off and then washed with diethyl ether. Thus 1.42g (19% of theory) of the initial amount of the target compound are obtained. The mother liquor was concentrated and the residue was slurried again in diethyl ether and filtered. After washing with diethyl ether and drying in vacuo, 5.62g (77% of theory) of the title compound remain.

LC/MS [ method 5 ]]：R_t＝1.78min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.83(d，6H)，2.85(t，2H)，6.56(br.t，1H)，7.46(t，1H)，7.77(d，1H)，7.82(s，1H)，7.88(d，1H)，8.07(s，1H)，10.22(s，1H).

Example 33A

2- (2-phenylbenzoyl) -N-isobutylsemicarbazide

1.00g (4.71mmol) of 2-phenylbenzoylhydrazine is placed in 10ml of tetrahydrofuran at room temperature. 0.51g (5.15mmol) of isobutyl isocyanate dissolved in 2ml of tetrahydrofuran are added dropwise rapidly with stirring. The mixture was first stirred further at room temperature and then allowed to stand overnight. Addition of equal volumes of diethyl ether and 10ml of cyclohexane resulted in the separation of a small amount of solid, which was filtered off and discarded. Concentration of the filtrate gave 1.53g (about 100% of theory) of a slightly THF-moist product, which was further used as such.

LC/MS [ method 8 ]]：R_t＝2.1min。

Example 34A

2- (4-chlorobenzoyl) -N-methylaminourea

To 500mg (2.93mmol) of 4-chlorobenzoyl hydrazine in 15ml of dichloromethane were added 575mg (2.93mmol) of 4-nitrophenyl methylcarbamate and 417mg (3.22mmol) of N, N-diisopropylethylamine and the mixture was stirred at room temperature overnight. Concentrated, the residue is purified by preparative HPLC [ method 9] and 410mg (61% of theory) of the target compound are thus obtained.

LC/MS [ method 5 ]]：R_t＝1.24min

¹H-NMR(400MHz，DMSO-d₆): δ ═ 2.57(d, 3H), 6.45(br.d, 1H), 7.56, 7.58(AA 'part of the AA' BB 'system, 2H), 7.89(br.s, 1H), 7.89, 7.91 (BB' part of the AA 'BB' system, 2H), 10.19(s, 1H).

Example 35A

N-methyl-2- (4-methylbenzoyl) -semicarbazide

To 500mg (3.33mmol) of 4-methylbenzoyl hydrazine in 15ml of dichloromethane were added 653mg (3.33mmol) of 4-nitrophenyl methylcarbamate and 473mg (3.22mmol) of N, N-diisopropylethylamine and the mixture was stirred at room temperature overnight. The precipitate formed was recovered by filtration, washed with diethyl ether and dried in vacuo. Thus 602mg (87% of theory) of the target compound are obtained.

LC/MS [ method 7 ]]：R_t＝0.94min。

Example 36A

5- (4-chlorophenyl) -4-cyclopropyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one

14.65g (57.7mmol) of 2- (4-chlorobenzoyl) -N-chloropropylaminourea from example 2A are heated under reflux in 60ml of 2N aqueous sodium hydroxide overnight. After cooling, the mixture was acidified to pH1 with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was stirred with dichloromethane and the resulting precipitate was filtered off, washed with dichloromethane and dried in vacuo. 10.9g (69% of theory) of the target compound are thus obtained.

LC/MS [ method 7 ]]：R_t＝1.57min

¹H-NMR(400MHz，DMSO-d₆): δ -0.50-0.62 (m, 2H), 0.79-0.93(m, 2H), 3.10(dddd, 1H), 7.57, 7.59(AA 'part of AA' BB 'system, 2H), 7.79, 7.81 (BB' part of AA 'BB' system, 2H)，11.85(s，1H).

Example 37A

4-cyclopropyl-5- (2-fluorophenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one

0.89g (3.75mmol) of 2- (2-fluorobenzoyl) -N-cyclopropylsemicarbazide from example 3A was heated under reflux in 3.75ml of 2N aqueous sodium hydroxide for approximately 45 h. To complete the reaction, 5ml of 6N aqueous sodium hydroxide were further added and the mixture was heated again at reflux for 6 hours. After cooling, it was acidified with 1N hydrochloric acid with stirring and the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. 0.74g (73% of theory) of the target compound are thus obtained, which is reacted further without further purification.

LC/MS [ method 4 ]]：R_t＝1.66min。

Example 38A

4-cyclopropyl-5- (2, 4-difluorophenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one

1.00g (3.92mmol) of N-cyclopropyl-2- (2, 4-difluorobenzoyl) -semicarbazide from example 5A were heated under reflux in 4ml of 4N aqueous sodium hydroxide for 28 h. After cooling, it was acidified to about pH2 with 2N and diluted with water and extracted four times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, concentrated and the residue was dried in vacuo. Thus 0.415g (31% of theory) of the target compound are obtained, which is likewise reacted further.

LC/MS [ method 7 ]]：R_t＝1.38min。

Example 39A

5- (2-chlorophenyl) -4-cyclopropyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one

7.00g (27.6mmol) of 2- (2-chlorobenzoyl) -N-cyclopropylsemicarbazide from example 10A were heated under reflux in 30ml of 3N aqueous sodium hydroxide for approximately 60 h (tested for conversion by LC/MS analysis). After cooling, it was acidified with 1N hydrochloric acid and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. 3.32g (48% of theory) of the target compound are thus obtained.

LC/MS [ method 7 ] ]：R_t＝1.38min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.49-0.56(m，2H)，0.60-0.67(m，2H)，2.80(dddd，1H)，7.46-7.67(m，4H)，11.86(br.s，1H).

The following were obtained identically:

the following [ method 9] is obtained identically after further purification by preparative HPLC:

example 49A

5- (4-chlorophenyl) -4- (2-methoxyethyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one

1.28g (4.71mmol) of 2- (4-chlorobenzoyl) -N- (2-methoxyethyl) -semicarbazide from example 13A were heated under reflux in 10ml of 3N aqueous sodium hydroxide overnight. After cooling, it is acidified with 1N hydrochloric acid to approximately pH2.5 with ice-cooling and the precipitate formed is filtered off and dried in vacuo. 1.09g (92% of theory) of the target compound are thus obtained, which is reacted without further purification.

LC/MS [ method 7 ]]：R_t＝1.53min

¹H-NMR(400MHz，DMSO-d₆): δ — 3.11(s, 3H), 3.45(t, 2H), 3.83(t, 2H), 7.58, 7.60(AA 'part of AA' BB 'system, 2H), 7.70, 7.72 (BB' part of AA 'BB' system, 2H), 11.98(s, 1H).

The following were obtained identically:

the following [ method 12] is obtained identically after further purification by preparative HPLC:

example 63A

4-cyclopropyl-5- (2-methoxyphenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one

700mg (2.81mmol) of N-cyclopropyl-2- (2-methoxybenzoyl) -semicarbazide from example 14A are heated under reflux in 10ml of 3N aqueous sodium hydroxide overnight. After cooling, it is acidified to pH5-6 with dilute hydrochloric acid and the mixture is concentrated and the residue is purified by preparative HPLC [ method 12 ]. Thus 240mg (37% of theory) of the target compound are obtained.

LC/MS [ method 5 ]]：R_t＝1.49min

¹H-NMR(400MHz，DMSO-d₆): δ is 0.37-0.50(m, 2H), 0.53-0.67(m, 2H), 2.76(dddd, 1H), 3.84(s, 3H), 7.05(t, 1H), 7.17(t, 1H), 7.34(dd, 1H), 7.53(ddd, 1H), approximately 11.5-12 (wide, 1H).

Example 64A

5- (4-chlorophenyl) -4-methyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one

400mg (1.78mmol) of 2- (4-chlorobenzoyl) -N-methylsulfamide from example 34A in 7ml of 3N aqueous sodium hydroxide are heated at reflux overnight. After cooling, the pH is adjusted to about 11 with aqueous citric acid and the precipitate formed is filtered off, washed with water and dried in vacuo. 350mg (95% of theory) of the target compound are thus obtained.

LC/MS [ method 7 ]]：R_t＝1.39min

¹H-NMR(400MHz，DMSO-d₆): δ — 3.24(s, 3H), 7.59, 7.61(AA 'part of AA' BB 'system, 2H), 7.71, 7.73 (BB' part of AA 'BB' system, 2H), 11.96(s, 1H).

The following were obtained identically:

example 68A

[3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid ethyl ester

To 500mg (2.12mmol) of 5- (4-chlorophenyl) -4-cyclopropyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one from example 36A and 260mg (2.12mmol) of ethyl chloroacetate in 10ml of acetonitrile are added 586mg (4.24mmol) of potassium carbonate and the mixture is heated under reflux for 2 hours with stirring. After concentration, the residue taken up in water is extracted with dichloromethane, the organic phase is dried over sodium sulfate and concentrated once more. Purification by flash chromatography on silica gel (eluent: first dichloromethane and then dichloromethane/methanol 100: 1) gives 448mg (66% of theory) of the target compound.

MS[CIpos]：m/z＝339(M+NH₄)⁺，322(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ is 0.50-0.64(m, 2H), 0.83-0.97(m, 2H), 1.21(t, 3H), 3.21(dddd, 1H), 4.15(q, 2H), 4.62(s, 2H), 7.59, 7.61(AA 'part of AA' BB 'system, 2H), 7.81, 7.83 (BB' part of AA 'BB' system, 2H).

Example 69A

[3- (4-chlorophenyl) -4- (2-methoxyethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid ethyl ester

To 1.09g (4.30mmol) of 5- (4-chlorophenyl) -4- (2-methoxyethyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one from example 49A and 1.19g (8.59mmol) of potassium carbonate in 20ml of acetonitrile are added 527mg (4.30mmol) of ethyl chloroacetate and the mixture is heated at reflux for 3 hours with stirring. The crude product produced is purified by preparative HPLC [ method 9] to yield 810mg (42% of theory) of the target compound.

LC/MS [ method 5 ]]：R_t＝2.16min

¹H-NMR(400MHz，DMSO-d₆): δ is 1.21(t, 3H), 3.11(s, 3H), 3.47(t, 2H), 3.89(t, 2H), 4.16(q, 2H), 4.67(s, 2H), 7.60, 7.63(AA 'part of AA' BB 'system, 2H), 7.72, 7.74 (BB' part of AA 'BB' system, 2H).

The following are obtained identically after purification by preparative HPLC [ method 11 ]:

the following are obtained identically after purification by preparative HPLC [ method 12 ]:

example 78A

[3- (4-chlorophenyl) -4- (4-methoxyphenylmethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid ethyl ester

To 2.90g (9.18mmol) of 5- (4-chlorophenyl) -4- (4-methoxyphenylmethyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one from example 55A and 1.13g (9.18mmol) of ethyl chloroacetate in 60ml of acetonitrile are added 2.54g (18.4mmol) of potassium carbonate and the mixture is heated under reflux overnight with stirring. After concentration, the residue was partitioned between ethyl acetate and water and the aqueous phase was extracted three more times with ethyl acetate. The organic phases, which are combined by evaporation and dried over magnesium sulfate, yield 3.58g (97% of theory) of the title compound.

LC/MS [ method 8 ]]：R_t＝2.54min

¹H-NMR(400MHz，DMSO-d₆): δ is 1.22(t, 3H), 3.70(s, 3H), 4.18(q, 2H), 4.73(s, 2H), 4.94(s, 2H), 6.83, 6.85(AA 'part of AA' BB 'system, 2H), 6.97, 6.99 (BB' part of AA 'BB' system, 2H), 7.55 (center of AA 'BB' system, 4H).

The following were obtained identically:

the following are obtained identically after further purification by preparative HPLC [ method 12 ]:

example 84A

[ 4-isobutyl-5-oxo-3- (3-thienyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid methyl ester

LC/MS [ method 8 ] ]：R_t＝2.06min。

Example 85A

Rac-ethyl 2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] propionate

To 500mg (2.12mmol) of 5- (4-chlorophenyl) -4-cyclopropyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one from example 36A in 5ml acetonitrile were added 384mg (2.12mmol) ethyl 2-bromopropionate and 1.38g (4.24mmol) cesium carbonate and the reaction mixture was heated at 85 ℃ overnight. After concentration in vacuo, the residue was partitioned between water and dichloromethane and the separated organic phase was dried over sodium sulfate and evaporated again. After purification of the residue by flash chromatography on silica gel (eluent: first dichloromethane and then dichloromethane/methanol 200: 1), 729mg (97% of theory) of the target compound are obtained.

HPLC [ method 2 ]]：R_t＝4.47min

MS[CIpos]：m/z＝353(M+NH₄)⁺，336(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.49-0.65(m, 2H), 0.84-0.96(m, 2H), 1.16(t, 3H), 1.56(d, 3H), 3.21(dddd, 1H), 4.12(q, 2H), 4.94(q, 1H), 7.59, 7.61(AA 'part of the AA' BB 'system, 2H), 7.81, 7.83 (BB' part of the AA 'BB' system, 2H).

The following are obtained identically after further purification by preparative HPLC:

example 86A

2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -2-methyl-propionic acid ethyl ester

HPLC [ method 2 ]]：R_t＝4.75min

MS[CIpos]：m/z＝367(M+NH₄)⁺，350(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ is 0.48-0.61(m, 2H), 0.82-0.96(m, 2H), 1.15(t, 3H), 1.64(s, 6H), 3.17(dddd, 1H), 4.12(q, 2H), 7.59, 7.61(AA 'part of AA' BB 'system, 2H), 7.81, 7.84 (BB' part of AA 'BB' system, 2H).

Example 87A

3- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] propionic acid ethyl ester

To 500mg (2.12mmol) of 5- (4-chlorophenyl) -4-cyclopropyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one from example 36A in 5ml of acetonitrile are added 290mg (2.12mmol) of ethyl 3-chloropropionate and 586mg (4.24mmol) of potassium carbonate and the reaction mixture is heated at 85 ℃ overnight. 1.38g (4.24mmol) cesium carbonate and a spatula tip of potassium iodide were added and the mixture was stirred at 85 ℃ for a further 4 hours. After concentration in vacuo, the residue was partitioned between water and dichloromethane and the separated organic phase was dried over sodium sulfate and evaporated again. After purification of the residue by flash chromatography on silica gel (eluent: first dichloromethane and then dichloromethane/methanol 100: 1), 580mg (80% of theory) of the target compound are obtained.

HPLC [ method 2 ]]：R_t＝4.18min

MS[ESIpos]：m/z＝336(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ is 0.50-0.63(m, 2H), 0.81-0.95(m, 2H), 1.15(t, 3H), 3.15(dddd, 1H), 2.72(t, 2H), 3.96(t, 2H), 4.05(q, 2H), 7.58, 7.60(AA 'part of AA' BB 'system, 2H), 7.78, 7.80 (BB' part of AA 'BB' system, 2H).

Example 88A

[ [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid

The method A comprises the following steps:

4.84g (15.0mmol) of [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid ethyl ester from example 69A are placed in 12ml of methanol and stirred at room temperature for 2 hours with 4ml of 20% aqueous potassium hydroxide. Concentrated and adjusted to about pH1 with 2N hydrochloric acid. The precipitated solid was filtered off, washed with water and dichloromethane and then dried in vacuo. 4.06g (95% of theory) of the target compound are thus obtained.

MS[ESIpos]：m/z＝294(M+H)⁺；[ESIneg]：m/z＝292(M-H)^-

¹H-NMR(400MHz，DMSO-d₆): δ is 0.50-0.64(m, 2H), 0.82-0.97(m, 2H), 3.20(dddd, 1H), 4.47(s, 2H), 7.58, 7.61(AA 'part of AA' BB 'system, 2H), 7.81, 7.83 (BB' part of AA 'BB' system, 2H).

The method B comprises the following steps:

to 700mg (2.97mmol) of 5- (4-chloro-phenyl) -4-cyclopropyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one from example 49A and 821mg (5.94mmol) of potassium carbonate in 14.6ml of acetonitrile are added 364mg (2.97mmol) of ethyl chloroacetate and the mixture is heated under reflux for 3 hours with stirring. After this time, it was concentrated, taken up in 10ml of methanol, 1ml of 20% aqueous potassium hydroxide was added, and the mixture was stirred at room temperature for 4 hours. For work-up, the reaction mixture was diluted with water, acidified to about pH3 with 2N hydrochloric acid and then extracted five times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. 684mg (79% of theory) of the target compound are thus obtained.

The following were obtained identically for example 88A/method a:

example 95A

[ 4-cyclopropyl-3- (2-methoxyphenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid

In 0.3ml of methanol was placed 140mg (0.44mmol) of ethyl [ 4-cyclopropyl-3- (2-methoxyphenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetate from example 72A and stirred overnight at room temperature with 0.12ml of 20% aqueous potassium hydroxide. Then concentrated and adjusted to about pH1 with 1N hydrochloric acid. The precipitated solid was filtered off, washed with diethyl ether and then dried in vacuo. Thus 81mg (63% of theory) of the target compound are obtained.

HPLC [ method 1]：R_t＝3.61min

MS[ESIpos]：m/z＝290(M+H)⁺；[ESIneg]：m/z＝288(M-H)^-

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.38-0.51(m，2H)，0.57-0.72(m，2H)，2.86(dddd，1H)，3.86(s，3H)，4.46(s，2H)，7.06(t，1H)，7.19(d，1H)，7.33(d，1H)，7.55(t，1H)，13.07(br.s，1H).

Example 96A

[3- (4-chlorophenyl) -4- (4-methoxyphenylmethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid

Ethyl [3- (4-chlorophenyl) -4- (4-methoxyphenylmethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetate from example 78A (3.58 g) (8.91mmol) was placed in 40ml of methanol and stirred overnight at room temperature with 4ml of 20% aqueous potassium hydroxide. Adjusted to pH6 with 1N hydrochloric acid and purified by preparative HPLC [ method 12 ]. Thus 2.71g (81% of theory) of the target compound are obtained.

LC/MS [ method 5 ] ]：R_t＝1.94min

¹H-NMR(400MHz，DMSO-d₆): δ — 3.70(s, 3H), 4.60(s, 2H), 4.93(s, 2H), 6.83, 6.85(AA 'part of AA' BB 'system, 2H), 6.98, 7.00 (BB' part of AA 'BB' system, 2H), 7.56 (center of AA 'BB' system, 4H), 13.19(br.s, 1H).

The following were obtained identically:

the following were obtained identically for example 88A/method B:

example 104A

[3- (3-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid

LC/MS [ method 8 ]]：R_t＝1.92min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.52-0.66(m，2H)，0.82-0.97(m，2H)，3.25(dddd，1H)，7.56(t，1H)，7.62(br.d，1H)，7.77(d，1H)，7.83(br.s，1H)，13.17(br.s，1H).

Example 105A

Rac-2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] propionic acid

630mg (1.88mmol) of rac-ethyl-2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] propionate from example 85A are placed in 8ml of methanol and treated with 4ml of 20% aqueous potassium hydroxide and stirred at room temperature for 2 hours. The methanol was removed in vacuo, the aqueous residue was acidified with 2N hydrochloric acid, extracted with dichloromethane, and the organic phase was dried over sodium sulfate and evaporated in vacuo. 463mg (80% of theory) of the target compound are thus obtained.

HPLC [ method 2 ]]：R_t＝3.96min

MS[ESIpos]：m/z＝307(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ is 0.47-0.68(m, 2H), 0.82-0.97(m, 2H), 1.54(d, 3H), 3.20(dddd, 1H), 4.83(q, 1H), 7.58, 7.60(AA 'part of the AA' BB 'system, 2H), 7.81, 7.83 (BB' part of the AA 'BB' system, 2H), 13.02(s, 1H).

The following were obtained identically:

example 106A

2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -2-methylpropionic acid

HPLC [ method 2 ]]：R_t＝4.17min

MS[ESIpos]：m/z＝322(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ is 0.48-0.61(m, 2H), 0.81-0.95(m, 2H), 1.64(s, 6H), 3.17(dddd, 1H), 7.58, 7.60(AA 'part of AA' BB 'system, 2H), 7.80, 7.83 (BB' part of AA 'BB' system, 2H), 12.88(s, 1H).

Example 107A

3- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] propionic acid

In 1.5ml of methanol was placed 560mg (1.67mmol) of ethyl 3- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] propionate from example 87A, treated with 0.5ml of 20% aqueous potassium hydroxide and stirred at room temperature for 2 hours. The methanol was removed in vacuo, the aqueous residue was acidified to pH1 with 2N hydrochloric acid and the resulting precipitate was isolated by filtration. 439mg (approximately 73% of theory) of the target compound were thus obtained.

HPLC [ method 2 ]]：R_t＝3.81min

MS[ESIpos]：m/z＝308(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ is 0.50-0.63(m, 2H), 0.80-0.97(m, 2H), 2.66(t, 2H), 3.15(dddd, 1H), 3.92(t, 2H), 7.58, 7.60(AA 'part of the AA' BB 'system, 2H), 7.78, 7.80 (BB' part of the AA 'BB' system, 2H), 12.36(s, 1H).

Example 108A

[3- (4-methoxyphenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid ethyl ester

To 479mg (2.00mmol) of N- (ethoxycarbonyl) -4-methoxyphenyl carboxylic thioamide [ E.P.Papadopoulos, J.Org.chem ] in 10ml of ethanol.41(6)，962-965(1976)]618mg (4.00mmol) of hydrazinoacetic acid ethyl ester hydrochloride are added and the mixture is heated at reflux for six hours. After cooling, the resulting suspension was stirred with diethyl ether and the precipitate was isolated by filtration. The crude product is stirred with water, filtered again and dried in vacuo to yield 167mg (30% of theory) of the target compound.

LC/MS [ method 7 ]]：R_t＝1.54min

¹H-NMR(400MHz，DMSO-d₆): δ is 1.21(t, 3H), 3.81(s, 3H), 4.16(q, 2H), 4.57(s, 2H), 7.04, 7.06(AA 'part of AA' BB 'system, 2H), 7.72, 7.74 (BB' part of AA 'BB' system, 2H), 12.20(s, 1H).

Example 109A

4-Ethyl- [3- (4-methoxyphenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid ethyl ester

The method A comprises the following steps:

in 0.5ml dimethylformamide 6.1mg (0.15mmol) sodium hydride (60% in mineral oil) were placed and treated with 40mg (0.14mmol) ethyl [3- (4-methoxyphenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetate from example 108A in 2ml dimethylformamide. Stirring was carried out at room temperature for 10 minutes, after which 22mg (0.012ml, 0.14mmol) of iodoethane were added and stirring was continued at room temperature overnight. For work-up, the reaction mixture is treated with 2ml of water, adjusted to pH2 with 1N hydrochloric acid and purified by preparative HPLC. Thus 4.1mg (9% of theory) of the target compound are obtained.

LC/MS [ method 4 ]]：R_t＝2.20min

¹H-NMR(400MHz，DMSO-d₆): δ is 1.10(t, 3H), 1.21(t, 3H), 3.74(q, 2H), 3.83(s, 3H), 4.15(q, 2H), 4.63(s, 2H), 7.09, 7.11(AA 'part of AA' BB 'system, 2H), 7.72, 7.74 (BB' part of AA 'BB' system, 2H).

In addition, 3.8mg (9% of theory) of ethyl [ 5-ethoxy-3- (4-methoxyphenyl) -1H-1, 2, 4-triazol-1-yl ] -acetate are isolated:

LC/MS [ method 4 ]]：R_t＝2.59min

¹H-NMR(400MHz，DMSO-d₆): δ is 1.21(t, 3H), 1.36(t, 3H), 3.79(s, 3H), 4.17(q, 2H), 4.49(q, 2H), 4.87(s, 2H), 6.98, 7.01(AA 'part of the AA' BB 'system, 2H), 7.82, 7.85 (BB' part of the AA 'BB' system, 2H).

The method B comprises the following steps:

to 200mg (0.912mmol) of 4-ethyl-5- (4-methoxyphenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one from example 66A and 252mg (1.82mmol) of potassium carbonate in 1.8ml of acetonitrile are added 112mg (0.912mmol) of ethyl chloroacetate and the mixture is heated under reflux for 3 hours with stirring. The crude product produced is purified by preparative HPLC to obtain 212mg (76% of theory) of the target compound [ method 9 ].

Example 110A

4-Ethyl- [3- (4-methoxyphenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid

205mg (0.67mmol) of 4-ethyl- [3- (4-methoxyphenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetate from example 109A are dissolved in 0.46ml of methanol, treated with 0.18ml of 20% aqueous potassium hydroxide and stirred overnight. The pH of 1 was next brought about with 1N hydrochloric acid, evaporated and the residue dried in vacuo. 207mg of the title compound are thus obtained as crude product, which is likewise reacted further.

LC/MS [ method 4 ]]：R_t＝1.65min。

The following were obtained identically:

example 111A

4-methyl- [3- (4-methylphenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid

LC/MS [ method 4 ]]：R_t＝1.65min。

Example 112A

2-bromo-1- (4-chlorophenyl) propan-1-one

3000mg (17.791mmol) of 1- (4-chlorophenyl) propan-1-one are placed in 15ml of dichloromethane and treated with one drop of hydrobromic acid. The mixture is stirred at 35 ℃ and 2843mg (17.791mmol) of bromine are added dropwise so that the reaction solution is decolorized again after each addition. Three hours after the start of the reaction, the mixture was evaporated to dryness. 4490mg (96% of theory) of the target compound are obtained.

HPLC [ method 2 ]]：R_t＝4.92min

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.78(d，3H)，5.82(q，1H)，7.64(d，2H)，8.05(d，2H).

Example 113A

N- [2- (4-chlorophenyl) -2-oxoethyl ] -N' -cyclopropylurea

1000mg (4.853mmol) of 2-amino-1- (4-chlorophenyl) ethanone hydrochloride are placed in 20ml of dichloromethane, cooled to 0 ℃ and treated dropwise with a solution of 363mg (4.367mmol) of cyclopropyl isocyanate in 2ml of dichloromethane. Stirring is carried out at 0 ℃ for a further 10 minutes and then a solution of 627mg (4.853mmol) of N, N-diisopropylethylamine in 4ml of dichloromethane is added dropwise. After stirring at room temperature for two hours, the reaction mixture is evaporated and the crude product is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol 100: 1). 1000mg (73% of theory) of the target compound are obtained.

MS[CIpos]：m/z＝270(M+NH₄)⁺

HPLC [ method 2 ]]：R_t＝3.99min。

The following were prepared identically:

example 117A

N- [2- (4-chlorophenyl) -1-methyl-2-oxoethyl ] -glycine ethyl ester

200mg (0.808mmol) of 2-bromo-1- (4-chlorophenyl) propan-1-one from example 112A are dissolved in 1ml of acetonitrile and treated with 226mg (1.616mmol) of glycine ethyl ester hydrochloride and 209mg (1.616mmol) of N, N-diisopropylethylamine. After stirring overnight at room temperature, the reaction mixture was evaporated and the residue was partitioned between water and dichloromethane. The organic phase was separated, dried over sodium sulfate and concentrated. The crude product is purified by flash chromatography on silica gel (eluent: first dichloromethane and then dichloromethane/methanol 200: 1). 91mg (42% of theory) of the target compound are thus obtained.

MS[CIpos]：m/z＝270(M+H)⁺

HPLC [ method 2 ]]：R_t＝3.77min

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.15(t，3H)，1.17(d，3H)，3.33(s，2H)，4.05(q，2H)，4.40(q，1H)，7.61(d，2H)，8.01(d，2H).

Example 118A

5- (4-chlorophenyl) -1-cyclopropyl-1, 3-dihydro-2H-1, 2, 1-imidazol-2-one

1525mg (6.035mmol) of N- [2- (4-chlorophenyl) -2-oxoethyl ] -N' -cyclopropylurea from example 113A are suspended in 25ml of concentrated hydrochloric acid, treated with 25ml of methanol and stirred at room temperature for one hour. The reaction mixture was evaporated to dryness and the residue was purified by flash chromatography on silica gel (eluent: dichloromethane/methanol 100: 1, then 50: 1). 1300mg (90% of theory) of the target compound are obtained.

MS[CIpos]：m/z＝252(M+NH₄)⁺

HPLC [ method 2 ]]：R_t＝3.92min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.46(m，2H)，0.78(m，2H)，2.95(tt，1H)，6.62(d，1H)，7.44(d，2H)，7.54(d，2H)，10.17(s，1H).

The following were prepared identically:

example 121A

5- (4-chlorophenyl) -1-ethyl-1, 3-dihydro-2H-imidazol-2-one

990mg (4.113mmol) of N- [2- (4-chlorophenyl) -2-oxoethyl ] -N' -ethylurea from example 115A are suspended in 16ml of concentrated hydrochloric acid, treated with 16ml of methanol and stirred at room temperature for one hour. The reaction mixture was evaporated to dryness, the residue was extracted with dichloromethane, and the organic phase was dried over sodium sulfate and concentrated again. The crude product is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol 100: 1, then 50: 1) and 701mg (77% of theory) of the target compound are thus obtained.

MS[ESIpos]：m/z＝223(M+H)⁺

HPLC [ method 2 ]]：R_t＝3.94min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.99(t，3H)，3.66(q，2H)，6.60(d，1H)，7.43(d，2H)，7.48(d，2H)，10.28(s，1H).

Example 122A

[4- (4-chlorophenyl) -3-cyclopropyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid ethyl ester

740mg (3.15mmol) of 5- (4-chlorophenyl) -1-cyclopropyl-1, 3-dihydro-2H-imidazol-2-one from example 118A are dissolved in 15ml of acetonitrile and treated with 386mg (3.15mmol) of ethyl chloroacetate and 872mg (6.31mmol) of potassium carbonate. The mixture was stirred at reflux overnight. After concentration, the residue is partitioned between dichloromethane and water, the organic phase is separated and dried over sodium sulfate and concentrated again. The crude product is purified by flash chromatography on silica gel (eluent: first dichloromethane and then dichloromethane/methanol 200: 1 → 100: 1)) and thus yields 602mg (57% of theory) of the target compound.

MS[ESIpos]：m/z＝321(M+H)⁺

HPLC [ method 2 ]]：R_t＝4.33min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.47(m，2H)，0.81(m，2H)，1.21(t，3H)，3.04(tt，1H)，4.14(q，2H)，4.40(s，2H)，6.77(s，1H)，7.47(d，2H)，7.55(d，2H).

Example 123A

(3-cyclopropyl-2-oxo-4-phenyl-2, 3-dihydro-1H-imidazol-1-yl) -acetic acid ethyl ester

270mg (1.35mmol) of 1-cyclopropyl-5-phenyl-1, 3-dihydro-2H-imidazol-2-one from example 119A are dissolved in 5ml of acetonitrile and treated with 165mg (1.35mmol) of ethyl chloroacetate and 373mg (2.70mmol) of potassium carbonate. The mixture was stirred at reflux for 4 hours, after which 165mg (1.35mmol) of ethyl chloroacetate were added. After stirring at reflux overnight the reaction mixture was evaporated. The residue was partitioned between dichloromethane and water, the organic phase was separated and dried over sodium sulfate and concentrated again. The crude product is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200: 1, then 100: 1) and thus yields 353mg (91% of theory) of the target compound.

MS[ESIpos]：m/z＝287(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.47(m，2H)，0.78(m，2H)，1.21(t，3H)，3.04(tt，1H)，4.14(q，2H)，4.40(s，2H)，6.70(s，1H)，7.32(t，2H)，7.42(t，2H)，7.51(d，2H).

Example 124A

[4- (4-bromophenyl) -3-cyclopropyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid ethyl ester

392mg (1.40mmol) of 5- (4-bromophenyl) -1-cyclopropyl-1, 3-dihydro-2H-imidazol-2-one from example 120A are dissolved in 7.7ml of acetonitrile, treated with 172mg (1.40mmol) of ethyl chloroacetate and 388mg (2.81mmol) of potassium carbonate and heated at reflux for two hours. After cooling, filtration, the filtrate was evaporated and the residue was partitioned between ethyl acetate and water, the organic phase was separated, dried over sodium sulfate and concentrated again. 502mg (98% of theory) of the target compound are thus obtained, which are reacted without further purification.

LC/MS [ method 7 ]]：R_t＝2.07min

¹H-NMR(400MHz，DMSO-d₆): δ is 0.40-0.53(m, 2H), 0.74-0.88(m, 2H), 1.21(t, 3H), 3.04(dddd, 1H), 4.14(q, 2H), 4.40(s, 2H), 6.78(s, 1H), 7.47, 7.49(AA 'part of AA' BB 'system, 2H), 7.59, 7.61 (BB' part of AA 'BB' system, 2H).

Example 125A

2- [4- (4-chlorophenyl) -3-cyclopropyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -propionic acid ethyl ester

500mg (2.13mmol) of 5- (4-chlorophenyl) -1-cyclopropyl-1, 3-dihydro-2H-imidazol-2-one from example 118A are dissolved in 5ml of acetonitrile and treated with 386mg (2.13mmol) of ethyl 2-bromopropionate and 1388mg (4.26mmol) of cesium carbonate. The mixture was stirred at reflux overnight. After concentration, the residue is partitioned between dichloromethane and water, the organic phase is separated and dried over sodium sulfate and concentrated again. The crude product is purified by flash chromatography on silica gel (eluent: first dichloromethane and then dichloromethane/methanol 200: 1 → 100: 1)) and thus 338mg (45% of theory) of the target compound are produced.

MS[ESIpos]：m/z＝335(M+H)⁺

HPLC [ method 2 ]]：R_t＝4.50min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.43(m，1H)，0.51(m，1H)，0.81(m，2H)，1.18(t，3H)，2.94(d，3H)，3.04(tt，1H)，4.12(q，2H)，4.74(q，1H)，6.92(s，1H)，7.47(d，2H)，7.58(d，2H).

Example 126A

[4- (4-chlorophenyl) -3-cyclopropyl-5-methyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid ethyl ester

355mg (1.32mmol) of N- [2- (4-chlorophenyl) -1-methyl-2-oxoethyl ] -glycine ethyl ester from example 117A are taken in 5ml of tetrahydrofuran, treated with 109mg (1.32mmol) of cyclopropyl isocyanate and stirred at room temperature overnight. The reaction mixture was evaporated and the residue was purified by flash chromatography on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 200: 1 → 100: 1). 425mg (91% of theory) of the target compound are thus obtained.

MS[ESIpos]：m/z＝335(M+H)⁺

HPLC [ method 1]：R_t＝4.49min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.14(m，1H)，0.25(m，1H)，0.39(m，1H)，0.78(m，1H)，1.21(t，3H)，2.23(tt，1H)，2.50(s，3H)，3.32(s，2H)，4.11(q，2H)，7.45(d，2H)，7.51(d，2H).

Example 127A

[4- (4-chlorophenyl) -3-ethyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid

685mg (3.076mmol) of 5- (4-chlorophenyl) -1-ethyl-1, 3-dihydro-2H-imidazol-2-one from example 119A are placed in 10ml of acetonitrile, treated with 377mg (3.076mmol) of ethyl chloroacetate and 850mg (6.152mmol) of potassium carbonate and stirred at reflux overnight. The reaction mixture was evaporated, the residue partitioned between dichloromethane and water, the organic phase separated and dried over sodium sulfate and concentrated again. The crude product is purified by flash chromatography on silica gel (eluent: first dichloromethane and then dichloromethane/methanol 100: 1 → 50: 1) and thus yields 226mg (26% of theory) of the target compound.

MS[ESIpos]：m/z＝281(M+H)⁺

HPLC [ method 2 ]]：R_t＝3.89min

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.02(t，3H)，3.69(q，2H)，4.13(s，2H)，6.70(s，1H)，7.41(d，2H)，7.49(d，2H)，10.30(br.s，1H).

Example 128A

(3-cyclopropyl-2-oxo-4-phenyl-2, 3-dihydro-1H-imidazol-1-yl) -acetic acid

350mg (1.222mmol) of ethyl (3-cyclopropyl-2-oxo-4-phenyl-2, 3 dihydro-1H-imidazol-1-yl) -acetate from example 123A are taken up in 2ml of methanol, treated with 0.5ml of 20% aqueous potassium hydroxide and stirred at room temperature for two hours. The methanol was removed on a rotary evaporator and the residue was acidified with 2N hydrochloric acid and extracted with dichloromethane. The organic phase was separated, dried over sodium sulfate and concentrated. Purification was carried out by flash chromatography on silica gel (eluent: dichloromethane/methanol first 50: 1, then 25: 1). 166mg (53% of theory) of the target compound are thus obtained.

MS[ESIpos]：m/z＝259(M+H)⁺

HPLC [ method 2 ]]：R_t＝3.84min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.47(m，2H)，0.78(m，2H)，3.04(tt，1H)，4.30(s，2H)，6.69(s，1H)，7.32(t，1H)，7.41(t，2H)，7.51(d，2H)，12.96(br.s，1H).

Example 129A

[4- (4-bromophenyl) -3-cyclopropyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid

502mg (1.28mmol) of ethyl [4- (4-bromophenyl) -3-cyclopropyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl) -acetate from example 124A are taken up in 0.94ml of methanol, treated with 0.34ml of 20% aqueous potassium hydroxide and stirred at room temperature overnight. Adjusted to pH3 with 1N hydrochloric acid, the resulting precipitate was recovered by filtration, and the product was washed with water and dried in vacuo. 369mg (80% of theory) of the target compound are thus obtained, which are reacted without further purification.

LC/MS [ method 7 ]]：R_t＝1.71min

¹H-NMR(400MHz，DMSO-d₆): δ is 0.40-0.53(m, 2H), 0.74-0.88(m, 2H), 3.03(dddd, 1H), 4.30(s, 2H), 6.78(s, 1H), 7.46, 7.49(AA 'part of the AA' BB 'system, 2H), 7.59, 7.61 (BB' part of the AA 'BB' system, 2H), 12.98(br.s, 1H).

The following were prepared identically:

example 133A

2-chloro-N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide

2.5g (12.3mmol) of the compound from example 1A and 1.70g (12.3mmol) of potassium carbonate are placed in 30ml of dichloromethane and slowly treated at RT with a solution of 1.46g (12.9mmol) of chloroacetyl chloride in 5ml of dichloromethane. The mixture was stirred at RT for 3 hours and then treated with 150ml of water and slowly with 30ml of 1N hydrochloric acid. Extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate and the solvent was removed on a rotary evaporator. Thus 2.65g (77% of theory) of the title compound are obtained.

LC/MS [ method 17 ]]：R_t＝3.37min；m/z＝280(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.59(s，6H)，4.05(s，2H)，7.50-7.67(m，4H)，8.60(s，1H).

Example 134A

2-chloro-N- [2- (trifluoromethyl) benzyl ] acetamide

Analogously to example 133A, 2.43g (68% of theory) of the title compound are obtained from 2.5g (14.3mmol) of 2-trifluoromethylbenzylamine and 1.69g (15.0mmol) of chloroacetyl chloride.

LC/MS [ method 18 ]]：R_t＝2.00min；m/z＝252(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.18(s，2H)，4.49(d，J＝6Hz，2H)，7.47-7.52(m，2H)，7.68(t，J＝7.5Hz，1H)，7.73(d，J＝7.8Hz，1H)，8.81(br.t，1H).

Example 135A

5-bromo-4- (2-fluorobenzyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one

Step a):preparation of N- (2-fluorobenzyl) -2-formyl semicarbazide

Under argon, 1.99g (33mmol) of formylhydrazine are placed in 80ml of THF. The solution was heated to 50 ℃ and treated dropwise with a solution of 5.00g (33mmol) of 2-fluorobenzyl isocyanate in 50ml of THF and the resulting mixture was stirred at 50 ℃ for a further 30 minutes. The solvent was then removed on a rotary evaporator. The residue is stirred with diethyl ether, the precipitate is filtered off with suction, then washed with diethyl ether and the white solid is dried under high vacuum. 5.73g (82% of theory) of the target product are obtained.

LC/MS [ method 7 ]]：R_t＝0.88min；m/z＝212(M+H)⁺。

Step b):preparation of 4- (2-fluorobenzyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one

The product from step a (5.73g, 27.1mmol) was stirred in 60ml of 3M aqueous sodium hydroxide under reflux for 5 hours. The mixture was then cooled in an ice bath and slowly acidified to pH2 with 1N hydrochloric acid. The precipitated solid is filtered off under suction, then washed with water and dried under high vacuum. 3.38g (64% of theory) of the target product are obtained.

LC/MS [ method 17 ]]：R_t＝1.35min；m/z＝194(M+H)⁺。

Step c):preparation of 5-bromo-4- (2-fluorobenzyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one

The product from step b (3.35g, 17.3mmol) was placed in 37ml of water together with sodium hydroxide (970mg, 24.2 mmol). Bromine (893. mu.l, 17.3mmol) was added dropwise at RT with stirring. During the addition, a light brown solid precipitated. Stirring was continued overnight at RT. The precipitated solid is filtered off with suction, washed with a little more water and then dried under high vacuum. 4.25g of the target product are obtained with sufficient purity (about 83% by LC/MS).

LC/MS [ method 8 ]]：R_t＝1.81min；m/z＝272(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.84(s，2H)，7.14-7.28(m，3H)，7.35-7.42(m，1H)，12.22(s，1H).

Example 136A

5-bromo-4- (2-methoxyethyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one

The title compound was prepared in analogy to the synthetic sequence described for example 135A starting from 2-methoxyethyl isocyanate.

LC/MS [ method 3 ]]：R_t＝2.12min；m/z＝222(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.24(s，3H)，3.51(d，J＝5.5Hz，2H)，3.72(d，J＝5.5Hz，2H)，12.10(s，1H).

Example 137A

5-bromo-4- (3-fluorobenzyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one

The title compound was prepared in analogy to the synthetic sequence described for example 135A starting from 3-fluorobenzyl isocyanate.

LC/MS [ method 8 ]]：R_t＝1.79min；m/z＝272(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.81(s，2H)，7.04-7.12(m，2H)，7.15(dt，1H)，7.43(q，1H)，12.3(s，1H).

Example 138A

[ 3-bromo-4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid methyl ester

300mg (1.1mmol) of the compound from example 135A together with 150mg (1.38mmol) of methyl chloroacetate and 168mg (1.21mmol) of potassium carbonate in 10ml of acetonitrile are stirred at reflux for 2 hours. After cooling, the mixture was diluted with ethyl acetate and treated with 1N hydrochloric acid. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulfate and freed of volatile constituents on a rotary evaporator. The residue was dried under high vacuum. The product thus obtained (360mg, purity by LC/MS approx 73%) was used without further purification in the next synthetic step.

LC/MS [ method 17 ]]：R_t＝2.83min；m/z＝344(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.70(s，3H)，4.59(s，2H)，4.92(s，2H)，7.15-7.30(m，3H)，7.35-7.43(m，1H).

Example 139A

[ [ 3-bromo-4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid

The compound from example 138A (360mg) was dissolved in 10ml methanol and treated with 4.2ml 1M aqueous lithium hydroxide. The mixture was stirred at RT overnight and then methanol was removed. The residue was diluted with 200ml of water and slowly acidified with 1N hydrochloric acid to pH 2. The aqueous phase was extracted three times with ethyl acetate, the combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue was dissolved in a little DMSO and purified by preparative HPLC (method 20). 246mg (0.75mmol) of the title compound are obtained

LC/MS [ method 19 ]]：R_t＝2.00min：m/z＝330(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.53(s，2H)，4.91(s，2H)，7.15-7.30(m，3H)，7.35-7.45(m，1H)，13.10(br.s，1H).

Example 140A

2- [ 3-bromo-4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- {2- [ (2-trifluoromethyl) phenyl ] ethyl } -acetamide

246mg (0.64mmol) of the compound from example 139A and 121mg of HOBt (0.90mmol) are placed in 5ml of DMF and treated with 172mg of EDC (0.90 mmol). After stirring for 20 min at RT, 2- (2-trifluoromethylphenyl) ethylamine (139mg, 0.74mmol) was added and the mixture was stirred for a further 1h at RT. The reaction mixture was then separated directly by preparative HPLC (method 20). 321mg (99% of theory) of the title compound are isolated.

LC/MS [ method 17 ]]：R_t＝3.60min；m/z＝503(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.90(t，2H)，3.29-3.37(m，2H)，4.36(s，2H)，4.90(s，2H)，7.19-7.29(m，3H)，7.37-7.50(m，3H)，7.62(t，1H)，7.69(d，1H)，8.33(t，1H).

Example 141A

2- [ 3-bromo-4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [ (3-trifluoromethyl) phenyl ] ethyl } -acetamide

703mg (2.15mmol) of the compound from example 135A are stirred overnight at reflux together with 600mg (2.15mmol) of 2-chloro-N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide (example 133A) and 593mg (4.29mmol) of potassium carbonate in 15ml of acetonitrile. After cooling, the mixture is filtered and the filtrate is purified directly by preparative HPLC (method 20). 780mg (71% of theory) of the title compound are obtained.

LC/MS [ method 17 ]]；R_t＝3.73min；m/z＝515(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.59(s，6H)，4.43(s，2H)，4.86(s，2H)，7.10-7.26(m，3H)，7.34-7.41(m，1H)，7.50-7.58(m，2H)，7.61(s，1H)，7.65(br.d，J～6.8Hz，1H)，8.54(s，1H).

Example 142A

2- [ 3-bromo-4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [ (2-trifluoromethyl) benzyl ] -acetamide

312mg (0.95mmol) of the compound from example 135A are stirred overnight at reflux together with 240mg (0.95mmol) of 2-chloro-N- [2- (trifluoromethyl) benzyl ] -acetamide (example 134A) and 264mg (1.21mmol) of potassium carbonate in 6ml of acetonitrile. After cooling, the mixture was treated with water and extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate and the volatile components were removed on a rotary evaporator. The residue was purified by preparative HPLC (method 20). 385mg (79% of theory) of the title compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.46min；m/z＝487(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.48(d，J＝5.6Hz，2H)，4.52(s，2H)，4.90(s，2H)，7.18-7.29(m，3H)，7.36-7.43(m，1H)，7.49(t，J＝7.6Hz，1H)，7.54(d，J＝7.6Hz，1H)，7.67(t，J＝7.6Hz，1H)，7.73(d，J＝7.6Hz，1H)，8.74(t，J＝5.8Hz，1H).

Example 143A

2- [ 3-bromo-4- (2-methoxyethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [ (3-trifluoromethyl) phenyl ] ethyl } -acetamide

0.82g of the compound from example 136A (91% purity, 3.58mmol) are stirred overnight at reflux together with 1.0g (3.58mmol) of 2-chloro-B- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] -ethyl } -acetamide (example 133A) and 0.99g (7.15mmol) of potassium carbonate in 25ml of acetonitrile. After cooling, the mixture was treated with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and the volatile components were removed on a rotary evaporator. The residue was dried under high vacuum. 1.47g (88% of theory) of the title compound are obtained.

LC/MS [ method 17 ]]：R_t＝3.24min；m/z＝465(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.58(s，6H)，3.22(s，3H)，3.50(t，2H)，3.74(t，2H)，4.39(s，2H)，7.50-7.57(m，2H)，7.60(s，1H)，7.65(br.d，1H)，8.55(s，1H).

Example 144A

2- (3-bromo-4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -N- { 1-methyl-1- [ (3-trifluoromethyl) phenyl ] ethyl } -acetamide

438mg (2.15mmol) of 5-bromo-4-cyclopropyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one (for preparation see EP 0425948-A2, example II-3) are stirred at reflux overnight together with 600mg (2.15mmol) of 2-chloro-N- { 1-methyl-1- [3- (trifluoromethyl) ethyl } -acetamide (example 133A) and 593mg (4.29mmol) of potassium carbonate in 15ml of acetonitrile. After cooling, the mixture was treated with water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and freed of volatile constituents on a rotary evaporator. The residue was dried under high vacuum. 860mg (90% of theory) of the title compound are obtained as a light brown solid.

LC/MS [ method 17 ]]：R_t＝3.35min；m/z＝447(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.86-0.92(m，2H)，0.92-1.01(m，2H)，1.58(s，6H)，2.80(m，1H)，4.33(s，2H)，7.50-7.57(m，2H)，7.59(s，1H)，7.65(m，1H)，8.50(s，1H).

Example 145A

2- (3-bromo-4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -N- { (2-trifluoromethyl) benzyl ] -acetamide

By the same method as described in example 144A, starting from 487mg (2.38mmol) of 5-bromo-4-cyclopropyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one (for preparation see EP 0425948-A2, examples II-3) and 600mg (2.38mmol) of 2-chloro-N- [2- (trifluoromethyl) benzyl ] -acetamide (example 134A), 900mg (90% of theory) of the title compound are obtained as a light brown solid.

LC/MS [ method 17 ]]：R_t＝3.02min；m/z＝419(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.90-1.03(m，4H)，2.85(m，1H)，4.41(s，2H)，4.48(d，2H)，7.45-7.54(m，2H)，7.69(t，1H)，7.72(d，1H)，8.54(t，1H).

Example 146A

[ 3-bromo-4- (3-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid methyl ester

1.50g (4.69mmol) of the compound from example 137A are stirred under reflux for 4 hours together with 508mg (4.69mmol) of methyl chloroacetate and 1.30g (9.4mmol) of potassium carbonate in 33ml of acetonitrile. After cooling, the mixture was neutralized with 1N hydrochloric acid and diluted with ethyl acetate. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulfate and freed of volatile constituents on a rotary evaporator. The residue was dissolved in 20ml of dichloromethane and absorbed onto 3g of celite. After removal of the solvent on a rotary evaporator, the solid is transferred to a silica gel column and purified by elution with cyclohexane/ethyl acetate (gradient 5: 1 → 1: 1). 1.36g (84% of theory) of the title compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.07min；m/z＝344(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.70(s，3H)，4.69(s，2H)，4.90(s，2H)，7.08(br.d，2H)，7.17(br.t，1H)，7.45(q，1H).

Example 147A

[3- (4-chloro-2-methoxyphenyl) -4- (3-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid methyl ester

Under argon, 250mg (0.73mmol) of the compound from example 146A and 190mg (1.07mmol) of 4-chloro-2-methoxyphenylboronic acid are dissolved in 7ml of degassed DMF. A pre-degassed solution of sodium carbonate (2N in water, 1.09ml, 2.18mmol) and 42mg of tetrakis (triphenylphosphine) palladium (0.036mmol) were added. The resulting mixture was heated and stirred at 90 ℃ for 8 hours. After cooling to RT, the mixture was acidified with 10% hydrochloric acid and filtered. The filtrate was purified by preparative HPLC (method 20). 159mg (54% of theory) of the title compound and 54mg (18% of theory) of the corresponding acid formed by hydrolysis are obtained.

LC/MS [ method 17 ]]：R_t＝3.54min；m/z＝406(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.69(s，3H)，3.72(s，3H)，4.72(s，4H)，6.78(br.d，1H)，6.82(d，1H)，7.05(dt，1H)，7.07(dd，1H)，7.23(d，1H)，7.25(d，1H)，7.31(dt，1H).

Example 148A

[3- (4-chloro-2-methoxyphenyl) -4- (3-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid

159mg (0.39mmol) of the compound from example 147A in 4ml of methanol are treated with 1.57ml of 1N aqueous lithium hydroxide solution (1.57mmol) in water and the resulting mixture is stirred at RT overnight. The methanol was removed on a rotary evaporator, the residue was diluted with water and the resulting aqueous phase was extracted twice with dichloromethane. These organic phases were discarded. The aqueous phase is then acidified with 1N hydrochloric acid and extracted three times with dichloromethane. The extracts were combined, dried over magnesium sulfate, the solvent removed on a rotary evaporator and the residue dried under high vacuum. 144mg (94% of theory) of the title compound are obtained.

LC/MS [ method 17 ]]：R_t＝3.20min；m/z＝392(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.69(s，3H)，4.57(s，2H)，4.71(s，2H)，6.76-6.84(m，2H)，7.05(dt，1H)，7.07(dd，1H)，7.23(d，1H)，7.24(d，1H)，7.29(dt，1H)，13.2(br.s，1H).

Example 149A

[4- (3-Fluorobenzyl) -3- (2-hydroxyphenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid methyl ester

By the method described for example 147A, starting from 250mg (0.73mmol) of the compound from example 146A and 138mg (1.02mmol) of 2-hydroxyphenylboronic acid, 22mg (8% of theory) of the title compound and 222mg (85% of theory) of the corresponding acid formed by hydrolysis are obtained (cf. example 150A).

LC/MS [ method 17 ]]：R_t＝2.94min；m/z＝358(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.72(s，3H)，4.70(s，2H)，4.82(s，2H)，6.73(br.d，1H)，6.79(d，1H)，6.83(t，1H)，6.98(d，1H)，7.03(dt，1H)，7.12(dd，1H)，7.28(dt，1H)，7.35(ddd，1H)，10.04(s，1H).

Example 150A

[4- (3-Fluorobenzyl) -3- (2-hydroxyphenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid

The title compound was either obtained directly as a side-component in the synthesis of example 149A or could be produced by hydrolysis of the methyl ester from example 149A by the same method as described in example 148A.

LC/MS [ method 17 ]]：R_t＝3.20min；m/z＝392(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.55(s，2H)，4.82(s，2H)，6.75(br.d，1H)，6.79(d，1H)，6.83(t，1H)，6.98(d，1H)，7.02(dt，1H)，7.12(dd，1H)，7.26(dt，1H)，7.35(ddd，1H)，10.04(s，1H)，13.2(br.s，1H).

Example 151A

N- (2-fluorobenzyl) -2- (5-chlorothiophene-2-carbonyl) -semicarbazide

3.53g (20mmol) of 5-chloro-2-thiophenecarbonyl hydrazide are dissolved in 100ml of THF with heating and the solution is then cooled again to RT. 3.08g (20.4mmol) of 2-fluorobenzyl isocyanate are added dropwise rapidly, during which a thick suspension is formed. Further stirring was carried out overnight at RT and then dilution with 100ml of diethyl ether. The precipitate was isolated by filtration, washed with diethyl ether and dried under high vacuum. 6.3g of a solid (96% of theory) are obtained, which is reacted further without additional purification.

MS[DCI/NH₃]：m/z＝328(M+H)⁺，345(M+NH₄)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.27(d，2H)，7.12(br.s，1H)，7.12-7.19(m，2H)，7.23(d，1H)，7.25-7.31(m，1H)，7.35(t，1H)，7.70(d，1H)，8.12(s，1H).

Example 152A

5- (5-chlorothien-2-yl) -4- (2-fluorobenzyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one

6.3g (19.2mmol) of the compound from example 151A are heated in 38.4ml of 4N aqueous sodium hydroxide at reflux overnight. After cooling to RT, the mixture was diluted with water and adjusted to pH 10 by addition of 1N hydrochloric acid. The product was extracted several times with ethyl acetate. The combined organic phases are washed with water to neutral pH, then with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent was removed on a rotary evaporator. 4.07g (68% of theory) of the title compound are obtained.

MS[DCI/NH₃]：m/z＝310(M+H)⁺，327(M+NH₄)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝5.08(s，2H)，7.03(t，1H)，7.13-7.26(m，4H)，7.31-7.38(m，1H)，12.25(br.s，1H).

Example 153A

[3- (5-Chlorothiophen-2-yl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid methyl ester

2.39g (7.71mmol) of the compound from example 152A are heated at reflux overnight in 79ml of acetonitrile together with 1.05g of methyl chloroacetate (9.6mmol) and 1.17g of potassium carbonate (8.5 mmol). After cooling to RT, the mixture was diluted with ethyl acetate. The resulting organic phase is washed with 1N hydrochloric acid, then with saturated sodium chloride solution, dried over sodium sulfate and the solvent is removed on a rotary evaporator. The product was dried under high vacuum. 2.9g (92% of theory) of the title compound are obtained.

LC/MS [ method 7 ]]：R_t＝2.30min；m/z＝382(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.71(s，3H)，4.75(s，2H)，5.15(s，2H)，7.02(t，1H)，7.13-7.28(m，4H)，7.32-7.39(m，1H).

Example 154A

[3- (5-chlorothien-2-yl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid

2.90g (7.60mmol) of the ester from example 153A are dissolved in 77ml of methanol and treated with 1N aqueous lithium hydroxide solution (30.3ml, 30.4 mmol). The mixture was stirred at RT overnight, after which methanol was removed on a rotary evaporator and diluted with 200ml of water. After addition of 1N hydrochloric acid to pH 2, the product precipitated out as a white solid, which was isolated by filtration and dried in high vacuum. 2.45g (88% of theory) of the title compound are obtained.

LC/MS [ method 7 ]]：R_t＝1.93min；m/z＝368(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.60(s，2H)，5.13(s，2H)，7.03(t，1H)，7.12-7.28(m，4H)，7.32-7.38(m，1H)，13.23(br.s，1H).

Example 155A

[3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid methyl ester

Starting from the compound from example 40A and methyl chloroacetate, the title compound was obtained by the same method as described in example 153A.

LC/MS [ method 8 ]]：R_t＝2.45min；m/z＝375(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.71(s，3H)，4.75(s，2H)，5.05(s，2H)，7.03(t，1H)，7.11(t，1H)，7.16(d，1H)，7.50-7.60(m，4H).

Example 156A

[3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid

The title compound was prepared in analogy to example 154A by hydrolysis of the ester from example 155A. Purity by LC/MS and NMR was about 86%.

LC/MS [ method 17 ]]：R_t＝3.17min；m/z＝361(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.60(s，2H)，5.04(s，2H)，7.03(t，1H)，7.06-7.17(m，2H)，7.27-7.32(m，1H)，7.52-7.58(m，4H)，13.18(br.s，1H).

Example 157A

[ 5-chloro-2- (trifluoromethyl) phenyl ] methylamine hydrochloride

To an ice-cooled solution of 5-chloro-2- (trifluoromethyl) benzonitrile (1.50g, 7.3mmol) in 45ml of anhydrous THF under argon was slowly added dropwise borane-THF complex (29.2 mmol). After the addition was complete, the mixture was heated at reflux for 1 hour, after which it was stirred overnight at RT with cooling. Then 30ml of 1N hydrochloric acid were added dropwise with ice-cooling. THF was removed on a rotary evaporator. The precipitated solid was filtered off and discarded. The filtrate was diluted with water and extracted twice with dichloromethane. These organic phases were likewise discarded. The acidic aqueous phase is adjusted to pH 14 with 1N aqueous sodium hydroxide and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue was taken up in 20ml of diethyl ether and treated with 3ml of a 4N solution of hydrogen chloride in dioxane, during which the product precipitated. The solvent was removed completely on a rotary evaporator, followed by high vacuum. 1.89g (99% of theory) of the title compound are isolated.

LC/MS [ method 17 ]]；R_t＝1.02min；m/z＝210(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.17(s，2H)，7.85(d，1H)，7.89(s，1H)，7.92(d，1H)，8.70(br.s，3H).

In analogy to example 157A, the following amines (as hydrochloride salts) were obtained from the corresponding nitriles by reduction with borane:

example 162A

1- [2- (trifluoromethyl) benzyl ] cyclopropylamine hydrochloride

To a solution of 1.3g 2- (trifluoromethyl) phenylacetonitrile (7.2mmol) and 2.20g (7.7mmol) titanium (IV) isopropoxide in 50ml diethyl ether, 4.68ml (14.0mmol) of a 3M solution of ethylmagnesium bromide in diethyl ether are slowly added dropwise at RT under argon. Stirring was carried out at RT for 1 hour, after which 1.78ml of boron trifluoride-diethyl ether complex were treated and stirred at RT for a further 30 minutes. For work-up, 50ml of 2M aqueous sodium hydroxide were added and the mixture was extracted three times with diethyl ether. The combined organic phases are extracted twice with 70ml of 1N hydrochloric acid each time. The combined aqueous phases are then adjusted to pH 14 with 2N aqueous sodium hydroxide and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator to a volume of about 30 ml. Treated with 4ml of a 4N solution of hydrogen chloride in dioxane. The precipitated solid is filtered off under suction and dried under high vacuum. 670mg (38% of theory) of the title compound are obtained.

LC/MS [ method 17 ]]：R_t＝1.02min；m/z＝210(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.64(m，2H)，1.01(m，2H)，3.27(s，2H)，7.50(t，1H)，7.61(d，2H)，7.68(t，1H)，7.72(d，1H)，8.50(br.s，3H).

Example 163A

2-methyl-2- [3- (trifluoromethyl) phenyl ] -propionitrile

500mg (2.7mmol) of 3- (trifluoromethyl) phenylacetonitrile in 6ml of anhydrous diethyl ether are treated with 316mg (8.1mmol) of sodium amide under argon with gentle cooling. The mixture was then cooled to 0 ℃ and treated with 1.53g (10.8mmol) of methyl iodide. After 30 min, the ice bath was removed and the reaction mixture was further stirred at RT overnight. Thereafter, 2ml of saturated ammonium chloride solution was added. The mixture was diluted with ether and washed twice with water. The organic phase was dried over magnesium sulfate and the solvent was removed on a rotary evaporator. The residue (reddish liquid) corresponded to the pure title compound (545mg, 95% of theory).

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.76(s，6H)，7.70(t，1H)，7.75(d，1H)，7.82(s，1H)，7.88(d，1H).

Example 164A

2-methyl-2- [3- (trifluoromethyl) phenyl ] -propylamine hydrochloride

The title compound was obtained in analogy to example 157A by borane reduction of the nitrile from example 163A.

LC/MS [ method 3 ]]：R_t＝2.59min；m/z＝218(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.49(s，6H)，3.11(s，2H)，7.59-7.68(m，2H)，7.71(s，1H)，7.76(d，1H)，7.78(br.s，3H).

Example 165A

2-methyl-2- [2- (trifluoromethyl) phenyl ] -propionitrile

A solution of 2.0g (10.8mmol)2- (trifluoromethyl) phenylacetonitrile and 6.13g (43mmol) iodomethane in 16ml DMSO was slowly treated with 3.16ml 50% aqueous sodium hydroxide so that the reaction temperature was maintained between 40 ℃ and 45 ℃. After the addition was complete, the mixture was stirred at RT overnight. Diluted with water and extracted three times with dichloromethane. The combined organic phases were washed with water, dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue corresponds to the title compound (2.30g, 100% of theory).

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.80(s，6H)，7.63(t，1H)，7.72-7.82(m，2H)，7.85(d，1H).

Example 166A

2-methyl-2- [2- (trifluoromethyl) phenyl ] -propylamine hydrochloride

The title compound was obtained in analogy to example 157A by borane reduction of the nitrile from example 165A.

LC/MS [ method 8 ]]：R_t＝1.10min；m/z＝218(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.50(s，6H)，3.15(s，2H)，7.53(t，1H)，7.65-7.74(m，2H)，7.85(d，1H)，7.90(br.s，3H).

Example 167A

2- [3- (trifluoromethyl) phenyl ] propionitrile

1.0g (5.4mmol) of 3- (trifluoromethyl) phenylacetonitrile and 767mg of iodomethane (5.4mmol) are placed in 5ml of toluene at 80 ℃ and slowly treated with a suspension of 50% sodium amide in toluene. The mixture was then stirred at 80 ℃ for a further 1 hour, after which it was cooled to RT and treated with water, then dichloromethane. The organic phase is separated, washed with water, dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The residue (1.7g, 84% of theory) contained the title compound with a purity of about 53% by GC/MS and the next reaction was used without purification.

GC/MS [ method 21]：R_t＝3.42min；m/z＝199(M)⁺。

Example 168A

2- [3- (trifluoromethyl) phenyl ] propanamine hydrochloride

The title compound (crude product) was obtained in analogy to example 157A by borane reduction of the nitrile from example 167A (31% of theory yield).

LC/MS [ method 3 ]]：R_t＝2.52min；m/z＝204(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.29(d，3H)，3.00-3.11(m，2H)，3.13-3.25(m，1H)，7.55-7.69(m，4H)，7.98(br.s，3H).

Example 169A

2-amino-1- [2- (trifluoromethyl) phenyl ] ethanone hydrochloride

1.0g (3.75mmol) 2-bromo-1- [ (2-trifluoromethyl) phenyl]A solution of ethanone in 4ml acetonitrile was treated with 413mg (4.34mmol) of diformylamide sodium (diformylamide sodium) at RT and stirred for 2.5 h. Next, the suspension was heated to 70 ℃ and hot filtered. The solid was washed with 2ml of hot acetonitrile. The combined filtrates were freed of solvent on a rotary evaporator. According to LC/MS [ method 8; r_t＝2.00min；m/z＝260(M+H)⁺]The dark oily residue corresponds to the glyoxal intermediate stage. The residue was treated with 10ml of 5% ethanolic hydrogen chloride solution and stirred at RT for two days. The volatile components are removed on a rotary evaporator. The yellow solid obtained is stirred in 20ml of diethyl ether for 10 minutes at reflux and the suspension is then cooled to RT. The white solid was filtered off under suction, washed with diethyl ether and dried under high vacuum. 570mg (64% of theory) of the title compound are obtained.

HPLC [ method 2 ] ]：R_t＝3.19min；

MS(DCI/NH₃)：m/z＝204(M+H)⁺，221(M+NH₄)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.53(s，2H)，7.80-7.90(m，2H)，7.95(d，1H)，8.03(d，1H)，8.49(br.s，3H).

Example 170A

[ 2-chloro-3- (trifluoromethyl) phenyl ] -methylammonium-trifluoroacetate salt

1.75gRInk-(0.96 mmol). The polymer is filtered off under suction, washed three times in succession with DMF, methanol and dichloromethane each time and then allowed to swell in 10ml of trimethyl orthoformate (TMOF). 400mg (1.9mmol) of 2-chloro-3- (trifluoromethyl) benzaldehyde are added and the suspension is stirred for 5 hours. The polymer is then filtered off, washed three times successively with DMF, methanol and dichloromethane each time and dried on a rotary evaporator. The polymer was again pre-expanded in 10ml TMOF, after which 987mg (3.84mmol) tetrabutylammonium borohydride were added and 878. mu.l (15mmol) acetic acid was slowly added. The suspension was stirred at RT overnight. The polymer is filtered off under suction and washed five times successively with DMF, methanol and dichloromethane each time. This was followed by stirring with 20ml of trifluoroacetic acid/dichloromethane (1: 1). After 1 hour, the polymer is filtered off under suction and washed with dichloromethane. The filtrate was freed of volatile constituents on a rotary evaporator and the residue was dried briefly under high vacuum. 170mg (> 50%) of the title compound are obtained in an acceptable purity (> 27% of theory), which is further used in this form.

LC/MS [ method 3 ]]：R_t＝2.30min；m/z＝210(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.25(q，2H)，7.69(t，1H)，7.88(d，1H)，7.85(d，1H)，8.32(br.s，3H).

Example 171A

[ 2-methyl-3- (trifluoromethyl) phenyl ] -methylammonium-trifluoroacetate salt

The title compound was produced from 2-methyl-3- (trifluoromethyl) benzaldehyde by the same method as described in example 170A (yield: 49% of theory).

LC/MS [ method 3 ]]：R_t＝2.36min；m/z＝190(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.44(s，3H)，4.17(q，2H)，7.49(t，1H)，7.68(d，1H)，7.72(d，1H)，8.22(br.s，3H).

Example 172A

[2- (trifluoromethyl) phenyl ] -glycine methyl ester hydrochloride

300mg (1.37mmol) DL- [2- (trifluoromethyl) phenyl ] -glycine are placed in 9ml methanol and slowly treated at RT with 130. mu.l thionyl chloride. The solution was heated at reflux overnight before cooling to RT and removing the volatile components on a rotary evaporator. Since the residue still contains about 44% of starting material by LC/MS, it is reacted again under the conditions described above. After this time, the conversion is complete. 371mg (93% of theory) of the title compound are obtained.

LC/MS [ method 3 ]]：R_t＝2.14min；m/z＝233(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.72(s，3H)，5.27(s，1H)，7.66-7.78(m，2H)，7.84(t，1H)，7.89(d，1H)，9.21(br.s，3H).

Example 173A

N-tert-Butoxycarbonyl- [3- (trifluoromethyl) phenyl ] -glycine

226mg (1.03mmol) of DL- [3- (trifluoromethyl) phenyl ] -glycine are dissolved in 10ml of aqueous 5% sodium bicarbonate solution and treated with 4ml of dioxane. 261 μ l (1.13mmol) of di-tert-butyl dicarbonate are added and the mixture is stirred at RT overnight. For work-up, the solution was carefully acidified with 1N hydrochloric acid to pH 2. The precipitated product is redissolved by addition of acetonitrile and purified by preparative HPLC (method 20). 135mg (41% of theory) of the title compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.53min；m/z＝319(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.39(s，9H)，5.28(d，1H)，7.59(t，1H)，7.68(d，1H)，7.72(d，1H)，7.79(s，1H)，7.80(d，1H)，12.99(br.s，1H).

Example 174A

{2- (dimethylamino) -2-oxo-1- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester

125mg (392. mu. mol) of the compound from example 173A and 95mg of HOBt (705. mu. mol) are placed in 8ml of DMF and treated at RT with 135mg (705. mu. mol) of EDC. After 20 min, a solution of 2M dimethylamine in THF (294 μ l, 587 μmol) was added and the mixture was stirred at RT overnight. After addition of 1ml of 1N hydrochloric acid, the mixture is separated directly by preparative HPLC (method 20). 90mg (64% of theory) of the title compound are obtained.

LC/MS [ method 17 ]]：R_t＝3.55min；m/z＝347(M+H)⁺。

Example 175A

2-dimethylamino-2-oxo-1- [3- (trifluoromethyl) phenyl ] ethane hydrochloride

130mg (375. mu. mol) of the compound from example 174A are stirred at RT in 2ml of a 4M solution of hydrogen chloride in dioxane. After complete conversion, the volatile constituents are removed on a rotary evaporator and the residue is dried under high vacuum. 105mg (99% of theory) of the title compound are obtained.

LC/MS [ method 3 ]]：R_t＝2.42min；m/z＝247(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝5.70(s，1H)，7.72(t，1H)，7.80(d，1H)，7.83(d，1H)，7.95(s，1H)，8.75(br.s，3H).

Alternatively, cleavage of the tert-butoxycarbonyl protecting group may be carried out by treating the compound from example 174A with excess trifluoroacetic acid in dichloromethane. After removal of the volatile components on a rotary evaporator, the product is obtained as trifluoroacetate salt.

Example 176A

N-tert-Butoxycarbonyl- [2- (trifluoromethyl) phenyl ] -glycine

1.0g (4.56mmol) DL- [2- (trifluoromethyl) phenyl ] -glycine was dissolved in 30ml of aqueous 5% sodium bicarbonate solution and treated with 4ml dioxane. 1.15ml (5.02mmol) of di-tert-butyl dicarbonate are added and the mixture is stirred at RT overnight. For work-up, the reaction mixture is poured into 100ml of 1N hydrochloric acid and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and the volatile components were removed on a rotary evaporator. The residue was dried under high vacuum. 1.26g (86% of theory) of the title compound are obtained.

MS[DCI/NH₃]：m/z＝337(M+NH₄)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.35(s，9H)，5.49(d，1H)，7.55(t，1H)，7.61(d，1H)，7.69(t，1H)，7.72(d，1H)，7.82(d，1H)，12.99(br.s，1H).

The following compounds were produced from example 173A or example 176A and the corresponding amine (here methylamine was used as a solution in ethanol; ammonia was used as a 33% aqueous solution) by the same amidation/Boc cleavage reaction sequence as described in examples 174A and 175A:

example 187A

2- (2, 3-dichlorobenzyl) -2-methylpropanenitrile

From 1.00g of 2, 3-dichlorophenylacetonitrile (5.37mmol), 1.10g of the title compound (96% of theory) are obtained by the method described in example 165A.

GC/MS [ method 21]：R_t＝5.56min；m/z＝213(M)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.81(s，6H)，7.46(t，1H)，7.55(dd，1H)，7.72(dd，1H).

Example 188A

2- (2, 6-dichlorobenzyl) -2-methylpropanenitrile

From 500mg of 2, 6-dichlorophenylacetonitrile (2.69mmol) 262mg (46% of theory) and 135mg (25% of theory) of the monomethylated derivative are obtained by the method described in example 165A (cf. example 189A).

GC/MS [ method 21]：R_t＝5.71min；m/z＝213(M)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.01(s，6H)，7.49(t，1H)，7.54(d，2H).

Example 189A

2- (2, 3-dichlorobenzyl) propionitrile

The title compound was obtained as a by-product in the preparation of example 188A.

GC/MS [ method 21]：R_t＝5.28min；m/z＝199(M)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(d，3H)，4.97(q，1H)，7.42(t，1H)，7.56(d，2H).

Example 190A

2- [2, 3-dichlorophenyl ] -2-methylpropylamine hydrochloride

The title compound was obtained in analogy to example 157A by borane reduction of the nitrile from example 187A.

LC/MS [ method 17 ]]：R_t＝1.71min；m/z＝218(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.51(s，6H)，3.40(s，2H)，7.38(t，1H)，7.42(d，1H)，7.63(d，1H)，7.80(br.s，3H).

Example 191A

2- [2, 6-dichlorophenyl ] -2-methylpropylamine hydrochloride

The title compound was obtained in analogy to example 157A by borane reduction of the nitrile from example 188A.

LC/MS [ method 3 ]]：R_t＝2.48min；m/z＝218(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.72(s，6H)，3.50(s，2H)，7.29(t，1H)，7.47(d，2H)，8.00(br.s，3H).

Example 192A

2- (2, 6-dichlorophenyl) -propylamine hydrochloride

The title compound was obtained in analogy to example 157A by borane reduction of the nitrile from example 189A.

LC/MS [ method 3 ]]：R_t＝2.39min；m/z＝204(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.40(d，3H)，3.25(dd，1H)，3.35(dd，1H)，3.93(m，1H)，7.32(t，1H)，7.45(d，1H)，7.51(d，1H)，8.07(br.s，3H).

Example 193A

3- { [ (benzyloxy) carbonyl ] amino } -2- [2- (trifluoromethyl) phenyl ] propanoic acid ethyl ester

The LDA solution was prepared under argon by slowly adding dropwise n-butyllithium solution (1.6M in hexane, 2.6ml, 4.13mmol) to a solution of 591. mu.l diisopropylamine (4.21mmol) in 3ml anhydrous THF at-15 ℃ and stirring for 10 min at 0 ℃. The LDA solution was cooled to 70 deg.C and slowly treated with a solution of 500mg of ethyl 2- (trifluoromethyl) phenylacetate and N-methoxymethylbenzyl carbamate (350mg, 1.79mmol) in 3ml of THF. After 15 minutes at-70 ℃ 1.17ml (3.95mmol) of titanium (IV) isopropoxide are added. The mixture was stirred at this temperature for a further 1 hour, after which it was left overnight at-60 ℃. It was then allowed to warm to 0 ℃ over an hour and stirred at this temperature for an additional hour. The mixture is treated with 20ml of 1N hydrochloric acid and extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate and freed of volatile constituents on a rotary evaporator. The residue was dried under high vacuum. 450mg (49% of theory, approximately 92% purity) of the title compound are obtained.

MS[DCI/NH₃]：m/z＝413(M+NH₄)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.00(t，3H)，3.35(m，1H)，3.69(m，1H)，3.99-4.11(m，2H)，4.23(t，1H)，4.99(s，2H)，7.26-7.38(m，5H)，7.48-7.56(m，2H)，7.62-7.75(m，3H).

Example 194A

3-amino-2- [2- (trifluoromethyl) phenyl ] propanoic acid ethyl ester hydrochloride

450mg (1.05mmol) of the compound from example 193A are dissolved in 10ml of ethanol and hydrogenated under hydrogen (atmospheric pressure) with 50mg of palladium (10% on activated carbon) as catalyst. After 18 hours the reaction run showed complete conversion. The catalyst was filtered off and the filtrate was freed of volatile constituents on a rotary evaporator. The residue was taken up in 10ml of diethyl ether and treated with 0.4ml of a 4M solution of hydrogen chloride in dioxane. The precipitated solid is filtered off under suction and dried under high vacuum. 262mg (84% of theory) of the title compound are obtained.

LC/MS [ method 3 ]]：R_t＝2.52min；m/z＝262(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.11(t，3H)，3.06(m，1H)，3.51(m，1H)，4.07-4.18(m，2H)，4.31(m，1H)，7.53(d，1H)，7.59(t，1H)，7.22(d，1H)，7.80(d，1H)，8.18(br.s，3H).

Example 195A

3- { [ (benzyloxy) carbonyl ] amino } -2- [3- (trifluoromethyl) phenyl ] propanoic acid ethyl ester

By the same method as described in example 193A, from 700mg (3.02mmol) of ethyl 3- (trifluoromethyl) phenylacetate 334mg (28% of theory) of the title compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.83min；m/z＝396(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.12(t，3H)，3.40(m，1H)，3.60(m，1H)，4.00(t，1H)，4.03-4.15(m，2H)，4.99(s，2H)，7.22-7.38(m，5H)，7.46(t，1H)，7.52-7.70(m，4H).

Example 196A

3-amino-2- [3- (trifluoromethyl) phenyl ] propanoic acid ethyl ester hydrochloride

In analogy to the preparation of example 194A, 220mg of the title compound (purity approximately 87%, 81% of theory) are obtained from 315mg of the compound from example 195A. It was used without further purification.

LC/MS [ method 8 ]]：R_t＝1.27min；m/z＝262(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.12(t，3H)，3.20(m，1H)，3.51(m，1H)，4.12(q，2H)，4.22(t，1H)，7.07-7.25(m，4H)，8.11(br.s，3H).

Example 197A

1- (2, 3-dichlorobenzyl) cyclopropylamine hydrochloride

723mg (53% of theory) of the title compound are obtained by the method described in example 162A from 1.00g of 2, 3-dichlorophenylacetonitrile (5.37 mmol).

LC/MS [ method 3 ]]：R_t＝2.48min；m/z＝216(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.71(m，2H)，0.98(m，2H)，3.23(s，2H)，7.38(t，1H)，7.46(d，1H)，7.60(d，1H)，8.41(br.s，3H).

Example 198A

1- (2, 6-dichlorobenzyl) cyclopropylamine hydrochloride

From 1.30g of 2, 6-dichlorophenylacetonitrile (6.99mmol), 1.24g of the title compound (62% of theory) are obtained by the method described in example 162A.

LC/MS [ method 8 ]]：R_t＝0.94min；m/z＝216(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.35(m，2H)，0.91(m，2H)，3.52(s，2H)，7.36(t，1H)，7.50(d，2H)，8.59(br.s，3H).

Example 199A

1- [2, 3-bis (trifluoromethyl) phenyl ] ethylidene ammonium (ethaniminium) chloride

A solution of 200mg (0.84mmol)2, 3-bis (trifluoromethyl) benzonitrile in 2.5ml toluene under argon is heated to reflux and treated with 3.59ml methylmagnesium bromide (1.4M solution in toluene/THF 3: 1; 5 mmol). Stirring was continued at reflux temperature for a further 3 hours before cooling to RT. Next, 10ml of a saturated sodium carbonate solution was added dropwise. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were extracted twice with 1N hydrochloric acid. The combined aqueous phases are adjusted to pH 12 with 2N aqueous sodium hydroxide and extracted twice with dichloromethane. The organic phases were combined, dried over sodium sulfate and filtered. The filtrate was treated with 1ml of a 4N solution of hydrogen chloride in dioxane and then the solvent was removed on a rotary evaporator. 172mg (67% of theory) of the title compound are obtained.

MS[DCI/NH₃]：m/z＝256(M+H)⁺，273(M+NH₄)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.82(s，3H)，8.11(d，1H)，8.17(t，1H)，8.31(d，1H)，13.35(br.s，2H).

Example 200A

1- [2, 3-bis (trifluoromethyl) phenyl ] ethylamine hydrochloride

170mg (0.58mmol) of the compound from example 199A are dissolved in 4ml of methanol and treated at RT with 147mg (2.33mmol) of sodium cyanoborohydride and then 334. mu.l of acetic acid. The mixture was stirred at RT overnight, after which it was diluted with water and extracted twice with dichloromethane. The acidic aqueous phase was adjusted to pH 14 with 2N aqueous sodium hydroxide and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered. The filtrate was treated with 1ml of a 4N solution of hydrogen chloride in dioxane and then the solvent was removed on a rotary evaporator. The residue was dried under high vacuum and corresponded to the title compound (160mg, 93% of theory).

MS[DCI/NH₃]：m/z＝258(M+H)⁺，275(M+NH₄)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(d，3H)，4.65(q，1H)，8.03-8.11(m，2H)，8.39(d，1H)，8.78(br.s，3H).

Example 201A

[3- (trifluoromethyl) phenyl ] -p-toluenesulfonylhydrazone

A solution of 2.35g (12.6mmol) p-toluenesulfonhydrazide in 5ml methanol was slowly treated with 2.00g 3- (trifluoromethyl) benzaldehyde at RT. Stirring was carried out overnight at RT and then the solvent was removed on a rotary evaporator. The residue was taken up in 40ml cyclohexane/dichloromethane (5: 1) and stirred overnight. The precipitated solid is filtered off with suction, washed with a little cyclohexane/dichloromethane (5: 1) and dried under high vacuum. 1.27g of the title compound are obtained. Since the mother liquor still contains a lot of product, it is concentrated to a volume of about 10ml on a rotary evaporator. The precipitated solid is again suction-filtered, washed with a little cyclohexane/ethyl acetate (5: 1) and dried under high vacuum. 2.02g of the title compound are obtained (84% of theory for the total yield).

LC/MS [ method 19 ]]：R_t＝3.62min；m/z＝343(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.36(s，3H)，7.40(d，2H)，7.63(t，1H)，7.72-7.79(m，3H)，7.85-7.90(m，2H)，8.00(s，1H)，11.70(s，1H).

Example 202A

cis-N- {2- [3- (trifluoromethyl) phenyl ] cyclopropyl } phthalimide

1.00g (2.92mmol) of the compound from example 201A in 14ml of THF are treated slowly with 4.38ml of LiHMDS (1M solution in THF, 4.38mmol) at-78 ℃ under argon. After 15 minutes at this temperature, the reaction mixture was allowed to warm to RT. THF was removed on a rotary evaporator. To the remaining lithium salt were added 67mg of benzyltriethylammonium chloride (0.29mmol), 13mg of rhodium acetate dimer (29. mu. mol), 2.02g N-vinylphthalimide (11.68mmol) and then 14ml of dioxane. The reaction mixture was stirred at RT overnight, after which water was poured in and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue was purified by preparative HPLC (by method 20, but replacing acetonitrile/formic acid with acetonitrile/0.3% hydrochloric acid). The product-containing components are freed of volatile constituents on a rotary evaporator and the residue is dried under high vacuum. 346mg of the title compound (purity approximately 73%, 26% of theory) are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.30(t，3H)，1.68(m，1H)，2.01(m，1H)，2.70(q，1H)，3.16(m，1H)，7.27(s，1H)，7.32-7.41(m，3H)，7.69-7.80(m，4H).

Example 203A

Cis-2- [3- (trifluoromethyl) phenyl ] cyclopropylamine hydrochloride

346mg (0.76mmol) of the compound from example 202A are stirred in 3ml of ethanol with 185. mu.l (3.8mmol) of hydrazine hydrate at 40 ℃ for 3 hours and then all volatile constituents are removed on a rotary evaporator. The residue was treated with 3-4ml DMSO, filtered and the filtrate purified by preparative HPLC (method 20). The product-containing fractions were treated with 3ml of 1N hydrochloric acid and the volatile components were removed on a rotary evaporator. The residue was dried under high vacuum and corresponded to the title compound (66mg, 36% of theory).

LC/MS [ method 23]：R_t＝0.65min；m/z＝202(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.31-1.37(m，2H)，2.49(m，1H)，2.89(m，1H)，7.56-7.73(m，4H)，8.14(br.s，3H).

Example 204A

Difluoro- [3- (trifluoromethyl) phenyl ] -acetonitrile

A solution of 500mg of [3- (trifluoromethyl) phenyl ] -acetonitrile (2.70mmol) in 12ml of anhydrous THF is treated dropwise at-78 ℃ with 3.50ml of tert-butyllithium solution (1.7M in pentane, 5.94 mmol). The brown reaction mixture is stirred at-78 ℃ for 1 h, after which a solution of 2.04g (6.5mmol) of N-fluorobenzenesulfonic acid imine in 12ml of THF is added. Stirring was continued for a further 2 hours at-78 ℃ and the reaction was stopped by addition of 0.1M hydrochloric acid. After warming to RT, the mixture was extracted twice with dichloromethane. The combined organic phases are washed with dilute sodium bicarbonate solution, then with saturated sodium chloride solution, and then dried over sodium sulfate and the solvent is removed on a rotary evaporator. The residue was purified by preparative HPLC (method 20). The product-containing fractions were freed of acetonitrile on a rotary evaporator and the remaining aqueous phase was extracted with dichloromethane. The organic phase was dried over magnesium sulfate and the solvent was removed on a rotary evaporator. 85mg of the title compound are obtained in a purity of approximately 81% (12% of theory).

GC/MS [ method 21]：R_t＝1.49min；m/z＝221(M)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.35-7.43(m，2H)，7.63-7.70(m，2H).

Example 205A

2, 2-difluoro-2- [3- (trifluoromethyl) phenyl ] ethylamine hydrochloride

Borane reduction of the compound from example 204A by the method described in example 157A yielded 73mg (68% of theory) of the title compound.

LC/MS [ method 23]：R_t＝0.69min；m/z＝226(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.37(t，2H)，7.81(t，1H)，7.94-8.03(m，3H)，8.71(br.s，3H).

Example 206A

2- (4-chlorobenzoyl) -N-allylsemicarbazide

19.00g (111.4mmol) of 4-chlorobenzoyl hydrazine are placed in 150ml of THF under argon. 9.44g (111.6mmol) of allyl isocyanate dissolved in 110ml of THF are added dropwise at 50 ℃ and the mixture is stirred further overnight at 50 ℃. After evaporation of the solvent in vacuo, ether was added to the residue and the solid formed was isolated and purified by filtration and further washed with ether. 26.80g (95% of theory) of the target compound are thus obtained.

LC/MS [ method 18 ]]：R_t＝1.51min；MS[ESIpos]：m/z＝254(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.60-3.70(m，2H)，5.01(d，1H)，5.15(d，1H)，5.80(m，1H)，6.70(s，1H)，7.56(d，2H)，7.90(d，2H)，7.92(s，1H)，10.21(s，1H).

The following compounds were prepared identically:

example 210A

5- (4-chlorophenyl) -4-allyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one

26.80g (105.6mmol) of 2- (4-chlorobenzoyl) -N-allylsemicarbazide from example 206A are heated under reflux in 211ml of 3N aqueous sodium hydroxide overnight. After cooling, the pH is adjusted to 10 with 6N hydrochloric acid, during which the product precipitates almost completely. The precipitate was suction-filtered, washed with copious amounts of water and then stirred with methanol. An insoluble white precipitate remained, which was filtered off. The filtrate was concentrated in vacuo and the remaining residue was dried under high vacuum. 21.5g (86% of theory) of the target compound are thus obtained.

LC/MS [ method 18 ]]：R_t＝1.79min；MS[ESIpos]：m/z＝236(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.30-4.35(m，2H)，4.90(d，1H)，5.12(d，1H)，5.85(m，1H)，7.57(d，2H)，7.63(d，2H)，12.06(s，1H).

The following compounds were prepared identically:

example 214A

[3- (4-chlorophenyl) -4-allyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid methyl ester

To 21.50g (91.2mmol) of 5- (4-chlorophenyl) -4-allyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one from example 210A and 11.88g (109.5mmol) of methyl chloroacetate in 350ml of acetonitrile are added 13.87mg (100.35mmol) of potassium carbonate and the mixture is heated under reflux for 5 hours with stirring. The residue which is then concentrated and taken up in ethyl acetate is washed with 1N hydrochloric acid and then with saturated sodium chloride solution. The organic phase was dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo. After purification by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2: 1), 24.00g (85% of theory) of the title compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.70(s，3H)，4.36-4.43(m，2H)，4.72(s，2H)，4.93(d，1H)，5.15(d，1H)，5.86(m，1H)，7.60(d，2H)，7.66(d，2H).

The following compounds were prepared identically:

example 218A

[3- (4-chlorophenyl) -4-allyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid

4.88g (15.9mmol) of ethyl [3- (4-chlorophenyl) -4-allyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetate from example 214A are placed in 48ml of methanol and stirred at room temperature for 2 hours with 5ml of 20% aqueous potassium hydroxide. The solution was concentrated to about half, then diluted with water and extracted with ethyl acetate. The aqueous phase is acidified with approximately 2ml of concentrated hydrochloric acid and extracted twice with 100ml of ethyl acetate each time. The final organic extracts were combined, dried over sodium sulfate, filtered and concentrated in vacuo. After drying under high vacuum, 4.20g (90% of theory) of the target compound are thus obtained.

LC/MS [ method 8 ]]：R_t＝2.93min；MS[ESIpos]：m/z＝294(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.36-4.43(m，2H)，4.59(s，2H)，4.93(d，1H)，5.15(d，1H)，5.87(m，1H)，7.60(d，2H)，7.67(d，2H)，13.17(s，1H).

The following compounds were prepared identically:

example 222A

[3- (4-chlorophenyl) -5-oxo-4, 5-1H-1, 2, 4-triazol-1-yl ] -acetic acid methyl ester

Under argon, 200mg (0.65mmol) of the compound from example 214A, 49 μ l of formic acid (1.3mmol), 226 μ l of triethylamine (1.63mmol) and 38mg of tetrakis (triphenylphosphine) palladium (0) (32 μmol) were dissolved in 2ml of degassed dioxane and stirred at reflux temperature overnight. To dissolve the precipitated solid, the reaction mixture was diluted with 20ml of methanol after cooling to RT. The palladium catalyst was filtered off and the filtrate was freed of volatile constituents on a rotary evaporator. The residue is stirred with 5ml of acetonitrile and then filtered off with suction. The solid was washed with acetonitrile and dried under high vacuum. It corresponds to the title compound with a purity of about 76% (130mg, 57% of theory) and is used without further purification in the next reaction.

LC/MS [ method 19 ]]：R_t＝2.34min；m/z＝268(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.70(s，3H)，4.63(s，2H)，7.59(d，2H)，7.80(d，2H).

Example 223A

{4- [4- (tert-butoxy) -4-oxo-n-butyl ] -3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -acetic acid methyl ester

A solution of 130mg (0.38mmol) of the compound from example 222A in 1ml of DMF and 2ml of DME at 0 ℃ is treated with 505. mu.l of a solution of LiHMDS (1M in THF, 505. mu. mol) under argon. The cooling bath was removed before 113mg (505. mu. mol) of tert-butyl 4-bromobutyrate was added and the mixture was stirred at RT for 15 minutes. The mixture was stirred at 70 ℃ overnight. After cooling, 0.5ml of 1N hydrochloric acid was added. The reaction mixture was then separated directly by preparative HPLC (method 20). 48mg (30% of theory) of the title compound are obtained.

LC/MS [ method 17 ]]：R_t＝3.67min；m/z＝410(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.31(s，9H)，1.69(quin，2H)，2.12(t，2H)，3.70(s，3H)，3.79(t，2H)，4.69(s，2H)，7.52(d，2H)，7.70(d，2H).

Example 224A

{4- [4- (tert-butoxy) -4-oxo-n-butyl ] -3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -acetic acid

A solution of 48mg (117. mu. mol) of the compound from example 223A in 2ml of methanol was treated with 1N aqueous lithium hydroxide solution (470. mu.l, 470. mu. mol). After 1 hour at RT, methanol was removed on a rotary evaporator. The residue was dissolved in dimethyl sulfoxide and purified by preparative HPLC. 41mg (88% of theory) of the title compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.48min；m/z＝396(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.33(s，9H)，1.68(quin，2H)，2.14(t，2H)，3.77(t，2H)，4.54(s，2H)，7.61(d，2H)，7.70(d，2H)，13.14(br.s，1H).

Example 225A

[3- (4-chlorophenyl) -4- (2-oxoethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid methyl ester

In 20ml dioxane and 9ml water 1.00g (3.25mmol) of the compound from example 214A and 217mg OsEnCat40 (microencapsulated osmium tetroxide, 0.3mmol/g, 65 μmol) were placed and slowly treated with 2.09g (9.8mmol) sodium periodate at RT. This was allowed to react with vigorous stirring (1-4 days) until HPLC testing of the mixture showed sufficient conversion. For work-up, the osmium catalyst was removed by filtration, followed by washing with dioxane and the entire filtrate was freed of organic solvent on a rotary evaporator. The aqueous residue was diluted with more water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. The oily residue was dried under high vacuum. 948mg (purity approx 84%, 79% of theory) of the title compound are obtained.

LC/MS [ method 17 ]]：R_t＝1.89min；m/z＝310(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝3.79(s，3H)，4.61(s，2H)，4.67(s，2H)，7.37-7.59(m，4H)，9.62(s，1H).

Example 226A

[3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid methyl ester (racemate)

To a solution of 948mg (2.57mmol) of the compound from example 225A in 17ml of THF are added 6.69ml of a 0.5M solution of (trifluoromethyl) trimethoxysilane in THF and 39. mu.l of a 1M solution of tetra-n-butylammonium fluoride in THF (39. mu. mol) one after the other at 0 ℃. The temperature was allowed to rise to RT and the mixture was stirred for an additional 1 hour. For working up, the reaction mixture is treated with 8ml of 1N hydrochloric acid. After stirring for 1 hour at RT, THF was removed on a rotary evaporator. The aqueous residue was extracted with ethyl acetate. The organic phase is washed twice with water and once with saturated sodium chloride solution, dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The residue is purified by chromatography on silica gel (flow agent: dichloromethane/methanol 100: 1 → 100: 2). 630mg (65% of theory) of the title compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.23min；m/z＝380(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.70(s，3H)，3.84(dd，1H)，4.00(dd，1H)，4.25(m，1H)，4.71(s，2H)，6.91(d，1H)，7.63(d，2H)，7.76(d，2H).

The racemate from example 226A can be separated into enantiomers by HPLC in chiral phase separation [ column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 430mmx40 mm; eluent: step gradient iso-hexane/ethyl acetate 1: 1 → ethyl acetate → iso-hexane/ethyl acetate 1: 1; flow rate: 80 ml/min; temperature: 24 ℃; and (4) UV detection: 260 nm ]. In this way, 265mg of the first eluting enantiomer 1 (example 227A) and 271mg of the later eluting enantiomer 2 (example 228A) were obtained from 615mg of the racemic compound.

Example 227A

[3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid methyl ester (enantiomer 1)

The first eluted enantiomer from the racemate separation of example 226A.

R_t3.21min [ [ column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 250mmx4.6 mm; eluent: iso-hexane/ethyl acetate 1: 1; flow rate: 1 ml/min; and (4) UV detection: 260nm]。

Example 228A

[3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid methyl ester (enantiomer 2)

The enantiomer separated from the racemate of example 226A eluted last.

R_t4.48min [ [ column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 250mmx4.6 mm; eluent: iso-hexane/ethyl acetate 1: 1; flow rate: 1 ml/min; and (4) UV detection: 260nm]。

Example 229A

[3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid (enantiomer 1)

The enantiomerically pure ester from example 227A (265mg, 0.70mmol) was dissolved in 14ml methanol and treated with 2.8ml 1M aqueous lithium hydroxide. The mixture was stirred at RT for 1 hour and then methanol was removed on a rotary evaporator. The residue was diluted with 200ml of water and extracted once with dichloromethane. The organic phase was discarded. The aqueous phase was slowly acidified with 1N hydrochloric acid to pH 2. The product was extracted three times with dichloromethane, the combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue was dried under high vacuum. 142mg (56% of theory) of the title compound are thus obtained. Since the aqueous phase still contained more product, it was evaporated to dryness on a rotary evaporator and the residue was dissolved in a little dimethyl sulfoxide and purified by preparative HPLC (method 20). 71mg (28% of theory) of the pure title compound are obtained.

[α]_D ²⁰Not 3.4 ° (methanol, c not 0.37g/100ml)

LC/MS[ method 17 ]]：R_t＝2.83min；m/z＝366(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.84(dd，1H)，4.00(dd，1H)，4.25(m，1H)，4.58(s，2H)，6.91(d，1H)，7.63(d，2H)，7.78(d，2H)，13.20(br.s，1H).

Example 230A

[ [3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid (enantiomer 2)

In analogy to example 229A, 210mg (80% of theory) of the title compound are obtained from 271mg of the enantiomerically pure ester from example 228A.

[α]_D ²⁰Not-4.6 ° (methanol, c not 0.44g/100ml)

LC/MS [ method 17 ]]：R_t＝2.83min；m/z＝366(M+H)⁺

Example 231A

{ [2- (4-chlorophenyl) -2-oxoethyl ] amino } acetic acid methyl ester

A solution of glycine methyl ester hydrochloride (5.00g, 39.8mmol) in 80ml of methyl isobutyl ketone was treated with 12.6g of sodium carbonate and the mixture was stirred at RT overnight. Next, a solution of 2-bromo-1- (4-chlorophenyl) ethanone (8.37g, 35.8mmol) in 40ml of methyl isobutyl ketone was added dropwise to the suspension. The mixture was stirred at RT for a further 1h, after which the solid was suction-filtered and washed with 55ml of methyl isobutyl ketone. The filtrate was acidified with 12ml of 6N hydrochloric acid and then treated with 6.4ml of isopropanol. The precipitated solid is filtered off with suction, washed with a little methyl isobutyl ketone, then stirred in 240ml of acetonitrile and again suction-filtered. Thus 3.41g (34% of theory) of the pure title compound are obtained.

LC/MS [ method 3 ]]：R_t＝2.20min；m/z＝242(M+H)⁺.

Example 232A

[4- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid methyl ester

To a solution of 995mg (12.27mmol) of potassium isocyanate in 11ml of methanol/water (7: 3) is added dropwise a solution of 3.41g (12.27mmol) of the compound from example 231A in 14ml of methanol/water (7: 3). It was stirred at RT for 1 hour. The thick suspension was diluted with 7.4ml of water and 39ml of methanol to facilitate stirring, then heated at reflux for 1 hour and then allowed to stand overnight at RT. After cooling to 0 ℃ the precipitate was filtered off, washed with ice-cold water and dried in a drying cabinet at 60 ℃ overnight. 2.84g (76% of theory) of the title compound are obtained.

LC/MS [ method 4 ]]：R_t＝2.03min；m/z＝267(M+H)⁺.

Example 233A

[4- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid

770mg (2.89mmol) of [4- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid methyl ester from example 232A are placed in 20ml of methanol, treated with 5.8ml of a 1M aqueous lithium hydroxide solution and stirred at room temperature for 18 hours. The methanol was then removed on a rotary evaporator and the residue was acidified with 1N hydrochloric acid. The precipitate formed is filtered off under suction, washed with water and dried under high vacuum. 690mg (94% of theory) of the target compound are thus obtained.

LC/MS [ method 17 ]]：R_t＝2.19min；MS[ESIpos]：m/z＝253(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.30(s，2H)，7.08(s，1H)，7.41(d，2H)，7.51(d，2H)，10.08(s，1H)，13.01(s，1H).

Example 234A

2- [4- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) -phenyl ] ethyl } -acetamide

318mg (1.26mmol) of [4- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid from example 233A are placed in 10ml of DMF and treated with 221mg (1.64mmol) of HOBt and 314mg (1.64mmol) of EDC hydrochloride. After stirring for 10 min, 332mg (1.64mmol) of 1-methyl-1- [ (3-trifluoromethyl) phenyl ] ethylamine from example 1A were added and the mixture was stirred at room temperature overnight. For working up, the reaction mixture is stirred with 100ml of water. Next, the resulting precipitate was suction-filtered, washed with water and dried under high vacuum. Further purification was performed by preparative HPLC [ method 10 ]. 209mg (38% of theory) of the target compound are thus obtained.

LC/MS [ method 17 ]]：R_t＝3.57min；MS[ESIpos]：m/z＝438(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，4.26(s，2H)，6.96(s，1H)，7.32-7.69(m，8H)，8.71(s，2H)，10.71(s，1H).

Example 235A

1- [2- (5-chloro-2-thienyl) -2-oxoethyl ] -3- (2-fluorobenzyl) -urea

850mg (4.007mmol) of 2-amino-1- (4-chloro-2-thienyl) ethanone hydrochloride are placed in 26ml of dichloromethane, cooled to 0 ℃ and treated dropwise with a solution of 606mg (4.007mmol) of 2-fluorobenzyl isocyanate in 2ml of dichloromethane. It is stirred for a further 10 minutes at 0 ℃ and then a solution of 518mg (4.007mmol) of N, N-diisopropylethylamine in 4ml of dichloromethane is added dropwise. After stirring at room temperature for two hours the reaction mixture was evaporated and the crude product (1300mg, 99% of theory) was reacted further without purification.

LC/MS [ method 8 ]]：R_t＝2.11min；MS[ESIpos]：m/z＝327(M+H)⁺

Example 236A

5- (5-chloro-2-thienyl) -1- (2-fluorobenzyl) -1, 3-dihydro-2H-imidazol-2-one

1300mg (approx.4.0 mmol) of 1- [2- (5-chloro-2-thienyl) -2-oxoethyl ] -3- (2-fluorobenzyl) -urea (example 235A) are suspended in 15ml of concentrated hydrochloric acid, diluted with 15ml of methanol and stirred at RT for 2 hours. The suspension is filtered, the filtrate is concentrated in vacuo and the residue is purified by preparative HPLC [ method 10 ]. 220mg (18% of theory) of the target compound are thus obtained.

LC/MS [ method 7 ]]：R_t＝2.10min；MS[ESIpos]：m/z＝309(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.90(s，2H)，6.78-7.38(m，7H)，10.61(s，1H).

Example 237A

[4- (5-chloro-2-thienyl) -3- (2-fluorobenzyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid ethyl ester

650mg (2.15mmol) of 5- (5-chloro-2-thienyl) -1- (2-fluorobenzyl) -1, 3-dihydro-2H-imidazol-2-one from example 236A, 516mg (4.21mmol) of ethyl chloroacetate and 582mg (4.21mmol) of potassium carbonate are stirred at 80 ℃ in 12ml of acetonitrile for 7 hours. The reaction solution was diluted with ethyl acetate and washed three times with saturated sodium chloride solution. The organic phase was dried over sodium sulfate. After filtration through a drying agent, the filtrate was concentrated in vacuo. After purification by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate first 5: 1, then 1: 1), 610mg (74% of theory) of the target compound are obtained.

LC/MS [ method 17 ]]：R_t＝3.74min；MS[ESIpos]：m/z＝395(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.22(t，3H)，4.18(q，2H)，4.51(s，2H)，4.97(s，2H)，6.86-6.94(m，2H)，6.98(s，1H)，7.05(d，1H)，7.10-7.22(m，2H)，7.27-7.36(m，1H).

Example 238A

[4- (5-chloro-2-thienyl) -3- (2-fluorobenzyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid

In analogy to the procedure of example 129A, from 165mg (0.418mmol) of the compound from example 237A 150mg (99% of theory) of the target compound are obtained.

LC/MS [ method 7 ]]：R_t＝2.01min；MS[ESIpos]：m/z＝367(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.40(s，2H)，4.97(s，2H)，6.82-6.95(m，2H)，6.98(s，1H)，7.04-7.22(m，3H)，7.25-7.36(m，1H).

Example 239A

[4- (4-chlorophenyl) -3- (cyclopropylmethyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid methyl ester

300mg (1.13mmol) of the compound from example 232A together with 1.10g (3.38mmol) of cesium carbonate are placed in 12ml of acetone and treated with 456mg (3.38mmol) of bromo-methylcyclopropane. It was stirred at 50 ℃ for 2 hours. The reaction mixture is then diluted with 10ml of each ethyl acetate and water and acidified with 1N hydrochloric acid. The phases were separated and the aqueous phase was again extracted with 10ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Further purification was performed by preparative HPLC [ method 10 ]. Thus 60mg (17% of theory) of the target compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.28min；MS[ESIpos]：m/z＝321(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.05(m，2H)，0.39(m，2H)，0.76(m，1H)，3.60(d，2H)，3.70(s，3H)，4.46(s，2H)，6.73(s，1H)，7.40-7.55(m，4H).

Example 240A

[4- (4-chlorophenyl) -3- (cyclopropylmethyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid

In analogy to the procedure of example 129A, starting from 87mg (0.271mmol) of methyl [4- (4-chlorophenyl) -3- (cyclopropylmethyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetate from example 239A to 84mg (100% of theory) of the title compound is obtained.

LC/MS [ method 17 ]]：R_t＝2.86min；MS[ESIpos]：m/z＝307(M+H)⁺

¹H-NMR(500MHz，DMSO-d₆)：δ＝0.05(m，2H)，0.28(m，2H)，0.65(m，1H)，3.60(d，2H)，4.33(s，2H)，6.73(s，1H)，7.40-7.55(m，4H)，13.03(br.s，1H).

Example 241A

2- [3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide

2.00g (4.12mmol) of 2- [3- (4-chlorophenyl) -4-allyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide from example 371 are dissolved in 20ml of degassed dioxane and treated with 97mg of tetrakis (triphenylphosphine) -palladium (0) (0.084mmol), 1.46ml (10.44mmol) of triethylamine and 0.32ml (8.35mmol) of formic acid under argon and stirred for two hours at 85 ℃. The suspension was then allowed to cool to room temperature and the precipitated crystals were filtered off under suction and washed with isopropanol. The mother liquor is concentrated in vacuo and treated with isopropanol, during which crystallization further precipitates, which is likewise suction-filtered and washed with isopropanol. Thus a total of 1.56g (85% of theory) of the target compound are obtained

LC/MS [ method 8 ]]：R_t＝2.47min；MS[ESIpos]：m/z＝439(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，4.61(s，2H)，7.50-7.70(m，6H)，7.78(d，2H)，8.55(s，1H)，12.27(s，1H).

The following compounds were obtained identically:

example 246A

2- [ (3-chloro-4-methyl-2-thienyl) carbonyl ] -N-isobutylsemicarbazide

1.00g (5.25mmol) of 3-chloro-4-methylthiophene-2-ylcarboxhydrazide (carboxylic acid hydrazide) was placed in 10ml of THF at room temperature. 520mg (5.25mmol) of isobutyl isocyanate dissolved in 2ml of THF are added rapidly with stirring. The mixture was further stirred at room temperature overnight. For work-up, the reaction mixture is treated with 10ml of diethyl ether, cooled to about 0 ℃ in a water/ice bath and the resulting precipitate is recovered by filtration, washed with diethyl ether and dried in vacuo. Thus 1.29g (85% of theory) of the target compound are obtained.

LC/MS [ method 7 ]]：R_t＝1.63min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.84(d，6H)，1.59-1.73(m，1H)，2.18(s，3H)，2.86(t，2H)，6.37(t，1H)，7.60(s，1H)，7.92(s，1H)，9.70(s，1H).

Example 247A

5- (3-chloro-4-methyl-2-thienyl) -4-isobutyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one

A suspension of 1.28g (4.42mmol) of 2- [ (3-chloro-4-methyl-2-thienyl) carbonyl ] -N-isobutylsemicarbazide from example 246A in 12ml of 3N aqueous sodium hydroxide was first heated overnight at reflux. After cooling, it was filtered. The filtrate contained impure product. While the filtered solids largely correspond to the starting material. The solid was again taken up in about 15ml of 3N ethanol in aqueous sodium hydroxide and heated again under reflux overnight. After neutralization with 1N hydrochloric acid and concentration, the residue is purified by preparative HPLC together with the concentrated filtrate from the aqueous reaction [ method 12 ]. After evaporation and drying of the product components, 562mg (47% of theory) of the target compound are thus obtained.

LC/MS [ method 8 ]]：R_t＝2.13min.

Example 248A

2- [3- (3-chloro-4-methyl-2-thienyl) -4-isobutyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid ethyl ester

To a suspension of 560mg (2.06mmol) of 5- (3-chloro-4-methyl-2-thienyl) -4-isobutyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one from example 247A and 253mg (2.06mmol) of ethyl chloroacetate in 10ml of acetonitrile, 570mg (4.12mmol) of potassium carbonate are added and heated at reflux for 4 hours. For work-up, it was concentrated, the residue taken up in water and extracted three times with ethyl acetate. The combined organic phases are concentrated and the crude product remaining as residue is purified by preparative HPLC [ method 12 ]. 705mg (96% of theory) of the target compound are thus obtained.

LC/MS [ method 5 ]]：R_t＝2.49min.

Example 249A

2- [3- (3-chloro-4-methyl-2-thienyl) -4-isobutyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid

700mg (1.96mmol) of ethyl 2- [3- (3-chloro-4-methyl-2-thienyl) -4-isobutyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetate from example 248A are placed in 10ml of methanol and treated with 1ml of 20% aqueous potassium hydroxide. It is stirred at room temperature overnight, the reaction mixture is then adjusted to pH 6 with 1N hydrochloric acid and purified directly by preparative HPLC [ method 12 ]. Thus 555mg (86% of theory) of the target compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.17min；

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.72(d，6H)，1.71-1.86(m，1H)，2.23(s，3H)，3.45(d，2H)，4.56(s，2H)，7.72(s，1H)，13.15(br.s，1H).

Example 250A

2- [3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [3- (trifluoromethyl) phenylmethyl ] -acetamide

To 780mg (1.47mmol) of 2- [3- (4-chlorophenyl) -4- (4-methoxyphenylmethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [3- (trifluoromethyl) phenyl-methyl ] -acetamide from example 153 in 10ml of trifluoroacetic acid was added 31.8mg (0.294mmol) of anisole and stirred at reflux for 72H. For work-up, the reaction mixture was added to water after cooling and the mixture was extracted with ethyl acetate. The organic phase is concentrated and the residue is taken up in methanol and purified by preparative HPLC [ method 12 ]. In this way 360mg (60% of theory) of the target compound are obtained.

LC/MS [ method 5 ]]：R_t＝2.22min；

¹H-NMR(400MHz，DMSO-d₆): δ — 4.40(d, 2H), 4.45(s, 2H), 7.54-7.65(m, 6H), 7.79, 7.81 (BB ' part of AA ' BB ' system, 2H), 8.70(t, 1H), 12.35(s, 1H).

Example 251A

3- (nitromethyl) -3- [3- (trifluoromethyl) phenyl ] oxetane

A solution of 103mg of 1-bromo-3- (trifluoromethyl) benzene (0.46mmol) in 4ml of anhydrous THF was slowly treated with a solution of n-butyllithium (1.6M in hexane, 312. mu.l, 0.50mmol) at-78 ℃. After stirring at-78 ℃ for 15 minutes, 50mg (0.43mmol) of 3-nitromethyleneoxetane [ preparation: G.Wuitschik et al, Angew.chem.int.Ed.45(46), 7736-7739(2006) ] in 2ml THF. The mixture was stirred at-78 ℃ overnight and then the reaction was stopped by adding 5ml of saturated ammonium chloride solution at-78 ℃. After warming to RT, the mixture was diluted with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and the volatile components were removed on a rotary evaporator. The oily residue was dried briefly under high vacuum. 53mg (33% of theory) of the title compound are obtained in a purity of approximately 70%.

GC/MS [ method 21]：R_t＝5.44min；m/z＝201[M-CH₂NO₂]⁺

¹H-NMR(400MHz，CDCl₃)：δ＝4.95(d，2H)，5.07(s，2H)，5.09(d，2H)，7.31(d，1H)，7.36(s，1H)，7.53(t，1H)，7.60(d，1H).

Example 252A

1- {3- [3- (trifluoromethyl) phenyl ] oxetan-3-yl } -methylamine hydrochloride

50mg of the compound from example 251A (0.134mmol) are hydrogenated in 2ml of ethanol overnight at RT in the presence of 15mg (0.11mmol) of palladium hydroxide (20% on activated carbon) under 1atm of hydrogen. The catalyst was then filtered off and the filtrate was diluted with water, adjusted to pH 1 with 1N hydrochloric acid and washed twice with dichloromethane. The aqueous phase is adjusted to pH 13 with 2N aqueous sodium hydroxide and extracted three times with dichloromethane. The latter organic phases were combined, dried over sodium sulfate and filtered. The filtrate was treated with 200 μ l of 4N hydrogen chloride in dioxane and concentrated on a rotary evaporator. The residue was dried under high vacuum. 20mg of the title compound are obtained which are further used as crude product (purity approx. 60%).

LC/MS [ method 22 ]]：R_t＝0.47min；m/z＝231[M+H]⁺.

The application example is as follows:

example 1

2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [3- (trifluoromethyl) phenylmethyl ] ethyl } -acetamide

In 2ml dimethylformamide were placed 50.0mg (0.170mmol) of [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 88A and 32.8mg (0.187mmol) of 3-trifluoromethylbenzylamine and treated with 27.6mg (0.204mmol) of HOBt. After stirring for 10 min, 42.4mg (0.221mmol) EDC hydrochloride are added and the mixture is stirred at room temperature overnight. For work-up, the reaction mixture was partitioned between dichloromethane and water, the organic phase was separated, dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200: 1, then 100: 1) and thus yields 76mg (99% of theory) of the target compound

MS[ESIpos]：m/z＝451(M+H)⁺

HPLC [ method 1]：R_t＝4.74min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.59(m，2H)，0.90(m，2H)，3.18(tt，1H)，4.40(d，2H)，4.44(s，2H)，7.53-7.66(m，6H)，7.80(d，2H)，8.67(t，1H).

The following compounds were prepared identically:

example 27

2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- {1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide

40.0mg (0.136mmol) of [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 88A, 28.3mg (0.150mmol) of 1- [ (3-trifluoromethyl) phenyl ] -ethylamine and 22.1mg (0.163mmol) of HOBt are placed in 1ml of dimethylformamide and treated with 33.9mg (0.177mmol) of EDC hydrochloride. The mixture was stirred at room temperature overnight and then treated with 15ml of water for workup. The resulting precipitate is isolated by filtration and then purified by preparative HPLC [ method 9 ]. Thus 20mg (32% of theory) of the target compound are obtained.

LC/MS [ method 7 ]]：R_t＝2.34min

¹H-NMR(400MHz，DMSO-d₆): δ is 0.50-0.64(m, 2H), 0.82-0.96(m, 2H), 1.39(d, 3H), 3.17(dddd, 1H), 4.42(s, 2H), 5.00(dq, 1H), 7.52-7.69(m, 4H), 7.57, 7.60(AA 'part of AA' BB 'system, 2H), 7.78, 7.80 (BB' part of AA 'BB' system, 2H), 8.71(d, 1H).

The following compounds were prepared identically:

further, the following are obtained identically:

example 75

2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide

In 2ml dimethylformamide were placed 70.0mg (0.238mmol) of [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 88A and 53.3mg (0.262mmol) of 1-methyl-1- [ (3-trifluoromethyl) -phenyl ] ethylamine from example 1A and treated with 38.6mg (0.286mmol) of HOBt. After stirring for 10 min, 59.4mg (0.310mmol) EDC hydrochloride are added and the mixture is stirred at room temperature overnight. For work-up, the reaction mixture was partitioned between dichloromethane and water, and the organic phase was separated, dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200: 1, then 100: 1). 76mg (85% of theory) of the target compound are thus obtained.

HPLC [ method 1]：R_t＝4.79min

MS[ESIpos]：m/z＝479(M+H)⁺；[ESIneg]：m/z＝477(M-H)^-

¹H-NMR(400MHz，DMSO-d₆): δ is 0.48 to 0.61(m, 2H), 0.81 to 0.95(m, 2H), 1.59(s, 6H), 3.15(dddd, 1H), 4.42(s, 2H), 7.48 to 7.69(m, 4H), 7.57, 7.59(AA 'part of the AA' BB 'system, 2H), 7.77, 7.79 (BB' part of the AA 'BB' system, 2H), 8.55(s, 1H).

Example 76

2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [1- (3, 5-dichlorophenyl) -1-methylethyl ] acetamide

In 2ml of dimethylformamide were placed 70.0mg (0.238mmol) of [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 88A and 48.6mg (0.238mmol) of 2- (3, 5-dichlorophenyl) propan-2-amine and treated with 38.6mg (0.286mmol) of HOBt. After stirring for 10 min, 59.4mg (0.310mmol) EDC hydrochloride are added and the mixture is stirred at room temperature overnight. Without further work-up, the mixture is purified directly by preparative HPLC [ method 10 ]. 70mg (61% of theory) of the target compound are thus obtained.

MS[ESIpos]：m/z＝479(M+H)⁺

HPLC [ method 1]：R_t＝4.99min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.57(m，2H)，0.89(m，2H)，1.54(s，6H)，3.16(tt，1H)，4.42(s，2H)，7.33(d，2H)，7.39(t，1H)，7.58(d，2H)，7.80(d，2H)，8.53(s，1H).

Example 77

2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- (1-methyl-1-phenylethyl) acetamide

In 2ml dimethylformamide were placed 70.0mg (0.238mmol) of [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 88A and 32.2mg (0.238mmol) of 2-phenylpropan-2-amine and treated with 38.7mg (0.286mmol) of HOBt. After stirring for 10 min, 59.4mg (0.310mmol) EDC hydrochloride are added and the mixture is stirred at room temperature overnight. Thereafter, 32.2mg (0.238mmol) of 2-phenylpropan-2-amine, 38.7mg (0.286mmol) of HOBt and 59.4mg (0.310mmol) of EDC hydrochloride are again added to the reaction mixture and stirred at room temperature for a further two hours. Without further work-up, the mixture is purified directly by preparative HPLC [ method 10 ]. 44mg (45% of theory) of the target compound are thus obtained.

MS[ESIpos]：m/z＝411(M+H)⁺

HPLC [ method1]：R_t＝4.99min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.55(m，2H)，0.89(m，2H)，1.56(s，6H)，3.15(tt，1H)，4.41(s，2H)，7.17(t，1H)，7.27(t，2H)，7.35(d，2H)，7.59(d，2H)，7.79(d，2H)，8.34(s，1H).

Example 78

N- [1- (3-chlorophenyl) cyclobutyl ] -2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetamide

In 2ml dimethylformamide 57.2mg (0.262mmol)1- (3-chlorophenyl) cyclobutylamine hydrochloride are placed and treated with 26.5mg (0.262mmol) triethylamine. After stirring for 10 min, 70.0mg (0.238mmol) of [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 88A and 38.7mg (0.286mmol) of HOBt were added. After stirring for a further 10 minutes, the mixture is treated with 59.4mg (0.310mmol) of EDC hydrochloride and stirred at room temperature overnight. For work-up, the reaction mixture was partitioned between dichloromethane and water, and the organic phase was separated, dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200: 1, then 100: 1) and 66mg (61% of theory) of the target compound are thus produced.

MS[ESIpos]：m/z＝457(M+H)⁺

HPLC [ method 2 ]]：R_t＝4.82min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.57(m，2H)，0.89(m，2H)，1.83(m，1H)，2.02(m，1H)，2.44(t，4H)，3.16(tt，1H)，4.39(s，2H)，7.25(br.d，1H)，7.31-7.41(m，3H)，7.58(d，2H)，7.79(d，2H)，8.83(s，1H).

Example 79

N- [1- (3-chlorophenyl) cyclohexyl ] -2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetamide

In 2ml dimethylformamide were placed 70.0mg (0.238mmol) of [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 88A and 50.0mg (0.238mmol) of 1- (3-chlorophenyl) -cyclohexylamine and treated with 38.7mg (0.286mmol) of HOBt. After stirring for 10 min, 59.4mg (0.310mmol) EDC hydrochloride are added and the mixture is stirred at room temperature overnight. Thereafter, 50.0mg (0.238mmol) of 1- (3-chlorophenyl) -cyclohexylamine, 38.7mg (0.286mmol) of HOBt and 59.4mg (0.310mmol) of EDC hydrochloride are again added to the reaction mixture and stirred first at room temperature for two hours and then at 60 ℃ overnight. The mixture is stirred for a final two hours at 80 ℃ and purified directly by preparative HPLC [ method 10] to yield 6mg (5% of theory) of the target compound without further work-up.

LC/MS [ method 7 ]]：R_t＝2.64min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.56(m，2H)，0.89(m，2H)，1.49-1.69(m，8H)，2.25(m，2H)，3.16(tt，1H)，4.49(s，2H)，7.22(br.d，1H)，7.27-7.38(m，3H)，7.59(d，2H)，7.79(d，2H)，8.11(s，1H).

Example 80

2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- {1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (enantiomer A)

2000.0mg (6.809mmol) of [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 88A and 1417.0mg (7.490mmol) of 1- [ (3-trifluoromethyl) -phenyl ] ethylamine were placed in 10ml of dimethylformamide and treated with 1104.0mg (8.171mmol) of HOBt. After stirring for 10 min, 1697.0mg (8.852mmol) of EDC hydrochloride are added and the mixture is stirred at room temperature overnight. For work-up, the reaction mixture was partitioned between dichloromethane and water, and the organic phase was separated, dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200: 1, then 100: 1). Subsequent separation of the enantiomers by preparative HPLC [ method 14] on the chiral phase yields 1460mg (46% of theory) of the enantiomerically pure target compound (see example 81).

MS[ESIpos]：m/z＝465(M+H)⁺

HPLC [ method 2 ]]：R_t＝4.74min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.57(m，2H)，0.89(m，2H)，1.39(d，3H)，3.17(tt，1H)，4.42(s，2H)，5.00(dq，1H)，7.52-7.68(m，6H)，7.79(d，2H)，8.69(d，1H).

Chiral HPLC [ method 14]：R_t＝2.02min.

Example 81

2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- {1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide (enantiomer B)

2000.0mg (6.809mmol) of [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 88A and 1417.0mg (7.490mmol) of 1- [ (3-trifluoromethyl) -phenyl ] ethylamine were placed in 10ml of dimethylformamide and treated with 1104.0mg (8.171mmol) of HOBt. After stirring for 10 min, 1697.0mg (8.852mmol) of EDC hydrochloride are added and the mixture is stirred at room temperature overnight. For work-up, the reaction mixture was partitioned between dichloromethane and water, and the organic phase was separated, dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200: 1, then 100: 1). Subsequent separation of the enantiomers by preparative HPLC [ method 14] on the chiral phase yields 1260mg (40% of theory) of the enantiomerically pure target compound (see example 80).

MS[ESIpos]：m/z＝465(M+H)⁺

HPLC [ method 2 ]]：R_t＝4.74min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.58(m，2H)，0.89(m，2H)，1.40(d，3H)，3.17(tt，1H)，4.43(s，2H)，5.01(dq，1H)，7.52-7.68(m，6H)，7.79(d，2H)，8.70(d，1H).

Chiral HPLC [ method 14]：R_t＝2.71min.

Example 82

N- (5-bromo-2-fluorophenylmethyl) -2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetamide

In 1.5ml dimethylformamide were placed 40.0mg (0.144mmol) of [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 93A, 36.0mg (0.150mmol) of 5-bromo-2-fluorobenzylamine hydrochloride, 22.1mg (0.163mmol) of HOBt and 17.6mg (0.136mmol) of N, N-diisopropylethylamine and treated with 33.9mg (0.177mmol) of EDC hydrochloride. After stirring at room temperature overnight, it was diluted with 15ml of water and extracted with ethyl acetate. After evaporation of the organic phase, the crude product is purified by preparative HPLC [ method 13 ]. Thus 21mg (32% of theory) of the target compound are obtained.

LC/MS [ method 5 ]]：R_t＝2.39min

¹H-NMR(400MHz，DMSO-d₆): δ is 0.53-0.67(m, 2H), 0.83-0.98(m, 2H), 3.18(dddd, 1H), 4.34(d, 2H), 4.45(s, 2H), 7.15-7.23(m, 1H), 7.47-7.53(m, 2H), 7.59, 7.61(AA 'part of AA' BB 'system, 2H), 7.82, 7.84 (BB' part of AA 'BB' system, 2H), 8.62(t, 1H).

Example 83

2- [3- (4-chlorophenyl) -4- (2-methoxyethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [3- (trifluoromethyl) phenylmethyl ] acetamide

In 2ml of dimethylformamide 50.0mg (0.160mmol) of 2- [3- (4-chlorophenyl) -4- (2-methoxyethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 90A, 30.9mg (0.176mmol) of 3-trifluoromethylbenzylamine and 40.0mg (0.209mmol) of HOBt are placed and treated with 26.0mg (0.192mmol) of EDC hydrochloride. After stirring overnight at room temperature, it was diluted with 15ml of water and the resulting precipitate was recovered by filtration. The crude product was washed with water and dried in vacuo. 66.9mg (89% of theory) of the target compound are thus obtained.

LC/MS [ method 7 ]]：R_t＝2.24min

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.13(s，3H)，3.50(t，2H)，3.88(t，2H)，4.41(d，2H)，4.50(s，2H)，7.54-7.65(m，6H)，7.70-7.75(m，2H)，8.71(t，1H).

The following compounds were obtained identically:

further, the following are obtained identically:

example 126

2- [ 4-cyclopropyl-3- (2-fluorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- (2-phenylethyl) -acetamide

40.0mg (0.144mmol) of [ 4-cyclopropyl-3- (2-fluorophenyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-yl ] -acetic acid from example 92A, 19.2mg (0.159mmol) of 2-phenylethylamine and 23.4mg (0.173mmol) of HOBt are placed in 2ml of dimethylformamide and treated with 36.0mg (0.188mmol) of EDC hydrochloride. After stirring at room temperature overnight, it was diluted with 10ml of water and extracted with ethyl acetate. After evaporation of the organic phase, the crude product is purified by preparative HPLC [ method 9 ]. Thus 32.0mg (58% of theory) of the target compound are obtained.

LC/MS [ method 4 ]]：R_t＝2.13min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.45-0.58(m，2H)，0.68-0.82(m，2H)，2.72(t，2H)，2.90-2.98(m，1H)，3.29(t，2H)，4.34(s，2H)，7.17-7.24(m，3H)，7.24-7.31(m，2H)，7.35-7.47(m，2H)，7.57-7.69(m，2H)，8.17(t，1H).

The following were obtained identically:

example 136

2- [ 4-cyclopropyl-3- (2-methoxyphenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [3- (trifluoromethyl) phenylmethyl ] acetamide

Method a):

76mg (0.26mmol) of [ 4-cyclopropyl-3- (2-methoxyphenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetic acid from example 95A and 45mg (0.28mmol) of carbonyldiimidazole are stirred in 1ml of 1, 2-dichloroethane until the initial evolution of gas has ended. A solution of 51mg (0.29mmol) of 3-trifluoromethylbenzylamine in 0.55ml of 1, 2-dichloroethane is added and stirred at 70 ℃ overnight. For work-up, the solvent is removed in vacuo and the residue is purified by preparative HPLC [ method 11 ]. Thus 46mg (39% of theory) of the target compound are obtained.

Method b):

in 3.2ml of dimethylformamide were placed 150mg (0.52mmol) of [ 4-cyclopropyl-3- (2-methoxyphenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 95A, 100mg (0.57mmol) of 3-trifluoromethylbenzylamine and 84mg (0.62mmol) of HOBt and treated with 129mg (0.67mmol) of EDC hydrochloride. Stirring overnight at room temperature and then purification directly by preparative HPLC [ method 11 ]. 222mg (96% of theory) of the target compound are thus obtained.

LC/MS [ method 7 ]]：R_t＝2.05min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.41-0.55(m，2H)，0.58-0.72(m，2H)，2.86(dddd，1H)，3.86(s，3H)，4.42(d，2H)，4.43(s，2H)，7.06(t，1H)，7.19(d，1H)，7.33(dd，1H)，7.52-7.65(m，5H)，8.65(t，1H).

Example 137

2- [3- (3-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [3- (trifluoromethyl) phenylmethyl ] -acetamide

In 0.75ml of dimethylformamide were placed 30.0mg (0.102mmol) of [3- (3-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 104A, 19.7mg (0.112mmol) of 3-trifluoromethylbenzylamine and 16.6mg (0.123mmol) of HOBt and treated with 25.5mg (0.133mmol) of EDC hydrochloride. Stirring was carried out at room temperature overnight and the reaction solution was directly purified by preparative HPLC [ method 9 ]. Thus 20mg (43% of theory) of the target compound are obtained.

LC/MS [ method 7 ]]：R_t＝2.27min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.53-0.68(m，2H)，0.83-0.98(m，2H)，3.22(dddd，1H)，4.41(d，2H)，4.46(s，2H)，7.53-7.64(m，6H)，7.74-7.83(m，2H)，8.66(t，1H).

The following were obtained identically:

example 141

2- [3- (4-chlorophenyl) -4- (3-fluorophenylmethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [3- (trifluoromethyl) phenylmethyl ] acetamide

200mg (0.66mmol) of 5- (4-chlorophenyl) -4- (3-fluorophenylmethyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one from example 41A, 193mg (0.69mmol) of 2-chloro-N- [3- (trifluoromethyl) phenylmethyl ] acetamide [ prepared according to EP 0163607, example 28 ] and 182mg (1.32mmol) of potassium carbonate are suspended in 2.5ml of acetonitrile and heated at reflux overnight. After cooling, it is diluted with water and purified by preparative HPLC [ method 9] and thus 219mg (64% of theory) of the target compound are obtained.

LC/MS [ method 7 ]]：R_t＝2.57min

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.44(d，2H)，4.58(s，2H)，5.01(s，2H)，6.93-7.01(m，2H)，7.09(td，1H)，7.36(dt，1H)，7.49-7.67(m，8H)，8.76(t，1H).

The following were obtained identically:

the following are likewise obtained:

example 1532- [3- (4-chlorophenyl) -4- (4-methoxyphenylmethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl]-N- [3- (trifluoromethyl) phenylmethyl]Acetamide

1.00g (3.17mmol) of 5- (4-chlorophenyl) -4- (4-methoxyphenylmethyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one from example 55A, 0.80g (3.17mmol) of 2-chloro-N- [3- (trifluoromethyl) phenylmethyl ] acetamide and 0.88g (6.33mmol) of potassium carbonate are suspended in 20ml of acetonitrile and heated at reflux for 8 hours. After this time the mixture was concentrated in vacuo and the residue was taken up in water and extracted three times with ethyl acetate. The combined organic phases are concentrated and the residue is purified by preparative HPLC [ method 12 ]. And 1.07g (64% of theory) of the target compound are thus obtained.

LC/MS [ method 5]]：R_t＝2.67min

¹H-NMR(400MHz，DMSO-d₆): δ — 3.70(s, 3H), 4.43(d, 2H), 4.6(s, 2H), 4.92(s, 2H), 6.83, 6.86(AA 'part of AA' BB 'system, 2H), 7.02, 7.04 (BB' part of AA 'BB' system, 2H), 7.51-7.66(m, 8H), 8.75(t, 1H).

The following were obtained identically:

a database of further application examples was prepared by parallel synthesis as follows:

0.12mmol of the corresponding amine and 0.10mmol of the corresponding triazolylacetic acid are dissolved in 0.6ml of dimethyl sulfoxide and treated with 25.8mg (0.2mmol) of N, N-diisopropylethylamine and 41.7mg (0.130mmol) of TBTU and shaken at room temperature overnight. The reaction solution was filtered and the filtrate was purified by preparative LC/MS [ method 6 ]. In this way the following are obtained:

example 186

2- [3- (4-chloroethyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [ (1S) -1- (1-naphthyl) ethyl ] propanamide (diastereomer A)

100.0mg (0.325mmol) of 2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -propionic acid from example 105A are placed in 2ml of DMF and treated with 61.2mg (0.357mmol) of (1S) -1- (1-naphthyl) ethylamine, 52.7mg (0.390mmol) of HOBt and 81.0mg (0.422mmol) of EDC hydrochloride. The mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water and the organic phase was separated, dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: first dichloromethane and then dichloromethane/methanol 100: 1) and is then further separated by preparative HPLC on the chiral phase [ method 15 ]. 52mg (35% of theory) of the diastereomerically pure target compound are thus obtained (cf. example 187).

MS[ESIpos]：m/z＝461(M+H)⁺

HPLC [ method 2 ]]：R_t＝4.84min

Chiral HPLC [ method 15]：R_t＝2.49min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.52(m，2H)，0.87(m，2H)，1.50(d，3H)，1.53(d，3H)，3.13(tt，1H)，4.80(q，1H)，5.68(dq，1H)，7.43(t，1H)，7.48-7.61(m，5H)，7.74(d，2H)，7.82(d，1H)，7.93(m，1H)，8.05(m，1H)，8.54(d，1H).

Example 187

2- [3- (4-chloroethyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [ (1S) -1- (1-naphthyl) ethyl ] propanamide (diastereomer B)

100.0mg (0.325mmol) of 2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -propionic acid from example 105A are placed in 2ml of DMF and treated with 61.2mg (0.357mmol) of (1S) -1- (1-naphthyl) ethylamine, 52.7mg (0.390mmol) of HOBt and 81.0mg (0.422mmol) of EDC hydrochloride. The mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water and the organic phase was separated, dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: first dichloromethane and then dichloromethane/methanol 100: 1) and is then further separated by preparative HPLC on the chiral phase [ method 15 ]. 51mg (34% of theory) of the diastereomerically pure target compound are thus obtained (cf. example 186).

MS[ESIpos]：m/z＝461(M+H)⁺

HPLC [ method 2 ]]：R_t＝4.84min

Chiral HPLC [ method 15]：R_t＝5.03min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.57(m，2H)，0.89(m，2H)，1.51(br.d，6H)，3.16(tt，1H)，4.78(q，1H)，5.67(dq，1H)，7.46-7.61(m，6H)，7.78(d，2H)，7.83(d，1H)，7.94(br.d，1H)，8.06(br.d，1H)，8.60(d，1H).

Example 188

2- [3- (4-chloroethyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [ (1R) -1- (1-naphthyl) ethyl ] propanamide (diastereomer A)

100.0mg (0.325mmol) of 2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -propionic acid from example 105A are placed in 2ml of DMF and treated with 61.2mg (0.357mmol) of (1R) -1- (1-naphthyl) ethylamine, 52.7mg (0.390mmol) of HOBt and 81.0mg (0.422mmol) of EDC hydrochloride. The mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water and the organic phase was separated, dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: first dichloromethane and then dichloromethane/methanol 100: 1) and is then further separated by preparative HPLC on the chiral phase [ method 16 ]. 44mg (29% of theory) of the diastereomerically pure target compound are thus obtained (cf. example 189).

MS[ESIpos]：m/z＝461(M+H)⁺

HPLC [ method 2 ]]：R_t＝4.84min

Chiral HPLC [ method 16]：R_t＝2.43min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.52(m，2H)，0.87(m，2H)，1.50(d，3H)，1.53(d，3H)，3.13(tt，1H)，4.80(q，1H)，5.68(dq，1H)，7.43(t，1H)，7.47-7.61(m，5H)，7.74(d，2H)，7.82(d，1H)，7.93(m，1H)，8.05(m，1H)，8.53(d，1H).

Example 189

2- [3- (4-chloroethyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [ (1R) -1- (1-naphthyl) ethyl ] propanamide (diastereomer B)

100.0mg (0.325mmol) of 2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -propionic acid from example 105A are placed in 2ml of DMF and treated with 61.2mg (0.357mmol) of (1R) -1- (1-naphthyl) ethylamine, 52.7mg (0.390mmol) of HOBt and 81.0mg (0.422mmol) of EDC hydrochloride. The mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water and the organic phase was separated, dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: first dichloromethane and then dichloromethane/methanol 100: 1) and is then further separated by preparative HPLC on the chiral phase [ method 16 ]. 58mg (39% of theory) of the diastereomerically pure target compound are thus obtained (cf. example 188).

MS[ESIpos]：m/z＝461(M+H)⁺

HPLC [ method 2 ]]：R_t＝4.84min

Chiral HPLC [ method 16]：R_t＝6.14min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.57(m，2H)，0.89(m，2H)，1.51(br.d，6H)，3.16(tt，1H)，4.77(q，1H)，5.67(dq，1H)，7.46-7.61(m，6H)，7.78(d，2H)，7.83(br.d，1H)，7.94(br.d，1H)，8.06(br.d，1H)，8.60(d，1H).

Example 190

Rac-2- (3-cyclopropyl-2-oxo-4-phenyl-2, 3-dihydro-1H-imidazol-1-yl) -N- [1- (2-naphthyl) ethyl ] -acetamide

40mg (0.155mmol) of (3-cyclopropyl-2-oxo-4-phenyl-2, 3-dihydro-1H-imidazol-1-yl) -acetic acid from example 128A, 29.2mg (0.17mmol) of 1- (2-naphthyl) ethylamine, 38.6mg (0.20mmol) of EDC hydrochloride and 25.1mg (0.19mmol) of HOBt are dissolved in 1.5ml of anhydrous DMF and stirred at RT overnight. The crude product was purified by preparative HPLC [ method 10 with the addition of 0.01M hydrochloric acid in water. A yield of 41mg (63% of theory) of the title compound is obtained.

HPLC [ method 2 ]]：R_t＝4.44min

MS[ESIpos]：m/z＝412(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.46(m，2H)，0.78(m，2H)，1.47(d，3H)，3.00(m，1H)，4.28(s，2H)，5.08(m，1H)，6.65(s，1H)，7.25-7.54(m，8H)，7.77-7.93(m，4H)，8.70(d，1H).

Example 191

Rac-2- [4- (4-bromophenyl) -3-cyclopropyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -N- {1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide

In 1.5ml dimethylformamide were placed 40.0mg (0.119mmol) of 4- (4-bromophenyl) -3-cyclopropyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid from example 129A, 24.7mg (0.130mmol) of 1- [ (3-trifluoromethyl) phenyl ] -ethylamine and 19.2mg (0.142mmol) of HOBt and treated with 29.6mg (0.154mmol) of EDC hydrochloride. It is stirred at room temperature overnight, then with 15ml of water, and the resulting precipitate is isolated and the crude product is purified by preparative HPLC [ method 13 ]. 23mg (38% of theory) of the target compound are thus obtained.

LC/MS [ method 7 ]]：R_t＝2.43min

¹H-NMR(400MHz，DMSO-d₆): δ is 0.39-0.53(m, 2H), 0.73-0.88(m, 2H), 1.39(d, 3H), 3.00(dddd, 1H), 4.25 (center of AB system, 2H), 4.99(dq, 1H), 6.72(s, 1H), 7.44, 7.46(AA 'part of AA' BB 'system, 2H), 7.52-7.68(m, 4H), 7.57, 7.59 (BB' part of AA 'BB' system, 2H), 8.71(d, 1H).

The following were obtained identically:

example 194

2- [4- (4-chlorophenyl) -3-cyclopropyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -N- [3- (trifluoromethyl) phenylmethyl ] acetamide

In 1.5ml of dimethylformamide were placed 50.0mg (0.171mmol) of 4- (4-chlorophenyl) -3-cyclopropyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid from example 130A, 32.9mg (0.188mmol) of 3-trifluoromethylbenzylamine and 27.7mg (0.205mmol) of HOBt and treated with 42.6mg (0.222mmol) of EDC hydrochloride. It was stirred at room temperature overnight, then stirred with 19ml of water and the resulting precipitate recovered by filtration. The crude product was washed with water and dried in vacuo. 65mg (85% of theory) of the target compound are thus obtained.

LC/MS [ method 4 ]]：R_t＝2.59min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.42-0.55(m，2H)，0.73-0.88(m，2H)，3.02(dddd，1H)，4.27(s，2H)，4.39(d，2H)，6.76(s，1H)，7.43-7.66(m，8H)，8.66(t，1H).

Example 195

Rac-2- [4- (4-chlorophenyl) -3-cyclopropyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -N- {1- [3- (trifluoro-methyl) phenyl ] ethyl } acetamide

In 1.5ml dimethylformamide were placed 50.0mg (0.171mmol) 4- (4-chlorophenyl) -3-cyclopropyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid from example 130A, 35.5mg (0.188mmol)1- [3- (trifluoromethyl) phenyl ] -ethylamine and 27.7mg (0.205mmol) HOBt and treated with 42.6mg (0.222mmol) EDC hydrochloride. It was stirred at room temperature overnight, then stirred with 19ml of water and the resulting precipitate recovered by filtration. The crude product was washed with water, dried in vacuo and purified by preparative HPLC [ method 9 ]. 14mg (18% of theory) of the target compound are thus obtained.

LC/MS [ method 7 ]]：R_t＝2.38min

¹H-NMR(400MHz，DMSO-d₆): δ is 0.39-0.53(m, 2H), 0.73-0.87(m, 2H), 1.39(d, 3H), 3.00(dddd, 1H), 4.25 (center of AB system, 2H), 7.54-7.64(m, 4H), 7.58, 7.60(AA ' part of BB ' system, 2H), 7.51, 7.53 (BB ' part of AA ' BB ' system, 2H), 7.54-7.69(m, 4H), 8.71(d, 1H).

The following were obtained identically:

example 196

Rac-2- [4- (4-chlorophenyl) -3-cyclopropyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -N- [1- (2-naphthyl) ethyl ] acetamide

LC/MS [ method 7 ]]：R_t＝2.38min

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.39-0.53(m，2H)，0.73-0.88(m，2H)，1.47(d，3H)，3.01(dddd，1H)，4.27(s，2H)，5.07(dq，1H)，6.72(s，1H)，7.41-7.54(m，7H)，7.81(s，1H)，7.84-7.91(m，3H)，8.70(d，1H).

Example 197

2- [4- (4-chlorophenyl) -3-cyclopropyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -N- [ (1S) -1- (1-naphthyl) ethyl ] acetamide

150mg (0.512mmol) of [4- (4-chlorophenyl) -3-cyclopropyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid from example 130A, 96.5mg (0.564mmol) of (1R) -1- (1-naphthyl) ethylamine, 128mg (0.67mmol) of EDC hydrochloride and 83.1mg (0.62mmol) of HOBt are dissolved in 2ml of anhydrous dimethylformamide and stirred at room temperature overnight. The crude product is purified by flash chromatography on silica gel (eluent: first dichloromethane and then dichloromethane/methanol 100: 1). A yield of 172mg (75% of theory) of the title compound is obtained.

HPLC [ method 2 ]]：R_t＝4.78min

MS[ESIpos]：m/z＝446(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.45(m，2H)，0.79(m，2H)，1.51(d，3H)，3.00(m，1H)，4.25(d，2H)，5.70(m，1H)，6.70(s，1H)，7.40-7.61(m，8H)，7.84(d，1H)，7.95(d，1H)，8.10(d，1H)，8.76(d，1H).

The following were obtained analogously to examples 190 and 197:

example 213

2- [4- (4-chlorophenyl) -3-cyclopropyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -N- [3- (trifluoromethyl) phenylmethyl ] propanamide

50mg (0.163mmol) of 2- (4- [ 4-chlorophenyl ] -3-cyclopropyl-2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -propionic acid from example 131A, 31.4mg (0.179mmol) of 3-trifluoromethylbenzylamine, 40.6mg (0.212mmol) of EDC hydrochloride and 26.4mg (0.196mmol) of HOBt are dissolved in 1ml of anhydrous dimethylformamide and stirred at room temperature overnight the mixture is partitioned between water and dichloromethane and the separated organic phase is dried over sodium sulfate and concentrated the remaining crude product is purified by flash chromatography on silica gel (flow agent: first dichloromethane and then dichloromethane/methanol 100: 1 → 50: 1) 42mg (56% of theory) of the title compound are thus obtained.

MS[ESIpos]：m/z＝464(M+H)⁺；[ESIneg]：m/z＝462(M-H)^-

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.42-0.54(m，2H)，0.75-0.87(m，2H)，1.47(d，3H)，3.02(dddd，1H)，4.37(d，2H) 4.74(q, 1H), 6.91(s, 1H), 7.44, 7.47(AA 'part of the AA' BB 'system, 2H), 7.53-7.63(m, 4H), 7.55, 7.57 (BB' part of the AA 'BB' system, 2H), 8.75(t, 1H).

The following were obtained identically:

example 216

2- [3- (4-chloro-2-methoxyphenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [ 1-methyl-1- (3-trifluoromethyl-phenyl) ethyl ] -acetamide

70mg (0.14mmol) of the bromide from example 141A and 35.4mg (2-methoxy-4-chlorophenyl) boronic acid (0.19mmol) are dissolved in 1.75 degassed DMF under argon and treated with 204. mu.l of degassed solution of 2M sodium carbonate in water (0.41 mmol). About 8mg of tetrakis (triphenylphosphine) palladium (about 7. mu. mol) was added and the mixture was heated at 90 ℃ for 5 hours. After cooling, filtration, the solid was washed with a little DMSO and the entire filtrate was separated by preparative HPLC (method 20). 65mg (83% of theory) of the title compound are obtained.

LC/MS [ method 7 ]]：R_t＝2.63min；m/z＝577(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，3.68(s，3H)，4.49(s，2H)，4.71(s，2H)，6.96-7.08(m，4H)，7.16(d，1H)，7.19-7.28(m，2H)，7.48-7.57(m，2H)，7.62(s，1H)，7.67(d，1H)，8.51(br.s，1H).

The following examples were prepared by the same method from the corresponding boronic acids (all commercially available) and the starting bromides described. In some cases, the boronic acid is replaced with the corresponding 4, 4, 5, 5-tetramethyl-1, 2, 3-cyclopentylborane derivative (cyclic tetramethylethylene glycol borate).

Example 244

2- [3- (4-chloro-2-hydroxyphenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [ 1-methyl-1- (3-trifluoromethyl-phenyl) ethyl ] -acetamide

A solution of 41mg (71. mu. mol) of the compound from example 216 under argon was treated at-20 ℃ with 355. mu.l of a solution of boron tribromide in dichloromethane (355. mu. mol). The cooling bath was removed and the reaction mixture was further stirred at RT overnight. The reaction was stopped by adding 750. mu.l of methanol. The volatile components are removed on a rotary evaporator and the residue is purified by preparative HPLC (method 20). 15mg (38% of theory) of the title compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.72min；m/z＝563(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，4.49(s，2H)，4.71(s，2H)，6.86(dd，1H)，6.96(d，1H)，6.96-7.07(m，4H)，7.23(m，1H)，7.49-7.56(m，2H)，7.52(s，1H)，7.58(d，1H)，8.52(s，1H)，10.89(br.s，1H).

Example 245

2- [3- (4-chloro-2-hydroxyphenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [ (2-trifluoromethyl-phenyl) methyl ] -acetamide

The title compound was prepared by the same method as described for example 244, starting from example 227.

LC/MS [ method 7 ]]：R_t＝2.33min；m/z＝535(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.50(d，2H)，4.55(s，2H)，4.86(s，2H)，6.89(dd，1H)，6.98(d，1H)，7.02-7.10(m，3H)，7.12(d，1H)，7.25(m，1H)，7.49(t，1H)，7.59(d，1H)，7.65(t，1H)，7.72(d，1H)，8.54(t，1H)，10.90(br.s，1H).

Example 246

2- [3- (5-chlorothien-2-yl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [ 1-methyl-1- (3-trifluoromethyl-phenyl) ethyl ] -acetamide

The carboxylic acid from example 154A (150mg, 0.41mmol) and 1-methyl-1- (3-trifluoromethyl-phenyl) ethylamine (example 1A, 91.2mg, 0.45mmol) were placed in 4ml of DMF and treated with 66.1mg (0.49mmol) of HOBt at RT. After 10 min, 101.6mg (0.53mmol) EDC were added and the mixture was stirred at RT overnight. Followed by treatment with water and ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, then with saturated sodium chloride solution, dried by filtration through an Extrelut cartridge and freed of volatile components on a rotary evaporator. The residue was purified by chromatography on silica gel (Biotage filter 25M, eluent: cyclohexane/ethyl acetate 1: 1). 192mg (85% of theory) of the title compound are thus obtained.

LC/MS [ method 8 ]]：R_t＝2.92min；m/z＝553(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.72(s，6H)，4.53(s，2H)，5.15(s，2H)，6.63(s，1H)，6.86(d，1H)，6.94(d，1H)，7.04-7.11(m，3H)，7.30(m，1H)，7.43(t，1H)，7.49(d，1H)，7.58(d，1H)，7.59(s，1H).

The compounds in the table below were prepared identically. The amines used here are commercially available.

Example 253

2- [4- (3-fluorobenzyl) -3- (2-hydroxyphenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [ 1-methyl-1- (3-trifluoromethyl-phenyl) ethyl ] -acetamide

The carboxylic acid from example 150A (50mg, 0.15mmol) and HOBt (35.4mg, 0.26mmol) were placed in 1ml DMF and treated with 50.3mg (0.26mmol) EDC at RT. After 20 min, 1-methyl-1- (3-trifluoromethyl-phenyl) ethylamine (example 1A, 44.4mg, 0.22mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was then separated directly by preparative HPLC (method 20). 24mg (31% of theory) of the title compound are obtained.

LC/MS [ method 17 ]]：R_t＝3.68min；m/z＝529(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.59(s，6H)，4.48(s，2H)，4.78(s，2H)，6.72(d，1H)，6.76(d，1H)，6.82(t，1H)，6.94-7.03(m，2H)，7.08(dd，1H)，7.23(dt，1H)，7.33(dt，1H)，7.48-7.56(m，2H)，7.63(s，1H)，7.67(d，1H)，8.53(s，1H)，10.33(s，1H).

Post-treatment alternative:

at the end of the reaction, the reaction mixture can be treated with 1N hydrochloric acid (2-8 ml per mmol of carboxylic acid used) directly before the solution is separated by preparative HPLC (method 20). For larger amounts (> 0.4mmol of carboxylic acid used), the crude product is worked up by extraction, for example as described in example 246, before purification by preparative HPLC.

The compounds in the table below were prepared analogously to example 253. Amine starting materials are commercially available unless otherwise indicated. When the amine starting material was used as the salt (hydrochloride or trifluoroacetate salt), 1 equivalent of N, N-diisopropylethylamine was added to the reaction mixture.

Example 263

2- [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [ 1-methyl-1- (3-trifluoromethyl-phenyl) ethyl ] -acetamide

100mg (0.36mmol) of the compound from example 133A, 108.6mg (0.36mmol) of the compound from example 40A and 98.8mg (0.72mmol) of potassium carbonate are stirred at reflux temperature in 2.7ml of acetonitrile overnight. After cooling, the mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the volatile components were removed on a rotary evaporator. The residue was dried under high vacuum. 192mg (98% of theory) of the title compound are obtained.

LC/MS [ method 7 ]]：R_t＝2.70min；m/z＝547(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，4.52(s，2H)，5.00(s，2H)，6.98-7.16(m，3H)，7.25-7.32(m，1H)，7.48-7.56(m，6H)，7.62(s，1H)，7.67(d，1H)，8.58(s，1H).

Example 264

2- [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [2- (2-trifluoromethyl-phenyl) ethyl ] -acetamide

The carboxylic acid from example 156A (60mg, 0.14mmol) and HOBt (27.0mg, 0.20mmol) were placed in 0.86ml DMF and treated with 38.2mg (0.20mmol) EDC at RT. After 20 min, 27mg of 2- (2-trifluoromethyl-phenyl) ethylamine (0.14mmol) were added and the mixture was stirred at RT overnight. The reaction mixture was then separated directly by preparative HPLC (method 20). 69mg (91% of theory) of the title compound are obtained.

LC/MS [ method 7 ]]：R_t＝2.57min；m/z＝533(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝2.92(t，2H)，3.35(q，2H)，4.44(s，2H)，5.03(s，2H)，7.06-7.19(m，3H)，7.28-7.35(m，1H)，7.43(t，1H)，7.49(d，1H)，7.60(t，1H)，7.68(d，1H)，8.32(t，1H).

The compounds in the table below were prepared identically. Amine starting materials are commercially available unless otherwise indicated. If the amine starting material is used as the salt (hydrochloride or trifluoroacetate salt), 1 equivalent of N, N-diisopropylethylamine is added to the reaction mixture.

Example 300

N- { [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } - (2-trifluoromethyl) -D-phenylalanine

The compound from example 287 (50mg, 0.085mmol) was treated with 1M aqueous lithium hydroxide (423. mu.l) in 5ml methanol and the mixture was stirred at RT overnight. It is then acidified to pH 1 with 1N hydrochloric acid, treated with 30ml of water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and freed of volatile constituents on a rotary evaporator. The residue was dried under high vacuum. 44mg (90% of theory) of the title compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.76min；m/z＝577(M+H)⁺.

Example 301

N^α- { [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl]Acetyl } -N, N-dimethyl-2-trifluoromethyl-L-phenylalanine amide

24mg (42. mu. mol) of N- { [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } - (2-trifluoromethyl) -L-phenylalanine [ prepared analogously to example 287 starting from example 156A and L-2-trifluoromethylphenylalanine methyl ester and then hydrolyzed analogously to example 300 methyl ester ] and 8mg of HOBt (58. mu. mol) are placed in 1ml of DMF and treated with 11mg (58. mu. mol) of EDC at RT. After 20 min, a solution of 2M dimethylamine in THF (25 μ l, 50 μmol) was added and the mixture was stirred at RT overnight. After addition of 1ml of 1N hydrochloric acid, the mixture is separated directly by preparative HPLC (method 20). 16mg (64% of theory) of the title compound are obtained.

LC/MS [ method 19 ]]：R_t＝3.68min；m/z＝604(M+H)⁺.

Example 302

N- { 2-amino-oxo-1- [2- (trifluoromethyl) phenyl ] ethyl } -2- [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetamide

200mg of the compound from example 293 (347. mu. mol) are stirred in 36ml of methanol for 2 hours at RT with 3.47ml of 1N aqueous lithium hydroxide solution. The mixture is then adjusted to pH 2 with 1N hydrochloric acid. Methanol was removed on a rotary evaporator and the residual mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the volatile components were removed on a rotary evaporator. The carboxylic acid thus obtained is dried under high vacuum [ quantitative yield, LC/MS [ method 17 ]]：R_t＝3.67min；m/z＝563(M+H)⁺]。

23mg (41. mu. mol) of the carboxylic acid obtained above and 10mg of HOBt (74. mu. mol)) were placed in 0.9ml of DMF and treated with 14mg (74. mu. mol)) of EDC at RT. After 20 min, aqueous ammonia solution (32%, 1.09g, 20mmol) was added and the mixture was stirred at RT overnight. After addition of 1ml of 1N hydrochloric acid, the mixture is separated directly by preparative HPLC (method 20). 13mg (57% of theory) of the title compound are obtained.

LC/MS [ method 22 ]]：R_t＝1.94min；m/z＝562(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.50(d，1H)，4.68(d，1H)，5.02(s，2H)，5.66(d，1H)，7.01-7.18(m，3H)，7.27-7.34(m，1H)，7.44(s，1H)，7.52(s，4H)，7.54(t，1H)，7.64(d，1H)，7.65(s，1H)，7.69-7.75(m，2H)，9.04(d，1H).

Example 303

2- [3- (4-chlorophenyl) -4- (cyclopropyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [2- (2-trifluoromethyl-phenyl) ethyl ] -acetamide

The carboxylic acid from example 88A (50mg, 0.14mmol) and HOBt (35mg, 0.26mmol) were placed in 3ml DMF and treated with 49mg (0.26mmol) EDC at RT. After 20 min, 41mg2- (2-trifluoromethyl-phenyl) ethylamine (0.21mmol) was added and the mixture was stirred at RT overnight. After addition of 1ml of 1N hydrochloric acid, the mixture is separated directly by preparative HPLC (method 20). 51mg (77% of theory) of the title compound are obtained.

LC/MS [ method 19 ]]：R_t＝3.50min；m/z＝465(M+H)⁺

¹H-NMR (400MHz，DMSO-d₆)：δ＝0.56-0.63(m，2H)，0.87-0.94(m，2H)，2.89(t，2H)，3.17(m，1H)，3.30-3.37(m，2H)，4.33(s，2H)，7.43(t，1H)，7.47(d，1H)，7.57-7.64(m，3H)，7.68(d，1H)，7.81(d，2H)，8.25(t，1H).

Example 342

2- [3- (4-chlorophenyl) -4- (cyclopropyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [2- (2-chloro-phenyl) -3-hydroxypropyl ] -acetamide

Prepared by the method described in example 303 from the carboxylic acid from example 88A and 2- (2-chlorophenyl) -3-hydroxypropylamine [ preparation: see arch.301，750(1968)]The title compound was obtained in 83% yield.

LC/MS [ method 19 ]]：R_t＝2.99min；m/z＝461(M+H)⁺.

Example 343

2- ({ [3- (4-chlorophenyl) -4- (2-methoxyethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetyl } amino) -N-cyclopropyl-2- [3- (trifluoromethyl) phenyl ] -acetamide

The carboxylic acid from example 90A (25mg, 81. mu. mol) and HOBt (20mg, 145. mu. mol) were placed in 1.7ml of DMF and treated with 28mg (145. mu. mol) EDC at RT. After 20 minutes, 36mg (97. mu. mol) of amine trifluoroacetate from example 181A and 28. mu.l (161. mu. mol) of N, N-diisopropylethylamine are added and the mixture is stirred overnight at RT. After addition of 1ml of 1N hydrochloric acid, the mixture is separated directly by preparative HPLC (method 20). 30mg (67% of theory) of the title compound are obtained.

LC/MS [ method 23]：R_t＝2.09min；m/z＝552(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.27-0.35(m，1H)，0.39-0.47(m，1H)，0.56-0.70(m，2H)，2.58-2.66(m，1H)，3.11(s，3H)，3.46(t，2H)，3.87(t，2H)，4.57(m[AB]，2H)，5.48(d，1H)，7.57-7.63(m，3H)，7.65-7.73(m，4H)，7.76(s，1H)，8.53(d，1H)，9.05(d，1H).

The compounds in the table below were prepared identically. Amine starting materials are commercially available unless otherwise indicated.

Example 354

2- [3- (4-chlorophenyl) -4- (2-methoxyethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [2, 2-diethoxy-2- (pyridin-2-yl) ethyl) ] -acetamide hydrochloride

80mg (92% of theory) of the title compound are obtained by the method described in example 343 from the carboxylic acid from example 90A (50mg, 160. mu. mol) and 2, 2-diethoxy-2- (pyridinyl-2-yl) ethylamine dihydrochloride (68mg, 240. mu. mol; see Synthesis, 1980(4), 329) for preparation.

LC/MS [ method 8 ]]：R_t＝2.09min；m/z＝504(M+H)⁺.

Example 355

2- [3- (4-chlorophenyl) -4- (cyclopropyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { (1RS, 2RS) - [2- (3-trifluoromethyl-phenyl) cyclopropyl ] } -acetamide

The carboxylic acid from example 88A (28mg, 96. mu. mol) and HOBt (19mg, 0.14mmol) were placed in 1ml of DMF and treated with 28mg (0.14mmol) of EDC at RT. After 20 min, 25mg (0.11mmol) of the compound from example 203A and 23. mu.l N, N-diisopropylethylamine (134. mu. mol) are added and the mixture is stirred at RT for 5 h. The mixture was then separated directly by preparative HPLC (method 20). 39mg (86% of theory) of the title compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.57min；m/z＝477(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.50-0.60(m，2H)，0.83-0.92(m，2H)，1.14(m，1H)，1.35(m，1H)，2.31(m，1H)，3.01(m，1H)，3.14(m，1H)，4.01(d，1H)，4.19(d，1H)，7.38-7.52(m，4H)，7.59(d，2H)，7.73(d，2H)，8.20(d，1H).

Example 356

2- [3- (4-chlorophenyl) -4- (cyclopropyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- {2, 2-difluoro-2- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide

Starting from example 88A and example 205A, the title compound was obtained in 68% yield by the method described in example 355.

LC/MS [ method 23]：R_t＝2.30min；m/z＝501(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.54-0.60(m，2H)，0.86-0.93(m，2H)，3.17(m，1H)，3.94(dt，2H)，4.36(s，2H)，7.59(d，2H)，7.71-7.81(m，3H)，7.82-7.88(m，2H)，7.91(d，1H)，8.59(t，1H).

Example 357

2- [3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { (1RS, 2RS) - [2- (3-trifluoromethyl-phenyl) cyclopropyl ] } -acetamide

The carboxylic acid from example 229A (enantiomer 1; 35mg, 96. mu. mol) and HOBt (19mg, 0.14mmol) were placed in 1ml of DMF and treated with 28mg (0.14mmol) of EDC at RT. After 20 min, 25mg (0.11mmol) of the compound from example 203A and 23. mu.l (0.13mmol) of N, N-diisopropylethylamine were added and the mixture was stirred at RT overnight. The mixture was then separated directly by preparative HPLC (method 20). 46mg (88% of theory) of the title compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.67min；m/z＝549(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.15(q，1H)，1.37(dt，1H)，2.33(q，1H)，3.03(m，1H)，3.80(dd，1H)，3.93(br.d，1H)，4.06(dd，1H)，4.25(m，1H)，4.26(dd，1H)，6.89(d，1H)，7.40-7.52(m，4H)，7.60-7.65(m，2H)，7.66-7.72(m，2H)，8.25(dd，1H).

Example 365

4- {3- (4-chlorophenyl) -1- [2- ({ 2-methyl-2- [2- (trifluoromethyl) phenyl ] propyl } amino) -2-oxoethyl ] -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl } -butyric acid tert-butyl ester

The carboxylic acid from example 224A (20mg, 51. mu. mol), HOBt (13mg, 91. mu. mol) and N, N-diisopropylethylamine (13. mu.l, 76. mu. mol) were placed in 0.75ml DMF and treated with 17.4mg (91. mu. mol) EDC at RT. After 20 min, 17mg (66 μmol) of the compound from example 166A were added and the mixture was stirred at RT overnight. The mixture was then separated directly by preparative HPLC (method 20). 24mg (80% of theory) of the title compound are obtained.

LC/MS [ method 22 ]]：R_t＝2.54min；m/z＝595(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.35(s，9H)，1.39(s，6H)，1.69(quin，2H)，2.14(t，2H)，3.45(d，2H)，3.75(t，2H)，4.45(s，2H)，7.45(t，1H)，7.56-7.69(m，6H)，7.75(d，1H)，7.91(t，1H).

Example 366

4- {3- (4-chlorophenyl) -1- [2- ({2- (dimethylamino) -2-oxo-1- [3- (trifluoromethyl) phenyl ] -ethyl } -amino) -2-oxoethyl ] -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl } -butyric acid tert-butyl ester

Starting from example 224A and example 175A (as trifluoroacetate salt), the title compound was obtained in analogy to example 365.

LC/MS [ method 22 ]]：R_t＝2.32min；m/z＝624(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.32(s，9H)，1.69(quin，2H)，2.14(t，2H)，2.85(s，3H)，2.99(s，3H)，3.75(t，2H)，4.50(m，2H)，5.99(d，1H)，7.58-7.72(m，7H)，7.77(s，1H)，8.99(d，1H).

Example 367

4- {3- (4-chlorophenyl) -1- [2- ({ 2-methyl-2- [2- (trifluoromethyl) phenyl ] propyl } amino) -2-oxoethyl ] -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl } -butyric acid

The compound from example 365 (22mg, 37 μmol) was stirred overnight at RT with 1ml of a 4M solution of hydrogen chloride in dioxane. The solvent was then removed on a rotary evaporator. The residue was taken up in DMSO and purified by preparative HPLC (method 20). 14mg (70% of theory) of the title compound are obtained.

LC/MS [ method 22 ]]：R_t＝1.98min，m/z＝539(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.39(s，6H)，1.69(quin，2H)，2.18(t，2H)，3.45(d，2H)，3.74(t，2H)，4.35(s，2H)，7.44(t，1H)，7.56-7.63(m，3H)，7.63-7.68(m，3H)，7.77(d，1H)，7.91(t，1H)，12.12(br.s，1H).

Example 368

4- {3- (4-chlorophenyl) -1- [2- ({2- (dimethylamino) -2-oxo-1- [3- (trifluoromethyl) phenyl ] -ethyl } -amino) -2-oxoethyl ] -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl } -butyric acid

Starting from example 366, the title compound was obtained in analogy to example 367.

LC/MS [ method 22 ]]：R_t＝1.80min；m/z＝568(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.69(quin，2H)，2.17(t，2H)，2.85(s，3H)，2.99(s，3H)，3.75(t，2H)，4.50(m，2H)，5.99(d，1H)，7.57-7.73(m，7H)，7.76(s，1H)，8.99(d，1H)，12.11(br.s，1H).

Example 369

2- [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [1- (isoquinolin-1-yl) ethyl ] -acetamide

In analogy to example 264 from the carboxylic acid from example 156A (40mg, 0.11mmol) and 26.7mg (0.16mmol) 1-isoquinolin-1-ylethylamine [ preparation: see chem.108，3771-3778(1975)]The title compound was prepared. Yield: 70% of theory

LC/MS [ method 17 ]]：R_t＝3.47min；m/z＝516(M+H)⁺.

Example 370

2- [3- (4-chlorophenyl) -4- (cyclopropyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 3-dimethylamino-3-oxo-2- [2- (trifluoromethyl) phenyl ] propyl } -acetamide

The compound from example 317 (55mg, 102 μmol) was hydrolyzed to the corresponding carboxylic acid (52mg) in analogy to example 300. 30mg of the acid (59. mu. mol) was then reacted with dimethylamine in analogy to example 301 to yield the title compound (31mg, 98% of theory).

LC/MS [ method 22 ]]：R_t＝1.93min；m/z＝536(M+H)⁺.

Example 371

2- [3- (4-chlorophenyl) -4-allyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide

In 50ml dimethylformamide were placed 1.98g (6.74mmol) of [3- (4-chlorophenyl) -4-allyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 218A and 1.51g (7.42mmol) of 1-methyl-1- [ (3-trifluoromethyl) -phenyl ] ethylamine from example 1A and treated with 1.09g (8.09mmol) of HOBt. After stirring for 10 min, 1.68g (8.76mmol) EDC hydrochloride are added and the mixture is stirred at RT overnight. For working up, the reaction mixture is stirred with 500ml of water. Next, the resulting precipitate was suction-filtered, washed with water and dried under high vacuum. Thus 2.41g (75% of theory) of the target compound are obtained.

LC/MS [ method 7 ]]：R_t＝2.49min；MS[ESIpos]：m/z＝479(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，4.30-4.38(m，4H)，4.50(s，2H)，4.92(d，1H)，5.11(d，1H)，5.82(m，1H)，7.50-7.70(m，8H)，8.55(s，1H).

The following compounds were prepared identically:

example 378

2- [3- (4-chlorophenyl) -4- (2-methoxyethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N-1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl-acetamide

In 60ml dimethylformamide were placed 2.90g (9.30mmol) of [3- (4-chlorophenyl) -4- (2-methoxyethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 90A and 2.08g (10.23mmol) of 1-methyl-1- [ (3-trifluoromethyl) -phenyl ] ethylamine from example 1A and treated with 1.51g (11.2mmol) of HOBt. After stirring for 10 min, 2.32g (12.1mmol) EDC hydrochloride are added and the mixture is stirred at RT overnight. For working up, the reaction mixture is stirred with 500ml of water. Next, the resulting precipitate was suction-filtered, washed with water and dried under high vacuum. Thus 3.27g (71% of theory) -of the target compound are obtained.

LC/MS [ method 19 ]]：R_t＝3.60min；MS[ESIpos]：m/z＝497(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，3.10(s，3H)，3.45(t，2H)，3.84(t，2H)，4.47(s，2H)，7.48-7.72(m，8H)，8.56(s，1H).

The following compounds were prepared identically:

example 396

2- [3- (4-chlorophenyl) -4- (2-hydroxyethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N-1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl-acetamide

2.95g (5.94mmol) 2- [3- (4-chlorophenyl) -4- (2-methoxyethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N-1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl-acetamide from example 378 are dissolved in 40ml chloroform and treated at RT with 6.76ml (47.5mmol) iodo-trisilane. Stir at RT for 1 hour. Next, a mixture of 40ml of methanol and 5.99g (47.5mmol) of sodium sulfite was added with vigorous stirring with ice-cooling. The reaction solution was diluted with 100ml of water and extracted twice with 50ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was dissolved in 50ml of isopropanol. After addition of approximately 50ml of water, the desired product precipitates out. The mixture was stirred at RT for one hour. Next, the crystals were suction-filtered and washed with a little water and a little cyclohexane. After drying under high vacuum, 2.56g (89% of theory) of the target compound are thus obtained.

LC/MS [ method 17 ]]：R_t＝3.45min；MS[ESIpos]：m/z＝483(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，3.54(q，2H)，3.75(t，2H)，4.47(s，2H)，5.00(t，1H)，7.48-7.78(m，8H)，8.55(s，1H).

The following compounds were prepared identically:

example 401

2- [3- (4-chlorophenyl) -4- (2-oxoethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N-1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl-acetamide

0.5g (1.04mmol) of 2- [3- (4-chlorophenyl) -4- (2-hydroxyethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N-1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl-acetamide from example 396 are dissolved in 30ml of dichloromethane and treated with 0.57g (1.35mmol) of 1, 1, 1-tris- (acetoxy) -1, 1-dihydro-1, 2-phenyliodoxy) -3- (1H) -one (Dess-Martin Periodinan) at 0 ℃. Stir at RT for 18 hours. Thereafter, 0.38g (0.90mmol) of dess-Martin reagent was further added. After 3 hours, the suspension is purified directly by flash chromatography on silica gel (eluent: dichloromethane/ethyl acetate/methanol 100: 1). The product thus obtained is taken up in 50ml of ethyl acetate and washed once with 50ml of 0.05N hydrochloric acid. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Thus 0.32g (64% of theory) of the target compound are obtained.

LC/MS [ method 19 ]]：R_t＝3.21min；MS[ESIpos]：m/z＝481(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝1.71(s，6H)，4.52(s，2H)，4.49(s，2H)，6.55(s，1H)，7.44-7.70(m，8H)，9.61(s，1H).

The following compounds were prepared identically:

Example 403

2- [3- (4-chlorophenyl) -4- (3-methoxybenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N-1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl-acetamide

75mg (0.17mmol) of 2- [3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide from example 241A and 84mg (0.26mmol) of cesium carbonate are suspended in 2.5ml of acetone and treated with 45mg (0.22mmol) of 3-methoxybenzyl chloride. Stirring was carried out at 50 ℃ for 6 hours and then at RT for 18 hours. The suspension is treated with 1ml of water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered. After evaporation of the organic phase, the crude product is purified by preparative HPLC [ method 10 ]. 55.6mg (58% of theory) of the target compound are thus obtained.

LC/MS [ method 18 ]]：R_t＝2.78min；MS[ESIpos]：m/z＝559(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，3.60(s，3H)，4.54(s，2H)，4.95(s，2H)，6.59-6.64(m，2H)，6.75-6.80(m，1H)，7.18(t，1H)，7.46-7.72(m，8H)，8.58(s，1H).

The following compounds were prepared identically:

example 423

2- [3- (4-chlorophenyl) -4- (2-methylpropan-2-en-1-yl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N-1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl-acetamide

75mg (0.17mmol) of 2- [3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide from example 241A and 84mg (0.26mmol) of cesium carbonate are suspended in a mixture of 2.5ml of acetone and 0.5ml of DMF and treated with 185mg (1.12mmol) of 1-bromo-2-fluoro-2-methylpropane. Stirring was carried out at 50 ℃ for 18 hours. The suspension is then treated with 1ml of water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered. After evaporation, the crude product is purified by preparative HPLC [ method 10 ]. 37.3mg (44% of theory) of the target compound are obtained.

LC/MS [ method 7 ]]：R_t＝2.56min；MS[ESIpos]：m/z＝493(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，1.62(s，3H)，3.60(s，3H)，4.27(s，2H)，4.46(s，1H)，4.52(s，2H)，4.80(s，1H)，7.48-7.70(m，8H)，8.54(s，1H).

The following compounds were prepared identically:

example 425

(2Z) -3-3- (4-chlorophenyl) -1- [2- (1-methyl-1- [3- (trifluoromethyl) phenyl ] ethylamino) -2-oxoethyl ] -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl-acrylic acid ethyl ester

And

example 426

(2E) -3-3- (4-chlorophenyl) -1- [2- (1-methyl-1- [3- (trifluoromethyl) phenyl ] ethylamino) -2-oxoethyl ] -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl-acrylic acid ethyl ester

75mg (0.17mmol) of 2- [3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide from example 241A and 84mg (0.26mmol) of cesium carbonate are suspended in 2.5ml of acetone and treated with 40mg (0.22mmol) of cis-3-bromoethyl acrylate. Stirring was carried out at 50 ℃ for 18 hours. The suspension is then treated with 1ml of water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered. After evaporation, the crude product is purified by preparative HPLC [ method 10 ]. The Z-and E-isomers of the title compound were obtained in isolated form.

Z-isomer (example 425):

yield: 32.1mg (35% of theory)

LC/MS [ method 8 ]]：R_t＝2.79min；MS[ESIpos]：m/z＝537(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.01(t，3H)，1.60(s，6H)，3.90(q，2H)，4.50(s，2H)，6.09(d，1H)，6.90(d，1H)，7.48-7.70(m，8H)，8.56(s，1H).

E-isomer (example 426):

Yield: 43.4mg (49% of theory)

LC/MS [ method 8 ]]：R_t＝2.91min；MS[ESIpos]：m/z＝537(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.20(t，3H)，1.60(s，6H)，4.14(q，2H)，4.52(s，2H)，6.72(d，1H)，7.41(d，1H)，7.48-7.70(m，8H)，8.60(s，1H).

Example 427

4- (3- (4-chlorophenyl) -1- [2- (1-methyl-1- [3- (trifluoromethyl) phenyl ] ethylamino) -2-oxoethyl ] -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-ylmethyl) -benzoic acid methyl ester

100mg (0.23mmol) of 2- [3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide from example 241A and 111mg (0.34mmol) of cesium carbonate and 34mg (0.23mmol) of sodium iodide are suspended in 2.5ml of acetone and treated with 55mg (0.30mmol) of 4- (chloromethyl) -benzoic acid methyl ester. Stirring was carried out at 50 ℃ for 4 hours. The suspension is then treated with 1.5ml of water and extracted four times with 2ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate and filtered. After evaporation, the crude product is purified by preparative HPLC [ method 10 ]. 56.6mg (42% of theory) of the target compound are thus obtained.

LC/MS [ method 19 ]]：R_t＝3.84min；MS[ESIpos]：m/z＝587(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，3.81(s，3H)，4.54(s，2H)，5.07(s，2H)，7.21(d，2H)，7.43-7.71(m，8H)，7.86(d，2H)，8.60(s，1H).

The following compounds were prepared identically:

example 430

2- [3- (4-tert-butylbenzyl) -3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N-1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl-acetamide

75mg (0.17mmol) of 2- [3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide from example 241A and 84mg (0.26mmol) of cesium carbonate and 25mg (0.17mmol) of sodium iodide are suspended in 2.5ml of DMF and treated with 50mg (0.22mmol) of 1- (bromomethyl) -4-tert-butylbenzene. Stir at RT for 1 hour. After filtration through a Millipore filter, the suspension was directly purified by preparative HPLC [ method 9 ]. 44mg (44% of theory) of the target compound are thus obtained.

LC/MS [ method 7 ]]：R_t＝3.09min；MS[ESIpos]：m/z＝585(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.21(s，9H)，1.60(s，6H)，4.52(s，2H)，4.94(s，2H)，6.99(d，2H)，7.29(d，2H)，7.50-7.70(m，8H)，8.59(s，1H).

The following compounds were prepared identically:

example 433

2- [3- (4-chlorophenyl) -4- (3-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N-1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl-acetamide

75mg (0.17mmol) of 2- [3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide from example 241A are dissolved in a mixture of 0.6ml of DMF and 1.1ml of 1, 2-Dimethoxyethane (DME). Cooled to 0 ℃ and treated with 9mg (0.22mmol) of sodium hydride. After 10 min, 45mg (0.51mmol) of lithium bromide were added and the mixture was then stirred at RT for 15 min. Next, 42mg (0.22mmol) of 3-fluorobenzyl bromide dissolved in 0.3ml DME was added and the mixture was stirred at 75 ℃ for 5 hours. The reaction mixture was then diluted with ethyl acetate, filtered through a silica gel/Extrelut filter cartridge, washed with ethyl acetate and concentrated in vacuo. The crude product is taken up in acetonitrile and purified by preparative HPLC [ method 10 ]. 68mg (72% of theory) of the target compound are thus obtained.

LC/MS [ method 8 ]]：R_t＝2.91min；MS[ESIpos]：m/z＝547(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，4.54(s，2H)，4.99(s，2H)，6.85-6.95(m，2H)，7.02-7.11(m，1H)，7.28-7.36(m，1H)，7.45-7.72(m，8H)，8.60(s，1H).

The following compounds were prepared identically:

example 441

2- [4- (2-chloroethyl) -3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [2- (trifluoromethyl) -benzyl ] -acetamide

500mg (1.01mmol) of 2- [3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [2- (trifluoromethyl) benzyl ] -acetamide from example 243A and 230mg (1.01mmol) of benzyltriethylammonium chloride are dissolved in 10ml of toluene. Next, a solution of 658mg (2.02mmol) cesium carbonate in 1.0ml water was added and the mixture was stirred vigorously at RT for 30 minutes. After addition of 1.92g (10.13mmol) of 1-iodo-2-chloroethane, the mixture was heated at 80 ℃ for 7 hours with vigorous stirring. The suspension was then diluted with ethyl acetate and washed once with water, 10% sodium thiosulfate and saturated ammonium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC [ method 9 ]. 195mg (41% of theory) of the target compound are thus obtained.

LC/MS [ method 7 ]]：R_t＝2.31min；MS[ESIpos]：m/z＝473/475(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.79(t，2H)，4.10(t，3H)，4.50(d，2H)，4.56(d，2H)，4.99(s，2H)，6.85-6.95(m，2H)，7.50(t，1H)，7.52-7.73(m，7H)，8.70(t，1H).

The following compounds were prepared identically:

example 443

2- [3- (4-chlorophenyl) -5-oxo-4- (2-oxobutyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N-1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl-acetamide

94mg (0.21mmol) of 2- [3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide from example 241A and 97.7mg (0.30mmol) of cesium carbonate are suspended in 2.5ml of DMF and treated with 50mg (0.30mmol) of 1-bromo-2-butanone (90%). Stirring was carried out at 75 ℃ for 3 hours. The suspension is then diluted with 10ml of ethyl acetate and washed twice with 5ml of water each time and once with 5ml of saturated sodium chloride solution. The organic phase was dried over sodium sulfate and filtered. After concentration, the crude product is purified by preparative thin-layer chromatography on silica gel (eluent: dichloromethane/methanol 10: 1). 64.8mg (59% of theory) of the target compound are thus obtained.

LC/MS [ method 19 ]]：R_t＝3.66min；MS[ESIpos]：m/z＝509(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.88(t，3H)，1.60(s，6H)，2.50(q，2H)，4.49(s，2H)，4.77(s，2H)，6.59-6.64(m，2H)，6.75-6.80(m，1H)，7.18(t，1H)，7.46-7.72(m，8H)，8.55(s，1H).

Example 444

2- [3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [2- (trifluoromethyl) benzyl ] -acetamide

100mg (0.24mmol) of 2- [3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [2- (trifluoromethyl) benzyl ] -acetamide from example 243A and 119mg (0.37mmol) of cesium carbonate are placed in 0.6ml of DMSO and treated with 137mg (1.22mmol) of 1, 1, 1-trifluoro-2, 3-epoxypropane. Stirring was carried out at 120 ℃ for 3 hours. Next, 137mg (1.22mmol) of 1, 1, 1-trifluoro-2, 3-epoxypropane were again added and the mixture was further stirred for hours. The suspension was then cooled to RT, diluted with ethyl acetate and washed three times with saturated ammonium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC [ method 10 ]. Thus 30.6mg (24% of theory) of the target compound are obtained.

LC/MS [ method 17 ]]：R_t＝3.69min；MS[ESIpos]：m/z＝523(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝3.83(dd，1H)，3.98(dd，1H)，4.30(m，1H)，4.47-4.60(m，4H)，6.90(d，1H)，7.46-7.81(m，8H)，8.70(t，1H).

The following compounds were prepared identically:

by preparative HPLC on chiral phase [ Daicel Chiralcel OD-H, 5 μm, 250mmx20 mm; eluent: isohexane/isopropanol 3: 1; flow rate: 15 ml/min; temperature: 30 ℃; and (4) UV detection: 220nm ]The racemate from example 447 was separated into enantiomers (see examples 448 and 449). Optical rotation of enantiomer alpha_DThe assay is as follows [ Perkin-Elmer Polarimeter 341; wavelength: 589 nm; solvent: methanol; layer thickness：100mm]：

Example 450

2- [3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide (racemate)

3.61g (8.23mmol) of 2- [3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide from example 241A and 3.75g (11.52mmol) of cesium carbonate are dissolved in 20ml of DMF and treated with 2.22g (11.52mmol) of 1, 1, 1-trifluoro-2, 3-epoxypropane. Stirring was carried out at 75 ℃ for 2.5 hours. The suspension is then diluted with 30ml of ethyl acetate and washed twice with 20ml of water each time. The organic phase was dried over sodium sulfate and filtered. After concentration, the crude product is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate first 5: 1 and then 1: 1). Thus 3.14g (69% of theory) of the target compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.75min；MS[ESIpos]：m/z＝551(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝1.72(s，6H)，3.99(dd，1H)，4.06(dd，1H)，4.41-4.58(m，3H)，4.85(m，1H)，6.45(s，1H)，7.40-7.63(m，8H).

By preparative HPLC on chiral phase [ Daicel Chiralpak AD-H, 5 μm, 250mmx20 mm; eluent: isohexane/isopropanol 85: 15; flow rate: 15 ml/min; temperature: 40 ℃; and (4) UV detection: 220nm ], separation of the racemate from example 450 into enantiomers (see examples 451 and 452):

Example 451

2- [3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide (enantiomer 1)

Yield: 1.31g (29% of theory)

R_t4.02min [ Daicel Chiralpak AD-H, 5 μm, 250 mmx4.6mm; eluent: isohexane/isopropanol 85: 15; flow rate: 1.0 ml/min; temperature: 40 ℃; and (4) UV detection: 220nm]。

Example 452

2- [3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide (enantiomer 2)

Yield: 1.20g (26% of theory)

R_t4.71min [ Daicel Chiralpak AD-H, 5 μm, 250 mmx4.6mm; eluent: isohexane/isopropanol 85: 15; flow rate: 1.0 ml/min; temperature: 40 ℃; and (4) UV detection: 220nm]。

Example 453

2- [3- (4-chlorophenyl) -4- (3-hydroxypropyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [3- (trifluoromethyl) benzyl ] acetamide

And

example 454

2- [3- (4-chlorophenyl) -4- (2-hydroxypropyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [3- (trifluoromethyl) benzyl ] acetamide

100mg (0.22mmol) of 2- [ 4-allyl-3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [3- (trifluoromethyl) benzyl ] -acetamide from example 372 are dissolved in 5ml of THF and treated with 0.67ml of a 1M solution of borane-THF complex in THF at 0 ℃. Stir at RT for 18 hours. The reaction solution was then cooled again to 0 ℃ and 4.5ml of 10% aqueous sodium hydroxide and 4.5ml of 30% hydrogen peroxide solution were added. After stirring for 3 hours, the mixture is poured into 10ml of water and extracted three times with 15ml of ethyl acetate each time. The combined organic phases were washed with 5ml of a 10% sodium thiosulfate solution and 5ml of a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC [ method 10 ]. The isomeric alcohols are obtained in isolated form.

Example 453

Yield: 20mg (19% of theory)

LC/MS [ method 18 ]]：R_t＝2.18min；MS[ESIpos]：m/z＝469(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.68(quin，2H)，3.27-3.40(m，2H)，3.80(t，2H)，4.41(d，2H)，4.45-4.56(m，3H)，7.52-7.73(m，8H)，8.68(t，1H).

Example 454

Yield: 13mg (13% of theory)

LC/MS [ method 18 ]]：R_t＝2.18min；MS[ESIpos]：m/z＝469(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.0(d，3H)，3.52-3.68(m，2H)，3.86(m，1H)，4.36-4.56(m，4H)，5.04(d，1H)，7.51-7.67(m，6H)，7.80(d，2H)，8.68(t，1H).

The following compounds were prepared identically:

example 457

2- {3- (4-chlorobenzyl) -5-oxo-4- [ (1E) -prop-1-en-1-yl ] -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- [3- (trifluoromethyl) benzyl ] -acetamide

22mg (0.047mmol) of 2- [3- (4-chlorophenyl) -4- (2-hydroxypropyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [3- (trifluoromethyl) benzyl ] -acetamide from example 454 are dissolved in 1ml of pyridine and treated with 9.6mg (0.084mmol) of methanesulfonyl chloride at RT. Stir at RT for 2 hours. Next, it was diluted with 5ml of ethyl acetate and washed three times with 5ml of 1N hydrochloric acid each time. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved in 1ml of anhydrous methanol and treated with 20mg (0.94mmol) of sodium methoxide and stirred at RT for 18 hours. To complete the reaction, 81mg (0.38mmol) further sodium methoxide is added and the mixture is further stirred at RT for 48 hours. The mixture is neutralized with 0.5ml of 1N hydrochloric acid and purified directly by preparative HPLC [ method 10 ]. Thus 4.8mg (23% of theory) of the target compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.66min；MS[ESIpos]：m/z＝451(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝1.80(d，3H)，4.55(d，2H)，4.62(s，2H)，6.19-6.34(m，3H)，6.67(m，1H)，7.43-7.59(m，8H).

Example 458

2- {3- (4-chlorophenyl) -4- [2- (dimethylamino) ethyl ] -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide

And

example 459

2- [3- (4-chlorophenyl) -5-oxo-4-vinyl-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide

35mg (0.07mmol) of 2- [4- (2-chloroethyl) -3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide from example 442 are dissolved in 0.7ml of DMF and treated at RT with 127mg (1.56mmol) of dimethylamine hydrochloride, 10.5ml (0.07mmol) of sodium iodide and 106mg (0.77mmol) of potassium carbonate. Stirred in a closed vessel at 100 ℃ for 24 hours. After cooling, it was diluted with 5ml of water and extracted twice with 5ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1: 1) first gives the 4-vinyl derivative (example 459). By further elution with dichloromethane/7N methanol in ammonia (10: 1), the 4- [2- (dimethyl-amino) ethyl ] derivative is obtained (example 458), which is further purified by preparative thick-layer chromatography (eluent: dichloromethane/ethyl acetate/7N methanol in ammonia 10: 0.5).

Example 458

Yield: 7.6mg (21% of theory)

LC/MS [ method 8 ]]：R_t＝1.60min；MS[ESIpos]：m/z＝510(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，1.98(s，6H)，2.29(t，2H)，3.79(t，2H)，4.46(s，2H)，7.48-7.70(m，8H)，8.54(s，1H).

Example 459

Yield: 6.8mg (21% of theory)

LC/MS [ method 8 ]]：R_t＝2.62min；MS[ESIpos]：m/z＝465(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，4.50(s，2H)，5.10(d，1H)，5.74(d，1H)，6.61(dd，1H)，7.49-7.70(m，8H)，8.60(s，1H).

The following compounds were prepared identically:

example 462

2- [3- (4-chlorophenyl) -4- (2-morpholin-4-ylethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } acetamide

0.10g (0.21mmol) of 2- [3- (4-chlorophenyl) -4- (2-oxoethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide from example 401 are dissolved in 30ml of dichloromethane and 0.4ml of DMF and stirred at RT with 22mg (0.2mmol) of morpholine for 1 hour. Next, 66mg (0.31mmol) of sodium triacetoxyborohydride are added and the mixture is stirred at RT for 18 h. The reaction mixture is treated with 10ml of saturated sodium bicarbonate solution and extracted three times with 10ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC [ method 10 ]. 11.0mg (10% of theory) of the target compound are obtained.

LC/MS [ method 17 ]]：R_t＝2.78min；MS[ESIpos]：m/z＝552(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.59(s，6H)，2.16(m，4H)，2.34(t，2H)，3.31(m，4H)，3.80(t，2H)，4.46(s，2H)，7.48-7.72(m，8H)，8.54(s，1H).

The following compounds were prepared identically:

example 466

[3- (4-chlorophenyl) -5-oxo-1- (2-oxo-2- [3- (trifluoromethyl) benzyl ] aminoethyl) -1, 5-dihydro-4H-1, 2, 4-triazol-4-yl ] -acetic acid

119mg (0.23mmol) of [3- (4-chlorophenyl) -5-oxo-1- (2-oxo-2- { [3- (trifluoromethyl) -benzyl ] amino } ethyl) -1, 5-dihydro-4H-1, 2, 4-triazol-4-yl ] -acetic acid tert-butyl ester from example 420 are dissolved in 9ml of dichloromethane and treated with 3ml of trifluoroacetic acid. Stir at RT for 24 hours. The reaction mixture is then treated with 10ml of toluene and concentrated under reduced pressure. Further 10ml of toluene were added and the mixture was evaporated again. This step is repeated again. The crude product is then freed of solvent residues under high vacuum. Thus 110mg (quantitative) of the target compound was obtained.

LC/MS [ method 7 ]]：R_t＝2.00min；MS[ESIpos]：m/z＝469(M+H)⁺

¹H-NMR(500MHz，DMSO-d₆)：δ＝4.41(s，2H)，4.52(2s，4H)，7.52-7.66(m，8H)，8.76(t，1H)，13.30(br.s，1H).

Example 467

3- (4-chlorophenyl) -1- [2- (1-methyl-1- [3- (trifluoromethyl) phenyl ] ethylamino) -2-oxoethyl ] -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl-acetic acid

237mg (0.45mmol) of ethyl {3- (4-chlorophenyl) -1- [2- ({ 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } amino) -2-oxoethyl ] -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl ] -acetate from example 429 are dissolved in 3ml of methanol and treated with 0.9ml of 1N aqueous lithium hydroxide solution. Stir at RT for 24 hours. The reaction mixture was then concentrated under reduced pressure. 5ml of water are added and the mixture is acidified with 1ml of 1N hydrochloric acid and extracted twice with 10ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The remaining product was freed of solvent residues under high vacuum. 220mg (97% of theory) of the target compound are thus obtained.

LC/MS [ method 17 ]]：R_t＝3.49min；MS[ESIpos]：m/z＝497(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，4.50(2s，4H)，7.48-7.70(m，8H)，8.57(s，1H)，13.30(br.s，1H).

The following compounds were prepared identically:

example 471

3- (3- (4-chlorophenyl) -1- [2- (1-methyl-1- [3- (trifluoromethyl) phenyl ] ethylamino) -2-oxoethyl ] -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-ylmethyl) -benzoic acid

180mg (0.31mmol) of methyl 3- (3- (4-chlorophenyl) -1- [2- (1-methyl-1- [3- (trifluoromethyl) phenyl ] ethylamino) -2-oxoethyl ] -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-ylmethyl) -benzoate (example 411) are dissolved in 3ml of methanol and 3ml of THF, treated with 0.3ml of aqueous sodium hydroxide 2N and stirred at 70 ℃ for 1 hour. The reaction mixture was then added to about 10ml of water, brought to pH 4 with 1N hydrochloric acid and stirred at RT for 2 hours. The precipitate formed is filtered off under suction, washed with water and the solvent residue is removed under high vacuum. 154mg (88% of theory) of the target compound are obtained.

LC/MS [ method 17 ]]：R_t＝3.69min；MS[ESIpos]：m/z＝573(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，4.52(s，2H)，5.05(s，2H)，7.28(d，1H)，7.40(t，1H)，7.47-7.72(m，6H)，7.80(d，2H)，8.60(s，1H)，13.02(br.s，1H).

The following compounds were prepared identically:

example 475

3- (3- (4-chlorophenyl) -1- [2- (1-methyl-1- [3- (trifluoromethyl) phenyl ] ethylamino) -2-oxoethyl ] -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-ylmethyl) -N, N-dimethylbenzamide

30mg (0.052mmol) of 3- (3- (4-chlorophenyl) -1- [2- (1-methyl-1- [3- (trifluoromethyl) phenyl ] ethylamino) -2-oxoethyl ] -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-ylmethyl) -benzoic acid (example 471) are placed in 0.5ml of DMF and treated with 9.2mg (0.068mmol) of HOBt and 13.0mg (0.068mmol) of EDC hydrochloride. After stirring for 10 min, 6.0mg (0.073mmol) dimethyl-amine hydrochloride and 10.2mg (0.079mmol) N, N-diisopropylethylamine are added and the mixture is stirred at RT overnight. Without further work-up, the crude product is purified directly by preparative HPLC [ method 10 ]. Thus 29.8mg (95% of theory) of the target compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.59min；MS[ESIpos]：m/z＝600(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，2.66(s，3H)，2.85(s，3H)，4.55(s，2H)，5.02(s，2H)，7.04(s，1H)，7.12(d，1H)，7.23(d，1H)，7.33(t，1H)，7.45-7.75(m，8H)，8.60(s，1H).

The following compounds were prepared identically:

example 479

2- {3- (4-chlorophenyl) -4- [3- (hydroxymethyl) benzyl ] -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide

30mg (0.052mmol) of 3- (3- (4-chlorophenyl) -1- [2- (1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl-amino) -2-oxoethyl ] -5-oxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-ylmethyl) -benzoic acid (example 471) are dissolved in 2ml of THF and treated with 24mg (0.24mmol) of triethylamine and 33mg (0.24mmol) of isobutyl chloroformate. Stirring is carried out at RT for 1 hour, then a solution of 24mg (0.63mmol) of sodium borohydride in 0.05ml of water is added slowly. After 1h, the mixture is treated with 0.06ml (1.05mmol) of acetic acid and then concentrated in vacuo. The residue is taken up in 10ml of ethyl acetate and washed with 10ml of water. The aqueous phase is re-extracted once with 10ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC [ method 10 ]. 23mg (79% of theory) of the target compound are thus obtained.

LC/MS [ method 19 ]]：R_t＝3.53min；MS[ESIpos]：m/z＝559(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，4.40(d，2H)，4.52(s，2H)，4.96(s，2H)，5.15(t，1H)，6.89(d，1H)，7.04(s，1H)，7.14-7.26(m，2H)，7.47-7.59(m，6H)，7.65(s，1H)，7.69(d，1H)，8.60(s，1H).

Example 480

2- [3- (4-chlorophenyl) -4- (2-fluoroethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl) ethyl ] -acetamide

50mg (0.10mmol) of 2- [3- (4-chlorophenyl) -4- (2-hydroxyethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide from example 396 are dissolved in 1.5ml of dichloromethane and treated with 20.5. mu.l (0.155mmol) of diethylaminosulfur trifluoride at-10 ℃. Warm to RT in 1 hour. Next, the reaction solution was treated with 5ml of water and extracted twice with 5ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC [ method 10 ]. Thus 37mg (73% of theory) of the target compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.63min；MS[ESIpos]：m/z＝485(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，4.00(t，1H)，4.07(t，1H)，4.43(s，2H)，4.44(t，1H)，4.62(t，1H)，7.48-7.70(m，8H)，8.59(s，1H).

The following compounds were prepared identically:

example 482

2- [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [2- (methylsulfonyl) benzyl ] -acetamide

55mg (0.11mmol) of 2- [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [2- (methylthio) benzyl ] -acetamide from example 394 are dissolved in 3ml of chloroform and treated at RT with 82mg (0.33mmol) of m-chloroperbenzoic acid. After 1 hour, the reaction solution was diluted with 10ml of dichloromethane and washed with 5ml of saturated sodium bicarbonate solution. The aqueous phase is extracted once with 10ml of dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is purified by preparative thick-layer chromatography (eluent: dichloromethane/methanol 20: 1). 18mg (30% of theory) of the target compound are thus obtained.

LC/MS [ method 23]：R_t＝2.08min；MS[ESIpos]：m/z＝529(M+H)⁺

1H-NMR(400MHz，DMSO-d6)：δ＝3.32(s，3H)，4.60(s，2H)，4.77(d，2H)，5.04(s，2H)，7.03-7.20(m，3H)，7.25-7.49(m，1H)，7.48-7.72(m，7H)，7.93(d，1H)，8.80(t，1H).

Example 483

2- [3- (4-chlorophenyl) -5-oxo-4- (2-hydroxybutyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide (racemate)

62mg (0.12mmol) of 2- [3- (4-chlorophenyl) -5-oxo-4- (2-oxobutyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide from example 443 are dissolved in 2ml of methanol and treated with 4.7mg (0.12mmol) of sodium borohydride at RT. Stir at RT for 1 hour. After which it was treated with a saturated ammonium chloride solution and extracted with 10ml ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. Thus 57mg (92% of theory) of the target compound are obtained.

LC/MS [ method 23]：R_t＝2.26min；MS[ESIpos]：m/z＝511(M+H)⁺.

On chiral phase by preparative HPLC [ Sepaserve sepapaak-2, 5 μm, 250mmx20 mm; eluent: isohexane/ethanol 70: 30; flow rate: 15 ml/min; temperature: 35 ℃; and (4) UV detection: 220nm ] separation of the racemate from example 483 into enantiomers (see examples 484 and 485):

example 484

2- [3- (4-chlorophenyl) -5-oxo-4- (2-hydroxybutyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide (enantiomer 1)

Yield: 19mg (31% of theory)

R_t5.55min [ [ Sepaserve sepapaak-2, 5 μm, 250 mmx4.6mm; eluent: isohexane/ethanol 70: 30; flow rate: 1 ml/min; temperature: 35 ℃; and (4) UV detection: 220nm]

¹H-NMR(400MHz，CDCl₃)：δ＝0.95(t，3H)，1.40-1.52(m，2H)，1.72(s，6H)，1.90(br.s，1H)，3.67-3.87(m，2H)，3.93(m，1H)，4.50(s，2H)，6.63(s，1H)，7.35-7.65(m，8H).

Example 485

2- [3- (4-chlorophenyl) -5-oxo-4- (2-hydroxybutyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide (enantiomer 2)

Yield: 21mg (33% of theory)

R_t7.44min [ [ Sepaserve sepapaak-2, 5 μm, 250 mmx4.6mm; eluent: isohexane/ethanol 70: 30; flow rate: 1 ml/min; temperature: 35 ℃; and (4) UV detection: 220nm]。

Example 486

2- [3- (4-chlorophenyl) -4- (2-cyclopropyl-2-hydroxyethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide

103mg (0.21mmol) of 2- [3- (4-chlorophenyl) -4- (2-oxoethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide from example 401 are dissolved in 1ml of THF and treated with 1.1ml (0.54mmol) of cyclopropylmagnesium bromide (0.5M solution in THF) at-78 ℃. Stirring was carried out at RT for 3 hours and then at 50 ℃ for a further 2 hours. For working up, treatment was carried out with saturated ammonium chloride solution and extraction was carried out twice with 10ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC [ method 10 ]. 12mg (11% of theory) of the target compound are thus obtained.

LC/MS [ method 8 ]]：R_t＝2.61min；MS[ESIpos]：m/z＝523(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝0.22(m，1H)，0.33(m，1H)，0.50(m，2H)，0.71(m，1H)，1.72(s，6H)，2.68(d，1H)，3.34(m，1H)，3.91(dd，1H)，3.99(dd，1H)，4.50(s，2H)，6.62(s，1H)，7.37-7.65(m，8H).

The following were prepared identically:

example 488

2- {3- (4-chlorophenyl) -4- [ (1-hydroxycyclopropyl) methyl ] -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl } -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide

72mg (0.14mmol) of 2- [3- (4-chlorophenyl) -4- (2-oxoethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide from example 401 together with 4mg (0.014mmol) of titanium (IV) isopropoxide are dissolved in 0.45ml of diethyl ether and 0.3ml of THF and treated at RT over 1 hour with 108. mu.l (0.32mmol) of ethylmagnesium bromide (3M solution in diethyl ether) diluted with 0.4ml of diethyl ether. Further stirred at RT for 10 min. For working up, the mixture is poured into 10ml of ice-cold 10% sulfuric acid and extracted twice with 10ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC [ method 10 ]. Thus 5mg (7% of theory) of the target compound are obtained.

LC/MS [ method 8 ]]：R_t＝2.54min；MS[ESIpos]：m/z＝509(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝0.51(m，2H)，0.81(m，2H)，1.72(s，6H)，3.82(br.s，1H)，3.95(d，2H)，4.52(s，2H)，6.62(s，1H)，7.37-7.62(m，8H).

Example 489

2- [3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoro-2-oxopropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide

1.2g (2.18mmol) of 2- [3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide from example 452 were dissolved in 30ml of dichloromethane and treated with 1.2g (2.83mmol) of 1, 1, 1-tris (acetoxy) -1, 1-dihydro-1, 2-benziodo-3- (1H) -one (dess-martin reagent) at 0 ℃. Stir at RT for 3 hours. The reaction solution is then diluted with 30ml of ethyl acetate and washed three times with 15ml of 1N aqueous sodium hydroxide each time. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate first 4: 1 and then 1: 1). 0.90g (75% of theory) of the target compound are obtained.

LC/MS [ method 22 ]]：R_t＝2.25min；MS[ESIpos]：m/z＝549(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，4.08(s，2H)，4.48(s，2H)，7.44-7.71(m，8H)，8.54(s，1H).

Further application examples were prepared by parallel synthesis as follows:

in 0.2ml of DMSO was placed 0.10mmol of the corresponding amine component and treated with 0.10mmol of triazolylacetic acid from example 90A (dissolved in 0.2ml of DMSO). Next, it was treated with 25.8mg (0.2mmol) of N, N-diisopropylethylamine and 41.7mg (0.130mmol) of TBTU and the mixture was shaken at RT overnight. The reaction solution was then filtered and the filtrate was purified by preparative LC/MS [ method 24 ]. In this way the following are obtained:

Example 496

2- [3- (3-chloro-4-methyl-2-thienyl) -4-isobutyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [3- (trifluoromethyl) phenylmethyl ] -acetamide

40.0mg (0.121mmol) of 2- [3- (3-chloro-4-methyl-2-thienyl) -4-isobutyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 249A and 23.4mg (0.133mmol) of 3-trifluoromethyl-benzylamine are placed in 1.5ml of DMF and treated with 19.7mg (0.146mmol) of HOBt. 30.2mg (0.158mmol) EDC hydrochloride are added and the mixture is stirred at RT overnight. For work-up, the reaction mixture is stirred with approximately 15ml of water and the precipitate formed is filtered off, washed with water and dried in vacuo. 43mg (73% of theory) of the target compound are thus obtained.

LC/MS [ method 7 ]]：R_t＝2.52min；

¹.H-NMR(400MHz，DMSO-d₆)：δ＝0.73(d，6H)，1.73-1.85(m，1H)，2.23(s，3H)，3.45(d，2H)，4.41(d，2H)，4.52(s，2H)，7.52-7.65(m，4H)，7.72(s，1H)，8.73(t，1H).

Embodiment 497

2- [3- (3-chloro-4-methyl-2-thienyl) -4-isobutyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [2- (trifluoromethyl) phenylmethyl ] -acetamide

40.0mg (0.121mmol) of 2- [3- (3-chloro-4-methyl-2-thienyl) -4-isobutyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -acetic acid from example 249A and 23.4mg (0.133mmol) of 2-trifluoromethyl-benzylamine are placed in 1.5ml of DMF and treated with 19.7mg (0.146mmol) of HOBt. 30.2mg (0.158mmol) EDC hydrochloride are added and the mixture is stirred at RT overnight. For work-up, the reaction mixture is stirred with approximately 15ml of water, saturated with sodium chloride and extracted with ethyl acetate. The organic phase was separated and concentrated, and the residue was dissolved in methanol and purified by preparative HPLC [ method 12 ]. 26mg (44% of theory) of the target compound are thus obtained.

LC/MS [ method 7 ]]：R_t＝2.52min；

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.73(d，6H)，1.72-1.87(m，1H)，2.23(s，3H)，3.45(d，2H)，4.49(d，2H)，4.57(s，2H)，7.49(t，1H)，7.56(d，1H)，7.65(t，1H)，7.69-7.75(m，2H)，8.73(t，1H).

Example 498

[3- (4-chlorophenyl) -5-oxo-1- (2-oxo-2- { [3- (trifluoromethyl) phenylmethyl ] amino } ethyl) -1, 5-dihydro-4H-1, 2, 4-triazol-4-yl ] -acetic acid tert-butyl ester

To 150.0mg (0.365mmol) of (0.365mmol)2- [3- (4-chlorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- [3- (trifluoromethyl) phenylmethyl ] -acetamide from example 242A and 178.5mg (0.548mmol) cesium carbonate in 5.0ml acetone are added 92.6mg (0.475mmol) of tert-butyl bromoacetate and heated at reflux for 5 hours. For work-up, the reaction mixture was concentrated after cooling, the residue was partitioned between water and ethyl acetate, the organic phase was separated and the aqueous phase was re-extracted several times with ethyl acetate. The combined organic phases are concentrated and the residue is purified by preparative HPLC [ method 12 ]. 139mg (73% of theory) of the target compound are thus obtained.

LC/MS [ method 7 ]]：R_t＝2.56min；

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.28(s，9H)，4.41(d，2H)，4.54(d，4H)，7.53-7.65(m，8H)，8.75(t，1H).

Example 499

2- [4- (4-chlorophenyl) -2-oxo-3- (3, 3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide (racemate)

In 0.45ml DMF was placed 174mg (0.397mmol)2- [4- (4-chlorophenyl) -2-oxo-2, 3 dihydro-1H-imidazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide, 12.8mg (0.04mmol) tetra-N-butylammonium bromide and 37.5mg (0.199mmol) potassium carbonate and treated with 49.0mg (0.437mmol)1, 1, 1-trifluoro-2, 3-epoxypropane. Stirring was carried out at 130 ℃ for 1 hour. The suspension is diluted with 5ml of ethyl acetate and washed twice with 5ml of water each time. The organic phase was dried over sodium sulfate and filtered. After evaporation the crude product is purified by preparative HPLC [ method 10 ]. 48mg (22% of theory) of the target compound are obtained.

LC/MS [ method 19 ]]：R_t＝3.76min；MS[ESIpos]：m/z＝550(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，3.73(dd，1H)，3.87(dd，1H)，4.23(m，1H)，4.31(s，2H)，6.15(s，1H)，6.20(d，1H)，7.45-7.70(m，8H)，8.56(s，1H).

On the chiral phase by preparative HPLC [ Daicel Chiralpak AD-H, 5 μm, 250mmx20 mm; eluent: isohexane/isopropanol 85: 15; flow rate: 15 ml/min; temperature: 40 ℃; and (4) UV detection: 220nm ], separation of the racemate from example 499 into enantiomers (see examples 500 and 501):

example 500

2- [4- (4-chlorophenyl) -2-oxo-3- (3, 3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide (enantiomer 1)

R_t7.23min [ [ Daicel Chiralpak AD-H, 5 μm, 250 mmx4.6mm; eluent: isohexane/isopropanol 85: 15; flow rate: 1.0 ml/min; temperature: 40 ℃; and (4) UV detection: 220nm]。

Example 501

2- [4- (4-chlorophenyl) -2-oxo-3- (3, 3, 3-trifluoro-2-hydroxypropyl) -2, 3-dihydro-1H-imidazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide (enantiomer 2)

R_t5.43min [ [ Daicel Chiralpak AD-H, 5 μm, 250 mmx4.6mm; eluent: isohexane/isopropanol 85: 15; flow rate: 1.0 ml/min; temperature: 40 ℃; and (4) UV detection: 220nm]。

Example 502

2- [4- (5-chloro-2-thienyl) -3- (2-fluorobenzyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -N- { 1-methyl-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide

45mg (0.123mmol) of [4- (5-chloro-2-thienyl) -3- (2-fluorobenzyl) -2-oxo-2, 3-dihydro-1H-imidazol-1-yl ] -acetic acid from example 238A, 20mg (0.147mmol) of HOBt and 31mg (0.159mmol) of EDC hydrochloride are placed in 1.5ml of DMF and stirred for 10 minutes. Next, 30mg (0.147mmol) of 1-methyl-1- [ (3-trifluoromethyl) phenyl ] ethylamine from example 1A was added and the mixture was stirred at RT overnight. For working up, the reaction mixture is stirred with 2ml of water and extracted twice with 5ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC [ method 10 ]. Thus 50mg (74% of theory) of the target compound are obtained.

LC/MS [ method 8 ]]：R_t＝3.00min；MS[ESIpos]：m/z＝552(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝1.60(s，6H)，4.36(s，2H)，4.93(s，2H)，6.82(d，1H)，6.84(s，1H)，6.88(t，1H)，7.05(d，1H)，7.07(t，1H)，7.16(t，1H)，7.30(m，1H)，7.48-7.58(m，2H)，7.63(s，1H)，7.67(d，1H)，8.56(s，1H).

The following compounds were prepared identically:

example 509

2- [3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 2-amino-2-oxo-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide

The carboxylic acid from example 229A (enantiomer 1; 23mg, 63. mu. mol) and HOBt (13mg, 94. mu. mol) were placed in 0.91ml of DMF and treated with 18mg (94. mu. mol) EDC at RT. After 20 min, 25mg (0.11mmol) of the compound from example 184A and 22. mu.l (0.13mmol) of N, N-diisopropylethylamine were added and the mixture was stirred at RT overnight. 1ml of 1N hydrochloric acid are then added and the mixture is separated directly by preparative HPLC (method 20). 26mg (73% of theory) of the title compound are obtained.

LC/MS [ method 23]：R_t＝2.06min；m/z＝566(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ ═ 3.82(dd, 1H), 3.96(br.d, 1H), 4.26(m, 1H), 4.50-4.70(m, 2H [ ABM system)])，5.51(d，1H)，6.89(t，1H)，7.33(s，1H)，7.57-7.65(m，3H)，7.68(d，1H)，7.70-7.77(m，3H)，7.81(s，1H)，7.88(s，1H)，9.99(d，1H).

Example 510

2- ([3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] acetylamino) -N-cyclopropyl-2- [3- (trifluoromethyl) phenyl ] -acetamide

In analogy to the preparation of example 509, 27mg (65% of theory) of the title compound were obtained from 25mg (69 μmol) of the carboxylic acid from example 229A and 31mg (82 μmol) of the compound from example 181A.

LC/MS [ method 23]：R_t＝2.24min；m/z＝606(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝0.25-0.35(m，1H)，0.39-0.48(m，1H)，0.55-0.71(m，2H)，258-2.69(m, 1H), 3.82(dd, 1H), 3.96(br.d, 1H), 4.26(m, 1H), 4.53-4.65(m, 2H [ ABM system)])，5.48(d，1H)，6.89(t，1H)，7.57-7.79(m，8H)，8.53(d，1H)，9.06(d，1H).

Example 511

2- [3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- { 2-morpholin-4-yl-2-oxo-1- [3- (trifluoromethyl) phenyl ] ethyl } -acetamide

In analogy to the preparation of example 509, 36mg (97% of theory) of the title compound were obtained from 21mg (58 μmol) of the carboxylic acid from example 229A and 28mg (70 μmol) of the compound from example 177A.

LC/MS [ method 8 ]]：R_t＝2.57min；m/z＝636(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ ═ 3.18-3.39(m, 2H), 3.40-3.66(m, 6H), 3.83(dd, 1H), 3.97(br.d, 1H), 4.26(m, 1H), 4.49-4.59(m, 2H [ ABM system) ])，6.03(d，1H)，6.90(dd，1H)，7.59-7.79(m，8H)，8.53(d，1H)，9.07(d，1H).

Example 512

2- [3- (4-chlorophenyl) -5-oxo-4- (3, 3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1, 2, 4-triazol-1-yl ] -N- ({3- [3- (trifluoromethyl) phenyl ] oxetan-3-yl } methyl) -acetamide

24.8mg (68. mu. mol) of the carboxylic acid from example 229A (enantiomer 1) in 710. mu.l of DMF are treated with 14mg (102. mu. mol) of HOBt, 20mg (102. mu. mol) of EDC, 20mg (75. mu. mol) of the compound from example 252A and 17. mu. l N, N-diisopropylethylamine (95. mu. mol). The reaction mixture was stirred at RT overnight and then isolated directly by preparative HPLC (method 20). The product-containing fractions were combined and concentrated on a rotary evaporator. The residue comprises the title compound and by-products and is further purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 7: 1). Thus 9mg (23% of theory) of the title compound are obtained.

LC/MS [ method 22 ]]：R_t＝2.07min；m/z＝579[M+H]⁺

¹H-NMR(400MHz，DMSO-d₆): δ ═ 3.82(dd, 1H), 3.95(dd, 1H), 4.26(m, 1H), 4.36(m, 2H [ AB-system)])，4.75(m，2H)，4.83(d，2H)，4.89(d，2H)，6.90(d，1H)，7.46-7.76(m，8H)，8.29(t，1H).

B.Evaluation of pharmacological Activity

The pharmacological activity of the compounds according to the invention can be shown in the following tests:

abbreviations:

EDTA ethylene diamine tetraacetic acid

DMEM Darbeike improved Eagle culture medium

FCS fetal calf serum

HEPES 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid

SmGM smooth muscle cell growth medium

Tris-HCl 2-amino-2- (hydroxymethyl) -1, 3-propanediol hydrochloride

UtSMC uterine smooth muscle cells

B-1.In vitro cell assay for determining vasopressin receptor activity

The identification of agonists and antagonists of the V1 a-and V2-vasopressin receptors in humans and rats and the quantification of the activity of the compounds according to the invention are carried out by recombinant cell lines. These cells were originally derived from Hamster Ovary epithelial cells (Chinese Hamster Ovary, CHO K1, ATCC: American type Culture Collection, Manassas, VA 20108, USA). The test cell lines showed compositionally modified forms of the calcium-sensitive photoprotein aequorin, which, when reconstituted with the cofactor coelenterazine, luminesces at increasing free calcium concentrations [ Rizzto R, Simpson AW, Brini M, Pozzan T, Nature @358，325-327(1992)]. In addition, the cells were stably transfected with human or rat V1 a-or V2 receptors. In the case of Gs-coupled V2 receptors, cells are stabilized with further promiscuous G_α16Protein-encoding Gene transfection [ Amatruda TT, Steele DA, Slepak VZ, Simon MI, Proceedings in the National Academy of Science USA 88，5587-5591(1991)]. Test cells of the produced vasopressin receptor respond to stimulation of the recombinantly expressed vasopressin receptor with an intracellular release of calcium ions, which can be quantified with appropriate photometry by the production of aequorin luminescence [ Milligan G, Marshall F, Rees S, Trends in pharmaceutical Sciences17，235-237(1996)]。

Test procedure:

on the day before the assay, cells were cultured (autostratert) in medium (DMEM, 10% FCS, 2mM glutamine, 10mM HEPES) in 384-well microtiter plates and maintained in cell culture chambers (96% atmospheric humidity, 5% v/v CO₂37 ℃ C.). On the day of the experiment, the medium was coated with Tilode solution (140mM NaCl, 5mM KCl, 1mM MgCl)₂，2mM CaCl₂20mM glucose, 20mM HEPES), which solution additionally comprises the cofactor coelententerazine (50 μm) and the microtiter plates were then incubated for a further 3-4 hours. Test substances at various concentrations are placed in the wells of a microtiter plate in advance for 10 to 20 minutes, after which the agonist [ Arg ] is added⁸]Vasopressin and the resulting optical signal is immediately measured in a photometer. Computing IC by computer program GraphPad PRISM (version 3.02)₅₀The value is obtained.

The following table shows the representative IC of the compounds according to the invention in cell lines transfected with the human V1 a-or V2 receptor ₅₀The value:

watch (A)

Example No. 2	IC₅₀hV1a[μM]	IC₅₀hV2[μM]
			25	6.3	0.18
28	0.030	0.18
			29	0.17	0.009
59	1.1	0.009
			63	0.038	＞10
75	0.39	0.026
			84	0.32	0.008
101	0.094	1.1
			143	0.96	0.006
145	0.095	0.007
			151	3.4	0.93
153	0.042	0.012
			159	0.44	0.42
207	0.23	0.063
			209	0.14	0.26
214	6.3	0.18
			216	0.073	0.006
219	0.090	0.009
			221	0.165	0.030
227	0.008	0.037
			230	0.783	0.083
241	0.076	0.271
			251	0.037	0.013
252	0.018	0.447
			260	0.030	0.154
262	0.157	0.005
			265	0.028	0.749
284	0.009	0.191

Example No. 2	IC₅₀hV1a[μM]	IC₅₀hV2[μM]
			288	0.761	0.666
296	0.054	0.009
			305	0.093	0.784
313	0.003	1.025
			320	0.024	1.517
321	0.050	0.51
			325	0.107	0.028
340	0.039	1.149
			348	0.004	0.217
357	0.338	0.005
			359	0.019	0.009
364	0.022	0.008
			386	0.611	0.023
394	0.019	0.019
			415	0.870	0.026
421	0.032	0.088
			423	0.157	0.015
433	0.199	0.009
			439	0.058	0.077
443	0.093	0.023
			451	0.012	0.002
457	0.043	0.029
			462	0.373	0.046
467	0.439	0.026
			471	0.039	0.002
475	0.328	0.020
			476	1.229	0.094
482	0.009	0.25
			485	0.012	0.002
489	0.035	0.002

Example No. 2	IC₅₀hV1a[μM]	IC₅₀hV2[μM]
			494	0.049	0.257
496	0.166	0.576
			501	0.012	0.003
503	0.025	0.221
			508	0.005	0.336
509	0.008	0.004
			510	0.004	0.007
511	0.004	0.011

B-2.Membrane preparation for determining oxytocin receptor affinity for smooth muscle cells of human uterus In the binding study of

Smooth muscle cells of human uterus (UtSMC; Cambrex Bio Science, Walkersville, USA) were cultured in SmGM-2 medium (Cambrex Bio Science, Inc.). After 80% fusion had been achieved, the cells were suspended in 10ml of ice-cold homogenization buffer (10mM Tris-HCl, 5mM EDTA, pH 7.4)/175cm²Cell culture flasks and homogenized by an Ultra-Turrax apparatus. The slurry was centrifuged at 1000g and 4 ℃ for 10 minutes. The supernatant was removed and centrifuged at 35000g and 4 ℃ for 20 minutes. Membrane pellets with oxytocin receptor in 10ml binding buffer (50mM Tris-HCl, 10mM MgCl)₂pH 7.4) and stored at-80 ℃. For the binding experiment, 100. mu.g of the membrane preparation was combined with the radiation-ligand [ alpha ], [ 2 ]³H]Oxytocin (0.5nM) mixed and concomitant at room temperature in buffer with 0.1% bovine serum albuminThe test compound concentration was increased for 60 minutes. The incubation was stopped by centrifugation at 10000g for 10 min followed by washing with 0.1% bovine serum albumin in binding buffer at 4 ℃. Further centrifugation was carried out at 10000g and 4 ℃ for 10 minutes. The precipitate was resuspended in 0.1ml of 1N aqueous sodium hydroxide and transferred to a scintillation vial. After addition of 4ml Ultima Gold scintillator, the bound radioactivity on the membrane was quantified by means of a LS6000IC scintillation counter (Beckman Coulter). The radioactive intensity in the presence of 1 μm oxytocin was defined as nonspecific binding. Computing IC by computer program GraphPad PRISM (version 3.02) ₅₀The value is obtained.

B-3.In vivo assays to determine cardiovascular effects; blood pressure measurement for anesthetized rats

Male Wistar (Wistar) rats (350-;) It is prefilled with an isotonic sodium chloride solution (500i.e./ml) containing heparin, introduced into the femoral artery and vein and bandaged thereafter. The test substance is administered by syringe through the intravenous route. The arterial cannula is connected to a pressure transducer which inputs its signal into an assay computer equipped with suitable recording software. On the basis of the continuously recorded pressure curve, the systolic and diastolic blood pressure are determined and from this the arterial mean pressure is calculated and the heart rate is determined. In a further development of the test device, the abdominal cavity was also opened, the bladder appeared and a plastic tube was inserted into the bladder through a small incision and fixed by suturing, through which the urine was continuously collected.

In a typical experiment, test animals are dosed with a bolus injection of a defined amount of Arg-vasopressin in isotonic sodium chloride solution, and after the blood pressure again reaches the starting value, the substance to be tested is dosed as a bolus in a suitable solvent. Thereafter, the same amount of Arg-vasopressin was again administered as started at defined intervals. The extent and time of the blood pressure-increasing effect of the test substance against Arg-vasopressin were determined on the basis of the blood pressure values. Control animals were given solvent only and no test substance.

Compared to solvent control, the compounds according to the invention lead to an inhibition of the increase in blood pressure caused by Arg-vasopressin after intravenous administration.

B-4.In vivo assay to determine cardiovascular effects: for awareness in metabolic cages Diuresis study in mice

Wistar rats (300-450g body weight) remain freely accessible to food (Altromin) and drinking water. During the experiment, the animals remained in metabolic cages suitable for this weight class of rats for 4-6 hours (Techniplast Germany Ltd., D-82383 Hohenpei. beta. enberg) respectively with free access to drinking water. At the start of the experiment, the animals were dosed with the substance to be tested in a volume of 3ml of the appropriate solvent per kg of body weight via a gastric feeding tube into the stomach. Animals as controls were given solvent only. Control and substance tests were performed in parallel on the same day. The control group and the substance dose group each consisted of 3-6 animals. During the experiment, urine excreted by the animals was collected continuously in a collection container on the floor of the cage. For each animal, the urine volume per unit time was determined separately and the concentration of sodium and/or potassium ions excreted in the urine was determined by standard flame photometry. To obtain a sufficient amount of urine, the animals were dosed with a defined amount of water (typically 10 ml/kg body weight) at the beginning of the experiment via a gastric feeding tube. The body weight of individual animals was measured before the start of the experiment and after the end of the experiment.

The compounds according to the invention lead to an increase in urination after oral administration, mainly due to increased water drainage (aquaresis), compared to the control administration of solvents.

C.Application examples of pharmaceutical compositions

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

sheet:

composition (A):

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

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

Production:

the mixture of compound, lactose and starch according to the invention was granulated with a 5% solution (w/w) of PVP in water. After drying, the granules were mixed with magnesium stearate for 5 minutes. The mixture was compressed with a conventional tablet press (tablet size: see above). As a guideline, a pressure of 15kN was used for compression.

Orally administrable suspensions:

composition (A):

1000mg of a compound according to the invention, 1000mg of ethanol (96%), 400mg(Xanthan Gum from FMC, Pa., USA) and 99g of water.

10ml of oral suspension corresponds to a single dose with 100mg of the compound according to the invention.

Production:

rhodigel is suspended in ethanol and a compound according to the invention is added to the suspension. Water was added with stirring. The mixture was stirred for about 6 hours until the swelling of the Rhodigel was complete.

Orally administrable solutions:

composition (A):

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

Production:

the compounds according to the invention are suspended in a mixture of polyethylene glycol and polysorbate with stirring. The stirring process is continued until the compound according to the invention is completely dissolved.

In vivo solution:

the compounds according to the invention are dissolved in physiologically compatible solvents (e.g. isotonic sodium chloride solution, 5% glucose solution and/or 30% PEG 400 solution) at concentrations below the saturation solubility. The solution was sterile-filtered and filled into sterile and pyrogen-free injection containers.

Claims

1. A compound having the following formula (I),

wherein

A represents a group represented by the formula (I),

R¹is represented by (C)₁-C₆) Alkyl which may be mono-or di-substituted, identically or differently selected from fluorine, oxo, hydroxy, methoxy, ethoxy, trifluoroMethyl, cyclopropyl and phenyl groups,

or

R¹Represents vinyl, allyl or cyclopropyl,

R²represents phenyl or thienyl, which may be substituted one to two times, identically or differently, by a radical selected from the group consisting of fluorine, bromine, chlorine, methyl and methoxy,

L¹represents-CH₂-，

Meaning the binding site to the N atom of the amide group,

q means the number 0 or 1,

R^6Ameaning either hydrogen or a methyl group, or a mixture thereof,

R^6Bmeaning hydrogen, methyl, trifluoromethyl or have the formula-C (═ O) -NR¹⁷R¹⁸A group of (1), wherein

Or

R¹⁷And R¹⁸Together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, piperidine or morpholine ring,

Or

R^6AAnd R^6BAre linked together and together with the carbon atom to which they are attached form a group of formula

R^7AMeaning hydrogen, fluorine or methyl,

R^7Bmeaning hydrogen, fluorine, methyl OR having the formula-C (═ O) -OR²³or-C (═ O) -NR²⁴R²⁵A group of (1), wherein

R²³、R²⁴And R²⁵Independently of one another, hydrogen, methyl or ethyl,

or

R²⁴And R²⁵Together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, piperidine or morpholine ring,

or

R^7AAnd R^7BTogether form an oxo group, which is,

or

R^7AAnd R^7BAre linked to each other and together form- (CH)₂)_sA bridge of which

s means the number 2, 3, 4 or 5,

and one CH of the bridge₂The group can be replaced by-O-,

or

L²Represents a group of the formula

And

and salts thereof.

2. A compound of formula (I) as defined in claim 1, wherein

A represents a group represented by the formula (I),

R¹is represented by (C)₁-C₄) Alkyl, 2-methoxyethyl, cyclopropyl, benzyl or 1-phenylethyl, wherein the phenyl ring in said benzyl-and 1-phenylethyl groups may be substituted by fluorine, chlorine, methyl, or methoxy,

L¹represents-CH₂-，

L²represents-CH₂-，-CH(CH₃) -or-C (CH)₃)₂-，

And

and salts thereof.

3. A process for the production of a compound of formula (I) as defined in claim 1 or 2, characterized in that

Wherein A, L¹，R¹And R²Each having the meaning as claimed in any of claims 1 to 2, coupled with compounds of the formula (III)

R³-L²-NH₂ (III)，

Wherein L is²And R³Having the meaning as claimed in any of claims 1 to 2,

or

Wherein A, R¹And R²Each having the meaning as claimed in any of claims 1 to 2,

with a compound of the formula (V)

Wherein L is¹，L²And R³Each having the meaning as claimed in any of claims 1 to 2,

and

x represents a leaving group selected from halogen, mesylate or tosylate, and the resulting compound of formula (I) is optionally converted to their salt with the appropriate (I) solvent and base or acid or (ii) base or acid in the absence of a solvent.

4. Use of a compound of formula (I) as defined in claim 1 or 2 for the preparation of a medicament for the treatment and/or prevention of cardiovascular diseases.

5. Use of a compound of formula (I) as defined in claim 1 or 2 for the preparation of a medicament for the treatment and/or prevention of acute and chronic cardiac insufficiency, hypervolemic and isovolemic hyponatremia, chronic interstitial hepatitis, ascites, oedema and vasopressin dyssecretosis Syndrome (SIADH).

6. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or 2, in combination with inert, non-toxic, pharmacologically acceptable additives.

7. Medicament comprising a compound of formula (I) as defined in claim 1 or 2 in combination with one or more further active substances selected from the group consisting of diuretics, angiotensin AII antagonists, ACE inhibitors, beta-blockers, mineralocorticoid receptor antagonists, organic nitrates, NO donors and substances with positive inotropic action.

8. A medicament according to claim 7 for the treatment and/or prevention of acute and chronic cardiac insufficiency, hypervolemic and isovolemic hyponatremia, chronic interstitial hepatitis, ascites, oedema and vasopressin dyssecretosis Syndrome (SIADH).